Chapter 33

Psychopharmacology

David R. DeMaso, Heather J. Walter

Psychopharmacology is the first-line treatment for several child and adolescent psychiatric disorders (e.g., ADHD, schizophrenia, bipolar) and is used adjunctively with psychosocial treatments for other disorders (or coexisting conditions), including anxiety, depression, autism spectrum, tic, trauma-related, and obsessive-compulsive disorders. Although pediatric primary care practitioners (PCPs) may routinely manage medications for attention-deficit/hyperactivity disorder (ADHD), anxiety, and depression, they may be called on to manage psychotropic medications with which they have had less experience. As such, it is useful for PCPs to be familiar with basic information about child and adolescent psychopharmacology. Before prescribing a psychotropic medication, PCPs should review full prescribing information for each medication (in package inserts or at reliable websites such as the National Institutes of Health DailyMed * ) to obtain complete and up-to-date information about indications, contraindications, warnings, interactions, and precautions.

Pediatric prescribers should be aware of “best practice” principles that underlie medication assessment and management by child and adolescent psychiatrists (Table 33.1 ), so as to consider extrapolation of these principles to prescribing in the primary care setting. The use of medication involves a series of interconnected steps, including performing an assessment, constructing working diagnoses and an explanatory formulation, deciding on treatment and a monitoring plan, obtaining treatment assent/consent, and implementing treatment.

Table 33.1

Best Principles for Use of Psychotropic Medications With Children and Adolescents

1. 1. Before initiating pharmacotherapy, a psychiatric evaluation is completed.
2. 2. Before initiating pharmacotherapy, a medical history is obtained, and a medical evaluation is considered when appropriate.
3. 3. The prescriber communicates with other professionals to obtain collateral history and collaborate in the monitoring of outcome and side effects during the medication trial.
4. 4. The prescriber develops a psychosocial and psychopharmacologic treatment plan based on the best available evidence.
5. 5. The prescriber develops a plan to monitor the patient during the medication trial.
6. 6. The prescriber is cautious when the medication trial cannot be appropriately monitored.
7. 7. The prescriber educates the patient and family about the patient's diagnosis and treatment plan.
8. 8. The prescriber obtains and documents informed consent before initiating the medication trial and at appropriate intervals during the trial.
9. 9. The informed-consent process focuses on the risks and benefits of the proposed and alternative treatments.
10. 10. The medication trial should involve an adequate dose of medication for an adequate duration.
11. 11. The prescriber reassesses the patient if the patient fails to respond to the medication trial as expected.
12. 12. The prescriber has a clear rationale for using medication combinations.
13. 13. The prescriber has a specific plan for medication discontinuation.

Adapted from American Academy of Child and Adolescent Psychiatry: Practice parameter on the use of psychotropic medication in children and adolescents. J Am Acad Child Adolesc Psychiatry 48(9):961–973, 2009.

Questions remain about the quality of the evidence supporting the use of many psychotropic medications in children and adolescents. Therefore, cognitive, emotional, and behavioral symptoms are targets for medication treatment when (1) there is no or insufficient response to available evidence-based psychosocial interventions, (2) the patient's symptoms convey significant risk of harm, or (3) the patient is experiencing significant distress or functional impairment. Common target symptoms include agitation, aggression, anxiety, depression, hyperactivity, inattention, impulsivity, mania, obsessions, compulsions, and psychosis (Table 33.2 ). All these can be quantitatively measured with standardized symptom rating scales to establish baseline symptom severity and facilitate “treating to target.”

