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Archive for the ‘Psychiatry’ Category

Adult ADHD And Women: Many Fall Through The Cracks!

In ADHD, ADHD Adult, General Psychology, Psychiatry on Sunday, 30 March 2014 at 04:30

http://www.adultadhdblog.com/2014/03/28/adult-adhd-and-women-2/

possible autism cure?

In Autism Spectrum Disorders, Medication, Psychiatry on Friday, 28 March 2014 at 04:08

http://www.stonehearthnewsletters.com/autistic-brain-could-be-rebalanced-with-low-doses-of-antianxiety-drugs/autism/

Phillip Seymour Hoffman did not have choice or free will and neither do you.

In ADHD, Anxiety, Brain imaging, Brain studies, Child/Adolescent Psychology, General Psychology, Medicine, Mood Disorders, Neuropsychology, Neuroscience, Psychiatry on Tuesday, 11 March 2014 at 12:37

one of the best things about this subject that i’ve read in a long time.  give it a read. it makes you think.

Phillip Seymour Hoffman did not have choice or free will and neither do you..

suicide is not painless…

In General Psychology, Psychiatry, School Psychology on Wednesday, 19 February 2014 at 17:30

http://mag.newsweek.com/2013/05/22/why-suicide-has-become-and-epidemic-and-what-we-can-do-to-help.html

Asperger Syndrome Revisited

In Autism Spectrum Disorders, General Psychology, Psychiatry, School Psychology, Special Education on Wednesday, 11 December 2013 at 05:59

Asperger Syndrome Revisited

By: Lee Wilkinson, Ph.D.

The deletion of Asperger’s disorder (Asperger’s syndrome) as a separate diagnostic category from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has been widely publicized. The new DSM-5 category of autism spectrum disorder (ASD), which subsumes the previous DSM-IV diagnoses of autistic disorder (autism), Asperger’s disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS), reflects the scientific consensus that symptoms of the various DSM-IV subgroups represent a single continuum of impairment that varies in level of severity and need for support.

An important feature of the DSM-5 criteria for ASD is a change from three symptom domains (triad) of social impairment, communication deficits and repetitive/restricted behaviors, interests, or activities to two domains (dyad); social/communication deficits and fixated and repetitive pattern of behaviors. Several social/communication criteria were merged to clarify diagnostic requirements and reflect research indicating that language deficits are neither universal in ASD, nor should they be considered as a defining feature of the diagnosis. The criteria also feature dimensions of severity that include current levels of language and intellectual functioning as well as greater flexibility in the criteria for age of onset and addition of symptoms not previously included in the DSM-IV such as sensory interests and aversions.

DSM-IV Criteria in Practice

Problems in applying the DSM-IV criteria were a key consideration in the decision to delete Asperger’s disorder as a separate diagnostic entity. Numerous studies indicate that it is difficult to reliably distinguish between Asperger syndrome, autism, and other disorders on the spectrum in clinical practice (Attwood, 2006; Macintosh & Dissanayake, 2006; Leekam, Libby, Wing, Gould & Gillberg, 2000; Mayes & Calhoun, 2003; Mayes, Calhoun, & Crites, 2001; Miller & Ozonoff, 2000; Ozonoff, Dawson, & McPartland, 2002; Witwer & Lecavalier, 2008). For example, children with autism who develop proficient language have very similar trajectories and later outcomes as children with Asperger disorder (Bennett et al., 2008; Howlin, 2003; Szatmari et al., 2000) and the two are indistinguishable by school-age (Macintosh & Dissanayake, 2004), adolescence (Eisenmajer, Prior, Leekam, Wing, Ong, Gould & Welham 1998; Ozonoff, South and Miller 2000) and adulthood (Howlin, 2003). Individuals with Asperger disorder also typically meet the DSM-IV communication criterion of autism, “marked impairment in the ability to initiate or sustain a conversation with others,” making it is possible for someone who meets the criteria for Asperger’s disorder to also meet the criteria for autistic disorder.

Treatment and Outcome

Another important consideration was response to treatment. Intervention research cannot predict, at the present time, which particular intervention approach works best with which individual. Likewise, data is not available on the differential responsiveness of children with Asperger’s disorder and high-functioning autism to specific interventions (Carpenter, Soorya, & Halpern, 2009). There are no empirical studies demonstrating the need for different treatments or different responses to the same treatment, and in clinical practice the same interventions are typically offered for both autism and Asperger’s disorder (Wilkinson, 2010). Treatments for impairments in pragmatic (social) language and social skills are the same for both groups.

Application of the New Criteria

It’s important to remember that in the DSM, a mental disorder is conceptualized as a clinically important collection of behavioral and psychological symptoms that causes an individual distress, disability or impairment. The objective of new DSM-5 criteria for ASD is that every individual who has significant “impairment” in social-communication and restricted and repetitive behavior or interests should meet the diagnostic criteria for ASD.  Because language impairment/delay is not a necessary criterion for diagnosis, anyone who demonstrates severe and sustained impairments in social skills and restricted, repetitive patterns of behavior, interests, or activities in the presence of generally age-appropriate language acquisition and cognitive functioning, who might previously have been given a diagnosis of Asperger’s disorder, will now meet the criteria for ASD.

The new DSM-5 criteria for ASD have created significant controversy over concerns that it would exclude many individuals currently diagnosed with Asperger syndrome and PDD-NOS, and thus make it difficult for them to access services. However, recently published field trials suggest that the revisions actually increase the reliability of diagnosis, while identifying the large majority of those who would have been diagnosed under the DSM-IV-TR. Of the small numbers who were not included, most received the new diagnosis of “social communication disorder.” Moreover, the accuracy of non-spectrum classification (specificity) made by DSM-5 was better than that of DSM-IV, indicating greater effectiveness in distinguishing ASD from non-spectrum disorders such as language disorders, intellectual disability, attention-deficit/hyperactivity disorder (ADHD), and anxiety disorders. It is also important to note that all individuals who have a DSM-IV diagnosis on the autism spectrum, including those with Asperger syndrome and PDD-NOS, will be able to retain an ASD diagnosis. This means that no one should “lose” their diagnosis because of the changes in diagnostic criteria.  According to DSM-5, individuals with a well-established DSM-IV diagnosis of Autistic Disorder, Asperger’s Disorder, or PDD-NOS should be given a diagnosis of ASD.  Those who have marked deficits in social communication, but whose symptoms do not meet the criteria for ASD, should be evaluated for Social (Pragmatic) Communication Disorder.

Conclusion

In conclusion, the DSM-5 category of autism spectrum disorder (ASD), which subsumes the current diagnoses of autistic disorder, Asperger’s disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS), better describes our current understanding about the clinical presentation and course of the neurodevelopmental disorders. Conceptualizing autism as a spectrum condition rather than a categorical diagnostic entity is in keeping with the extant research suggesting that there is no clear evidence that Asperger’s disorder and high-functioning autism are different disorders. As Gillberg (2001) notes, the terms Asperger’s syndrome and high-functioning autism are more likely “synonyms” than labels for different disorders. Lord (2011) also comments that although there has been much controversy about whether there should be separate diagnoses, “Most of the research has suggested that Asperger’s syndrome really isn’t different from other autism spectrum disorders.” “The take-home message is that there really should be just a general category of autism spectrum disorder, and then clinicians should be able to describe a child’s severity on these separate dimensions.” Unfortunately, many individuals may have been advised (or assumed) that a diagnosis of Asperger’s disorder was separate and distinct from autistic disorder and that intervention/treatment, course, and outcome were clinically different for each disorder. While including Asperger’s Disorder under the DSM-5 category of ASD will likely continue to require a period of transition and adjustment, the proposed dimensional approach to diagnosis will likely result in more effective identification, treatment, and research for individuals on the spectrum.

References

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders. Washington, DC: Author.

American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders(4th ed., text rev.). Washington, DC: Author.

American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders(5th ed.). Washington, DC: Author.

Attwood, T. (2006). The complete guide to Asperger’s syndrome. London: Jessica Kingsley.

Carpenter, L. A., Soorya, L. & Halpern, D. (2009). Asperger’s syndrome and high- functioning autism. Pediatric Annals, 38, 30-35.

Eisenmajer, R., Prior, M., Leekam, S., Wing, L., Ong, B., Gould, J. & Welham, M. (1998)

Delayed Language Onset as a Predictor of Clinical Symptoms in Pervasive Developmental Disorders. Journal of Autism and Developmental Disorders, 28, 527–34.

Gillberg, C (2001). Asperger’s syndrome and high functioning autism: Shared deficits or

different Disorders? Journal of Developmental and Learning Disorders, 5, 79-94.

Howlin, P. (2003). Outcome in high-functioning adults with autism with and without early language delays: Implications for the differentiation between autism and Asperger syndrome. Journal of Autism and Developmental Disorders, 33, 3–13.

Leekam, S., Libby, S., Wing, L., Gould, J. & Gillberg, C. (2000) Comparison of ICD-10 and Gillberg’s criteria for Asperger syndrome. Autism, 4, 11–28.

Lord, C. et al. (2011). A multisite study of the clinical diagnosis of different autism spectrum disorders. Archives of General Psychiatry. doi:10.1001/archgenpsychiatry.2011.148

Macintosh, K., & Dissanayake, C. (2006). Social skills and problem behaviors in school aged children with high-functioning autism and Asperger’s disorder. Journal of Autism and Developmental Disorders, 36, 1065–1076.

Macintosh, K.E., & Dissanayake, C. (2004). Annotation: The similarities and differences

between autistic disorder and Asperger’s disorder: A review of the empirical evidence. Journal of Child Psychology and Psychiatry, 45, 421–434.

Mayes, S., & Calhoun, S. (2003). Relationship between Asperger syndrome and high functioning autism. In M. Prior (Ed.), Learning and behavior problems in Asperger syndrome (pp. 15-34). New York: Guilford Press.

Mayes SD, Calhoun SL, Crites DL (2001) Does DSM-IV Asperger’s disorder exist? Journal of Abnormal Child Psychology, 29, 263–271.

Miller, J. N., & Ozonoff, S. (2000). The external validity of Asperger disorder: Lack of evidence from the domain of neuropsychology. Journal of Abnormal Psychology, 109, 227–238.

Ozonoff, S., Dawson, G., & McPartland, J. (2002). A parent’s guide to Asperger syndrome and high-functioning autism: How to meet the challenges and help your child to thrive. New York: Guilford Press.

Ozonoff, S., South, M., & Miller, J. N. (2000). DSM-IV-defined Asperger syndrome: Cognitive, behavioral and early history differentiation from high-functioning autism. Autism, 4, 29–46.

Szatmari, P., Bryson, S.E., Streiner, D.L., Wilson, F.J., Archer, L., & Ryerse, C. (2000). Two year outcome of preschool children with autism or Asperger’s syndrome. American Journal of Psychiatry, 15, 1980–1987.

Szatmari, P., Bryson, S., Duku, E., Vaccarella, L., Zwaigenbaum, L., Bennett, L. & Boyle, M.H. (2009). Similar developmental trajectories in autism and Asperger syndrome: from early childhood to adolescence. Journal of Child Psychology and Psychiatry, 50, 1459-1467.

Wilkinson, L. A. (2008). Adults with Asperger syndrome: A childhood disorder grows up. The Psychologist, 21, 764-770.

Wilkinson, L. A. (2010). A best practice guide to assessment and intervention for Asperger syndrome and autism in schools. London: Jessica Kingsley Publishers.

Wilkinson, L. A. (Ed.) (in press). Autism spectrum disorder in children and adolescents: Evidence-based assessment and intervention in schools. American Psychological Association (APA): Washington, DC.

Williams, K., Tuck, M., Helmer, M., Bartak, L., Mellis, C. & Peat, J.K. (2008). Diagnostic labelling of autism spectrum disorders in NSW. Journal of Paediatrics and Child Health, 44, 108-113.

Wing, L. (2005). Problems of categorical classification systems. In F. R. Volkmar, R. Paul, A. Klin, & D. Cohen (Eds.),Handbook of autism and pervasive developmental disorders: Vol. 1. Diagnosis, development, neurobiology, and behavior (3rd ed., pp. 583–605). New York: John Wiley.

Witwer, A.N., & Lecavalier, L. (2008). Validity of autism spectrum disorder subtypes. Journal of Autism and Developmental Disorders, 38, 1611–1624.

Lee A. Wilkinson, PhD, CCBT, NCSP is author of the award-winning book, A Best Practice Guide to Assessment and Intervention for Autism and Asperger Syndrome in Schools, published by Jessica Kingsley Publishers.

Retrieved from: http://bestpracticeautism.blogspot.com/2013/12/asperger-syndrome-revisited.html?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+BestPracticeAutism+%28Best+Practice+Autism%29

 

Drug Firm Pays Billions for Misbranding Antipsychotics

In Medication, Medicine, Psychiatry on Thursday, 5 December 2013 at 10:04

December 04, 2013

Drug Firm Pays Billions for Misbranding Antipsychotics

Vabren Watts

Johnson & Johnson was sued for failing to report data suggesting increased risks for stroke and diabetes associated with the antipsychotic Risperdal.

Pharmaceutical giant Johnson & Johnson (J&J) announced November 4 that it will plead guilty to a single misdemeanor charge that it misbranded the atypical antipsychotic drug Risperdal for uses not approved as safe and effective by the Food and Drug Administration (FDA).

A part of one of the largest health care fraud settlements in U.S. history, the pharmaceutical company has agreed to pay $2.2 billion to resolve criminal and civil investigations, the U.S. Department of Justice announced.

Risperdal (risperidone)—a dopaminergic antagonist—was FDA approved to treat schizophrenia in 1993 and approved in 2003 to treat mixed episodes associated with bipolar I disorder. A complaint filed by the U.S. Court for the Eastern District of Pennsylvania alleged that Janssen Pharmaceuticals, a J&J subsidiary and Risperdal’s developer, began to market the drug from 1999 through 2005 to remedy agitation associated with dementia in the elderly and psychiatric disorders in children—indicating to physicians and other prescribers that Risperdal was safe and effective for these unapproved indications and populations.

According to the FDA, J&J received several warnings regarding its misleading marketing tactics targeted to physicians and consumers. After a whistleblower complaint was filed, the FDA Office of Criminal Investigations initiated a probe concerning J&J’s alleged misconduct.

“When pharmaceutical companies ignore the FDA’s requirements, they not only risk endangering the public’s health but also damaging the trust that patients have in their doctors and their medications,” said FDA Commissioner Margaret Hamburg, M.D. “The FDA relies on data from rigorous scientific research to define and approve the uses for which a drug has been shown to be safe and effective…. Pharmaceutical manufacturers that ignore the FDA’s regulatory authority do so at their own peril.”

The Department of Justice further alleged that J&J was aware that Risperdal posed serious health risks, including increased risks for the onset of diabetes, breast development in boys, and strokes in elderly patients.

During the investigation, a physician who worked on a J&J study claimed that the company was “purposely withholding the findings” that showed that Risperdal increased risk for stroke in elderly patients after the company combined negative data with other studies to make it appear that there was an overall lower risk for adverse events. In addition, the company promoted Risperdal as “uncompromised by safety concerns (does not cause diabetes),” ignoring data that indicated otherwise.

As a result of its practices and misconduct, the company has agreed to submit to stringent requirements under a corporate integrity agreement with Department of Health and Human Services Office of the Inspector General. The agreement is designed to increase accountability and transparency and prevent future fraud.

Psychiatric News contacted J&J to ask how the company plans to regain trust among clinicians and consumers. Michael Ullmann, J&J vice president and general counsel, replied in a statement saying, “This resolution allows us to move forward and continue to focus on delivering innovative solutions that improve and enhance the health and well-being of patients around the world. We remain committed to working with the U.S. Food and Drug Administration and others to ensure greater clarity around the guidance for pharmaceutical industry practices and standards.”

Though J&J acknowledged that it improperly marketed Risperdal to older adults for unapproved uses, the pharmaceutical firm admitted to no wrongdoing for accusations that it promoted drug use in children and the developmentally disabled and that it provided kickbacks to doctors and pharmacists in exchange for writing more prescriptions.

The agreement will also resolve similar misbranding accusations for the company’s heart failure drug, Natrecor, and newer antipsychotic drug, Invega.

Retrieved from: http://psychnews.psychiatryonline.org/newsarticle.aspx?articleid=1788265

Continued Increases in Adhd Diagnoses, Treatment With Meds Among US Children

In ADHD, ADHD child/adolescent, ADHD stimulant treatment, Child/Adolescent Psychology, Psychiatry, Psychopharmacology on Tuesday, 26 November 2013 at 07:09

Continued Increases in Adhd Diagnoses, Treatment With Meds Among US Children

Nov. 22, 2013 — A new study led by the CDC reports that half of U.S. children diagnosed with ADHD received that diagnosis by age 6.

The study published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) found that an estimated two million more children in the United States (U.S.) have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) between 2003-04 and 2011-12. One million more U.S. children were taking medication for ADHD between 2003-04 and 2011-12. According to the study conducted by the Centers for Disease Control and Prevention (CDC):

* 6.4 million children in the U.S. (11 percent of 4-17 year olds) were reported by their parents to have received an ADHD diagnosis from a healthcare provider, a 42 percent increase from 2003-04 to 2011-12.

* Over 3.5 million children in the U.S. (6 percent of 4-17 year olds) were reported by their parents to be taking medication for ADHD, a 28 percent increase from 2007-08 to 2011-12.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders of childhood. It often persists into adulthood. Children with ADHD may have trouble paying attention and/or controlling impulsive behaviors. Effective treatments for ADHD include medication, mental health treatment, or a combination of the two. When children diagnosed with ADHD receive proper treatment, they have the best chance of thriving at home, doing well at school, and making and keeping friends.

According to CDC scientists, children are commonly being diagnosed at a young age. Parents report that half of children diagnosed with ADHD were diagnosed by 6 years of age, but children with more severe ADHD tended to be diagnosed earlier, about half of them by the age of 4.

“This finding suggests that there are a large number of young children who could benefit from the early initiation of behavioral therapy, which is recommended as the first-line treatment for preschool children with ADHD,” said Susanna Visser, of the Centers for Disease Control and Prevention, lead author of the study.

The study increases our knowledge of ADHD treatment. Nearly 1 in 5 or 18 percent of children with ADHD did not receive mental health counseling or medication in 2011-2012. Of these children, one-third were reported to have moderate or severe ADHD.

“This finding raises concerns about whether these children and their families are receiving needed services,” said Dr. Michael Lu, Senior Administrator, Health Resources and Service Administration (HRSA).

The study also found that:

* Seven in 10 children (69 percent) with a current diagnosis of ADHD were taking medication to treat the disorder.

* Medication treatment is most common among children with more severe ADHD, according to parent reports.

* States vary widely in terms of the percentage of their child population diagnosed and treated with medication for ADHD. The percentage of children with a history of an ADHD diagnosis ranges from 15 percent in Arkansas and Kentucky to 4 percent in Nevada.

Nearly one in five high school boys and one in 11 high school girls in the U.S. were reported by their parents as having been diagnosed with ADHD by a healthcare provider. For this study, data from the 2011-2012 National Survey of Children’s Health (NSCH) were used to calculate estimates of the number of children in the U.S. ages 4-17 that, according to a parent, had received a diagnosis of ADHD by a healthcare provider and were currently taking medication for ADHD. The NSCH is conducted in collaboration between HRSA and CDC.

Retrieved from:  http://www.sciencedaily.com/releases/2013/11/131122112708.htm?goback=%2Egde_2450083_member_5810692543100264452#%21

Insomnia and Heart Failure Risk: Something to Lose Sleep Over?

In Neuropsychology, Neuroscience, Psychiatry on Tuesday, 21 May 2013 at 06:55

Insomnia and Heart Failure Risk: Something to Lose Sleep Over?

By: Shelley Wood

Clinical Context

Insomnia can lead to activation of the neuroendocrine system, which in turn may promote a higher risk for cardiovascular disease. The authors of the current study previously used the same study cohort to evaluate the risk for acute myocardial infarction (AMI) associated with insomnia. Their results, which were published in the November 8, 2011, issue of Circulation, demonstrated that mild, intermittent sleep problems were not associated with a higher risk for AMI. However, insomnia almost every night and nonrestorative sleep experienced more than once per week were associated with increases in the risk for AMI of more than 40%.

The current study by Laugsand and colleagues examines whether insomnia can affect the risk for incident heart failure.

Study Synopsis and Perspective

Insomnia symptoms in middle age are strongly associated with the subsequent development of heart failure, a large Norwegian cohort study has found[1]. The analysis, which considered over 54 000 men and women, linked insomnia symptoms and heart failure, even in subjects who had never experienced a coronary event.

While the study does not demonstrate causation, researchers led by Dr Lars E Laugsand (Norwegian University of Science and Technology, Trondheim) say their findings have important implications for patient management and, potentially, reducing progression to heart failure.

“If subsequent studies confirm our findings and if causality is better established, the observed prospective association between insomnia and HF [heart failure] risk could have implications for cardiovascular prevention, since insomnia is an easily recognizable and potentially manageable condition,” the authors write.

Speaking with heartwire , Laugsand stressed that the findings do not have immediate implications for physicians, beyond the fact that sleep is important to good health generally.

“I think cardiologists should talk to their patients about sleep problems, but I think it’s a little too early to say that anything should be implemented in the CV [cardiovascular] risk assessment,” he said. “More research is clearly needed to evaluate the possible underlying mechanisms.”

For example, he continued, the chronic activation of stress responses seen in insomnia could be expected to have an impact on the heart. “Patients who are stressed both at night and during the day have increased BP [blood pressure], increased release of stress hormones, increased heart rate, etc, and all of these factors are related to HF, so that’s a potential link between the neuroendocrine system and the sympathetic nervous system. We cannot say this is the case from our study,” but it’s a plausible link, he said.

Community-Based Analysis

Laugsand et al reviewed baseline data relating to insomnia symptoms from the Nord-Trøndelag Health Study on the 54 279 patients enrolled between 1995 and 1997, none of whom had HF at the study outset. By 2008, 1412 patients had developed heart failure.

In a range of analyses that took into account different factors, such as age, cardiovascular disease risk factors, or psychological factors, insomnia symptoms remained strongly correlated with new-onset heart failure, with more symptoms linked with higher risk. For example, subjects who reported having “difficulty initiating sleep” on “almost every night” had a 27% to 66% risk of developing heart failure (depending on the model used), compared with subjects with no insomnia symptoms. By contrast, patients who reported “difficulty initiating sleep” on a frequent basis, in addition to “difficulty maintaining sleep” and feeling that their sleep was “nonrestorative,” had a risk of heart failure that ranged from two to five times higher than in subjects with no insomnia symptoms.

Women were at an increased risk of having heart failure in relation to certain insomnia risk factors and for cumulative measures of insomnia, compared with men, but Laugsand was reluctant to make much of this observation. “You cannot say from these numbers that insomnia is more dangerous for women than men when it comes to having heart failure,” he said. They have a higher relative risk, but that might be due to their lower baseline risk of HF.”

The next step, said Laugsand, would be a trial treating patients for insomnia to see whether such a strategy could mitigate the development of heart failure.

“That would be the ultimate goal, to do a randomized controlled trial. This study is an observational study and saying anything too firm about causality is difficult,” he cautioned. “But from the studies done in insomnia and other sleep problems, we know that sleep problems affect the physiology of the heart.”

References

  1. Laugsand LE, Strand LB, Platou, et al. Insomnia and the risk of incident heart failure: A population study. Eur Heart J 2013; DOI: 10.1093/eurheartj/eht019. Available at: http://eurheartj.oxfordjournals.org.

Study Highlights

  • Study data were derived from the Nord-Trøndelag cohort, which reflects the general population of Norway. Study recruitment began in 1995. The current study focused on individuals between 20 and 89 years old without a history of heart failure.
  • Participants completed a thorough examination at the outset of the study, including questions regarding insomnia and the use of hypnotic medications. The insomnia history focused on difficulty falling asleep (early insomnia), waking during sleep (middle insomnia), and nonrestorative sleep. A laboratory assessment was also part of the initial examination.
  • The main study outcome was incident heart failure, which was identified from hospital diagnoses and national death registers.
  • The study analyzed the risk for heart failure associated with insomnia, and researchers adjusted their analyses to account for demographic data and traditional cardiovascular risk factors. Researchers also performed an analysis that accounted for patients’ other chronic diseases.
  • 54,279 participants provided study data. The rates of severe insomnia in the study cohort varied between 2.5% and 8.1%, depending on which domain of insomnia was being queried.
  • Older adults and women were more likely to have insomnia. Insomnia was closely related to depression, anxiety, and the presence of cardiovascular risk factors.
  • During a mean evaluation period of 11.3 years, there were 1412 incident cases of heart failure. 408 of these cases were reported from the death registry.
  • In fully adjusted analyses, including psychiatric diagnoses, the presence of early insomnia, middle insomnia, or nonrestorative sleep individually did not significantly increase the risk for heart failure, even when these symptoms were severe.
  • However, there was a dose-dependent positive effect on the risk for heart failure with a greater number of insomnia symptoms. The presence of 1 insomnia symptom was associated with a hazard ratio (HR) for heart failure of 0.96 (95% [confidence interval] CI, 0.57 – 1.61). Having 2 or 3 of these symptoms was associated with respective HRs of 1.35 (95% CI, 0.72 – 2.50) and 4.53 (95% CI, 1.99 – 10.31).
  • The presence of nonrestorative sleep was associated with a higher risk for incident heart failure among women vs men.
  • Exclusion of cases of heart failure diagnosed early during follow-up failed to significantly alter the main study outcome.

Clinical Implications

  • A previous study of the current cohort of adults found that severe, but not mild, insomnia was independently associated with a higher risk for AMI.
  • In the current study by Laugsand and colleagues, only the presence of multiple insomnia symptoms was significantly associated with a higher risk for incident heart failure.

Retrieved from: http://www.medscape.org/viewarticle/781692

what they eyes say about adhd…

In ADHD, ADHD Adult, ADHD child/adolescent, Child/Adolescent Psychology, General Psychology, Neuropsychology, Psychiatry on Tuesday, 21 May 2013 at 06:51

Eye May Be Key to More Accurate ADHD Diagnosis

Megan Brooks

SAN FRANCISCO — Examining the retina may aid in the diagnosis of attention-deficit/hyperactivity disorder (ADHD), new research suggests.

A small study by investigators at Albert-Ludwigs University of Freiburg, Germany, showed that patients with ADHD displayed significantly elevated “background noise” on a pattern electroretinogram (PERG) compared with their healthy peers.

Altered visual signal processing may be a “neuronal correlate for ADHD,” study presenter Emanuel Bubl, MD, told Medscape Medical News. “If we can replicate this finding, it would be of great clinical importance because it would be an objective marker of ADHD.”

Dr. Bubl presented the study here at the American Psychiatric Association’s 2013 Annual Meeting.

PERG — which is a kin to an electrocardiogram of the retina — provides an electrophysiologic measurement of the activity of the retinal ganglion cells.

“This technique is an easy-to-apply and already well-established instrument in ophthalmology. With adaption, it could be widely used,” Dr. Bubl said.

Inattention and distractability are core symptoms of ADHD, but a “clearcut neuronal correlate is missing. Any attempt to find objective markers of ADHD would be very helpful in this context,” Dr. Bubl said.

Dr. Bubl and colleagues used PERG to measure the response of the retina to a checkerboard visual stimuli in 20 patients with ADHD and 20 healthy control participants.

“An elevated neuronal noise or background firing has been proposed as an underlining pathophysiological mechanism and treatment target. We found evidence for an early alteration in visual perception or signal transmission in patients with ADHD, with significantly elevated neuronal noise (P < .014),” said Dr. Bubl. In particular, neuronal noise significantly correlated with inattention, as measured with the Conners’ Adult ADHD Rating Scale.

“The results might explain why patients with ADHD are easily distracted,” Dr. Bubl added.

With more study, the results could have potentially important clinical implications. “With ADHD, there is a debate about the existence of the disease on the one hand and a growing concern about overdiagnosing ADHD and prescription of medication on the other,” he said.

With PERG, the diagnosis of ADHD could be “objectified by measurable signals, and this would be dramatically helpful in the controversial public discussion.” Use of PERG might also help in determining the effects of methylphenidate or psychotherapy on ADHD.

The authors report no relevant financial relationships.

The American Psychiatric Association’s 2013 Annual Meeting. Abstract SCR02-2. Presented May 18, 2013.

Retrieved from: http://www.medscape.com/viewarticle/804409?src=nl_topic&uac=184795PG

and more dsm-v controversy…

In Child/Adolescent Psychology, DSM-V, Neuropsychology, Psychiatry, School Psychology on Tuesday, 21 May 2013 at 06:48

DSM-V: Past Imperfect

By: Nassir Ghaemi, MD, MPH

 Thoughts on a New DSM

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is here. We might as well pretend that Ronald Reagan is still president. Radical changes were made, with limited scientific evidence, when DSM-III was published in 1980 (the year Reagan was elected); even the tiniest changes, with great scientific evidence, are now the subject of outrage.

For me, DSM-5 is a disappointment. I take no pleasure in making this judgment. I wish I could say that DSM revisions are increasingly scientific and getting us closer to truths. But this simply hasn’t happened.

DSM-5 is a disappointment for me not because it is much different from DSM-IV, but because it is so similar. Almost 2 decades after the fourth revision in 1994, despite thousands of research studies on psychiatric conditions, our profession hardly can bring itself to change anything of importance. The radical bipolar/major depressive disorder (MDD) dichotomy is unchanged and untouchable — the third rail of US psychiatry — despite numerous studies casting doubt on the validity of the MDD definition and providing support for broader definitions of bipolar disorder.

The personality disorder concept was nothing but the description of psychoanalytic speculations in 1980. It has remained basically unchanged, despite little research evidence of validity. Personality traits, one of the most well-proven facts in psychology, were recommended by the DSM-5 task force but vetoed by the American Psychiatric Association Board of Trustees. Science was rejected; psychoanalytic tradition was not.

Clinicians may have assumed that we have scientific validity for most of the approximately 400 diagnoses in DSM-5; we have hardly any validity data for the vast majority of those diagnoses, and we have notable validity evidence for numerous concepts that are excluded.

The claim in the Reagan presidency was that DSM would provide reliability; we could agree on definitions. Then, we would do more research so that definitions would evolve toward better validity. Reliability would lead to validity.

When Bill Clinton was president and DSM-IV was published in 1994, a change happened: DSM became an end in itself. The DSM-IV leadership explicitly stated that unless a very high bar of scientific evidence was reached, no changes were allowed. The bar kept being moved higher and higher for science, and lower and lower for politics. The DSM-IV leadership called it “pragmatism”: DSM changes were made on the basis of what that leadership thought was best for patients, they said, and for the profession.

Reliability had become an end in itself; validity no longer mattered because, in a species of extreme social constructionism, the DSM-IV leadership saw the nosology as a way to influence practice, not as a way to discover causes of and treatments for mental illnesses. (They didn’t bother with the question of how you could practice well if you didn’t find out the causes and treatments of illnesses.)

There were hopes that DSM-5 would be different, with scientifically based changes. But a major backlash came: The DSM-IV leadership opposed changes on “pragmatic” grounds, and many in the larger public criticized DSM on social constructionist grounds, as just a means for psychiatrists to make money and influence people. Major changes became minor, and even the minor ones were often dropped to an appendix for further research, which is likely to be ignored.

After 2 decades of being a loyal follower of DSM, the debates of recent years led me to make a sad but definite conclusion: DSM has caused stagnation in psychiatry. If DSM categories are devised primarily because professional leaders want to achieve some clinical or even economic goals, there is no reason why nature should play along. By being “pragmatic” and not scientific, DSM has doomed biological and pharmacologic research in psychiatry to failure for 2 generations.

Now I see a generational change. The leaders of the DSM-III, -IV, and -5 workgroups are often literally the same people, representatives of the 1970’s/1980’s generation in psychiatry. Some of us in later generations do not venerate DSM as the bible of psychiatry, as it’s often called; we instead question it as theology instead of science. Recently, the leadership of the National Institute of Mental Health (NIMH) reached the same conclusion and stated it forcefully: DSM criteria are not scientifically valid, and patients deserve better.

DSM-5 is out, and clinicians will use it, but unfortunately it represents a failed past. Those of us who grew up in that past, and have seen how it has led us to stand still, are inclined to agree with the NIMH that our future deserves to be different.

Retrieved from: http://www.medscape.com/viewarticle/804102?src=nl_topic&uac=184795PG

Use DSM-5 ‘Cautiously, If at All,’ DSM-IV Chair Advises

By: Pam Harrison

On the eve of the official launch of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Allen Frances, MD, chair of the DSM-IV Task Force and one of the new manual’s staunchest critics, is advising physicians to use the DSM-5 “cautiously, if at all.”

“Psychiatric diagnosis is facing a renewed crisis of confidence caused by diagnostic inflation,” Dr. Frances, Duke University, Durham, North Carolina, writes in a new commentary published online May 17 in the Annals of Internal Medicine.

Unlike the DSM-IV, which held the line against diagnostic inflation, he states, “The DSM-5, the recently published fifth edition of the diagnostic manual, ignored this risk and introduced several high-prevalence diagnoses at the fuzzy boundary with normality.”

For example, the DSM-5 opens the door for patients worried about having a medical illness to be diagnosed with somatic symptom disorder.

Normal grief may be misdiagnosed as major depressive disorder, and the forgetfulness of old age may now be interpreted as mild neurocognitive disorder.

“The already overused diagnosis of attention-deficit disorder will be even easier to apply to adults thanks to criteria that have been loosened further,” Dr. Frances adds.

Other changes in the DSM-5 will allow clinicians to label a child with temper tantrums as having disruptive mood dysregulation disorder, and overeating can now be called binge eating disorder.

Real Danger

The real danger in diagnostic inflation is overdiagnosis and overtreatment of patients who are essentially well, he says.

“Drug companies take marketing advantage of the loose DSM definitions by promoting the misleading idea that everyday life problems are actually undiagnosed psychiatric illness caused by a chemical imbalance and requiring a solution in pill form,” Dr. Frances writes.

“New psychiatric diagnoses are now potentially more dangerous than new psychiatric drugs.”

Quite apart from the risk for overtreatment, however, is the risk of neglecting patients with clear psychiatric illness whose access to care has been sharply reduced by slashed state mental health budgets.

As Dr. Frances points out, only one third of persons with severe depression receive mental health care, and a large percentage of the swollen prison population in the United States is made up of true psychiatric patients who have no other place to go.

More damning, however, is the flawed process by which committee members of the DSM-5 arrived at their expanded diagnoses, in Dr. Frances’ view.

As he states, the DSM-5 did not address professional, public, and press charges that its changes lacked sufficient scientific support and defied clinical common sense.

Field trials produced reliability results that did not meet historical standards, and deadlines were consistently missed, he adds.

The American Psychiatric Association also refused a petition from an independent scientific review of the DSM-5 that was endorsed by more than 50 mental health associations.

Dr. Frances said he personally found the DSM-5 process “secretive, closed, and disorganized.”

“I believe that the American Psychiatric Association (APA)’s financial conflict of interest, generated by DSM publishing profits needed to fill its budget deficit, led to premature publication of an incompletely tested and poorly edited product,” Dr. Frances states.

“The problems associated with the DSM-5 prove that the APA should no longer hold a monopoly on psychiatric diagnosis…. The codes needed for reimbursement are available for free on the Internet.”

The APA declined to comment.

Ann Intern Med. Published online May 17, 2013. Full article

DSM-5: Past Imperfect. Medscape. May 18, 2013.

Retrieved from: http://www.medscape.com/viewarticle/804378DSM-5 Officially Launched, but Controversy Persists

By: Caroline Cassels

SAN FRANCISCO — After more than a decade of development and more than 2 years of frequently searing controversy, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has finally been released.

Here at the American Psychiatric Association’s (APA’s) 2013 Annual Meeting, the APA leadership officially launched the manual, which is widely known by clinicians and patients alike as the “Bible of Psychiatry.”

“This is really an important day. I have been involved with the DSM-5 almost from the beginning, and I have seen the work unfold over the past decade. There have been literally hundreds of people, experts from all over the world, from different disciplines, who have contributed [to the DSM-5],” outgoing APA president Dilip Jeste, MD, told reporters attending a press briefing here.

“What we are seeing is a clinical manual based on the best science available…for today’s patients, this is the best manual that we could develop,” Dr. Jeste added.

Key changes in the new edition include a new chapter organization that shows how mental disorders may relate to one another on the basis of underlying vulnerabilities or symptom characteristics.

In addition, in DSM-5, disorders are organized in the context of age — that is, along a developmental lifespan within each chapter — as well as sex and cultural expectations.

What’s New

According to DSM-5 Task Force chair David Kupfer, MD, although the number of disorders are “about the same” as in the last edition of DSM, several new disorders have been added, including binge eating disorder, disruptive mood dysregulation disorder, and hoarding disorder.

A new section for the manual, Section III, describes several conditions that warrant more research before they can be considered as formal disorders in the main part of the manual.

The changes to the manual are designed to help clinicians more precisely identify mental disorders and improve diagnosis while maintaining the continuity of care.

“We expect these changes to help clinicians better serve patients and to deepen our understanding of these disorders based on new research.”

However, not everyone is as enthusiastic about the manual’s release. Allen Frances, MD, who chaired the DSM-IV Task Force and is among the DSM-5’s staunchest critics, told Medscape Medical News that he is filled with “sadness and worry — and I am not a person usually given to either emotion.”

He added that he is very concerned that the “DSM 5 will result in the mislabeling of potentially millions of people who are basically normal. This would turn our current diagnostic inflation into hyperinflation and exacerbate the excessive use of medication in the ‘worried well.’ ”

“DSM-5 turns grief into Major Depressive Disorder; temper tantrums into Disruptive Mood Dysregulation; the expectable forgetting of old age into Mild Neurocognitive Disorder; worrying about illness into Somatic Symptom Disorder; gluttony into Binge Eating Disorder; and anyone who wants a stimulant for recreation or performance enhancement can claim Attention Deficit Disorder,” he said.

“Don’t Buy It, Don’t Use It”

However, incoming APA president Jeffrey Lieberman, MD, told reporters that the idea that the revisions to the manual will lead to overtreatment is “inaccurate and unwarranted.”

“The DSM is a diagnostic guide that reflects what we currently know about how best to define disorders. How it is applied is something that reflects clinical practice,” he said.

The manual’s diagnostic criteria, he added, are based on the current state of the scientific evidence to “verify the existence of a certain condition that we know to be impairing and distressing and enduring for people,” Dr. Lieberman added.

Dr. Frances also expressed concern that the new manual will divert scarce mental health care resources away from those who need it most.

“While we are overtreating people with everyday problems who don’t need it, we are shamefully neglecting the people with moderate to severe psychiatric problems who desperately do.”

His advice to frontline clinicians regarding the DSM-5? “Don’t buy it, don’t use it, don’t teach it. There is nothing at all official about DSM-5, and the codes for reimbursement are available for free on the Internet or in DSM-IV. APA is price-gouging a badly flawed document, no one need feel captive to it.”

NIMH Blog Not an Indictment of DSM-5?

Dr. Frances is not alone in his criticism of the manual. An April 29 blog post by Thomas Insel, MD, director of the National Institute of Mental Health (NIMH), and published on the NIMH Web site stated that although the upcoming manual is reliable, it lacks validity.

As reported by Medscape Medical News at that time, Dr. Insel pointed out that unlike diagnostic criteria for other diseases, the DSM-5 criteria are based on consensus rather than objective laboratory measures, and he noted that the NIMH will be “re-orienting its research away from DSM-5 categories.”

Toward that end, Dr. Insel went on to announce the launch of the NIMH Research Domain Criteria (RDoC) in a first step toward “precision medicine.”

Following Dr. Insel’s blog post, on May 14, the APA and the NIMH issued a joint statement in which the organizations emphasized the need to work together for the good of patients.

Nevertheless, the statement underscored the fact that the NIMH’s position on the DSM-5 had not changed and that “the diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”

However, Dr. Lieberman, who has since collaborated with Dr. Insel, said that the blog post should not be viewed as an indictment of the DSM-5 but rather as an expression of frustration that psychiatry does not yet have the biologically based diagnostic tools as other areas of medicine.

“Even though his blog was interpreted this way, we don’t think Tom intended to impugn the DSM so much as to say that he wanted to exhort the biomedical research community to try and break new ground that will lead to more dynamic and fundamental changes in psychiatric diagnosis,” said Dr. Lieberman.

The DSM-5 is available immediately in print, and an electronic version will be available later this year.

The American Psychiatric Association’s 2013 Annual Meeting. Opening press conference. May 18, 2013.

Retrieved from: http://www.medscape.com/viewarticle/804410

NIMH abandoning DSM V

In General Psychology, Neuropsychology, Psychiatry on Wednesday, 8 May 2013 at 08:03

National Institute of Mental Health abandoning the DSM

In a potentially seismic move, the National Institute of Mental Health – the world’s biggest mental health research funder, has announced only two weeks before the launch of the DSM-5diagnostic manual that it will be “re-orienting its research away from DSM categories”.

In the announcement, NIMH Director Thomas Insel says the DSM lacks validity and that “patients with mental disorders deserve better”.

This is something that will make very uncomfortable reading for the American Psychiatric Association as they trumpet what they claim is the ‘future of psychiatric diagnosis’ only two weeks before it hits the shelves.

As a result the NIMH will now be preferentially funding research that does not stick to DSM categories:

Going forward, we will be supporting research projects that look across current categories – or sub-divide current categories – to begin to develop a better system. What does this mean for applicants? Clinical trials might study all patients in a mood clinic rather than those meeting strict major depressive disorder criteria. Studies of biomarkers for “depression” might begin by looking across many disorders with anhedonia or emotional appraisal bias or psychomotor retardation to understand the circuitry underlying these symptoms. What does this mean for patients? We are committed to new and better treatments, but we feel this will only happen by developing a more precise diagnostic system.

As an alternative approach, Insel suggests the Research Domain Criteria (RDoC) project, which aims to uncover what it sees as the ‘component parts’ of psychological dysregulation by understanding difficulties in terms of cognitive, neural and genetic differences.

For example, difficulties with regulating the arousal system might be equally as involved in generating anxiety in PTSD as generating manic states in bipolar disorder.

Of course, this ‘component part’ approach is already a large part of mental health research but the RDoC project aims to combine this into a system that allows these to be mapped out and integrated.

It’s worth saying that this won’t be changing how psychiatrists treat their patients any time soon. DSM-style disorders will still be the order of the day, not least because a great deal of the evidence for the effectiveness of medication is based on giving people standard diagnoses.

It is also true to say that RDoC is currently little more than a plan at the moment – a bit like the Mars mission: you can see how it would be feasible but actually getting there seems a long way off. In fact, until now, the RDoC project has largely been considered to be an experimental project in thinking up alternative approaches.

The project was partly thought to be radical because it has many similarities to the approach taken by scientific critics of mainstream psychiatry who have argued for a symptom-based approach to understanding mental health difficulties that has often been rejected by the ‘diagnoses represent distinct diseases’ camp.

The NIMH has often been one of the most staunch supporters of the latter view, so the fact that it has put the RDoC front and centre is not only a slap in the face for the American Psychiatric Association and the DSM, it also heralds a massive change in how we might think of mental disorders in decades to come.

Link to NIMH announcement ‘Transforming Diagnosis’.

Retrieved from: http://mindhacks.com/2013/05/03/national-institute-of-mental-health-abandoning-the-dsm/

transforming diagnosis

In Brain imaging, General Psychology, Neuropsychology, Psychiatry on Wednesday, 8 May 2013 at 07:58

http://www.nimh.nih.gov/about/director/2013/transforming-diagnosis.shtml.

ADHD into adulthood

In ADHD, ADHD Adult, ADHD child/adolescent, Neuropsychology, Psychiatry on Sunday, 7 April 2013 at 07:39

Kids’ ADHD May Continue Into Adulthood

By Crystal Phend, Senior Staff Writer, MedPage Today

Published: March 04, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Childhood attention deficit-hyperactivity disorder (ADHD) may carry over into adulthood in 29% of cases, with a higher risk of other psychiatric disorders, a population-based study showed.

Almost 60% of kids diagnosed with ADHD in the study had at least one other psychiatric disorder at around age 30, which was nearly three times the odds seen among other children followed (P<0.01), according to a report in the April issue of Pediatrics.

Suicide by that age was substantially more common with childhood ADHD as well, although overall mortality wasn’t, wrote William Barbaresi, MD, of Boston Children’s Hospital, and colleagues.

“It is concerning that only a minority of children with ADHD reaches adulthood without suffering serious adverse outcomes, suggesting that the care of childhood ADHD is far from optimal,” they wrote. “Our results also indicate that clinicians, insurers, and healthcare systems must be prepared to provide appropriate care for adults with ADHD.”

The key message is that ADHD shouldn’t be ignored in childhood or adulthood, Rachel Fargason, MD, of the University of Alabama at Birmingham, commented in an interview with MedPage Today.

“There has always been the question of whether childhood ADHD persists into adulthood,” she noted.

Previous studies from the 1980s suggested it did, but by looking at the worst cases — people who presented in psychiatric clinics — rather than the typical child in the general population, Fargason explained.

The study included 5,718 individuals from the same birth cohort in the area around Rochester, Minn., where the Mayo Clinic is based. They were followed to an average age of 27 to 29 years using school and medical records to look for ADHD and other outcomes.

The prospective portion of the study included 367 adults who had childhood ADHD and could have their vital status confirmed.

Seven (1.9%) had died by the time of follow-up, yielding a standardized mortality ratio 1.88-fold higher than seen in the rest of the cohort that didn’t have childhood ADHD.

Although that overall survival impact didn’t reach statistical significance, the difference in suicide did.

The standardized mortality ratio was 3.83 for suicide among childhood ADHD cases versus others (P=0.032).

Notably, five of the seven deaths in the childhood ADHD group occurred in the setting of comorbid substance use and psychiatric disorders.

“This finding suggests the psychiatric comorbidities associated with ADHD may place patients at risk for early death, although the relatively small number of cases precludes a statistical analysis,” the researchers noted.

Childhood ADHD was associated with a 57% rate of one or more other psychiatric disorders at follow-up compared with 35% among controls, for an odds ratio of 2.6 (95% CI 1.8 to 3.8).

The rate was higher for those whose ADHD persisted into adulthood, with an OR 4.8-fold higher than in those whose ADHD didn’t persist (81% versus 47%).

The most common adult psychiatric problems after childhood ADHD were:

  • Alcohol dependence or abuse (26%)
  • Antisocial personality disorder (17%)
  • Substance dependence or abuse (16%)
  • Current or past history of hypomanic episode (15%)
  • Generalized anxiety disorder (14%)
  • Current major depressive episode (13%)

Altogether, only 38% of individuals who had ADHD as a child experienced no mental health problems in adulthood.

Study limitations included use of administrative and school record data to determine childhood ADHD as well as the relatively small number of deaths, which may have limited ability to detect differences in early death risk.

The population studied is primarily a white, middle-class community, which might impact generalizability, Barbaresi’s group added.

“It is possible, if not likely, that the magnitude of the adverse outcomes in this cohort would be even greater in populations with additional challenges such as higher rates of poverty,” they noted.

Retrieved from: http://www.medpagetoday.com/Pediatrics/ADHD-ADD/37637?goback=%2Egde_985117_member_219365690

Barbaresi WJ, et al “Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study” Pediatrics 2013; DOI: 10.1542/peds.2012-2354.

preschoolers and adhd…a six-year follow up.

