Published November 22, 2006 Psychotropics in Children and Adolescents Catherine Tom-Revzon, PharmD Arnold & Marie Schwartz College of Pharmacy and Health Sciences| Long Island University, Brooklyn Children’s Hospital at Montefiore, Bronx Bernard Lee, PharmD New York Presbyterian Hospital, New York US Pharm. 2006;11:HS-30-HS-37. Despite the gaps in knowledge regarding the safety and efficacy of psychotropic medications in children and adolescents, health care providers continue to prescribe these agents to treat mental disorders, including major depression, bipolar disorder, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, substance abuse and dependence, and eating disorders. Many of these disorders were once considered problems experienced in adulthood only, but an estimated one in 10 children and adolescents in the United States suffers from mental illness that is severe enough to lead to personal, social, and/or academic impairment. Recently, these illnesses have been better documented and fully recognized in childhood and adolescence. An increase in prescribing rates of stimulants, antidepressants, clonidine, and antipsychotics in preschoolers has been observed.1 Of note, most of these agents are not FDA-approved for use in the pediatric population or have limited indications in school-age children and/or adolescents. Diagnosing a mental disorder in children, especially preschool children, can be difficult. Comorbidities are common and may complicate management, requiring polypharmacy, although many of the illnesses can be transient or may be adequately managed with cognitive behavioral therapy (CBT) alone to improve deficits in daily functioning.2 Some symptoms can be treated with psychotropic medications (e.g., antidepressants, anxiolytics, hypnotics, antipsychotics, neuroleptics, and stimulants) as adjunct therapy. However, these medications should be recommended judiciously, particularly if it is an off-label indication, at the lowest possible doses, to reduce side-effect potential. To complicate matters further, children are in a constant state of rapid change physically, cognitively, and emotionally, throughout their developmental years. Physicians should heed this fact when selecting psychotropic medication(s), as it may affect adherence to the regimen. Often, the dosage and indication for psychotropic medications are based on extrapolated adult data, which are not always appropriate for very young children, school-age prepubertal children, or adolescents. Some toxicities in adults have yet to be discovered in children. Furthermore, long-term consequences from administration of psychotropic medications at a young age, especially on the brain, are unknown. The bottom line is that more epidemiologic and clinical research is needed.1,3 The FDA's Modernization Act and Best Pharmaceuticals for Children Act provide incentives for the pharmaceutical industry to conduct studies in the pediatric population. 3 However, the growing concern about the safety of these psychotropic medications in children and adolescents is offset by evidence indicating that treatment benefits outweigh the risks of the medications.4 Clinical pharmacy has become more important than ever, with the growing need to learn more about children who are treated for all ranges of mental illness. (See Table 1) Antidepressants Major Depressive Disorder: Childhood depression is among the most prevalent of pediatric mood disorders and is a leading cause of morbidity and mortality in children. Although major depressive disorder (MDD), the most severe form of depression, has not been consistently linked to suicide, it remains an important contributor to suicidal behavior and suicide.5,6 Since 2000, approximately 2% of children and 4% to 8% of adolescents with MDD have died due to self-harm, the third leading cause of death among children.7-9 Nonetheless, suicide secondary to depression is preventable. Combining therapy with CBT is a crucial component of complete and balanced MDD management. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is recommended as first-line therapy initially at 10 to 20 mg every 24 hours for children ages 8 to 18 years. Dose titration to the lowest effective dose (range, 10 to 60 mg/day) in increments of 10 mg should be done after four to six weeks of observation and follow-up postinitiation.10 If fluoxetine is not effective, other SSRIs (e.g., sertraline, citalopram, escitalopram, fluvoxamine, paroxetine) and mixed reuptake inhibitors (e.g., venlafaxine, mirtazapine, bupropion) should be considered as second- and third-line options, respectively. Other reasons for switching medications include intolerance, comorbid diseases, potential drug interactions, and drug formulation. Close monitoring for suicidal ideation, at least during the first month following drug initiation, is strongly recommended. Notably, limited