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31.18d Pharmacotherapy

adolescents in residential facilities. J Behav Health Serv Res. 2013;40:97–110. Noftle JW, Cook S, Leschied A, St Pierre J, Stewart SL, Johnson AM. The trajectory of change for children and youth in residential treatment. Child Psychiatry Hum Dev. 2011;42:65–77. 31.18d Pharmacotherapy Over the last decade, increasing evidence has emerged regarding the efficacy and safety of psychopharmacological agents to treat child and adolescent psychiatric disorders. Randomized placebo-controlled trials have confirmed the short-term efficacy of selective serotonin reuptake inhibitors (SSRIs), for depressive disorders, anxiety, and OCD; second-generation antipsychotics (SGAs) for psychosis and aggression; and multiple central nervous system stimulants for ADHD. Published data support the short-term efficacy and safety of fluoxetine, sertraline, fluvoxamine, and escitalopram in the treatment of youth depression, anxiety disorders and OCD. First-line evidence-based treatment for ADHD, has preferentially shifted toward longacting stimulant medications, including methylphenidate preparations (Concerta) and amphetamine and amphetamine salt preparations (Adderall XR). Significant progress in the field has been made through multi-site, National Institute of Mental Health (NIMH)–funded research comparing types of treatment with treatment combinations of pharmacological interventions and psychosocial treatments, for disorders including OCD and major depressive disorders, and anxiety disorders. Studies repeatedly found that cognitive-behavioral psychotherapy in combination with an SSRI has advantages over either alone. Another area of progress has been evidence-based treatment of ADHD in younger age groups. The NIMH Preschooler with ADHD Treatment Study (PATS) was the first multisite study of ADHD preschool children, treated first with a parent training component and followed, if necessary, by administration of methylphenidate. This regimen was found to be effective and safe. Double-blind, placebo-controlled studies have provided evidence for the efficacy of fluoxetine, sertraline, and escitalopram treatment for depressive disorders in youth, and the Food and Drug Administration (FDA) has approved both fluoxetine and escitalopram in the treatment of adolescent depression. Fluoxetine, sertraline, and fluvoxamine have been shown to have positive results based on randomized controlled trials (RCTs) in the treatment of OCD in youth. Although the FDA has not yet approved SSRIs in the treatment of child and adolescent anxiety, positive random-controlled trials (RCTs) exist for fluoxetine, sertraline, paroxetine, and fluvoxamine in the treatment of youth anxiety. In 2004, the FDA released a statement on the recommendation of the Psychopharmacologic Drugs and Pediatric Advisory Committees of a “black-box” warning relating to an increased risk for suicidality in pediatric patients for all antidepressant medications. The advisory committees came to the conclusion that an increased risk of suicidal behaviors existed, although there were no suicides completed among the data reviewed. All of the antidepressant medications must include the black

box warning for pediatric patients regardless of whether they have been studied in pediatric populations. Currently, the SGAs, also known as serotonin-dopamine antagonists (SDAs), have generally replaced the conventional antipsychotics (dopamine receptor antagonists) in the treatment of psychotic disorders and for aggressive behavior management. THERAPEUTIC CONSIDERATIONS As psychopharmacologic interventions for childhood psychiatric disorders have gained an evidence base, establishing a therapeutic alliance, identifying and monitoring target symptoms, and promoting medication compliance are important components of successful clinical outcomes. Teamwork between the child, parents, and psychiatrist is critical in successful treatment of childhood disorders with psychopharmacologic agents. An evaluation for psychopharmacotherapy must first include an assessment of a child’s psychopathology and physical condition to rule out any predisposition for side effects (Table 31.18d-1). An assessment of the child’s caregivers focuses on their ability to provide a safe, consistent environment in which a clinician can conduct a drug trial. The physician must consider the risk-to-benefit ratio and must explain it to the patient, if he or she is old enough, and to the child’s caregivers and others (e.g., child welfare workers) who may be involved in the decision to medicate. Table 31.18d-1 Diagnostic Processes of Biological Therapy The clinician must obtain baseline ratings before medicating. Behavioral rating scales help objectify the child’s response to medication. The physician generally starts at a low dose and titrates upward on the basis of the child’s response and the appearance of adverse effects. Optimal drug trials cannot be rushed (e.g., by insurance-imposed, inadequately short hospital stays or by infrequent outpatient visits), nor can drug trials be prolonged by the physician’s insufficient contact with the patient and the caregivers. The success of drug trials often hinges on the physician’s daily accessibility. CHILDHOOD PHARMACOKINETICS Compared with adults, children have greater hepatic capacity, more glomerular filtration, and less fatty tissue. Thus, stimulants, antipsychotics, and tricyclic drugs are eliminated more rapidly by children than by adults; lithium (Eskalith) may also be eliminated more rapidly, and children may be less able to store drugs in their fat. Because of children’s quick elimination, the half-lives of many medications may be shorter in children than in adults.