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Neuropsychology, Psychiatry on Wednesday, 6 March 2013 at 16:04

http://www.jaacap.com/article/S0890-8567(12)00993-8/abstract

“ADHD in preschoolers is a relatively stable diagnosis over a 6-year period. The course is generally chronic, with high symptom severity and impairment, in very young children with moderate-to-severe ADHD, despite treatment with medication. Development of more effective ADHD intervention strategies is needed for this age group.”

genes, genes…

In ADHD, ADHD Adult, ADHD child/adolescent, Autism Spectrum Disorders, General Psychology, Genes, Neuropsychology, Neuroscience, Personality Disorders, Psychiatry on Friday, 1 March 2013 at 06:15

i love gwas and really feel it will continue to broaden our understanding of psychiatric illnesses and, hopefully, lead to better treatment options.

Five Major Psychiatric Disorders Genetically Linked

By: Caroline Cassels

In the largest genetic study of psychiatric illness to date, scientists have discovered genetic links between 5 major psychiatric disorders.

Investigators from the Cross-Disorder Group of the Psychiatric Genomics Consortium have found that autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share common genetic risk factors.

Specifically, the results of the genome-wide association study (GWAS) reveal single-nucleotide polymorphisms (SNPs) in 2 genes —CACNA1C and CACNB2 — both of which are involved in the balance of calcium in brain cells, are implicated in several of these disorders, and could provide a potential target for new treatments.

“This analysis provides the first genome-wide evidence that individual and aggregate molecular genetic risk factors are shared between 5 childhood-onset or adult-onset psychiatric disorders that are treated as distinct categories in clinical practice,” study investigator Jordan Smoller, MD, Massachusetts General Hospital, Boston, said in a release.

The study was published online February 28 in the Lancet.

Potential Therapeutic Target

The researchers note that findings from family and twin studies suggest that genetic risks for psychiatric disorders do not always map to current diagnostic categories and that “doubt remains about the boundaries between the syndromes and the disorders that have overlapping foundations or different variants of one underlying disease.”

“The pathogenic mechanisms of psychiatric disorders are largely unknown, so diagnostic boundaries are difficult to define. Genetic risk factors are important in the causation of all major psychiatric disorders, and genetic strategies are widely used to assess potential overlaps,” the investigators write.

The aim of the study was to identify specific variants underlying genetic effects shared between 5 major psychiatric disorders: ASD, ADHD, BD, MDD, and schizophrenia.

The researchers analyzed genome-wide SNP data for the 5 disorders in 33,332 cases and 27,888 control participants of European ancestry. They identified 4 risk loci that have significant and overlapping links with all 5 diseases. These included regions on chromosomes 3p21 and 10q24, and SNPs in the gene CACNA1C,which has previously been linked to bipolar disorder and schizophrenia, and in theCACNB2 gene.

Polygenic risk scores confirmed cross-disorder effects, most strongly between adult-onset disorders BD and MDD and schizophrenia. Further pathway analysis corroborated that calcium channel activity could play an important role in the development of all 5 disorders.

“Significant progress has been made in understanding the genetic risk factors underlying psychiatric disorders. Our results provide new evidence that may inform a move beyond descriptive syndromes in psychiatry and towards classification based on underlying causes.

“These findings are particularly relevant in view of the imminent revision of classifications in the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases,” said Dr. Smoller.

The investigators add that the study results “implicate a specific biological pathway — voltage-gated calcium-channel signalling — as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease.”

In an accompanying editorial, Alessandro Serretti, MD, PhD, and Chiara Fabbri, MD, from the University of Bologna, Italy, assert that “the main innovative contribution of the present study is the combination of qualitative and quantitative analyses of the shared genetic features associated with vulnerability of these 5 disorders.”

They add, “the present study might contribute to future nosographic systems, which could be based not only on statistically determined clinical categories, but also on biological pathogenic factors that are pivotal to the identification of suitable treatments.”

The authors and editorialists have reported no relevant financial relationships.

Retrieved from: http://www.medscape.com/viewarticle/779979?src=nl_topic

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

Background

Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

Methods

We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.

Findings

SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10−8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.

Interpretation

Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

Funding-National Institute of Mental Health.

Retrieved from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)62129-1/abstract

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
Cross-Disorder Group of the Psychiatric Genomics Consortium
The Lancet – 28 February 2013
DOI: 10.1016/S0140-6736(12)62129-1

Large study shows substance abuse rates higher in teenagers with ADHD

In ADHD, ADHD Adult, ADHD child/adolescent, Fitness/Health, Psychiatry, School Psychology on Sunday, 24 February 2013 at 10:03

Large study shows substance abuse rates higher in teenagers with ADHD.

what causes depression? a possible answer.

In Genes, Genomic Medicine, Mood Disorders, Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology on Thursday, 21 February 2013 at 06:54

Potential Cause of Depression Identified

By: Meagan Brooks

A protein involved in synaptic structure has been identified as a potential cause of depression, a finding that according to researchers has “enormous therapeutic potential for the development of biomarkers and novel therapeutic agents.”

Investigators at the Mount Sinai School of Medicine in New York City found decreased expression of Rac1 in the postmortem brains of people with major depressive disorder (MDD) and in mice subjected to chronic stress. They were able to control the depressive response in mice by manipulating the expression of Rac1.

“Our study is among only a few in depression research in which 2 independent human cohorts and animal models validate each other. Rac1 has enormous therapeutic potential, and I look forward to investigating it further,” study investigator Scott

Looking for Drug Targets

Rac1 is a small Rho GTPase protein involved in modulating synaptic structure.

“There is a hypothesis that depression and stress disorders are caused by a restructuring of brain circuitry,” Dr. Russo explained in an interview with Medscape Medical News.

The scientists subjected mice to repeated bouts of social stress and then evaluated the animals for changes in gene expression in the nucleus accumbens (NAc), the brain’s reward center.

The researchers found that expression of Rac1 was significantly downregulated in the brains of mice for at least 35 days following the end of the chronic social stressor. Rac1 was not affected by only a single episode of stress, indicating that only prolonged stressors that induce depression are capable of downregulating Rac1.

The scientists note that chronic stress in the mice caused epigenetic changes in chromatin that led to Rac1 downregulation.

They were able to control the depressive response to chronic stress to some extent by chronic antidepressant treatment. Histone deacetylase (HDAC) inhibitors were “extremely effective in both normalizing the reduction in Rac1 and also promoting antidepressant responses,” Dr. Russo told Medscape Medical News.

“What we think is happening is that chronic stress leads to a lasting change in the ability of our genes to transcribe this RAC1 gene, and if you target the epigenome, you can reverse that loss of Rac1 and promote synapses and more normal healthy responses,” he said.

As in the mice, Rac1 expression was also strongly downregulated in the NAc in postmortem brains of patients with MDD, who displayed similar epigenetic changes. In most of the individuals with MDD who were taking antidepressants at the time of death, Rac1 expression was not restored to the levels seen in control participants, “suggesting a need for more direct RAC1-targeting strategies to achieve therapeutic effects,” the authors write.

“Currently, there aren’t any approved drugs or even experimental drugs that target Rac1 that are safe and effective,” Dr. Russo said. “It would be nice if we could team up with some chemists or pharma and figure out if there are some safe and effective Rac activators.”

However, there are caveats to that, he said.

“It might be difficult to target Rac specifically, because it is involved in cell proliferation and restructuring so it may be difficult to get a compound that doesn’t cause cancer. It might be better to screen for targets that more generally regulate synaptic plasticity. Ketamine is a drug that does this, and there is huge interest in ketamine” in depression, Dr. Russo said.

Experts Weigh In

Commenting on the findings for Medscape Medical News, David Dietz, PhD, assistant professor of pharmacology and toxicology, State University of New York at Buffalo, who was not involved in the research, said the study “is exquisitely well done. The researchers did an excellent job of translating their findings in the rodent model to the human condition.”

Maria V. Tejada-Simon, PhD, who also was not involved in this research but who has studied Rac1, noted that her group has been “highlighting the importance of Rac1 in the brain in general, and in psychiatric diseases in particular, for a while now. Therefore, I am not surprised that Rac1 has been found to be also associated to stress disorders and depression.”

“Mood disorders have been linked to changes in synaptic structure, and it is certain that small GTPases such as Rac1 have a tremendous role as modulators of these processes. However, we need to understand that alterations in Rac1 signaling are not likely to be the primary defect in mood disorders.

“Thus, targeting Rac1 to moderate clinical symptoms (while there is potential for a translational approach there) has to be done very carefully, given the broad role of Rac1 in many cellular functions involving the actin cytoskeleton,” said Dr. Tejada-Simon, assistant professor of pharmacology and adjunct assistant professor of biology and psychology at University of Houston College of Pharmacy in Texas.

“The highlight of this research is in identifying a possible mechanism by which we can study pathways that are involved in remodeling of the brain; we might be able to find something a little bit more specific down the line,” Dr. Dietz said.

He noted that Rac1 has also been linked to addiction.

“It’s well known that there is comorbidity between depression and addiction, that one may lead to the other, so there seems to be something fundamentally related between Rac1 and these 2 psychiatric disease states.”

The research was supported by the National Institute of Mental Health and the Johnson and Johnson International Mental Health Research Organization Rising Star Award (presented to Dr. Russo). The other authors, Dr. Tejada-Simon, and Dr. Dietz have disclosed no relevant financial relationships.

Nat Med. Published online February 17, 2013. Abstract

Retrieved from: http://www.medscape.com/viewarticle/779544?src=nl_topic

Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression

Sam A Golden, Daniel J Christoffel, Mitra Heshmati, Georgia E Hodes, Jane Magida,Keithara Davis, Michael E Cahill, Caroline Dias, Efrain Ribeiro, Jessica L Ables, Pamela J Kennedy, Alfred J Robison, Javier Gonzalez-Maeso, Rachael L Neve, Gustavo Turecki, Subroto Ghose, Carol A TammingaScott J Russo

Nature Medicine(2013) doi:10.1038/nm.3090; Received 11 October 2012.  Accepted 14 January 2013.  Published online 17 February 2013.

Abstract:

Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase–related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat–induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.

Retrieved from: http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.3090.html

wired for anxiety?

In Anxiety, Child/Adolescent Psychology, General Psychology, Psychiatry, School Psychology on Sunday, 10 February 2013 at 08:31

Are We All Just Wired for Anxiety?

By: Ben Michaels, Ph.D.

 Michael Shermer’s TEDTalk, “The Pattern Behind Self-deception” is both groundbreaking and earth-shattering. The neuroscience Shermer cites in his talk is tight, his examples are strong and his conclusions far-reaching. The implications that many have drawn from his talk regarding larger belief systems are beyond my expertise as a clinical psychologist and so I will (wisely or cowardly — you choose) sidestep these arguments.

I do however, think that one of the factors that Dr. Shermer stumbles upon in his talk has a wide applications for the field of clinical psychology, which is this:

If Shermer is right (and he is), and that our default setting is to see patterns where they don’t exist because the cost of being wrong (that there is no pattern) is usually much higher than the cost of being right (that there is a pattern) then I have some bad news for you:

We are all just wired for anxiety.

Let me break it down:

Let’s say something bad happens to us: We have a breakup, a breakdown, a trauma, an insult or injury of any kind. This leads us to seek out patterns in our environments that could signify the possibility of future pain. In fact, Shermer says that when we feel uncertain (like after a trauma) we will be even more prone to seeking out patterns, possibly seeing them where they don’t exist.

This desperate pattern seeking is, in essence, the pernicious spiral of anxiety: We are afraid of what’s next so our minds exit the present to try to solve an unsolveable math problem about our futures. The reason the problem is unsolveable is that all of the variables don’t yet exist. The key variable being the actual event.

If this tendency is our natural weakness, we must overcome it by using our natural strength: Thinking and testing our beliefs.

For example, I once worked with a handsome young man, who we will call, Nate, who was constantly told that he was “ugly” and “stupid” by his abusive father. When he first came to me, Nate was convinced that no woman would ever want to date him, let alone, marry him.

I responded to him by saying, maybe he’s right maybe no woman would have him, but there is only one way to find out: test his beliefs in the real world. I told him that if he asked out all the women in the world and none of them want to date him, than his anxiety would be justified If at least one woman wanted to then it would not be.

He realized that this was absurd, but after a great deal of relentless pushing, Nate agreed to try to approach a few women over time.

Fourteen months later he was engaged. He is now happily married and currently expecting his third child.

Science/Empiricism = 1; Anxiety/Fear = 0

The takeaway is this: We may indeed be wired for anxiety, but that does not mean that anxiety is our fate. If we use the gift of our minds well, we can overcome our wiring.

If you read this and are feeling anxious or are buried under the weight of any false belief because of your wiring, do the hard thing: Test it out. The only thing you have to lose is your anxiety!

Ideas are not set in stone. When exposed to thoughtful people, they morph and adapt into their most potent form. TEDWeekends will highlight some of today’s most intriguing ideas and allow them to develop in real time through your voice! Tweet #TEDWeekends to share your perspective or emailtedweekends@huffingtonpost.com to learn about future weekend’s ideas to contribute as a writer.

Retrieved from: http://www.huffingtonpost.com/ben-michaelis-phd/wired-for-anxiety_b_2599944.html?utm_source=linkedin&utm_medium=social&utm_content=2c773f97-31e5-4b88-bbb2-fa255a762ed1

Click here to read the original op-ed from the TED speaker who inspired the post and watch the TEDtalk below:

http://www.huffingtonpost.com/michael-shermer/what-is-skepticism-anyway_b_2581917.html?ir=TED+Weekends&ref=topbar

 

ABCs and ADHD…

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Psychiatry, School Psychology on Wednesday, 9 January 2013 at 07:04

The ABCs of ADHD

Learn about the specific characteristics of a child with ADHD and how it impacts their lives.

By Melvyn Hyman

Who today has not heard the term “attention deficit hyperactivity disorder,” or ADHD? No other term in the diagnostic lexicon has more information and misinformation attached to it than ADHD. Everyone you ask — parents, doctors, teachers, psychologists, nurses, neighbors or relatives — will have an opinion on this disorder, and likely their opinions will all differ. Some will toss it off and say, “Boys will be boys.” Some will insist that a child be medicated right away. Others will be adamant that children should never be medicated. Others will claim that eliminating sugar from the diet will eliminate the problem. Still others will question whether there is anything to the diagnosis at all.

Since first identified as a diagnosis, ADHD has been given a great deal of attention by neurologists and psychologists. ADHD is now widely recognized as a legitimate mental health problem. Although its exact definition continues to be debated, ADHD is thought to be a neurological impairment, probably originating in the frontal lobes of the brain, affecting a child’s ability to control his or her impulses. Lacking the ability to control their impulses, these children do and say whatever occurs to them from minute to minute. They are quite literally out of control.

There has been a great deal of research to understand just what causes children have ADHD. Among the identified causes are: heredity (a parent or other close relative with ADHD, although it may have gone unrecognized); problems at birth; and possibly some kind of early emotional trauma that had an effect on the processing mechanisms of the brain.

In some ways, children with ADHD are no different from their peers. One key diagnostic feature noted in children with ADHD is the intense, often frantic quality of their activity. These children are on the move most of the time: climbing the cupboards, tearing about the room, turning over every object that isn’t nailed down — an unending streak of activity and mischief. They quickly wear out their clothes and toys, and usually have more than their share of accidents.

Short Attention Spans
Children with ADHD also have extremely short attention spans. They seem to have difficulty sitting still or waiting their turn. This may be because they are so easily distracted. It often seems that they fail to remember instructions given by a parent or teacher in the time it takes to get from one end of the room to the other. They appear to live only in the present. They don’t seem to think about future consequences. They sometimes can’t remember what they did only moments earlier.

The behavior of a child with ADHD is qualitatively different from the occasional episodes of increased activity in children who do not have ADHD. Every child fidgets or misbehaves from time to time. Children with ADHD, however, are a constant challenge. Their behaviors cause frustration and anger for those around them. Without proper help, these children can become sad or even depressed due to their very accurate perception that the people around them disapprove of everything they do.

Ironically, these very same overactive children can become completely absorbed in a specific activity or task. They sometimes become so over-focused that being asked to shift their attention causes great upset and anger. It is as if the mechanism in the brain that controls their impulsiveness has now gone into overdrive. Once engaged, they can’t let go. Another theory is that these children have learned to compensate for their distractibility by focusing so completely on an activity that they cannot easily alter the track of their attention. They find change initiated by others to be threatening and difficult. This is very confusing for adults because it seems inconsistent with the general stereotypes about ADHD. Puzzled parents often ask things like: “How is it he can remember every arcane move in a video game but can’t remember to take out the garbage?” or “Why can she sit still to watch MTV for hours but can’t sit still through one classroom lesson?”

Friendships and ADHD
Children with ADHD also wear out friendships. Their behavior can be so thoughtless and aggravating, even exhausting, that other children start to avoid them. They miss usual social cues and often blurt out what they are thinking whether or not it is at all appropriate or tactful. Usually good-hearted and wanting friends, they are often mystified by others’ negative reactions to them. It is important to understand that children with ADHD are not trying to be annoying or malicious. In fact, they often seem surprised and embarrassed when their behavior results in rejection by others.

Evaluation for ADHD includes a family history, a medical exam, psychological testing, and, very importantly, a compilation of ratings on paper and pencil behavioral scales completed by parents and teachers who know the child well. A skilled neuropsychologist will recognize patterns in all of these data that generally point to a diagnosis of ADHD.

Treatment of ADHD
It is generally believed that children with ADHD benefit most from a multidisciplinary approach that comes at the problem in many ways simultaneously. On the medical front, stimulants such as Cylert (premoline), Dexedrine (dextroamphetamine), and Ritalin (methylphenidate) are the medications most often used to treat ADHD in the United States; antidepressants are sometimes prescribed as well. These medications increase activity in the frontal lobes of the brain where impulsivity is managed.

Parents and teachers of children with ADHD must be educated about how to best manage their particular child. Many adults make the mistake of getting into power struggles with these children, trying to control them with harsh disciplinary methods. Children with ADHD really can’t help being the way they are. Yelling, scolding, nagging, and punishing will only make them feel and behave worse. Even more than most children, these children need clear and kind guidance, with an emphasis on what they are doing right.

Early identification of special services in the schools can be very helpful. These children do better is a less stimulating, more orderly environment. They benefit from small classes that are fairly quiet. Activities need to be short and focused, with many opportunities for small successes. Parents and teachers should ideally keep in close contact with each other, sharing what they find to be effective for the child in question.

Finally, physical activity can sometimes help children with ADHD channel some of their excessive energy. They tend to do better at individual sports like swim team, rock climbing, weight lifting, or figure skating. Team sports (where a great deal is going on at once) can sometimes be overstimulating and frustrating for these children.

The goal, of course, is for children with ADHD to get the most enjoyment, learning and growth from each day of their lives. With teaching, encouragement, and support, these children can learn to monitor and manage their symptoms and move on with life.

Retrieved from: http://www.everydayhealth.com/adhd/add-adhd-facts.aspx?xid=tw_adhdfacts_20120217_ABCs

DSM-V…out with the old and in with the new…

In Autism Spectrum Disorders, General Psychology, Psychiatry, School Psychology on Thursday, 6 December 2012 at 11:20

http://www.cbsnews.com/8301-204_162-57556754/aspergers-syndrome-dropped-from-american-psychiatric-association-manual/

ADHD medication could help cut crime rates, Swedish study finds

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Medication, Psychiatry, Psychopharmacology on Thursday, 22 November 2012 at 08:32

ADHD medication could help cut crime rates, Swedish study finds

Many ADHD (attention-deficit hyperactivity disorder) sufferers are less likely to commit a crime while on appropriate medication, a Swedish study found.

Freya Petersen

November 22, 2012

Many ADHD (attention-deficit hyperactivity disorder) sufferers are less likely to commit a crime while on appropriate medication, a Swedish study found.

The study, by researchers at the Karolinska Institute in Stockholm, found that while people with ADHD were far more likely to break the law, the use of Ritalin, Adderall and other drugs to curb hyperactivity and boost attention markedly reduced rates of reoffending, the Associated Press reported.

The researchers focused on older teens and adults with ADHD, studying a Swedish registry of more than 25,650 people with ADHD and comparing their medication history with criminal records from 2006 to 2009, WebMD reported.

The number of crimes committed was about a third or more lower in those taking medication, the study found.

Lead author Paul Lichtenstein said in a statement quoted by Reuters:

“It’s said that roughly 30 to 40 percent of long-serving criminals have ADHD. If their chances of recidivism can be reduced by 30 percent, it would clearly affect total crime numbers in many societies.”

Support groups and preventative medicine experts seized on the study results, saying better access to medication could reduce crime.

They also said it demonstrated the efficacy of medications in older patients.

About 5 percent of children in the US and other Western countries reportedly have ADHD, characterized by impulsiveness, hyperactivity and difficulty paying attention.

While children are routinely given medication to help them focus in school, many sufferers retain symptoms into adulthood.

The AP quoted Dr. William Cooper, a pediatrics and preventive medicine professor at Vanderbilt University in Nashville, as saying:

“There definitely is a perception that it’s a disease of childhood and you outgrow your need for medicines. We’re beginning to understand that ADHD is a condition for many people that really lasts throughout their life.”

The findings were published in Thursday’s New England Journal of Medicine.

Retrieved from: http://www.globalpost.com/dispatch/news/health/121122/adhd-attention-deficit-hyperactivity-disorder-crime-sweden-swedish-study?utm_source=twitterfeed&utm_medium=twitter

Girls with ADHD often diagnosed later than boys

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Child/Adolescent Psychology, Psychiatry, School Psychology on Saturday, 10 November 2012 at 11:06

Girls with ADHD often diagnosed later than boys.

Gargling Sugar Water Can Boost Your Self-Control

In ADHD, ADHD Adult, ADHD child/adolescent, Alternative Health, Psychiatry on Saturday, 10 November 2012 at 10:54

Gargling Sugar Water Can Boost Your Self-Control.

and they call it…nomophobia…

In Psychiatry, Uncategorized on Friday, 2 November 2012 at 18:05

Are you Afraid to Be Without Your Phone?

ATLANTA -Do you feel like you can’t live without your phone? You may suffer from nomophobia.

Nomophobia is the fear of being without your cell phone. And before you laugh, there are  support groups for people who say they suffer from it. Doctors say that some people’s anxiety over their mobile devices is starting to cross the line.
If you want to study the importance of our mobile devices in our lives, just spend an afternoon in Centennial Olympic Park and people watch. You’ll see people texting, taking pictures, checking a map, some talking – mostly you will see smartphones in action no matter what you’re doing.

One study by the group SecureEnvoy found that Nomophobia has increased since 2008, from 55 percent of the population to 66 percent in 2012.

“For some people, they might worry that they are going to miss a phone call, an important meeting, miss a contact. For some people, it’s simply their connection to the outside world. It’s a way they read what’s going on with politics. It’s a way to keep up with news. With some people, it’s their security blanket.  It’s just something that makes them feel right at times,” said Dr. Josh Spitalnick.

What about kids? Psychotherapist Suzanne Maiden specializes in treating children. She says a mobile phone for a child is their connection to loved ones and their friends.

“Here we are setting our kids up almost that they have immediate access.  What happens when that stops? What happens if they lose their phone, they drop it in water, it gets broken etc.  Kids can panic,” said Maiden.

Maiden says there are times when you might consider getting treatment for nomophobia.

“If it starts causing problems in your relationships, at work, in your own life — it’s dictating your routines, then maybe talking with someone who treats anxiety disorders is a good thing,” said Spitalnick.

If it has to be treated, it’s is handled like any other phobia.  If it is starting to affect your relationships, starting to affect your daily routine, talk to your doctor about it.

Retrieved from: http://www.myfoxatlanta.com/story/19958517/people-beginning-to-fear-being-without-mobile-devices?autoStart=true&topVideoCatNo=default&clipId=7902465

asd…intervene early, see positive changes.

In Autism Spectrum Disorders, Psychiatry, School Psychology, Special Education on Friday, 2 November 2012 at 06:04

Early Autism Intervention Normalizes Brain Activity

Pam Harrison

Early behavioral intervention is associated with normalized patterns of brain activity along with improvements in social behavior in young children with autism spectrum disorder (ASD), a new nationwide study shows.

The multicentre study conducted by investigators at the University of North Carolina, Chapel Hill, showed that 73% of children who received the Early Start Denver Model (ESDM) intervention showed greater brain activation when viewing faces than when viewing objects.

This was very similar to typically developing children, 71% of whom showed the same brain activation pattern when viewing faces rather than objects.

In contrast, 64% of ASD children who received the control community intervention showed a greater response to objects than to faces, the opposite response from that seen in ESDM recipients.

Previous research has shown that ASD children typically respond more to nonsocial than to social stimuli.

“Those of us in the intervention field always assumed that improving children’s learning had to change brain function — that is how we learn,” Sally Rogers, PhD, University of California, Davis, MIND Institute, told Medscape Medical News.

“This evidence confirms how we understand learning — it’s not a surface change [but rather] a change in brain activation and patterns of brain connection.

“So I think behavioral intervention can be seen as a biological intervention because it changes the biology of brain activity.”

The study is published in the November issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

Intensive Therapy

A previous report from a randomized trial indicated that ESDM, a developmental behavioral intervention, resulted in gains in IQ, language, and adaptive behavior in children with ASD (Pediatrics 2010;125:e17-e23).

The current report describes electroencephalographic (EEG) activity, a secondary outcome measurement from the same study.

A total of 48 children aged 18 to 30 months who had been diagnosed with ASD were randomly assigned to receive ESDM or referral to community intervention for 2 years.

Children randomly assigned to ESDM received the intervention for 2 hours, twice a day, 5 days a week for 2 years.

The community intervention group received comprehensive diagnostic evaluations, interventional recommendations, and community referrals.

The children enrolled in the study represented the full range of severity of ASD in early childhood, and as Dr. Rogers emphasized, they were not picked because they had mild symptoms.

Two types of brain activity measurements were collected in response to social (faces) and nonsocial (toys) stimuli.

“The first reflected early-stage perceptual processing of faces versus objects,” the authors state, “[and] the second set of measurements reflected the degree of attention engagement…and active cognitive processing of the stimulus.”

Children randomly assigned to either intervention arm did not differ from typical children in early-stage perceptual face processing, the researchers point out.

In contrast, EEG measurements reflecting patterns of attention engagement and active cognitive processing of social stimuli showed that children who received the ESDM intervention exhibited brain activity that was comparable to age-matched typical children in that both allotted greater attentional and cognitive resources during viewing of social stimuli than to nonsocial stimuli.

These patterns were different from patterns observed in children who received the community intervention, who allotted greater attentional and cognitive resources to viewing of nonsocial stimuli than to social stimuli.

Powerful Intervention

“This is a very powerful intervention,” Dr. Rogers emphasized. For example, almost none of the children had speech prior to the ESDM intervention.

The average IQ prior to the intervention was only 65, she added.

Following the intervention, the average IQ was in the 80s.

“This means that these children no longer had intellectual disability as a group, so it was a huge change, and almost all of the children were able to use language effectively and functionally as well,” Dr. Rogers said.

Children with good EEG data who received the ESDM intervention also differed significantly on behavioral outcomes in autism symptoms, IQ, language, and adaptive and social behavior.

“Many public services provide interventions for young ASD children, but too many children are getting a hodgepodge of interventions,” Dr. Rogers observed.

“But national standards require we use evidence-based intervention, and what this study demonstrated is the importance of using evidence-based interventions and delivering them with enough intensity so they can have maximal effect.”

New Target, Potential Biomarker

Thomas Insel, MD, National Institute of Mental Health, noted in a press release on the study that this may be the first demonstration that a behavioral intervention for autism is associated with changes in brain function as well as positive changes in behavior.

“By studying changes in the neural response to faces, Dawson and her colleagues have identified a new target and a potential biomarker that can guide treatment development,” Dr. Insel added.

The study was funded by the National Institute of Mental Health. Dr. Dawson and Dr. Rogers are authors of the book Early Start Denver Model for Young Children with Autism, from which they receive royalties. Dr. Insel has disclosed no relevant financial relationships.

J Am Acad Child Adolesc Psychiatry. 2012:51:1150-1160. Abstract

Retrieved from: http://www.medscape.com/viewarticle/773641

Early Behavioral Intervention Is Associated With Normalized Brain Activity in Young Children With Autism 

 

 

 

http://www.jaacap.com/article/S0890-8567(12)00643-0/abstract

Objective

A previously published randomized clinical trial indicated that a developmental behavioral intervention, the Early Start Denver Model (ESDM), resulted in gains in IQ, language, and adaptive behavior of children with autism spectrum disorder. This report describes a secondary outcome measurement from this trial, EEG activity.

Method

Forty-eight 18- to 30-month-old children with autism spectrum disorder were randomized to receive the ESDM or referral to community intervention for 2 years. After the intervention (age 48 to 77 months), EEG activity (event-related potentials and spectral power) was measured during the presentation of faces versus objects. Age-matched typical children were also assessed.

ResultsThe ESDM group exhibited greater improvements in autism symptoms, IQ, language, and adaptive and social behaviors than the community intervention group. The ESDM group and typical children showed a shorter Nc latency and increased cortical activation (decreased α power and increased θ power) when viewing faces, whereas the community intervention group showed the opposite pattern (shorter latency event-related potential [ERP] and greater cortical activation when viewing objects). Greater cortical activation while viewing faces was associated with improved social behavior.

Conclusions

This was the first trial to demonstrate that early behavioral intervention is associated with normalized patterns of brain activity, which is associated with improvements in social behavior, in young children with autism spectrum disorder.

Retrieved from: http://www.jaacap.com/article/S0890-8567(12)00643-0/abstract

The Serotonin Hypothesis, Informed Consent and SSRI Antidepressants

In Medication, Mood Disorders, Neuropsychology, Neuroscience, Psychiatry on Wednesday, 31 October 2012 at 15:36

The Serotonin Hypothesis, Informed Consent and SSRI Antidepressants.

happy birthday, glutamate.

In Medication, Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology, Uncategorized on Wednesday, 31 October 2012 at 15:20

Twenty Five Years of Glutamate in Schizophrenia

Daniel C. Javitt

Schizophr Bull. 2012;38(5):911-913. © 2012 Oxford University Press

Abstract and Introduction

Abstract

At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently led to development of alternative, glutamatergic conceptualizations. This special issue traces the historic development of the phencyclidine (PCP) model of schizophrenia from the initial description of the psychotomimetic effects of PCP in the early 1960s, through discovery of the link to N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the 1980s, and finally to the development of NMDA-based treatment strategies starting in the 1990s. NMDAR antagonists uniquely reproduce both positive and negative symptoms of schizophrenia, and induce schizophrenia-like cognitive deficits and neurophysiological dysfunction. At present, there remain several hypotheses concerning mechanisms by which NMDAR dysfunction leads to symptoms/deficits, and several theories regarding ideal NMDAR-based treatment approaches as outlined in the issue. Several classes of agent, including metabotropic glutamate agonists, glycine transport inhibitors, and D-serine-based compounds are currently in late-stage clinical development and may provide long-sought treatments for persistent positive and negative symptoms and cognitive dysfunction in schizophrenia.

Introduction

The mid-20th century was an exciting period for drug development in psychiatry. Antipsychotics were developed based on the seminal observations of Delay and Deniker and linked to D2 blockade shortly thereafter. By 1971, clozapine, the current “gold standard” treatment for schizophrenia, had already been marketed. Antidepressants were developed based on clinical observations with isoniazid (INH) in the 1950s; benzodiazepines were developed based upon GABA receptor-binding assays in the 1960s; and definitive studies demonstrating efficacy of lithium were performed by the early 1970s. Decades later, these classes of compounds continue to form the core of today’s psychopharmacological armamentarium.

In the midst of this transformational period, initial reports appeared as well for a class of novel sedative agent termed “dissociative anesthetics” exemplified by the molecules phencyclidine (PCP, “angel dust”) and ketamine. In monkeys, these compounds produced behavioral symptoms closely resembling those of schizophrenia, including behavioral withdrawal at low dose and catalepsy at high dose (figure 1). Domino and Luby[1] describe the critical steps by which he and his contemporaries verified the unique clinical effects of these compounds in man. The initial characterizations of PCP as causing a centrally mediated sensory deprivation syndrome and producing electroencephalography changes similar to those in schizophrenia were, in retrospect, particularly critical.

Figure 1.

Effect of phencyclidine (PCP) on behavior in monkey, showing dissociation at low dose (A) and catatonia at high dose (B). From Chen and Weston.12

Although the clinical effects of PCP were well documented by the early 1960s, it took another 20 years to characterize these effects at the molecular level. As described by Coyle,[2] key milestones along the way included the pharmacological identification of the PCP receptor in 1979; demonstration of electrophysiological interactions between PCP and N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the early 1980s followed shortly thereafter by pharmacological confirmation; identification of the glycine modulatory site of the NMDAR in 1987; and confirmation of the psychotomimetic effects of ketamine in the mid-1990s. Although researchers still disagree to the paths leading from NMDAR blockade to psychosis, few currently dispute the concept that NMDAR serve as the molecular target of PCP, ketamine, dizocilpine (MK-801), and a host of other clinical psychotomimetic agents.[2–4]

At their simplest, glutamatergic models predict that compounds stimulating NMDAR function should be therapeutically beneficial in schizophrenia.[2,4] Potential sites for intervention include the glycine/D-serine and redox sites of the NMDAR, as well as pathways regulating glutamate, glycine/D-serine, and glutathione synthesis/release.[4] D-Cycloserine, a partial NMDAR glycine-site agonist, may enhance learning and neural plasticity across a range of disorders, including schizophrenia.[5] In addition to providing new drug targets, glutamatergic models provide effective explanation for the hippocampal activation deficits,[6] positive and negative symptoms, distributed neurocognitive deficits, and sensory processing abnormalities[4] that are critical components of the pathophysiology of schizophrenia.

Since the original description, several variations have been developed with somewhat different treatment predictions. The term “NMDA receptor hypofunction” was originally developed to describe the vacuolization and neurodegeneration seen within specific brain regions following high-dose NMDAR antagonist administration.[7] In animal models, neurotoxic effects of PCP were reversed by numerous compounds, including benzodiazepines and α2 adrenergic agonists that ultimately proved ineffective in clinical studies. Nevertheless, this model may explain the pattern of persistent frontotemporal neurocognitive deficits observed in some ketamine abusers.[8] Subsequent hyperglutamatergic models focused on the excess glutamate release induced by NMDAR antagonists, particularly in prefrontal cortex, and prompted studies with compounds, such as lamotrigine or metabotropic glutamate receptor (mGluR) 2/3 agonists, that inhibit presynaptic glutamate release.[9] GABAergic models focus on NMDAR antagonist-induced downregulation of parvalbumin (PV) expression in interneurons and resultant local circuit level (gamma) dysfunction, and suggest use of subunit selective GABAA receptor modulators.[10]

More than 50 years after the initial characterization of PCP, and 25 years after the identification of NMDARs as the molecular target of PCP, we still do not know whether the novel pharmacology of dissociative anesthetics can be translated into effective clinical treatments. Encouraging small-scale single site studies have been published with NMDAR agonists, but have not yet been replicated in academic multicenter trials. Encouraging phase 2 results have also recently been reported by Roche with glycine transport inhibitors.[4] Nevertheless, phase 3 studies remain ongoing and results cannot be predicted. Additional beneficial effects may be observed in obsessive-compulsive disorder, substance abuse and Parkinsons disease.[4] Conversely, NMDAR antagonists, such as ketamine, may be therapeutically beneficial in treatment-resistant depression or autism, suggesting complementary pathology across a range of disorders.[11] More than anything else, 50 years of research shows that treatment development in neuropsychiatric disorders is a journey and not a destination, although fortunately one where the end now finally seems in sight.

Retrieved from: http://www.medscape.com/viewarticle/771599?src=nl_topic

References

  1. Domino EF, Luby ED. Phencyclidine/schizophrenia: one view toward the past, the other to the future Schizophr Bull. 2012.In press.
  2. Coyle JT. The NMDA receptor and schizophrenia: a brief history Schizophr Bull. 2012.In press
  3. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia Am J Psychiatry 1991 148 1301–1308
  4. Javitt DC. Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull In press.
  5. Goff D. D-cycloserine: an evolving role in learning and neuroplasticity in schizophrenia.Schizophr Bull In press.
  6. Tamminga CA, Southcott S, Sacco C, Gao XM, Ghose S. Glutamate dysfunction in hippocampus: relevance of dentate gyrus and ca3 signaling.Schizophr Bull. 2012. In press
  7. Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia J Psychiatr Res.1999 33 523–533
  8. Morgan CJ, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study Addiction 2010 105 121–133
  9. Moghaddam B, Krystal JH. Capturing the angel in angel dust: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans Schizophr Bull. In press.
  10. Lewis DA, Gonzalez-Burgos G. NMDA receptor hypofunction, parvalbumin-positive neurons and cortical gamma oscillations in schizophrenia. Schizophr Bull In press.
  11. Javitt DC, Schoepp D, Kalivas PW, et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med. 2011;3:102mr102.
  12. Chen GM, Weston JK. The analgesic and anesthetic effects of 1-(1-phenylcyclohexyl)-piperidine HCl in the monkey Anesth Analg. 1960 39 132–137

important information regarding child abuse

In Child/Adolescent Psychology, Psychiatry, School Psychology on Wednesday, 31 October 2012 at 08:12

please be proactive if you suspect child abuse.  you are not determining that there is definitive abuse if you report, that determination is made by the respective agencies responsible for child welfare.  ignoring it will not make the problem go away and can have deleterious effects for children.

How Child Abuse Primes the Brain for Future Mental Illness

By: Maia Szalvitz

Child maltreatment has been called the tobacco industry of mental health. Much the way smoking directly causes or triggers predispositions for physical disease, early abuse may contribute to virtually all types of mental illness.

Now, in the largest study yet to use brain scans to show the effects of child abuse, researchers have found specific changes in key regions in and around the hippocampus in the brains of young adults who were maltreated or neglected in childhood. These changes may leave victims more vulnerable to depression, addiction and post-traumatic stress disorder (PTSD), the study suggests.

Harvard researchers led by Dr. Martin Teicher studied nearly 200 people aged 18 to 25, who were mainly middle class and well-educated. They were recruited through newspaper and transit ads for a study on “memories of childhood.” Because the authors wanted to look specifically at the results of abuse and neglect, people who had suffered other types of trauma like car accidents or gang violence were excluded.

MORE: Study: How Chronic Stress Can Lead to Depression

Child maltreatment often leads to conditions like depression and PTSD, so the researchers specifically included people with those diagnoses. However, the study excluded severely addicted people and people on psychiatric medications, because brain changes related to the drugs could obscure the findings.

Overall, about 25% of participants had suffered major depression at some point in their lives and 7% had been diagnosed with PTSD. But among the 16% of participants who had suffered three or more types of child maltreatment  — for example, physical abuse, neglect and verbal abuse — the situation was much worse. Most of them — 53% — had suffered depression and 40% had had full or partial PTSD.

The aftermath of that trauma could be seen in their brain scans, whether or not the young adults had developed diagnosable disorders. Regardless of their mental health status, formerly maltreated youth showed reductions in volume of about 6% on average in two parts of the hippocampus, and 4% reductions in regions called the subiculum and presubiculum, compared with people who had not been abused.

That’s where this study begins to tie together loose ends seen in prior research. Previous data have suggested that the high levels of stress hormones associated with child maltreatment can damage the hippocampus, which may in turn affect people’s ability to cope with stress later in life. In other words, early stress makes the brain less resilient to the effects of later stress. “We suspect that [the reductions we saw are] a consequence of maltreatment and a risk factor for developing PTSD following exposure to further traumas,” the authors write.

Indeed, brain scans of adults with depression and PTSD often show reductions in size in the hippocampus. Although earlier research on abused children did not find the same changes, animal studies on early life stress have suggested that measurable differences in the hippocampus may not arise until after puberty. The new study suggests that the same is true for humans.

MORE: Nurturing Moms May Boost Children’s Brain Growth

The findings also help elucidate a possible pathway from maltreatment to PTSD, depression and addiction. The subiculum is uniquely positioned to affect all of these conditions. Receiving output from the hippocampus, it helps determine both behavioral and biochemical responses to stress.

If, for example, the best thing to do in a stressful situation is flee, the subiculum sends a signal shouting “run” to the appropriate brain regions. But the subiculum is also involved in regulating another brain system that, when overactive during chronic high stress such as abuse, produces toxic levels of neurotransmitters that kill brain cells — particularly in the hippocampus.

It can be a counterproductive feedback loop: high levels of stress hormones can lead to cell death in the very regions that are supposed to tell the system to stop production.

What this means is that chronic maltreatment can set the stress system permanently on high alert. That may be useful in some cases — for example, for soldiers who must react quickly during combat or for children trying to avoid their abusers — but over the long term, the dysregulation increases risk for psychological problems like depression and PTSD.

MORE: Boxer Quanitta Underwood’s Inspiring Fight Against Sexual Abuse — and for Olympic Gold

The subiculum also regulates the stress response of a key dopamine network, which may have implications for addiction risk. “It is presumably through this pathway that stress exposure interacts with the dopaminergic reward system to produce stress-induced craving and stress-induced relapse,” the authors write.

In other words, dysregulation of the stress system might lead to intensified feelings of anxiety, fear or lack of pleasure, which may in turn prompt people to escape into alcohol or other drugs.

With nearly 4 million children evaluated for child abuse or neglect in the U.S. every year — a problem that costs the U.S. $124 billion in lost productivity and health, child welfare and criminal justice costs — child maltreatment isn’t something we can afford to ignore.

Even among the most resilient survivors, the aftereffects of abuse may linger. Not only are such children at later risk for mental illness, but because of the way trauma affects the stress system, they are also more vulnerable to developing chronic diseases like diabetes, high blood pressure, heart attack and stroke.

We can do better for our kids.

The study was published in the Proceedings of the National Academy of Sciences.

Maia Szalavitz is a health writer at TIME.com. Find her on Twitter at @maiasz. You can also continue the discussion on TIME Healthland’s Facebook page and on Twitter at @TIMEHealthland.
Retrieved from: http://healthland.time.com/2012/02/15/how-child-abuse-primes-the-brain-for-future-mental-illness/#ixzz2AsTNhYSB

dream a little dream of me…

In Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology on Tuesday, 23 October 2012 at 09:51

What Physicians Need to Know about Dreams and Dreaming

James F. Pagel

Abstract

Purpose of review: An overview of the current status of dream science is given, designed to provide a basic background of this field for the sleep-interested physician.

Recent findings: No cognitive state has been more extensively studied and is yet more misunderstood than dreaming. Much older work is methodologically limited by lack of definitions, small sample size, and constraints of theoretical perspective, with evidence equivocal as to whether any special relationship exists between rapid eye movement (REM) sleep and dreaming. As the relationship between dreams and REM sleep is so poorly defined, evidence-based studies of dreaming require a dream report. The different aspects of dreaming that can be studied include dream and nightmare recall frequency, dream content, dreaming effect on waking behaviors, dream/nightmare associated medications, and pathophysiology affecting dreaming.

Summary: Whether studied from behavioral, neuroanatomical, neurochemical, pathophysiological or electrophysiological perspectives, dreaming reveals itself to be a complex cognitive state affected by a wide variety of medical, psychological, sleep and social variables.

Introduction

As most individuals experience the cognitive mentation that we call dreams during sleep, any physician treating sleep needs to have at least a basic understanding of dreaming. It was just 50 years ago that polysomnography allowed for sleep to be electrophysiologically staged. Although sleep had yet to be examined, a huge literature existed on dreaming and, through psychoanalysis, the use of dreams in the treatment of the spectrum of mental illness. Today, the scientific study of dreams has come full circle. We now know a huge amount about sleep, its associated pathophysiology, and treatment, yet what we know scientifically about the dream state is far less than what we thought we knew a generation ago. Much older work was not evidence based, and was methodologically limited by lack of definitions, small sample size, and the constraints of theoretical perspective. After 50 years of dogmatic insistence that rapid eye movement (REM) sleep is dreaming, most researchers in the field now accept that the evidence is overwhelming that REM sleep occurs without dreaming and dreaming without REM sleep.[1] Evidence remains equivocal as to whether any special relationship exists between REM sleep and dreaming.[2•] It is unclear as to what part, if any, of the highly developed neuroanatomical and neurochemical model for REM sleep is applicable to the cognitive state of dreaming.

Definitions: What is a Dream?

Early in the 20th century, Sigmund Freud and his adherents developed the psychoanalytic techniques of free association and dream analysis for use in diagnosing and treating individuals with psychiatric illnesses. Freud focused on the psychopathologic associations of bizarre and unusual dreams, eventually giving us a definition of dreaming as ‘wish fulfillment.’ Psychoanalysts stretched the definition of dreaming to include parasomnias and the REM sleep-associated states of narcolepsy, defining dreams as bizarre, hallucinatory mental activity that can occur in either sleep or wake.[3] This psychoanalytic definition of dreaming became the generally accepted definition for this phenomenon among many psychiatrists and neuroscientists.

From its initial discovery, REM sleep = dreaming was proof of the correlate between psychoanalysis and brain structure, a postulate at the basis of grand theories of dreaming including Activation, Input, Modulation (AIM), now termed protoconsciousness theory and the most developed and widely accepted theory of central nervous system (CNS) functioning.[4] It is a primary postulate of AIM that the neurons and neurochemicals that modulate REM sleep alter dreaming and other conscious states in a similar manner. The AIM model has been adopted and extended into proposals that REM sleep dreaming is the process that organizes neural nets in higher cortical regions.[5] These theories postulate that the cognitive activity of dreaming is based on the CNS activation associated with REM sleep, with dreaming an upper cerebral cognitive process utilizing the CNS activation associated with a primitive electrophysiological state of activation that we call REM sleep. If REM sleep is dreaming, animal models and scanning studies of REM sleep as reported in the popular and scientific press can be construed to be studies of the cognitive state of dreaming. Such studies must be considered suspect, however, as dreaming occurs throughout sleep in forms (except for nightmares) indistinguishable from REM sleep dreaming.[6]

Most sleep medicine physicians consider dreaming to be mentation reported as occurring in sleep by a human participant. This definition contradicts the psychoanalytic definition for dreaming, restricting dreaming to sleep irrespective of content. This definition also differs from the REM sleep = dreaming model in requiring a dream report. Because of this conflation of contradicting definitions, it is important for anyone interested in perusing either scientific or popular literature to note what the author may be referring to in any discussion of dreams and dreaming.[7]

Evidence-based Research Into Dreaming

Characteristics of the dream state amenable to scientific study include recall, content, dream incorporation into waking, and associated pathophysiology.

Dream Recall

Collection methodology including time since waking, process, and defined state characteristics affect reported dream recall frequency. Sleep stage of origin is a primary variable known to affect dream recall frequency. Multiple studies indicate that dream recall reported from REM sleep and sleep onset is in the range of 80%. Although recall from stage 2 varies through the night, recall approximates the 40% recall from stage 3.[8] Recall is generally higher for women and in the young.[9] Increased dream salience and intensity, typical of nightmares, also results in an increase in recall. Significant subjective and objective insomnia is associated with diminished dream recall.[10] Bi-basilar frontal CNS damage can be associated with a loss of dreaming.[11] Although some individuals report that they do not dream, most have experienced dreams at some point in their lives. The much smaller percentage of sleep laboratory patients that have never experienced dreaming (0.038%) do not report dreams in the laboratory when awakened from either REM sleep or non-REM sleep.[12] Despite their lack of dream recall, these individuals have no obvious memory impairment and function normally in our society.