data exist on the safety and efficacy of antidepressants and mood stabilizers in school-age prepubertal children. Eating Disorders: Eating disorders usually develop during adolescence but can also occur in early childhood. They can coexist with depression, substance abuse, and anxiety disorders. Females are more likely to suffer from an eating disorder than are males. About 0.5% to 3.7% of females suffer from anorexia nervosa, and 1.1% to 4.2% from bulimia nervosa. Nonpharmacologic treatment is recommended to restore weight lost. Established weight gain is followed by SSRI treatment for weight maintenance and resolution of mood and anxiety symptoms. Fluoxetine is the only SSRI approved for reducing symptoms of bulimia nervosa.11 Side Effects of Antidepressants: Notable side effects with antidepressants include sedation, especially the tricyclic antidepressants (TCAs) trazadone, mirtazapine, and nefazodone. While most SSRIs cause insomnia, paroxetine may induce mild sedation. SSRIs may also cause declines in daytime and driving performance and increase potential for involvement in motor vehicle accidents.12 Although akathisia is a common result of antipsychotic use, SSRIs can also produce akathisia. Serum electrolytes should be checked if patients taking SSRIs present with unexplained mental slowing, somnolence, reduced food intake, vomiting, or seizures.13 TCAs can cause weight gain.14 Furthermore, compliance may be affected by their unpleasant taste, ability to alter taste modalites, and effect of xerostomia.15 SSRIs have recently gained a great deal of attention after data from the landmark trial Treatment for Adolescents with Depression Study, were published in 2004.16 Despite significant improvements in Clinical Global Impression in groups treated with fluoxetine and decreases in the overall suicidal ideation by the end of the study, the elevated risk for harm-related adverse events, both suicide related or otherwise, was alarming. None of the odds ratios for suicide-related events was statistically significant. In September 2004, a causal link was established between the newer antidepressants used for MDDs. Subsequently in October 2004, the FDA mandated changes in antidepressant advertisements, package inserts, and information sheets to include a black box warning about the increased risk of suicidality.17 Mood Stabilizers Pediatric bipolar disorder can result in impaired family and peer relationships, poor academic performance, higher levels of substance abuse, increased rates of suicide attempts and completion, legal difficulties, and multiple hospitalizations. In fact, 30% to 40% of pediatric psychiatric inpatients have bipolar disorder. Children and adolescents with bipolar disorder often present with severe mood swings, disruptive behaviors, short sleep periods, intrusiveness, and hypersexuality. 18 They are also more prone to violence.19 Cycles of manic symptoms, major depression, and cyclothymia can occur.18 Of note, antidepressants and corticosteroids can result in a mimicry of mood disorders and should be included in the diagnostic differential.18 Comorbidities such as ADHD and conduct disorder (CD) are common in children and adolescents. Lithium: Lithium is FDA approved for the treatment of acute mania and bipolar disorder in adolescents or children (ages 12 to 18), especially if the patient presents with classic euphoric mania without psychotic symptoms.18 It has the longest history of use in children and adolescents and should be considered first.19 Dosage should be titrated to 30 mg/kg/day in two to three divided doses, for a target serum concentration of 0.8 to 1.2 mEq/L. Common side effects are hypothyroidism, nausea, polyuria, polydipsia, tremor, acne, and weight gain. The latter two side effects may be not be well tolerated by adolescents; thus, compliance may become an issue. Monitoring of serum lithium levels and renal and thyroid function are recommended at baseline and every six months.13,18,19 Electrocardiography may also be useful.19 Anticonvulsants: Sodium divalproex is widely used in children and adolescents with bipolar depression and aggressive behavior, but few controlled trials have been conducted.18,19 The dose should be initiated at 20 mg/kg/day, which produces a serum level of 80 to 120 mcg/mL. Common side effects include weight gain, nausea, sedation, and tremor. Until the risk of polycystic ovary disease is clearly defined, weight or menstrual abnormalities, hirsutism, and acne should be monitored.18 Valproic acid can also have a mild antithyroid effect.13 Monitoring of the complete blood count (CBC), liver function tests (LFTs), thyroid function tests, weight, and serum valproic levels is advised. Females should also avoid pregnancy, since the drug is teratogenic.19 Carbamazepine is used as monotherapy or adjunctive therapy for bipolar disorder