Table 33.2

Target Symptom Approach to Psychopharmacologic Management

TARGET SYMPTOM	MEDICATION CONSIDERATIONS
Agitation	Atypical antipsychotic Typical antipsychotic Anxiolytic
Aggression	Stimulant Atypical antipsychotic
Anxiety	Antidepressant Anxiolytic (only situational anxiety)
Depression	Antidepressant
Hyperactivity, inattention, impulsivity	Stimulant α-Agonist Atomoxetine
Mania	Atypical antipsychotic Lithium
Obsessions, compulsions	Antidepressant
Psychosis	Atypical antipsychotic Typical antipsychotic
Tics	α-Agonist Atypical antipsychotic Typical antipsychotic

Adapted from Shaw RJ, DeMaso DR: Clinical manual of pediatric psychosomatic medicine: mental health consultation with physically ill children and adolescents, Washington, DC, 2006, American Psychiatric Press, p 306.

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.

Table 33.3

Select Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms

GENERIC (BRAND) APPROXIMATE DURATION OF ACTION	FDA APPROVED (Pediatric age range in years)	TARGET SYMPTOMS	DAILY STARTING DOSE	DAILY THERAPEUTIC DOSAGE RANGE*	SELECT MEDICAL MONITORING AND PRECAUTIONS
STIMULANTS
Long Acting
OROS methylphenidate (Concerta) 12 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	18 mg	Age 6-12: 18-54 mg Age >12: 18-72 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse; potential for GI obstruction
Dexmethylphenidate (Focalin XR) † 10-12 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	5 mg	5-30 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Amphetamine combination (Adderall XR) † 12 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	5 mg	5-30 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Lisdexamfetamine (capsule † and chewable) (Vyvanse) 12 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	20 mg	20-70 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Methylphenidate transdermal (Daytrana) 12 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	10 mg	10-30 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse; skin reactions
Methylphenidate suspension (Quillivant XR) 12 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	20 mg	20-60 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Intermediate Acting
Methylphenidate (Metadate CD, Ritalin LA) 8 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	10 mg	10-60 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Dextroamphetamine (Dexedrine Spansule) 8 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	5 mg	5-40 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Methylphenidate chewable (Quillichew ER) 8 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	20 mg	20-60 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Short Acting
Dexmethylphenidate (Focalin) 4-5 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	5 mg	5-20 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Methylphenidate (Ritalin, Methylin) 4 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	5 mg	5-60 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Amphetamine combination (Adderall) 4-5 hr	ADHD (3+)	Inattention Hyperactivity Impulsivity	Age 3-5: 2.5 mg Age ≥6: 5 mg	5-40 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
Dextroamphetamine (Dexedrine) 4 hr	ADHD (3+)	Inattention Hyperactivity Impulsivity	Age 3-5: 2.5 mg Age ≥6: 5 mg	5-40 mg	Personal and family CV history; personal seizure history; Ht, Wt, BP, P; bipolar or psychotic symptoms; substance abuse
SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITOR
Atomoxetine (Strattera) 24 hours	ADHD (6+)	Inattention Hyperactivity Impulsivity	<70 kg: 0.5 mg/kg/day >70 kg: 40 mg	<70 kg: 0.5-1.2 mg/kg/day >70 kg: 40-100 mg	Personal and family CV history; BP, P; liver injury; suicidal ideation; bipolar or psychotic symptoms
ALPHA (α)-AGONISTS
Short Acting
Clonidine (Catapres) 4 hr	None	Inattention Hyperactivity Impulsivity	0.05 mg	27-40.5 kg: 0.05-0.2 mg 40.5-45 kg: 0.05-0.3 mg >45 kg: 0.05-0.4 mg	CV history; BP, P; rebound hypertension; cardiac conduction abnormalities
Guanfacine (Tenex) 6 hr	None	Inattention Hyperactivity Impulsivity	0.5 mg	27-40.5 kg: 0.5-2 mg 40.5-45 kg: 0.5-3 mg >45 kg: 0.5-4 mg	CV history; BP, P; rebound hypertension; cardiac conduction abnormalities
Long Acting
Clonidine (Kapvay) 12 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	0.1 mg	0.1-0.4 mg	CV history; BP, P; rebound hypertension; cardiac conduction abnormalities
Guanfacine (Intuniv) 24 hr	ADHD (6+)	Inattention Hyperactivity Impulsivity	1 mg	Monotherapy : 25-33.9 kg: 2-3 mg 34-41.4 kg: 2-4 mg 41.5-49.4 kg: 3-5 mg 49.5-58.4 kg: 3-6 mg 58.5-91 kg: 4-7 mg >91 kg: 5-7 mg Adjunctive (with stimulant): 0.05-0.12 mg/kg/day	CV history; BP, P; rebound hypertension, cardiac conduction abnormalities

