▪ Pediatric Psychopharmacology

SPECIFIC DRUG TREATMENTS

Stimulants

Clinical Applications and Empirical Support

The stimulants (Table 21.1), especially the short- and long-acting forms of methylphenidate and amphetamine, are first-line treatments for attention-deficit/hyperactivity disorder (ADHD). The most commonly used stimulants for the treatment of patients with ADHD include methylphenidate, dextroamphetamine and the mixed preparation of D,L-amphetamine. Immediaterelease methylphenidate has been studied more carefully than the other stimulants and remains the most commonly used agent in clinical practice. Although less well studied, the amphetamine products and extended-release formulations of methylphenidate have short-term efficacy and safety profiles that are comparable to methylphenidate.

The empirical basis for the use of stimulants in children with ADHD rests on findings from hundreds of short-term, randomized, placebo-controlled studies conducted over the past 30 to 40 years. Results from controlled studies over the past decade provide additional information about dose response, similarities and differences in response across stimulant preparations, and the importance of clinical monitoring to achieve optimal response.

To date, only methylphenidate has been evaluated in long-term studies. With its sample size of 576 children, the Multimodal Treatment Study of children with ADHD (MTA) provided convincing evidence for the long-term benefits of methylphenidate. In the MTA study, children were randomly assigned to one of four treatment groups: medication management (primarily methylphenidate administered in a systematic fashion with close monitoring); an intensive behavioral treatment program; combined medication management and the same behavioral treatment program; or community care, which served as the control group. After 14 months of treatment, all four groups showed improvement compared with baseline. Comparisons across the four groups showed that the combined treatment group and the medication management group did significantly better than the community care group and the behavioral treatment only group across a range of outcomes.

A variety of extended-release formulations, both formulated with methylphenidate and with D,L-amphetamine, are available. These longer acting preparations are as effective as the
immediate-release compounds and show similar side effect profiles. The advantage of the long-acting preparations is that children do not need to take a dose in school, which may enhance compliance. The longer duration formulations may minimize the behavioral rebound often seen with immediate-release formulations.

TABLE 21.1 STIMULANTS AND STIMULANT ALTERNATIVES

Drug	Mechanism of Action	Main Indications and Clinical Uses	Dosage mg/d	Schedule	Adverse Effects	Comments	Select Brand Names and Preparations Available
Methylphenidate	Dopamine presynaptic release and reuptake blockade	ADHD	15-60 (Ritalin) 18-54 mg/d (Concerta)	BID/TID (MPH); QD (Concerta)	Insomnia, decreased appetite, weight loss, dysphoria/Possible reduction in growth velocity during long term use/Withdrawal and rebound hyperactivity/Unmasking or induction of tics. Possible induction/accelaraion of mania/psychosis.	Longer acting preparations may have lower peak and valley effects and less rebound hyperactivity	Ritalin/Methilyn: 5, 10, 20 mg t; Sustained release t, 20 mg Concerta: 18, 36 mg
Dextroamphetamine			10-40	BID/TID			Dexedrine: 5, mg t; Sustained release spansules, 5, 10, 15 mg
Amphetamine compound			10-40	QD/BID			Adderal: 5, 10, 20, 30 mg; Adderal XR: 5, 10, 15, 20, 25, 30 c
Pemoline			37.5-112.5	QD	Same as other stimulants/Abnormal liver function tests and serious hepatotoxicty	Liver monitoring necessary (2/month minimum suggested). Rarely used any more given hepatotoxic concerns	Cylert: 18.75, 37.5, 75 t, 37.5 mg chewable t
Atomoxetine	Selective noradrenergic reuptake inhibitor		10-80	QD/BID	Loss of appetite, dizziness, nausea; rare instances of hepatotoxicity have been reported	Technically an antidepressant and not a stimulant, but used only in the treatment of ADHD.	Strattera: 10, 18, 25, 40, 60, 80 mg c
Note: Doses are provided as general guidelines only, and are not meant to be definitive.
All doses must be individualized and monitored through the appropriate clinical and/or laboratory means.
Abbreviations: c (capsule), t (tablet)

Adverse Effects

Growth retardation, presumed to be secondary to stimulant-induced appetite suppression, has been a common concern among clinicians and families alike. Based on data from a large cohort of clinic cases treated with stimulants, it appears that slowed growth may be temporary and that children with ADHD may be shorter than their age mates before puberty but catch up in adolescence. Height and weight should be monitored regularly in children treated with stimulants and tracked during long-term maintenance.