Little evidence indicates that clinicians can predict a child’s blood level from the dosage or a treatment response from the plasma level. Relatively low serum levels of haloperidol seem to be adequate to treat Tourette’s disorder in children. No correlation is seen between the methylphenidate (Ritalin) serum level and a child’s response. The data are incomplete and conflicting about major depressive disorder and serum levels of tricyclic drugs. Serum level is related to response for tricyclic drugs in the treatment of enuresis. With lithium therapy, a ratio of lithium concentration in saliva to that in serum can be established for a child by averaging three to four individual ratios. The average ratio can then be used to convert subsequent saliva levels to serum levels and, thus, avoid some venipuncture in children who are stressed by blood tests. As with serum levels, regular clinical monitoring for adverse effects is necessary. Table 31.18d-2 lists representative agents, their indications, dosages, adverse reactions, and monitoring requirements. Table 31.18d-2 Pharmacologic Agents for Psychiatric Disorders in Children Adolescents

STIMULANT AGENTS, ATOMOXETINE, AND α-AGONIST AGENTS Stimulant pharmacologic agents remain the primary treatment for ADHD in children, adolescents, and adults. Multiple studies support the efficacy of stimulant medications for ADHD. Current practice is leaning toward more use of once-a-day, long-acting preparations of stimulants such as methylphenidate, amphetamine and amphetamine salts, and dex-methylphenidate (Focalin LA). The most frequently researched and used stimulant is methylphenidate. Dextroamphetamine (Dexedrine) has comparable efficacy and, unlike methylphenidate, is approved by the FDA for children 3 years of age and older; the starting age for methylphenidate is 6 years. The amphetamine, Adderall, combines dextroamphetamine and amphetamine salts. The extended-release preparations, such as Concerta and Adderall XR, have the advantages of coverage of symptoms throughout the school day without the necessity of taking another dose, as well as a more continuous delivery of medication. Stimulants reduce hyperactivity,

inattentiveness, and impulsivity in about 75 percent of children with ADHD. The effects are not paradoxical, because normal children respond similarly. The dose-related adverse effects of stimulants are listed in Table 31.18d-3. Table 31.18d-3 Common Dose-Related Side Effects of Stimulants The methylphenidate transdermal patch (Daytrana) is approved by the FDA for the treatment of ADHD in children age 6 to 12 years. Daytrana comes in patches that can deliver 15 mg, 20 mg, and 30 mg when worn for 9 hours per day. The medication begins to have its effects on the target symptoms of ADHD approximately 2 hours after the patch is placed, and continues to deliver medication throughout the wear time. Given that its active ingredient is methylphenidate, the side effects are generally the same as those for methylphenidate, except for the potential skin irritation that may emerge from wearing the patch. The patch should not be worn in the presence of a heating pad or electric blanket because heat increases the rate of methylphenidate delivery into the skin. Patients with glaucoma or known hypersensitivity to methylphenidate products should not begin treatment with Daytrana. Daytrana has the advantages of being able to deliver medication until the patch is removed and, for children who are unable to swallow pills, Daytrana offers a unique administration option. Lisdexamfetamine dimesylate (LDX), sold as Vyvanse, is a pro-drug of dextroamphetamine upon cleavage of the lysine portion of the molecule. LDX was created to be longer lasting than dextroamphetamine and less likely to become a drug of abuse because it requires enzymes to convert it to dextroamphetamine. LDX has been approved by the FDA for the treatment of ADHD in children 6 to 12 years of age as well as in adults with ADHD. In contrast to Adderall, which contains approximately 75 percent dextroamphetamine, LDX comprises the dextro enantiomer only. In trials, LDX has also been shown to be effective and safe in the treatment of adolescents with ADHD. Similar to other stimulant agents, the most common side effects of LDX were decreased appetite, headache, insomnia, decreased weight, and irritability. Recent studies support the use of atomoxetine (Strattera), a norepinephrine reuptake inhibitor, as an efficacious nonstimulant treatment for ADHD in children and adolescents. Atomoxetine is well absorbed after ingestion and reaches its maximal plasma concentration after about 1 to 2 hours. Common side effects of atomoxetine include abdominal discomfort, decreased appetite, dizziness, and irritability. Rarely, minor increases in blood pressure and heart rate have been noted. Atomoxetine is metabolized by the cytochrome P450 (CYP) 2D6 hepatic enzyme system, and a fraction of the population (about 7 percent of Caucasians and 2 percent of African Americans) are poor metabolizers, which may increase the plasma half-life by about fivefold. When combined with other medications that inhibit CYP 2D6, such as fluoxetine and