^* Doses shown in table may exceed maximum recommended dose for some children.

^† Capsule contents may be sprinkled on soft food.

FDA, U.S. Food and Drug Administration; CV, cardiovascular; Ht, height; Wt, weight; BP, blood pressure; P, pulse; GI, gastrointestinal.

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.

Table 33.4

Select Medications for Depression and Anxiety in Children and Adolescents

GENERIC (BRAND)	FDA APPROVED (Pediatric age range in years)	TARGET SYMPTOMS	DAILY STARTING DOSE	DAILY THERAPEUTIC DOSAGE RANGE*	SELECT MEDICAL MONITORING AND PRECAUTIONS
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Citalopram (Celexa)	None	Depression Anxiety Obsessions/compulsions	10 mg	10-40 mg	Suicidal ideation; QT prolongation at doses >40 mg; abnormal bleeding; mania; SS, DS
Escitalopram (Lexapro)	Depression (12-17)	Depression Anxiety Obsessions/compulsions	5 mg	5-20 mg	Suicidal ideation; abnormal bleeding; mania; SS, DS
Fluoxetine (Prozac)	Depression (8-17) OCD (7-17)	Depression Anxiety Obsessions/compulsions	Age 6-12: 10 mg Age 13-17: 20 mg	Depression: 10-20 mg Anxiety, OCD: 10-60 mg	Suicidal ideation; abnormal bleeding; mania; SS
Sertraline (Zoloft)	OCD (6-17)	Depression Anxiety Obsessions/compulsions	Age 6-12: 12.5-25 mg Age 13-17: 25-50 mg	12.5-200 mg	Suicidal ideation; abnormal bleeding; mania; SS, DS
ATYPICAL ANTIDEPRESSANTS
Bupropion (Wellbutrin XL)	None	Depression	150 mg	150-300 mg	Suicidal ideation; neuropsychiatric reaction, seizures (>300 mg/day), BP; mania; contraindicated in patients with seizure and eating disorders
Duloxetine (Cymbalta)	Anxiety (7-17)	Depression Anxiety	30 mg	30-60 mg	Suicidal ideation; BP, P; liver damage; severe skin reactions; abnormal bleeding; mania; SS, DS
Mirtazapine (Remeron)	None	Depression	7.5 mg	7.5-45 mg	Suicidal ideation; weight; somnolence; agranulocytosis; QT prolongation; mania; SS, DS
Venlafaxine (Effexor XR)	None	Depression Anxiety	37.5 mg	37.5-225 mg	Suicidal ideation; BP; abnormal bleeding; mania; SS, DS
TRICYCLIC ANTIDEPRESSANTS
Clomipramine (Anafranil)	OCD (10-17)	Obsessions Compulsions	25 mg	25-200 mg	Suicidal ideation; BP; P; ECG; blood level; mania; SS; seizures; DS
ANXIOLYTIC AGENTS (SITUATIONAL USE)
Lorazepam (Ativan)	None	Anxiety	0.5 mg	0.5-2 mg	Respiratory depression; sedation; physical and psychological dependence; paradoxical reactions
Clonazepam (Klonopin)	None	Panic	0.5 mg	0.5-1 mg	Respiratory depression; sedation; physical and psychological dependence; paradoxical reactions; suicidal ideation
Hydroxyzine (Atarax, Vistaril)	Anxiety	Anxiety	50 mg	Age <6: 50 mg Age >6: 50-100 mg	QT prolongation

^* Doses shown in table may exceed maximum recommended dose for some children.