and violent behavior. The dose should be titrated slowly, and frequent monitoring of serum concentrations is necessary if patients are concurrently taking other medications that affect the CYP-450 system. It also is a CYP-450 enzyme inducer. Side effects include aplastic anemia, severe dermatologic reactions (e.g., Stevens-Johnson syndrome), hyponatremia, nausea, and sedation.13,18 Monitoring of CBC, LFTs, serum electrolytes, and serum carbamazepine level (for toxicity) is recommended. Females taking oral contraceptives should be counseled about using an additional mode of contraception or abstinence. Weight gain is also a concern for 25% of patients.19 Oxcarbazepine is an analog to carbamazepine and appears to be promising in adults with mania.20 In children ages 7 to 18 years with bipolar I disorder, it is no better than placebo,21 but anecdotally it is an effective treatment for aggression.19 As with carbamazepine, hyponatremia can occur, although less frequently in children, and monitoring is recommended.13,18 Females should be counseled about effective contraception. Antipsychotics: Atypical antipsychotics provide a broader spectrum of efficacy with a better safety profile than the older antipsychotics and are preferred in practice. The atypical agents block dopamine2 neurotransmission and increase serotonin levels. They are prescribed to treat not only schizophrenia but also acute bipolar mania, bipolar depression, treatment-resistant depression, and posttraumatic stress disorder due to their mood-stabilizing properties.18 None has been approved for use in the pediatric population, but clozapine, risperidone, olanzapine, and quetiapine have been studied for mania and may be effective, especially if psychotic symptoms are also present.2,18 They appear to be clinically more efficacious than traditional mood stabilizers.2 Risk of weight gain with atypical antipsychotics appears to be higher in children.13 Significant weight gain can increase morbidity secondary to metabolic syndrome involving type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease.13,22 A personal and family history, along with baseline measurements of waist circumference, blood pressure, fasting blood glucose, and fasting lipid profile, should be obtained prior to initiating antipsychotics, with reassessments at four, eight, and 12 weeks after initiating or changing therapy. Further evaluations should be performed every three months.14,18,23 The propensity for weight gain and development of the metabolic syndrome is highest with clozapine and olanzapine, followed by risperidone, quetia pine, ziprasidone, and aripiprazole.13 Akathisia can also occur with high doses, rapid increments of dosage, and higher drug potency. Neuroleptic malignant syndrome has been reported with atypical antipsychotics as well. Patients who are agitated, dehydrated, malnourished, taking large doses of higher-potency antipsychotics, or undergoing rapid increments of dosage should be monitored closely.13 Longer-term use resulted in mild to moderate tremor, muscle rigidity, and restlessness in a small number of patients.21 Hyperprolactinemia is more pronounced in postpubertal children and adolescents than in adults.13 Monitoring for amenorrhea or oligomenorrhea, breast enlargement or engorgement, galactorrhea, decreased libido, erectile dysfunction, osteoporosis, and hirsutism is recommended.13 Serum prolactin levels should be checked only if the patient is symptomatic, and dosage of the current antipsychotic should be reduced or the patient should be switched to a different drug if prolactin levels are above normal but less than 200 ng/mL. Levels above 200 ng/mL require further medical work-up. In some patients, symptoms may resolve within six to 12 months of continued treatment.13 Autism and Other Pervasive Developmental Disorders: Autism affects one in 500 children.24 Symptoms of autism, such as stereotypies, compulsions, aggression, extreme intolerance of change, and self-injurious behavior, can be treated with antipsychotics.3,22 However, the safety and efficacy of this practice have not been determined. 3 The onset of autism, other pervasive disorders, and ADHD typically occurs during preschool years. Risperidone is the best-studied agent in treating symptoms of autism spectrum disorder. A recent six-month trial of risperidone versus placebo in 5- to 17-year-olds demonstrated that risperidone, at mean doses of 1.5 to 1.8 mg, prolonged relapse time and decreased irritability scores. However, increased appetite and weight gain were common side effects with risperidone, causing two patients to withdraw from the study prematurely.22 Characteristics of oppositional defiant disorder (ODD), such as frequent and consistent temper tantrums or outbursts of rage, can be mistaken as defiant behavior. Diagnosed as early as age 3 (typically ages 6 to 10), it