Dream Content

Guttenberg’s first printed book was the Bible, but his second was the Oneirocritica, an interpretation of the meaning of dream symbols.[13] Mankind’s focus on dream content likely predates the development of either printing or writing.[2•] Dream content has been incorporated into the worlds’ major religions, philosophies, literature, and science. The argument can cogently be made that the structure and narrative form of language itself is derived from our attempts to organize and share our dreams. Most dreams are narratives occurring, and often presented without applied organization, grammar, or expectation of critique. In the dream, we can literally observe the ‘thinking of the body,’ and with it, the birth of the literary process. Our dreams can be considered an exercise in pure storytelling whose end is nothing more (or less) than the organization of experience into set patterns that help to maintain order for the thinking system.[14]

Freud postulated that an individual’s psychic structure could be inferred from information derived from the associative interpretation of dreams, and then could be utilized in developing a therapeutic plan for the treatment of psychiatric symptoms.[15] He stated, ‘Psychoanalysis is related to psychiatry approximately as histology is related to anatomy’.[16] For more than a generation, psychiatrists were trained in the method, with the data derived from psychoanalytic techniques used to make diagnoses and form treatment plans. Although psychoanalysis was utilized with occasional success in treating psychiatric illness, most of the evidence attesting to its therapeutic efficacy was anecdotal and subjective.[3]

More recent studies of dream content have attempted to address the significant methodological problems of transference, collection and interpretation that led to the nonreplicable characteristics of dream content studies. Methodologically sound studies have been developed that utilize computerized analysis of the validated Hall and Van de Castle content system.[17] Such studies have shown few, if any, significant differences in dream content between personality types, psychopathologic diagnoses, or socio-ethnic groups.[18] The primary significant correlate for dream content has proven to be waking experience, supporting the so-called continuity hypothesis – dream content reflects our waking experience.[18] Dream researchers have persisted in developing alternative content scales in order to support theoretical perspectives.[19] Although few of these scales have been validated or subjected to independent analysis, the best data is for Hartmann’s analysis of personality correlates (boundaries) that affect both dream recall frequency and content.[20]

Studies have also started to address other aspects of dream content. Visual imagery, the primary characteristic of most reported dreams, follows an operative pattern in dreaming that can be studied and applied externally to filmmaking methodology.[6] Memories follow characteristic patterns in both dream-associated sleep and varied waking states.[21•] Emotions, particularly negative emotions, are routinely incorporated into dreaming.[22]

Dream Incorporation Into Waking Behavior

Many individuals use their dreams. As in recall, dream-use tends to be sex-based and age-based (higher in women and the young).[23] Although ethnic and cultural differences in dream-use exist, such variations do not tend to be present in general population samples.[24] Dream use is significantly higher among individuals reporting creative interests.[25] Among successfully creative individuals, dream and nightmare recall, as well as dream incorporation into work and waking behavior is much higher than in the general population, suggesting that one function of dreaming may be in the creative process.[6,26]

Medications Inducing Disturbed Dreaming and Nightmares

Until recently, neurochemists interested in dreaming focused their studies on the effects of various neurochemicals on REM sleep based on the belief that medications affecting dreaming would be the same ones known to affect REM sleep. Acetylcholine is the primary neuromodulator affecting REM sleep.[27] A wide variety of pharmaceutical agents have anticholinergic activity, and the reported side effects of some of these agents include nightmares, disordered dreaming and hallucinations. This has led some authors to postulate that cholinergic effects of medications induce nightmares, hallucinations, and psychosis.[28] Based on this theoretical construct, the anticholinesterase agents in widespread use for the treatment of the cognitive effects of Alzheimer’s disease should alter dreaming. These agents, however, are reported to induce the side effect of disturbed dreaming or nightmares in only 0.4% of clinical trial participants.[29]

Agents that suppress REM sleep such as ethanol and benzodiazepines induce episodes of REM sleep rebound on withdrawal. These REM sleep rebound episodes have been associated with reports of nightmares and disturbed dreaming, and were considered the primary mechanism for drug-induced disordered dreaming and nightmares. However, nightmares and disordered dreaming are often reported as part of the withdrawal syndrome from addictive medications such as cannabis, cocaine and opiates that, which are not known to affect REM sleep. This suggests that during withdrawal from addictive agents, disturbed dreaming and nightmares may be an intrinsic part of that process rather than occurring secondary to REM sleep rebound.[29,30]

Data based on clinical trials and case reports of effects and side effects of clinically utilized pharmaceutical agents indicate that a much different pattern of medications induce disordered dreaming and nightmares than those known to affect REM sleep.[29] The spectrum of medications affecting dreaming indicates that the state is neurochemically complex with medications influencing the neurotransmitters/neuromodulators dopamine, nicotine, histamine, GABA, serotonin, nicotine, and norepinephrine altering dreaming and reported nightmare frequency in 1–5% of patients using these medications.[29] Medications with clinical cognitive effects and/or side-effects of arousal (insomnia) and/or sedation are those that most commonly alter the reported frequency of disordered dreaming and nightmares ( ).

Among drug classes of prescription medications in clinical use, β-blockers affecting norepinephrine neuroreceptors are most likely to result in patient complaints of disturbed dreaming. The strongest clinical evidence for a specific drug to induce disordered dreaming or nightmares is for the selective serotonin reuptake inhibitor paroxetine – a medication known to suppress REM sleep. Because of the high frequency of use of over-the-counter preparations containing type-1 antihistamines for sleep induction and the treatment of allergies, such preparations are likely responsible for most reports of drug-induced disordered dreaming and nightmares.[29]

Table 1.  Cognitive effects and side effects of medications: neurotransmitter/neuromodulator-associated central nervous system effects

Basis for central nervous system activity Sleepiness Insomnia Alterations in dreaming
Neuromodulator and/or neurotransmitter mediated effects
   Serotonin +++ ++ +++
   Norepinephrine ++ ++ +++
   Dopamine +++ +++ +++
   Histamine +++ + ++
   GABA +++ + ++
   Acetylcholine ++
   Adenosine + +++
   Nicotine +++ +++
Other medication effects
   Effects on inflammation ++ ++ ++
   Addictive drug withdrawal + +++ +++
   Altered conscious interaction with environment +++ + ++
   Alterations in sleep associated disease +++ +++ +

+++, majority of drugs with this activity cause this effect in more than 5% of patients; ++, some drugs with this activity induce this effect in 1–5% of patients; +, an idiosyncratic effect for some agents in this group or withdrawal effect; −reported in less than 1% of patients using agents affecting this neurotransmitter/neuromodulator [29]

Pathophysiology of Dreaming And Nightmares

Although changes in dreaming are sometimes reported, most reports of pathophysiological correlates for dreaming are reports of nightmares – coherent dream sequences usually occurring in REM sleep that become increasingly more disturbing as they unfold and usually resulting in awakening.[31]

Dream-like Parasomnias

Dreaming (cognitive narrative, feeling, or awareness of dreaming on awakening) occurs in association with many parasomnias – unwanted behaviors occurring during sleep.

Parasomnias are in general classified based on sleep stage of origin.

Disorders of Arousal

The disorders of arousal occurring out of deep sleep are associated with dream mentation up to 40% of the time. Somambulism is characterized by autonomic and inappropriate behaviors, frantic attempts to escape a perceived threat, and fragmentary recall. Sleep terrors and confusional arousals are associated with incoherent vocalizations, intense autonomic discharge, confusion and disorientation, and fragmentary dream recall.[32]

Hypnogognic Phenomena

The sleep onset nightmares typical of posttraumatic stress disorder (PTSD) and sleep onset sleep paralysis can occur without the classic REM sleep association. Sleep onset PTSD nightmares often induce distress that interferes with the initiation of sleep. Hypnogogic hallucinations are primarily visual and have coherent dream storylines that are perceived as potentially real. Although commonly experienced (prevalence rates vary from 25 to 37%), such experiences are also a part of the classic tetrad of narcolepsy.[33] The regularly experienced hypnogogic hallucinations reported by 40–60% of individuals carrying the diagnosis of narcolepsy with cataplexy may have more complex storylines than those reported in the general population.[3,34] Sleep starts, most commonly experienced at sleep onset, can be associated with the impression of falling.

Rapid Eye Movement Sleep-associated Parasomnias 

REM sleep is classically associated with dream-like parasomnias. Some of these parasomnias can also occur outside REM sleep. PTSD nightmares and sleep paralysis can occur at sleep onset. REM sleep behavior disorder (RBD) phenomena can also occur in association with arousal disorders.

Nightmare Disorder

Nightmare disorder is characterized by recurrent nontrauma-related REM sleep dreams that result in intense anxiety, fear or terror, and a coherent dream story usually involving imminent physical danger for the dreamer. Associated insomnia and difficulty returning to sleep are usually present. As in most parasomnias, arousals associated with obstructive sleep apnea (OSA) or periodic limb movement disorder can result in increased symptomatology; however, in patients with the disordered sleep associated with moderate to severe OSA, normal dreaming is maintained while reported nightmares actually decline in frequency.[35] Personality patterns typically present in individuals with frequent nightmares include fantasy proneness, psychological absorption, dysphoric daydreaming and ‘thin’ boundaries.[20] Such individuals are more likely to have a creative or artistic focus in their daily lives. Some of these individuals may utilize their dreams and nightmares in highly successful creative careers in writing, acting and film.[36 

Posttraumatic Stress Disorder-associated Nightmares

Frequent nightmares are the most common symptom of PTSD, affecting approximately 25% of individuals who have experienced severe emotional or physical trauma.[37] The nightmares that characterize PTSD are frightening and sometimes stereotypic dreams that can include re-experiencing of the individual’s trauma. Nightmares may be a failure of emotional processing systems that are active during sleep, particularly REM sleep.[22,38] Significant improvement in both sleep onset and maintenance insomnia has been achieved in PTSD patients with the use of both cognitive/behavioral and medication approaches that demonstrably reduce the frequency and distress associated with these disturbing dreams.[39]

Rapid Eye Movement Sleep Behavior Disorder (RBD) and Sleep Paralysis

In patients with RBD, vivid dreams are often ‘acted out.’ Such dream-related behavior can be violent and can result in injury to the victim or bedpartner. In contrast to those who experience sleep terrors, the victim will often recall coherent dream stories that, in a minority of cases, correlate with observed RBD behaviors.[40] RBD events can occur outside the sleep stage for which it is named.[41] During REM sleep associated with sleep paralysis, the inability to perform voluntary movements on waking, with full recall of dreaming, can lead to intense anxiety.

Other Dream-like Parasomnias

Sleep talking (somniloquy), which usually occurs in stage-2 non-REM sleep but which can accompany any stage of sleep, may include embarrassing waking content. Anxiety and panic attacks, also predominately occurring in stage-2, may also include coherent dream content. Sleep related dissociative disorder occurring in individuals with waking dissociative disorders is characterized by re-experiencing of trauma that presents during nighttime awakenings. Nocturnal partial epileptic seizures can include thoughts and hallucinations.[42]

Conclusion 

The recent progress that researchers have made in understanding dreams has been incremental, and is not nearly as exciting as the simplified insights, at the time regarded as breakthroughs into the process of consciousness, that were once attributed to dreaming. This recent work indicates that dreaming is a complex cognitive state whether viewed from behavioral, neuroanatomical, neurochemical, pathophysiological or electrophysiological perspectives. Our dreams are what we remember in the morning of the cognition taking place in our CNS during sleep. It is recommended that physicians treating sleep and its disorders be familiar with current knowledge of the science of dreaming. 

Sidebar

Key Points

  • Dreaming is not limited to rapid eye movement (REM) sleep, but rather occurs throughout sleep.
  • Dreaming defined as cognitive narrative, feeling, or awareness of dreaming on awakening occurs in association with many parasomnias.
  • Dreaming is a complex cognitive state whether viewed from behavioral, neuroanatomical, neurochemical, pathophysiological or electrophysiological perspectives.
  • Medications affecting the neurotransmitters/neuromodulators dopamine, nicotine, histamine, gamma-aminobutyric acid (GABA), serotonin, nicotine, and norepinephrine alter dreaming and reported nightmare frequency.

References

  1. Solms M. Dreaming and REM sleep are controlled by different brain mechanisms. In: Pace-Schott E, Solms M, Blagtove M, Harnad S, editors. Sleep and dreaming: scientific advances and reconsiderations. Cambridge, UK: Cambridge University Press; 2003. pp. 51–58.
  2. Pagel JF. REMS and dreaming – historical perspectives. In: Mallick BN, Pandi Perumal SR, McCarley RW, Morrison AR, editors. Rapid eye movement sleep – regulation and function. Cambridge, UK: Cambridge University Press; 2011. pp. 1–14.
    • This book providesa state of the art analysis of the highly developed neuroanatomic and neurochemical model for REM sleep.
  3. Pagel JF, Scrima L. Psychoanalysis and narcolepsy. In: Goswami M, Pandi-Perumal SR, Thorpy M, editors. Narcolepsy – a clinical guide. New York, NY: Springer/Humana Press; 2010. pp. 129–134.
  4. Hobson J. Dream life: an experimental memoir. Cambridge, MA: MIT Press; 2011.
  5. Crick F, Mitchenson G. The function of dream sleep. Nature 1983; 304:111– 114.
  6. Pagel JF. The limits of dream – a scientific exploration of the mind/brain interface. Oxford, UK: Academic Press (Elsiever); 2008.
  7. Pagel JF, Blagrove M, Levin R, et al. Defining dreaming – a paradigm for comparing disciplinary specific definitions of dream, Dreaming 2001; 11:195–202.
  8. Foulks D. Data constraints on theorizing about dream function, In: Moffitt A, Kramer M, Hoffmann R, Albany, editors. The functions of dreaming. New York: SUNY Press; 1993. pp. 11–20.
  9. Schredl M, Lahl O. Gender, sex role orientation, and dream recall frequency. Dreaming 2010; 20:19–24.
  10. Pagel JF, Shocknasse S. Dreaming and insomnia: polysomnographic correlates of reported dream recall frequency. Dreaming 2007; 17:140–151.
  11. Kaplan-Solmes K, Solmes M. Clinical studies in neuro-psychoanalysis: introduction to depth neuropsychology. New York & London: Karnac Books; 2000.
  12. Pagel JF. Nondreamers. Sleep Med 2003; 4:235–241.
  13. Hunt H. Dreams as literature/science: an essay. Dreaming 1991; 1:235–242.
  14. States BO. Dreaming and Storytelling. Ithaca NY: Cornell University Press; 1993. p. 53.
  15. Freud S. New Introductory lectures on psychoanalysis. Harmondsworth, UK; Penguin: 1933/1973. p.83.
  16. Freud S. Psychoanalysis and psychiatry general theory of the neuroses, In: Ed. J. Strachey, editor. Introductory lectures on psychoanalysis trans, New York, NY; W. W. Norton: 1917/1966. p. 255.
  17. Hall C, Van de Castle R. The content analysis of dreams. New York, NY: Appleton-Century-Crofts; 1966.
  18. Domhoff GW. The scientific study of dreams; neural networks, cognitive development and content analysis. Washington DC: American Psychological Association; 2003.
  19. Kramer M. The dream experience: a systemic exploration. New York & London: Routledge; 2007:; pp. 51–53.
  20. Hartmann E, Kunzendorf R. The central image (CI) in recent dreams, dreams that stand out, and earliest dreams: relationship to boundaries. Imagination, Cogn Pers 2006; 25:383–392.
  21. Kozmova M. Dreamers as agents making strategizing efforts exemplify core aggregate of executive function in nonlucid dreaming. Int J Dream Res 2012; 5:47–67.
    An in-depth study into the incorporation of forms of thinking into dreaming.
  22. Levin R, Fireman G, Nielsen T. Disturbed dreaming, and emotional dysregulation. In: Pagel JF, editor. Dreaming and nightmares – sleep medicine clinics, vol. 5. Philadelphia, PA: Saunders; 2010. pp. 229–240.
  23. Pagel JF, Vann B. The effects of dreaming on awake behavior. Dreaming 1992; 2:229–237.
  24. Pagel JF, Vann B. Cross-cultural dream use in Hawaii. Hawaii Med J 1993; 52:44–45.
  25. Pagel JF, Kwiatkowski CF. Creativity and dreaming: correlation of reported dream incorporation into awake behavior with level and type of creative interest. Creativity Res J 2003; 15:199–205.
  26. Hartmann E. The dream always makes new connections: the dream is a creation not a replay, In: Pagel JF, editor. Dreaming and nightmares – sleep medicine clinics, vol. 5. Philadelphia, PA: Saunders; 2010. pp. 241–248.
  27. Watson C, Baghdoyan H, Lydic R. REM Sleep regulation by cholinergic neurons: highlights from 1999 to 2009, In: Mallick BN, Pandi Perumal SR, McCarley RW, Morrison AR, editors. Rapid eye movement sleep – regulation and function, Cambridge, UK: Cambridge University Press; 2011. pp. 194– 205.
  28. Perry E, Perry R. Acetylcholine and hallucinations: disease related compared to drug induced alterations in human consciousness. Brain Cogn 1995; 28: 240–258.
  29. Pagel JF. Drugs, dreams and nightmares. In: Pagel JF, editor. Dreaming and nightmares – sleep medicine clinics, vol. 5. Philadelphia, PA: Saunders; 2010. pp. 277–288.
  30. Wade DT, Makela PM, House H, et al. Long term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler 2006; 12:639–645.
  31. International Classification of Sleep Disorders – Diagnostic and Coding Manual (ICD-11). In: Pagel JF, Nielsen T, editors. Parasomnias: recurrent nightmares, Winchester, IL; American Academy of Sleep Medicine; 2005. pp.155–158.
  32. International Classification of Sleep Disorders – Diagnostic and Coding Manual (ICD-11). Disorders of arousal, Winchester, IL; American Academy of Sleep Medicine; 2005. pp. 139–145.
  33. Ohayon M. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res 2000; 97:153–164.
  34. Scrima L. Dreaming epiphenomina of narcolepsy, In: Pagel JF, editor. Dreaming and nightmares – sleep medicine clinics, vol. 5. Philadelphia, PA: Saunders; 2010. pp. 261–276.
  35. Pagel JF. The nightmares of sleep apnea: nightmare frequency declines with increasing Apnea Hypopnea Index (AHI). J Clin Sleep Med 2010; 6:69–74.
  36. Pagel JF, Kwiatkowski C, Broyles K. Dream use in film making. Dreaming 1999; 9:247–296.
  37. Iaboni A. Moldofsky H. Sleep and posttraumatic stress disorder, In: Pandi-Perumal SR, Kramer M, editors. Sleep and mental illness. Cambridge, UK. Cambridge University Press; 2010. pp. 323–340.
  38. Pagel JF. Diagnoses altering nightmare recall frequency: nightmares and emotional processing? In: Columbus AM, editors. Advances in psychology research, vol 71. New York, NY: Nova Publishers; 2010. pp. 237–248.
  39. Pagel JF. The treatment of parasomnias, In: Kushida C. Handbook of sleep disorders. London: Informa; 2008. pp. 523–534.
  40. Valli K, Frauscher B, Gschliesser V, et al. Can observers link dream content to behaviors in rapid eye movement sleep behavior disorder? A cross-sectional experimental pilot study. J Sleep Res 2012; 21:21–29.
  41. Schenck CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and neuroscience perspective 16 years after its formal identification in SLEEP. Sleep 2002; 25:120–138.
  42. Johanson M, Valli K, Revonsuo A, Wedlund J. Content analysis of subjective experiences in partial epileptic seizures. Epilepsy Behav 2008; 12:170–182.

Curr Opin Pulm Med. 2012;18(6):574-579

Retrieved from: http://www.medscape.com/viewarticle/772192_2

 

adhd…under and over diagnosed.

In ADHD, ADHD Adult, ADHD child/adolescent, Psychiatry, School Psychology on Sunday, 21 October 2012 at 09:47

Attention Deficit Hyperactivity Disorder is Both Under and Over Diagnosed, Study Suggests

ScienceDaily (Oct. 19, 2012)

Attention Deficit Hyperactivity Disorder is both under and over diagnosed. That’s the result of one of the largest studies conducted on ADHD in the United States, published in the Journal of Attention Disorders.

A substantial number of children being treated for ADHD may not have the disorder, while many children who do have the symptoms are going untreated, according to the 10-year Project to Learn about ADHD in Youth (PLAY) study funded by the National Center on Birth Defects and Developmental Disabilities of the Centers of Disease Control and Prevention

“Childhood ADHD is a major public health problem. Many studies rely on parent reporting of an ADHD diagnosis, which is a function of both the child’s access to care in order to be diagnosed, and the parent’s perception that there is a problem,” said Robert McKeown, of the University of South Carolina’s Arnold School of Public Health, who led the South Carolina portion of the study.

“Further complicating our understanding of the prevalence of ADHD and its treatment is that the diagnosis often is made by a clinician who has little experience assessing and diagnosing mental disorders. As a result, ADHD is both under and over diagnosed,” said McKeown, distinguished professor emeritus in the department of epidemiology and biostatistics.

The study, conducted between 2002-2012, was a collaborative research project with the University of South Carolina’s Arnold School and School of Medicine and the University of Oklahoma’s Health Sciences Center.

“To our knowledge, this is the largest community-based epidemiologic study of ADHD to date,” McKeown said.

The study found that 8.7 percent of children in the community sample in South Carolina had enough symptoms to fit the ADHD diagnosis at the time of the initial assessment. The percentage was 10.6 in Oklahoma.

The report also revealed that the number of parents in the community sample who reported that their children were taking ADHD medication was 10.1 percent in South Carolina and 7.4 percent in Oklahoma. Yet, of the children taking ADHD medication, only 39.5 percent in South Carolina and 28.3 percent in Oklahoma actually met the case definition of ADHD.

“ADHD is not a snap diagnosis. It requires data from several sources and across several domains and considerable expertise to diagnose accurately and differentiate from other possible problems,” McKeown said.

The CDC reports that ADHD is one of the most common neurobehavioral disorders of childhood. Often first diagnosed in childhood, ADHD affects a child’s ability to do well in school and his or her ability to make and keep friends. While many children “outgrow” the disorder, ADHD can continue into adulthood, impacting the individual’s ability to work and function in society.

McKeown said the study found that many children taking ADHD medication did not meet the ADHD diagnostic criteria.

“These children had more ADHD symptoms, on average, than the other comparison children. Many children meeting case criteria had not been previously identified and were not receiving medication treatment, suggesting that the condition remains underdiagnosed,” he said.

The study was designed to follow children from elementary school through adolescence (ages 5 — 13) and investigate the short- and long-term outcomes of children with ADHD. Teachers screened 10,427 children in four school districts across the two states where the study was conducted. ADHD ratings by teacher and parent reports of diagnosis and medication treatment were used to determine whether children were high or low risk for ADHD.

Study questions focused on the prevalence and treated prevalence of ADHD in children; the existence of other health problems in children with ADHD, and the types and rates of health risk behaviors in children with ADHD. The study also looked at treatment patterns, both past and current, of children with ADHD.

“The findings of our study suggest that a fair number of children are being treated who do not meet case criteria and that there are children who do meet criteria but are not being treated,” McKeown said. “ADHD is not a snap diagnosis. It requires data from several sources and across several domains and considerable expertise to diagnose accurately and differentiate from other possible problems.”

Children and adolescents with ADHD also were found to have high rates of other disorders, including oppositional defiant disorder and conduct disorder. They also were more likely to engage in risky or impulsive behaviors, he said.

“We will follow up on these initial reports as the children age to determine what, if any, changes have occurred in the symptom patterns, as well as in the types of health risk behaviors,” McKeown said.

“We hope that this will shed light on the prevalence and the treatment of ADHD and will lead practitioners to seek consultation if they are not trained to assess, diagnose and treat ADHD,” he said. “We also hope it will lead parents and practitioners to assess all the treatment options to determine what works best for each child.”

USC researchers involved in the study included Dr. Steven Cuffe of the University of Florida College of Medicine-Jacksonville, formerly of the USC School of Medicine; Arnold School doctoral student Lorie L. Geryk; and Matteo Botai of the Karolinska Institutet in Sweden and Joseph R. Holbrook of the CDC, both formerly at the Arnold School.

University of South Carolina (2012, October 19). Attention deficit hyperactivity disorder is both under and over diagnosed, study suggests.ScienceDaily. Retrieved October 21, 2012, from http://www.sciencedaily.com­ /releases/2012/10/121019141124.htm

Retrieved from: http://www.sciencedaily.com/releases/2012/10/121019141124.htm

exercise and adhd…

In ADHD, ADHD Adult, ADHD child/adolescent, Fitness/Health, Neuropsychology, Psychiatry, School Psychology, Special Education on Sunday, 21 October 2012 at 09:43

Exercise May Lead to Better School Performance for Kids with ADHD

ScienceDaily (Oct. 16, 2012)

A few minutes of exercise can help children with attention deficit hyperactivity disorder perform better academically, according to a new study led by a Michigan State University researcher.

The study, published in the current issue of the Journal of Pediatrics, shows for the first time that kids with ADHD can better drown out distractions and focus on a task after a single bout of exercise. Scientists say such “inhibitory control” is the main challenge faced by people with the disorder.

“This provides some very early evidence that exercise might be a tool in our nonpharmaceutical treatment of ADHD,” said Matthew Pontifex, MSU assistant professor of kinesiology, who led the study. “Maybe our first course of action that we would recommend to developmental psychologists would be to increase children’s physical activity.”

While drugs have proven largely effective in treating many of the 2.5 million school-aged American children with ADHD, a growing number of parents and physicians worry about the side effects and costs of medication.

In the study, Pontifex and colleagues asked 40 children aged 8 to 10, half of whom had ADHD, to spend 20 minutes either walking briskly on a treadmill or reading while seated. The children then took a brief reading comprehension and math exam similar to longer standardized tests. They also played a simple computer game in which they had to ignore visual stimuli to quickly determine which direction a cartoon fish was swimming.

The results showed all of the children performed better on both tests after exercising. In the computer game, those with ADHD also were better able to slow down after making an error to avoid repeat mistakes — a particular challenge for those with the disorder.

Pontifex said the findings support calls for more physical activity during the school day. Other researchers have found that children with ADHD are less likely to be physically active or play organized sports. Meanwhile, many schools have cut recess and physical education programs in response to shrinking budgets.

“To date there really isn’t a whole lot of evidence that schools can pull from to justify why these physical education programs should be in existence,” he said. “So what we’re trying to do is target our research to provide that type of evidence.”

Pontifex conducted the study for his doctoral dissertation at the University of Illinois before joining the MSU faculty. His co-investigators included his adviser, kinesiology professor Charles Hillman, and Daniel Picchietti, a pediatrician at the Carle Foundation Hospital in Champaign, Ill. The research was funded by the National Institute of Child Health and Human Development.

Michigan State University (2012, October 16). Exercise may lead to better school performance for kids with ADHD. ScienceDaily. Retrieved October 21, 2012, from http://www.sciencedaily.com­ /releases/2012/10/121016132109.htm

Retrieved from: http://www.sciencedaily.com/releases/2012/10/121016132109.htm

more on men and adhd…

In ADHD, ADHD Adult, ADHD child/adolescent, Psychiatry on Thursday, 18 October 2012 at 07:49

Men Diagnosed with Childhood ADHD Struggle More with Jobs, Relationships

ADHD can have lingering effects among men

By: Alexandra Sifferlin

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder among children, and as incidence of the condition continue to rise, parents and patients are asking what happens next. How does ADHD affect children as they become teens and adults and start to form relationships, find jobs and establish families of their own? Does the condition put them at a disadvantage for coping with life’s inevitable challenges?

With 5.4 million children ever diagnosed with ADHD in the U.S., and 3% to 7% of school-aged children currently struggling with the condition, it’s worth considering how ADHD affects their adult lives. Rachel Klein of the Child Study Center at New York University Langone Medical Center and her colleagues studied the potentially long-term effects of ADHD among men who were diagnosed as kids. In their 33-year follow-up study, Klein and her team looked at 135 middle-aged men with childhood ADHD who were referred to the study by their teachers when they were between six to 12 years old. The researchers compared this group to 136 men without ADHD and found that  men with ADHD struggled more in occupational, educational, economic and social arenas later in life compared to men without the diagnosis.

At the 33-year follow-up, when the men were in their forties, those with childhood-diagnosed ADHD without conduct disorders had about 2.5 years fewer years of education compared to the other men; only 3.7% had higher degrees compared to nearly 30% of the control group. The majority (84%) were holding jobs, but at significantly lower positions than peers without ADHD and were therefore at a financial disadvantage. On average, the researchers say, the ADHD group earned $40,000 less in salary than their unaffected counterparts.

Socially, men with ADHD also struggled with higher divorce rates, more antisocial personality disorders and substance abuse. On the positive side, however, they did not have higher rates of mood and anxiety disorders, like depression.

Overall, the ADHD adults showed higher rates of psychiatric hospitalizations and incarcerations, which the authors conclude supports a continued need for monitoring and treatment of kids with ADHD, even when a conduct disorder is not present. Dr. Klein says even when children with ADHD are not disruptive, they may still be at a higher risk for developing antisocial behaviors later on, like lying, stealing and cheating.
But addressing the needs of children with ADHD, by providing academic support in school to help them overcome their frustrations and challenges in paying attention and retaining what they learn, and by giving them emotional support from the family, can given these students the coping skills they need to meet their adult challenges — in the workplace, in relationships and in social interactions —as well.

“One of the very important messages [from our findings] is that most kids [with ADHD] do OK, and some do very well. As a group they did well,” says Klein. While ADHD’s effect can linger into adulthood, it doesn’t have to be either debilitating or inevitable. “It does affect their lives, but not to the point that they’re very badly off,” she says.

The study was published online in the journal Archives of General Psychiatry.

Retrieved from: http://healthland.time.com/2012/10/16/men-diagnosed-with-childhood-adhd-struggle-more-with-jobs-relationships/#ixzz29eNljos5

adhd…a longitudinal follow-up

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Brain imaging, Brain studies, Neuropsychology, Neuroscience, Psychiatry, School Psychology on Tuesday, 16 October 2012 at 07:34

Men Diagnosed with ADHD as Children had Worse Outcomes as Adults, Study Says

ScienceDaily (Oct. 15, 2012) — Men who were diagnosed as children with attention-deficit/hyperactivity disorder (ADHD) appeared to have significantly worse educational, occupational, economic and social outcomes in a 33-year, follow-up study that compared them with men without childhood ADHD, according to a report published Online First by Archives of General Psychiatry, a JAMA Network publication.

ADHD has an estimated worldwide prevalence of 5 percent, so the long-term outcome of children with ADHD is a major concern, according to the study background.

Rachel G. Klein, Ph.D., of the Child Study Center at NYU Langone Medical Center in New York, and colleagues report the adult outcome (follow-up at average age of 41 years) of boys who were diagnosed as having ADHD at an average age of 8 years. The study included 135 white men with ADHD in childhood, free of conduct disorder (probands), and a comparison group of 136 men without childhood ADHD.

“On average, probands had 2½ fewer years of schooling than comparison participants … 31.1 percent did not complete high school (vs. 4.4 percent of comparison participants) and hardly any (3.7 percent) had higher degrees (whereas 29.4 percent of comparison participants did). Similarly, probands had significantly lower occupational attainment levels,” the authors note. “Given the probands’ worse educational and occupational attainment, their relatively poorer socioeconomic status at [follow-up at average age of 41 years] is to be expected. Although significantly fewer probands than comparison participants were employed, most were holding jobs (83.7 percent). However, the disparity of $40,000 between the median annual salary of employed probands and comparisons is striking.”

In further comparisons of the two groups, the men who were diagnosed with ADHD in childhood also had more divorces (currently divorced, 9.6 percent vs. 2.9 percent, and ever been divorced 31.1 percent vs. 11.8 percent); and higher rates of ongoing ADHD (22.2 percent vs. 5.1 percent, the authors suspect the comparison participants’ ADHD symptoms might have emerged during adulthood), antisocial personality disorder (ASPD, 16.3 percent vs. 0 percent) and substance use disorders (SUDs, 14.1 percent vs. 5.1 percent), according to the results.

During their lifetime, the men who were diagnosed with ADHD in childhood (the so-called probands) also had significantly more ASPD and SUDs but not mood or anxiety disorders and more psychiatric hospitalizations and incarcerations than comparison participants. And relative to the comparison group, psychiatric disorders with onsets at 21 years of age or older were not significantly elevated in the probands, the study results indicate.

The authors note the design of their study precludes generalizing the results to women and all ethnic and social groups because the probands were white men of average intelligence who were referred to a clinic because of combined-type ADHD.

“The multiple disadvantages predicted by childhood ADHD well into adulthood began in adolescence, without increased onsets of new disorders after 20 years of age. Findings highlight the importance of extended monitoring and treatment of children with ADHD,” the study concludes.

Retrieved from: http://www.sciencedaily.com/releases/2012/10/121015162407.htm

 

                                                                                             

Brain Gray Matter Deficits at 33-Year Follow-up in Adults With Attention-Deficit/Hyperactivity Disorder Established in Childhood

Erika Proal, PhD; Philip T. Reiss, PhD; Rachel G. Klein, PhD; Salvatore Mannuzza, PhD; Kristin Gotimer, MPH; Maria A. Ramos-Olazagasti, PhD; Jason P. Lerch, PhD; Yong He, PhD; Alex Zijdenbos, PhD; Clare Kelly, PhD; Michael P. Milham, MD, PhD; F. Xavier Castellanos, MD

Arch Gen Psychiatry. 2011;68(11):1122-1134. doi:10.1001/archgenpsychiatry.2011.117.

 

Context  Volumetric studies have reported relatively decreased cortical thickness and gray matter volumes in adults with attention-deficit/hyperactivity disorder (ADHD) whose childhood status was retrospectively recalled. We present, to our knowledge, the first prospective study combining cortical thickness and voxel-based morphometry in adults diagnosed as having ADHD in childhood.

Objectives  To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis, including persistent vs remitting ADHD.

Design  Cross-sectional analysis embedded in a 33-year prospective follow-up at a mean age of 41.2 years.

Setting  Research outpatient center.

Participants  We recruited probands with ADHD from a cohort of 207 white boys aged 6 to 12 years. Male comparison participants (n = 178) were free of ADHD in childhood. We obtained magnetic resonance images in 59 probands and 80 comparison participants (28.5% and 44.9% of the original samples, respectively).

Main Outcome Measures  Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses.

Results  The cortex was significantly thinner in ADHD probands than in comparison participants in the dorsal attentional network and limbic areas (false discovery rate < 0.05, corrected). In addition, gray matter was significantly decreased in probands in the right caudate, right thalamus, and bilateral cerebellar hemispheres. Probands with persistent ADHD (n = 17) did not differ significantly from those with remitting ADHD (n = 26) (false discovery rate < 0.05). At uncorrected P < .05, individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex, insula, parahippocampus, and prefrontal regions.

Conclusions  Anatomic gray matter reductions are observable in adults with childhood ADHD, regardless of the current diagnosis. The most affected regions underpin top-down control of attention and regulation of emotion and motivation. Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal, cerebellar, and thalamic circuitry.

Retrieved from: http://archpsyc.jamanetwork.com/article.aspx?articleid=1107429

Depression 101…

In Mood Disorders, Psychiatry, School Psychology on Tuesday, 16 October 2012 at 07:15

Depression 101: Treatment & Tips To Ward Off Depression

Depression is a common mental health illness in the US and around the world. In fact, the Center for Disease Control and Prevention states that 1 in 10 adults in the US report experiencing depression. What is most troubling to me is that only about 51% of those people suffering from depression seek out treatment according to the National Institute of Mental Health. Depression may begin at any age and may be caused by any number of triggers such as bullying, parental or marital conflict, sense of isolation, loss, seasonal causes, etc.

As a result, I wanted to write a blog post specifically on depression, its treatment, and offer wellness tips to ward off depression. Please note that depression is one of several mood disorders and is different than bipolar, dysthymia, and other mood disorders. This blog post will focus on depression technically known as Major Depressive Disorder. I also want to make it very clear that depression is a treatable illness but, like many illnesses, it can require ongoing “maintenance.”

First let me review the symptoms of depression, followed by the treatment, and then offer some tips to ward off depression.

Symptoms of Depression: To meet criteria, five or more symptoms must be present for at least a 2 week period according to the Diagnostic and Statistical Manual of Mental Disorders. It is also very important to rule out physiological effects of a substance/drug, other psychiatric disorders such as bereavement, and medical conditions such as thyroid problems that may cause depressive symptoms.

  Sad or depressed mood most of the day, almost every day.

  Anhedonia, which is loss of interest in previously enjoyed activities.

  Sleep problems, usually hypersomnia but can also be insomnia.

  Weight gain or loss not due to diet or exercise.

  Low of energy or fatigue even with sufficient rest.

  Psychomotor agitation or retardation, which is usually moving or talking slower.

  Poor concentration or ability to think.

  Feeling of worthlessness or excessive guilt.

  Thoughts of death or suicide, which could be the most serious of all the symptoms and must be taken seriously even in children.

Here are some other symptoms to look for that are frequently present in depression:

  Thoughts of helplessness

  Thoughts of hopelessness

  Isolation

  Changes in appetite

  Irritability

  Crying

  Decrease in sex drive

Treatment for Depression

Treatment for depression begins with an evaluation by a licensed mental health professional to determine severity of depression, to rule out other possible issues, and to refer for appropriate services. Treatment usually entails either counseling or psychotropic medication or a combo of both, depending on severity. Severe depression usually requires a psychiatric evaluation by a psychiatrist for psychotropic medication to help improve symptoms enough for counseling to be effective, while mild to moderate depression can usually be treated with counseling alone. It is important to know there are a countless approaches to counseling such as cognitive behavior, psychodynamic, humanistic, and many more. Many approaches explore the person’s feelings, thoughts, and behaviors. The trust developed between the client-therapist relationship is what many approaches have in common and what research has found to be an essential ingredient to effective treatment. That is why it is imperative that one choose a therapist that is a good fit.

In addition, there are other interventions or activities such as exercise and meditation that have been found to be effective treatment for mild to moderate depression. Family therapy can also be helpful at alleviating tensions at home that may be impacting one’s depression and hindering treatment progress.

Tips to Ward Off Depression

  Exercise Regularly as it has been found to be fantastic not only for managing stress and preventing physical problems but also at reducing depression and anxiety.

  Be Present is where people often report being happy while being in the future can create anxiety and being in the past can lead to feelings of regret, guilt, and depression. Focus on being more mindful about how you are feeling right now rather than how you felt weeks or years ago.

  Seek Support from licensed mental health professionals, friends, family and even animals, whom can be helpful. Surround yourself with people that are positive and validating.

  Know the Signs of depression so that you know when you or someone you in your life needs help.

  Know your Depression and be proactive. If you know that you happen to be extra susceptible to depression during the winter months, prepare for it by scheduling regular activities or seeking extra support during this time.

  Get Outside because sunlight can be helpful and so can nature. Experiencing the grandeur nature can help put one’s problems into perspective and when our problems seem small they don’t bother us as much.

  Find Meaning or a reason for living as it can be a powerful motivation to keep living. One’s meaning can be their partner, children, or even a cause.

  Sleep is vital to good health and mental functioning. Avoid sleep problems by having a regular bedtime even on weekends, keeping distractions from the bedroom (e.g., TV), and creating a bedtime that is conducive for relaxation.

  Visit Your Primary Care Doctor regularly to prevent, catch, or treat medical illnesses early that can create depressive symptoms.

  Eat Healthy meals to improve physical, mental, and emotional functioning. Eating unhealthy foods erodes your physical health, impairs cognitive functioning, and also impacts how you feel about yourself.

  Respect your Emotions rather than stuffing them. Bottling your feelings can be toxic to your body while expressing how you feel can be very relieving especially when your feelings are validated.

Author: Yoendry Torres, Psy.D., Clinical Psychologist

Retrieved from: http://www.intuitionwellness.com/blog/2012/10/12/depression-101-treatment-tips-to-ward-off-depression/

The Unfulfilled Promises of Psychotropics

In Brain studies, Medication, Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology on Sunday, 14 October 2012 at 11:33

The Unfulfilled Promises of Psychotropics

By Richard Kensinger, MSW

I remember thinking over 40 years ago when I began my clinical career, that with the rapid advances made in psychotropic agents, psychotherapy would become a venture of the past. A recent editorial published in Schizophrenia Bulletindispels my myth of becoming unemployed.

Psychopharmacology is in crisis. The data are in, and it is clear that a massive experiment has failed: despite decades of research and billions of dollars invested, not a single mechanistically novel drug has reached the psychiatric market in more than 30 years. Indeed, despite enormous effort, the field has not been able to escape the “me too/me (questionably) better” straightjacket. In recent years, the appreciation of this reality has had profound consequences for innovation in psychopharmacology because nearly every major pharmaceutical company has either reduced greatly or abandoned research and development of mechanistically novel psychiatric drugs. This decision is understandable because pharmaceutical and biotechnology executives see less risky opportunities in other therapeutic areas, cancer and immunology being the current pipeline favorites. Indeed, in retrospect, one can wonder why it took so long for industry to abandon psychiatry therapeutics. So how did we get here and more importantly, what do we need to do to find a way forward?

The discovery of all three major classes of psychiatric drugs, antidepressants, antipsychotics, and anxiolytics, came about on the basis of serendipitous clinical observation. At the time of their discoveries, the mechanisms by which these molecules produce their effects were unknown, and it was only later that antipsychotics were shown to be D2 receptor antagonists, antidepressants monoamine reuptake inhibitors, and anxiolytics GABA receptor modulators. It is interesting and perhaps instructive to consider whether any of these classes of drugs could have been discovered by current drug discovery strategies. For example, what genetic or preclinical data exist that point to the D2 dopamine receptor as a likely target for antipsychotic activity? Presently there are no genetic data that suggest that this receptor is expressed or functions abnormally in psychotic disorders (emphasis added). And without the benefit of the prior clinical validation, it is difficult to see how preclinical data alone would point to the D2 receptor as an interesting potential target for the treatment of psychotic disorders. The same can be said for monoamine transporters with respect to depression where, like psychosis, there are no animal models based on disease pathophysiology and no compelling preclinical data pointing to these as potential targets for antidepressant drugs. This raises a troubling question: if in retrospect the three major classes of currently prescribed psychiatric drugs would likely never have been discovered using current drug discovery strategies, why should we believe that such strategies are likely to bear fruit now or in the future?

Given that there cannot be a coherent biology for syndromes as heterogeneous as schizophrenia, it is not surprising that the field has failed to validate distinct molecular targets for the purpose of developing mechanistically novel therapeutics. Although it has taken our field too long to gain this insight, we seem to be getting there. For example, at the 2011 meeting of the American College of Neuropsychopharmacology, the need for change and the need for new strategies were predominant themes.

In summation the excitement in the past two decades about the “Decades of the Brain” are fading to realism. Our human genome is much more complex than we can imagine. Half of our genes are devoted to brain form and function. The interaction between geneotype and phenotype is also more complex that we realize. Thus, we are approaching this science with more skepticism and realism.

Reference

Fibiger HC (2012). Psychiatry, the pharmaceutical industry, and the road to better therapeutics. Schizophrenia bulletin, 38 (4), 649-50 PMID: 22837348

Retrieved from: http://brainblogger.com/2012/10/08/the-unfulfilled-promises-of-psychotropics/

 

adhd… a “made up” disorder, redux

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Medication, Psychiatry, Psychopharmacology on Friday, 12 October 2012 at 17:38

and here we go, folks! on the heels of my post, 10 October 2012, regarding the good doctor anderson (http://wp.me/p2IpfL-9p), the debate is starting yet once again.  sigh.  you know, this gets a bit boring after a while.   but i do believe we have vastly improved mechanisms of study (fmri, genomic medicine…fantastic stuff!) and robust set of data and literature to support that it’s a valid disorder.  and, i hesitate to even take a stand as to which i ascribe to.  in the end, you are allowed to believe what you want, as long as you aren’t hurting anybody else (if you are hurting yourself) by holding those beliefs.  i would just like to see the actual data that these people base their opinions on.  i don’t believe there is a place for opinions is science.  and diagnosing and prescribing is done based mostly on quantitative data.  

the data (quantitative) speaks for itself , imo.  and to me, the best decisions are made when examining QUANTITATIVE data.  but, as i’ve told you in something i wrote at some point (one musing or another…), i am a ‘quantoid.’  i will always be biased towards quantifiable data.  that’s me.  come to your own conclusions.  i just prefer to come to mine quantifiably.    and that’s a WHOLE other post!  at any rate, as you see below, the debate continues…pick a side.

Should Children Take ADHD Drugs — Even If They Don’t Have The Disorder?

Emily Willingham, Contributor

The discussion is at least twice as old as my 10-year-old son with attention deficit/hyperactivity disorder (ADHD): Should we medicate children with ADHD drugs just to keep order in the classroom or help the child be competitive among peers? I know it’s at least 20 years old, this argument, because it was a subject of almost daily discussion in teachers’ lounges when I taught middle school in the ’90s, and because the tension among teachers, parents, and the children taking the drugs often spilled into the hallways. And this all was in private schools. I can only imagine that the intensity was multifold in the public school setting.

The age of a controversy, as anyone in public health can tell you, doesn’t necessarily diminish its relevance or the passions it inspires. That’s why this piece by Alan Schwarz in the New York Times has yielded some serious angst in many circles. It takes as its center a doctor who, Schwarz writes, prescribes ADHD drugs off-label for children he avers don’t have ADHD, saying that because the schools won’t do what they should to help low-income kids learn, we “have to modify the kid.”

This physician, Dr. Michael Anderson, also happens to be among those who dismiss ADHD is a “made-up” disorder, in spite of considerable evidence linking specific gene variants to ADHD and suggesting a large genetic component [PDF]. He’s another contributor to the ever-present backlash against ADHD as a diagnostic entity, but instead of blaming lazy parents this time, he blames the school system, one that neglects children whose behaviors in a classroom might be ameliorated by an appropriate environment, in the absence of which, medications have to do the job. He certainly has a point … to a point.

His attitude about ADHD, though, is what’s fueled the concerns I’ve seen about this article, particularly from people who love someone with ADHD. ADHD, you see, has a terrible reputation, one that suffers in large part because of abuse of drugs used to treat the condition. Many, many drugs exist that people use off-label to self medicate or boost performance. But I can’t think of drugs whose abuse stigmatizes the disorder for which they’re actually used as much as ADHD drugs do. And abuse of ADHD meds is inextricably linked with skepticism about the ADHD diagnosis: neurobiological conditions that overlap with the typical zones of behavior suffer from this kind of skepticism, but ADHD stands out. Blame for the drug abuse and diagnostic overuse heaps on doctors, parents, teachers, society, and people diagnosed with it. Are any of these groups to blame for the existence of ADHD? Generally, no. But some are to blame for its bad reputation and the abuse of the drugs used to treat it.

Drugs to treat ADHD work, as I’ve written before, but they carry known risks, and we still won’t know for some years what the long-term outcomes are following their use in childhood. Schwarz describes in his article a child taking the medication Adderallwho begins see people and hear voices that aren’t there, a rare side effect of the drug. That child is no longer on Adderall and instead is now takingRisperdal, a psychotropic medication with indications for schizophrenia and irritability associated with autism. It is not an “ADHD drug,” and it too carries potential risks that need to underweigh its benefits to warrant its use. One of the primary benefits of ADHD medications for children with the condition, in addition to the academic, is that the perceived improvement in behavior can translate into better social relationships and a reduction in the constant messages that they receive that they are a “bad person.” Whether or not they ultimately absorb that message as an inherent part of themselves remains to be seen.

In addition to prescribing Adderall to this boy, Anderson also prescribed it to two of the child’s siblings. In the article, the parents think that this prescription is an off-label use of Adderall, and the article holds up these two children as examples of using this drug to improve behavior and classroom performance in the absence of an ADHD indication. Yet Anderson then is reported as saying that all of the children for whom he has prescribed ADHD medications have met the criteria for ADHD, including these two children, whose parents don’t seem to know that. In other words, this story is about children who meet the ADHD criteria receiving drugs to treat ADHD and experiencing benefits, not about a broader use of ADHD drugs off-label to level the classroom playing field.