OCD, Obsessive-compulsive disorder; BP, blood pressure; P, pulse; ECG, electrocardiogram; SS, serotonin syndrome; DS, discontinuation syndrome.

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 D₂ receptors) and second-generation (mixed dopaminergic and serotonergic antagonists) agents (Table 33.5 ).

Table 33.5

Select Medications for Psychosis, Mania, Irritability, Agitation, Aggression, and Tourette Disorder in Children and Adolescents

GENERIC (BRAND)	FDA APPROVED (Pediatric age range in years)	TARGET SYMPTOMS	DAILY STARTING DOSE	DAILY THERAPEUTIC DOSAGE RANGE*	SELECT MEDICAL MONITORING AND PRECAUTIONS
SECOND-GENERATION ANTIPSYCHOTICS
Aripiprazole (Abilify) Available in liquid preparation	Bipolar (10-17) Schizophrenia (13-17) Irritability in autism (6-17) Tourette (6-17)	Mania Psychosis Irritability Aggression Agitation Vocal/motor tics	Bipolar, schizophrenia: 2 mg Autism: 2 mg Tourette: 2 mg	Bipolar, schizophrenia: 10-30 mg Autism: 5-15 mg Tourette: 5-20 mg	BMI, BP, P, fasting glucose and lipids, abnormal movements; compulsive behaviors; neuroleptic malignant syndrome; leukopenia, neutropenia, agranulocytosis; seizures
Olanzapine (Zyprexa) Available in liquid, dissolvable, and IM preparations	Bipolar (13-17) Schizophrenia (13-17)	Mania Psychosis Agitation	2.5 mg	2.5-20 mg	BMI, BP, P, fasting glucose and lipids, abnormal movements; skin rash (DRESS); neuroleptic malignant syndrome; leukopenia, neutropenia, agranulocytosis; seizures
Quetiapine (Seroquel)	Bipolar (10-17) Schizophrenia (13-17)	Mania Psychosis Agitation	25 mg bid	Bipolar: 400-600 mg Schizophrenia: 400-800 mg	BMI, BP, P, fasting glucose and lipids, abnormal movements; ophthalmologic exam; neuroleptic malignant syndrome; leukopenia, neutropenia, agranulocytosis; seizures; QT prolongation
Risperidone (Risperdal) Available in liquid and dissolvable preparations	Bipolar (10-17) Schizophrenia (13-17) Irritability in autism (5-17)	Mania Psychosis Irritability Aggression Agitation	Bipolar, schizophrenia: 0.5 mg Autism: <20 kg: 0.25 mg ≥20 kg: 0.5 mg	Bipolar, schizophrenia: 1-6 mg Autism: 0.5-3 mg	BMI, BP, P, fasting glucose and lipids, prolactin, abnormal movements; neuroleptic malignant syndrome; leukopenia, neutropenia, agranulocytosis; seizures
Paliperidone (Invega) Available in liquid and IM preparations	Schizophrenia (12-17)	Psychosis	3 mg	<51 kg: 3-6 mg ≥51 kg: 3-12 mg	BMI, BP, P, fasting glucose and lipids, prolactin, abnormal movements, QT prolongation; neuroleptic malignant syndrome; potential for GI obstruction; leukopenia, neutropenia, agranulocytosis; seizures
Lurasidone (Latuda)	Schizophrenia (13-17)	Psychosis	40 mg	40-80 mg	BMI, BP, P, fasting glucose and lipids, prolactin, abnormal movements; neuroleptic malignant syndrome; leukopenia, neutropenia, agranulocytosis; seizures
Asenapine (Saphris)	Bipolar (10-17)	Mania Psychosis	2.5 mg twice daily	5-20 mg	BMI, BP, P, fasting glucose and lipids, prolactin, abnormal movements; QT prolongation; neuroleptic malignant syndrome; leukopenia, neutropenia, agranulocytosis; seizures
FIRST-GENERATION ANTIPSYCHOTIC
Haloperidol (Haldol) Available in liquid and IM preparations	Psychosis Tourette disorder Severe behavioral disorders Agitation (3-17)	Mania Psychosis Irritability Aggression Agitation Vocal/motor tics	0.05 mg/kg/day	0.05-0.15 mg/kg/day	BP, P; abnormal movements; QT prolongation; neuroleptic malignant syndrome; encephalopathy when combined with lithium; leukopenia, neutropenia, agranulocytosis
MOOD STABILIZER
Lithium carbonate Available in liquid preparation	Bipolar (12-17)	Mania	Acute mania: 1800 mg/day Target level: 1.0-1.5 mEq/L	Long-term control: 900-1200 mg/day Target level: 0.6-1.2 mEq/L	Serum level, CBC/diff, thyroid function, BUN/creatine, UA, electrolytes, FBS; ECG; encephalopathy when combined with haloperidol

