Psychopharmacology

Stimulants and Other ADHD Medications

Stimulants are sympathomimetic drugs that act both in the central nervous system (CNS) and peripherally by enhancing dopaminergic and noradrenergic transmission ( Table 33.3 ). Strong evidence exists for the effectiveness of these medications for the treatment of ADHD and aggression, as well as moderate evidence for the treatment of hyperactivity in autism spectrum disorder (ASD). In some cases, stimulants are used adjunctively with antidepressants in the treatment of depression and as monotherapy for fatigue or malaise associated with chronic physical illnesses.

No major differences in efficacy or tolerability have been found between different classes of stimulants, and no consistent patient profile identifies those who will respond preferentially to one class over another. The most common (generally dose-dependent) side effects of stimulants include headache, stomachache, appetite suppression, weight loss, blood pressure (BP) and heart rate increases, and delayed sleep onset. Less common side effects include irritability (particularly prominent in younger children), aggression, social withdrawal, and hallucinations (visual or tactile). Amphetamine preparations prescribed concurrently with serotonergic antidepressants can be associated with the development of serotonin syndrome.

Stimulants have been associated with elevations in mean BP (<5 mm Hg) and pulse (<10 beats/min); a subset of individuals (5–10%) may have greater increases. The rate of sudden death in pediatric patients taking stimulants is comparable to children in the general population; the hazard ratio for serious cardiovascular (CV) events is 0.75 (although up to a 2-fold increase in risk could not be ruled out). Moreover, a case series analysis of children with a CV incident and treatment with methylphenidate demonstrated an increased risk of arrhythmia (incidence rate ratio, 1.61) that was highest in the presence of congenital heart disease. The U.S. Food and Drug Administration (FDA) recommends that stimulants should be avoided in the presence of structural cardiac abnormalities (e.g., postoperative tetralogy of Fallot, coronary artery abnormalities, subaortic stenosis, hypertrophic cardiomyopathy) and patient symptoms (syncope, palpitations, arrhythmias) or family history (e.g., unexplained sudden death) suggestive of CV disease. In these circumstances, cardiology consultation is recommended before prescribing. Routine electrocardiograms (ECGs) are not recommended in the absence of cardiac risk factors.

Atomoxetine is a selective inhibitor of presynaptic norepinephrine reuptake; it increases dopamine and norepinephrine in the prefrontal cortex ( Table 33.3 ). It is less effective for the treatment of ADHD and aggression than stimulants, but atomoxetine has a longer duration of action (approximately 24 hr). Atomoxetine can have an onset of action within 1-2 wk of starting treatment, but there is an incrementally increasing response for up to 24 wk or longer. Common side effects of atomoxetine include nausea, headache, abdominal pain, insomnia, somnolence, erectile dysfunction, irritability, fatigue, decreased appetite, weight loss, and dizziness, along with nonclinical increases in heart rate and BP. Potential serious neuropsychiatric reactions include psychosis, mania, panic attacks, aggressive behavior, depression, seizures, and suicidal thinking. Atomoxetine carries an FDA warning regarding the risk of suicidal thinking and the need to monitor this closely. Atomoxetine also has been associated with hepatotoxicity and should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Because of the risk of sudden death, atomoxetine generally should be avoided in youth with known serious structural cardiac abnormalities, cardiomyopathy, heart rhythm abnormalities, or other serious cardiac problems.

The α-adrenergic agents clonidine and guanfacine , along with the longer-acting preparation of each, are presynaptic adrenergic agonists that appear to stimulate inhibitory presynaptic autoreceptors in the CNS ( Table 33.3 ). The extended-release formulation of guanfacine has moderate to strong evidence for the monotherapy of ADHD and weaker evidence as adjunctive therapy to stimulant medication. Combination stimulant/α-agonist therapy is superior to monotherapy with either and to placebo for improving inattention and working memory. Extended-release guanfacine also has moderate evidence for effective treatment of ADHD with comorbid oppositional defiant disorder (ODD), favorably affecting both symptom clusters, as well as for the treatment of agitation in autism.

Sedation, somnolence, headache, abdominal pain, hypotension, bradycardia, cardiac conduction abnormalities, dry mouth, depression, and confusion are potential side effects of clonidine and guanfacine. Abrupt withdrawal can result in rebound hypertension; overdose can result in death.