Other common side effects include sleep disturbance, depressed mood, stomachaches, headaches, overfocusing on details, tics and mannerisms, and picking at skin. Insomnia can be difficult to sort out because many children with ADHD have sleep difficulties before receiving stimulant medications. Thus, the child’s sleep history should be documented before treatment and monitored throughout. As noted, it is common practice for the third dose of methylphenidate to be lower than the first two to minimize a possible rebound effect. The administration of clonidine as an aid for sleep has been proposed, but its use is controversial. Data regarding the emergence of tics after stimulant treatment have been contradictory, and the issue remains unresolved. Nonetheless, children with tic disorders should be monitored carefully when treated with stimulants. Dose reduction may be sufficient, but discontinuation may be warranted in some cases.

Antidepressants

The antidepressants include a group of chemically diverse compounds that have been shown to be effective in the treatment of adults with major depression. More recently, several antidepressants have been used in the treatment of adults with a range of other disorders, including obsessive-compulsive disorder (OCD), generalized anxiety disorder, panic disorder, social phobia, and posttraumatic stress disorder. These broader clinical applications are likewise being implemented with increasing frequency in the pediatric population even though the level of empirical support varies widely. Antidepressants can be classified according to (1) chemical similarity (e.g., tricyclic compounds, and within these, secondary and tertiary amines), (2) primary mode of action (e.g., the selective serotonin reuptake inhibitors [SSRIs], selective norepinephrine reuptake inhibitors, or monoamine oxidase inhibitors), and (3) miscellaneous, newer antidepressants (e.g., bupropion, venlafaxine, or mirtazapine). The SSRIs are by far the most extensively used antidepressant class in children and adolescents and the class with the best empirical support. Because of these facts and the recent controversy over their potential association with suicidal thoughts, plans, and self-injurious behavior, the SSRIs are discussed first.

Selective Serotonin Reuptake Inhibitors

The SSRIs are a group of chemically unrelated compounds that potently inhibit the return of serotonin into presynaptic neurons (Table 21.2A). Currently marketed SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram.

Clinical Applications and Empirical Support

As a group, these medications are generally well tolerated, can typically be given once a day, and do not require blood level monitoring or electrocardiographic (ECG) monitoring. Early clinical trials looked at the use of clomipramine and fluoxetine in children and adolescents. Several large placebo-controlled clinical trials were conducted in pediatric populations with
sertraline and fluvoxamine in OCD, with fluoxetine and paroxetine in depression, and with fluvoxamine in non-OCD anxiety disorders. In each of these studies, the SSRI was superior to placebo in the primary outcome measure of interest.