^* Doses shown in table may exceed maximum recommended dose for some children.

BMI, Body mass index; BP, blood pressure; P, pulse; IM, intramuscular; GI, gastrointestinal; CBC/diff, complete blood count with differential; BUN, blood urea nitrogen; UA, urinalysis; FBS, fasting blood sugar; ECG, electrocardiogram.

The second-generation (or atypical ) antipsychotics (SGAs) have relatively strong antagonistic interactions with 5-HT₂ 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.

Table 33.6

Adverse Effects for Select Antipsychotic Medications

ADVERSE EFFECT	ARIPIPRAZOLE (ABILIFY)	OLANZAPINE (ZYPREXA)	QUETIAPINE (SEROQUEL)	RISPERIDONE (RISPERDAL)	PALIPERIDONE (INVEGA)	LURASIDONE (LATUDA)	HALOPERIDOL (HALDOL)
Weight gain	0/+	+++	++	++	++	0/+	+
QTc interval	0/+	0/+	+	+	+	0/+	0/+
Sedation	0/+	+/++	++	+	0/+	+/++	+
Prolactin increase	0	+	0	+++	+++	+	++/+++
Lipid increase	0/+	+++	++	+	+	0/+	0/+
Diabetes	0/+	+++	++	+	+	0/+	0/+
Anticholinergic	0	++	+/++	0	0	0	0
Acute parkinsonism	+	0/+	0	++	++	+/++	+++
Akathisia	++	+	+	+	+	+/++	+++
Tardive dyskinesia	0/+	0/+	0/+	0/+	0/+	0/+	++
Withdrawal dyskinesia	+/++	0/+	0/+	+	+	+	++
Orthostasis	0/+	++	++	+	+	0/+	0
Seizures	0/+	0/+	0/+	0/+	0/+	0/+	0/+

0 = none; 0/+ = minimal; + = mild; ++ = moderate; +++ = severe.

Adapted from Correll CU: Antipsychotic medications. In Dulcan MK, editor: Dulcan's textbook of child and adolescent psychiatry, ed 2, Washington, DC, 2016, American Psychiatric Press, pp 795–846.

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.

Table 33.7

Metabolic Monitoring Parameters Based on ADA/APA Consensus Guidelines

	BASELINE	WEEK 4	WEEK 8	WEEK 12	EVERY 3 MO THEREAFTER	ANNUALLY
Medical history*	X			X		X
Weight (BMI)	X	X	X	X	X	X
Waist circumference	X			X		X
Blood pressure	X			X		X
Fasting glucose/HbA1c	X			X		X
Fasting lipids	X			X		X

^* Personal and family history of obesity, hypertension, and cardiovascular disease.

BMI, Body mass index; Hb, hemoglobin.