Antidepressants

Antidepressant drugs act on pre- and postsynaptic receptors affecting the release and reuptake of brain neurotransmitters, including norepinephrine, serotonin, and dopamine ( Table 33.4 ). There is strong evidence for the effectiveness of antidepressant medications in the treatment of anxiety and obsessive-compulsive disorders and weaker evidence for the treatment of depressive disorders. Suicidal thoughts have been reported during treatment with all antidepressants. The overall risk difference of suicidal ideation/attempts across all randomized controlled trials (RCTs) of antidepressants and indications has been reported as 0.7%, corresponding to a number needed to harm of 143. All antidepressants carry an FDA warning for suicidality; careful monitoring is recommended during the initial stages of treatment and following dose adjustments.

The selective serotonin reuptake inhibitor (SSRI) fluoxetine outperforms all other antidepressants (both SSRI and non-SSRI) studied and is the only SSRI separating from placebo in studies of depressed preadolescents . SSRIs have a large margin of safety. Side effects to SSRIs generally manifest in the first few weeks of treatment, and many will resolve with time. More common side effects include nausea, irritability, insomnia, appetite changes, weight loss/gain, headaches, dry mouth, dizziness, bruxism, diaphoresis, tremors, akathisia, restlessness, and behavioral activation. Approximately 5% of youth taking SSRIs, particularly children, develop behavioral activation (increased impulsivity, agitation, and irritability) that can be confused with mania, but the activation symptoms typically resolve when the dose is decreased or the medication discontinued. Sexual side effects are common, including decreased libido, anorgasmia, and erectile dysfunction. There is an increased risk of bleeding, especially when used with aspirin or nonsteroidal antiinflammatory drugs (NSAIDs).

SSRIs can be associated with abnormal heart rhythms, and citalopram causes dose-dependent QT-interval prolongation, contraindicating doses >40 mg/day. Patients with diabetes may experience hypoglycemia during SSRI treatment and hyperglycemia on discontinuation. Discontinuation symptoms (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania) are common with short-acting SSRIs (sertraline, citalopram, escitalopram), leading to a recommendation for divided doses if these medications are used at higher doses and graduated reduction if discontinued.

The serotonin syndrome is characterized by the triad of mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), and neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination). Serotonin syndrome results from excessive agonism of the CNS and peripheral nervous system serotonergic receptors and can be caused by a range of drugs, including SSRIs, valproate, and lithium. Interactions that can cause serotonin syndrome include SSRIs with linezolid (antibiotic with monoamine oxidase inhibitor properties) and with antimigraine preparations, as well as with amphetamine preparations, trazodone, buspirone, and venlafaxine. Serotonin syndrome is generally self-limited and can resolve spontaneously after the serotonergic agents are discontinued. Patients with severe disease require the control of agitation, autonomic instability, and hyperthermia as well as administration of 5-hydroxytryptamine (5-HT _2A , serotonin) antagonists (e.g., cyproheptadine).

The non-SSRI antidepressants include bupropion, duloxetine, venlafaxine, and mirtazapine ( Table 33.4 ). These medications all lack rigorous evidence to support their effectiveness in children and adolescents, and as such should not be considered first-line options. Bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI) , appears to have an indirect mixed-agonist effect on dopamine and norepinephrine transmission. No rigorous studies of bupropion for anxiety or depression have been conducted with children or adolescents, although some evidence suggests that bupropion may be effective for smoking cessation and ADHD in youth. Common side effects include irritability, nausea, anorexia, headache, and insomnia. Dose-related seizures (0.1% risk at 300 mg/day and 0.4% risk at 400 mg/day) have occurred with bupropion, so it is contraindicated in those with epilepsy, eating disorders, or at risk for seizures.

Duloxetine and venlafaxine are serotonin-norepinephrine reuptake inhibitors (SNRIs) . Duloxetine has FDA approval for treatment of generalized anxiety disorder in children and adolescents, but studies of duloxetine for depression in youth have been negative. There is some evidence in adults that duloxetine can be useful for fibromyalgia and chronic musculoskeletal pain, an effect that has also been observed in children and adolescents. Common side effects of duloxetine include nausea, diarrhea, decreased weight, and dizziness. Increases in heart rate and BP have been noted, and BP should be monitored at each visit and with each dosage change. In addition, there have been reports of hepatic failure, sometimes fatal; duloxetine should be discontinued and not resumed in patients who develop jaundice or other evidence of liver dysfunction. Duloxetine also has been associated with severe skin reactions (erythema multiforme and Stevens-Johnson syndrome).

