Managing Adverse Effects to Optimize Treatment for ADHD

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Medication, Psychiatry, School Psychology on Sunday, 16 September 2012 at 10:35

Managing Adverse Effects to Optimize Treatment for ADHD



Attention-deficit/hyperactivity disorder (ADHD) begins in early childhood, and at least 50% of children will go on to have symptoms and impairment in adulthood.[1] Treatment requires a combination of medication and counseling, and adherence to medication therapy is essential for good outcomes. Managing adverse effects is a key component of effective treatment. Diagnosis and treatment of psychiatric comorbidity, which is common, is another essential aspect of care. This review will examine common adverse effects, prescribing medication successfully, deciding when to switch to an alternative medication, and some aspects of using concomitant medication.

Initiating Treatment


According to the text revision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), the diagnosis of ADHD requires symptom onset before age 7 years. When evaluating children, parent and teacher input is essential and easy to obtain. Although some investigators have suggested that adult-onset ADHD is possible,[2] a full evaluation of an adult involves attempts to document symptoms and impairment in childhood. Interviews with parents and examination of school or medical records are often helpful.

Monitoring treatment success requires documentation of baseline functional impairment. In adults, collateral interviews with partners or even coworkers, with the patient’s permission, may be illuminating. Adults with ADHD experience important consequences from their impaired functioning. In a case-control study of 500 adults, those with ADHD had lower educational attainment, less job stability, lower incomes, and less successful relationships.[3] The evaluating clinician should investigate all of these areas.

The other essential aspect of evaluation is screening for comorbidity. In many cases, ADHD is not the chief complaint but comes to light during evaluation of another symptom. The most prevalent comorbid conditions are depression, bipolar disorder, and anxiety disorders.[4] Substance-use disorders including nicotine dependence are also more common in people with ADHD than in the general population.

Patient Education

Once the diagnosis is established, the physician should explain the implications and the proposed treatment plan. Educating patients and families about both the therapeutic and adverse effects of pharmacotherapy will help them know what to expect. Describing the benefits of treatment, including possible improvements in psychosocial outcomes, will allow a fully informed decision.

After learning about the side-effect profile of psychostimulants, a few patients who are ambivalent about medication may reject that treatment option. Nonstimulants should also be discussed to provide the full range of options, but the clinician should mention the trade-off of lower efficacy of nonstimulants compared with psychostimulants.[5] Once a patient has consented to a specific medication, the physician should explain the minimum trial duration necessary to determine a response and the dose-adjustment schedule. Clearly worded written information about the medication is usually appreciated by patients and their families. The informed-consent process should be documented.

Managing Adverse Effects

The common adverse effects of treatment are inherent in the pharmacodynamics of stimulant medication. Enhanced catecholamine neurotransmission in the central and autonomic nervous systems can cause insomnia, anorexia, and increased heart rate and blood pressure. These effects are most noticeable at the outset of treatment and after increases in dose. Patients often adjust to them during the ensuing weeks but may require encouragement during that interval.


Studies show that adults and children with untreated ADHD experience sleep anomalies compared with control subjects. A review of sleep studies of unmedicated children found evidence of more nocturnal motor activity and daytime somnolence compared with controls.[6] An actigraphic study of 33 adults with ADHD and 39 control subjects found similar differences between the groups at baseline, and sleep latency was prolonged in the ADHD subjects.[7] After treatment with methylphenidate, the adult patients continued to experience prolonged sleep latency and less total sleep duration, but sleep efficiency improved.

In a study that used the most comprehensive method of evaluating sleep, polysomnography in a sleep lab, 34 untreated adults with ADHD had increased nocturnal activity, reduced sleep efficiency, more awakenings, and reduced REM sleep compared with control subjects.[8] For 10 patients who were treated with open-label methylphenidate, repeat polysomnography showed better sleep efficiency, and the patients also reported improved restorative value of sleep.

Clinicians can conclude from these studies that the effect of medication on sleep may be beneficial in at least some patients, but further research with more subjects and with a variety of medications is needed. The fact remains that many patients treated with psychostimulants complain of initial insomnia, so an approach to manage this problem is necessary. Clinicians should document sleep patterns and complaints before treatment to help interpret problems that may arise after medication is prescribed.

