Perspective

Challenges and Promises of Pediatric ® °-m*PsychopharmacologyLisa L. Giles, MD; D. Richard Martini, MDFrom the Departments of Pediatrics and Psychiatry, University of Utah School of Medicine and Department of Psychiatry and Behavioral Health, Primary Children’s Hospital, Salt Lake City, Utah The authors declare that they have no conflict of interest.Address correspondence to Lisa L. Giles, MD, Department of Psychiatry and Behavioral Health, Primary Children’s Hospital, 100 N Mario Capecchi Dr, Salt Lake City, UT 84113 (e-mail: Lisa.giles@hsc.utah.edu).Received for publication March 25, 2015; accepted March 28, 2016.

Abstract

Most prescriptions for psychotropic medications are written by primary care physicians, yet pediatricians, many of whom are teaching residents and medical students about pediatric psycho­pharmacology, often feel inadequately trained to treat mental health concerns. Over the past several decades, the number, size, and quality of psychopharmacologic studies in youth has greatly increased. Here we review the current evidence for effi­cacy and safety of each of the major pharmacologic drug classes in youth (psychostimulants, antidepressants, mood stabilizers, and antipsychotics). Psycho ;limulants have a robust body of literature supporting their evidence as first-line treatment for attention-deficit/hyperactivity disorder. Selective serotonin re­uptake inhibitors (SSRls) have documented efficacy for pediat­ric depression and multiple different anxiety disorders with childhood onset. Combining cognitive-behavioral therapy with SSRI treatment enhances treatment benefit and minimizes adverse events of medication. Mood stabilizers, including lithium and anticonvulsant medications, have a less robust

strength of evidence and come with more problematic side effects. However, they are increasingly prescribed to youth, often to treat irritability, mood lability, and aggression, along with treatment of bipolar disorder. Antipsychotics have long been a mainstay of treatment for childhood-onset schizo­phrenia, and in recent years, the evidence base for providing an­tipsychotics to youth with bipolar mania and autistic disorder has grown. Most concerning with antipsychotics are the meta­bolic side effects, which appear even more problematic in youth than adults. By better understanding the evidence-based psy­chopharmacologic interventions, academic pediatricians will be able to treat patients and prepare future pediatrician to address the growing mental health care needs of youth.

Keywords: antidepressants; antipsychotics; pediatrics; psy­chiatry; psychopharmacology; stimulants

Academic Pediatrics 2016;16:508-518

OVER THE PAST several decades, the field of pediatric psychopharmacology has evolved from reliance on case re­ports, uncontrolled case series, and extrapolations from studies in adults to larger cohort studies and randomized placebo-controlled trials. 1'2 At the same time, the development of validated age-appropriate clinical mea­sures more clearly defines pediatric psychopathology. These advancements have led to a much better understand­ing of the efficacy and tolerability of major psychotropic drug classes in pediatrics. With growing evidence, the acceptance of medication use in children with mental illness is expanding.2

The growing acceptance of pediatric psychopharmacol­ogy has at the same time created a series of challenges, which in recent years have led to controversies. There is a debate about the overdiagnosis of psychiatric disorders in childhood, the appropriateness of the diagnoses used to justify psychopharmacologic treatment, and the use of psychotropic medications for conditions with little evi­dence of benefit in the literature. 1’3'4 Concerns have been

raised about treatment approaches that focus too narrowly on pharmacologic management and underutilize psychotherapeutic, behavioral, and family interventions. 1'2 Additionally, there is growing awareness of the long-term adverse effects of medications and the lack of knowledge about the effects of psychotropic medi­cations on development. 1 6

The majority of prescriptions for psychotropic medica­tions are written by primary care physicians, 3 '7 yet pediatricians often feel inadequately trained to treat mental health concerns.8 In light of the ongoing challenges facing pediatric providers, many of whom are teaching residents and medical students about pediatric psychophar­macology, along with the increase in the number, size, and quality of psychopharmacologic studies in youth, we un­dertook to summarize the evidence-based psychopharma­cologic interventions for pediatric mental disorders. With specific focus on the major pharmacologic drug classes in youth (psychostimulants, antidepressants, mood stabi­lizers, antipsychotics), we discuss the current evidence

Academic pediatricsCopyright © 2016 by Academic Pediatric Association 508

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A c a d e m ic Pediatrics Ped iatric Ps y c h o p h a r m a c o lo g y 509

for the efficacy and safety of these drug classes, identify the knowledge gaps, and review current practice guidelines. This review of the literature is not intended to provide specific treatment recommendations or focus on the array of nonpharmacologic interventions crucial to treat mental illness in youth.