Venlafaxine has only negative trials for the treatment of depression in children and adolescents, but does have favorable evidence for the treatment of anxiety. Side effects are similar to SSRIs, including hypertension, irritability, insomnia, headaches, anorexia, nervousness, and dizziness, and dropout rates are high in clinical trials of venlafaxine. BP should be monitored at each visit and with each dosage change. Discontinuation symptoms (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, seizures) are more pronounced with venlafaxine than the other non-SSRI antidepressants. In addition, suicidal thinking and agitation may be more common with venlafaxine than with other antidepressants, requiring close monitoring. In light of the substantial adverse effects, venlafaxine likely should be considered to be a third-line medication.

Mirtazapine is both a noradrenergic and a specific serotonergic antidepressant. Mirtazapine has only negative trials for the treatment of depression in youth and has no rigorous evidence of effectiveness for any other child or adolescent psychiatric disorder. Mirtazapine is associated with a risk for substantial weight gain and more rarely, hypotension, elevated liver enzymes, agranulocytosis, and QT prolongation. While its sedating properties have led to its adjunctive use for insomnia in adults with depressive/anxiety disorders, there is no evidence for use of mirtazapine in childhood sleep disorders.

The tricyclic antidepressants (TCAs) have mixed mechanisms of action; for example, clomipramine is primarily serotonergic, and imipramine is both noradrenergic and serotonergic. With the advent of the SSRIs, the lack of efficacy studies, particularly in depression, and more serious side effects, the use of TCAs in children has declined. Clomipramine is used in the treatment of obsessive-compulsive disorder ( Table 33.4 ). Unlike the SSRIs, the TCAs may be helpful in pain disorders. They have a narrow therapeutic index, with overdoses being potentially fatal. Anticholinergic symptoms (e.g., dry mouth, blurred vision, constipation) are the most common side effects. TCAs can have cardiac conduction effects in doses >3.5 mg/kg. BP and ECG monitoring is indicated at doses above this level.

Anxiolytic agents, including lorazepam, clonazepam, and hydroxyzine, have been effectively used for the short-term relief of the symptoms of acute anxiety ( Table 33.4 ). They are less effective as chronic (>4 mo) anxiolytic medications, particularly when one is used as monotherapy. Chronic use carries a significant risk of physical and psychological dependence.

Antipsychotics

Based on their mechanism of action, antipsychotic medications can be divided into first-generation (blocking dopamine D ₂ receptors) and second-generation (mixed dopaminergic and serotonergic antagonists) agents ( Table 33.5 ).

The second-generation (or atypical ) antipsychotics (SGAs) have relatively strong antagonistic interactions with 5-HT ₂ receptors and perhaps more variable activity at central adrenergic, cholinergic, and histaminic sites, which might account for the varying side effects, particularly metabolic, noted among these agents. The SGAs have moderate evidence for the treatment of agitation in autism and for the treatment of schizophrenia, bipolar disorder, and aggression. Haloperidol is a high-potency antipsychotic that is the first-generation (or typical ) antipsychotic most commonly used in treatment of agitation and schizophrenia.

The SGAs have significant side effects, including sedation, extra­pyramidal symptoms, weight gain, metabolic syndrome, diabetes, hyperlipidemia, hyperprolactinemia, hematologic effects (e.g., leukopenia, neutropenia), elevated liver transaminases, seizures, and CV effects ( Table 33.6 ). They have an FDA warning for increased risk of diabetes. Youth appear to be more sensitive to sedation, extrapyramidal side effects (except akathisia), withdrawal dyskinesia, prolactin abnormalities, weight gain, hepatotoxicity, and metabolic abnormalities. The development of diabetes or tardive dyskinesia appears less prevalent than in adults, although this may be a function of short follow-up periods because these side effects may not emerge until adulthood.

The management of adverse effects should be proactive with baseline assessment and ongoing monitoring ( Table 33.7 ). Abnormal movements (dystonia, akathisia, tardive dyskinesia) need periodic assessment using a standardized instrument such as the Abnormal Involuntary Movement Scale (AIMS). Valbenazine is FDA approved for the treatment of tardive dyskinesia in adults. The need for antiparkinsonian agents may be a consideration, particularly for patients at risk for acute dystonia or who have a previous history of dystonic reactions. CV effects of SGAs include prolongation of the QTc interval, tachycardia, orthostatic hypertension, and pericarditis. In patients with a personal or family history of cardiac abnormalities, including syncope, palpitations, arrhythmias, or sudden unexplained death, a baseline ECG with subsequent monitoring should be considered, along with cardiology consultation before prescribing. Alternative pharmacology should be considered if the resting heart rate exceeds 130 beats/min, or the PR, QRS, and QTc exceed 200, 120, and 460 milliseconds (msec), respectively.