Sleep hygiene, consisting of simple behavioral approaches to promote sound sleep (eg, creating a restful environment and avoiding caffeine), is an inexpensive intervention for all patients with insomnia. In a study of initial insomnia in 27 children 6-14 years treated for ADHD with psychostimulants, the researchers provided a sleep hygiene intervention to which 5 of the children responded.[9] They randomly assigned the nonresponders to either 5 mg of melatonin or placebo. Adverse effects of placebo and melatonin were not significantly different. The investigators found the combination of sleep hygiene and melatonin to be safe and effective, with an effect size of 1.7.

Although comparable randomized, controlled trial data do not exist for adults, mirtazapine has been reported as safe and effective for adults taking psychostimulants.[10]

Atomoxetine may have an effect on sleep that is different from that of psychostimulants, including reduced sleep latency but less efficiency. In a randomized, double-blinded, crossover trial, methylphenidate treatment for children with ADHD caused more initial insomnia but fewer awakenings compared with atomoxetine treatment.[11] Switching to atomoxetine may be considered for patients who prefer it or who do not respond to adjunctive interventions for stimulant-associated insomnia.

Appetite and Growth

Appetite reduction is common with psychostimulants and also can occur with nonstimulants, including atomoxetine and bupropion. This may be accompanied by nausea and abdominal pain in some patients. Some adults treated with psychostimulants may regard appetite suppression with resultant weight loss as beneficial. With long-acting stimulants, appetite returns later in the day.

Simple approaches to this problem include eating breakfast before taking medication. Having food in the stomach may also help reduce abdominal symptoms. Children in particular should have a nutritious, high-calorie snack in the evening if their food intake has been low since breakfast. However, parents should be warned to monitor evening intake of empty calories, such as candy and chips.

Weight loss or a downward shift of weight percentile is typical in children treated with psychostimulants. Short-term reduction in height growth rate during the initial 1-3 years of treatment with psychostimulants is well documented. In a literature review article, Poulton[12] concluded that a mean 1 cm/year deficit in height occurs during that interval. Less conclusive findings included a possible negative correlation between dose and growth, greater growth effect from dextroamphetamine than from methylphenidate, and rebound in growth of height and weight after discontinuation of stimulants.

More controversial is the effect on final stature. According to Poulton, “It would appear that most children achieve a satisfactory adult height, but there may be an important subgroup whose growth is permanently attenuated.”[12] Clinicians must discuss this with parents, many of whom will already have some concerns about the issue, and monitor children’s height and weight, ideally at each visit.

Research on atomoxetine is less comprehensive, but available evidence suggests a short-term downward shift in height and weight percentile. The effect on height may be minimal,[13] but longer-term studies are needed.

In a child or adult with worrisome weight loss, or if a child’s parents are anxious about growth deceleration, switching to another medication should be considered. Substituting methylphenidate for amphetamine would be more rational than substituting amphetamine for methylphenidate, but a nonstimulant is more likely to be ameliorative.

Affective Symptoms

Irritability, dysphoria, and (rarely) suicidal ideation can occur during treatment of ADHD.[14] Atomoxetine carries an FDA warning of a 0.4% incidence of suicidal ideation that has occurred in children during the first month of therapy.[15] No completed suicides have been reported, but discontinuation of atomoxetine is indicated if suicidal thoughts emerge. Minor mood changes and irritability occur with both psychostimulants and atomoxetine. Little evidence is available to guide intervention, but if the symptom is severe, the clinician may consider dose reduction, switching to an alternative psychostimulant, or trying an antidepressant nonstimulant such as bupropion or nortriptyline.

Psychosis and Mania

As dopamine transmission agonists, psychostimulants at excessive and prolonged doses would be expected to provoke psychotic symptoms or mania. These are well-reported but uncommon adverse effects during treatment in children, with an incidence estimated at 0.25%.[16] Emergent delusions, hallucinations, mania, or disorganized behavior requires treatment discontinuation. Most such symptoms resolve, but in a few cases, a bipolar disorder may be unmasked, which takes treatment priority.