Forbes writer Matthew Herper blogged today that the NYT piece “hits the problem with ADHD drugs: they work.” Yes, they do. They work for ADHD, based on the only examples provided in this article, not more broadly for low-income children who just need more drug-induced focus in the classroom. Whether the doctor “rails” against the diagnostic criteria or not, the children taking–and responding to–Adderall in this article all met the criteria for an ADHD diagnosis. Indeed, low-income children are most likely to meet the diagnostic criteria for ADHD yet least likely to receive appropriate pharmaceutical intervention for it.  So whether he likes it or not, the doctor, by applying existing criteria, might have appropriately identified and treated children with ADHD who otherwise would have fallen through the cracks.

That doesn’t mean that we’re not still facing a brave new world in which college students pop Adderall for exams or driven high-school students are torn between the med boost and simply making it on their own, as they are. As Herper notes, there’s an important national conversation to be had around ADHD drugs and their off-label use to level the field or give an advantage. In his post, Herper asks, “Can we avoid a world in which thinkers are forced into brain-doping in the same way athletes have been pushed to chemically modify their bodies?” In neither case do we know the long-term positive or negative outcomes for the individuals being doped, whether for brain or brawn. I can’t speak about athletes, but as someone who has taught thousands of students from ages 5 to 65, I can say this: What we, in our short-sightedness, view as a childhood deficit because of its interference with classroom function can often yield our most beautiful manifestations of human thought and diversity later in life. Do medications help children with ADHD? Yes, they do. But … and I think this is the real point of the Schwarz piece, even as the examples simply bear out efficacy of ADHD meds for ADHD: We can’t look to the children for what needs “fixing.” For that, we must look to ourselves, and the depth and breadth of our problems with education in this country aren’t something even a full-scale, population-wide pill can fix.

Retrieved from: http://www.forbes.com/sites/emilywillingham/2012/10/09/adhd-drugs-for-children-who-dont-have-adhd-is-it-ok/

 

ketamine isn’t just for kitties anymore…

In Medication, Mood Disorders, Neuroscience, Psychiatry, Psychopharmacology on Thursday, 11 October 2012 at 14:43

Ketamine a Viable Option for Severe Depression?

Megan Brooks

October 11, 2012 — The discovery that ketamine produces rapid antidepressant effects in patients with severe treatment-resistant depression is fueling basic neuroscience research, leading to a greater understanding of the neurobiology of depression and maybe more effective treatments, a new review suggests.

Ketamine, an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, is best known in medicine as an anesthetic but also has some notoriety as a street drug, sometimes dubbed “Special K,” and is taken illicitly for its psychedelic effects.

However, recently ketamine has gained interest among researchers for its potential as a unique, rapid-acting antidepressant.

Typical antidepressants such as the serotonin selective reuptake inhibitors (SSRIs) take weeks to months to have an effect and are only moderately effective, leaving more than one third of depressed patients resistant to drug therapy.

“The rapid therapeutic response of ketamine in treatment-resistant patients is the biggest breakthrough in depression research in half a century,” review author Ronald Duman, PhD, professor of psychiatry and neurobiology at Yale University in New Haven, Connecticut, said in a statement.

However, Dr. Dunham told Medscape Medical News, although clearly promising for depression, ketamine does have some roadblocks.

“It produces transient side effects [for about 1 hour], including mild hallucinations and dissociative effects in some patients, subsequent to the antidepressant response. Ketamine is also a drug of abuse, so caution is needed when considering widespread use of this agent.”

“Nevertheless, there are millions of depressed patients who do not respond to conventional antidepressants and are in dire need of a drug like ketamine,” Dr. Duman added.

With Dr. Duman and coauthor George Aghajanian, MD, professor emeritus of psychiatry at Yale University, the review was published October 5 in Science.

Timely, Authoritative

Commenting for Medscape Medical News, James W. Murrough, MD, from Mount Sinai School of Medicine’s Mood and Anxiety Disorders Program in New York City, described the article as a “timely, well written, and authoritative review by 2 neuroscience researchers who have really done the bulk of the work looking at the biological basis for how ketamine might bring about a rapid antidepressant effect.”

The original link between ketamine and relief of depression was made by John Krystal, MD, chair of the Department of Psychiatry at Yale, and Dennis Charney, MD, formerly of Yale, now professor of psychiatry, neuroscience, and pharmacology and dean at Mount Sinai School of Medicine.

In 2000, they published results of a small, double-blinded, placebo-controlled study showing that intravenous infusions of ketamine produced significant and rapid antidepressant effects (Berman et al; Biol Psychiatry, 2000;47:351-354).

“That was the first controlled study that showed that ketamine had sort of an unexpected rapid antidepressant effect in patients,” said Dr. Murrough. “We knew it was a glutamate antagonist, but at this time (in 2000), the role of glutamate in depression was not at all on the radar.”

That study was followed by an article published in 2006 that also showed rapid (within 2 hours) and significant antidepressant effects after a single infusion of ketamine in 18 patients with treatment-resistant depression (Zarate Jr et al; Arch Gen Psychiatry, 2006;63:856-864).

Since then, a number of studies replicated and extended the findings — including a study by Carlos Zarate Jr, MD, and colleagues published in 2010 in Archives of General Psychiatry and reported by Medscape Medical News at the time.

These studies sent neuroscientists on a quest to figure out at a cellular level, using animal models, how ketamine worked and what it could reveal about depression.

Jury Still Out

The literature suggests that depression is caused by disruption of homeostatic mechanisms that control synaptic plasticity, resulting in destabilization and loss of synaptic connections in mood and emotion circuitry, the authors note. Ketamine appears to target synaptic dysfunction in depression.

The findings highlight the “central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response,” the review authors write.

Is ketamine currently used to treat refractory depression?

“A year ago, I would have said no, it’s not being used clinically. But in the last year, I’ve run into patients who’ve said they had been treated with low-dose ketamine by their psychiatrist, and doctors at national meetings who’ve said they’ve used it in their practice, but it’s very sparse, it’s far from widespread,” said Dr. Murrough.

It is important to note, he added, that to date, most of the research has been limited to the effects of a single dose.

At a medical conference in June, as reported by Medscape Medical News, Dr. Murrough and colleagues demonstrated that administration of 6 low-dose infusions of ketamine over 2 weeks improved symptoms in a small study of patients with treatment-resistant depression.

It helped “at least while they were getting the ketamine, then there was a relapse that came in as few as a couple days to several months or longer in a few cases,” he said.

Dr. Murrough said he and his colleagues are now “closing out” another study of ketamine that should be published in a couple of months. Other trials are ongoing.

“The jury is still out on whether ketamine itself could be developed into a bona fide treatment. We happen to believe that it can be. We advocate a cautious approach, but we are cautiously optimistic that ketamine could be a treatment option for severe refractory depression,” he said.

“The benchmark treatment right now for severe refractory depression is electroconvulsive therapy [ECT],” Dr. Murrough pointed out, “so you’d have to believe that ketamine has a worse risk-benefit profile than ECT, and so far, we don’t see that; it appears to be very well tolerated.”

Dr. Duman and Dr. Aghajanian have disclosed no relevant financial relationships. In the past 2 years, Dr. Murrough has received research support from Evotec Neurosciences and Janssen Research & Development. Dr. Charney has been named as an inventor on a use patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the US Food and Drug Administration for this indication, Dr. Charney and Mount Sinai School of Medicine could benefit financially.

Science. 2012;338:68-72. Abstract

Retrieved from: http://www.medscape.com/viewarticle/772467?src=nl_topic

ADHD…a “made up” disorder???

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Medication, Neuropsychology, Psychiatry, Psychopharmacology, School Psychology on Thursday, 11 October 2012 at 10:37

while i do think adhd is the “diagnosis of the day” and it may be over-diagnosed, i DO NOT agree that it is a “made up”  disorder or “an excuse.”  you only have to look at the latest studies that compare treated and untreated brains of those diagnosed with adhd to see that there are real neurological and neuroanatomical deficits that can arise if adhd is left untreated (for one example, see: Adult ADHD: New Findings in Neurobiology and Genetics ; Scott H. Kollins, Ph.D.  http://www.medscape.org/viewarticle/765528).  

if you think you or someone you know has adhd, the following lists suggestions to make sure you receive a valid diagnosis and what to help to facilitate that*:

A good evaluation may consist of many of the following:

  • Collection of rating scales and referral information before or during the evaluation  
  • An interview with the student and parents
  • A review of previous records that may document impairments (i.e. problems in school, socially, or at home that you believe can be attributed to ADHD.  A good doctor knows exactly what questions to ask.
  • A general medical examination when medication might be part of treatment or coexisting medical conditions need to be evaluated (if the physician hasn’t already done this). 

 What to take along to facilitate these steps:  

  • Any records from schools you.your child attended and any other documentation of problems that could be related to ADHD or another disorder 
  • A list of family members with mental health known disorders
  • A description of impairments during childhood (i.e. elementary school), as well as more recent ones (i.e. middle school).  This can be done via SST notes, progress reports, psychological evaluations, IEP’s, etc.

*adapted from: Barkley, Russell A. (2011-04-04). Taking Charge of Adult ADHD (Kindle Locations 464-483). Guilford Press. Kindle Edition.

Attention Disorder or Not, Pills to Help in School

Alan Schwarz

CANTON, Ga. — When Dr. Michael Anderson hears about his low-income patients struggling in elementary school, he usually gives them a taste of some powerful medicine: Adderall.

The pills boost focus and impulse control in children with attention deficit hyperactivity disorder. Although A.D.H.D is the diagnosis Dr. Anderson makes, he calls the disorder “made up” and “an excuse” to prescribe the pills to treat what he considers the children’s true ill — poor academic performance in inadequate schools.

“I don’t have a whole lot of choice,” said Dr. Anderson, a pediatrician for many poor families in Cherokee County, north of Atlanta. “We’ve decided as a society that it’s too expensive to modify the kid’s environment. So we have to modify the kid.”

Dr. Anderson is one of the more outspoken proponents of an idea that is gaining interest among some physicians. They are prescribing stimulants to struggling students in schools starved of extra money — not to treat A.D.H.D., necessarily, but to boost their academic performance.

It is not yet clear whether Dr. Anderson is representative of a widening trend. But some experts note that as wealthy students abuse stimulants to raise already-good grades in colleges and high schools, the medications are being used on low-income elementary school children with faltering grades and parents eager to see them succeed.

“We as a society have been unwilling to invest in very effective nonpharmaceutical interventions for these children and their families,” said Dr. Ramesh Raghavan, a child mental-health services researcher at Washington University in St. Louis and an expert in prescription drug use among low-income children. “We are effectively forcing local community psychiatrists to use the only tool at their disposal, which is psychotropic medications.”

Dr. Nancy Rappaport, a child psychiatrist in Cambridge, Mass., who works primarily with lower-income children and their schools, added: “We are seeing this more and more. We are using a chemical straitjacket instead of doing things that are just as important to also do, sometimes more.”

Dr. Anderson’s instinct, he said, is that of a “social justice thinker” who is “evening the scales a little bit.” He said that the children he sees with academic problems are essentially “mismatched with their environment” — square pegs chafing the round holes of public education. Because their families can rarely afford behavior-based therapies like tutoring and family counseling, he said, medication becomes the most reliable and pragmatic way to redirect the student toward success.

“People who are getting A’s and B’s, I won’t give it to them,” he said. For some parents the pills provide great relief. Jacqueline Williams said she can’t thank Dr. Anderson enough for diagnosing A.D.H.D. in her children — Eric, 15; Chekiara, 14; and Shamya, 11 — and prescribing Concerta, a long-acting stimulant, for them all. She said each was having trouble listening to instructions and concentrating on schoolwork.

“My kids don’t want to take it, but I told them, ‘These are your grades when you’re taking it, this is when you don’t,’ and they understood,” Ms. Williams said, noting thatMedicaid covers almost every penny of her doctor and prescription costs.

Some experts see little harm in a responsible physician using A.D.H.D. medications to help a struggling student. Others — even among the many like Dr. Rappaport who praise the use of stimulants as treatment for classic A.D.H.D. — fear that doctors are exposing children to unwarranted physical and psychological risks. Reported side effects of the drugs have included growth suppression, increased blood pressure and, in rare cases, psychotic episodes.

The disorder, which is characterized by severe inattention and impulsivity, is an increasingly common psychiatric diagnosis among American youth: about 9.5 percent of Americans ages 4 to 17 were judged to have it in 2007, or about 5.4 million children, according to the Centers for Disease Control and Prevention.

The reported prevalence of the disorder has risen steadily for more than a decade, with some doctors gratified by its widening recognition but others fearful that the diagnosis, and the drugs to treat it, are handed out too loosely and at the exclusion of nonpharmaceutical therapies.

The Drug Enforcement Administration classifies these medications as Schedule II Controlled Substances because they are particularly addictive. Long-term effects of extended use are not well understood, said many medical experts. Some of them worry that children can become dependent on the medication well into adulthood, long after any A.D.H.D. symptoms can dissipate.

According to guidelines published last year by the American Academy of Pediatrics, physicians should use one of several behavior rating scales, some of which feature dozens of categories, to make sure that a child not only fits criteria for A.D.H.D., but also has no related condition like dyslexia or oppositional defiant disorder, in which intense anger is directed toward authority figures. However, a 2010 study in the Journal of Attention Disorders suggested that at least 20 percent of doctors said they did not follow this protocol when making their A.D.H.D. diagnoses, with many of them following personal instinct.

On the Rocafort family’s kitchen shelf in Ball Ground, Ga., next to the peanut butter and chicken broth, sits a wire basket brimming with bottles of the children’s medications, prescribed by Dr. Anderson: Adderall for Alexis, 12; and Ethan, 9; Risperdal (an antipsychotic for mood stabilization) for Quintn and Perry, both 11; and Clonidine (a sleep aid to counteract the other medications) for all four, taken nightly.

Quintn began taking Adderall for A.D.H.D. about five years ago, when his disruptive school behavior led to calls home and in-school suspensions. He immediately settled down and became a more earnest, attentive student — a little bit more like Perry, who also took Adderall for his A.D.H.D.

When puberty’s chemical maelstrom began at about 10, though, Quintn got into fights at school because, he said, other children were insulting his mother. The problem was, they were not; Quintn was seeing people and hearing voices that were not there, a rare but recognized side effect of Adderall. After Quintn admitted to being suicidal, Dr. Anderson prescribed a week in a local psychiatric hospital, and a switch to Risperdal.

While telling this story, the Rocaforts called Quintn into the kitchen and asked him to describe why he had been given Adderall.

“To help me focus on my school work, my homework, listening to Mom and Dad, and not doing what I used to do to my teachers, to make them mad,” he said. He described the week in the hospital and the effects of Risperdal: “If I don’t take my medicine I’d be having attitudes. I’d be disrespecting my parents. I wouldn’t be like this.”

Despite Quintn’s experience with Adderall, the Rocaforts decided to use it with their 12-year-old daughter, Alexis, and 9-year-old son, Ethan. These children don’t have A.D.H.D., their parents said. The Adderall is merely to help their grades, and because Alexis was, in her father’s words, “a little blah.”

”We’ve seen both sides of the spectrum: we’ve seen positive, we’ve seen negative,” the father, Rocky Rocafort, said. Acknowledging that Alexis’s use of Adderall is “cosmetic,” he added, “If they’re feeling positive, happy, socializing more, and it’s helping them, why wouldn’t you? Why not?”

Dr. William Graf, a pediatrician and child neurologist who serves many poor families in New Haven, said that a family should be able to choose for itself whether Adderall can benefit its non-A.D.H.D. child, and that a physician can ethically prescribe a trial as long as side effects are closely monitored. He expressed concern, however, that the rising use of stimulants in this manner can threaten what he called “the authenticity of development.”

“These children are still in the developmental phase, and we still don’t know how these drugs biologically affect the developing brain,” he said. “There’s an obligation for parents, doctors and teachers to respect the authenticity issue, and I’m not sure that’s always happening.”

Dr. Anderson said that every child he treats with A.D.H.D. medication has met qualifications. But he also railed against those criteria, saying they were codified only to “make something completely subjective look objective.” He added that teacher reports almost invariably come back as citing the behaviors that would warrant a diagnosis, a decision he called more economic than medical.

“The school said if they had other ideas they would,” Dr. Anderson said. “But the other ideas cost money and resources compared to meds.”

Dr. Anderson cited William G. Hasty Elementary School here in Canton as one school he deals with often. Izell McGruder, the school’s principal, did not respond to several messages seeking comment.

Several educators contacted for this article considered the subject of A.D.H.D. so controversial — the diagnosis was misused at times, they said, but for many children it is a serious learning disability — that they declined to comment. The superintendent of one major school district in California, who spoke on the condition of anonymity, noted that diagnosis rates of A.D.H.D. have risen as sharply as school funding has declined.

“It’s scary to think that this is what we’ve come to; how not funding public education to meet the needs of all kids has led to this,” said the superintendent, referring to the use of stimulants in children without classic A.D.H.D. “I don’t know, but it could be happening right here. Maybe not as knowingly, but it could be a consequence of a doctor who sees a kid failing in overcrowded classes with 42 other kids and the frustrated parents asking what they can do. The doctor says, ‘Maybe it’s A.D.H.D., let’s give this a try.’ ”

When told that the Rocaforts insist that their two children on Adderall do not have A.D.H.D. and never did, Dr. Anderson said he was surprised. He consulted their charts and found the parent questionnaire. Every category, which assessed the severity of behaviors associated with A.D.H.D., received a five out of five except one, which was a four.

“This is my whole angst about the thing,” Dr. Anderson said. “We put a label on something that isn’t binary — you have it or you don’t. We won’t just say that there is a student who has problems in school, problems at home, and probably, according to the doctor with agreement of the parents, will try medical treatment.”

He added, “We might not know the long-term effects, but we do know the short-term costs of school failure, which are real. I am looking to the individual person and where they are right now. I am the doctor for the patient, not for society.

Retrieved from: http://www.nytimes.com/2012/10/09/health/attention-disorder-or-not-children-prescribed-pills-to-help-in-school.html?pagewanted=all&pagewanted=print

autism and schizophrenia…a collision

In Autism Spectrum Disorders, Psychiatry, School Psychology on Tuesday, 9 October 2012 at 06:35

When the autism and schizophrenia spectrums collide

Spectrum. The name conjures up white light separating out through a prism, the multi-coloured rainbow, and even that wonderful 8-bit computer made by Sir Clive Sinclair (yes, I had one of those you Commodore people).

When it comes to autism and schizophrenia,the concept of a spectrum invokes similar ideas of different variations or colours on a theme, separate but linked, patterns of symptoms which stem from a single source but diffuse outwards with fuzzy boundaries. It almost sounds a little bit ‘Sixties’ if I’m truly honest.

For quite a few people, including those on the DSM-V ‘how are we going to redefine autism‘ committee, spectrum is something really being taken on board as the ever-approaching deadline for revision comes closer and closer into view. That’s not to say everyone is particularly happy with the formal spectrum-ing of autism as per this recent review by Luke Tsai* (open-access) who prefers the term ‘autism continuum disorder’, but there you go. Indeed scroll down to the descriptor of autism at the bottom of this blog and I use the word ‘tapestry’ which also might be a good description of the heterogeneity present. (Note to self: this description will need updating next year).

You’re probably wondering why I’m going on about spectrum; well its all to do with this paper by Prof. Kenneth Gadow** and how the autism spectrum and the schizophrenia spectrum might be colliding a little more than we perhaps first thought.

This is not the first time that I’ve talked about autism and schizophrenia overlapping as per this post on some very interesting research indicating that around about 40% of one cohort of people with schizophrenia also presented with symptoms congruent with an autism diagnosis.

Prof. Gadow reports a few interesting things from the other direction insofar as his cohort of children diagnosed with an autism spectrum disorder (ASD) presenting with quite a few characteristics more usually associated with the schizophrenia spectrum disorders (SSDs). In a little more detail (sorry that I can’t link to the full-text paper):

  • Building on previous research by the author***, the aim of the study was multi-fold primarily looking at the risk of SSD symptoms in ASD and also looking at how a comorbid diagnosis of ADHD may moderate that risk of SSD symptoms.
  • Consecutive child referrals (aged 6-12 years) to a developmental or child psychiatry outpatient clinic were included for study.
  • Samples were divided up as follows: Autism (N=147) of which n=50 were diagnosed with an ASD only and n=97 diagnosed with ASD & attention-deficit hyperactivity disorder (ADHD). Controls (N=335) included n=146 asymptomatic and n=188 (I assume the missing participant was excluded for some important reason).
  • The primary schedule of choice was the Child and Adolescent Symptom Inventory-4R (CASI-4R) completed by mums and teachers of participants. In particular, the subscales on Schizoid Personality and Schizophrenia and their combining to form a global SSD score were a focus for this study.
  • Results (a few of them anyway): well, mums and teachers showed some overlap in their scoring of participants (always a relief for a questionnaire) bearing in mind contextual differences. Both children with ASD with and without ADHD “had more severe global SSD ratings than their respective controls” but as with many things linked to autisms, there was quite a bit of variability among participant scores.
  • A diagnosis of ADHD whether associated with ASD or not, seemed to confer a greater risk of SSD symptoms pointing to a likely link between ADHD and SSD.
  • An interesting finding this one: the combination of ASD and ADHD and the pattern of SSD symptoms appearing (e.g. disorganised behaviour and negative symptoms – inappropriate laughter, crying and little interest in doing things) “supports the more general notion that certain combinations of disorders may be better conceptualized as unique clinical conditions“. Now think back to that spectrum – continuum argument and the DSM-5 move away from discrete diagnoses….?
  • Another quote from the paper: “findings provide additional support for an interrelation between ASD and SSD symptoms“.

A few things come to mind from these results. First is this suggestion that some cases of childhood ASD present with patterns of symptoms more readily tied into SSD. As per my previous post on this ‘overlap’, the great scientific machine seems to be doing yet another revolution as autism, once considered to be pretty ‘similar’ to schizophrenia (remember childhood schizophrenia) then departed on it’s own journey, and now appears to be heading back towards schizophrenia or at least SSD.

I’m making no value judgements either way on this process given the likely opinions that might be raised on this matter in terms of diagnostic identity, management options and indeed how autism and schizophrenia have tended to become represented among the general population. If there is an upside to this partial reunification, I suppose it is that shared genetics (and epigenetics), biochemistry (see this post for example) and other areas might open up some interesting avenues for further study. With my own research hat on, I’m thinking Dohan and his hypotheses on gluten in cases of schizophrenia and autism. There are most likely going to be others.

Second is this issue of discrete clinical conditions potentially being present from the current study. Again its all about historical trends in science, and whether people talk about specific clinical entities (diagnostic boxes with names and formal criteria) or ‘lumping things together’ as per the use of terms like spectrum. I admit also to being pretty intrigued by the suggestion of a possible new clinical entity represented by ASD, ADHD and SSD symptoms. I’m no expert, and please don’t take my word as Gospel, but there seem to be some hints of diagnoses like pathological demand avoidance (PDA) also being detailed here. Just a thought.

Finally bearing in mind the Gadow study was based on a paediatric population, one has to wonder how this complex pattern of symptoms will eventually play out into adulthood. Bearing in mind that autism is seemingly protective of nothing when it comes to comorbidity, I think many working at the coalface will know of people diagnosed with autism who seem to develop clinical signs and symptoms more readily associated with the schizophrenia spectrum disorders as maturity sets in. The question is whether the criteria used in the current study could somehow be predictive of those who are at greater risk and whether plans and processes could be set in place to moderate this risk.

I’m going to stop there save any charges of over-analysing the paper from Prof. Gadow and its important findings. Reiterating the complex nature of both ASD and SSD and the areas of overlap which seem to be present, how we understand such conditions and indeed label them actually might turn out to be an important point not just from a identity point of view but also conceptually, onward to planning for / mitigating risk and improving overall quality of life.

Without trying to make light of spectrums, may be you remember this theme tune by the Spectrum?

*Tsai L. Sensitivity and specificity: DSM-IV versus DSM-5 criteria for autism spectrum disorder. Am J Psychiatry. 2012; 169: 1009-1011.

** Gadow KD. Schizophrenia spectrum and attention-deficit/hyperactivity disorder symptoms in autism spectrum disorder and controls. J Am Acad Child Adolesc Psychiatry. 2012; 51: 1076-1084.

*** Gadow KD. & Devincent CJ. Comparison of children with autism spectrum disorder with and without schizophrenia spectrum traits: gender, season of birth, and mental health risk factors. JADD. February 2012.

Gadow KD (2012). Schizophrenia spectrum and attention-deficit/hyperactivity disorder symptoms in autism spectrum disorder and controls. Journal of the American Academy of Child and Adolescent Psychiatry, 51 (10), 1076-84 PMID: 23021482

Retrieved from: http://questioning-answers.blogspot.co.uk/2012/10/when-autism-and-schizophrenia-spectrums.html

The Energetic Brain…a great reference for ADHD

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Medication, Neuropsychology, Psychiatry, Psychopharmacology, School Psychology on Sunday, 7 October 2012 at 09:27

everything you ever wanted to know about adhd. a wonderful reference!

http://www.amazon.com/The-Energetic-Brain-Understanding-ebook/dp/B006RDCF0M/ref=sr_1_1?s=digital-text&ie=UTF8&qid=1349616011&sr=1-1&keywords=the+energetic+brain

FDA approves liquid, extended-release ADHD medication

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Medication, Psychiatry, Psychopharmacology on Sunday, 7 October 2012 at 07:14

FDA Approves Liquid, Extended-Release ADHD Med

Caroline Cassels

October 1, 2012 — The US Food and Drug Administration (FDA) has approved a once-daily liquid medication for the treatment of attention-deficit/hyperactivity disorder (ADHD).

In a news release, drug manufacturer NextWave Pharmaceuticals announced FDA approval of its drug Qullivant XR (methylphenidate hydrochloride), the first once-daily, oral-suspension medication for the treatment of ADHD.

According to the company, the central nervous system stimulant is the first extended-release, once-daily liquid ADHD medication on the market. It helps control ADHD symptoms within 45 minutes of administration and lasts for 12 hours.

“The approval of Quillivant XR fills a void that has long existed in the treatment of ADHD. We routinely see the struggles of patients who have difficulty swallowing pills or capsules. Having the option of a once-daily liquid will help alleviate some of these issues while still providing the proven efficacy of methylphenidate for 12 hours after dosing,” said Ann Childress, MD, president of the Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada, who was also an investigator in a clinical trial that tested the drug.

The company notes that the drug’s efficacy was evaluated in a randomized, double-blind , placebo-controlled, crossover, multicenter classroom study of 45 children with ADHD.

Quillivant XR is a federally controlled substance (CII) because of its potential for abuse and/or dependence.

The drug is expected to be available in pharmacies in January 2013.

Retrieved from: http://www.medscape.com/viewarticle/771878?src=nl_topic

 

New Depression Guidelines

In Psychiatry on Thursday, 4 October 2012 at 11:52

New Depression Guideline Goes Beyond Symptom Relief

Kate Johnson

October 2, 2012 (Montreal, Canada) — The treatment of major depressive disorder (MDD) should go beyond the goal of symptom relief to include a more global target of improving patients’ overall and occupational functioning.

This shift is reflected in new consensus recommendations currently being finalized by the Canadian Network for Mood and Anxiety Treatments (CANMAT).

“The focus on symptoms doesn’t necessarily make sense for our patients because they’re primarily concerned about their functioning. And so we think we need to move the bar now — raise the bar — in terms of our assessment of outcomes. The ideal outcome really should be functional recovery,” Raymond Lam, MD, executive chair of the network, told delegates attending the Canadian Psychiatric Association (CPA) 62nd Annual Conference.

Studies show that MDD has a significant impact on work functioning, yet roughly 70% of people with MDD remain at work.

“Our view is that unless there are safety issues, it’s better for patients to be trying to stay at work while they’re being treated rather than being off work. The longer they’re off work, the harder it is to get them back,” said Dr. Lam, who is also professor of psychiatry and head of the Mood and Anxiety Disorders Program, University of British Columbia in Vancouver, Canada.

Because “the trajectory and time course of functional improvement may not mirror that of symptom improvement,” treatment that addresses symptoms alone may miss an important part of the picture, he said.

Subtle Outcomes

According to a needs assessment survey done primarily with family physicians, although most physicians recognize that functioning is a major determinant in treating people with depression, “there is a knowledge gap in terms of how functioning issues present,” Dr. Lam added.

To rate and monitor improvement in work functioning outcomes, the CANMAT statement recommends the use of clinician-rated scales such as the Health and Work Performance Questionnaire (HPQ) and the Lam Employment Absence and Productivity Scale (LEAPS) (BMC Psychiatry 2009;9:78-85), which was developed by Dr. Lam.

A new study by Dr. Lam’s group, which is currently under review, shows how such work performance scales are able to pick up subtle outcomes that can be missed on general symptom scales such as the Montgomery-Åsberg Depression Rating Scale (MADRS).

The Worker Outcome Research and Knowledge about Escitalopram and Related Treatments (WORKER) study is the first randomized controlled trial of pharmacotherapy and psychotherapy focusing specifically on work productivity outcomes, said Dr. Lam.

Better Productivity

A total of 105 employed patients with MDD were randomly assigned to undergo treatment with either escitalopram (10 – 20 mg/day) for 12 weeks plus 8 one-half-hour sessions of telephone cognitive-behavioral therapy (CBT) or escitalopram alone with adherence reminder calls.

Symptom response and remission were measured on the MADRS, and functioning was measured on both the HPQ and the LEAPS as well as a third functioning scale, the Sheehan Disability Scale (SDS).

After 12 weeks, there was no significant difference between the groups in terms of symptom outcome, with MADRS responder rates at 56% for patients in the combination therapy group vs 53% for patients receiving escitalopram alone (MADRS scores, 15.7 vs 14.3).

However, on the outcome of work functioning, participants receiving combination therapy had greater improvements than those receiving escitalopram alone on both the HPQ (1.2 vs 0.5, P < .05) and the LEAPS (3.9 vs 2.5, P < .04).

“We think these are clinically relevant differences in work productivity,” he said.

There were no differences between the groups on the SDS, “but the SDS is really a global measure and only has 1 item on overall work and role function,” he explained. “Using a 1-item scale may not be sensitive enough in a relatively small sample.”

The findings show that although symptoms can resolve with medication alone, there was residual functional impairment

“People’s occupational functioning obviously improved when they were on the antidepressant alone, it’s just they got a bump-up in terms of productivity with the combined treatment…. This is why we feel it’s so important to incorporate functional outcome measures, because we may be missing the fact that some treatments are going to be better for functioning than others.”

A “Practical Goal”

After attending the presentation, conference delegate Derryck Smith, MD, clinical professor of psychiatry, University of British Columbia, who is also a psychiatrist in private practice in Vancouver, said he agreed with the recommendations.

“We’re trying to get people better, not just get rid of symptoms. We have to work towards a practical goal,” he told Medscape Medical News.

“We need to help make people more successful in their life in general, in their relationships, as well as how they’re doing in their job…and maybe even in the physical aspects — are they back to running, for example? Are they back to their hobbies? Are they doing well socially?

“Even if their symptoms are reduced, you may have to find out why they’re not back at work. Maybe it’s because they’re not sleeping, maybe it’s because they’re having cognitive difficulties,” he said.

He added that the current DSM-IV diagnostic criteria include “a unique cluster of symptoms that defines an illness, but you always have to have functional impairment to make the diagnosis, and it doesn’t define what functional impairment is.”

He said that objective functional outcome measures are much needed for this assessment.

Canadian Psychiatric Association (CPA) 62nd Annual Conference. Abstracts Ps5b and S11. Presented September 29, 2012.

Retrieved from: http://www.medscape.com/viewarticle/771998?src=nl_topic

 

Psychostimulant treatment and the developing cortex

In ADHD, ADHD child/adolescent, ADHD stimulant treatment, Medication, Psychiatry, Psychopharmacology on Wednesday, 3 October 2012 at 06:19

a brief report on stimulant treatment in children and adolescents.  2008 publication but still useful information.

Psychostimulant Treatment and the Developing Cortex in Attention Deficit Hyperactivity Disorder

Shaw P, Sharp WS, Morrison M, et al
Am J Psychiatry. 2008 Sep 15.

http://www.medscape.org/viewarticle/583251

This study examined whether stimulants for attention-deficit/hyperactivity disorder (ADHD) were associated with differences in cerebral cortex development.

Study Design: Neuroanatomic MRI was used to assess the change in cortical thickness in 43 youths with ADHD; mean age at the first scan was 12.5 years, mean age at the second scan was 16.4 years. Of the 43 adolescents, 24 were treated with stimulants between scans while 19 were not treated between scans. Investigators included an additional comparison to a large sample of (n=294) of typically developing control youths.

Results: The rate of change of the cortical thickness in the right motor strip, the left middle/inferior frontal gyrus, and the right parieto-occipital region was different between the adolescents taking stimulants as compared with those not taking stimulants. Specifically, the study found more rapid cortical thinning in the group of patients not taking stimulants (mean cortical thinning of 0.16 mm/year [SD=0.17], compared with 0.03 mm/year [SD=0.11] in the group taking stimulants). Furthermore, comparison against the controls without ADHD showed that cortical thinning in the group not taking stimulants was in excess of age-appropriate rates.

Conclusion: These findings show no evidence that stimulant treatment is associated with slowing of overall growth of the cortical mantle.

Commentary: This is a remarkable paper from the Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, and the Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. The authors suggest that psychostimulant-induced improvements in cognition and action might foster cortical development within the normative range, as an example of activity-dependent neuroplasticity. The authors note that a randomized trial would be a better scientific design, but in the interim, this study shows the importance of comparisons with controls/normative data.

the state of anxiety in the united states

In ADHD, Anxiety, Medication, Psychiatry, Psychopharmacology on Wednesday, 3 October 2012 at 05:51

Some Facts about Anxiety in the United States:

Anxiety disorders are the most common mental illness in the U.S., affecting 40 million adults in the United States age 18 and older (18% of U.S. population).

Anxiety disorders are highly treatable, yet only about one-third of those suffering receive treatment.

Anxiety disorders cost the U.S. more than $42 billion a year, almost one-third of the country’s $148 billion total mental health bill, according to “The Economic Burden of Anxiety Disorders,” a study commissioned by ADAA (The Journal of Clinical Psychiatry,60(7), July 1999).

More than $22.84 billion of those costs are associated with the repeated use of health care services; people with anxietydisorders seek relief for symptoms that mimic physical illnesses.

People with an anxiety disorder are three to five times more likely to go to the doctor and six times more likely to be hospitalized for psychiatric disorders than those who do not suffer from anxiety disorders.

Anxiety disorders develop from a complex set of risk factors, including genetics, brain chemistry, personality, and life events.

 

Facts: Anxiety and Stress-Related Disorders

Generalized Anxiety Disorder (GAD)

GAD affects 6.8 million adults, or 3.1% of the U.S. population.
Women are twice as likely to be affected as men.

Obsessive-Compulsive Disorder (OCD)
2.2 million, 1.0%
Equally common among men and women.
The median age of onset is 19, with 25 percent of cases occurring by age 14. One-third of affected adults first experienced symptoms in childhood.

  • Hoarding is the compulsive purchasing, acquiring, searching, and saving of items that have little or no value.

Panic Disorder

6 million, 2.7%
Women are twice as likely to be affected as men.
Very high comorbidity rate with major depression.

Posttraumatic Stress Disorder (PTSD)
7.7 million, 3.5%
Women are more likely to be affected than men.
Rape is the most likely trigger of PTSD: 65% of men and 45.9% of women who are raped will develop the disorder.
Childhood sexual abuse is a strong predictor of lifetime likelihood for developing PTSD.

Social Anxiety Disorder
15 million, 6.8%
Equally common among men and women, typically beginning around age 13.
According to a 2007 ADAA survey, 36% of people with social anxiety disorder report experiencing symptoms for 10 or more years before seeking help.

Specific Phobias
19 million, 8.7%
Women are twice as likely to be affected as men.

Related Illnesses 

Many people with an anxiety disorder also have a co-occurring disorder or physical illness, which can make their symptoms worse and recovery more difficult. It’s essential to be treated for both disorders.

Children 

Anxiety disorders affect one in eight children. Research shows that untreated children with anxiety disorders are at higher risk to perform poorly in school, miss out on important social experiences, and engage in substance abuse.

Anxiety disorders also often co-occur with other disorders such as depression, eating disorders, and attention-deficit/hyperactivity disorder (ADHD).

Older Adults

Anxiety is as common among older adults as among the young. Generalized anxiety disorder (GAD) is the most common anxiety disorder among older adults, though anxiety disorders in this population are frequently associated with traumatic events such as a fall or acute illness. Read the best way to treat anxiety disorders in older adults.

Treatment Options

Anxiety disorders are treatable, and the vast majority of people with an anxiety disorder can be helped with professional care. Several standard approaches have proved effective:

Retrieved from: http://www.adaa.org/about-adaa/press-room/facts-statistics

 

The United States of Anxiety

By Ben Michaelis, Ph.D.

America is in an acute state of anxiety. For those of you who were concerned during the debt ceiling discussions, have been fearful during the stock market gyrations and are now panicking about your job, family and future, take a moment, take a deep breath and imagine that there is a better way. Because there is.

As human beings, our minds are prewired to react more strongly to negative information than positive information. This makes sense from an evolutionary psychology perspective: Negative information may mean threats to our survival, such as predators who may try to eat us. This is the reason that when a stranger gives you a nasty look it stays on your mind longer than when someone flashes a smile at you. This natural bias towards focusing on the negative becomes even more pronounced during times of uncertainty. When we don’t know where to turn, anything that seems potentially dangerous grabs our attention and activates our primitive survival instincts.

The fight or flight system is quite useful when you are facing a specific physical threat, but it is not helpful when you are facing general uncertainty, which is really what this is about. In fact, our survival instincts actually steer us in the wrong direction and can quickly make the situation worse. What is needed during periods of uncertainty is not this primitive instinct toward biological survival, which drove investors to “sell, sell sell!” on Monday, but rather the capacity to use our higher brain centers to imagine a different future.

As a clinical psychologist, I don’t treat nations, I treat people. In my work, I often see patients who experience intense, runaway anxiety (not unlike what happened on Monday) at just the time of a triumph or when things are about to turn for the better. Giving into the fear of the moment is both psychologically unpleasant and socially contagious. When other people see, or sense, that you are afraid, they focus on their instinctive reaction to seeing your fear and begin to experience terror themselves. Societal fear can quickly create an environment where your fears can come true simply by people behaving as though they are true. Regardless of the headlines suggesting the end is nigh, try taking a beat and doing something different: Imagine that all is not lost. Consider the ways that the future might actually be better than the present or the past.

When I am with a patient who is in the grip of such a panic, I suggest following these three steps in order to shift from fear to faith:

  1. Recognize: If you can recognize that you are in a state of panic, you are, frankly, more than halfway to stopping it. If you are not sure if you are in a state of panic, ask yourself this question: “Can I choose to stop these unpleasant, spiraling thoughts if I want to?” If the answer to the question is, “Yes,” then go ahead and do it. If the answer is “No,” then you have just realized that you are panicking.
  2. Refocus: Focus your energy on your five senses. Ask yourself: “What am I smelling?” “What am I seeing?” “What am I hearing?” “What are the tastes in my mouth?” and “How is my body feeling?” If you intentionally bring your focus away from the scenarios of Armageddon (not the Bruce Willis version) that you are cooking up and unto your present circumstances, you will break the chain of runaway thinking, because you can’t do both simultaneously. Even if you only get a brief respite any break, no matter how small, is enough to change the direction of your anxiety and help you take an active approach to problem solving.
  3. Re-imagine: Take your doomsday scenario and re-write it so that you are not stuck with the same old script. Write a Hollywood ending if you like. If you are scared that you will lose all of your money in the stock market, imagine the opposite. Picture the market changing direction, and that you will have more than you will ever need. If you have been out of work and are afraid that you will never get another job, imagine that you will be inundated with job offers. I am not suggesting that by simply imagining these things that they will happen, only that by doing so you can stop the spiral of anxiety and start thinking and planning for your next steps. That shift can make all of the difference between fueling the contagion of panic and returning to a more balanced state where you can actually effect real change in your life.

Your imagination is your greatest cognitive gift. It is also our greatest national asset. The ability to imagine a different and better future is the first step toward creating one. By recognizing, refocusing and re-imagining your circumstances you will feel better in the moment and shift from fear to faith. Using your mind’s eye to envision a positive outcome can help calm you down and make better momentary decisions. Plus, you might just inspire others to do the same.

Retrieved from: http://www.huffingtonpost.com/ben-michaelis-phd/americans-anxiety-stress_b_925420.html

 

are we over-medicating?

In ADHD, Anxiety, Brain imaging, Brain studies, Medication, Psychiatry, Psychopharmacology on Wednesday, 3 October 2012 at 05:39

this is one author’s opinion on anxiety and “the little blue pill.”  while anxiety is a VERY REAL and often debilitating condition for some, many wonder if anxiety medications (such as xanax and valium) are too readily prescribed and taken.  in my work as a school psychologist, i am asked constantly if i think adhd is over-diagnosed and children are over-medicated.  my answer is based in my belief that most psychological conditions are brain-based (this is becoming especially evident in light of new ways to examine the brain, i.e. genomic medicine, advanced brain imaging, etc.).  not treating those who have a REAL diagnosis has deleterious effects, but do i think that there are many physicians who will prescribe medications without possibly doing a full evaluation?  yes, i do.  but, i also think there are some VERY savvy parents who know what to say to get their kids medication that they *think* will give them an advantage over others.  while stimulants have a paradoxical effect on those with adhd (meaning they are stimulants but do not act as a stimulant behaviorally, i.e. not hyping kids up, but stimulating parts of the brain that are responsible for attending, focus, etc., thus appearing to calm them down), they also act as true stimulants for those that do not have a valid adhd diagnosis.  there are many stories of all-night study sessions in college and kids who use stimulants to stay awake and keep studying (i have even heard about kids who purchase stimulants just as they would marijuana or other drugs and crush it up and snort it for a cocaine-like effect).  the effect of a stimulant on someone without adhd is much like that of someone on cocaine.  they are ‘stimulated.’  so, while i believe the author has some valid points related to medication, i also believe that people who TRULY have a diagnosis of anxiety, adhd, depression, etc., do more harm than good when they do not take medication.  that is my personal opinion based on the many studies of those with treated issues versus those who do not seek treatment or were not treated until adulthood.  the differences in neuroanatomy and structural changes in the brain show that medication does work IF properly prescribed.  my personal opinion is if you think you are suffering from a brain-based disorder (adhd, anxiety, etc.), do yourself a favor and go to a PSYCHIATRIST.  while pediatricians and general practitioners are good at what they do and are knowledgeable about so many things, you wouldn’t go to an ophthalmologist for a broken leg, so why would you go to a pediatrician for a psychiatric issue?  psychiatrists’ entire business is of the mind and it is their job to keep up with the latest research and medications.  why go to anyone BUT a specialist?  once again, this is nothing more than my PERSONAL opinion.  

Valium’s Contribution to the New Normal

OPINION

By Robin Marantz Henig

IT wasn’t funny, really, but everybody laughed at the scene in the 1979 film “Starting Over” when Burt Reynolds’s character had a panic attack in the furniture department of Bloomingdale’s (something to do with terror at the prospect of buying a couch). “Does anyone have a Valium?” his brother called out as Burt hyperventilated. The punch line: Every woman in the store reached into her purse and pulled out a little vial of pills.

Nor was it surprising that all those Bloomie’s shoppers could be so helpful, since by that time Valium, which had been introduced in 1963, was the best-selling prescription drug in America, with billions of blue or yellow or white pills, each stamped with a trademark V, sold every year.

Valium was, significantly, one of the first psychoactive drugs to be used on a large scale on people who were basically fine. It has since been surpassed by other drugs, like the popular tranquilizer Xanax. But with the pharmaceutical giant Roche announcing that it will soon close the Nutley, N.J., plant where Valium and its predecessor, Librium, were developed, it’s a good time to remember how revolutionary these “minor tranquilizers” were half a century ago. These were the drugs that gave us a new way to slay our inner demons, medicating our way to a happier life.

How did Roche convince physicians that it was O.K. to offer their patients a bottled form of serenity? How did the physicians persuade their patients? And how did the company’s success in this venture shape our collective attitudes toward normal versus abnormal, stoic versus foolhardy, and the various ways available to cope with the ups and downs of daily life?

Marketing, essentially — which was first put into action with Librium, one of those evocative drug names that pharmaceutical companies invent. Librium was introduced in 1960 and promptly outsold its predecessors, the barbiturates, because it had fewer side effects. (Barbiturates were serious downers, making people sleepy and zombielike, and they were habit-forming; Marilyn Monroe died from an overdose.)

“A Whole New World … of Anxiety” read one of the early Roche ads for Librium, featuring a young woman with a pageboy hairdo holding an armload of books, wearing a short stadium coat and heading off to college. The copy made it sound as though every step in this “whole new world” called out for a tranquilizer. “The new college student may be afflicted by a sense of lost identity in a strange environment … Her newly stimulated intellectual curiosity may make her more sensitive to and apprehensive about unstable national and world conditions.”

The ad lists other sources of “anxiety” in a college student’s life — new friends, new influences, stiff competition for grades and tests of her moral fiber — that could just as easily be seen as growing pains, or as a healthy response to the turbulent world of the 1960s, when this ad appeared in The Journal of the American College Health Association. But Roche wanted doctors to believe that they were problems, not adventures, and that they warranted a prescription for Librium.

The next step was to develop something better — stronger, faster acting, less toxic. The Roche chemist who had originally stumbled upon Librium, Leo Sternbach, went back to the lab and tweaked the compound. Then he tested the drug on humans — in this case, the mothers-in-law of a few Roche executives. The executives thought that the new drug, Valium, rendered their mothers-in-law significantly less annoying.

In retrospect, Librium turned out to be a great first act, teaching Roche how to pitch a psychoactive drug to doctors of healthy patients who just needed a little something to unjangle their nerves. By the time Valium arrived, Roche was poised to dominate the field. In 1974, Americans filled nearly 60 million prescriptions for Valium.

Taking a pill to feel normal, even a pill sanctioned by the medical profession, led to a strange situation: it made people wonder what “normal” really was. What does it mean when people feel more like themselves with the drug than without it? Does the notion of “feeling like themselves” lose its meaning if they need a drug to get them there?

At the same time that Valium became famous for being in everyone’s medicine chest (or in every department store shopper’s purse), it also became famous for ruining lives. Elizabeth Taylor said she was addicted to Valium plus whiskey, Jack Daniel’s in particular. Tammy Faye Bakker said she was addicted to Valium plus nasal spray. Elvis Presley’s personal poison was Valium mixed with an assortment of other prescriptions. And Karen Ann Quinlan, the young woman languishing in a chronic vegetative state while her parents fought all the way to the New Jersey Supreme Court for the right to remove her from life support, originally lapsed into a coma in 1975 from a combination of Valium and gin.

Nearly 50 years after Valium was introduced and aggressively marketed, we’ve learned its lessons well. My generation of aging baby boomers does its brain styling, by and large, with antidepressantsProzac, Wellbutrin, CelexaPaxilZoloft. And for my daughters’ generation, the millennials, the pills of choice tend to be Ritalin and Adderall, for mental focus.

But when Americans are feeling out of sorts, we are still more likely to turn to anti-anxiety drugs than to any other kind. The leading successor to Valium, Xanax, outsells every other psychiatric drug on the market (48.7 million prescriptions last year). And even Valium is still out there, the classic little-black-dress of tranquilizers. In 2011, 14.7 million prescriptions were written for the drug that first made its cultural mark as a Rolling Stones song (“Mother’s Little Helper”) back in 1966.