The cytochrome P450 (CYP) enzymes metabolize the antipsychotics and as such necessitate that the PCP and psychiatrist are alert for potential drug-drug interactions that may impact the serum levels of all patient medications. CYP3A4 is mainly relevant to lurasidone, quetiapine, olanzapine, and haloperidol, whereas CYP2D6 predominately clears aripiprazole and risperidone. Asenapine is metabolized by CYP1A2 as well as direct glucuronidation by UGT1A4. Because <10% of paliperidone undergoes CYP first-pass metabolism, there is a lower likelihood of drug-drug interactions.

Primary prevention strategies to manage weight and metabolic dysfunction include educating the youth and family about healthy lifestyle behaviors and selecting an agent that has the lowest likelihood of impacting metabolic status. Secondary strategies would include intensifying healthy lifestyle instructions, consideration of switching agents, and a weight loss treatment program. Consideration of weight management interventions and increased monitoring of blood glucose and lipid levels should be implemented if weight gain exceeds the 90th percentile of body mass index (BMI) for age, or a change of 5 BMI units in youth who were obese at the initiation of treatment. Tertiary strategies, where diabetes, hypertension, obesity, or another metabolic abnormality has occurred, require more intensive weight reduction interventions, changing medication, and consultation with a medical subspecialist. Metformin has been used to treat severe weight gain associated with antipsychotic medication. Extrapyramidal adverse effects are generally dose and titration rate dependent and may respond to dose or titration rate reductions. More disabling effects may benefit from adjunctive treatment (e.g., anticholinergics, antihistamines).

Neuroleptic malignant syndrome is a rare, potentially fatal reaction that can occur during antipsychotic therapy. The syndrome generally manifests with fever, muscle rigidity, autonomic instability, and delirium. It is associated with elevated serum creatine phosphokinase levels, a metabolic acidosis, and high end-tidal CO ₂ excretion. It has been estimated to occur in 0.2–1% of patients treated with dopamine-blocking agents. Malnutrition and dehydration in the context of an organic brain syndrome and simultaneous treatment with lithium and antipsychotic agents (particularly haloperidol) can increase the risk. Mortality rates may be as high as 20–30% as a result of dehydration, aspiration, kidney failure, and respiratory collapse. Differential diagnosis of neuroleptic malignant syndrome includes infections, heat stroke, malignant hyperthermia, lethal catatonia, agitated delirium, thyrotoxicosis, serotonin syndrome, drug withdrawal, and anticholinergic or amphetamine, ecstasy, and salicylate toxicity.

Mood Stabilizers

Because of their limited evidence of effectiveness and concerns about safety, mood-stabilizing medications (see Table 33.5 ) have limited use in the treatment of child and adolescent psychiatric disorders. For the treatment of bipolar mania in adolescents, atypical antipsychotics are considered first-line therapy.

Of the mood stabilizers, lithium alone has rigorous support for the treatment of bipolar mania. Lithium's mechanism of action is not well understood; proposed theories relate to neurotransmission, endocrine effects, circadian rhythm, and cellular processes. Common side effects include polyuria and polydipsia, hypothyroidism, hyperparathyroidism, weight gain, nausea, abdominal pain, diarrhea, acne, and CNS symptoms (sedation, tremor, somnolence, memory impairment). Periodic monitoring of lithium levels along with thyroid and renal function is needed. Lithium serum levels of 0.8-1.2 mEq/L are targeted for acute episodes and 0.6-0.9 mEq/L are targeted for maintenance therapy. Acute overdose (level > 1.5 mEq/L) manifests with neurologic symptoms (e.g., tremor, ataxia, nystagmus, hyperreflexia, myoclonus, slurred speech, delirium, coma, seizures), and altered renal function. Toxicity is enhanced when dehydrated or with drugs that affect renal function, such as NSAIDs or angiotensin-converting enzyme (ACE) inhibitors. Neuroleptic malignant syndrome has been reported in patients concurrently taking antipsychotic drugs and lithium.