Stimulants and Other Attention-Deficit/ Hyperactivity Disorder Medications

Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent mental disorder in children under age 18 and occurs in approximately 8% of youth.9'10 The research database for the safety and efficacy of psychostimulants and other medications for ADHD has continually grown, including more recent research in preschoolers. There is strong support for the use of stimulants as first-line treatment for ADHD and growing evidence for the use of nonstimulant medication as second-line agents. All stimulant medications currently US Food and Drug Administration (FDA) approved for ADHD are either methylphenxate or amphetamine deriv­atives, both of which enhance the neurotransmission of dopamine. Nonstimulants approved by the FDA for ADHD in children age 6 and over include atomoxetine, a selective norepinephrine-reuptake inhibitor, and two selec­tive alpha-adrenoceptor agonists (a-agonists), extended- release clonidine, and guanfacine.

Evidence for Efficacy

There are 2 high-quality, seminal studies comparing stimulant treatment with psychosocial interventions that have clearly influenced the guidelines used to treat ADHD.1112 The details are listed in Table 1. The Multi­modal Treatment Study of Children With ADHD (MTA) demonstrated that combined treatment did not yield signif­icantly greater benefits than medication management alone for core ADHD symptoms, although there was evidence of modest advantages for non-ADHD symptoms and other functional outcomes.11,13 In the Preschool ADHD Treatment Study (PATS), msthylphenidate appeared effective in treating preschoolers with ADHD, but at lower weight-adjusted doses, smaller effect sizes, and with different side effect profiles compared with school- age children. 1“ 14 There have been no major differences

in efficacy or tolerability between methylphenidate and amphetamine-based medications and no consistent patient profile that preferentially identifies those who will respond to methylphenidate- versus amphetamine-based stimu­lants.9

Nonstimulant medications, including clonidine, guanfa­cine, and atomoxetine, while shown to be effective for the treatment of children and adolescents with ADHD, have much smaller effect sizes than stimulants.15,16 Clinical consensus suggests that a-agonists may be more successful in treating the hyperactivity/impulsive symptoms than the inattention symptoms of ADHD and also may be helpful to address comorbid tics and/or insomnia.9 Both extended-release clonidine and guanfa­cine also have evidence for their usefulness in combination with stimulants for the treatment of ADHD when stimu­lants are only partially effective, resulting in FDA indica­tion for combination use.16

Evidence for Safety

All stimulant formulations have roughly similar adverse event profiles, including a potential for delayed onset of sleep, appetite suppression, weight loss, headache, and abdominal pain. Less common adverse effects include tics and emotional lability or irritability. Emotional side ef­fects may be more frequent in younger children and those with developmental delay.1,14

Stimulants have been associated with elevations in mean blood pressure (<5 mm Hg) and heart rate (< 10 beats/min). A subset of individuals (5-10%) may have an even greater increase in heart rate or blood pressure at any given time.17,18 Although one matched case-control study compared children who died of sudden death with those who died in motor vehicle accidents and found a significant association of stimulant use with sudden death, other studies have shown that the rate of sudden death in pediatric patients taking psychostimulants is comparable to children in the general population: both are extremely rare.1,9,19 On the basis of these data, the FDA decided against a boxed warning on stimulants. Although there are no data to suggest that youth with underlying cardiac abnormalities or a strong family history of cardiac disease are at a greater risk for cardiac complications from stimulant medications, the potential risk is quite concerning. The American Heart Association and the

Table 1. Seminal Randomized Studies Comparing Stimulant Treatment With Psychosocial Interventions

StudySample

Size Age DiagnosisRandomly Assigned Treatment Groups

StudyDuration Conclusion

Multimodal Treatment Study of Children With ADHD (MTA)11

579 7-9.9 y ADHD,combinedtype

Programmed behavioral intervention, immediate-release methylphenidate alone, combination of the 2, or community treatment

14 mo All 4 treatment groups improved, with the greatest improvement in both groups with medications (no significant difference with combination vs medication alone).

Preschool ADHD Treatment Study (PATS)12

303 3-5.5 y ADHD,combinedtype

Immediate-release methylphenidate, placebo

14 mo Immediate-release methylphenidate was significantly superior to placebo.

ADHD indicates attention-deficit/hyperactivity disorder.

