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Archive for the ‘Psychopharmacology’ Category

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

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

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

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

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

 

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

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

 

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

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

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

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:

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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.

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