As Roche closes its New Jersey headquarters, it plans to open a smaller research facility in Manhattan in late 2013, part of a wave that city officials hope will turn New York into a biotech mecca. The company’s transition reminds us of a phenomenon that’s become so common we no longer even think of it as weird: the oxymoronic attainment, through using drugs to make you feel more like yourself, of an artificially induced normal.

Robin Marantz Henig is a contributing writer for The New York Times Magazine and the co-author, with her daughter Samantha Henig, of the forthcoming “Twentysomething: Why Do Young Adults Seem Stuck?”

Retrieved from: http://www.nytimes.com/2012/09/30/sunday-review/valium-and-the-new-normal.html?ref=opinion&_r=0

an interesting perspective on medication…

In Medication, Psychiatry on Monday, 1 October 2012 at 17:18

while there is DEFINITELY a need for medication (imo), do some abuse it?  and, if so, isn’t that the war on drugs  we should be waging?

Fighting the Wrong War on Drugs

By Allen Frances, MD | August 29, 2012


Since Richard Nixon was president, we have been fighting a drug war we can’t possibly win. Meanwhile, we have barely begun to fight a different drug war we couldn’t possibly lose.

The losing battle is against illegal drugs. Interdiction has been as big a bust as Prohibition of alcohol(Drug information on alcohol) in the 1930s. Occasionally arresting a drug kingpin or confiscating a few million of dollars worth of contraband heroin or cocaine makes for a nice headline, but this doesn’t stop the flow.

The beneficiaries of our war on drugs have been the cartels and the narco-terrorists; the casualties are the failing states they can buy or bully. The Mexican government is fighting what amounts to an undeclared civil war against cartels armed to the teeth and flowing with money—both from north of the border. We have unwittingly created a terrific business model for the drug dealers and a disaster for the states where they deal.

That other drug war, which we couldn’t possibly lose, is against the excessive use of legal drugs that is promoted by our own pharmaceutical companies. Astounding fact: prescription drugs are now responsible for more accidental overdoses and deaths than street drugs.

Polypharmacy is rampant and uncontrolled with military personnel, the elderly, and children particularly vulnerable to its risks. Michael Jackson is just the most high–profile poster victim of this growing epidemic of legal drug abuse. The drug cocktails are sometimes prescribed by dangerous high-flying doctors, sometimes by multiple doctors who just aren’t aware of the other’s existence, and prescription drugs are also widely available for purchase on the street.

There is no one cause of this mess, and there won’t be one cure. Doctors, drug companies, patients, politicians, and our fragmented health care system are all to blame. But the elephant in the room is Big Pharma. It has hijacked the practice of medicine, using its enormous profits to unduly influence physicians, physician groups, academics, consumer advocacy groups, the Internet, the press, and the government. Misleading “disease mongering” promotional programs saturate the media with direct-to-consumer drug advertising that is illegal everywhere else in the world except New Zealand and the developing nations.

The result: a ridiculously high proportion of people have come to rely on antidepressants, antipsychotics, antianxiety agents, sleeping pills, and pain meds. Psychiatric meds are among the very top best sellers for the drug companies—over $16 billion for antipsychotics; almost $12 billion for antidepressants, and more than $7 billion for ADHD drugs. One in 5 Americans takes a psychiatric drug, 1 in 5 women is on an antidepressant.

Seventy percent of these pills are prescribed by primary care doctors with little training in their proper use, under intense pressure from drug salespeople and misled patients, after rushed 7-minute appointments and subject to no systematic auditing.

The free market in drug salesmanship has led to promiscuous drug use, needless side effects, and wasted resources—a kind of societal overdose. The government has unwittingly aided and abetted Pharma. The cash-strapped FDA is beholden to industry for funding.

And it gets worse. Big Pharma all too often also goes illegal to push even more product. The multi-billion dollar criminal and civil penalties recently levied on several different drug companies provide clear evidence of the pervasive extent of drug company wrongdoing—but have not been big enough to deter it. A billion dollars must seem like chump change—just the cost of doing business.

Pretty bleak. But if we ever had the political will to begin it, we couldn’t possibly lose a war to tame the dangerous use of legal drugs. The solutions are crystal clear and a cinch to implement—if we were really determined to solve the problem:

(1) Sharply restrict drug company marketing and lobbying. Pharma now spends almost twice as much money pushing drug sales as on research—we would have better medicines and less legal drug abuse if this were reversed.

(2) Make the punishments for marketing malfeasance much more of a deterrent to underhanded drug pushing. This could be done by levying much bigger megafines on the companies and also by holding the executives personally responsible and perhaps by reducing the period of product patent protection.

(3) Develop a computerized real-time national system to identify and prevent polypharmacy. Credit card companies can abort a suspicious $100 transaction before the fact. Why can’t we apply the same technology preemptively to prevent a patient from collecting potentially lethal pills?

(4) Closely monitor the prescribing habits of doctors to correct or eject the “Dr Feelgoods.”

(5) It would greatly improve the quality of our health care system and greatly reduce its costs if all doctors, professional associations, consumer groups, and politicians were prevented from accepting drug company funding. Do drug companies really need this much “free speech”? It makes no sense to have the FDA funded by drug companies.

What are the political prospects of my twin proposals—to begin the winable war against the overuse of legal drugs and to drop the losing war against illegal drugs?

You guessed it—zero and zero. The first will be doomed by Pharma’s political punch; the latter by the irrational victory of hope and ideology over experience.

Retrieved from: http://www.psychiatrictimes.com/blog/frances/content/article/10168/2099456

Information regarding the upcoming DSM V

In Neuropsychology, Psychiatry, School Psychology on Wednesday, 26 September 2012 at 08:00

DSM-5: Finding a Middle Ground

Nassir Ghaemi, MD

DSM-5: Validity vs Reliability

This year’s American Psychiatric Association (APA) annual meeting was probably the last before the publication of theDiagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), scheduled for May of next year. Hence, there was a sense of tense uncertainty in the many sessions addressing potential DSM-5 revisions.

DSM-5 Task Force Vice Chair Darrel Regier headed a symposium reviewing results of field trials on the reliability of proposed DSM-5 criteria. The trials were meant to assess whether clinicians can use the proposed criteria consistently and provided kappa values for the individual proposals.

Kappa values reflect the agreement in a rating by 2 different persons, after correction for chance agreement. From a statistical perspective, kappa values greater than 0.5 are generally considered good. As an example, 70% agreement between raters translates to a kappa value of 0.4.

Results of the field trials showed good agreement for such disorders as major neurocognitive disorder, autism spectrum disorders, and post-traumatic stress disorder, with kappa values of 0.78, 0.69, and 0.67, respectively. However, poor kappa values, in the range of 0.20-0.40, were reported for commonly diagnosed conditions, such as generalized anxiety disorder and major depressive disorder. All of the observed kappa values in the DSM-5 field trials translate to agreement between clinicians of around 50%.

Is this good or bad? A recent editorial[1] by DSM-5 leaders makes comparisons with other medical settings, and the claim is that most medical diagnoses involve diagnostic kappa values similar to those in the DSM-5 field trials. I spoke with prominent psychiatrists at this year’s meeting who were involved in some of these DSM studies and discussions; they expressed unhappiness with the kappa values in DSM-5 field trials, and some pointed out that kappa values in the DSM-III were higher.

So, the reliability of DSM-5 criteria seems to have declined compared to DSM-III. Is this a problem? It might be, but it might not be.

Reliability only means that we agree. It doesn’t mean that we agree on what is right. Validity is a separate issue. It could be that criteria are changed so that they are more valid — that is, actually true — but this could increase unreliability; raters might have to use, for instance, some criteria that are less objective and hence less replicable.

We will see. DSM-5 might be more valid but less reliable than DSM-IV and DSM-III. If so, that’s progress, in a way.

It is also important to think about other medical studies with low reliability. We should be careful about criticizing certain diagnoses, such as bipolar disorder (as some have[2]), without an awareness that this is the case for almost all our diagnoses. The problem of reliability is a general one, not a problem about claimed “overdiagnosis” of some conditions.

In my view, it is definitely time for a new edition of DSM; we can’t pretend that something written almost 2 decades ago is anywhere near up to date, with a generation of new research. Some of the proposed changes in DSM-5 — for example, the inclusion of antidepressant-induced mania as part of bipolar disorder; the inclusion of dimensions for axis II personality conditions; and the removal of nosologically nonspecific axis II diagnoses, such as “histrionic” personality — are consistent with an update based on convincing new research. But other changes, such as the wish to discourage the diagnosis of childhood bipolar disorder by making up a new category based on limited data (temper dysregulation disorder), merely repeat the mistakes of DSM-IV. Making up diagnoses because we don’t like others is not a scientifically sound way to revise a profession’s diagnostic system, and it won’t serve us well for the next 20 years.

But DSM-IV Has Limitations, Too

Also at this year’s APA meeting, Steven Hyman, a psychiatrist and neurobiology researcher who is former head of the National Institute of Mental Health, gave a plenary lecture on DSM-5 that was refreshingly honest in its appreciation of the limitations that the DSM-IV has placed on research. Rewinding to DSM-III, from the 1980s, he made the point that although that edition was a major advance, it is now out of date, and that DSM-IV, which merely continued the basic DSM-III structure, needs major changes. “The DSM-III was a brilliant document that could not have foreseen the science. It’s time to move on scientifically,” said Hyman.

Hyman noted that DSM-III actually hinders science. Researchers have difficulty getting funding from the National Institutes of Health or publishing papers that go outside DSM criteria: “For example, it was very hard to get a grant to test the hypothesis that maybe the apparent comorbidity of multiple anxiety disorder and mood disorders was just that there was a single underlying process or single disorder that got expressed with different symptom complexes in different times in life.”

There was a name for that condition — neurotic depression — and Sir Martin Roth, the great British psychopathologist, warned repeatedly in the 1970s and 1980s that it would be a mistake for DSM-III to remove it. DSM-III made that mistake, and the field has since acted like it would be a sin to study the matter any further.

There are many examples of this ilk in DSM-III and DSM-IV. Some who are upset with proposed changes in DSM-5 are diagnostic conservatives who seem to think that all our questions were answered in 1980 and 1994.

Dr. Hyman has been influential in designing the new Research Domain Criteria (RDOC), an attempt to create a DSM for research that begins with biological, rather than clinical, terms. I agree with the need for a DSM for research, but I don’t think our biological knowledge is advanced enough yet — despite all the advances that have been made — to build a diagnostic system from them, even for research purposes.

I think we should have a new DSM just for research: a system of Research Diagnostic Criteria (RDC), like what was created in the 1970s that led to DSM-III to begin with. I’ve started that process with my colleagues in the world of bipolar disorder research. We will publish a new RDC for bipolar disorder within the coming year — before DSM-5, I hope. If we do so, I hope that colleagues in other specialties in psychiatry will produce similar RDCs.

With these new publications, psychiatry may then be in a position for real advance. We will then have 3 nosologies, all complementary to each other and able to improve the others:

  1. DSM-5: a nosology based on a mix of research, economic concerns, social preferences, and professional consensus that is used for basic practice, insurance reimbursement, and short-term consensus.
  2. RDOC: a nosology based solely on biological research that is used for research.
  3. RDC: a nosology based solely on clinical research that is used for research.

In summary, DSM-5 is on its way, and May 2013 is as good a date as any for its publication. In some places, it will be a much-needed advance over the now-outdated DSM-IV. But in other places, it keeps old categories that are not as well proven as they should be, and it even adds a few new categories that are mainly based on professional, economic, and social concerns rather than on sufficient scientific evidence.

References

  1. Kraemer HC, Kupfer DJ, Clarke DE, Narrow WE, Regier DA. DSM-5: how reliable is reliable enough? Am J Psychiatry. 2012;169:13-15. http://ajp.psychiatryonline.org/article.aspx?articleid=181221 Accessed May 15, 2012.
  2. Zimmerman M, Ruggero CJ, Chelminski I, Young D. Is bipolar disorder overdiagnosed? J Clin Psychiatry. 2008;69:935-940.

Retrieved from: http://www.medscape.com/viewarticle/764740?src=ptalk

ADHD medication and cardiovascular risk

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Medication, Psychiatry, Psychopharmacology on Wednesday, 26 September 2012 at 07:20

i believe many people may hold some misconceptions related to stimulant medication in treating ADHD.  in fact, i have a personal story related to that.  a friend of mine needed to go to the emergency room for a cut that needed stitches.  while in triage, the nurse took her blood pressure and it was quite elevated.  the nurse questioned her about her bp and asked if she was diagnosed with high blood pressure (this person is an avid athlete and has never had issues with high bp).  once the nurse saw on her intake form that she took 10mg. of adderall a day for adult ADHD, she told my friend that that medicine was “toxic” and the she needed to stop it “right away” and go to her doctor immediately for a cardiac assessment.  she repeatedly stated that the adderall she was taking was going to do her harm and she MUST stop taking it right away!  my friend was somewhat startled at the nurse’s vehement opinions regarding the adderall.  what i do know is that, when i am hurt or in a tense situation (i.e. the emergency room and in pain), my blood pressure might temporarily go up.  i also know that i DO NOT have high blood pressure.  no mention of being anxious or in pain was made in relation to my friend’s high bp at that time.  on a side note, once my friend was out of the ER and we had gone to the pharmacy to get a prescription, she took it again and it was well within the normal range, showing she was just anxious/worried/in pain and her higher bp was a residual effect of that.  but…this does illustrate that there are times people believe that something is fact because of popular opinion, their own biases, etc., even when the literature may not support their belief/s.  so, in light of that, i wanted to share a post on stimulant medication and cardiovascular risk.  as you can see, it is not as clear-cut as our opinionated nurse thought it was.

ADHD Medications in Adults Yield Mixed Cardiovascular Risk Results

Deborah Brauser & Hien T. Nghiem, MD

In the United States, roughly 1.5 million adults use medications for attention-deficit/hyperactivity disorder (ADHD). These medications include amphetamines, atomoxetine, and methylphenidate. ADHD medications are known to increase both blood pressure (< 5 mm Hg) and heart rate (< 7 bpm). Given these effects, there are concerns regarding serious cardiovascular events related to taking ADHD medications.

The aim of this study by Hennessy and colleagues was to determine whether use of methylphenidate in adults is associated with elevated rates of serious cardiovascular events compared with rates in nonusers.

Study Synopsis and Perspective

Although adults prescribed the ADHD medication methylphenidate may be at increased risk for adverse cardiovascular events, this association may not be causal, new research suggests.

In a cohort study of almost 220,000 individuals, new users of methylphenidate had almost twice the risk for sudden death or ventricular arrhythmia than age-matched control participants had. They also had a significantly higher risk for all-cause death.

However, the medication dosage “was inversely associated with risk,” meaning it lacked a dose-response relationship, report the investigators.

“We were surprised by the risk findings. But the inverse associations leads us to be somewhat skeptical,” coinvestigator Sean Hennessy, PharmD, PhD, associate professor of epidemiology and pharmacology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, told Medscape Medical News.

“Ordinarily, if a drug increases the risk of adverse outcomes, that increase is going to be dose-dependent. We didn’t see that, and in fact, found an inverse relationship for death and other outcomes,” he explained.

Dr. Hennessy said that this could be due to “frail, elderly patients who have other things going on” and who are prescribed low-dose methylphenidate.

“Maybe baseline differences in those patients that aren’t captured in the medical claims data are responsible for the elevated risk of adverse outcomes we were seeing rather than it being a causal effect of the methylphenidate itself,” he opined.

“So I would say to wait for these findings to be replicated and clarified in other research before they are acted on clinically.”

The study is published in the February issue of the American Journal of Psychiatry.

Mixed Findings

According to the investigators, methylphenidate and other ADHD medications are used by almost 1.5 million adults in the United States — even though these medications have been shown to raise blood pressure and heart rate.

“Given these effects, case reports of sudden death, stroke, and myocardial infarction have led to regulatory and public concern about the cardiovascular safety of these drugs,” write the researchers.

However, in May 2011, and reported by Medscape Medical News at that time, the same group of researchers published a study in Pediatrics that showed no increased risk for cardiovascular events in children treated with ADHD medications.

In addition, researchers from Kaiser Permanente Northern California published a study in December 2011 in the Journal of the American Medical Association that examined risks in adults younger than age 65 years who were taking methylphenidate, amphetamine, atomoxetine, or pemoline.

The combined group of ADHD medication users showed no increased risk for serious cardiovascular events, including myocardial infarction, sudden cardiac death, or stroke, compared with the group of nonusers.

For this analysis, investigators examined records from Medicaid and commercial databases, representing 19 states, for adults in a broader age range. Included were 43,999 new users of methylphenidate and 175,955 individuals who did not use methylphenidate, amphetamines, or atomoxetine (for both groups, 55.4% were women).

In each group, 67.3% of the participants were between the ages of 18 and 47 years, 23.2% were between the ages of 48 and 64 years, and 9.5% were aged 65 years or older.

Primary cardiac events assessed included sudden death or ventricular arrhythmia, myocardial infarction, stroke, and a combination of stroke/myocardial infarction. All-cause death was a secondary measure.

Unexpected Results

Results showed that the adjusted hazard ratio (HR) for sudden death/ventricular arrhythmia for the methylphenidate users compared with the nonusers was 1.84 (95% confidence interval [CI], 1.33 – 2.55). For all-cause death, the HR was 1.74 (95% CI, 1.60 – 1.89).

Adjusted HRs for myocardial infarction and stroke (alone or in combination) were not statistically different between the 2 treatment groups.

For the participants who experienced a cardiovascular event, the median treatment dosage was 20 mg/day. No significant association was found for sudden death/ventricular arrhythmia between the patients who took more or less than 20 mg/day of methylphenidate.

“However, there were unexpected inverse associations” between high methylphenidate dosage and stroke, myocardial infarction, stroke/myocardial infarction, and all-cause death compared with low dosage, report the researchers. They add that this lack of a dose-response association discredits a causal relationship.

“Furthermore, the inverse relationships…may suggest that lower dosages were prescribed to the frailest patients, who might have had a greater risk of all-cause death and sudden death — that is, the results may have been affected by unmeasured confounding,” write the investigators.

Other limitations cited included the fact that the study was not randomized and that administrative databases do not include potential confounders such as smoking, blood pressure, substance use, and exercise use/nonuse.

Dr. Hennessy reported that the investigators also assessed cardiovascular risks in their study participants who were also taking amphetamines or atomoxetine. They will be publishing those results soon.

Findings “Generally Reassuring”

Christopher J. Kratochvil, MD, from the University of Nebraska Medical Center in Omaha, writes in an accompanying editorial that this and other studies are “generally reassuring and demonstrate movement in the right direction, with systematic retrospective analyses better informing us of issues related to cardiovascular safety with ADHD pharmacotherapy.”

“While gaps persist in the methodical and comprehensive assessments of the safety of ADHD medications, these studies add valuable information to our already large repository of safety and efficacy data…and better inform the risk-benefit analysis of their use,” writes Dr. Kratochvil, who was not involved with this research.

He adds that establishing a “robust” national electronic health records system containing detailed data elements will also offer considerable help to clinicians.

These large and more accessible databases “will allow us to improve our identification and understanding of rare but serious adverse effects and better address these questions of public health significance,” he concludes.

The study was funded through a sponsored research agreement with Shire Development, Inc., and by a Clinical and Translational Science Award from the National Institutes of Health. The study authors all receive salary support from Shire through their employers. All financial disclosures for the study authors and Dr. Kratochvil are listed in the original article.

Am J Psychiatry. 2012;169:112-114;178-185. Abstract, Editorial

Study Highlights

■This study was a nonrandomized cohort study of new users of methylphenidate based on administrative data from a 5-state Medicaid database (1999-2003) and a 14-state commercial insurance database (2001-2006).

■All new methylphenidate users with at least 180 days of prior enrollment were identified.

■Users were matched on data source, state, sex, and age to as many as 4 comparison participants who did not use methylphenidate, amphetamines, or atomoxetine.

■A total of 43,999 new methylphenidate users were identified and were matched to 175,955 nonusers.

■The main outcome measures were (1) sudden death or ventricular arrhythmia; (2) stroke; (3) myocardial infarction; and (4) a composite endpoint of stroke or myocardial infarction.

■Secondary outcomes included all-cause death and nonsuicide death.

■Results demonstrated that the age-standardized incidence rate per 1000 person-years of sudden death or ventricular arrhythmia was 2.17 (95% CI, 1.63 – 2.83) in methylphenidate users and 0.98 (95% CI, 0.89 – 1.08) in nonusers, for an adjusted HR of 1.84 (95% CI, 1.33 – 2.55).

■Dosage was inversely associated with the risks for stroke, myocardial infarction, stroke/myocardial infarction, and all-cause death.

■Adjusted HRs for stroke, myocardial infarction, and the composite endpoint of stroke or myocardial infarction did not differ statistically from one another.

■For the secondary outcome of all-cause death, methylphenidate demonstrated a positive association (adjusted HR, 1.74; 95% CI, 1.60 – 1.89). Nonsuicide deaths were nearly identical.

■Limitations of this study include the potential for unmeasured confounders (ie, smoking, blood pressure, nonprescribed aspirin use, substance misuse, and level of physical activity) because the study was not randomized.

Clinical Implications

■ADHD medications raise blood pressure by less than 5 mm Hg and heart rate by less than 7 bpm.

■Although initiation of methylphenidate was associated with a 1.8-fold increase in the risk for sudden death or ventricular arrhythmia, the lack of a dose-response relationship suggests that this association may not be a causal one.

Retrieved from: http://www.medscape.org/viewarticle/759069

First Direct Genetic Evidence for ADHD Discovered-2010

In ADHD, ADHD Adult, ADHD child/adolescent, Genes, Genomic Medicine, Neuropsychology, Psychiatry, School Psychology on Tuesday, 25 September 2012 at 06:20

an older article, but one i thought worthy of posting.

First Direct Genetic Evidence for ADHD Discovered

Caroline Cassels

September 29, 2010 — New research provides the first direct evidence that attention-deficit/hyperactivity disorder (ADHD) is genetic.

In a study published online September 30 in The Lancet, investigators from the University of Cardiff in the United Kingdom say their findings, which show that ADHD has a genetic basis, suggest it should be classified as a neurodevelopmental and not a behavioral disorder.

“We’ve known for many years that ADHD may well be genetic because it tends to run in families in many instances. What is really exciting now is that we’ve found the first direct genetic link to ADHD,” principal investigator Anita Thapar, MD, told reporters attending a press conference to unveil the study results.

In the genomewide analysis, 366 children 5 to 17 years of age who met diagnostic criteria for ADHD but not schizophrenia or autism and 1047 matched controls without the condition were included. Researchers found that compared with the control group without ADHD, children with the disorder were twice as likely — approximately 15% vs 7% — to have copy number variants (CNVs).

CNVs, explained study investigator Nigel M. Williams, PhD, are sections of the genome in which there are variations from the usual 2 copies of each chromosome, such that some individuals will carry just 1 (a deletion) and others will have 3 or more (duplications).

“If a gene is included in one of these copy number variants, it can have deleterious consequences,” said Dr. Williams.

Shared Biological Link

The study authors note that the increased rate of CNVs was particularly high among children with a combination of ADHD and learning disabilities but “there was also a significant excess in cases with no such disability.”

The researchers also found that CNVs overlap with chromosomal regions that have previously been linked to autism and schizophrenia. Although these disorders are thought to be completely separate, there is some overlap between ADHD and autism in terms of symptoms and learning difficulties.

We’ve looked at only 1 class of variation, but it’s an important one because it has been linked to other brain disorders.

This finding suggests there may be a shared biological basis for the 2 conditions and, according to investigators, provides the first direct evidence that ADHD is a neurodevelopmental condition.

“We found that the most significant excess of these types of copy number variants was on a specific region of chromosome 16. This chromosomal region includes a number of genes, including one that affects brain development,” said Dr. Thapar.

The team’s research marks the start of the “unraveling of the genetics” of ADHD, according to Dr. Thapar.

“We’ve looked at only 1 class of variation, but it’s an important one because it has been linked to other brain disorders,” she said.

Implications for DSM-5?

Dr. Thapar added that the study results also have direct implications for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which is currently under development by the American Psychiatric Association.

A “huge debate” about whether ADHD should be classified as a behavioral or neurodevelopmental disorder is ongoing. However, she said, these findings should help put this controversy to rest.

“Our results clearly show that ADHD should be considered a neurodevelopmental disorder,” she said.

In fact, Dr. Thapar noted that the study findings have been submitted to one of the DSM-5 work groups for consideration in the development of the new manual.

The investigators note that despite epidemiologic evidence derived from twin studies showing high heritability and the fact that ADHD is often accompanied by learning disabilities, there is still a great deal of public misunderstanding about the disorder.

Some people say this is not a real disorder, that it is the result of bad parenting. Children and parents can encounter much stigma because of this. So this finding of a direct genetic link to ADHD should help clear this misunderstanding and help address the issue of stigma.

“Some people say this is not a real disorder, that it is the result of bad parenting. Children and parents can encounter much stigma because of this. So this finding of a direct genetic link to ADHD should help clear this misunderstanding and help address the issue of stigma,” said Dr. Thapar.

Although there are no immediate treatment implications, Dr. Thapar said she hopes the research will have an immediate impact in terms of shifting public perception about ADHD and fuel further research into the biological basis of the disorder with a view to developing better, more effective therapies for affected individuals.

In an accompanying editorial, Peter H. Burbach, PhD, from the Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, the Netherlands, writes, “The first gains beyond today’s study might be initial insights into the pathogenesis and neurobiology of brain development as influenced by these genetic variants. This knowledge will eventually enter the clinic and might affect the way people think about and treat neurodevelopmental disorders by accounting for the biological consequence of the specific patient’s genotype.”

Lancet. Published online September 30, 2010.

Retrieved from: http://www.medscape.com/viewarticle/729652

Drug Therapy for Autism

In Autism Spectrum Disorders, Medication, Neuropsychology, Psychiatry, Psychopharmacology on Monday, 24 September 2012 at 16:10

Autism Patients Might Benefit from Drug Therapy

By SYDNEY LUPKIN | ABC News – Wed, Sep 19, 2012 2:37 PM EDT

Researchers have found a drug that can help patients with Fragile X syndrome, the most common cause of inherited intellectual impairment (formerly known as mental retardation), stay calm in social situations by treating their anxiety.

Dr. Elizabeth Berry-Kravis and her team found that a drug called Arbaclofen reduced social avoidance and repetitive behavior in Fragile X patients, especially those with autism, by treating their anxiety. The drug increases GABA, a chemical in the brain that regulates the excitatory system in Fragile X patients, who have been known to have too little GABA to do the job otherwise, causing their excitatory systems to “signal out of control” and make them anxious.

Such patients have been known to cover their ears or run away at their own birthdays because they are overwhelmed by the attention, but one trial participant said he was able to enjoy his birthday party for the first time in his life while he was on Arbaclofen, she said.

“I feel like it’s kind of the beginning of chemotherapy when people first realized you could use chemotherapy to treat cancer patients instead of just letting them die,” said Berry-Kravis, a professor of neurology and biochemistry at Rush University Medical Center in Chicago who has studied Fragile X for more than 20 years.

She said people used to think Fragile X patients couldn’t be helped either, but she and her team have proven that by using knowledge from existing brain mechanism studies, doctors can select medications to target specific problems in Fragile X patients’ brains.

Fragile X syndrome is a change in the FMRI gene, which makes a protein necessary for brain growth, and studies indicate it causes autism in up to one-third of patients diagnosed with it. Unlike Fragile X syndrome, which is genetic, autism is a behavioral diagnosis characterized by an inability to relate to other people or read social cues. Autism and Fragile X are linked, but not mutually exclusive. A core symptom of both is social withdrawal.

Sixty-three patients with Fragile X participated in Berry-Kravis’s placebo-controlled, double-blind clinical trial from December 2008 through March 2010. Of those, the patients with autism showed the biggest improvements in social behavior, Berry-Kravis said.

To psychologist Lori Warner, who directs the HOPE Center at Beaumont Children’s Hospital, the study is exciting because when her autistic patients are anxious, they often have a harder time learning the social cues they can’t read on their own.

“Reducing anxiety opens up your brain to be able to take in what’s happening in an environment and be able to learn from and understand social cues because you’re no longer frightened of the situation,” Warner said.

She works mostly with autism patients, and although some do have Fragile X as well, most do not.

Fragile X affects one in 4,000 men and one in 6,000 to 8,000 women, according to the Centers for Disease Control and Prevention.

Although Arbaclofen worked best on autistic Fragile X patients, further studies will be needed to prove whether it can help all autism patients, not just those with autism caused by Fragile X.

“There’s a difference between one person’s brain and another in how it’s set up,” Berry-Vargis said. “This is not a magic cure. It’s a step.”

Retrieved from: http://gma.yahoo.com/autism-patients-might-benefit-drug-therapy-183744169–abc-news-health.html

Perinatal Risk Factors for ADHD Confirmed

In ADHD, ADHD Adult, Psychiatry, School Psychology on Monday, 24 September 2012 at 16:06

important info!

Perinatal Risk Factors for ADHD Confirmed

Megan Brooks

September 13, 2012 — The combination of maternal gestational diabetes mellitus (GDM) and low socioeconomic status (SES) is a strong risk factor for childhood attention-deficit/hyperactivity disorder (ADHD), a study from Germany confirms.

Perinatal health problems, maternal smoking during pregnancy, and atopic eczema also raise the risk for ADHD, whereas fully breastfeeding appears to protect against ADHD, regardless of the duration of breastfeeding, the study showed.

“Modification of these environmental risk factors by evidence-based prevention programs may help to decrease the burden of ADHD,” write coinvestigators Jochen Schmitt, MD, MPH, of Technical University Dresden, and Marcel Romanos, MD, from the University Hospital of Würzburg, in Germany.

The study was published online September 10 in Archives of Pediatrics and Adolescent Medicine.

It follows a study published in the same journal earlier this year by Yoko Nomura, PhD, MPH, from the Department of Psychology, Queens College, City University of New York, and colleagues. That study, which included 212 preschool-age children, linked maternal GDM and low SES, especially in combination, to a heightened risk for childhood ADHD.

Nationwide Study

These latest findings from Dr. Schmitt and Dr. Romanos replicate this finding in a large nationwide representative sample of 3- to 17-year-olds who participated in the German Health Interview and Examination Survey for Children and Adolescents (n = 13,488).

The outcome of interest was childhood ADHD, and the primary exposures of interest were self-reported physician-diagnosed GDM (absent or present) and SES, classified as low, medium, or high on the basis of parental education, professional qualification, professional status, and family income.

The authors also considered age, sex, and a broad set of environmental exposures in the prenatal and perinatal period and in infancy as competing risk factors in multivariate analysis.

A total of 660 children (4.9%) had ADHD; the prevalence of GDM and low SES was 2.3% (n = 280) and 25.5% (n = 3420), respectively, the authors report.

Both maternal GDM and low SES were significantly related to ADHD. In multivariate regression modeling (based on 11,222 observations without any missing data), GDM and low SES were independent risk factors for childhood ADHD. The same was true for perinatal health problems, maternal smoking during pregnancy, and atopic eczema, whereas breastfeeding was protective.

Table: Risk for ADHD With Outcomes of Interest

Characteristic/Exposure aOR (95% CI)
Maternal GDM 1.91 (1.21 – 3.01)
Low SES 2.04 (1.56 – 2.68)
Smoking 1.48 (1.19 – 1.84)
Perinatal health problems 1.69 (1.40 – 2.03)
Atopic eczema 1.62 (1.30 – 2.02)
Breastfeeding 0.83 (0.69 – 0.996)

aOR = adjusted odds ratio; CI = confidence interval

The investigators note that their findings confirm those of Dr. Nomura and colleagues by showing an association between low SES, maternal GDM, and ADHD “and their additive interaction as risk factors for ADHD in a large population-based sample.”

The researchers say their study also extends previous research by showing that fully breastfeeding may have protective effects on childhood ADHD.

Fetus a “Captive Audience”

Dr. Nomura told Medscape Medical News that “being able to duplicate our findings in a different sample and a much larger sample is important.”

“I’m not sure if most doctors know that GDM is a risk factor for ADHD; biological and environmental risk factors for ADHD is a fairly new scientific field,” she added.

“ADHD is a highly hereditary illness, but it’s not only hereditary; we are beginning to gather information about environmental or biological causes and beginning to focus on perinatal risk factors for ADHD,” said Dr. Nomura.

“The fetus is a captive audience,” she noted, “and it seems like in utero exposure to a variety of things like excessive insulin, smoking, plastic materials, food dyes, toxic chemicals may cause epigenetic changes in brain development that may show up later in life.”

Arch Pediatr Adolesc Med. Published online September 10, 2012. Abstract

 

Tailoring Antidepressant Treatment

In ADHD, ADHD Adult, ADHD child/adolescent, Anxiety, Medication, Psychiatry, Psychopharmacology on Monday, 24 September 2012 at 07:13

Tailoring Antidepressant Treatment: Factors to Individualize Medication Selection Thomas L. Schwartz, MD; Daniel Uderitz, MD

In the realm of psychopharmacology, we often declare medications within their respective therapeutic classes as being equal. This is a byproduct related to the way medications achieve their indications for treatment for specific psychiatric disorders. In the case of antidepressant treatments, the US Food and Drug Administration (FDA) indicates that if a study can obtain a majority of patients improved by 50% compared with placebo, then a drug may become an antidepressant treatment. There are no standards for differentiating antidepressant treatments beyond this. Clinicians often note that all antidepressant treatments are not created equal, especially when applied to clinical situations and patients who are often complex and have comorbid conditions. The goal of this article is to sort out regimens that may convey certain advantages during the treatment in an individualized manner. This involves conceptualizing and utilizing monotherapies, combination therapies, and adjunctive treatments.

Monotherapies

The first-line treatment of patients with major depressive disorder (MDD) should start with an aggressive monotherapy. This occurs in clinical practice and is supported by many guidelines and reviews. The various antidepressant medications have unique properties that can be used to individualize treatments. Most psychiatrists can easily name their “favorite” antidepressant to use in certain situations. This is sometimes based on a simple bias, but often has evidence to back up clinical practice. Let us start with the mechanistically simple and move toward more complex ways to think about these medications. This includes thinking about FDA approvals, available guidelines, comorbidities, side effects, and more complex pharmacodynamic receptor-based neuropsychiatry.

A patient rarely comes to a psychiatrist without having a combination of psychiatric symptoms. Typically, clinicians screen patients and find that they often meet criteria for more than 1 Diagnostic and Statistical Manual of Mental Disorders Fourth Edition-Text Revision (DSM IV-TR) criteria.[1] At a minimum, the individual patient raises suspicion for various problem areas, even if they do not meet criteria for a specific disorder. In reviewing FDA guidelines, clinicians may quickly make simple decisions regarding treatment regimens that are more individualized based on these comorbidities and predominant symptoms. Of note, additional FDA approval or lack of approval for various indications does not necessarily mean that evidence does not support efficacy for other disorders. For example, the manufacturer may not have pursued FDA approval for other indications, or may have decided not to support randomized controlled trials to study another indication.

Single Indication

The first group of antidepressants approved by the FDA for the single indication of MDD include amitriptyline, citalopram, desipramine, desvenlafaxine, mirtazipine, nortriptyline, protriptyline, trazodone, trimipramine, vilazodone, and the monoamine oxidase inhibitor (MAOI) class.[2-4] Clinicians should know that these medications have only the 1 indication, and this clearly supports their use in MDD. However, many practitioners recognize that there are multiple other factors that allow these medications to be used in an off-label manner for various individuals. In a pure model, these antidepressants have regulatory data suggesting use only in patients with MDD but, as discussed, a lack of approval for other indications does not necessarily indicate a lack of supportive data or lack of efficacy.

Multiple Indications

Unlike those listed above, many antidepressants have other labeled or approved indications. These span a variety of comorbidities including anxiety disorders, seasonal affective disorder, sleep disorders, pain disorders, premenstrual dysphoric disorder, bulimia nervosa, and other miscellaneous indications. Given this, and assuming MDD is often complicated by comorbidity, let us evaluate a few comorbidities where data-driven decisions may help in individualizing treatments in patients who are depressed and simultaneously experience other psychiatric conditions.

Posttraumatic Stress Disorder

Patients with posttraumatic stress disorder often have comorbid depression. Only 2 antidepressants, the selective serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, are approved for this indication.[2] Multiple other medications have been recognized as effective off-label treatments for posttraumatic stress disorder, however; these include amitriptyline, fluoxetine, fluvoxamine, imipramine, and venlafaxine.[5-7] If a patient presents with MDD and posttraumatic stress disorder, these antidepressants may be considered if necessary to achieve efficacy for both conditions.

Obsessive-Compulsive Disorder

Several medications are approved for obsessive-compulsive disorder, including the tricyclic antidepressant clomipramine, and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline.[2] Venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI),[8] and the SSRI citalopram have shown some promise in obsessive compulsive disorder,[9] but have not yet received that indication from the FDA.

Panic Disorder

The SSRIs fluoxetine, paroxetine, and sertraline are approved for treatment of panic disorder, as is the SNRI venlafaxine.[2,10] Other antidepressants with an evidence base for use that are not approved include the TCAs clomipramine and imipramine, and the SSRI fluvoxamine.[6]

Anxiety Disorders

Social anxiety disorder. The SSRIs paroxetine and sertraline, and the SNRI, venlafaxine extended-release (ER) have been approved for the treatment of social anxiety disorder.[2] The SSRI fluoxetine is sometimes used for treatment of social anxiety disorder.

Generalized anxiety disorder. Four antidepressants have been indicated for the treatment of generalized anxiety disorder. These include the SSRI escitalopram and paroxetine, and the SNRI duloxetine and venlafaxine ER.[2,11]

Insomnia

Although sleep difficulties are a nearly universal symptom of depression, few antidepressants have an official indication for insomnia. Doxepin, a TCA, is the sole antidepressant labeled with this indication, when it is used at subtherapeutic antidepressant doses of 3 to 6 mg per day.[12] However, clinicians often use sedating antidepressants to induce sleep in those patients with MDD and insomnia (Schwartz TL. Novel hypnotics: moving beyond positive allosteric modulation of the GABA-A receptor. Manuscript submitted). These medications include the TCA amitriptyline, the tetracyclic mirtazapine, and the serotonin modulator trazodone.

Pain Syndromes

Duloxetine, an SNRI, is the only antidepressant medication that has official indications for treatment of pain syndromes.[2,10] These include chronic musculoskeletal pain, neuropathic pain (diabetic neuropathy in particular), and fibromyalgia. Alternatively, many of the TCAs, as well as other SNRI, have been studied for the treatment of pain syndromes, primarily involving neuropathic or chronic pain conditions.[13,14] Amitriptyline also is often used for migraine headaches. Unfortunately these other medications have not received official indications for these psychosomatic comorbidities.

Attention-Deficit/Hyperactivity Disorder

Some antidepressants have shown promise for the treatment of attention-deficit/hyperactivity disorder, but not enough to warrant a specific FDA indication. Nonetheless, these medications are used for the treatment of attention-deficit/hyperactivity disorder, particularly in patients with substance use disorder. Bupropion, desipramine, imipramine, nortriptyline, and venlafaxine have some evidence base to support their use.[15-19]

Other Comorbid Considerations

Premenstrual dysphoric disorder. The SSRI fluoxetine, paroxetine, and sertraline have been FDA approved for the treatment of premenstrual dysphoric disorder.[2]

Smoking cessation. Many patients who receive mental health treatment are also addicted to nicotine. Bupropion SR has received the indication for nicotine addiction.[2] Nortriptyline also has been shown to be helpful for smoking cessation efforts, but has not received an official indication.[20]

Miscellaneous. Bupropion XL carries a specific indication for prophylaxis of seasonal affective disorder and often is used off-label for the treatment of bipolar depression.[19,21,22] Fluoxetine is indicated for treatment of bulimia nervosa and sometimes is used for the treatment of Raynaud’ phenomenon.[2,19,23] Venlafaxine and paroxetine have data supporting use for the treatment of vasomotor hot flashes.[24,25] Finally, imipramine may be used in the treatment of enuresis.[26]

Take-Home Point

Clinicians should be aware of FDA approvals and the evidence base supporting the use of antidepressants in patients with MDD, who are often complex and suffering with other medical and psychiatric comorbidities. Choosing agents with indications that match the patient’s comorbid symptoms is one way to tailor and individualize treatment to each patient.

Beyond the simplistic but labor-intensive role of delineating specific comorbidities and focusing on antidepressant indications, is the imperative to develop a more complex individualized antidepressant treatment plan. If it were as simple as following the FDA labels and simple algorithms to make decisions, then much psychiatric education could be eliminated. A review of antidepressant mechanisms of action will allow us to further distinguish these medications, thus allowing more individualized treatments for MDD.

SSRI Class

The first and most commonly prescribed class of antidepressant is the SSRI. At the most basic understanding, these medications increase serotonin in the synapse and function ultimately to down-regulate serotonin receptors. However, as the science behind these medications is further explored, there is much more to these agents. When looking at the SSRI class as a whole, and in comparison with other antidepressant classes, a few general characteristics can be considered. The SSRI medications as a group are thought of as having fewer side effects than most other classes of antidepressants, and particularly the older classes of drugs. The most common and clinically relevant consideration for these medications is the development of gastrointestinal upset, sexual side effects, and weight gain.[27] The following delineates some of the subtle differences for each medication in this class and describes the benefits and drawbacks of treatment with each to help refine treatment selection.

Citalopram. Citalopram is one of the most widely used antidepressants today, and has a few properties that make it desirable. The medication has a long half-life of 23-45 hours, second only to fluoxetine,[2] and it is typically well tolerated in medically ill patients and the elderly.[19,28] Citalopram has weak H1 receptor antihistamine properties, and these properties provide anxiolytic and positively sedating effects.[27] Citalopram is made up of 2 mirror image enantiomers, each of which have different properties [27] that may lead to some inconsistencies in the property or function of the medication at lower doses. Citalopram is a weak inhibitor of CYP 2D6, with minimal drug-drug interactions.[30] Finally, recent FDA warnings have changed prescribing practices of this medication because of potential QTc prolongation at daily doses higher than 40 mg[29]; daily doses of 60 mg should no longer be used.

Benefits.Citalopram is a well-tolerated medication with mild antihistamine effects that may help with insomnia or mild anxieties. The longer half-life results in less withdrawal or discontinuation side effects.[31]

Drawbacks.Structural enantiomers result in this medication having less predictable effects at lower doses, and higher doses are contrary to FDA recommendations related to the potential for QTc prolongation. It has fewer FDA approvals for comorbid psychiatric disorders than other drugs in the SSRI class; as discussed earlier, this may simply reflect the manufacturer’s failure to seek approval for other indications.

Escitalopram. In contrast to the parent drug citalopram, escitalopram is separated and includes only the left enantiomer.[27] This results in the removal of much of the antihistamine and CYP 2D6 inhibitory properties.[19,27] It also results in more effective and predictable dose responses of the medication at the lower doses.

Benefits.Escitalopram has the benefit of better tolerability with less drug interactions. It may have less sedating effects, and is approved for generalized anxiety disorder as well as MDD.[2]

Drawbacks.Currently this is the only SSRI still on patent, and is thus more expensive than other, generic SSRI.

Fluoxetine. The first member of the SSRI class, fluoxetine has a few characteristics that make it desirable. Fluoxetine has mild serotonin 2C receptor antagonistic actions. This may result in the disinhibition of dopamine and norepinephrine release to the prefrontal cortex, which likely helps to improve concentration, energy, and executive functioning.[19,27] Furthermore, the serotonin 2C effects of this medication may contribute to the initial anorexic and ongoing anti-bulimic effects of this medication.[27] More recently, the effects of fluoxetine on the serotonin system have been combined with those of olanzapine, a second-generation antipsychotic, for the treatment of depression in patients with bipolar disorder and for treatment resistant unipolar depression.[19,27] Fluoxetine also may be a mild norepinephrine reuptake inhibitor, particularly at higher doses.

Fluoxetine significantly affects CYP 2D6 and 3A4 inhibition, and thus is highly likely to interact with other medications.[19,27] Finally, this medication has the longest half-life of the SSRIs, at 2-3 days, with an active metabolite that exists for 2 weeks.[2]

Benefits.Fluoxetine has action at the serotonin 2C receptor, and may affect norepinephrine levels at higher doses. The drug has the longest half-life among the SSRI, making it least likely to cause withdrawal. It is available as a once weekly dosing formulation and is approved for MDD, panic disorder, premenstrual dysphoric disorder, obsessive compulsive disorder, and bulimia nervosa.[2] It also has positive combination effects with the second generation antipsychotic olanzapine, and a combination formulation has been approved by the FDA for treating treatment-resistant and bipolar depression.*[19]

Drawbacks.The medication is likely to be activating in some patients, making it a more difficult option for those with insomnia, agitation, and intense anxiety.[19,27] Slower dose titration is warranted in these cases. Fluoxetine has a high degree of CYP 2D6 inhibition, resulting in significant drug-drug interactions.[19]

*Multiple trials of other second generation antipsychotics combined with various antidepressants including SSRI and SNRI have shown antidepressant efficacy for these combinations in patients with refractory depression.[32]

Paroxetine. The action of paroxetine is more complex than the previously described SSRI medications. In addition to serotonin reuptake inhibition, paroxetine functions with mild anticholinergic properties, mild norepinephrine reuptake inhibition (NRI), inhibition of nitric oxide synthetase, and potent inhibition of CYP 2D6 (similar to fluoxetine).[19,27] It has anticholinergic and antihistaminergic properties that may lend to its being calming and sedating, but also may increase dry mouth, blurred vision, and short term memory problems.[19,27] The NRI effects of the medication may contribute to clinical effectiveness. The effects on nitric oxide synthetase may cause sexual dysfunction.

Benefits.In addition to major depression, paroxetine is approved for various anxiety disorders, with possible calming/sedating effects. It is available in immediate- and slow-release preparations.

Drawbacks.Paroxetine has the potential for anticholinergic side effects[31] Its shorter half-life may result in more and more severe withdrawal side effects than other SSRI; paroxetine is also most strongly associated with weight changes, compared with other SSRI.[2] This medication also has a higher drug-drug interaction probability.

Sertraline. This SSRI may have dual mechanisms that distinguish it from other SSRIs. At higher doses, it acts as both a dopamine transporter inhibitor and a sigma 1 receptor binder.[27] The effects of dopamine transporter inhibition may result in improved energy, motivation, and concentration. Sigma 1 implications are not yet well understood, but some hypothetical benefit is attributed to their mild anxiolytic effects in psychotic and delusional depressions.[27]

Benefits.Sertraline is approved for MDD, many anxiety disorders, eating disorders, and premenstrual dysphoric disorder.[2] This medication has very little CYP 2D6 inhibition and therefore few drug-drug interactions.[19] It has a moderate half-life and thus the possibility of some withdrawal symptoms.

Drawbacks.Sertraline can be activating in patients with anxiety disorders, which may require slowly titrating doses; it is often associated with gastrointestinal distress.

Take-Home Point

The SSRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. However, a pharmacodynamic look into their wider mechanisms of action may suggest that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

SNRI Class

The next most common class of medications used for the treatment of MDD is the SNRI. This group of medications has a dual mechanism of action, increasing synaptic norepinephrine as well as serotonin.[19,27] In addition to increasing norepinephrine and serotonin levels throughout the brain, these medications may also boost dopamine in the prefrontal cortex, resulting in additional benefits.[27] In the prefrontal cortex, no dopamine transporters are there to recycle dopamine out of the synapse. Typically norepinephrine transporters remove dopamine in these areas, but with the inhibition of these, the dopamine effect in the dorsal lateral prefrontal cortex is more robust.[27] This activation in the brain has been correlated with antidepressant effects.