510 G iles an d Martini A c a d e m ic Pediatrics

American Academy of Pediatrics published a consensus statement with specific recommendations for historical and physical information to identify at-risk children with structural cardiac abnormalities and premedication cardio­vascular symptomatology. Routine ECGs are not indicated in the absence of other cardiac risk factors.20 21

Nonstimulant medications have a different side effect profile. Atomoxetine appears to have less pronounced ef­fects on appetite and sleep than stimulants, although it pro­duces more nausea and sedation. Atomoxetine carries a FDA boxed warning regarding the small risk of suicidal thinking, and clinicians should monitor for this, particu­larly in the first few months of treatment. Side effects of a-agonists include sedation, dizziness, and hypotension. Although concerns have been raised in the past for cardio­vascular side effects, including sudden death, associated with a-agonists (especially in combination with stimu­lants), no further relationships have been found.9 The patient’s blood pressure and pulse should be assessed peri­odically. a-agonists should be tapered over 1 to 2 weeks to avoid rebound hypertension.

C linical Use

After diagnosis of ADHD and assessment for cardiac risk factors, most guidelines recommend initiating treatment with a long-acting stimulant.9,10,22 Parent training and/or behavioral therapy should be the first line of treatment in children under the age of 6, and it is highly encouraged for children of all ages, especially if the child has accompanying oppositional symptoms.910 There is no evidence of a global “therapeutic” medication window in patients with ADHD. One study found that among school-age patients with ADHD, about a third had an initial optimal response to a low daily dose of methylphenidate, another third to a medium daily dose, and the remaining third to a high daily dose.22 Because each patient seems to have a unique dose-response curve, physicians should select a low starting dose, then titrate upward every 1 to 3 weeks until the maximum dose of the stimulant is reached (as defined by the package insert), symptoms of ADHD remit, or side effects prevent further titration. If the initial long-acting simulant is not effective or results in intolerable

side effects, a trial of a second stimulant (perhaps from a different class) is reasonable. In individuals with substance abuse or those unable to tolerate simulants, a nonstimulant medication, either an a-agonist or atomoxetine, is indi­cated. Youth treated with ADHD medications should be assessed periodically to monitor for side effects and assess the efficacy of treatment regimen, using standardized scales from multiple sources when available.9,10

AntidepressantsAnxiety and depression are commonly seen by pediatri­

cians, with 3% of youth having a current diagnosis of an anxiety disorder and 2% having depression.24 Over the past several decades, there has been growing evidence for the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) in pediatric depression and anxiety. Antidepres­sants have documented efficacy for pediatric depression, generalized anxiety disorder, separation anxiety, social anxiety, and childhood-onset obsessive-compulsive disor­der (OCD). Table 2 lists FDA indications for various antidepressants.

Evidence for Efficacy

There are 4 high-quality, National Institute of Mental Health-funded studies of OCD, anxiety disorders, and adolescent major depressive disorder (MDD) that compared antidepressants with cognitive-behavioral ther­apy (CBT), their combination, and placebo: Pediatric OCD Treatment Study (POTS); Child/Adolescent Anxiety Multimodal Study (CAMS); Treatment for Adolescents With Depression Study (TADS); and Treatment of SSRI- Resistant Depression in Adolescents (TORDIA)25-30 (Table 3). All trials suggested the efficacy of medication treatments combined with CBT. In the TADS trial, younger and less severely/chronically ill youth benefited more from therapy, and combination treatment resulted in reduction of suicidal events and overall decreased medication side ef­fects.28'29 By the end of 9 months and 1 year of treatment, combination, fluoxetine, and CBT responses were virtually identical, and patients staying in the study

Table 2. Commonly Used Antidepressant Dosing and Properties

MedicationFDA Approval

for Youth*Starting

Dose, mg/dncrements,

mgEffective Dose, mg

Maximum Dose, mg

EliminationHalf-Life

SSRIsCitalopram 10 10 20 40 35 hEscitalopram a12 y with MDD 5 5 10 20 30 hFluoxetine >8 y with MDD 10 10-20 20 60 2-6 d

Fluvoxamine>7 y with OCD >8 y with OCD 25 25 50 200 16 h

Paroxetine 10 10 20 60 20 hSertraline >6 y with OCD 25 12.5-25 50 200 26 h

SNRIsDuloxetine >7 y with GAD 30 30 60 120 12 hVenlafaxine 37.5 37.5-75 150 225 11 h

FDA indicates US Food and Drug Administration; SSRI, selective serotonin reuptake inhibitor; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; SNRI, serotonin norepinephrine reuptake inhibitor; and GAD, generalized anxiety disorder.

*As of January 2016.