rarely persists into adulthood.25 CD arises either before age 10 or between ages 10 and 17 and includes aggressive behavior (e.g., fighting, bullying, physical assault, intimidation, sexual coercion, and setting fires), nonaggressive behavior (e.g., vandalism, theft, and deceit), and rules violation (e.g., truancy and curfew). For most patients, CD resolves in adulthood, but many are at risk for substance dependence or abuse and anxiety, mood, and somatoform disorders.25 Treatment for both CD and ODD begins with family and individual psychotherapy, involving behaviorial and environmental changes. Indications for psychotropic medications include comorbid symptoms. Patients with ODD and ADHD may benefit from atomoxetine or stimulants, if they are prescribed cautiously.2,13,26 CD patients with impulsive aggressive behavior may respond to mood stabilizers (lithium or divalproex), clonidine, or atypical neuroleptics.4,21,24 Self-injurious and stereotypic behaviors respond to antipsychotics.2 A small study involving risperidone demonstrated efficacy in reducing aggression; olanzepine was shown to be somewhat effective in improving behavior in a case series; and 40% of patients with moderate pervasive developmental disorders who took quetiapine showed a decline in symptoms.27-29 Depression-related aggression that leads to violent behavior also responds to fluoxetine. Combination Therapy: Comorbidities warrant combination therapy for symptom reduction. For example, adolescents with bipolar disorder may benefit more from quetiapine and divalproex than from divalproex alone. In patients with ADHD and bipolar disorder, treatment with a mood stabilizer increases the efficacy of a stimulant.2 However, combination therapy may also increase the propensity for side effects. Weight gain, leading to more severe morbidity, may occur when antipsychotics are combined with lithium or valproic acid.13 Hypnotics/Anxiolytics Children and teens who experience anxiety demonstrate many similarities to adults who suffer from acute and chronic anxiety disorders.30 An anxiogenic response can be triggered by a variety of sources and is often associated with the onset of a chronic anxiety disorder.31 The short-term utilization of sedative hypnotics and anxiolytics in pediatric care has long been established in a variety of clinical settings.32 Calming a child with short-acting benzodiazepines or inhaled nitrous oxide prior to a major surgical procedure, dental intervention, or diagnostic imaging is safe and effective. Yet, the best treatment options for chronic pediatric anxiety disorders are still unclear. A majority of anxiety disorders in children are components or secondary manifestations of other coexisting disorders, such as depression. Acceptance of long-term pharmacotherapies with psychotropic agents, such as SSRIs (fluvoxamine, fluoxetine, and sertraline), high-potency benzodiazepines (clonazepam), and other agents (with the exception of TCAs), in conjunction with CBT, has been growing as a therapy option, especially in the setting of social anxiety disorders.33 CBT should always be an integral part of therapy. Fluvoxamine is recommended as the first-line agent initially, at a dose of 25 mg at bedtime for children ages 8 to 17 years. The dose should be titrated to the lowest effective dose (range, 50 to 200 mg/day divided twice daily) in 25-mg increments at four- to seven-day intervals.10 Other SSRIs (e.g., fluoxetine and sertraline) and mixed reuptake inhibitors (e.g., venlafaxine, mirtazapine, and bupropion) are acceptable second- and third-line therapy options, respectively, if fluvoxamine is not effective. Stimulants and Atomoxetine Stimulants are the best-studied psychotropic medications in school-age children and adolescents with ADHD. The prevalence of ADHD in the school setting averages 6.9% (range, 5.5% to 8.5%); in the community, it is 10.3% (range, 8.2% to 12.7%). 2,34 However, data on dosage for preschool children are still lacking. Methylpheni date is a dopamine reuptake inhibitor, while amphetamine blocks norepinephrine and dopamine reuptake. Atomoxetine is a nonstimulant that inhibits norepinephrine reuptake and is effective in some patients with ADHD, but its role in children has not been clearly defined.2,35 Clinically, there is no difference in efficacy between the stimulants, but guidelines recommend switching to a different agent if the response to one agent is suboptimal. The various dosage forms (immediate-release, intermediate-release, and delayed-release tablets, patches, and osmotic technology) offer flexibility in treatment regimens.2,35 Clonidine, an alpha2 adrenergic agonist, is frequently used to treat rebound symptoms that occur in the evening; the impulsivity, hyperactivity, and aggression symptoms of ADHD or another syndrome; or isolated symptoms.2 TCAs or bupropion can be considered if