From American Diabetes Association (ADA), American Psychiatric Association (APA), American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes, Diabetes Care 27:596–601, 2004.

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 CO₂ 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.

Medication Use in Physical Illness

There are special considerations in the use of psychotropic medications with physically ill children. Between 80% and 95% of most psychotropic medications are protein bound, the exceptions being lithium (0%), methylphenidate (10–30%), and venlafaxine (25–30%). As a result, psychotropic levels may be directly affected because albumin binding is reduced in many physical illnesses. Metabolism is primarily through the liver and gastrointestinal (GI) tract, with excretion via the kidney. Therefore, dosages may need to be adjusted in children with hepatic or renal impairment.

Hepatic Disease

Lower doses of medications may be required in patients with hepatic disease. Initial dosing of medications should be reduced, and titration should proceed slowly. In steady-state situations, changes in protein binding can result in elevated unbound medication, resulting in increased drug action even in the presence of normal serum drug concentrations. Because it is often difficult to predict changes in protein binding, it is important to maintain attention to the clinical effects of psychotropic medications and not rely exclusively on serum drug concentrations.

In acute hepatitis, there is generally no need to modify dosing because metabolism is only minimally altered. In chronic hepatitis and cirrhosis, hepatocytes are destroyed, and doses may need to be modified.

Medications with high baseline rates of liver clearance (e.g., haloperidol, sertraline, venlafaxine, TCAs) are significantly affected by hepatic disease. For drugs that have significant hepatic metabolism, intravenous administration may be preferred because parenteral administration avoids first-pass liver metabolic effects, and the dosing and action of parenteral medications are similar to those in patients with normal hepatic function. Valproic acid can impair the metabolism of the hepatocyte disproportionate to the degree of hepatocellular damage. In patients with valproate-induced liver injury, low albumin, high prothrombin, and high ammonia levels may be seen without significant elevation in liver transaminases.

Gastrointestinal Disease

Medications with anticholinergic side effects can slow GI motility, affecting absorption and causing constipation. SSRIs increase gastric motility and can cause diarrhea. SSRIs can increase the risk of GI bleeding, especially when administered with NSAIDs. Extended-release or controlled-release preparations of medications can reduce GI side effects, particularly where gastric distress is related to rapid increases in plasma drug concentrations.

Renal Disease

With the exceptions of lithium and gabapentin, psychotropic medications do not generally require significant dosing adjustments in kidney failure. It is important to monitor serum concentrations in renal insufficiency, particularly for medications with a narrow therapeutic index; cyclosporine can elevate serum lithium levels by decreasing lithium excretion. Patients with kidney failure and those on dialysis appear to be more sensitive to TCA side effects, possibly because of the accumulation of hydroxylated tricyclic metabolites.

Because most psychotropic medications are highly protein bound, they are not significantly cleared by dialysis. Lithium is essentially completely removed by dialysis, and the common practice is to administer lithium after dialysis. Patients on dialysis often have significant fluid shifts and are at risk for dehydration, with neuroleptic malignant syndrome more likely in these situations.

Cardiac Disease

Antipsychotics, TCAs, and citalopram (>40 mg/day) can lead to prolongation of the QTc interval, with increased risk of ventricular tachycardia and ventricular fibrillation, particularly in patients with structural heart disease. Patients with a baseline QTc interval of >440 msec should be particularly considered at risk. The normal QTc value in children is 400 msec (±25-30 msec). A QTc value that exceeds 2 SD (>450-460 msec) is considered too long and may be associated with increased mortality. An increase in the QTc from baseline of >60 msec is also associated with increased mortality.

There is increased risk of morbidity and mortality in patients with preexisting cardiac conduction problems. Some of the calcium channel–blocking agents (e.g., verapamil) can slow atrioventricular conduction and can theoretically interact with TCAs. Patients with Wolff-Parkinson-White syndrome who have a short PR interval (<0.12 sec) and widened QRS interval associated with paroxysmal tachycardia are at high risk for life-threatening ventricular tachycardia that may be exacerbated by the use of antipsychotics, TCAs, and citalopram.