On the other hand, as the additional norepinephrine boost is added to the brain, it is not contained there. Norepinephrine effects are seen throughout the body, including the spinal cord, peripheral autonomic nervous system, heart, and bladder.[19,27] In the spinal cord this may reduce pain, but may also lead to side effects such as tremor, motor activation, and increased blood pressure and heart rate.[27] Also, these effects may allow a pseudo-anticholinergic effect resulting in such things as dry mouth, constipation, and urinary retention. However, these norepinephrine-related side effects do not rival those of the tricyclic antidepressant class.[31] Generally, the SNRIs are well tolerated, but the subtle increase in side effect burden needs to be considered.

Venlafaxine. Venlafaxine was the first SNRI and was initially approved in an immediate-release preparation. This medication is a substrate of CYP 2D6, and is converted into desvenlafaxine, an SNRI that was developed subsequently.[19,27] Unfortunately, the absorption of immediate-release venlafaxine is rapid, affording it remarkable side effects; this has been mitigated with an extended-release formulation that appears to be much better tolerated in practice. The medication also has a unique character, causing a varying ratio of serotonin to norepinephrine effects.[19,27] At low doses, there are fewer NRI properties (and more SRI properties) available and only at higher doses do the norepinephrine transporter inhibition properties increase more robustly.

Benefits.Compared with the SSRI, this medication has effects at both serotonin and norepinephrine receptors leading to its antidepressant effectiveness. The medication is very effective in the treatment of anxiety disorders, with multiple approved uses, likely comparable to sertraline and paroxetine.[2]

Drawbacks.The norepinephrine effects of the medication are much more robust only at higher doses and must be titrated. The medication has a short half-life resulting in many withdrawal side effects. There may be higher rates of nausea and dry mouth in comparison to some other antidepressants.[31] This medication may cause hypertension in some patients, and thus, blood pressure should be monitored.[19]

Desvenlafaxine. Desvenlafaxine is the active metabolite of venlafaxine,[19] and has the added benefit of a greater effect on norepinephrine transporter inhibition than its precursor at the initial dose levels. However, the effects on norepinephrine are less than those on serotonin.[27] Because it is the active metabolite of venlafaxine, it is less subjected to the genetic and drug-induced differences of CYP 2D6, which allows more consistent plasma levels of the medication.[27] It may be one of the “cleanest” antidepressant medications, given its extremely low vulnerability to cytochrome P450 metabolism, renal excretion, and low protein binding. The role of desvenlafaxine in the regulation of vasomotor symptoms (night sweats, hot flashes, insomnia, and related depression) in perimenopausal women is being investigated.[27]

Benefits.Although similar to extended-release venlafaxine, desvenlafaxine has a more balanced ratio of norepinephrine/serotonin properties, and it has one of the most favorable drug-drug interaction profiles.

Drawbacks.This medication has a short half-life and significant withdrawal side effects.[31]

Duloxetine. Duloxetine is unique among the SNRI class of drugs because, in addition to MDD, it is approved for treating a variety of pain syndromes.[2] This is related to the SNRI effect on the descending spinal norepinephrine pathways that reduce afferent pain fiber activity.[27] The increase in norepinephrine activity in spinal areas results in less thalamic input to the sensory cortex and therefore less perceived pain. The norepinephrine-facilitating effects in the prefrontal cortex also may show some benefit in treatment of cognitive symptoms prevalent in geriatric depression.[27]. Compared with venlafaxine, duloxetine has a lower incidence of treatment-related hypertension and milder withdrawal reactions. It is approved for MDD, generalized anxiety disorder, musculoskeletal pain, neuropathic pain, and fibromyalgia-related pain.[2]

Benefits.One of the only antidepressants approved for management of pain syndromes, duloxetine also has a more balanced norepinephrine to serotonin ratio at its initial doses.[28]

Drawbacks.Duloxetine is a mild to moderate CYP 2D6 inhibitor, which results in some drug-drug interactions.[19] In addition, it should not be used in alcoholic patients or those with renal and/or liver impairment.

Take-Home Point

The SNRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. As with the SSRI, a pharmacodynamic look into their wider mechanisms of action suggests that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This is clear when one considers the diverse FDA approvals for each and different potencies related to facilitating distinct ratios of serotonin to norepinephrine transporter inhibition. Again, this type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

TCA Class

This class is one of the oldest and still highly utilized classes of antidepressant in the history of psychopharmacology, and includes amitriptyline, imipramine, clomipramine, desipramine, trimipramine, and nortriptyline. The TCAs are often overlooked because of their relatively high level of side effects when compared with other classes of antidepressant, and because of high lethality in overdose. The TCAs have significant effects on the norepinephrine, serotonin, and to some extent dopamine activity in the brain.[19,27] The higher incidence of side effects are likely mediated through blockade of anticholinergic receptors (M1/M3), histamine receptors (H1), alpha 1 adrenergic receptors, and voltage-sensitive sodium channels.[19,27] Histamine blockade causes sedation and weight gain. Muscarinic blockade causes dry mouth, blurred vision, urinary retention, and constipation. Alpha 1 blockade causes orthostatic hypotension and dizziness. Sodium channel blockade affects the heart significantly, resulting in arrhythmias and conduction changes at higher doses.[27] This latter side effect results in significant risk of successful suicide with overdose, and renders TCAs difficult to use in medically comorbid patients.

Benefits.Overall, TCAs are very effective antidepressants. Indeed, early studies comparing TCA with SSRI medications found significantly higher remission rates with TCA than with SSRI in depressed, endogenous and inpatients samples.[33-36] However, in less severely depressed patients, there is not conclusive evidence of benefit of either class of antidepressant over another. Off-label, the use of TCAs in the treatment of pain, enuresis, and insomnia is widespread.[19] Availability of plasma level monitoring helps to guarantee therapeutic trials while minimizing toxicity.

Drawbacks.The significant adverse event profile causes an array of side effects that are often poorly tolerated and lead to medication noncompliance. Because of cardiac side effects, TCAs carry significant risk of death with overdose.

MAOI Class

This class of antidepressants has its own unique mechanism of action. MAOI has fallen into the realm of rarely used antidepressants in modern day psychopharmacology. This is related to the risks and side effects inherent to MAOI use. On the other hand, MAOI are among the most clinically powerful classes of antidepressant treatments. This class interferes with MAO enzyme subtypes A and B. The inhibition of these enzymes results in higher levels of serotonin and norepinephrine due to reduced catabolism of these neurotransmitters.[27] Moreover, by specifically lowering MAO-B activity, dopamine levels in the brain increase as well. Thus, all 3 monoamine neurotransmitter levels are robustly increased, which, in turn, affects a broad array of depressive symptoms.

The use of these medications may come at the cost of difficulty in using them. The most well-known drawback is that patients need to maintain a specific diet that is free of high tyramine foods, or risk the likelihood of hypertensive crisis related to the acute elevation of systemic norepinephrine, which also may result in stroke.[19,27] Foods to be avoided include tap beers, smoked meat or fish, fava beans, aged cheeses, sauerkraut, and soy. However, certain beers, wines, and cheeses are not contraindicated. These items need to be researched and discussed prior to starting a patient on the medication.

Drug-drug interactions are plentiful; combining an MAOI with other norepinephrine medications may increase blood pressure, and combining with a serotonin-based medication can cause serotonin syndrome.[19,27] Patients are also advised to avoid decongestants, stimulants, antidepressants, certain opioids, and appetite suppressants.[19,27]

The MAOI tranylcypromine may act similarly to an amphetamine in the frontal cortex, affording it some additional benefits.[27] Likewise, selegiline also involves breakdown into an amphetamine metabolite. Selegiline is more often used for Parkinson disease than depression.

Benefits.MAOIs are recognized as among the most potent of antidepressants in monotherapy, with effects on serotonin, dopamine, and norepinephrine. This class of antidepressant is often used for the patient who is refractory to other antidepressant trials.

Drawbacks.The MAOIs are associated with risks of hypertensive crisis and serotonin syndrome. There is a need to maintain a tyramine free diet except when using the low dose transdermal selegiline. Because of potential for drug-drug interactions, careful, ongoing monitoring of all additional medications (including over-the-counter medications) is essential.

Miscellaneous Antidepressants

Several other well-known antidepressant medications do not fit discretely into the 4 main antidepressant classes. Each has unique mechanisms that will be discussed similarly below.

Bupropion. This norepinephrine-dopamine receptor inhibitor (NDRI) medication is of particular use in a few subsets of patients. As the class name indicates, bupropion facilitates effects on norepinephrine and dopamine, blocking norepinephrine transporter and dopamine transporter activity at a moderate level, likely in the frontal cortex.[27] The unique properties of bupropion as an antidepressant may be related to its lack of serotonin activity. It is approved for smoking cessation and is used off-label to reduce craving for substances of abuse. Clinicians contend that the dopamine actions of this medication help to improve the loss of positive affect in MDD. Thus, it effectively increases joy, interest, pleasure, energy, enthusiasm, alertness, and self-confidence.[27] The norepinephrine and dopamine facilitation helps patients with attention-deficit/hyperactivity disorder as well.[19]

Several cases of psychosis and paranoia have been reported in patients taking bupropion, likely related to the dopamine effects of the drug.[37] Limited data suggest that this medication, like all antidepressants, may activate depressed patients with bipolar disorder, causing manic episodes. However, it is widely accepted that bupropion and the SSRI class may be less likely to activate mania compared with the TCA class of medications. Because it does not act on serotonin, this is one of the few antidepressants that does not cause sexual side effects or weight gain.[19,27] The medication is uniquely approved for the treatment of seasonal affective disorder.[2]

Benefits.Bupropion is indicated for the treatment of MDD, seasonal affective disorder, and nicotine dependence. It has very low sexual and weight gain side effect liability.

Drawbacks.There is limited serotonin activity with bupropion and less evidence for the treatment of anxiety. Bupropion lowers the seizure threshold in patients predisposed to these events (including patients with eating disorders and those with epilepsy).

Trazodone. Trazodone is a serotonin antagonist/reuptake inhibitor (SARI). It blocks serotonin 2A and 2C receptors and also acts as a mild serotonin reuptake inhibitor.[19,27] This medication typically is used at lower doses because of its properties as a strong antihistamine (H1) and alpha-1 adrenergic blocking medication. The blockade of these receptors causes significant sedation, which may help with insomnia, but may cause excessive somnolence and dizziness in the daytime. The blockade of serotonin also may explain trazodone’s properties as a hypnotic, providing more efficient sleep.[27] Although higher doses of this medication provide excellent benefit related to the synergistic effects of blocking serotonin 2A and 2C and by acting as a serotonin reuptake inhibitor, this medication is not typically given in full divided doses because of excessive side effects.[19,27] A new slow-release preparation has been approved to allow a better tolerated, full dose range.

Benefits.Trazodone is often called a sedating antidepressant. It helps insomnia, improves sleep efficiency, and has its action even at low doses. Sexual side effects and activating side effects are low.[19,27]

Drawbacks. Significant sedation may limit its use.

Mirtazapine. This medication is also considered to be sedating and is typically either avoided or sought because of its side effect profile. Side effects include sedation/hypnotic effects and appetite stimulation, but not sexual side effects. The lack of sexual side effects is again related to serotonin in that mirtazapine is not a serotonin reuptake inhibitor, but in this case acts as a serotonin 2A/2C receptor antagonist.[19,27] The blockade of these receptors may result in more dopamine and norepinephrine release in the prefrontal cortex. The histamine blockade (H1) results in sedation, anxiolytic/hypnotic effects, and weight gain.[19,27] Mirtazapine also acts as a 5HT3 receptor antagonist, resulting in reduction of gastrointestinal problems.[19,27] The primary mechanism of antidepressant action is through alpha 2/norepinephrine receptor antagonism. Through this antagonism, inhibition of norepinephrine is disinhibited through auto receptor blockade. This allows downstream effects on several pathways and may result in overall release of serotonin and norepinephrine. This effect can often be combined with an SNRI to obtain synergistic effects.[27]

Benefits.Mirtazapine has many unique mechanisms of actions that make it beneficial in particular populations. It lacks sexual side effects, reduces gastrointestinal upset, and is not activating. The sedating qualities of this medication are typically used to the medication’s and the patient’s benefit.

Drawbacks.Mirtazapine has significant weight gain/appetite stimulation effects, which could lead to metabolic disorders.

This review is both practical and factual. Clinicians ideally should be aware of regulatory approvals and appropriate use of them in certain patient populations. When used this way, clinicians may expect results comparable to those noted in the evidence base of regulatory trials. However, those who treat patients understand that not all are identical to those enrolled in research trials. What follows will provide some practical clinical approaches when responses do not meet expectations.

As noted, only one third of patients will fully remit on their first antidepressant trial.[38] These numbers hold true for patients who are fully treated with moderate to high dose SSRI for as long as 12 weeks. In clinical practice, patients may not even have such a rigorous dosing profile and failure rates are likely higher. What approaches should be taken when a patient is not responding to treatment?

Adherence and Dosing

First, ask and attempt to ensure adherence to the antidepressant treatment. This questioning should be nonjudgmental and empathic, as most patients will likely say they are compliant even when they are not. Oftentimes suggesting that most people tend to naturally miss a few doses and that you as the clinician are just checking up will diffuse the situation. As dosing becomes divided throughout the day and polypharmacy increases, compliance usually diminishes, making assessment for compliance and adherence to medical regimens even more important.

Tolerability

An important area to address to improve adherence to a regimen relates to side effects and antidepressant tolerability. Sometimes patients cease taking their antidepressant or fail to escalate the dose as advised when adverse effects are not well tolerated. Many mild side effects will dissipate over time and this should be discussed directly with the patient.[39] Patients should be instructed to inform prescribers of any moderate to severe side effects and the drug can then be safely stopped. Patients should also be told that there are many antidepressants, and these have different side effects.[2,39] For example, SSRI, SNRI, and NDRI may be activating, and thus cause insomnia or nervousness upon initiation of treatment. Patients may be switched to a less activating SARI or noradrenergic antagonist-selective serotonin antagonist mechanism-based product, as these tend to be less activating and more sedating.[2]

Some patients may experience drug-drug interactions depending upon their genetic make-up.[2] Switching away from hepatic inhibiting medications towards medications that are less likely to interact with other drugs may be warranted. Typical side effects of headaches, stomachaches, or even insomnia often can be treated very effectively with over the counter or prescription medications. Later onset side effects such as weight gain or sexual dysfunction may be more difficult to mitigate or treat. Open discussions with patients about these longer term risks are warranted because patients often have to stay on their antidepressants for a year or more to maintain remission and avoid a depressive relapse.[38] Because certain antidepressants may have a more, or less favorable weight or sexual side effect profile, they should be chosen based on a discussion about patient preference when possible.

Assuming adherence is adequate, the next step is to confirm that the antidepressant dose was at the moderate to high end of the approved range and has been taken for at least 4 to 6 weeks. If dosing is confirmed to be reasonable, consider a final maximization of dose or switch to a new antidepressant monotherapy.[39]

Switching Monotherapies

If it is necessary to consider switching monotherapies, no clear benefit has been attributed to any particular strategy.[38] Many experts agree, however, that a switch away from an SSRI is warranted if the fully dosed SSRI therapy has failed to improve the patient’s symptoms.[27,39] The theoretical implication is that the patient’s current depressive symptoms have been treated with aggressive serotonergic facilitation and that repeating this mechanism may not be fruitful. This suggests that, pharmacodynamically, the depression may not be entirely serotonin-based in regards to its etiology.[27,39] Given this, a cross titration on to an SNRI such as venlafaxine XR or duloxetine, a NDRI such as bupropion XL, a noradrenergic antagonist-selective serotonin antagonist such as mirtazapine, or a more aggressive serotonergic facilitating agent like a SARI such as trazodone ER or a serotonin partial agonist-reuptake inhibitor such as vilazodone theoretically may be warranted.[2]

One final concern regarding switching involves the use of generic vs brand-name drugs. The FDA ensures that the bioavailability between a brand name and its generic counterpart is approximately between 20% weaker and 20% stronger.[40,41] Most generics are highly comparable, but occasionally when a patient actually changes from one generic to another, the bioavailability could change from a 20% stronger to a 20% weaker generic drug and symptom relapse may occur. By contrast, going from a weaker to a stronger generic might actually improve depression outcomes but may also create new-onset side effects after months of stable treatment as the newer generic preparation is more potent, raising blood levels higher than previously. These types of events should be monitored and dosing adjusted as needed.

Finally, a generic drug may possess a different slow-release mechanism compared with the parent brand-name drug. Oftentimes the generic, despite being a slow-release drug itself may actually release active drug more quickly than the original brand’s slow-release technology. There may be no evidence of a clinical problem; however, some patients may develop side effects when taking the faster release preparation. In this case, the dose may need to be lowered while monitoring for relapse or a switch back to the brand-name slow-release product may be warranted.

In conclusion, this article seeks to identify treatments that match patients with MDD and their common comorbidities, as a first line approach to MDD management. Secondarily and more theoretically, patients’ MDD symptoms may be effectively treated if clinicians are aware of the neurotransmitters and receptors that each antidepressant modulates. Finally, patients may suffer issues with nonefficacy, noncompliance, and tolerability. Each patient is unique and these clinical situations may interfere with optimal depression outcomes. Each patient must be educated and given informed consent about the myriad effective antidepressant treatment options available.

Supported by an independent educational grant from Valeant Pharmaceuticals.

References:

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association; 2000.
  2. Stahl SM. Essential Psychopharmacology: The Prescriber’s Guide. Cambridge, Mass: Cambridge University Press; 2005.
  3. FDA Package Insert. Pristiq. Pfizer Inc. 2011.
  4. FDA Package Insert. Viibryd. Forest Laboratories, Inc. 2011.
  5. Davidson J, Baldwin D, Stein DJet al.Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry. 2006;63:1158-1165. Abstract
  6. Bandelow B, Zohar J, Hollander E, et al. World federation of societies of biological psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders — first revision. World J Biol Psychiatry. 2008;9:248-312. Abstract
  7. Benedek DM, Friedman MJ, Zatzick D, et al. Guideline watch (March 2009): practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder.
  8. Phelps NJ, Cates ME, The role of venlafaxine in the treatment of obsessive-compulsive disorder. Ann Pharmacother. 2005;39:136-140. Abstract
  9. Gartlehner G, Hansen RA, Reichenpfader U, et al. Drug class review: second-generation antidepressants: final update 5 report [internet].Portland, Ore: Oregon Health & Science University; March 2011.
  10. Effexor Prescribing Information. http://labeling.pfizer.com/showlabeling.aspx?id=100
  11. FDA Package Insert. Cymbalta. Lilly USA LLC. 2004/2011.
  12. FDA Package Insert. Silenor. Somaxon Pharmaceuticals Inc. 1969.
  13. Hsu, ES. Acute and chronic pain management in fibromyalgia: updates on pharmacotherapy. Am J Ther. 2011;18:487-509. Abstract
  14. Verdu B, Decosterd I, Buclin T, et al. Antidepressants for the treatment of chronic pain. Drugs. 2008;68:2611-2632. Abstract
  15. Prince JB, Wilens TE, Biederman J, et al. A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 2000;10:193-204. Abstract
  16. Pliszka SR. Non-stimulant treatment of attention-deficit/hyperactivity disorder. CNS Spectr. 2003;8:253-258. Abstract
  17. Wilens TE, Prince JB, Spencer T, et al, An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity disorder and bipolar disorder. Biol Psychiatry. 2003;54:9-16. Abstract
  18. Olvera RL, Pliszka SR, Luh J, et al. An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol. 1996;6:241-250. Abstract
  19. Sadock BJ, Sadock VA, et al. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Tenth ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2007:977-1126.
  20. Prochazka AV, Kick S, Steinbrunn C, et al. A randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation. Arch Intern Med. 2004;164:2229-2233. Abstract
  21. FDA Package Insert. Wellbutrin XL. GlaxoSmithKline. 2008.
  22. McIntyre RS, Mancini DA, McCann S, et al, Topiramate versus bupropion SR when added to mood stabilizer therapy fpr the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord. 2002;4:207-213. Abstract
  23. Coleiro B, Marshall SE, Denton CP, et al. Treatment of raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology. 2001;40:1038-1043. Abstract
  24. Stearns V, Beebe KL, Iyengar M, et al. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289:2827-2834. Abstract
  25. Evans ML, Pritts E, Vittinghoff E, et al. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005;105:161-166. Abstract
  26. Muller D, Roehr CC, Eggert P. Comparative tolerability of drug treatment for nocturnal enuresis in children. Drug Saf. 2004;27:717-727. Abstract
  27. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. Cambridge, Mass: Cambridge University Press; 2008:511-666.
  28. Spina E, Scordo MG. clinically significant drug interactions with antidepressants in the elderly. Drugs Aging. 2002;19:299-320. Abstract
  29. FDA Packet Insert. Celexa. Forest Laboratories, Inc. 2010/2011.
  30. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30:1206-1227. Abstract
  31. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758. Abstract
  32. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980-991. Abstract
  33. Danish University Antidepressant Group. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology (Berl). 1986;90:131-138. Abstract
  34. Danish University Antidepressant Group.Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Disord. 1990;18:289-299. Abstract
  35. Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry. 1994;151:1735-1739. Abstract
  36. Beasley CM Jr, Holman SL, Potvin JH. Fluoxetine compared with imipramine in the treatment of inpatient depression. A multicenter trial. Ann Clin Psychiatry. 1993;5:199-207. Abstract
  37. Bailey J. Acute psychosis after bupropion treatment in a healthy 28-year-old woman. J Am Board Fam Med. 2008;21:244.
  38. Rush AJ, Trivedi MH, Wisnewlski Sr, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163:1905-1917. Abstract
  39. Zajecka JM, Goldstein C. Combining medication to achieve remission. In: Schwartz T, Petersen T, eds. Depression: Treatment Strategies and Management. 2nd ed. New York: Informa; 2009.
  40. Park K, ed. Controlled Drug Delivery: Challenges and Strategies. Washington, DC: American Chemical Society; 1997.
  41. Orange book annual preface, statistical criteria for bioequivalence. In: Approved Drug Products with Therapeutic Equivalence Evaluations. 29th ed. US Food and Drug Administration Center for Drug Evaluation and Research; 2009-06-18, update 3-01-11. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.htm

Retrieved from:

Tailoring Antidepressant Treatment: Factors to Individualize Medication Selection Thomas L. Schwartz, MD; Daniel Uderitz, MD

In the realm of psychopharmacology, we often declare medications within their respective therapeutic classes as being equal. This is a byproduct related to the way medications achieve their indications for treatment for specific psychiatric disorders. In the case of antidepressant treatments, the US Food and Drug Administration (FDA) indicates that if a study can obtain a majority of patients improved by 50% compared with placebo, then a drug may become an antidepressant treatment. There are no standards for differentiating antidepressant treatments beyond this. Clinicians often note that all antidepressant treatments are not created equal, especially when applied to clinical situations and patients who are often complex and have comorbid conditions. The goal of this article is to sort out regimens that may convey certain advantages during the treatment in an individualized manner. This involves conceptualizing and utilizing monotherapies, combination therapies, and adjunctive treatments.

Monotherapies

The first-line treatment of patients with major depressive disorder (MDD) should start with an aggressive monotherapy. This occurs in clinical practice and is supported by many guidelines and reviews. The various antidepressant medications have unique properties that can be used to individualize treatments. Most psychiatrists can easily name their “favorite” antidepressant to use in certain situations. This is sometimes based on a simple bias, but often has evidence to back up clinical practice. Let us start with the mechanistically simple and move toward more complex ways to think about these medications. This includes thinking about FDA approvals, available guidelines, comorbidities, side effects, and more complex pharmacodynamic receptor-based neuropsychiatry.

A patient rarely comes to a psychiatrist without having a combination of psychiatric symptoms. Typically, clinicians screen patients and find that they often meet criteria for more than 1 Diagnostic and Statistical Manual of Mental Disorders Fourth Edition-Text Revision (DSM IV-TR) criteria.[1] At a minimum, the individual patient raises suspicion for various problem areas, even if they do not meet criteria for a specific disorder. In reviewing FDA guidelines, clinicians may quickly make simple decisions regarding treatment regimens that are more individualized based on these comorbidities and predominant symptoms. Of note, additional FDA approval or lack of approval for various indications does not necessarily mean that evidence does not support efficacy for other disorders. For example, the manufacturer may not have pursued FDA approval for other indications, or may have decided not to support randomized controlled trials to study another indication.

Single Indication

The first group of antidepressants approved by the FDA for the single indication of MDD include amitriptyline, citalopram, desipramine, desvenlafaxine, mirtazipine, nortriptyline, protriptyline, trazodone, trimipramine, vilazodone, and the monoamine oxidase inhibitor (MAOI) class.[2-4] Clinicians should know that these medications have only the 1 indication, and this clearly supports their use in MDD. However, many practitioners recognize that there are multiple other factors that allow these medications to be used in an off-label manner for various individuals. In a pure model, these antidepressants have regulatory data suggesting use only in patients with MDD but, as discussed, a lack of approval for other indications does not necessarily indicate a lack of supportive data or lack of efficacy.

Multiple Indications

Unlike those listed above, many antidepressants have other labeled or approved indications. These span a variety of comorbidities including anxiety disorders, seasonal affective disorder, sleep disorders, pain disorders, premenstrual dysphoric disorder, bulimia nervosa, and other miscellaneous indications. Given this, and assuming MDD is often complicated by comorbidity, let us evaluate a few comorbidities where data-driven decisions may help in individualizing treatments in patients who are depressed and simultaneously experience other psychiatric conditions.

Posttraumatic Stress Disorder

Patients with posttraumatic stress disorder often have comorbid depression. Only 2 antidepressants, the selective serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, are approved for this indication.[2] Multiple other medications have been recognized as effective off-label treatments for posttraumatic stress disorder, however; these include amitriptyline, fluoxetine, fluvoxamine, imipramine, and venlafaxine.[5-7] If a patient presents with MDD and posttraumatic stress disorder, these antidepressants may be considered if necessary to achieve efficacy for both conditions.

Obsessive-Compulsive Disorder

Several medications are approved for obsessive-compulsive disorder, including the tricyclic antidepressant clomipramine, and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline.[2] Venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI),[8] and the SSRI citalopram have shown some promise in obsessive compulsive disorder,[9] but have not yet received that indication from the FDA.

Panic Disorder

The SSRIs fluoxetine, paroxetine, and sertraline are approved for treatment of panic disorder, as is the SNRI venlafaxine.[2,10] Other antidepressants with an evidence base for use that are not approved include the TCAs clomipramine and imipramine, and the SSRI fluvoxamine.[6]

Anxiety Disorders

Social anxiety disorder. The SSRIs paroxetine and sertraline, and the SNRI, venlafaxine extended-release (ER) have been approved for the treatment of social anxiety disorder.[2] The SSRI fluoxetine is sometimes used for treatment of social anxiety disorder.

Generalized anxiety disorder. Four antidepressants have been indicated for the treatment of generalized anxiety disorder. These include the SSRI escitalopram and paroxetine, and the SNRI duloxetine and venlafaxine ER.[2,11]

Insomnia

Although sleep difficulties are a nearly universal symptom of depression, few antidepressants have an official indication for insomnia. Doxepin, a TCA, is the sole antidepressant labeled with this indication, when it is used at subtherapeutic antidepressant doses of 3 to 6 mg per day.[12] However, clinicians often use sedating antidepressants to induce sleep in those patients with MDD and insomnia (Schwartz TL. Novel hypnotics: moving beyond positive allosteric modulation of the GABA-A receptor. Manuscript submitted). These medications include the TCA amitriptyline, the tetracyclic mirtazapine, and the serotonin modulator trazodone.

Pain Syndromes

Duloxetine, an SNRI, is the only antidepressant medication that has official indications for treatment of pain syndromes.[2,10] These include chronic musculoskeletal pain, neuropathic pain (diabetic neuropathy in particular), and fibromyalgia. Alternatively, many of the TCAs, as well as other SNRI, have been studied for the treatment of pain syndromes, primarily involving neuropathic or chronic pain conditions.[13,14] Amitriptyline also is often used for migraine headaches. Unfortunately these other medications have not received official indications for these psychosomatic comorbidities.

Attention-Deficit/Hyperactivity Disorder

Some antidepressants have shown promise for the treatment of attention-deficit/hyperactivity disorder, but not enough to warrant a specific FDA indication. Nonetheless, these medications are used for the treatment of attention-deficit/hyperactivity disorder, particularly in patients with substance use disorder. Bupropion, desipramine, imipramine, nortriptyline, and venlafaxine have some evidence base to support their use.[15-19]

Other Comorbid Considerations

Premenstrual dysphoric disorder. The SSRI fluoxetine, paroxetine, and sertraline have been FDA approved for the treatment of premenstrual dysphoric disorder.[2]

Smoking cessation. Many patients who receive mental health treatment are also addicted to nicotine. Bupropion SR has received the indication for nicotine addiction.[2] Nortriptyline also has been shown to be helpful for smoking cessation efforts, but has not received an official indication.[20]

Miscellaneous. Bupropion XL carries a specific indication for prophylaxis of seasonal affective disorder and often is used off-label for the treatment of bipolar depression.[19,21,22] Fluoxetine is indicated for treatment of bulimia nervosa and sometimes is used for the treatment of Raynaud’ phenomenon.[2,19,23] Venlafaxine and paroxetine have data supporting use for the treatment of vasomotor hot flashes.[24,25] Finally, imipramine may be used in the treatment of enuresis.[26]

Take-Home Point

Clinicians should be aware of FDA approvals and the evidence base supporting the use of antidepressants in patients with MDD, who are often complex and suffering with other medical and psychiatric comorbidities. Choosing agents with indications that match the patient’s comorbid symptoms is one way to tailor and individualize treatment to each patient.

Beyond the simplistic but labor-intensive role of delineating specific comorbidities and focusing on antidepressant indications, is the imperative to develop a more complex individualized antidepressant treatment plan. If it were as simple as following the FDA labels and simple algorithms to make decisions, then much psychiatric education could be eliminated. A review of antidepressant mechanisms of action will allow us to further distinguish these medications, thus allowing more individualized treatments for MDD.

SSRI Class

The first and most commonly prescribed class of antidepressant is the SSRI. At the most basic understanding, these medications increase serotonin in the synapse and function ultimately to down-regulate serotonin receptors. However, as the science behind these medications is further explored, there is much more to these agents. When looking at the SSRI class as a whole, and in comparison with other antidepressant classes, a few general characteristics can be considered. The SSRI medications as a group are thought of as having fewer side effects than most other classes of antidepressants, and particularly the older classes of drugs. The most common and clinically relevant consideration for these medications is the development of gastrointestinal upset, sexual side effects, and weight gain.[27] The following delineates some of the subtle differences for each medication in this class and describes the benefits and drawbacks of treatment with each to help refine treatment selection.

Citalopram. Citalopram is one of the most widely used antidepressants today, and has a few properties that make it desirable. The medication has a long half-life of 23-45 hours, second only to fluoxetine,[2] and it is typically well tolerated in medically ill patients and the elderly.[19,28] Citalopram has weak H1 receptor antihistamine properties, and these properties provide anxiolytic and positively sedating effects.[27] Citalopram is made up of 2 mirror image enantiomers, each of which have different properties [27] that may lead to some inconsistencies in the property or function of the medication at lower doses. Citalopram is a weak inhibitor of CYP 2D6, with minimal drug-drug interactions.[30] Finally, recent FDA warnings have changed prescribing practices of this medication because of potential QTc prolongation at daily doses higher than 40 mg[29]; daily doses of 60 mg should no longer be used.

Benefits.Citalopram is a well-tolerated medication with mild antihistamine effects that may help with insomnia or mild anxieties. The longer half-life results in less withdrawal or discontinuation side effects.[31]

Drawbacks.Structural enantiomers result in this medication having less predictable effects at lower doses, and higher doses are contrary to FDA recommendations related to the potential for QTc prolongation. It has fewer FDA approvals for comorbid psychiatric disorders than other drugs in the SSRI class; as discussed earlier, this may simply reflect the manufacturer’s failure to seek approval for other indications.

Escitalopram. In contrast to the parent drug citalopram, escitalopram is separated and includes only the left enantiomer.[27] This results in the removal of much of the antihistamine and CYP 2D6 inhibitory properties.[19,27] It also results in more effective and predictable dose responses of the medication at the lower doses.

Benefits.Escitalopram has the benefit of better tolerability with less drug interactions. It may have less sedating effects, and is approved for generalized anxiety disorder as well as MDD.[2]

Drawbacks.Currently this is the only SSRI still on patent, and is thus more expensive than other, generic SSRI.

Fluoxetine. The first member of the SSRI class, fluoxetine has a few characteristics that make it desirable. Fluoxetine has mild serotonin 2C receptor antagonistic actions. This may result in the disinhibition of dopamine and norepinephrine release to the prefrontal cortex, which likely helps to improve concentration, energy, and executive functioning.[19,27] Furthermore, the serotonin 2C effects of this medication may contribute to the initial anorexic and ongoing anti-bulimic effects of this medication.[27] More recently, the effects of fluoxetine on the serotonin system have been combined with those of olanzapine, a second-generation antipsychotic, for the treatment of depression in patients with bipolar disorder and for treatment resistant unipolar depression.[19,27] Fluoxetine also may be a mild norepinephrine reuptake inhibitor, particularly at higher doses.

Fluoxetine significantly affects CYP 2D6 and 3A4 inhibition, and thus is highly likely to interact with other medications.[19,27] Finally, this medication has the longest half-life of the SSRIs, at 2-3 days, with an active metabolite that exists for 2 weeks.[2]

Benefits.Fluoxetine has action at the serotonin 2C receptor, and may affect norepinephrine levels at higher doses. The drug has the longest half-life among the SSRI, making it least likely to cause withdrawal. It is available as a once weekly dosing formulation and is approved for MDD, panic disorder, premenstrual dysphoric disorder, obsessive compulsive disorder, and bulimia nervosa.[2] It also has positive combination effects with the second generation antipsychotic olanzapine, and a combination formulation has been approved by the FDA for treating treatment-resistant and bipolar depression.*[19]

Drawbacks.The medication is likely to be activating in some patients, making it a more difficult option for those with insomnia, agitation, and intense anxiety.[19,27] Slower dose titration is warranted in these cases. Fluoxetine has a high degree of CYP 2D6 inhibition, resulting in significant drug-drug interactions.[19]

*Multiple trials of other second generation antipsychotics combined with various antidepressants including SSRI and SNRI have shown antidepressant efficacy for these combinations in patients with refractory depression.[32]

Paroxetine. The action of paroxetine is more complex than the previously described SSRI medications. In addition to serotonin reuptake inhibition, paroxetine functions with mild anticholinergic properties, mild norepinephrine reuptake inhibition (NRI), inhibition of nitric oxide synthetase, and potent inhibition of CYP 2D6 (similar to fluoxetine).[19,27] It has anticholinergic and antihistaminergic properties that may lend to its being calming and sedating, but also may increase dry mouth, blurred vision, and short term memory problems.[19,27] The NRI effects of the medication may contribute to clinical effectiveness. The effects on nitric oxide synthetase may cause sexual dysfunction.

Benefits.In addition to major depression, paroxetine is approved for various anxiety disorders, with possible calming/sedating effects. It is available in immediate- and slow-release preparations.

Drawbacks.Paroxetine has the potential for anticholinergic side effects[31] Its shorter half-life may result in more and more severe withdrawal side effects than other SSRI; paroxetine is also most strongly associated with weight changes, compared with other SSRI.[2] This medication also has a higher drug-drug interaction probability.

Sertraline. This SSRI may have dual mechanisms that distinguish it from other SSRIs. At higher doses, it acts as both a dopamine transporter inhibitor and a sigma 1 receptor binder.[27] The effects of dopamine transporter inhibition may result in improved energy, motivation, and concentration. Sigma 1 implications are not yet well understood, but some hypothetical benefit is attributed to their mild anxiolytic effects in psychotic and delusional depressions.[27]

Benefits.Sertraline is approved for MDD, many anxiety disorders, eating disorders, and premenstrual dysphoric disorder.[2] This medication has very little CYP 2D6 inhibition and therefore few drug-drug interactions.[19] It has a moderate half-life and thus the possibility of some withdrawal symptoms.

Drawbacks.Sertraline can be activating in patients with anxiety disorders, which may require slowly titrating doses; it is often associated with gastrointestinal distress.

Take-Home Point

The SSRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. However, a pharmacodynamic look into their wider mechanisms of action may suggest that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

SNRI Class

The next most common class of medications used for the treatment of MDD is the SNRI. This group of medications has a dual mechanism of action, increasing synaptic norepinephrine as well as serotonin.[19,27] In addition to increasing norepinephrine and serotonin levels throughout the brain, these medications may also boost dopamine in the prefrontal cortex, resulting in additional benefits.[27] In the prefrontal cortex, no dopamine transporters are there to recycle dopamine out of the synapse. Typically norepinephrine transporters remove dopamine in these areas, but with the inhibition of these, the dopamine effect in the dorsal lateral prefrontal cortex is more robust.[27] This activation in the brain has been correlated with antidepressant effects.

On the other hand, as the additional norepinephrine boost is added to the brain, it is not contained there. Norepinephrine effects are seen throughout the body, including the spinal cord, peripheral autonomic nervous system, heart, and bladder.[19,27] In the spinal cord this may reduce pain, but may also lead to side effects such as tremor, motor activation, and increased blood pressure and heart rate.[27] Also, these effects may allow a pseudo-anticholinergic effect resulting in such things as dry mouth, constipation, and urinary retention. However, these norepinephrine-related side effects do not rival those of the tricyclic antidepressant class.[31] Generally, the SNRIs are well tolerated, but the subtle increase in side effect burden needs to be considered.

Venlafaxine. Venlafaxine was the first SNRI and was initially approved in an immediate-release preparation. This medication is a substrate of CYP 2D6, and is converted into desvenlafaxine, an SNRI that was developed subsequently.[19,27] Unfortunately, the absorption of immediate-release venlafaxine is rapid, affording it remarkable side effects; this has been mitigated with an extended-release formulation that appears to be much better tolerated in practice. The medication also has a unique character, causing a varying ratio of serotonin to norepinephrine effects.[19,27] At low doses, there are fewer NRI properties (and more SRI properties) available and only at higher doses do the norepinephrine transporter inhibition properties increase more robustly.

Benefits.Compared with the SSRI, this medication has effects at both serotonin and norepinephrine receptors leading to its antidepressant effectiveness. The medication is very effective in the treatment of anxiety disorders, with multiple approved uses, likely comparable to sertraline and paroxetine.[2]

Drawbacks.The norepinephrine effects of the medication are much more robust only at higher doses and must be titrated. The medication has a short half-life resulting in many withdrawal side effects. There may be higher rates of nausea and dry mouth in comparison to some other antidepressants.[31] This medication may cause hypertension in some patients, and thus, blood pressure should be monitored.[19]

Desvenlafaxine. Desvenlafaxine is the active metabolite of venlafaxine,[19] and has the added benefit of a greater effect on norepinephrine transporter inhibition than its precursor at the initial dose levels. However, the effects on norepinephrine are less than those on serotonin.[27] Because it is the active metabolite of venlafaxine, it is less subjected to the genetic and drug-induced differences of CYP 2D6, which allows more consistent plasma levels of the medication.[27] It may be one of the “cleanest” antidepressant medications, given its extremely low vulnerability to cytochrome P450 metabolism, renal excretion, and low protein binding. The role of desvenlafaxine in the regulation of vasomotor symptoms (night sweats, hot flashes, insomnia, and related depression) in perimenopausal women is being investigated.[27]

Benefits.Although similar to extended-release venlafaxine, desvenlafaxine has a more balanced ratio of norepinephrine/serotonin properties, and it has one of the most favorable drug-drug interaction profiles.

Drawbacks.This medication has a short half-life and significant withdrawal side effects.[31]

Duloxetine. Duloxetine is unique among the SNRI class of drugs because, in addition to MDD, it is approved for treating a variety of pain syndromes.[2] This is related to the SNRI effect on the descending spinal norepinephrine pathways that reduce afferent pain fiber activity.[27] The increase in norepinephrine activity in spinal areas results in less thalamic input to the sensory cortex and therefore less perceived pain. The norepinephrine-facilitating effects in the prefrontal cortex also may show some benefit in treatment of cognitive symptoms prevalent in geriatric depression.[27]. Compared with venlafaxine, duloxetine has a lower incidence of treatment-related hypertension and milder withdrawal reactions. It is approved for MDD, generalized anxiety disorder, musculoskeletal pain, neuropathic pain, and fibromyalgia-related pain.[2]

Benefits.One of the only antidepressants approved for management of pain syndromes, duloxetine also has a more balanced norepinephrine to serotonin ratio at its initial doses.[28]

Drawbacks.Duloxetine is a mild to moderate CYP 2D6 inhibitor, which results in some drug-drug interactions.[19] In addition, it should not be used in alcoholic patients or those with renal and/or liver impairment.

Take-Home Point

The SNRI class is considered a homogeneous class of antidepressants because all are held to the same standard of passing FDA regulatory norms. As with the SSRI, a pharmacodynamic look into their wider mechanisms of action suggests that each drug is actually different in ways that may foster unique advantages or disadvantages for any given patient. This is clear when one considers the diverse FDA approvals for each and different potencies related to facilitating distinct ratios of serotonin to norepinephrine transporter inhibition. Again, this type of finding would not be apparent in a typical 300-subject regulatory trial, but is often noted in clinical practice, where the sample size comprises the one unique subject that the clinician is treating.

TCA Class

This class is one of the oldest and still highly utilized classes of antidepressant in the history of psychopharmacology, and includes amitriptyline, imipramine, clomipramine, desipramine, trimipramine, and nortriptyline. The TCAs are often overlooked because of their relatively high level of side effects when compared with other classes of antidepressant, and because of high lethality in overdose. The TCAs have significant effects on the norepinephrine, serotonin, and to some extent dopamine activity in the brain.[19,27] The higher incidence of side effects are likely mediated through blockade of anticholinergic receptors (M1/M3), histamine receptors (H1), alpha 1 adrenergic receptors, and voltage-sensitive sodium channels.[19,27] Histamine blockade causes sedation and weight gain. Muscarinic blockade causes dry mouth, blurred vision, urinary retention, and constipation. Alpha 1 blockade causes orthostatic hypotension and dizziness. Sodium channel blockade affects the heart significantly, resulting in arrhythmias and conduction changes at higher doses.[27] This latter side effect results in significant risk of successful suicide with overdose, and renders TCAs difficult to use in medically comorbid patients.

Benefits.Overall, TCAs are very effective antidepressants. Indeed, early studies comparing TCA with SSRI medications found significantly higher remission rates with TCA than with SSRI in depressed, endogenous and inpatients samples.[33-36] However, in less severely depressed patients, there is not conclusive evidence of benefit of either class of antidepressant over another. Off-label, the use of TCAs in the treatment of pain, enuresis, and insomnia is widespread.[19] Availability of plasma level monitoring helps to guarantee therapeutic trials while minimizing toxicity.

Drawbacks.The significant adverse event profile causes an array of side effects that are often poorly tolerated and lead to medication noncompliance. Because of cardiac side effects, TCAs carry significant risk of death with overdose.

MAOI Class

This class of antidepressants has its own unique mechanism of action. MAOI has fallen into the realm of rarely used antidepressants in modern day psychopharmacology. This is related to the risks and side effects inherent to MAOI use. On the other hand, MAOI are among the most clinically powerful classes of antidepressant treatments. This class interferes with MAO enzyme subtypes A and B. The inhibition of these enzymes results in higher levels of serotonin and norepinephrine due to reduced catabolism of these neurotransmitters.[27] Moreover, by specifically lowering MAO-B activity, dopamine levels in the brain increase as well. Thus, all 3 monoamine neurotransmitter levels are robustly increased, which, in turn, affects a broad array of depressive symptoms.

The use of these medications may come at the cost of difficulty in using them. The most well-known drawback is that patients need to maintain a specific diet that is free of high tyramine foods, or risk the likelihood of hypertensive crisis related to the acute elevation of systemic norepinephrine, which also may result in stroke.[19,27] Foods to be avoided include tap beers, smoked meat or fish, fava beans, aged cheeses, sauerkraut, and soy. However, certain beers, wines, and cheeses are not contraindicated. These items need to be researched and discussed prior to starting a patient on the medication.

Drug-drug interactions are plentiful; combining an MAOI with other norepinephrine medications may increase blood pressure, and combining with a serotonin-based medication can cause serotonin syndrome.[19,27] Patients are also advised to avoid decongestants, stimulants, antidepressants, certain opioids, and appetite suppressants.[19,27]

The MAOI tranylcypromine may act similarly to an amphetamine in the frontal cortex, affording it some additional benefits.[27] Likewise, selegiline also involves breakdown into an amphetamine metabolite. Selegiline is more often used for Parkinson disease than depression.

Benefits.MAOIs are recognized as among the most potent of antidepressants in monotherapy, with effects on serotonin, dopamine, and norepinephrine. This class of antidepressant is often used for the patient who is refractory to other antidepressant trials.

Drawbacks.The MAOIs are associated with risks of hypertensive crisis and serotonin syndrome. There is a need to maintain a tyramine free diet except when using the low dose transdermal selegiline. Because of potential for drug-drug interactions, careful, ongoing monitoring of all additional medications (including over-the-counter medications) is essential.

Miscellaneous Antidepressants

Several other well-known antidepressant medications do not fit discretely into the 4 main antidepressant classes. Each has unique mechanisms that will be discussed similarly below.

Bupropion. This norepinephrine-dopamine receptor inhibitor (NDRI) medication is of particular use in a few subsets of patients. As the class name indicates, bupropion facilitates effects on norepinephrine and dopamine, blocking norepinephrine transporter and dopamine transporter activity at a moderate level, likely in the frontal cortex.[27] The unique properties of bupropion as an antidepressant may be related to its lack of serotonin activity. It is approved for smoking cessation and is used off-label to reduce craving for substances of abuse. Clinicians contend that the dopamine actions of this medication help to improve the loss of positive affect in MDD. Thus, it effectively increases joy, interest, pleasure, energy, enthusiasm, alertness, and self-confidence.[27] The norepinephrine and dopamine facilitation helps patients with attention-deficit/hyperactivity disorder as well.[19]

Several cases of psychosis and paranoia have been reported in patients taking bupropion, likely related to the dopamine effects of the drug.[37] Limited data suggest that this medication, like all antidepressants, may activate depressed patients with bipolar disorder, causing manic episodes. However, it is widely accepted that bupropion and the SSRI class may be less likely to activate mania compared with the TCA class of medications. Because it does not act on serotonin, this is one of the few antidepressants that does not cause sexual side effects or weight gain.[19,27] The medication is uniquely approved for the treatment of seasonal affective disorder.[2]

Benefits.Bupropion is indicated for the treatment of MDD, seasonal affective disorder, and nicotine dependence. It has very low sexual and weight gain side effect liability.

Drawbacks.There is limited serotonin activity with bupropion and less evidence for the treatment of anxiety. Bupropion lowers the seizure threshold in patients predisposed to these events (including patients with eating disorders and those with epilepsy).

Trazodone. Trazodone is a serotonin antagonist/reuptake inhibitor (SARI). It blocks serotonin 2A and 2C receptors and also acts as a mild serotonin reuptake inhibitor.[19,27] This medication typically is used at lower doses because of its properties as a strong antihistamine (H1) and alpha-1 adrenergic blocking medication. The blockade of these receptors causes significant sedation, which may help with insomnia, but may cause excessive somnolence and dizziness in the daytime. The blockade of serotonin also may explain trazodone’s properties as a hypnotic, providing more efficient sleep.[27] Although higher doses of this medication provide excellent benefit related to the synergistic effects of blocking serotonin 2A and 2C and by acting as a serotonin reuptake inhibitor, this medication is not typically given in full divided doses because of excessive side effects.[19,27] A new slow-release preparation has been approved to allow a better tolerated, full dose range.