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generally retained their benefits.31 The TORDIA trial demonstrated that for adolescents with depression that does not respond to an initial SSRI, a switch to another an­tidepressant, combined with CBT, should be considered.30 Even if therapy was not feasible, simply changing medica­tions yielded a 40.5% improvement.30

There are multiple SSRI and SNRI randomized placebo- controlled trials in pediatric depression, which include both positive and negative outcomes. Some experts hypothesize that it is likely that study design rather than lack of efficacy accounts for the majority of failed trials in pediatric depres­sion.’" Multiple SSRIs, including sertraline, fluoxetine, paroxetine, and fluvoxamine, along with the SNRIs venla- faxine and duloxetine, have placebo-controlled data that indicate treatment superiority for acute management of broad pediatric anxiety disorders compared to placebo.33,34 SSRIs, including sertraline, fluoxetine, paroxetine, and fluvoxamine, have been shown to be effective in the treatment of pediatric OCD.35 In a review of both published and unpublished antidepressant trials in 2007, the calcu­lated number needed to treat (NNT) for MDD was 10 (although TADS alone suggested a NNT of 3), NNT for OCD was 6, and NNT for non-OCD anxiety was 3.32 In most antidepressant trials, the response rate for medication hovered around 60% independent of age, gender, or specific diagnosis.1 There is very limited research on the psycho- pharmacologic management of pediatric posttraumatic stress disorder (PTSD) and panic disorder. A large placebo-controlled trial of sertraline for pediatric PTSD failed to separate treatment from placebo.36

In general, there are few studies for the use of antide­pressants other than SSRIs or SNRIs in individuals under the age of 18 for either depression or anxiety. Although tri­cyclic antidepressants have been shown to be effective in the treatment of pediatric OCD and in adults with MDD, multiple negative randomized controlled trials of tricyclic antidepressants in pediatric depression and anxiety (other than OCD) have shown no significant difference from pla-cebo......... Studies of mirtazapine, buproprion, andbuspirone for either depression or anxiety failed to find a difference between active drug and placebo.1,34,39

Evidence for Safety

Common side effects in youth treated with SSRIs and SNRIs, including nausea and headaches, are usually tran­sient and easily managed. Side effects such as behavioral activation, agitation, restlessness, insomnia, disinhibition, and affective instability are less frequent. Rarely, antide­pressants cause manic or hypomanic symptoms.34'39

Over the past decade, there has been increased awareness of suicidal events as an adverse effect of antidepressant treatment. In September 2004, an FDA advisory committee reviewed results of a meta-analysis of 24 controlled clinical trials including 9 antidepressants and approximately 4400 pediatric patients.40 Although there were no completed sui­cides, the cumulative risk for suicidal thinking or behavior, collected as spontaneous adverse event reports, was approximately 4% with antidepressants versus 2% with placebo. Repeat analysis of the same data, however,

512 G iles and Martini Academic Pediatrics

suggested the increased risk difference was only 0.7% and the number needed to harm was 143.32 Epidemiologic evi­dence suggests that youth with depression receiving antide­pressants are at lower risk for death by suicide than untreated youth.21 In TADS, suicidality information was systematically collected, and about 30% of youth endorsed recent thoughts or behaviors before randomization. During the study, all 4 treatment groups had a decrease in suicidal­ity, although fluoxetine alone had the smallest reduction. Adding CBT to fluoxetine, seemed to eliminate the fluoxetine-associated risk for suicidal events and adverse events more generally.31 There were no suicidal events in the POTS, CAMS, or other anxiety trials, suggesting that the risk is largely confined to MDD trials.1 Taken together, these studies identify a positive benefit-to-risk ratio for short-term treatment with SSRI or SNRI medication in adolescents with MDD and in patients of all ages with anx­iety and OCD. Adding CBT to medication enhances bene­fits and minimizes adverse events.

Clinical Use

Therapy is generally considered to be primary treatment for depression and anxiety, likely including CBT, psycho­dynamic psychotherapy, and/or other parent-child and family therapy.39'41 When symptoms are moderate to severe, a combination of therapy and medications is considered the reference standard. SSRI medications are first line, with a trial of a second SSRI considered second line. Because there is no pressing evidence to suggest strong efficacy of a particular SSRI over another, the choice of which SSRI to use is based on a combination of side effect profile, drug half-life, drug-drug interactions, and so on. An adequate trial of SSRI involves 4 to 6 weeks at a therapeutic dose (Table 2). After 2 failed SSRI trials, consideration should be given to a non-SSRI medication, usually a SNRI, along with continued utilization of therapy interventions. Once effective treatment has been estab­lished, medication should be continued for at least 6 to 12 months to avoid relapses.39,41-43