TABLE 21.2A SSRI ANTIDEPRESSANTS

Drug	Mechanism of Action	Main Indications and Clinical Uses	Dosage mg/d	Schedule	Adverse Effects	Comments	Select Brand Names and Preparations Available
*A. Selective Serotonin Reuptake Inhibitors (SSRIs)*
Fluoxetine	Serotonin presynaptic reuptake blockade	Obsessive Compulsive Disorder/Major Depression/Other Anxiety Disorders	2.5-40	QD/FLV = BID	Irritability/Akathisia/Insomnia/Appetite decrease (acute use) or increase (chronic)/GI symptoms/Headaches/Dizziness/Flu-like symptoms during discontinuation/Complex drug interactions. All SSRIs have variable degrees of CYP inhibition (see previous chapter). Higher doses often needed for OCD. Exacerbation or new onset of suicidal ideation was initially reported for paroxetine in 2003; careful monitoring recommendations for all antidepressants followed a review of all clinical trials for child and adolescent depression (see text for details).	Only SSRI with FDA approval for the treatment of depression. Longest half life.	Prozac: 10 mg t/c 20 mg t, oral solution 20 mg/5 ml
Sertraline			25-200				Zoloft: 25, 50, 100 mg t
Paroxetine			10-30			SSRI originally associated with suicidal ideation; no longer recommended for use in children and adolescents.	Paxil: 10, 20, 30, 40 mg t Oral suspension 10 mg/5 ml
Fluvoxamine			12.5-200			Short half-life implies BID dosing and greater likleihood of withdrawal syndrome.	Luvox: 25, 50, 100 mg t
Citalopram			10-40			Most favorable drug interaction profiles among the SSRIs.	Celexa: 20, 40 t
l-Citalopram			10-20			Most favorable drug interaction profiles among the SSRIs.	Lexapro: 10, 20 t

Depression. Fluoxetine, sertraline, paroxetine, and citalopram have each been studied for the treatment of depression in children and adolescents. A landmark fluoxetine study in 1999 was the first to show superiority of an antidepressant over placebo for the treatment of depression in children and adolescents and was subsequently followed by a replication study. A randomized clinical trial of citalopram has also shown superiority over placebo.

The largest and most important study to date in this area is the Treatment for Adolescents with Depression Study (TADS). In it, 439 adolescents were randomly assigned to fluoxetine alone, cognitive behavior therapy (CBT) alone, their combination, or pill placebo for 12 weeks in the acute phase and for a 6-month extension. Results of the acute phase showed that combined treatment had the highest rate of positive response (71% for the combined treatment compared with 61% for medication alone, 43% for CBT alone, and 35% for placebo). The combined treatment group also had a slightly lower rate of suicidal ideation compared with the fluoxetine-only group. Fluoxetine alone and fluoxetine with CBT were both superior to placebo. However, combined treatment with fluoxetine and CBT was not significantly better than medication only, and CBT alone was not superior to placebo.

Concerns over the safety of the SSRIs in children and adolescents have become paramount. Extensive review by British and American regulatory agencies eventually led to their removal (in the United Kingdom) and the introduction of a U.S. Food and Drug Administration (FDA)— mandated black box warning (in the United States). A review was commissioned by the FDA of all clinical trials using SSRIs in the treatment of children and adolescents with depression and other indications (n >4,400 subjects across 26 controlled trials). This review showed an increase risk of new-onset suicidal ideation in SSRI-treated individuals versus those treated with placebo (occurring at respective rates of 4% and 2%, for a risk ratio of 1.95; 95% confidence interval, 1.28-2.98). All reported events referred to suicidal ideation rather than suicidal acts or completed suicides. It is important to note that data suggest that increasing rates of SSRI use during the past decade may be related to decreases in rates of completed suicide, particularly among adolescents and young adults. Taken together, these data support the judicious use of antidepressants in children and adolescents, particularly if other interventions have failed or are not available. When treatment with an SSRI is opted for, fluoxetine may be generally recommended as the first-line agent because of its FDA indication for depression and a lower reported rate of incident suicidal ideation. Guidelines from the FDA and the American Academy of Child and Adolescent Psychiatry call for intensive monitoring during the early phases of treatment: as often as weekly for the first 4 weeks, every other week for the next month, and monthly thereafter.

Obsessive-Compulsive Disorder. Sertraline and fluvoxamine have been evaluated in randomized, multisite, placebo-controlled trials of parallel groups. Using the Children’s Yale-Brown Obsessive Compulsive Scales (CYBOCS) as the primary outcome measure, both drugs were superior to placebo in improving obsessive-compulsive symptoms. Sertraline was evaluated in 187 subjects and was associated with at least a 25% improvement in the CYBOCS score in 53% of subjects compared with 37% for placebo. In a separate study of 120 children between the ages of 8 and 17 years, fluvoxamine at a mean daily dose of 165 mg was effective in 42% of children compared with 26% among those treated with placebo. Although these data suggest that the SSRIs are effective for the treatment of OCD in children and adolescents, the magnitude of response may not be large, as has been shown in a meta-analysis of all studies published through 2002.