the patient does not improve with stimulant therapy. It is well-known that stimulants may cause linear growth suppression, but the actual frequency and magnitude of this effect remains unknown.36 In most patients, the final adult height is reached. Atomoxetine causes minimal projected slowing of growth in height and weight loss in most patients.37 Height and weight at baseline should be measured and rechecked annually. Pharmacists can recommend lowering the dose of the stimulant, placing a child on a drug holiday, or switching therapy to atomoxetine in children who suffer from significant growth retardation or weight loss.13,35 Substance-Related Disorders: Many adolescents suffer from substance dependence or abuse. In a survey conducted in 2004, 9% of youths ages 12 to 17 suffer from this condition, using alcohol, cigarettes, or other illicit drugs. Some researchers have shown that up to 75% to 80% of adolescents have coexisting mental disorders with substance dependence or abuse; the most common are CD, ODD, ADHD, affective disorders, and anxiety disorders. These conditions may have been preexisting psychiatric disorders that triggered the onset of substance dependence or abuse. First-line treatment involves cognitive and behavioral programs with group therapy, family care, and legal, health, recreational, and educational services. Psychotropic medications are usually prescribed in children who have coexisting schizophrenia or ADHD. Bupropion is an option for adolescents with substance dependence or abuse, ADHD, and depression. Stimulants should be recommended with caution, due to the high abuse potential.38 Lithium can be useful for bipolar disorder and comorbid substance abuse. Adolescents with depression, anxiety, or substance abuse or dependence would benefit from an SSRI, not a TCA, which can have anticholinergic and cardiac side effects.39 Psychiatric Emergencies An emergencyincludes the onset of suicidality, homicidal or extreme violent urges, perceptual disturbances, disordered thought processes, or a change in cognitive state or abilities. When the child or adolescent has acute or unexplained changes in mental status, treatment with an immediate-acting antipsychotic given intramuscularly, with or without a benzodiazepine, is recommended.11 Olanzapine and ziprasidone are available as intramuscular formulations and are preferred over the older antipsychotics for safety reasons.11 Role of the Pharmacist The management of mental disorders can be complicated, and compliance can be compromised if pediatric patients and their caregivers are not properly educated about disease states and medications. Judicious selection of psychotropic medications and proper monitoring are important. While compliance can be enhanced with use of liquids, orally dissolving tablets, and sustained-release formulations,11 minimizing adverse effects by using the lowest effective dose and proper monitoring parameters is also essential. Due to all of the negative press about psychotropic medication use in the pediatric population, it is important to weigh the benefits against the risks of psychopharmacologic therapy. References 1. Zito JM, Safer DJ, dosReis S, et al. Trends in the prescribing of psychotropic medications to preschoolers. JAMA.2000;283:1025-1030. 2. Scheffer RE. Psychopharmacology: clinical implications of brain neurochemistry. Pediatr Clin N Am. 2006;54:767-775. 3. Vitiello B. Psychopharmacology for young children: clinical needs and research opportunities. Pediatrics. 2001;108:983-989. 4. Scheffer R, Kowatch R, Carmody T, et al. A randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder following mood stabilization with divalproex sodium. Am J Psychiatry.2005;162:58-64. 5. Shaffer D, Gould MS, Fisher P, et al. Psychiatric diagnosis in child and adolescent suicide. Arch Gen Psychiatry. 1996;53:339-348. 6. Gould MS, King R, Greenwald S, et al. Psychopathology associated with suicidal ideation and attempts among children and adolescents. J Am Acad Child Adolesc Psychiatry. 1998;37:915-923. 7. Fleming JE, Offord DR. Epidemiology of childhood depressive disorders: a critical review. J Am Acad Child Adolesc Psychiatry. 1990;29:571-580. 8. Lewinsohn PM, Clarke GN, Seeley JR, Rohde P. Major depression in community adolescents: Age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry. 1994;33:809-818. 9. Hoyert DL, Mathews TJ, Menacker F, et al. Annual summary of vital statistics: 2004. 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Practice parameter for the assessment and treatment of children and adolescents with substance use disorders. J Am Acad Child Adolesc Psychiatry. 2005;44:609-621. 39. Gee RL, Espiritu RC, Huang LN. Adolescents with co-occurring mental health and substance use disorders in primary care. Adolesc Med. 2006;17:427-452. To comment on this article, contact editor@uspharmacist.com.