Mood StabilizersMood stabilizers, including lithium and anticonvulsant

medications, are frequently prescribed to children and ad­olescents. Atypical antipsychotics are also used for mood stabilization and will be discussed separately. In adults, mood stabilizers are typically prescribed to treat bipolar disorder. However, in youth, bipolar disorder is much less common, with prevalence rates estimated to be be­tween 0.3% and 2%.44 Mood stabilizers are also used to treat irritability, mood lability, and aggression in the setting of disruptive behavioral disorders or autism spectrum dis­orders, although with no FDA indications. The only FDA indication for nonantipsychotic mood stabilizers in the pediatric population is the approval of lithium for the treat­ment of acute mania and bipolar maintenance treatment. The majority of prescrip:ions for mood stabilizers in pediatrics is off label, thus emphasizing the need for

involvement of child psychiatry and a multidisciplinary treatment approach.

Evidence for Efficacy

Lithium was the first medication approved by the FDA for the treatment of bipolar disorder in children and adoles­cents. Although there is significant evidence that lithium is effective in adults with bipolar disorder, until recently, there have been limited studies demonstrating its efficacy in pediatrics. As the result of a written request from the FDA, the Collaborative Lithium Trials were created to in­crease the knowledge base regarding the acute efficacy and long-term safety of lithium in pediatric bipolar.45,46 In a recently published double-blind, placebo-controlled 8-week study, lithium was superior to placebo in reducing manic symptoms in pediatric patients with bipolar I disor­der without associated weight gain.46 This study, along with several earlier studies, suggests that lithium produces clinical improvement but not total symptom remission in pediatric bipolar and that it may be most effective in the treatment of bipolar I disorder with symptoms of full­blown mania.45,47-49 In a recent randomized controlled trial, the Treatment of Early Age Mania (TEAM) study, comparing 3 different antimanic medications in pediatric patients with bipolar I disorder, manic or mixed phase, lithium was less efficacious that risperidone, perhaps as a result of the high comorbidity of the subjects.50"52 Patients with prepubertal onset of bipolar disorder, those with mixed manic episodes or rapid cycling, and comorbid ADHD, substance abuse, conduct disorder, or personality disorder seemed to not respond as well to lithium used alone.49’50’53 Lithium also has some evidence suggesting its usefulness in the treatment of aggressive behavior in children and adolescents with disruptive behavior disorders, although the quality of such evidence is considered low.54,55

Several anticonvulsant medications, including dival­proex, lamotrigine, and carbamazepine, are well docu­mented to be effective for the treatment of bipolar disorder in adults; however, evidence in children and adolescents is weaker. A recent analysis showed that anti­convulsants have a lower effect size than atypical antipsy­chotics for the treatment of pediatric mania.53 Divalproex sodium is effective in the treatment of adult mania, but ran­domized double-blind studies using the drug in younger patients showed inconsistent results, with an overall response rate near 40%.49,51’53 Divalproex did not appear to be as useful as risperidone in the recent TEAM study.50,51 There is limited evidence that divalproex can be effective in treating explosive temper and aggression in adolescents with conduct or other disruptive behavioral disorders.55

Data on the benefits of lamotrigine for adolescents with bipolar, manic, or mixed states have been based primarily on open-label studies with a response rate comparable to other commonly prescribed mood stabilizers. Lamotrigine demonstrated effectiveness in the treatment of the depres­sive phase of pediatric bipolar and unipolar disorder both in monotherapy and in combination with other

Academic Pediatrics Pediatric Psychopharmacology 513medications.49’56 A recent placebo-controlled and random­ized withdrawal study of lamotrigine demonstrated the effectiveness of the drug as an add-on medication for a select group of older adolescents.57 Carbamazepine is frequently used in the treatment of manic symptoms in adults. There are no placebo-controlled studies showing efficacy in pediatric populations, although open-label studies suggest efficacy.49'58

Evidence supporting the use of other anticonvulsants as mood stabilizers is meager. Topiramate is ineffective in the treatment of adult mania, and the single double-blind study in children failed to separate topiramate from placebo.49’59 The one mukisite randomized controlled trial of oxcarbazepine for acute mania in pediatric patients showed no evidence of improvement over placebo.60 Gabapentin has not been demonstrated to improve manic symptoms in either adults or children and may cause behavioral disinhibiiion in younger patients.61

Evidence for Safety

Common lithium side effects include weight gain, acne, polydipsia, polyuria, sedation, nausea, abdominal pain, diarrhea, tremor, hypothyroidism, and, with long-term treatment, nephrogenic diabetes insipidus. As a result, baseline laboratory evaluations should include serum elec­trolytes, renal function tests, thyroid function tests, and a complete blood count, with frequent monitoring throughout. Lithium is associated with congenital cardiac malformations, so a negative pregnancy test should be documented before starting treatment in an adolescent girl.