Benefits.Trazodone is often called a sedating antidepressant. It helps insomnia, improves sleep efficiency, and has its action even at low doses. Sexual side effects and activating side effects are low.[19,27]

Drawbacks. Significant sedation may limit its use.

Mirtazapine. This medication is also considered to be sedating and is typically either avoided or sought because of its side effect profile. Side effects include sedation/hypnotic effects and appetite stimulation, but not sexual side effects. The lack of sexual side effects is again related to serotonin in that mirtazapine is not a serotonin reuptake inhibitor, but in this case acts as a serotonin 2A/2C receptor antagonist.[19,27] The blockade of these receptors may result in more dopamine and norepinephrine release in the prefrontal cortex. The histamine blockade (H1) results in sedation, anxiolytic/hypnotic effects, and weight gain.[19,27] Mirtazapine also acts as a 5HT3 receptor antagonist, resulting in reduction of gastrointestinal problems.[19,27] The primary mechanism of antidepressant action is through alpha 2/norepinephrine receptor antagonism. Through this antagonism, inhibition of norepinephrine is disinhibited through auto receptor blockade. This allows downstream effects on several pathways and may result in overall release of serotonin and norepinephrine. This effect can often be combined with an SNRI to obtain synergistic effects.[27]

Benefits.Mirtazapine has many unique mechanisms of actions that make it beneficial in particular populations. It lacks sexual side effects, reduces gastrointestinal upset, and is not activating. The sedating qualities of this medication are typically used to the medication’s and the patient’s benefit.

Drawbacks.Mirtazapine has significant weight gain/appetite stimulation effects, which could lead to metabolic disorders.

This review is both practical and factual. Clinicians ideally should be aware of regulatory approvals and appropriate use of them in certain patient populations. When used this way, clinicians may expect results comparable to those noted in the evidence base of regulatory trials. However, those who treat patients understand that not all are identical to those enrolled in research trials. What follows will provide some practical clinical approaches when responses do not meet expectations.

As noted, only one third of patients will fully remit on their first antidepressant trial.[38] These numbers hold true for patients who are fully treated with moderate to high dose SSRI for as long as 12 weeks. In clinical practice, patients may not even have such a rigorous dosing profile and failure rates are likely higher. What approaches should be taken when a patient is not responding to treatment?

Adherence and Dosing

First, ask and attempt to ensure adherence to the antidepressant treatment. This questioning should be nonjudgmental and empathic, as most patients will likely say they are compliant even when they are not. Oftentimes suggesting that most people tend to naturally miss a few doses and that you as the clinician are just checking up will diffuse the situation. As dosing becomes divided throughout the day and polypharmacy increases, compliance usually diminishes, making assessment for compliance and adherence to medical regimens even more important.

Tolerability

An important area to address to improve adherence to a regimen relates to side effects and antidepressant tolerability. Sometimes patients cease taking their antidepressant or fail to escalate the dose as advised when adverse effects are not well tolerated. Many mild side effects will dissipate over time and this should be discussed directly with the patient.[39] Patients should be instructed to inform prescribers of any moderate to severe side effects and the drug can then be safely stopped. Patients should also be told that there are many antidepressants, and these have different side effects.[2,39] For example, SSRI, SNRI, and NDRI may be activating, and thus cause insomnia or nervousness upon initiation of treatment. Patients may be switched to a less activating SARI or noradrenergic antagonist-selective serotonin antagonist mechanism-based product, as these tend to be less activating and more sedating.[2]

Some patients may experience drug-drug interactions depending upon their genetic make-up.[2] Switching away from hepatic inhibiting medications towards medications that are less likely to interact with other drugs may be warranted. Typical side effects of headaches, stomachaches, or even insomnia often can be treated very effectively with over the counter or prescription medications. Later onset side effects such as weight gain or sexual dysfunction may be more difficult to mitigate or treat. Open discussions with patients about these longer term risks are warranted because patients often have to stay on their antidepressants for a year or more to maintain remission and avoid a depressive relapse.[38] Because certain antidepressants may have a more, or less favorable weight or sexual side effect profile, they should be chosen based on a discussion about patient preference when possible.

Assuming adherence is adequate, the next step is to confirm that the antidepressant dose was at the moderate to high end of the approved range and has been taken for at least 4 to 6 weeks. If dosing is confirmed to be reasonable, consider a final maximization of dose or switch to a new antidepressant monotherapy.[39]

Switching Monotherapies

If it is necessary to consider switching monotherapies, no clear benefit has been attributed to any particular strategy.[38] Many experts agree, however, that a switch away from an SSRI is warranted if the fully dosed SSRI therapy has failed to improve the patient’s symptoms.[27,39] The theoretical implication is that the patient’s current depressive symptoms have been treated with aggressive serotonergic facilitation and that repeating this mechanism may not be fruitful. This suggests that, pharmacodynamically, the depression may not be entirely serotonin-based in regards to its etiology.[27,39] Given this, a cross titration on to an SNRI such as venlafaxine XR or duloxetine, a NDRI such as bupropion XL, a noradrenergic antagonist-selective serotonin antagonist such as mirtazapine, or a more aggressive serotonergic facilitating agent like a SARI such as trazodone ER or a serotonin partial agonist-reuptake inhibitor such as vilazodone theoretically may be warranted.[2]

One final concern regarding switching involves the use of generic vs brand-name drugs. The FDA ensures that the bioavailability between a brand name and its generic counterpart is approximately between 20% weaker and 20% stronger.[40,41] Most generics are highly comparable, but occasionally when a patient actually changes from one generic to another, the bioavailability could change from a 20% stronger to a 20% weaker generic drug and symptom relapse may occur. By contrast, going from a weaker to a stronger generic might actually improve depression outcomes but may also create new-onset side effects after months of stable treatment as the newer generic preparation is more potent, raising blood levels higher than previously. These types of events should be monitored and dosing adjusted as needed.

Finally, a generic drug may possess a different slow-release mechanism compared with the parent brand-name drug. Oftentimes the generic, despite being a slow-release drug itself may actually release active drug more quickly than the original brand’s slow-release technology. There may be no evidence of a clinical problem; however, some patients may develop side effects when taking the faster release preparation. In this case, the dose may need to be lowered while monitoring for relapse or a switch back to the brand-name slow-release product may be warranted.

In conclusion, this article seeks to identify treatments that match patients with MDD and their common comorbidities, as a first line approach to MDD management. Secondarily and more theoretically, patients’ MDD symptoms may be effectively treated if clinicians are aware of the neurotransmitters and receptors that each antidepressant modulates. Finally, patients may suffer issues with nonefficacy, noncompliance, and tolerability. Each patient is unique and these clinical situations may interfere with optimal depression outcomes. Each patient must be educated and given informed consent about the myriad effective antidepressant treatment options available.

Supported by an independent educational grant from Valeant Pharmaceuticals.

References:

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association; 2000.
  2. Stahl SM. Essential Psychopharmacology: The Prescriber’s Guide. Cambridge, Mass: Cambridge University Press; 2005.
  3. FDA Package Insert. Pristiq. Pfizer Inc. 2011.
  4. FDA Package Insert. Viibryd. Forest Laboratories, Inc. 2011.
  5. Davidson J, Baldwin D, Stein DJet al.Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry. 2006;63:1158-1165. Abstract
  6. Bandelow B, Zohar J, Hollander E, et al. World federation of societies of biological psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders — first revision. World J Biol Psychiatry. 2008;9:248-312. Abstract
  7. Benedek DM, Friedman MJ, Zatzick D, et al. Guideline watch (March 2009): practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder.
  8. Phelps NJ, Cates ME, The role of venlafaxine in the treatment of obsessive-compulsive disorder. Ann Pharmacother. 2005;39:136-140. Abstract
  9. Gartlehner G, Hansen RA, Reichenpfader U, et al. Drug class review: second-generation antidepressants: final update 5 report [internet].Portland, Ore: Oregon Health & Science University; March 2011.
  10. Effexor Prescribing Information. http://labeling.pfizer.com/showlabeling.aspx?id=100
  11. FDA Package Insert. Cymbalta. Lilly USA LLC. 2004/2011.
  12. FDA Package Insert. Silenor. Somaxon Pharmaceuticals Inc. 1969.
  13. Hsu, ES. Acute and chronic pain management in fibromyalgia: updates on pharmacotherapy. Am J Ther. 2011;18:487-509. Abstract
  14. Verdu B, Decosterd I, Buclin T, et al. Antidepressants for the treatment of chronic pain. Drugs. 2008;68:2611-2632. Abstract
  15. Prince JB, Wilens TE, Biederman J, et al. A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 2000;10:193-204. Abstract
  16. Pliszka SR. Non-stimulant treatment of attention-deficit/hyperactivity disorder. CNS Spectr. 2003;8:253-258. Abstract
  17. Wilens TE, Prince JB, Spencer T, et al, An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity disorder and bipolar disorder. Biol Psychiatry. 2003;54:9-16. Abstract
  18. Olvera RL, Pliszka SR, Luh J, et al. An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol. 1996;6:241-250. Abstract
  19. Sadock BJ, Sadock VA, et al. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Tenth ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2007:977-1126.
  20. Prochazka AV, Kick S, Steinbrunn C, et al. A randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation. Arch Intern Med. 2004;164:2229-2233. Abstract
  21. FDA Package Insert. Wellbutrin XL. GlaxoSmithKline. 2008.
  22. McIntyre RS, Mancini DA, McCann S, et al, Topiramate versus bupropion SR when added to mood stabilizer therapy fpr the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord. 2002;4:207-213. Abstract
  23. Coleiro B, Marshall SE, Denton CP, et al. Treatment of raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology. 2001;40:1038-1043. Abstract
  24. Stearns V, Beebe KL, Iyengar M, et al. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289:2827-2834. Abstract
  25. Evans ML, Pritts E, Vittinghoff E, et al. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005;105:161-166. Abstract
  26. Muller D, Roehr CC, Eggert P. Comparative tolerability of drug treatment for nocturnal enuresis in children. Drug Saf. 2004;27:717-727. Abstract
  27. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. Cambridge, Mass: Cambridge University Press; 2008:511-666.
  28. Spina E, Scordo MG. clinically significant drug interactions with antidepressants in the elderly. Drugs Aging. 2002;19:299-320. Abstract
  29. FDA Packet Insert. Celexa. Forest Laboratories, Inc. 2010/2011.
  30. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30:1206-1227. Abstract
  31. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758. Abstract
  32. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980-991. Abstract
  33. Danish University Antidepressant Group. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology (Berl). 1986;90:131-138. Abstract
  34. Danish University Antidepressant Group.Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Disord. 1990;18:289-299. Abstract
  35. Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry. 1994;151:1735-1739. Abstract
  36. Beasley CM Jr, Holman SL, Potvin JH. Fluoxetine compared with imipramine in the treatment of inpatient depression. A multicenter trial. Ann Clin Psychiatry. 1993;5:199-207. Abstract
  37. Bailey J. Acute psychosis after bupropion treatment in a healthy 28-year-old woman. J Am Board Fam Med. 2008;21:244.
  38. Rush AJ, Trivedi MH, Wisnewlski Sr, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163:1905-1917. Abstract
  39. Zajecka JM, Goldstein C. Combining medication to achieve remission. In: Schwartz T, Petersen T, eds. Depression: Treatment Strategies and Management. 2nd ed. New York: Informa; 2009.
  40. Park K, ed. Controlled Drug Delivery: Challenges and Strategies. Washington, DC: American Chemical Society; 1997.
  41. Orange book annual preface, statistical criteria for bioequivalence. In: Approved Drug Products with Therapeutic Equivalence Evaluations. 29th ed. US Food and Drug Administration Center for Drug Evaluation and Research; 2009-06-18, update 3-01-11. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.htm

Retrieved from: http://www.medscape.org/viewarticle/755180

Autism Patients Might Benefit from Drug Therapy

In Medication, Psychiatry, School Psychology on Sunday, 23 September 2012 at 09:01

Autism Patients Might Benefit from Drug Therapy

By SYDNEY LUPKIN | ABC News – Wed, Sep 19, 2012 2:37 PM EDT

Researchers have found a drug that can help patients with Fragile X syndrome, the most common cause of inherited intellectual impairment (formerly known as mental retardation), stay calm in social situations by treating their anxiety.

Dr. Elizabeth Berry-Kravis and her team found that a drug called Arbaclofen reduced social avoidance and repetitive behavior in Fragile X patients, especially those with autism, by treating their anxiety. The drug increases GABA, a chemical in the brain that regulates the excitatory system in Fragile X patients, who have been known to have too little GABA to do the job otherwise, causing their excitatory systems to “signal out of control” and make them anxious.

Such patients have been known to cover their ears or run away at their own birthdays because they are overwhelmed by the attention, but one trial participant said he was able to enjoy his birthday party for the first time in his life while he was on Arbaclofen, she said.

“I feel like it’s kind of the beginning of chemotherapy when people first realized you could use chemotherapy to treat cancer patients instead of just letting them die,” said Berry-Kravis, a professor of neurology and biochemistry at Rush University Medical Center in Chicago who has studied Fragile X for more than 20 years.

She said people used to think Fragile X patients couldn’t be helped either, but she and her team have proven that by using knowledge from existing brain mechanism studies, doctors can select medications to target specific problems in Fragile X patients’ brains.

Fragile X syndrome is a change in the FMRI gene, which makes a protein necessary for brain growth, and studies indicate it causes autism in up to one-third of patients diagnosed with it. Unlike Fragile X syndrome, which is genetic, autism is a behavioral diagnosis characterized by an inability to relate to other people or read social cues. Autism and Fragile X are linked, but not mutually exclusive. A core symptom of both is social withdrawal.

Sixty-three patients with Fragile X participated in Berry-Kravis’s placebo-controlled, double-blind clinical trial from December 2008 through March 2010. Of those, the patients with autism showed the biggest improvements in social behavior, Berry-Kravis said.

To psychologist Lori Warner, who directs the HOPE Center at Beaumont Children’s Hospital, the study is exciting because when her autistic patients are anxious, they often have a harder time learning the social cues they can’t read on their own.

“Reducing anxiety opens up your brain to be able to take in what’s happening in an environment and be able to learn from and understand social cues because you’re no longer frightened of the situation,” Warner said.

She works mostly with autism patients, and although some do have Fragile X as well, most do not.

Fragile X affects one in 4,000 men and one in 6,000 to 8,000 women, according to the Centers for Disease Control and Prevention.

Although Arbaclofen worked best on autistic Fragile X patients, further studies will be needed to prove whether it can help all autism patients, not just those with autism caused by Fragile X.

“There’s a difference between one person’s brain and another in how it’s set up,” Berry-Vargis said. “This is not a magic cure. It’s a step.”

Retrieved from: http://gma.yahoo.com/autism-patients-might-benefit-drug-therapy-183744169–abc-news-health.html

More on insomnia…

In Medication, Neuropsychology, Psychiatry on Thursday, 20 September 2012 at 06:30

Expert Interview – Emerging Concepts and Therapies in Insomnia: An Expert Interview With Daniel Buysse, MD

Daniel J. Buysse, MD, 2006

http://www.medscape.org/viewarticle/519857

Editor’s Note:

Marni Kelman, MSc, Medscape Neurology & Neurosurgery Editorial Director, discussed emerging concepts and therapies in insomnia with Daniel Buysse, MD, Professor of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Insomnia in older adults, comorbid insomnia, new treatments on the horizon for insomnia, and new endpoints for therapeutic effectiveness of insomnia treatments were discussed.

Medscape: This issue of Current Perspectives in Insomnia includes a column on sleep disorders in older adults, with a focus on insomnia. What would you say is the impact of insomnia in older patients?

Dr. Buysse: The impact of insomnia in general is pretty wide-ranging, and some of those impairments are even greater in older people. Insomnia can have negative effects on a person’s mood the next day, on their concentration, on their energy level, or can cause fatigue or even sleepiness. Since older adults might experience these things for other reasons, insomnia tends to make them even worse.

Medscape: Are there any particular things that you take into consideration when you diagnose insomnia in an older patient?

Dr. Buysse: Because older adults will so commonly have medical or psychiatric comorbidity, it’s very important to look for those things. Older adults can have medical conditions that can cause pain, difficulty breathing, or impaired mobility, and all of those things can worsen insomnia. Older adults are also at risk for depression, which is the most common comorbid condition seen with insomnia. In addition, older adults are typically the ones who are taking the most medications, and because many medications can have effects on sleep, including insomnia, it’s very important to assess the effects of medications as well.

There are also a number of behavioral factors that can contribute to insomnia — things like going to bed early or spending too much time in bed — and those things, too, affect older adults disproportionately, since in older adults, limitations in daytime activities may leave them with fewer alternatives to going to bed. So, from both a medical perspective and a behavioral perspective, older adults are at risk.

There are a couple of sleep disorders that are more common in older adults that may be associated with insomnia symptoms, and those include restless legs syndrome and periodic limb movement disorder. There is almost certainly an increase in periodic limb movements with age, and again, this can lead to, or be associated with insomnia complaints. Older adults also have an increased incidence of sleep apnea, and compared to younger adults, sleep apnea may less commonly be associated with obesity, and less commonly associated with daytime sleepiness as the primary presenting complaint. The combination of sleep apnea with insomnia seems to be something that is disproportionately common in older adults.

The final sleep disorder that is common in older patients and that can cause insomnia is advanced sleep-phase syndrome. An individual with this syndrome feels very sleepy and goes to sleep early in the evening but then has insomnia characterized by early-morning awakening and an inability to return to sleep. This condition may be related to certain circadian changes that accompany aging.

Medscape: What special considerations do you take into account when you treat older patients with insomnia?

Dr. Buysse: With regard to medications, one needs to proceed a bit more cautiously for 2 reasons. First, older adults may have changes in drug-metabolizing enzymes, so they may metabolize drugs more slowly, or store drugs disproportionately longer because of an increase in the relative amount of body fat. This means that the same drug may have a longer than expected action in older adults. Second, older adults are typically on multiple medications, and some may have additive effects with some of the medications that we give for sleep.

With regard to behavioral treatments, I think the main thing to keep in mind is that older adults can and do benefit from those kinds of treatments as well. So the main message there is to not assume that older adults can’t learn these techniques; they can, and several studies have shown that they can be very effective.

Medscape: Are there particular types of medications that you use in the elderly and/or avoid?

Dr. Buysse: Generally, the approved hypnotic medications are appropriate for older adults, but you do need to be cautious, so it’s often wise to begin with a lower dose than you would use in younger and middle-aged adults. Because of the sensitivity that older people may have to the cognitive side effects of hypnotic drugs, in general, you would want to use a short-acting drug whenever possible to avoid the daytime cognitive and sedative consequences of hypnotic medications. The new hypnotic medication, ramelteon, may be particularly useful in older adults because it has very, very few — actually no — demonstrated cognitive side effects. So that may be a useful drug. The question there is whether it’s actually long enough acting to help with some of the sleep-maintenance problems that older adults might have.

Sedating antidepressants are pretty commonly used, as are antihistamines for the treatment of insomnia. Antihistaminic drugs should be approached with particular caution in the elderly because they often have anticholinergic effects that can worsen cognition and even lead to adverse consequences, such as delirium and urinary retention. One also needs to be careful when using sedating antidepressants in older adults.

Medscape: Another topic that we have discussed in this newsletter is insomnia associated with psychiatric and medical disorders. Are there particular considerations that you take into account when diagnosing those types of patients as well as treating them?

Dr. Buysse: The previous assumption was that if insomnia is associated with another condition, one would be best off just treating that other condition, and then the insomnia should get better. While there is clearly some evidence that treating comorbid conditions does lead to some improvement in insomnia, in many individuals insomnia may persist, even when the other disorder is adequately or optimally treated. In those cases, it may be useful to think of insomnia as a comorbid condition rather than as, strictly speaking, a symptom of that other disorder. If you think of insomnia as a comorbid condition, then in many cases it’s appropriate to direct treatment at the insomnia itself.

There is certainly emerging evidence that treating insomnia specifically does lead to improvement in sleep among patients with either medical conditions or psychiatric conditions. However, there is also a small, but growing, body of evidence that treating insomnia may actually lead to better outcomes of the comorbid medical or psychiatric condition itself.

Medscape: I would also like to ask for your feedback on emerging treatments for insomnia. Are there particular new therapeutic targets for therapy that you think are most promising?

Dr. Buysse: There are a lot of different therapeutic targets that are being examined, and I think the first general thing to say is that this is great because it’s unlikely that insomnia in all people results from the same problem. Therefore, having different ways to impact sleep just makes sense. The other point is that the regulation of sleep itself is very complex and involves multiple neurotransmitter systems. So again, having drugs that target different neurotransmitter systems just makes good sense.

Having said that, there are new agents under investigation that affect the GABA-benzodiazepine receptors and have modified-release preparations so that you can combine a reasonably long duration of action with a short half-life. That means that there is the possibility of providing adequate coverage of insomnia for the entire night, but rapid metabolism of the medication occurs toward the end of the night so that there are fewer daytime consequences.

That’s one strategy. Another strategy is to look at GABA reuptake or extrasynaptic GABA receptors. Other neurotransmitter systems are also being investigated, including serotonin 5HT2A receptors. Antagonists at that receptor have different effects on sleep, so that will be interesting to investigate. Different companies are looking into medications that interact with hypocretin or orexin receptors. That, too, promises, I think, to be a pretty exciting development.

Medscape: There has been some discussion about using new therapeutic endpoints for insomnia, for example, alertness, decreased depression, or decreased daytime napping. How do you feel about this, and what do you think are the most promising new endpoints that should be considered when looking at therapeutic effectiveness?

Dr. Buysse: I think that this is a very important area because patients with insomnia complain not only because their nighttime sleep is disturbed, but because that disturbance is associated with daytime consequences. Therefore, I think that the most interesting areas to look at are those that assess the daytime complaints presented by people with insomnia. One area is the routine assessment of mood symptoms and problems. We’ve been working on some data that show that it may be important not only to assess the person’s mood, but to evaluate how mood changes during the course of the day. So, looking at time-of-day effects may be very important. The second area to assess is fatigue, which is so commonly reported by people with insomnia and can be reliably measured with a number of rating scales. That should certainly be a focus of increased attention.

An area that has been somewhat perplexing, but very important, is the measurement of cognitive difficulties in people with insomnia. There have not been a lot of positive studies in this regard, so despite the fact that people complain of difficulty concentrating or problems with alertness, actually demonstrating impairments has generally not met with success. This may be due to the fact that the tools we have used have been of the wrong type or are not sensitive enough. So, I think trying to identify and develop tests that objectively measure daytime performance as related to the insomnia complaints would be very beneficial as well.

Medscape: What would you consider to be the biggest challenges in insomnia today?

Dr. Buysse: For behavioral and psychological treatments, the big challenge is making those treatments more widely available. We have several techniques that have demonstrated efficacy, but trying to really position them in the community so they have a wide impact is the challenge.

For medications, one of the biggest challenges is developing strategies for longer-term management of insomnia. We know that insomnia tends to be a chronic or recurring condition, and there is still uncertainty about the optimal way to manage chronic insomnia with medications.

The more general thing that I would say pertains to both behavioral and pharmacologic treatment: We really are in very substantial need of empirically supported treatment guidelines or treatment algorithms. We know that we have several efficacious treatments, but we don’t know how best to sequence them, how to target them to specific patients, and how to change from one to the other when the first treatment does not meet with success.

 

Get moving!

In Fitness/Health, Psychiatry, Well-being on Tuesday, 18 September 2012 at 16:29

The exercise effect

Evidence is mounting for the benefits of exercise, yet psychologists don’t often use exercise as part of their treatment arsenal. Here’s more research on why they should.

By Kirsten Weir

December 2011, Vol 42, No. 11

When Jennifer Carter, PhD, counsels patients, she often suggests they walk as they talk. “I work on a beautiful wooded campus,” says the counseling and sport psychologist at the Center for Balanced Living in Ohio.

Strolling through a therapy session often helps patients relax and open up, she finds. But that’s not the only benefit. As immediate past president of APA’s Div. 47 (Exercise and Sport Psychology), she’s well aware of the mental health benefits of moving your muscles. “I often recommend exercise for my psychotherapy clients, particularly for those who are anxious or depressed,” she says.

Unfortunately, graduate training programs rarely teach students how to help patients modify their exercise behavior, Carter says, and many psychologists aren’t taking the reins on their own. “I think clinical and counseling psychologists could do a better job of incorporating exercise into treatment,” she says.

“Exercise is something that psychologists have been very slow to attend to,” agrees Michael Otto, PhD, a professor of psychology at Boston University. “People know that exercise helps physical outcomes. There is much less awareness of mental health outcomes — and much, much less ability to translate this awareness into exercise action.”

Researchers are still working out the details of that action: how much exercise is needed, what mechanisms are behind the boost exercise brings, and why — despite all the benefits of physical activity — it’s so hard to go for that morning jog. But as evidence piles up, the exercise-mental health connection is becoming impossible to ignore.

Mood enhancement

If you’ve ever gone for a run after a stressful day, chances are you felt better afterward. “The link between exercise and mood is pretty strong,” Otto says. “Usually within five minutes after moderate exercise you get a mood-enhancement effect.”

But the effects of physical activity extend beyond the short-term. Research shows that exercise can also help alleviate long-term depression.

Some of the evidence for that comes from broad, population-based correlation studies. “There’s good epidemiological data to suggest that active people are less depressed than inactive people. And people who were active and stopped tend to be more depressed than those who maintain or initiate an exercise program,” says James Blumenthal, PhD, a clinical psychologist at Duke University.

The evidence comes from experimental studies as well. Blumenthal has explored the mood-exercise connection through a series of randomized controlled trials. In one such study, he and his colleagues assigned sedentary adults with major depressive disorder to one of four groups: supervised exercise, home-based exercise, antidepressant therapy or a placebo pill. After four months of treatment, Blumenthal found, patients in the exercise and antidepressant groups had higher rates of remission than did the patients on the placebo. Exercise, he concluded, was generally comparable to antidepressants for patients with major depressive disorder (Psychosomatic Medicine, 2007).

Blumenthal followed up with the patients one year later. The type of treatment they received during the four-month trial didn’t predict remission a year later, he found. However, subjects who reported regular exercise at the one-year follow-up had lower depression scores than did their less active counterparts (Psychosomatic Medicine, 2010). “Exercise seems not only important for treating depression, but also in preventing relapse,” he says.

Certainly, there are methodological challenges to researching the effects of exercise, from the identification of appropriate comparison groups to the limitations of self-reporting. Despite these challenges, a compelling body of evidence has emerged. In 2006, Otto and colleagues reviewed 11 studies investigating the effects of exercise on mental health. They determined that exercise could be a powerful intervention for clinical depression (Clinical Psychology: Science and Practice, 2006). Based on those findings, they concluded, clinicians should consider adding exercise to the treatment plans for their depressed patients.

Mary de Groot, PhD, a psychologist in the department of medicine at Indiana University, is taking the research one step further, investigating the role exercise can play in a particular subset of depressed patients: those with diabetes. It’s a significant problem, she says. “Rates of clinically significant depressive symptoms and diagnoses of major depressive disorder are higher among adults with diabetes than in the general population,” she says. And among diabetics, she adds, depression is often harder to treat and more likely to recur. The association runs both ways. People with diabetes are more likely to develop depression, and people with depression are also more likely to develop diabetes. “A number of studies show people with both disorders are at greater risk for mortality than are people with either disorder alone,” she says.

Since diabetes and obesity go hand-in-hand, it seemed logical to de Groot that exercise could effectively treat both conditions. When she reviewed the literature, she was surprised to find the topic hadn’t been researched. So, she launched a pilot project in which adults with diabetes and depression undertook a 12-week exercise and cognitive-behavioral therapy (CBT) intervention program (Diabetes, 2009). Immediately following the program, the participants who exercised showed improvements both in depression and in levels of A1C, a blood marker that reflects blood-sugar control, compared with those in a control group. She’s now undertaking a larger study to further explore exercise and CBT, both alone and in combination, for treating diabetes-related depression.

Fight-or-flight

Researchers have also explored exercise as a tool for treating — and perhaps preventing — anxiety. When we’re spooked or threatened, our nervous systems jump into action, setting off a cascade of reactions such as sweating, dizziness, and a racing heart. People with heightened sensitivity to anxiety respond to those sensations with fear. They’re also more likely to develop panic disorder down the road, says Jasper Smits, PhD, Co-Director of the Anxiety Research and Treatment Program at Southern Methodist University in Dallas and co-author, with Otto, of the 2011 book “Exercise for Mood and Anxiety: Proven Strategies for Overcoming Depression and Enhancing Well-being.”

Smits and Otto reasoned that regular workouts might help people prone to anxiety become less likely to panic when they experience those fight-or-flight sensations. After all, the body produces many of the same physical reactions — heavy perspiration, increased heart rate — in response to exercise. They tested their theory among 60 volunteers with heightened sensitivity to anxiety. Subjects who participated in a two-week exercise program showed significant improvements in anxiety sensitivity compared with a control group (Depression and Anxiety, 2008). “Exercise in many ways is like exposure treatment,” says Smits. “People learn to associate the symptoms with safety instead of danger.”

In another study, Smits and his colleagues asked volunteers with varying levels of anxiety sensitivity to undergo a carbon-dioxide challenge test, in which they breathed CO2-enriched air. The test often triggers the same symptoms one might experience during a panic attack: increased heart and respiratory rates, dry mouth and dizziness. Unsurprisingly, people with high anxiety sensitivity were more likely to panic in response to the test. But Smits discovered that people with high anxiety sensitivity who also reported high activity levels were less likely to panic than subjects who exercised infrequently (Psychosomatic Medicine, 2011). The findings suggest that physical exercise could help to ward off panic attacks. “Activity may be especially important for people at risk of developing anxiety disorder,” he says.

Smits is now investigating exercise for smoking cessation. The work builds on previous research by Bess Marcus, PhD, a psychology researcher now at the University of California San Diego, who found that vigorous exercise helped women quit smoking when it was combined with cognitive-behavioral therapy (Archives of Internal Medicine, 1999). However, a more recent study by Marcus found that the effect on smoking cessation was more limited when women engaged in only moderate exercise (Nicotine & Tobacco Research, 2005).

Therein lies the problem with prescribing exercise for mental health. Researchers don’t yet have a handle on which types of exercise are most effective, how much is necessary, or even whether exercise works best in conjunction with other therapies.

“Mental health professionals might think exercise may be a good complement [to other therapies], and that may be true,” says Blumenthal. “But there’s very limited data that suggests combining exercise with another treatment is better than the treatment or the exercise alone.”

Researchers are starting to address this question, however. Recently, Madhukar Trivedi, MD, a psychiatrist at the University of Texas Southwestern Medical College, and colleagues studied exercise as a secondary treatment for patients with major depressive disorder who hadn’t achieved remission through drugs alone. They evaluated two exercise doses: One group of patients burned four kilocalories per kilogram each week, while another burned 16 kilocalories per kilogram weekly. They found both exercise protocols led to significant improvements, though the higher-dose exercise program was more effective for most patients (Journal of Clinical Psychiatry, 2011).

The study also raised some intriguing questions, however. In men and women without family history of mental illness, as well as men with family history of mental illness, the higher-dose exercise treatment proved more effective. But among women with a family history of mental illness, the lower exercise dose actually appeared more beneficial. Family history and gender are moderating factors that need to be further explored, the researchers concluded.

Questions also remain about which type of exercise is most helpful. Most studies have focused on aerobic exercise, though some research suggests weight training might also be effective, Smits says. Then there’s the realm of mind-body exercises like yoga, which have been practiced for centuries but have yet to be thoroughly studied. “There’s potential there, but it’s too early to get excited,” he says.

Buffering the brain

It’s also unclear exactly how moving your muscles can have such a significant effect on mental health. “Biochemically, there are many things that can impact mood. There are so many good, open questions about which mechanisms contribute the most to changes in depression,” says de Groot.

Some researchers suspect exercise alleviates chronic depression by increasing serotonin (the neurotransmitter targeted by antidepressants) or brain-derived neurotrophic factor (which supports the growth of neurons). Another theory suggests exercise helps by normalizing sleep, which is known to have protective effects on the brain.

There are psychological explanations, too. Exercise may boost a depressed person’s outlook by helping him return to meaningful activity and providing a sense of accomplishment. Then there’s the fact that a person’s responsiveness to stress is moderated by activity. “Exercise may be a way of biologically toughening up the brain so stress has less of a central impact,” Otto says.

It’s likely that multiple factors are at play. “Exercise has such broad effects that my guess is that there are going to be multiple mechanisms at multiple levels,” Smits says.

So far, little work has been done to unravel those mechanisms. Michael Lehmann, PhD, a research fellow at the National Institute of Mental Health, is taking a stab at the problem by studying mice — animals that, like humans, are vulnerable to social stress.

Lehmann and his colleagues subjected some of their animals to “social defeat” by pairing small, submissive mice with larger, more aggressive mice. The alpha mice regularly tried to intimidate the submissive rodents through the clear partition that separated them. And when the partition was removed for a few minutes each day, the bully mice had to be restrained from harming the submissive mice. After two weeks of regular social defeat, the smaller mice explored less, hid in the shadows, and otherwise exhibited symptoms of depression and anxiety.

One group of mice, however, proved resilient to the stress. For three weeks before the social defeat treatment, all of the mice were subjected to two dramatically different living conditions. Some were confined to spartan cages, while others were treated to enriched environments with running wheels and tubes to explore. Unlike the mice in the bare-bones cages, bullied mice that had been housed in enriched environments showed no signs of rodent depression or anxiety after social defeat (Journal of Neuroscience, 2011). “Exercise and mental enrichment are buffering how the brain is going to respond to future stressors,” Lehmann says.

Lehmann can’t say how much of the effect was due to exercise and how much stemmed from other aspects of the stimulating environment. But the mice ran a lot — close to 10 kilometers a night. And other experiments hint that running may be the most integral part of the enriched environment, he says.

Looking deeper, Lehmann and his colleagues examined the mice’s brains. In the stimulated mice, they found evidence of increased activity in a region called the infralimbic cortex, part of the brain’s emotional processing circuit. Bullied mice that had been housed in spartan conditions had much less activity in that region. The infralimbic cortex appears to be a crucial component of the exercise effect. When Lehmann surgically cut off the region from the rest of the brain, the protective effects of exercise disappeared. Without a functioning infralimbic cortex, the environmentally enriched mice showed brain patterns and behavior similar to those of the mice who had been living in barebones cages.

Humans don’t have an infralimbic cortex, but we do have a homologous region, known as cingulate area 25 or Brodmann area 25. And in fact, this region has been previously implicated in depression. Helen Mayberg, MD, a neurologist at Emory University, and colleagues successfully alleviated depression in several treatment-resistant patients by using deep-brain stimulation to send steady, low-voltage current into their area 25 regions (Neuron, 2005). Lehmann’s studies hint that exercise may ease depression by acting on this same bit of brain.

Getting the payoff

Of all the questions that remain to be answered, perhaps the most perplexing is this: If exercise makes us feel so good, why is it so hard to do it? According to the Centers for Disease Control and Prevention, in 2008 (the most recent year for which data are available), some 25 percent of the U.S. population reported zero leisure-time physical activity.

Starting out too hard in a new exercise program may be one of the reasons people disdain physical activity. When people exercise above their respiratory threshold — that is, above the point when it gets hard to talk — they postpone exercise’s immediate mood boost by about 30 minutes, Otto says. For novices, that delay could turn them off of the treadmill for good. Given that, he recommends that workout neophytes start slowly, with a moderate exercise plan.

Otto also blames an emphasis on the physical effects of exercise for our national apathy to activity. Physicians frequently tell patients to work out to lose weight, lower cholesterol or prevent diabetes. Unfortunately, it takes months before any physical results of your hard work in the gym are apparent. “Attending to the outcomes of fitness is a recipe for failure,” he says.

The exercise mood boost, on the other hand, offers near-instant gratification. Therapists would do well to encourage their patients to tune into their mental state after exercise, Otto says — especially when they’re feeling down.

“Many people skip the workout at the very time it has the greatest payoff. That prevents you from noticing just how much better you feel when you exercise,” he says. “Failing to exercise when you feel bad is like explicitly not taking an aspirin when your head hurts. That’s the time you get the payoff.”

It may take a longer course of exercise to alleviate mood disorders such as anxiety or depression, Smits adds. But the immediate effects are tangible — and psychologists are in a unique position to help people get moving. “We’re experts in behavior change,” he says. “We can help people become motivated to exercise.”


Kirsten Weir is a writer in Minneapolis.

Retrieved from http://www.apa.org/monitor/2011/12/exercise.aspx

 

New autism research (with promising findings…)

In Autism Spectrum Disorders, Neuroscience, Psychiatry on Tuesday, 18 September 2012 at 16:24

some promising new studies on autism.  the first discusses the development of a genetic test that may be able to predict the risk of developing an asd.  while gene studies bring up both ethical and moral concerns for some, the findings and possible implications can not be dismissed.  the next study discusses the possibility of a drug involving glutamate receptor antagonists as a treatment for asd.  good stuff…ENJOY!

Genetic Test Predicts Risk for Autism Spectrum Disorder

Australian researchers have developed a genetic test that is able to predict the risk of developing autism spectrum disorder (ASD). (Credit: © Lucian Milasan / Fotolia)

ScienceDaily (Sep. 11, 2012) — A team of Australian researchers, led by University of Melbourne has developed a genetic test that is able to predict the risk of developing autism spectrum disorder (ASD).

Lead researcher Professor Stan Skafidas, Director of the Centre for Neural Engineering at the University of Melbourne said the test could be used to assess the risk for developing the disorder. “This test could assist in the early detection of the condition in babies and children and help in the early management of those who become diagnosed,” he said. “It would be particularly relevant for families who have a history of autism or related conditions such as Asperger’s syndrome,” he said.

Autism affects around one in 150 births and is characterized by abnormal social interaction, impaired communication and repetitive behaviours. The test correctly predicted ASD with more than 70 per cent accuracy in people of central European descent. Ongoing validation tests are continuing including the development of accurate testing for other ethnic groups.

Clinical neuropsychologist, Dr Renee Testa from the University of Melbourne and Monash University, said the test would allow clinicians to provide early interventions that may reduce behavioural and cognitive difficulties that children and adults with ASD experience. “Early identification of risk means we can provide interventions to improve overall functioning for those affected, including families,” she said.

A genetic cause has been long sought with many genes implicated in the condition, but no single gene has been adequate for determining risk. Using US data from 3,346 individuals with ASD and 4,165 of their relatives from Autism Genetic Resource Exchange (AGRE) and Simons Foundation Autism Research Initiative (SFARI), the researchers identified 237 genetic markers (SNPs) in 146 genes and related cellular pathways that either contribute to or protect an individual from developing ASD.

Senior author Professor Christos Pantelis of the Melbourne Neuropsychiatry Centre at the University of Melbourne and Melbourne Health said the discovery of the combination of contributing and protective gene markers and their interaction had helped to develop a very promising predictive ASD test.

The test is based on measuring both genetic markers of risk and protection for ASD. The risk markers increase the score on the genetic test, while the protective markers decrease the score. The higher the overall score, the higher the individual risk.

“This has been a multidisciplinary team effort with expertise across fields providing new ways of investigating this complex condition,” Professor Pantelis said.

The study was undertaken in collaboration with Professor Ian Everall, Cato Chair in Psychiatry and Dr Gursharan Chana from the University of Melbourne and Melbourne Health, and Dr Daniela Zantomio from Austin Health.

The next step is to further assess the accuracy of the test by monitoring children who are not yet diagnosed over an extended study. The study has been published today in the journal Molecular Psychiatry.


Story Source:

The above story is reprinted from materials provided by University of Melbourne.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

University of Melbourne (2012, September 11). Genetic test predicts risk for autism spectrum disorder. ScienceDaily. Retrieved September 18, 2012, from http://www.sciencedaily.com­ /releases/2012/09/120912093827.htm?goback=.gde_2514160_member_163245605

Retrieved from: http://www.sciencedaily.com/releases/2012/09/120912093827.htm?goback=.gde_2514160_member_163245605

***

Disorder of Neuronal Circuits in Autism is Reversible

14 September 2012 08:43 Universität Basel

People with autism suffer from a pervasive developmental disorder of the brain that becomes evident in early childhood. Peter Scheiffele and Kaspar Vogt, Professors at the Biozentrum of the University of Basel, have identified a specific dysfunction in neuronal circuits that is caused by autism. In the respected journal „Science“, the scientists also report about their success in reversing these neuronal changes. These findings are an important step in drug development for the treatment for autism.

According to current estimates, about one percent of all children develop an autistic spectrum disorder. Individuals with autism may exhibit impaired social behavior, rigid patterns of behavior and limited speech development. Autism is a hereditary developmental disorder of the brain. A central risk factor for the development of autism are numerous mutations in over 300 genes that have been identified, including the gene neuroligin-3, which is involved in the formation of synapses, the contact junction between nerve cells.

Loss of neuroligin-3 interferes with neuronal signal transmission

The consequences of neuroligin-3 loss can be studied in animal models. Mice lacking the gene for neuroligin-3 develop behavioral patterns reflecting important aspects observed in autism. In collaboration with Roche the research groups from the Biozentrum at the University of Basel have now identified a defect in synaptic signal transmission that interferes with the function and plasticity of the neuronal circuits. These negative effects are associated with increased production of a specific neuronal glutamate receptor, which modulates the signal transmission between neurons. An excess of these receptors inhibits the adaptation of the synaptic signal transmission during the learning process, thus disrupting the development and function of the brain in the long term.

Of major importance is the finding that the impaired development of the neuronal circuit in the brain is reversible.  When the scientists reactivated the production of neuroligin-3 in the mice, the nerve cells scaled down the production of the glutamate receptors to a normal level and the structural defects in the brain typical for autism disappeared. Hence, these glutamate receptors could be a suitable pharmacological target in order to stop the developmental disorder autism or even reverse it.

Vision for the future: Medication for autism

Autism currently cannot be cured.  At present, only the symptoms of the disorder can be alleviated through behavioral therapy and other treatment. A new approach to its treatment, however, has been uncovered through the results of this study. In one of the European Union supported projects, EU-AIMS, the research groups from the Biozentrum are working in collaboration with Roche and other partners in industry on applying glutamate receptor antagonists for the treatment of autism and hope, that in the future, this disorder can be treated successfully in both children and adults.

http://www.unibas.ch/index.cfm?uuid=BF9F46B0ADFE4138B2556373D7286FD5&type=search&show_long=1

  • Full bibliographic information: Baudouin S. J., Gaudias J., Gerharz S., Hatstatt L., Zhou K., Punnakkal P., Tanaka K. F., Spooren W., Hen R., De Zeeuw C.I., Vogt K., Scheiffele K.
    Shared Synaptic Pathophysiology in Syndromic and Non-syndromic Rodent Models of Autism
    Science; Published online September 13 (2012) | doi: 10.1126/science.1224159

 

Hypnotic use and side effects

In Insomnia, Medication, Neuropsychology, Psychiatry on Tuesday, 18 September 2012 at 05:25

chronic insomnia and sleep deprivation are major issues affecting over 30% of  the u.s population.  approximately 10 million people are prescribed hypnotics to treat insomnia.  while the concurrent effects from untreated insomnia are vast, and hypnotic use may be the only viable option, it is suggested that one educate themselves on the effects related to untreated insomnia (see previous post titled “the state of sleep in the u.s.”) and options for treatment as well as recent research regarding the side-effects of some treatments.  

Hypnotic Use Linked With Increased Risk for Early Death

Megan Brooks & Laurie Barclay, MD

http://www.medscape.org/viewarticle/759730

Clinical Context

In 2010, approximately 6% to 10% of US adults used a hypnotic drug for sleep problems. Earlier studies have suggested an association between hypnotic use and excess mortality rates.

The objectives of this study by Kripke and colleagues were to estimate the mortality risks and cancer risks associated with specific, currently popular hypnotics, using a matched cohort design and proportional hazards regression models. In addition, the investigators examined what degree of risk associated with hypnotic use could be explained by confounders and comorbid conditions.

Study Synopsis and Perspective

Adults who use hypnotics to help them sleep have a greater than 3-fold increased risk for early death, according to results of a large matched cohort survival analysis.

Hazard ratios were elevated in separate analyses for several commonly prescribed hypnotics and for newer shorter-acting drugs, the researchers say. The drugs included benzodiazepines, such as temazepam; nonbenzodiazepines, such as zolpidem, eszopiclone, and zaleplon; barbiturates; and sedative antihistamines.

“The take-home from the article is that the risks associated with hypnotics are very high, and certainly these possible risks outweigh any benefits of hypnotics,” first author Daniel F. Kripke, MD, co-director of research at the Scripps Clinic Viterbi Family Sleep Center in La Jolla, California, told Medscape Medical News.

“Our study is the 19th epidemiological study showing that hypnotics are significantly associated with excess mortality,” Dr. Kripke added, noting it is also the first to specify the drugs and the first to show dose-response. “Even considering that the epidemiologic studies show association and do not prove causality, the risks look much larger than the benefits,” Dr. Kripke added.

Their analysis also showed a 35% overall increased risk for cancer in hypnotics users. “The risks of hypnotics are similar to the risks of cigarettes,” Dr. Kripke said.

The associations were evident in every age but were greatest among those aged 18 to 55 years, the investigators note. “Rough order-of-magnitude estimates…suggest that in 2010, hypnotics may have been associated with 320,000 to 507,000 excess deaths in the USA alone,” they report.

The new report is published February 28 in BMJ Open.

Dr. Kripke, a long-time critic of hypnotics, emphasized that the data “apply only to the particular hypnotics studied when used as sleeping pills. They do not apply to drugs which were not tested.” Moreover, he said, they may not apply when the drugs are used other purposes, “in which they might be life-saving. Oddly enough, the data for use of benzodiazepines for anxiety may not be similar,” Dr. Kripke noted.

“Risks Outweigh Any Benefits”

In 2010, an estimated 6% to 10% of adults in the United States took a hypnotic drug to help them sleep, with the percentages probably higher in Europe, Dr. Kripke and colleagues note in their report.

Data for their analysis were derived from the electronic medical records of the Geisinger Health System, the largest rural integrated health system in the United States, serving a 41-county area of Pennsylvania with roughly 2.5 million people.

Study participants included 10,529 adults (mean age, 54 years) who received hypnotic prescriptions and 23,676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between 2002 and 2007.

“As predicted,” report the researchers, patients prescribed any hypnotic, even fewer than 18 pills per year, were significantly more likely to die during follow-up compared with those prescribed no hypnotics. A dose-response effect was evident, and the findings “were robust with adjustment for multiple potential confounders and consistent using multiple strategies to address confounding by health status,” they report.

Table 1. Risk for Death by Level of Hypnotic Use

Any Hypnotic

Hazard Ratio (95% Confidence Interval)

P Value

Up to 18 pills per year

3.60 (2.92 – 4.44)

<.001

18 – 132 pills per year

4.43 (3.67 – 5.36)

<.001

> 132 pills per year

5.32 (4.50 – 6.30)

<.001

Zolpidem was the most commonly prescribed hypnotic during the study interval, followed by temazepam; both were associated with significantly elevated risks for death, again in a dose-response fashion.