Adverse Effects. As a group, the SSRIs are generally well tolerated. In addition to their propensity for cytochrome P450-based drug interactions common side effects of the SSRIs in children and adolescents appear to be behavioral activation and gastrointestinal (GI) complaints such as nausea or diarrhea. Signs of behavioral activation include motor restlessness, insomnia, impulsiveness, disinhibited behavior, and garrulousness. The potential for behavioral activation
early in treatment underscores the importance of starting at low doses and moving upward slowly. As with other antidepressants, hypomania and mania have been reported, and peripubertal children may be at heightened risk. Other adverse effects include heartburn, decreased appetite, fatigue, and sexual side effects. Suicidal ideation is discussed above

A flu-like syndrome characterized by dizziness, moodiness, nausea, vomiting, myalgia, and fatigue occurring in association with the withdrawal or acute discontinuation of shorter acting SSRIs such as paroxetine, fluvoxamine, and sertraline has been described.

Drug Interactions

The use of combined psychotropic medications seems to be on the rise, underscoring the importance of monitoring drug-drug interactions in clinical practice. SSRIs vary in their potential for such interactions at particular P450 cytochromes. As illustrated previously, inhibition of the P450 cytochrome responsible for metabolizing an additive drug raises its serum level, thereby enhancing its beneficial or deleterious effects.

Tricyclic Antidepressants

Clinical Applications and Empirical Support

Tricyclic antidepressants (TCAs; Table 21.2B) have been used to treat several psychiatric disorders of childhood over the past 3 decades, including depression, ADHD, OCD, separation anxiety disorder, and enuresis. Studies have demonstrated the efficacy of desipramine in children with ADHD and of clomipramine for the treatment of OCD in children and adolescents. Because of concerns over cardiotoxicity associated with desipramine, TCAs are now generally reserved for treatment-resistant cases. TCAs continue to have a limited but important role in the treatment of patients with enuresis and treatment-refractory ADHD and OCD.

Clinical Management

For all of the TCAs, repeat vital signs and ECGs should be obtained during the dose adjustment phase and when the maintenance dose has been achieved. As part of the informed consent process, potential cardiac effects and the reason for repeat ECG monitoring should be discussed with the family and with the child in a developmentally appropriate manner. A corrected QT interval (QTc) above 450 msec, a QRS complex longer than 120 msec, or a PR interval greater than 200 msec warrants dose reduction followed by a repeat ECG. Exceeding these parameters should prompt treatment reevaluation and perhaps discontinuation. For patients showing clinical benefit and persistent ECG abnormalities, consultation with a pediatric cardiologist is in order.

Adverse Effects

The TCAs are associated with a range of adverse effects, including sedation, dizziness, dry mouth, excessive sweating, weight gain, urinary retention, tremor, and agitation. In addition to these largely anticholinergic-based side effects, TCAs can have dose-dependent adverse effects on cardiac conduction (which can be tracked with an expectable dose-dependent prolongation of the QTc) as well as on the seizure threshold. With regard to seizures, clomipramine may have the highest potential to lower the seizure threshold, so its dose and possible drug interactions need to be monitored closely.

OTHER ANTIDEPRESSANT MEDICATIONS (Table 21.2C)

Atomoxetine (Strattera)

Atomoxetine was originally developed for the treatment of depression, but it has never been marketed as an antidepressant. As noted previously, atomoxetine is a selective norepinephrine
reuptake inhibitor, a property that it shares with desipramine. Unlike desipramine, however, atomoxetine does not appear to prolong cardiac conduction times. Given the efficacy of desipramine for the treatment of patients with ADHD, atomoxetine was evaluated as a treatment for ADHD. After the completion of several placebo-controlled trials, atomoxetine was approved by FDA as a safe and effective treatment for children and adolescents with ADHD. In fact, it is the only approved, nonstimulant medication for the treatment of ADHD. It may also be useful in the treatment of comorbid oppositional defiant disorder.