Divalproex may cause decreased mean platelet count, increased mean ammonia level, weight gain, nausea, head­aches, tremor, and sedation. The association with polycy­stic ovarian syndrome in girls remains uncertain, but clinicians should nevertheless monitor for the presence of weight gain, menstrual abnormalities, hirsutism, and acne. Lamotrigine can cause life-threatening cutaneous re­actions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Carbamazepine has frequent drug- drug interactions as a result of the induction of the hepatic P450 isoenzyme system. Additional side effects may include nausea, sedation, agranulocytosis, aplastic anemia, hepatotoxicity, hyponatremia, and Stevens-Johnson syn­drome. Anticonvulsants may injure a fetus, so pregnancy tests should be administered to adolescent girls before the start of treatment, and patients should be advised of the possible teratogenic effects.

Clinical Use

Despite the lack of clear evidence, clinical consensus supports first-line treatment for pediatric bipolar disorder, including manic and mixed episodes, as lithium, dival­proex, carbamazepine, or an atypical antipsychotic approved for use by the FDA44’49’53 The decision of which mood stabilizer to use should be made by weighing the potential efficacy of a medication with its likely side effects. Mood stabilizers should be initiated only after thorough diagnostic assessment, usually by a

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514 Giles and Martini Academic Pediatrics

child and adolescent psychiatrist. Table 4 provides details of dosing and treatment strategies. Although progress has been made in the treatment of bipolar disorder in children and adolescents, there remain insufficient data on the effi­cacy and safety of these medications, particularly in children younger than 10 years of age or for psychiatric dis­orders beyond pediatric bipolar disorder. Providers should be cautious regarding the initiation and ongoing treatment of mood stabilizers, continually emphasizing the impor­tance of multidisciplinary collaboration.

Atypical AntipsychoticsAntipsychotics have long been a mainstay of treatment

for child- and adolescent-onset psychosis, which appears to be relatively rare. The worldwide prevalence of schizo­phrenia is generally held to be approximately 1 %, with about 1 % of individuals manifesting this disorder before age 13, and 18% to 33% of cases manifesting it before age 18.62'63 Older antipsychotics, including haloperidol and molindone, are FDA approved for the treatment of schizophrenia in adolescents, although as a result of concern for side effect profiles, the newer atypical antipsychotics are now generally considered first-line agents and will be the focus of this section.63 In recent years, new atypical antipsychotic medications continue to come on the market, and the overall evidence base for atypical antipsychotics in youth with schizophrenia, bipolar mania, and autistic disorder has grown. Atypical antipsychotics are also being used in the pediatric population for the management of aggressive and oppositional behaviors.64"456 Risperidone and aripiprazole have been approved by the FDA for the treatment of aggression and irritability in autistic children and adolescents. Risperidone, aripiprazole, olanzapine, quetiapine, paliperidone, and asenapine are approved by the FDA for the treatment of schizophrenia and/or bipolar I disorder in adolescents (Table 5).

Evidence for Efficacy

Placebo-controlled studies have demonstrated the short­term efficacy of risperidone, olanzapine, quetiapine, aripi­prazole, and paliperidone in the treatment of adolescent schizophrenia.1'63'67 One trial comparing ziprasidone with placebo was discontinued by the sponsor as a result of lack of efficacy.1 There have also been several head- to-head trials comparing antipsychotics, including the Treatment of Early-Onset Schizophrenia Spectrum Disor­ders (TEOSS) study, a federally funded, randomized double-blind trial, which showed no response difference between olanzapine, risperidone, or molindone, either acutely or in maintenance.68'6 ’ Clozapine has demonstrated superior efficacy in open-label studies and head-to-head comparison trials for treatment-refractory schizophrenia in children and adolescents.1,6"

A growing number of randomized controlled trials have demonstrated the efficacy of atypical antipsychotics, including olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and asenapine, in pediatric patients with bipo­lar I mania.1'70 Pooled analysis suggests that the NNT

ranged from 3 to 4, corresponding to large to moderate effect sizes.1 Few head-to-head studies between antipsy­chotics and traditional mood stabilizers exist, although an indirect comparison of placebo-controlled trials suggests the superiority of antipsychotics, albeit with increased side effects.5'' The recent TEAM study demonstrated the effectiveness of risperidone over lithium or divalproex both in treatment-naive youth and those whose disorder did not respond or only partially responded to an initial anti- manic medication trial.50'51 Evidence regarding the antipsychotic treatment of bipolar mania in children less than 10 years old and in bipolar depression is still limited.