Respiratory Disease

Anxiolytic agents can increase the risk of respiratory suppression in patients with pulmonary disease. In these situations, SSRIs and buspirone are good alternative medications to consider in treating disabling anxiety. Possible airway compromise caused by acute laryngospasm should be considered when dopamine-blocking antipsychotic agents are used.

Neurologic Disease

Psychotropic medications can be used safely with epilepsy following consideration of potential interactions among the medication, the seizure disorder, and the anticonvulsant. Any behavioral toxicity of anticonvulsants used either alone or in combination should be considered before proceeding with psychotropic treatment. Simplification of combination anticonvulsant therapy or a change to another agent can result in a reduction of behavioral or emotional symptoms and obviate the need for psychotropic intervention. Clomipramine and bupropion possess significant seizure-inducing properties and should be avoided when the risk of seizures is present.

Principles for Psychotropic Prescribing in Primary Care

Because nonpsychiatrist physicians (predominantly pediatricians) provide three quarters and two thirds, respectively, of all child and adolescent mental health visits in which new psychotropic medications are initiated, it can be helpful for PCPs to develop consultative relationships with child and adolescent psychiatrists who can advise about safe and effective psychotropic prescribing. If such consultation is not readily available, PCPs may benefit from following a standardized approach to prescribing that is feasible in the primary care setting (Table 33.8 ). This approach emphasizes baseline assessment with standardized rating scales to identify target symptoms and their level of severity; selection of FDA-approved medications for the target symptom and patient age range; adherence to recommendations regarding therapeutic dosage ranges; follow-up rating scale assessment to monitor medication response; sufficient duration of the medication trial; and switching to an alternative FDA-approved medication if the first medication trial is ineffective. Generally, consultation with a physician experienced in managing the child's disorder should occur if one is considering using multiple psychotropic medications, doses outside of therapeutic range, or non-FDA-approved medications.

Table 33.8

Principles for Psychotropic Prescribing in Primary Care

1. 1. Identify potential target symptoms through the systematic use (e.g., at all well-child visits) of broad-band mental health screening instruments, such as the Pediatric Symptom Checklist or the Strengths and Difficulties Questionnaire.
2. 2. Establish the baseline severity of identified target symptom(s) through the use of narrow-band symptom rating scales, such as the following (selected from instruments in the public domain):
   • a. Depression
     • • Mood and Feelings Questionnaire
     • • Centers for Epidemiologic Studies Depression Scale
     • • Patient Health Questionnaire-9
   • b. Anxiety
     • • Screen for Child Anxiety Related Disorders
   • c. ADHD, Behavior Problems
     • • Vanderbilt ADHD Diagnostic Rating Scale
     • • SNAP-IV 19
   • d. Aggression
     • • Outburst Monitoring Scale
3. 3. Select a medication that is FDA approved for the target symptom and age range; titrate as tolerated from starting dose to therapeutic dosage range.
4. 4. Treat to target : Readminister baseline symptom rating scale at regular intervals (at least monthly) to assess treatment response (reduction in rating scale score), with the goal of remission (rating scale score below clinical cutpoint).
5. 5. If medication trial is unsuccessful after adherence to therapeutic dose for adequate duration (typically 1-2 mo), consider 2nd trial of alternative medication with FDA approval for target symptom and age range, following same principles as for 1st trial.
6. 6. If 2nd medication trial is unsuccessful, consultation with a child and adolescent psychiatrist is recommended before resorting to medication doses outside therapeutic range, polypharmacy, or non–FDA-approved medications.

ADHD, Attention-deficit/hyperactivity disorder; FDA, U.S. Food and Drug Administration.

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^* https://dailymed.nlm.nih.gov/dailymed/index.cfm .