TABLE 21.2B TRICYCLIC ANTIDEPRESSANTS

Drug	Mechanism of Action	Main Indications and Clinical Uses	Dosage mg/d	Schedule	Adverse Effects	Comments	Select Brand Names and Preparations Available
*B. Tricyclic Antidepressants (TCAs)*
Impiramine	Norepinephrine >dopamine presynaptic reuptake blockade Anticholinergic, antihistamine, alpha-1 postsynaptic effects	MDD Enuresis ADHD ADHD+Tic disorders Anxiety disorders	2.5-5.0 mg/kg/d	QD/BID	Anticholinergic (dry mouth, constipation, blurred vision) Weight gain Cardiovascular (mild blood pressure and ECG conduction parameters with daily doses >3.5 mg/kg) Treatment requires serum levels and ECG monitoring	Serum levels can be useful in adjusting dosage, monitoring potential toxicity, determining metabolizer status	Imipramine hydrochloride: 10, 25, 50 mg t Imipramine pamoate: 75, 100, 125, 150 mg c Desipramine: 10, 25, 50, 75, 100, 150 mg t Nortriptyline: 10, 25, 50, 75 mg; elixir (?) Clomipramine: 25, 50, 75 t
Desipramine
Nortriptyline			2.0-3.0 mg/kg/d
Clomipramine	Same as other TCAs Serotonin presynaptic reuptake blockade	Same as other TCAs OCD

TABLE 21.2C OTHER ANTIDEPRESSANTS

Drug	Mechanism of Action	Main Indications and Clinical Uses	Dosage mg/d	Schedule	Adverse Effects	Comments	Select Brand Names and Preparations Available
*C. Other Antidepressants*
Bupropion	Unknown ?Norepinephrine > dopamine presynaptic reuptake blockade	MDD ADHD	3.0-6.0 mg/kg/d	TID	Irritability Insomnia Drug-induced seizures (in doses >6 mg/kg) Contraindicated in bulimia Seizures associated with >300 mg/day or >150 mg/dose.	Usfeul alternative to stimulants in ADHD, but exacerbation of tics has been reported	Wellbutrin: 75, 100 mg t Wellbutrin SR: 100, 150 t
Venlafaxine	Serotonin/norepinephrine presynaptic reuptake blockade	MDD	1.0-3.0 mg/kg/d	BID/TID	Similar to selective serotonin reuptake inhibitors Nausea, sleepiness, dizziness Dosedependent (?) sustained diastolic hypertension Exacerbation of suicidal ideation highest for venlafaxine; careful monitoring especially warranted with its use. Not recommended for routine use in children and adolescents.	Under 150 mg/d, similar to an SSRI; noradrenergic effects at higher doses	Effexor: 25, 37.5, 50, 75, 100 mg t Effexor XR: 37.5, 75, 150 mg c
Trazodone	Serotonin presynaptic reuptake blockade/5HT2a postsynaptic antagonism	Insomnia	25-200	QHS	Nausea, dry mouth, dizziness, consttipation/Orthostatic hypotension/Sedation/Priapism	Although the closely related compound, nefazodone, had less alpha antagonism than trazodone (i.e. less risk of hypotension and priapism), it is no longer used because of concerns over liver toxicity.	Trazodone: 50, 100, 150, 300 mg t
Mirtazapine	Alpha₂ presynaptic and 5HT_2A/3 postsynaptic antagonism	MDD	7.5-30	HS	Drowsiness (greater at low doses?) Appetite/weight gain	Useful alternative to SSRIs leading to activation?	Remeron: 7.5, 15 mg