Randomized controlled trials in pediatric patients with autism spectrum disorder demonstrated superior efficacy from risperidone and aripiprazole compared to placebo in reducing irritability.1,71,72 Although stereotypic and hyperactive behaviors also improved, the core deficits of verbal and nonverbal communication were not affected by antipsychotic treatment.1'71 The largest of these studies, conducted by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, demonstrated that risperidone plus parent training resulted in a greater reduction of maladaptive behaviors then medication treatment alone and resulted in lower risperidone dosing requirements.73

The majority of studies examining the use of antipsy­chotic medications in youth with aggressive behaviors involve risperidone. These studies suggest the effective­ness of risperidone in the treatment of disruptive behaviors in children with subaverage intelligence, aggression asso­ciated with conduct disorder, and aggression associated with ADHD.1’55 Risperidone was also shown to be effective for relapse prevention in youth with disruptive behavioral disorders over a 6-month period.74 Although a number of randomized controlled studies have demon­strated the efficacy of psychosocial and behavioral inter­ventions in reducing youth aggression, studies comparing antipsychotics with behavioral intervention, combination, and placebo are limited. In the Treatment of Severe Child­hood Aggression (TOSCA) study, augmented therapy (defined as parent training, stimulant, and risperidone) was superior to basic therapy (parent training, stimulant, and placebo) in reducing aggression and severity of ADHD and oppositional defiant disorder symptoms, with small to moderate effect sizes.75'76

There are a few randomized controlled trials in adoles­cents with Tourette disorder involving risperidone, aripi­prazole, and ziprasidone.77-71 Because they use varying methodologies, meaningful comparisons among studies are limited, and the overall evidence supporting efficacy and safety of the atypical antipsychotics for treatment of tics is still limited.80

Overall, the literature on the use of atypical antipsy­chotics in children is still limited in its scope and rigor. The strongest recommendations can be made for the use of these medications for schizophrenia and bipolar I disor­der, with less evidence for tic disorders and aggressive or disruptive behavior except in children with autism spectrum disorders.

A c a d e m ic P e d ia t r ic s P e d ia t r ic P s y c h o p h a r m a c o l o g y 515

Table 5. A typica l A n tipsycho tics D osing and Properties

M edication FDA Approva l fo r Youth*Starting

Dose E ffective Dose M axim um Dose

Asenapine • > 1 0 y w ith b ipo lar I, manic, or mixed

2.5 mg BID 5 m g BID 10 mg BID

Aripiprazole • > 1 0 y w ith b ipo ar I, manic, or m ixed

• > 1 3 y w ith schizophrenia• > 6 y w ith autistic disorder,

agitation• > 6 y w ith Tourette disorder

2 m g/d 10 m g/d 30 m g/d

Olanzapine • & 1 3 y w ith b po lar I, m anic or mixed

• > 1 3 y w ith schizophrenia• > 6 y w ith T ourette d isorder

2 .5 -5 m g/d 5 -1 0 m g/d 20 m g/d

Paliperidone • > 1 2 y w ith schizophrenia 3 m g/d 3 -1 2 m g/d 6 m g/d fo r youth < 5 0 kg,12 m g/d for youth > 5 0 kg

Quetiapine • > 1 0 y w ith bipolar I, manic, or mixed

• > 1 3 y w ith schizophrenia

2 5 -5 0 m g/d 40 0 -6 0 0 m g/d divided BID orT ID

60 0 -8 0 0 m g/d

Risperidone • > 1 0 y w ith bipolar I, manic, or 0 .25-0.5 2.5 m g/d for bipolar, 3 m g/d 3 m g/d for children, 6 m g/dmixed

• > 1 3 y w ith schizophrenia• > 5 y w ith autistic disorder,

agitation

m g/d for schizophrenia, 0.5-1 m g /d fo r autism

fo r adolescents

Ziprasidone 20 m g/d (with food)

6 0 -8 0 m g/d for youth < 4 5 kg, 120-160 m g/d fo r youth > 4 5 kg

80 m g/d for youth < 4 5 kg,160 m g/d fo r youth > 4 5 kg

FDA indicates US Food and Drug Adm inistra tion. *As of January 2016.