Cardiovascular Effects

Psychostimulants cause increased heart rate and blood pressure in adults and children. The effect is mild in most cases, but in adults, some patients with borderline baseline blood pressure may develop frank hypertension. In a 24-month study of 223 adults treated with mixed amphetamine salts, 5 subjects developed hypertension and 2 experienced palpitations or tachycardia that required medication discontinuation.[17]

In a manufacturer-sponsored review of clinical-trial data, atomoxetine was found to cause small but clinically insignificant effects on blood pressure and heart rate in children, adolescents, and adults.[18] Treatment discontinuation for these effects was necessary only in a few adults. In managing any patient on psychostimulants or atomoxetine, clinicians should document pulse rate and blood pressure at baseline and every 6 months, with more frequent monitoring of patients with elevated risk for hypertension.

A more controversial aspect of ADHD medications is the effect on cardiac conduction and the rare occurrence of sudden death. In an unpublished review of documented cases of sudden death in children and adults treated with stimulants or atomoxetine through 2005, many of these patients had an underlying cardiac anomaly discovered on autopsy or were taking other medications.[19] Furthermore, psychostimulants have little effect on the QTc interval. Data on atomoxetine are conflicting, with US trials suggesting no QTc effect.[14] A Europe-wide postmarketing surveillance study, however, found a small number of cases of QTc prolongation that resolved with medication discontinuation.[20]

Whether a baseline electrocardiogram (ECG) is necessary for every patient is a matter of debate among specialists. Dr. David Goodman, an ADHD researcher and clinician, recommends specific screening for cardiac risk.[21] The 5 items he inquires about are history of spontaneous syncope, exercise-induced syncope, exercise-induced chest pain, sudden death in family members age 30 years and younger, and a family history of structural or electrical abnormalities. An ECG — and in ambiguous situations, specialist consultation — would be appropriate before initiating medication in older adults or any patient with risk factors.

Complex Psychopharmacology

Because comorbidity is common with ADHD, clinicians may prescribe psychostimulants with other medications, such as antidepressants, mood stabilizers, or antipsychotics. In fact, experienced psychopharmacologists often prescribe psychostimulants adjunctively for adults with treatment-resistant depression. Atomoxetine metabolism and a small portion of amphetamine metabolism involve CYP2D6, so caution is appropriate when combining these medications with fluoxetine, paroxetine, or fluvoxamine, which inhibit the enzyme.

Tricyclic antidepressants have been safely prescribed with psychostimulants, although several case reports exist of increased adverse effects with the combination of imipramine and methylphenidate.[22] Psychostimulants combined with monoamine oxidase inhibitors may cause a hypertensive crisis; coadministration is contraindicated.

The comorbidity of bipolar disorder and ADHD remains an area of active research and controversy. In a recent randomized, controlled trial, 40 children 6-17 years old with bipolar mania or hypomania and ADHD received divalproex for 8 weeks.[23] The 30 whose mood stabilized but who had active ADHD symptoms received mixed amphetamine salts. The researchers reported no significant adverse effects or worsening of mania. Similar controlled trials in adults are lacking, but in a retrospective study of 16 adult patients with bipolar disorder who were receiving methylphenidate, 5 patients had comorbid ADHD.[24] The others received a stimulant for depression. The patients were also taking various mood stabilizers, including divalproex, lithium, carbamazepine, lamotrigine, and second-generation antipsychotics. The investigators concluded that the practice was safe and effective, although “mild to moderate side effects” occurred, the single most common of which was irritability.


Initiating treatment with psychostimulants is no different from initiating other psychiatric medications. The key steps are:

  • Obtaining baseline data and, in exceptional cases, specialist consultation;
  • Educating patients and families about risks and benefits;
  • Documenting informed consent; and
  • Monitoring adverse effects and intervening as needed.

Rare adverse effects, such as jaundice, skin reactions, vasculitis, and thrombocytopenia, are idiosyncratic, and routine testing for them is not cost-effective.[14] Any unusual complaints should prompt further investigation. Regular documentation of pulse and blood pressure (and growth in children) is mandatory. Most adverse effects can be managed by reassurance or dose reduction, but switching to a different agent may at times be necessary. Combining medications for comorbidities is justifiable and often safe if diagnoses and rationale are well documented, but evidence of efficacy is not well established.



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