Table 2. Risk for Death with Zolpidem and Temazepam

Agent (mg/y)

Hazard Ratio (95% Confidence Interval)

P Value

Zolpidem

5 – 130

3.93 (2.98 – 5.17)

<.001

130 – 800

4.54 (3.46 – 5.95)

<.001

> 800

5.69 (4.58 – 7.07)

<.001

Temazepam

10 – 240

3.71 (2.55 – 5.38)

<.001

240 – 1640

4.15 (2.88 – 5.99)

<.001

> 1640

6.56 (5.03 – 8.55)

<.001

“The death [hazard ratios] HR associated with prescriptions for less commonly prescribed hypnotic drugs were likewise elevated and the confidence limits of death hazards for each other hypnotic overlapped that for zolpidem, with the exception of eszopiclone, which was associated with higher mortality,” the investigators report.

Any hypnotic use in the upper third (>132 pills per year) was also associated with a modest but statistically significant increased risk for incident cancer (HR, 1.35; 95% CI, 1.18 – 1.55). The cancer risk was nearly 2-fold higher with temazepam (>1640 mg per year; HR, 1.99; 95% CI, 1.57 – 2.52).

Study Raises “Important Concerns”

Prior studies have shown multiple causal pathways by which hypnotics might raise the risk for death. For example, controlled trials have shown that hypnotics impair motor and cognitive skills, such as driving. Use of hypnotics has been linked to an increase in automobile crashes and an increase in falls due to hangover sedation. In some patients, hypnotics may increase or prolong sleep apneas and suppress respiratory drive. They may also increase incident depression.

“The meagre benefits of hypnotics, as critically reviewed by groups without financial interest… would not justify substantial risks,” the investigators write. They say a “consensus is developing that cognitive-behavioural therapy of chronic insomnia may be more successful than hypnotics.”

In a prepared statement, Trish Groves, MBBS, MRCPsych, editor-in-chief of BMJ Open, comments: “Although the authors have not been able to prove that sleeping pills cause premature death, their analyses have ruled out a wide range of other possible causative factors. So these findings raise important concerns and questions about the safety of sedatives and sleeping pills.”

American Academy of Sleep Medicine Urges Caution

In a statement, Nancy Collop, MD, president of the American Academy of Sleep Medicine (AASM) urged caution in interpreting these data.

“Although the study found that the use of hypnotic medication, or sleeping pills, was associated with an increased risk of mortality, a cause-and-effect relationship could not be established because the study only analyzed an insurance database,” Dr. Collop notes in the statement. “The authors also noted several other limitations to their study. For example, it was impossible for them to control for psychiatric conditions and anxiety, which is an area of significant concern to this study population.” In addition, she adds, those taking hypnotics had a “markedly greater rate of several comorbid health problems than the control group, suggesting they were a sicker population.”

AASM guidelines say that hypnotic medication prescribed appropriately and monitored carefully is a “reasonably” safe therapy that provides some improvement in people with insomnia, Dr. Collop notes in the statement. When possible, behavioral and cognitive therapies should be used and if needed supplemented with short-term use of hypnotics, the guidelines recommend. “Patients taking hypnotics should schedule regular follow-up visits with their physician, and efforts should be made to prescribe the lowest effective dose of medication and to reduce the medication’s usage when conditions allow,” the statement adds.

Effective treatment of insomnia is important because it’s associated with a “host” of comorbid conditions, including major depression and other psychiatric disorders, as well as increased for suicide, motor vehicle accidents, and possibly cardiovascular disease, Dr. Collop points out. Other research has shown widespread changes in physiology and the central nervous system associated with insomnia, and the “marked dysfunction and diminished quality of life” reported by some of those with insomnia are similar to that seen with major psychiatric or medical illnesses.

“We commend Drs. Kripke, Langer and Kline for contributing new scientific information to the study of sleep medicine,” Dr. Collop notes in the AASM statement. “We believe it is important for patients and physicians to be aware of how sleep issues impact health. But we caution physicians and patients to consider the years of research in support of limited hypnotics use, under the clinical guidelines of the AASM, before making any drastic changes in therapy.”

The AASM recommends that individuals with ongoing sleep problems should seek help from a board-certified sleep physician, “at one of 2,400 AASM-accredited sleep centers across the US.” A sleep center listing is found at the AASM’s site, www.sleepcenters.org.

In a competing interests statement, Dr. Kripke reports long-term criticism of hypnotic drugs at his nonprofit Web site. He also discloses a family interest in an investment corporation that has a small percentage of its assets in stock of sanofi-aventis and Johnson & Johnson. His 2 coauthors have disclosed no relevant financial relationships. Dr. Collop has disclosed no relevant financial relationships.

BMJ Open. Published online February 28, 2012. Abstract

Study Highlights

  • This matched cohort study took place at a large, integrated US health system.
  • The investigators extracted longitudinal electronic medical records for a 1-to-2 matched cohort survival analysis.
  • Patients who received hypnotic prescriptions (n = 10,529) were matched with 23,676 control participants with no hypnotic prescriptions.
  • Mean age was 54 years, and average duration of follow-up (between January 2002 and January 2007) was 2.5 years.
  • Data were adjusted for age, sex, smoking, body mass index, ethnicity, marital status, alcohol use, and history of cancer.
  • Cox proportional hazards models allowed calculation of HRs for death.
  • The Cox models were controlled for risk factors and used up to 116 strata, which exactly matched case patients and control participants by 12 classes of comorbidity.
  • Compared with patients who were prescribed no hypnotics, those who were prescribed any hypnotic had markedly increased hazards of dying.
  • There was a dose-response association. The HR was 3.60 (95% CI, 2.92 – 4.44) for 0.4 – 18 doses per year, 4.43 (95% CI, 3.67 – 5.36) for 18 to 132 doses per year, and 5.32 (95% CI, 4.50 – 6.30) for more than 132 doses per year.
  • In separate analyses, HRs were increased for several widely used hypnotics and for newer shorter-acting drugs, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates, and sedative antihistamines.
  • Among users in the highest tertiles of doses per year, the HRs for death were 5.3 for all hypnotics, 5.7 for zolpidem alone, and 6.6 for temazepam alone.
  • Patients in the highest tertile of hypnotic use had a significant (35%) increased risk for incident cancer (HR, 1.35; 95% CI, 1.18 – 1.55).
  • These findings were robust within groups having a comorbid condition, suggesting that the risks for death and cancer associated with hypnotic drugs were not explained by preexisting disease.
  • Hypnotic prescriptions were associated with increased diagnoses of esophageal regurgitation and peptic ulcer disease; the investigators note that increased regurgitation could cause esophageal damage and cancer.
  • On the basis of these findings, the investigators concluded that hypnotic prescriptions was associated with more than a 3-fold increased risk for death, even when the prescription was for less than 18 pills per year.
  • This association was also observed in separate analyses for several commonly used hypnotics and for newer, shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality rates.
  • Limitations of this study include possible residual confounding, lack of data on compliance with prescriptions, and inability to determine causality or to control for depression and other psychiatric symptoms.

Clinical Implications

  • Compared with control participants not receiving hypnotic prescriptions, patients receiving prescriptions for zolpidem, temazepam, and other commonly used hypnotics had a more than 3-fold risk for greater mortality in this matched cohort study. There appeared to be a dose-response relationship, but even patients prescribed less than 18 hypnotic doses per year had increased mortality rates.
  • Among patients prescribed hypnotics, the incidence of cancer was increased for several specific types of cancer, and those prescribed high doses had an increased overall rate of cancer of 35%.

Managing Adverse Effects to Optimize Treatment for ADHD

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Medication, Psychiatry, School Psychology on Sunday, 16 September 2012 at 10:35

Managing Adverse Effects to Optimize Treatment for ADHD

http://www.medscape.org/viewarticle/583252

Introduction

Attention-deficit/hyperactivity disorder (ADHD) begins in early childhood, and at least 50% of children will go on to have symptoms and impairment in adulthood.[1] Treatment requires a combination of medication and counseling, and adherence to medication therapy is essential for good outcomes. Managing adverse effects is a key component of effective treatment. Diagnosis and treatment of psychiatric comorbidity, which is common, is another essential aspect of care. This review will examine common adverse effects, prescribing medication successfully, deciding when to switch to an alternative medication, and some aspects of using concomitant medication.

Initiating Treatment

Diagnosis

According to the text revision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), the diagnosis of ADHD requires symptom onset before age 7 years. When evaluating children, parent and teacher input is essential and easy to obtain. Although some investigators have suggested that adult-onset ADHD is possible,[2] a full evaluation of an adult involves attempts to document symptoms and impairment in childhood. Interviews with parents and examination of school or medical records are often helpful.

Monitoring treatment success requires documentation of baseline functional impairment. In adults, collateral interviews with partners or even coworkers, with the patient’s permission, may be illuminating. Adults with ADHD experience important consequences from their impaired functioning. In a case-control study of 500 adults, those with ADHD had lower educational attainment, less job stability, lower incomes, and less successful relationships.[3] The evaluating clinician should investigate all of these areas.

The other essential aspect of evaluation is screening for comorbidity. In many cases, ADHD is not the chief complaint but comes to light during evaluation of another symptom. The most prevalent comorbid conditions are depression, bipolar disorder, and anxiety disorders.[4] Substance-use disorders including nicotine dependence are also more common in people with ADHD than in the general population.

Patient Education

Once the diagnosis is established, the physician should explain the implications and the proposed treatment plan. Educating patients and families about both the therapeutic and adverse effects of pharmacotherapy will help them know what to expect. Describing the benefits of treatment, including possible improvements in psychosocial outcomes, will allow a fully informed decision.

After learning about the side-effect profile of psychostimulants, a few patients who are ambivalent about medication may reject that treatment option. Nonstimulants should also be discussed to provide the full range of options, but the clinician should mention the trade-off of lower efficacy of nonstimulants compared with psychostimulants.[5] Once a patient has consented to a specific medication, the physician should explain the minimum trial duration necessary to determine a response and the dose-adjustment schedule. Clearly worded written information about the medication is usually appreciated by patients and their families. The informed-consent process should be documented.

Managing Adverse Effects

The common adverse effects of treatment are inherent in the pharmacodynamics of stimulant medication. Enhanced catecholamine neurotransmission in the central and autonomic nervous systems can cause insomnia, anorexia, and increased heart rate and blood pressure. These effects are most noticeable at the outset of treatment and after increases in dose. Patients often adjust to them during the ensuing weeks but may require encouragement during that interval.

Insomnia

Studies show that adults and children with untreated ADHD experience sleep anomalies compared with control subjects. A review of sleep studies of unmedicated children found evidence of more nocturnal motor activity and daytime somnolence compared with controls.[6] An actigraphic study of 33 adults with ADHD and 39 control subjects found similar differences between the groups at baseline, and sleep latency was prolonged in the ADHD subjects.[7] After treatment with methylphenidate, the adult patients continued to experience prolonged sleep latency and less total sleep duration, but sleep efficiency improved.

In a study that used the most comprehensive method of evaluating sleep, polysomnography in a sleep lab, 34 untreated adults with ADHD had increased nocturnal activity, reduced sleep efficiency, more awakenings, and reduced REM sleep compared with control subjects.[8] For 10 patients who were treated with open-label methylphenidate, repeat polysomnography showed better sleep efficiency, and the patients also reported improved restorative value of sleep.

Clinicians can conclude from these studies that the effect of medication on sleep may be beneficial in at least some patients, but further research with more subjects and with a variety of medications is needed. The fact remains that many patients treated with psychostimulants complain of initial insomnia, so an approach to manage this problem is necessary. Clinicians should document sleep patterns and complaints before treatment to help interpret problems that may arise after medication is prescribed.

Sleep hygiene, consisting of simple behavioral approaches to promote sound sleep (eg, creating a restful environment and avoiding caffeine), is an inexpensive intervention for all patients with insomnia. In a study of initial insomnia in 27 children 6-14 years treated for ADHD with psychostimulants, the researchers provided a sleep hygiene intervention to which 5 of the children responded.[9] They randomly assigned the nonresponders to either 5 mg of melatonin or placebo. Adverse effects of placebo and melatonin were not significantly different. The investigators found the combination of sleep hygiene and melatonin to be safe and effective, with an effect size of 1.7.

Although comparable randomized, controlled trial data do not exist for adults, mirtazapine has been reported as safe and effective for adults taking psychostimulants.[10]

Atomoxetine may have an effect on sleep that is different from that of psychostimulants, including reduced sleep latency but less efficiency. In a randomized, double-blinded, crossover trial, methylphenidate treatment for children with ADHD caused more initial insomnia but fewer awakenings compared with atomoxetine treatment.[11] Switching to atomoxetine may be considered for patients who prefer it or who do not respond to adjunctive interventions for stimulant-associated insomnia.

Appetite and Growth

Appetite reduction is common with psychostimulants and also can occur with nonstimulants, including atomoxetine and bupropion. This may be accompanied by nausea and abdominal pain in some patients. Some adults treated with psychostimulants may regard appetite suppression with resultant weight loss as beneficial. With long-acting stimulants, appetite returns later in the day.

Simple approaches to this problem include eating breakfast before taking medication. Having food in the stomach may also help reduce abdominal symptoms. Children in particular should have a nutritious, high-calorie snack in the evening if their food intake has been low since breakfast. However, parents should be warned to monitor evening intake of empty calories, such as candy and chips.

Weight loss or a downward shift of weight percentile is typical in children treated with psychostimulants. Short-term reduction in height growth rate during the initial 1-3 years of treatment with psychostimulants is well documented. In a literature review article, Poulton[12] concluded that a mean 1 cm/year deficit in height occurs during that interval. Less conclusive findings included a possible negative correlation between dose and growth, greater growth effect from dextroamphetamine than from methylphenidate, and rebound in growth of height and weight after discontinuation of stimulants.

More controversial is the effect on final stature. According to Poulton, “It would appear that most children achieve a satisfactory adult height, but there may be an important subgroup whose growth is permanently attenuated.”[12] Clinicians must discuss this with parents, many of whom will already have some concerns about the issue, and monitor children’s height and weight, ideally at each visit.

Research on atomoxetine is less comprehensive, but available evidence suggests a short-term downward shift in height and weight percentile. The effect on height may be minimal,[13] but longer-term studies are needed.

In a child or adult with worrisome weight loss, or if a child’s parents are anxious about growth deceleration, switching to another medication should be considered. Substituting methylphenidate for amphetamine would be more rational than substituting amphetamine for methylphenidate, but a nonstimulant is more likely to be ameliorative.

Affective Symptoms

Irritability, dysphoria, and (rarely) suicidal ideation can occur during treatment of ADHD.[14] Atomoxetine carries an FDA warning of a 0.4% incidence of suicidal ideation that has occurred in children during the first month of therapy.[15] No completed suicides have been reported, but discontinuation of atomoxetine is indicated if suicidal thoughts emerge. Minor mood changes and irritability occur with both psychostimulants and atomoxetine. Little evidence is available to guide intervention, but if the symptom is severe, the clinician may consider dose reduction, switching to an alternative psychostimulant, or trying an antidepressant nonstimulant such as bupropion or nortriptyline.

Psychosis and Mania

As dopamine transmission agonists, psychostimulants at excessive and prolonged doses would be expected to provoke psychotic symptoms or mania. These are well-reported but uncommon adverse effects during treatment in children, with an incidence estimated at 0.25%.[16] Emergent delusions, hallucinations, mania, or disorganized behavior requires treatment discontinuation. Most such symptoms resolve, but in a few cases, a bipolar disorder may be unmasked, which takes treatment priority.

Cardiovascular Effects

Psychostimulants cause increased heart rate and blood pressure in adults and children. The effect is mild in most cases, but in adults, some patients with borderline baseline blood pressure may develop frank hypertension. In a 24-month study of 223 adults treated with mixed amphetamine salts, 5 subjects developed hypertension and 2 experienced palpitations or tachycardia that required medication discontinuation.[17]

In a manufacturer-sponsored review of clinical-trial data, atomoxetine was found to cause small but clinically insignificant effects on blood pressure and heart rate in children, adolescents, and adults.[18] Treatment discontinuation for these effects was necessary only in a few adults. In managing any patient on psychostimulants or atomoxetine, clinicians should document pulse rate and blood pressure at baseline and every 6 months, with more frequent monitoring of patients with elevated risk for hypertension.

A more controversial aspect of ADHD medications is the effect on cardiac conduction and the rare occurrence of sudden death. In an unpublished review of documented cases of sudden death in children and adults treated with stimulants or atomoxetine through 2005, many of these patients had an underlying cardiac anomaly discovered on autopsy or were taking other medications.[19] Furthermore, psychostimulants have little effect on the QTc interval. Data on atomoxetine are conflicting, with US trials suggesting no QTc effect.[14] A Europe-wide postmarketing surveillance study, however, found a small number of cases of QTc prolongation that resolved with medication discontinuation.[20]

Whether a baseline electrocardiogram (ECG) is necessary for every patient is a matter of debate among specialists. Dr. David Goodman, an ADHD researcher and clinician, recommends specific screening for cardiac risk.[21] The 5 items he inquires about are history of spontaneous syncope, exercise-induced syncope, exercise-induced chest pain, sudden death in family members age 30 years and younger, and a family history of structural or electrical abnormalities. An ECG — and in ambiguous situations, specialist consultation — would be appropriate before initiating medication in older adults or any patient with risk factors.

Complex Psychopharmacology

Because comorbidity is common with ADHD, clinicians may prescribe psychostimulants with other medications, such as antidepressants, mood stabilizers, or antipsychotics. In fact, experienced psychopharmacologists often prescribe psychostimulants adjunctively for adults with treatment-resistant depression. Atomoxetine metabolism and a small portion of amphetamine metabolism involve CYP2D6, so caution is appropriate when combining these medications with fluoxetine, paroxetine, or fluvoxamine, which inhibit the enzyme.

Tricyclic antidepressants have been safely prescribed with psychostimulants, although several case reports exist of increased adverse effects with the combination of imipramine and methylphenidate.[22] Psychostimulants combined with monoamine oxidase inhibitors may cause a hypertensive crisis; coadministration is contraindicated.

The comorbidity of bipolar disorder and ADHD remains an area of active research and controversy. In a recent randomized, controlled trial, 40 children 6-17 years old with bipolar mania or hypomania and ADHD received divalproex for 8 weeks.[23] The 30 whose mood stabilized but who had active ADHD symptoms received mixed amphetamine salts. The researchers reported no significant adverse effects or worsening of mania. Similar controlled trials in adults are lacking, but in a retrospective study of 16 adult patients with bipolar disorder who were receiving methylphenidate, 5 patients had comorbid ADHD.[24] The others received a stimulant for depression. The patients were also taking various mood stabilizers, including divalproex, lithium, carbamazepine, lamotrigine, and second-generation antipsychotics. The investigators concluded that the practice was safe and effective, although “mild to moderate side effects” occurred, the single most common of which was irritability.

Conclusion

Initiating treatment with psychostimulants is no different from initiating other psychiatric medications. The key steps are:

  • Obtaining baseline data and, in exceptional cases, specialist consultation;
  • Educating patients and families about risks and benefits;
  • Documenting informed consent; and
  • Monitoring adverse effects and intervening as needed.

Rare adverse effects, such as jaundice, skin reactions, vasculitis, and thrombocytopenia, are idiosyncratic, and routine testing for them is not cost-effective.[14] Any unusual complaints should prompt further investigation. Regular documentation of pulse and blood pressure (and growth in children) is mandatory. Most adverse effects can be managed by reassurance or dose reduction, but switching to a different agent may at times be necessary. Combining medications for comorbidities is justifiable and often safe if diagnoses and rationale are well documented, but evidence of efficacy is not well established.

 

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis

In Neuroscience, Psychiatry, School Psychology on Thursday, 13 September 2012 at 13:03

Molecular Psychiatry advance online publication 11 September 2012; doi: 10.1038/mp.2012.126

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2012126a.html

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis
E Skafidas1, R Testa2,3, D Zantomio4, G Chana5, I P Everall5 and C Pantelis2,5

  1. 1Centre for Neural Engineering, The University of Melbourne, Parkville, VIC, Australia
  2. 2Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Parkville, VIC, Australia
  3. 3Department of Psychology, Monash University, Clayton, VIC, Australia
  4. 4Department of Haematology, Austin Health, Heidelberg, VIC, Australia
  5. 5Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia

Correspondence: Professor C Pantelis, National Neuroscience Facility (NNF), Level 3, 161 Barry Street, Carlton South, VIC 3053, Australia. E-mail: cpant@unimelb.edu.au

Received 6 July 2012; Accepted 9 July 2012
Advance online publication 11 September 2012

Abstract

Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test. This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN). Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective. Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets. In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.

Introduction

Autism spectrum disorders (ASDs) are a complex group of sporadic and familial developmental disorders affecting 1 in 150 births1 and characterized by: abnormal social interaction, impaired communication and stereotypic behaviors.2 The etiology of ASD is poorly understood, however, a genetic basis is evidenced by the greater than 70% concordance in monozygotic twins and elevated risk in siblings compared with the population.3, 4, 5 The search for genetic loci in ASD, including linkage and genome-wide association screens (GWAS), has identified a number of candidate genes and loci on almost every chromosome,6, 7, 8, 9, 10, 11 with multiple hotspots on several chromosomes (for example, CNTNAP2, NGLNX4, NRXN1, IMMP2L, DOCK4, SEMA5A, SYNGAP1, DLGAP2, SHANK2 and SHANK3),7, 12, 13, 14, 15 and copy number variations.9, 13, 16, 17, 18, 19, 20, 21 However, none of these have provided adequate specificity or accuracy to be used in ASD diagnosis. Novel approaches are required22 to examine multiple genetic variants and their additive contribution19, 23, 24 taking into account genetic differences between ethnicities and consideration of protective versus vulnerability single-nucleotide polymorphisms (SNPs).

The present study interrogated the Autism Genetics Resource Exchange (AGRE)25 SNP data with two aims: (1) to identify groups of SNPs that populate known cellular pathways that may be pathogenic or protective for ASD, and (2) to apply machine learning to identified SNPs to generate a predictive classifier for ASD diagnosis.26 The results were validated in two independent samples: the US Simons Foundation Autism Research Initiative (SFARI) and UK Wellcome Trust 1958 normal birth cohort (WTBC). This novel and strategic approach assessed the contribution of various SNPs within an additive SNP-based predictive test for ASD.

Materials and methods

The University of Melbourne Human Research Ethics Committee approved the study (Approval Numbers 0932503.1, 0932503.2).

Subjects

(i) Index sample: subject data from 2609 probands with ASD (including Autism, Asperger’s or Pervasive Developmental Disorder-not otherwise specified, but excluding RETT syndrome and Fragile X), and 4165 relatives of probands, was available from AGRE (http://www.agre.org); 1862 probands and 2587 first-degree relatives had SNP data from the Illumina 550 platform relevant to analyses (Figure 1a). Diagnosis of ASD was made by a specialist clinician and confirmed using the Autism Diagnostic Interview Revised (ADI-R27). Control training data was obtained from HapMap28 instead of relatives, as the latter may possess SNPs that predispose to ASD and skew analysis (Figures 1a and b).

Figure 1.

(a and b) Flow charts show the subjects used in the analyses. Key: AGRE, Autism Genetic Research Exchange; SFARI, Simons Foundation Autism Research Initiative; WTBC, Wellcome Trust 1958 normal birth cohort; CEU, of Central (Western and Northern) European origin; HAN, of Han Chinese origin; TSI, of Tuscan Italian origin; For panels 1a and b: ‘red boxes’—samples used in developing the predictive algorithm; ‘blue boxes’—samples used to investigate different ethnic groups; ‘green boxes’—validation sets; ‘light green boxes’—relatives assessed, including parents and unaffected siblings. Numbers in brackets represent numbers of males/females.

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(ii) Independent validation samples: 737 probands with ASD (ADI-R diagnosed) derived from SFARI; 2930 control subjects from WTBC (Figure 1b).

As SNP incidence rates vary according to ancestral heritage, HapMap data (Phase 3 NCBI build 36) was utilized to allocate individuals to their closest ethnicity. Individuals of mixed ethnicity were excluded; HapMap data has 1 403 896 SNPs available from 11 ethnicities. Any SNPs not included in the AGRE data measured on the Illumina 550 platform were discarded, resulting in 407 420 SNPs. Mitochondrial SNPs reported in AGRE, but not available in HapMap were excluded. The 30 most prevalent (>95%) SNPs within each ethnicity were identified and each ASD individual assigned to the group for which they shared the highest number of ethnically specific SNPs. HapMap groups were determined to be appropriate for analysis, as prevalence rates of the 30 SNPs relevant to each ethnicity were similar for each AGRE group assigned to that ethnicity, P<0.05.

Gene set enrichment analysis (GSEA)

Pathway analysis was selected because it depicts how groups of genes may contribute to ASD etiology (Supplementary S1) and mitigates the statistical problem of conducting a large number of multiple comparisons required in GWAS studies. The current pathway analysis differs from previous ASD analyses in three unique ways: (1) we divided the cohort into ethnically homogeneous samples with similar SNP rates; (2) both protective and contributory SNPs were accounted for in the analysis and (3) the pathway test statistic was calculated using permutation analysis. Although this is computationally expensive, benefits include taking account of rare alleles, small sample sizes and familial effects. It also relaxes the Hardy–Weinberg equilibrium assumption, that allele and genotype frequencies remain constant within a population over generations. Pathways were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and SNP-to-gene data obtained from the National Center for Biotechnology Information (NCBI). Intronic and exonic SNPs were included. AGRE individuals most closely matching the genetics of Utah residents of Western and Northern European (CEU), Tuscan Italian (TSI) and Han Chinese origin were used in the analysis. CEU individuals (975 affected individuals and 165 controls) were chosen as the index sample, representing the largest group affected in AGRE (Figure 1a). The CEU and Han Chinese had 116 753 SNPs that differed, whereas the CEU and TSI had 627 SNPs, differing in allelic prevalence at P<1 × 10−5. The pathway test statistic was calculated for CEU and Han individuals using a ‘set-based test’ in the PLINK29 software package, with P=0.05, r2=0.5 and permutations set to at least 2 000 000. Significance threshold was set conservatively at P<1 × 10−5, calculated from the number of pathways being examined (200). Therefore, significance was <0.05/200, set at <1 × 10−5 (see Supplementary S1).

Predicting ASD phenotype based upon candidate SNPs

For each individual, a 775-dimensional vector was constructed, corresponding to 775 unique SNPs identified as part of the GSEA. To examine whether SNPs could predict an individual’s clinical status (ASD versus non-ASD), two-tail unpaired t-tests were used to identify which of the 775 SNPs had statistically significant differences in mean SNP value (P<0.005). This significance level provided low classification error while maintaining acceptable variance in estimation of regression coefficients for each SNP’s contribution status, and provided the set of SNPs that maximized the classifier output between the populations (Figure 2 and Supplementary S2). This resulted in 237 SNPs selected for regression analysis. Each dimension of the vector was assigned a value of 0, 1 or 3, dependent on a SNP having two copies of the dominant allele, heterozygous or two copies of the minor allele. The ‘0, 1, 3’ weighting provided greater classification accuracy over ‘0, 1, 2’. Such approaches using superadditive models have been used previously to understand genetic interactions.30 The formula for the classifier and classifier performance are presented in Supplementary S3.

Figure 2.

Cumulative coefficient estimation error and percentage classification error as a function of P-value; P=0.005 provides good trade-off between classification performance and cumulative regression coefficient error.

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The CEU sample was divided into a training set (732 ASD individuals and 123 controls) and the remainder comprised the validation set. An affected individual was given a value of 10 and an unaffected individual a value of −10, providing a sufficiently large separation to maximize the distance between means (see Supplementary S3). Least squares regression analysis of the training set determined coefficients whose sum over product by SNP value mapped SNPs to clinical status. Kolmogorov–Smirnov goodness of fit test assessed the nature of distribution of SNPs by classification. At P=0.05, the distributions were accepted as being normally distributed, allowing determination of positive and negative predictive values (see ROC, Supplementary S4). The Durbin–Watson test was used to investigate the residual errors of the training set to determine if further correlations existed. At P=0.05, the residuals were uncorrelated. Regression coefficients were used to assess individual SNP contribution to clinical status.

AGRE validation

After analyzing the CEU training cohort, three cohorts were used for validation: 285 (243 probands, 42 controls) CEUs; a genetically similar TSI sample (65 patients, 88 controls); and a genetically dissimilar Han Chinese population (33 patients, 169 controls). To illustrate overlap in SNPs in first-degree relatives of individuals with ASD (n=1512), we mapped the SNPs of parents (n=1219; 581 male) and unaffected siblings (n=293; 98 male) of CEU origin who did not meet criteria for ASD. Finally, the accuracy of the predictive model was modified to test predictive ability using 10, 30 and 60 SNPs having the greatest weightings.

Independent validation

Samples included 507 CEU and 18 TSI subjects with ASD from SFARI, and 2557 CEU and 63 TSI from WTBC (Figure 1b).

Results

Identification of affected pathways

Analyses focused on 975 CEU ASD individuals, in which 13 KEGG pathways were significantly affected (P<1 × 10−5). The pathway analysis identified 775 significant SNPs perturbed in ASD. A number of the pathways were populated by the same genes and had inter-related functions (Table 1).

Table 1 – Statistically significant pathways for the CEU and Han Chinese.

Full table

The most significant pathways were: calcium signaling, gap junction, long-term depression (LTD), long-term potentiation (LTP), olfactory transduction and mitogen-activated kinase-like protein signaling. GSEA on the genetically distinct Han Chinese identified six pathways that overlapped with 13 pathways in the CEU cohort (estimate of this occurring by chance, P=0.05), including: purine metabolism, calcium signaling, phosphatidylinositol signaling, gap junction, long-term potentiation and long-term depression. Related to these pathways, the statistically significant SNPs in both populations were rs3790095 within GNAO1, rs1869901 within PLCB2, rs6806529 within ADCY5 and rs9313203 in ADCY2.

Diagnostic prediction of ASD

From the 775 SNPs identified within the CEU cohort, accurate genetic classification of ASD versus non-ASD was possible using 237 SNPs determined to be highly significant (P<0.005). Figure 3a shows the distribution of ASD and non-ASD individuals based on genetic classification. An individual’s clinical status was set to ASD if their score exceeded the threshold of 3.93. This threshold corresponds to the intersection points of the two normal curves. The theoretical classification error was 8.55%, and positive (ASD) and negative predictive values (controls) were 96.72% and 94.74%, respectively. Classification accuracy for the 285 CEU AGRE validation individuals was 85.6% and 84.3% for the TSI, while accuracy for the Han Chinese population was only 56.4%. Using the same classifier with the identical set of SNPs, accuracy of prediction of ASD in the independent data sets was 71.6%; positive and negative predictive accuracies were 70.8% and 71.8%, respectively.

Figure 3.

(a) Genetic-based classification of CEU population (AGRE and Controls) for ASD and non-ASD individuals, showing Gaussian approximation of distribution of individuals. As both the mapped ASD and control populations were well approximated by normal distributions, the asymptotic Test Positive Predictive Value (PPV) and Negative Predictive Value (NPV) was determined. For individuals with CEU ancestry, the PPV and NPV were 96.72% and 94.74%, respectively. (Note the test was substantially less predictive on individuals with different ancestry, that is, Han Chinese). (b) Genetic-based classification of CEU population, including first-degree relatives (parents and siblings of ASD children). Note that the distribution of relatives of ASD children maps between the ASD and the control groups, with no difference found between mothers and fathers (see Supplementary material S5). Key: ASD, autism spectrum disorder; relatives, first-degree relatives (parents and siblings); Siblings, siblings of ASD cases not meeting criteria for ASD; Autism Classifier Score, scores for each individual derived from the predictive algorithm, with greater values representing greater risk for autism.

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SNPs were compared with the affected and unaffected individuals. Figure 3b shows that relatives (parents and unaffected siblings combined) fall between the two distributions, with a mean score of 2.68 (s.d.=2.27). The percentage overlap of the relatives and affected individuals was 30.4%. The mean scores of the mothers and fathers did not differ (at P=0.05) with scores of 2.83 (s.d.=2.17) and 2.93 (s.d.=2.34), respectively (see Supplementary S5), whereas unaffected siblings (not meeting diagnostic criteria for ASD) fell between parents and cases (mean=4.74, s.d.=3.80). In testing the robustness of the predictive model, using fewer SNPs monotonically decreased accuracy in the AGRE-CEU analyses to 72% for 60 SNPs, 58% for 30 SNPs and 53.5% for 10 SNPs, with the distribution of parents being indistinguishable from controls.

Of the 237 SNPs within our classifier, presence of some contributed to vulnerability to ASD (Table 2a), whereas others were protective (Table 2b). Eight SNPs in three genes, GRM5, GNAO1 and KCNMB4, were highly discriminatory in determining an individual’s classification as ASD or non-ASD. For KCNMB4, rs968122 highly contributed to a clinical diagnosis of ASD, whereas rs12317962 was protective; for GNAO1, SNP rs876619 contributed, whereas rs8053370 was protective; for GRM5, SNPs rs11020772 was contributory, whereas rs905646 and rs6483362 were protective.

Table 2 – List of 15 most contributory (Table 2a) and 15 most protective (Table 2b) SNPs for ASD diagnosis in the CEU Cohort.

Full table

Discussion

Using pathway analysis, we have generated a genetic diagnostic classifier based on a linear function of 237 SNPs that accurately distinguished ASD from controls within a CEU cohort. This same diagnostic classifier was able to correctly predict and identify ASD individuals with accuracy exceeding 85.6% and 84.3% in the unseen CEU and TSI cohorts, respectively. Our classifier was then able to predict ASD group membership in subjects derived from two independent data sets with an accuracy of 71.6%, thus greatly adding strength to our original finding. However, the classifier was sub-optimal at predicting ASD in the genetically distinct Han Chinese cohort, which may be explained by differences in allelic prevalence. Although only 627 SNPs significantly differed between the TSI and CEU cohorts, this figure increased to 116 753 SNPs between the CEU and Han Chinese. It is likely that an additional set of SNPs may be predictive of ASD diagnosis in Han Chinese and that methods used for our classifier could be applicable to other ethnicities. Interestingly, parents and siblings of ASD-CEU individuals fell as distinct groups between the ASD and controls, reinforcing a genetic basis for ASD with neurobehavioral abnormalities reported in parents of ASD individuals also supporting our findings.31 When we altered the classifier by reducing the number of SNPs, not only did the predictive accuracy suffer but also the relatives merged into the control group. This suggests that use of relatives as controls in SNP GWAS studies is only valid when examining small numbers of SNPs and may not be appropriate when assessing genetic interactions.

There was considerable overlap in the pathways implicated in both the CEU and Han Chinese populations. The analysis demonstrated that SNPs in the Wnt signaling pathway contributed to a diagnosis of ASD in the CEU cohort, but not in the Han Chinese population. Although of interest, a firm conclusion regarding these differences and similarities will require replication in a larger Han Chinese population. Completion of diagnostic classification studies for other ethnic groups will invariably aid in identification of common pathological mechanisms for ASD.

The SNPs contributing most to diagnosis in our classifier corresponded to genes for KCNMB4, GNAO1, GRM5, INPP5D and ADCY8. The three SNPs that markedly skewed an individual towards ASD were related to the genes coding for KCNMB4, GNAO1 and GRM5. Homozygosity for KCNMB4 SNP carries a higher risk of ASD than SNPs related to GNAO1 and GRM5. By contrast, a number of SNPs protected against ASD, including rs8053370 (GNAO1), rs12317962 (KCNMB4), rs6483362 and rs905646 (GRM5). KCNMB4 is a potassium channel that is important in neuronal excitability and has been implicated in epilepsy and dyskinesia.32, 33 It is highly expressed within the fusiform gyrus, as well as in superior temporal, cingulate and orbitofrontal regions (Allen Human Brain Atlas, http://human.brain-map.org/), which are areas implicated in face identification and emotion face processing deficits seen in ASD.34 GNAO1 protein is a subgroup of Ga(o), a G-protein that couples with many neurotransmitter receptors. Ga(o) knockout mice exhibit ‘autism-like’ features, including impaired social interaction, poor motor skills, anxiety and stereotypic turning behavior.35 GNAO1 has also been shown to have a role in nervous development co-localizing with GRIN1 at neuronal dendrites and synapses,36 and interacting with GAP-43 at neuronal growth cones,37 with increased levels of GAP-43 demonstrated in the white matter adjacent to the anterior cingulate cortex in brains from ASD patients.38

In our findings, GRM5 SNPs have both a contributory (rs11020772) and protective (rs905646, rs6483362) effect on ASD. GRM5 is highly expressed in hippocampus, inferior temporal gyrus, inferior frontal gyrus and putamen (Allen Human Brain Atlas), regions implicated in ASD brain MRI studies.39 GRM5 has a role in synaptic plasticity, modulation of synaptic excitation, innate immune function and microglial activation.40, 41, 42, 43 GRM5-positive allosteric modulators can reverse the negative behavioral effects of NMDA receptor antagonists, including stereotypies, sensory motor gating deficits and deficits in working, spatial and recognition memory,44 features described in ASD.45, 46 With regard to GRM5’s involvement with neuroimmune function, this receptor is expressed on microglia,40, 47 with microglial activation demonstrated by us and others in frontal cortex in ASD.48, 49

Further, as GRM5 signaling is mediated via signaling through Gene Protein Couple Receptors, a possible interaction between GNAO1 and GRM5 is plausible. Genes such as PLCB2, ADCY2, ADCY5 and ADCY8 encode for proteins involved in G-protein signaling. Given this association, GRM5 may represent a pivotal etiological target for ASD; however, further work is needed in demonstrating these potential interactions and contribution to glutamatergic dysregulation in ASD.

In conclusion, within genetically homogeneous populations, our predictive genetic classifier obtained a high level of diagnostic accuracy. This demonstrates that genetic biomarkers can correctly classify ASD from non-ASD individuals. Further, our approach of identifying groups of SNPs that populate known KEGG pathways has identified potential cellular processes that are perturbed in ASD, which are common across ethnic groups. Finally, we identified a small number of genes with various SNPs of influential weighting that strongly determined whether a subject fell within the control or ASD group. Overall these findings indicate that a SNP-based test may allow for early identification of ASD. Further studies to validate the specificity and sensitivity of this model within other ethnic groups are required. A predictive classifier as described here may provide a tool for screening at birth or during infancy to provide an index of ‘at-risk status’, including probability estimates of ASD-likelihood. Identifying clinical and brain-based developmental trajectories within such a group would provide the opportunity to investigate potential psychological, social and/or pharmacological interventions to prevent or ameliorate the disorder. A similar approach has been adopted in psychosis research, which has improved our understanding of the disorder and prognosis for affected individuals.50

Conflict of interest

The authors declare no conflict of interest.

References

  1. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2002 Principal Investigators. Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, 14 sites, United States, 2002. MMWR Surveill Summ 2007; 56: 12–28. | PubMed |
  2. Association AP. Diagnostic and Statistical Manual of Mental Disorders. Revised 4th edn. Washington, DC, 2000.
  3. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63–77. | Article | PubMed | ISI | CAS |
  4. Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K et al. A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci USA 2007; 104: 12831–12836. | Article | PubMed | CAS |
  5. Cichon S, Craddock N, Daly M, Faraone SV, Gejman PV, Kelsoe J et al. Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry 2009; 166: 540–556. | Article | PubMed | ISI |
  6. Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 2008; 82: 150–159. | Article | PubMed | ISI | CAS |
  7. Weiss LA, Arking DE, Daly MJ, Chakravarti A. A genome-wide linkage and association scan reveals novel loci for autism. Nature 2009; 461: 802–808. | Article | PubMed | ISI | CAS |
  8. Sykes NH, Toma C, Wilson N, Volpi EV, Sousa I, Pagnamenta AT et al. Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection. Eur J Hum Genet 2009; 17: 1347–1353. | Article | PubMed | ISI |
  9. Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I et al. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry 2010; 15: 954–968. | Article | PubMed | ISI |
  10. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010; 466: 368–372. | Article | PubMed | ISI | CAS |
  11. State MW. Another piece of the autism puzzle. Nat Genet 2010; 42: 478–479. | Article | PubMed | CAS |
  12. Klauck SM. Genetics of autism spectrum disorder. Eur J Hum Genet 2006; 14: 714–720. | Article | PubMed | ISI | CAS |
  13. Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–328. | Article | PubMed | ISI | CAS |
  14. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358: 667–675. | Article | PubMed | ISI | CAS |
  15. Sousa I, Clark TG, Toma C, Kobayashi K, Choma M, Holt R et al. MET and autism susceptibility: family and case-control studies. Eur J Hum Genet 2009; 17: 749–758. | Article | PubMed |
  16. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T et al. Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449. | Article | PubMed | ISI | CAS |
  17. Kusenda M, Sebat J. The role of rare structural variants in the genetics of autism spectrum disorders. Cytogenet Genome Res 2008; 123: 36–43. | Article | PubMed |
  18. Losh M, Sullivan PF, Trembath D, Piven J. Current developments in the genetics of autism: from phenome to genome. J Neuropathol Exp Neurol 2008; 67: 829–837. | Article | PubMed |
  19. Buizer-Voskamp JE, Franke L, Staal WG, van Daalen E, Kemner C, Ophoff RA et al. Systematic genotype-phenotype analysis of autism susceptibility loci implicates additional symptoms to co-occur with autism. Eur J Hum Genet 2010; 18: 588–595. | Article | PubMed |
  20. Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, Vitkup D. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 2011; 70: 898–907. | Article | PubMed | ISI | CAS |
  21. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011; 70: 863–885. | Article | PubMed | ISI | CAS |
  22. Geschwind DH. Autism: many genes, common pathways? Cell 2008; 135: 391–395. | Article | PubMed | ISI | CAS |
  23. Freitag CM. The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry 2007; 12: 2–22. | Article | PubMed | ISI | CAS |
  24. Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012; 485: 242–245. | Article | PubMed | CAS |
  25. Geschwind DH, Sowinski J, Lord C, Iversen P, Shestack J, Jones P et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet 2001; 69: 463–466. | Article | PubMed | ISI | CAS |
  26. Guzzetta G, Jurman G, Furlanello C. A machine learning pipeline for quantitative phenotype prediction from genotype data. BMC Bioinformatics 2010; 11(Suppl 8): S3. | Article | PubMed |
  27. Lord C, Rutter M, Le Couteur A. Autism Diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994; 24: 659–685. | Article | PubMed | ISI | CAS |
  28. International HapMap Consortium. The International HapMap Project. Nature 2003; 426: 789–796. | Article | PubMed | ISI | CAS |
  29. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575. | Article | PubMed | ISI | CAS |
  30. Perez-Perez JM, Candela H, Micol JL. Understanding synergy in genetic interactions. Trends Genet 2009; 25: 368–376. | Article | PubMed | CAS |
  31. Mosconi MW, Kay M, D’Cruz AM, Guter S, Kapur K, Macmillan C et al. Neurobehavioral abnormalities in first-degree relatives of individuals with autism. Arch Gen Psychiatry 2010; 67: 830–840. | Article | PubMed |
  32. Cavalleri GL, Weale ME, Shianna KV, Singh R, Lynch JM, Grinton B et al. Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study. Lancet Neurol 2007; 6: 970–980. | Article | PubMed | ISI | CAS |
  33. Lee US, Cui J. {beta} subunit-specific modulations of BK channel function by a mutation associated with epilepsy and dyskinesia. J Physiol 2009; 587: 1481–1498. | Article | PubMed |
  34. Monk CS, Weng SJ, Wiggins JL, Kurapati N, Louro HM, Carrasco M et al. Neural circuitry of emotional face processing in autism spectrum disorders. J Psychiatry Neurosci 2010; 35: 105–114. | Article | PubMed |
  35. Jiang M, Gold MS, Boulay G, Spicher K, Peyton M, Brabet P et al. Multiple neurological abnormalities in mice deficient in the G protein Go. Proc Natl Acad Sci USA 1998; 95: 3269–3274. | Article | PubMed | CAS |
  36. Masuho I, Mototani Y, Sahara Y, Asami J, Nakamura S, Kozasa T et al. Dynamic expression patterns of G protein-regulated inducer of neurite outgrowth 1 (GRIN1) and its colocalization with Galphao implicate significant roles of Galphao-GRIN1 signaling in nervous system. Dev Dyn 2008; 237: 2415–2429. | Article | PubMed |
  37. Yang H, Wan L, Song F, Wang M, Huang Y. Palmitoylation modification of Galpha(o) depresses its susceptibility to GAP-43 activation. Int J Biochem Cell Biol 2009; 41: 1495–1501. | Article | PubMed |
  38. Zikopoulos B, Barbas H. Changes in prefrontal axons may disrupt the network in autism. J Neurosci 2010; 30: 14595–14609. | Article | PubMed | ISI | CAS |
  39. Toal F, Daly EM, Page L, Deeley Q, Hallahan B, Bloemen O et al. Clinical and anatomical heterogeneity in autistic spectrum disorder: a structural MRI study. Psychol Med 2010; 40: 1171–1181. | Article | PubMed | ISI |
  40. Drouin-Ouellet J, Brownell AL, Saint-Pierre M, Fasano C, Emond V, Trudeau LE et al. Neuroinflammation is associated with changes in glial mGluR5 expression and the development of neonatal excitotoxic lesions. Glia 2011; 59: 188–199. | Article | PubMed |
  41. Le Duigou C, Holden T, Kullmann DM. Short- and long-term depression at glutamatergic synapses on hippocampal interneurons by group I mGluR activation. Neuropharmacology 2011; 60: 748–756. | Article | PubMed |
  42. Popkirov SG, Manahan-Vaughan D. Involvement of the metabotropic glutamate receptor mGluR5 in NMDA receptor-dependent, learning-facilitated long-term depression in CA1 synapses. Cereb Cortex 2011; 21: 501–509. | Article | PubMed |
  43. Suzuki E, Okada T. Group I metabotropic glutamate receptors are involved in TEA-induced long-term potentiation at mossy fiber-CA3 synapses in the rat hippocampus. Brain Res 2010; 1313: 45–52. | Article | PubMed | CAS |
  44. Fowler SW, Ramsey AK, Walker JM, Serfozo P, Olive MF, Schachtman TR et al. Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats. Neurobiol Learn Mem 2011; 95: 73–79. | Article | PubMed | ISI |
  45. Sacco R, Curatolo P, Manzi B, Militerni R, Bravaccio C, Frolli A et al. Principal pathogenetic components and biological endophenotypes in autism spectrum disorders. Autism Res 2010; 3: 237–252. | Article | PubMed |
  46. Boyd BA, Baranek GT, Sideris J, Poe MD, Watson LR, Patten E et al. Sensory features and repetitive behaviors in children with autism and developmental delays. Autism Res 2010; 3: 78–87. | PubMed | ISI |
  47. Byrnes KR, Stoica B, Loane DJ, Riccio A, Davis MI, Faden AI. Metabotropic glutamate receptor 5 activation inhibits microglial associated inflammation and neurotoxicity. Glia 2009; 57: 550–560. | Article | PubMed |
  48. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57: 67–81. | Article | PubMed | ISI | CAS |
  49. Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 2010; 68: 368–376. | Article | PubMed | ISI |
  50. Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J, Phillips LJ et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003; 361: 281–288. | Article | PubMed | ISI |

Acknowledgements

Professor Christos Pantelis was supported by a NHMRC Senior Principal Research Fellowship (ID 628386). AGRE: We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M Lajonchere (PI). SFARI: We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A Beaudet, R Bernier, J Constantino, E Cook, E Fombonne, D Geschwind, R Goin-Kochel, E Hanson, D Grice, A Klin, D Ledbetter, C Lord, C Martin, D Martin, R Maxim, J Miles, O Ousley, K Pelphrey, B Peterson, J Piggot, C Saulnier, M State, W Stone, J Sutcliffe, C Walsh, Z Warren, E Wijsman). WTBC: We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G1234567 and the Wellcome Trust grant 012345.

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