Evidence for Safety

Patients gain weight on atypical antipsychotics, with clozapine and olanzapine posing the highest risk, followed by risperidone, quetiapine, and aripiprazole; on the basis of data from adults, ziprasidone, paliperidone, and asenapine present the lowest risk.1'63'81 Youth seem to be more prone to rapid and significant weight gain with antipsychotics than adults.'’3 There seem to be varying levels of choles­terol, triglyceride, and glucose elevation among the atyp­ical antipsychotics as well.53'81 The FDA boxed warning for atypical antipsychotics is based on an increased risk of diabetes while on these medications.63,82 Treating clinicians should review family history of diabetes, hypercholesterolemia, and hyperlipidemia at the start of treatment and use atypical antipsychotics with caution and frequent monitoring in these settings. The American Psychiatric Association guidelines on monitoring include the following: a personal and family history at baseline and annually; body mass index every 4 weeks; waist circumference at baseline anc annually; blood pressure at baseline, 12 weeks, and annually; fasting plasma glucose at baseline, 12 weeks, and annually; and fasting lipid profile at baseline and 12 weeks.83

Cardiovascular effects of atypical antipsychotics in chil­dren are described in short-term studies and include pro­longation of the QTc interval, tachycardia, orthostatic hypertension, and pericarditis.62’63 No long-term studies have yet determined the clinical relevance of these changes, there are no reports of sudden cardiac death on these medications, and a recent meta-analysis suggests

that the risk of pathological QTc prolongation remains low.84 Prolongation of the QTc interval, however, warrants close monitoring as a result of individual risk factors. Patients with a personal or family history of arrhythmias, cardiac abnormalities, or sudden unexplained cardiac death should receive a baseline ECG at the start of treatment. Pe­diatric cardiology consultation is warranted before starting antipsychotics in individuals with a history of arrhythmias, prolonged QT interval, or other ECG abnormalities.

Tardive dyskinesia and extrapyramidal side effects, although much less common than when typical antipsy­chotics are used, are still evident with atypical antipsy­chotics. Children appear to be at greater risk for these symptoms than adults.1,53 Neuroleptic malignant syndrome is a serious and life-threatening side effect of these medications that, although rare, must be considered when symptoms of autonomic instability, elevated temper­ature, and muscular rigidity with increased creatine kinase levels affect the patient. Clinicians should use the Abnormal Involuntary Movement Scale to assess for extra- pyramidal side effects at the start of treatment and period­ically when indicated.63'85 Antipsychotics should not be suddenly discontinued because concerns exist regarding withdrawal dyskinesias. They should be gradually discontinued as part of a comprehensive treatment plan.63

Clinical Use

The start of any medication regimen, including antipsy­chotics, should include a careful and thorough diagnostic assessment with the following: a history of comorbid

516 Giles and Martni Academic Pediatrics

medical conditions, a review of all medications currently administered to the patient, l multifaceted treatment plan that includes education on the diagnosis, a review of the risks and benefits of psychotropic medications, and consideration of all possible psychotherapeutic interven­tions.44'63 Youth that have severe mental illness warranting treatment with in antipsychotic medication require a multidisciplinary team, usually involving a child and adolescent psychiatrist in addition to multiple levels of psychosocial support. The recommendation from the American Academy of Child and Adolescent Psychiatry is that atypical antipsychotic medications be used as a substitute rather than an addition to a drug regimen.86 Clinicians shoulc carefully dose atypical anti- psychotics, beginning with smaller doses and gradually increasing it on the basis of the patient’s response. Pediatric doses should not exceed those recommended for adults. Table 5 provides more details on dosing strategies.

An adequate medication trial at an optimal dose should last 4 to 6 weeks before cons.dering a change. Atypical an- tipsychotics should not be prescribed for an indefinite period of time and should be part of a treatment plan that reevaluates the need for the medication according to the pa­tient’s presentation and the anticipated course of the illness.

ConclusionsOver the past 2 decades, considerable progress has been

made in psychopharmacologic treatment of youth with psychiatric illnesses, although larger and longer studies are still needed. Specifically helpful would be more clini­cally relevant studies, especially those looking at treatment in the primary care setting, where most youth present. Studies of medications in youth should include a closer examination of the neurodevelopmental and physiologic effects of psychopharmacological treatment over the long term. Ongoing drug development is focused on drug repur­posing, identifying intermediate phenotypes or specific biomarkers, and discovering more personalized pharmaco­genetics. Psychiatric medications in the pipeline include agents with neurotrophic, neuromodulatory, antiapoptotic, and anti-inflammatory capacity and those countering oxidative stress.1

The mental health needs of children and adolescents are vast and the numbers of pediatric mental health profes­sionals limited. Pediatricians need to become more comfortable managing drug regimens and initiating psychopharmacologic treatments. Academic pediatricians play a crucial role in disseminating the emerging knowl­edge that will make this possible.

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