paroxetine, diminished metabolism of atomoxetine can occur, and the dose may need to be decreased. Atomoxetine is generally initiated at 0.5 mg/kg given once per day and increased to a therapeutic dose ranging between 1.4 mg/kg and 1.8 mg/kg, either in one dose or in two divided doses. SECOND GENERATION ANTIPSYCHOTICS (SGAS) AND CONVENTIONAL ANTIPSYCHOTIC AGENTS The SGAs represent a major advance in the pharmacological treatment of schizophrenia in children and adolescents, as well as in adults. The atypical antipsychotic agents have largely replaced traditional antipsychotics because of their more favorable side-effect profiles, greater effectiveness for negative symptomatology, and mood-stabilizing effects. Although the SGAs are generally recommended currently as first-line agents in the treatment of psychotic disorders in children and adolescents, only one controlled NIMH trial has been conducted using an atypical agent in the treatment of schizophrenia for youth. This study examined clozapine and found it to be superior to haloperidol for treating positive and negative symptoms of schizophrenia in 21 youth. The serious drawbacks of clozapine, however, limit it as a first-line agent for this disorder. In the NIMH trial, five participants developed significant neutropenia, and two experienced seizures. Clozapine is generally used only for treatment-resistant schizophrenia. Open label trials in youth with schizophrenia have suggested efficacy of other atypical antipsychotic agents such as olanzapine, risperidone, and quetiapine. Case reports have suggested that ziprasidone is effective. One of the main side effects of the atypical antipsychotic agents is significant weight gain. A newer atypical agent, aripiprazole awaits clinical trials to confirm its potential to be an efficacious and more weight neutral agent for the treatment of childhood psychoses. Although conventional antipsychotics, such as haloperidol, loxapine (Loxitane), and thioridazine (Mellaril) have been shown to be significantly superior to placebo in the treatment of psychosis in youth, given their side effect profiles they are typically chosen as first-line treatments. Schizophrenia with onset in late adolescence is treated, as is adult-onset schizophrenia. Aggressive, explosive, and assaultive behaviors associated with disruptive behavior disorders, psychotic disorders, and posttraumatic stress disorders have been treated with antipsychotic agents with varying reports of success. Randomized controlled trials with several atypical antipsychotics, such as risperidone, olanzapine, quetiapine (Seroquel), and aripiprazole (Abilify), have provided evidence of effectiveness for behavioral improvement, with fewer long-term adverse effects than typical antipsychotics. When conduct disorder is associated with ADHD, a trial of a stimulant is indicated; stimulants are faster acting than atypical antipsychotics or mood-stabilizing agents used in clinical practice to control dangerously aggressive behaviors. The management of severe aggression, disruptive behavior, and ADHD remains a challenge. Combinations of antipsychotics with mood-stabilizing agents or stimulants are sometimes used in treatment-resistant cases, although few studies attest to the

efficacy or safety of drug combinations. Newer “atypical” antipsychotic medications— SDAs—such as risperidone, olanzapine, clozapine (Clozaril), ziprasidone (Geodon), and aripiprazole have enabled a wider range of treatment-resistant patients to benefit from neuroleptic treatment. The SDAs are believed to relieve both the positive and negative symptoms of schizophrenia and to produce less risk of extrapyramidal adverse effects and less potential for the development of tardive dyskinesia. Nevertheless, all antipsychotics pose some risk of extrapyramidal adverse effects and tardive dyskinesia. One challenge in obtaining optimal pharmacological treatment for children is to decrease maladaptive behaviors while promoting productive academic functioning. To this end, clinicians must consider adverse effects of medication that result in cognitive “dulling.” Certain pharmacological agents used in pediatric populations are associated with a specific disorder or with target symptoms that appear in several disorders. For example, haloperidol was shown in past studies to be effective in the treatment of Tourette’s disorder, but it has also been used to control severe aggression. The highpotency antipsychotics haloperidol and pimozide (Orap) still have the greatest body of evidence as effective medications for Tourette’s disorder, although they also have considerable drawbacks. Pimozide prolongs the QT interval and, thus, requires electrocardiography (ECG) monitoring. Clonidine, a presynaptic α-adrenergic blocking agent, is less effective than either of the above-mentioned antipsychotics, but has the advantage of avoiding the risk for tardive dyskinesia; sedation is a frequent side effect of clonidine. Tic disorders often coexist with ADHD in children and adolescents. Stimulant use is controversial; it can precipitate tics and should be avoided in these patients, although recent studies indicate that the prohibition may not be totally warranted. Clonidine sometimes reduces tics in both ADHD and the comorbid cases. SELECTIVE SEROTONIN REUPTAKE INHIBITOR (SSRI) ANTIDEPRESSANTS AND OTHER ANTIDEPRESSANTS SSRI antidepressants have been found in randomized clinical trials to have efficacy in the treatment of childhood anxiety disorders, depressive disorders, and OCD. A substantial evidence base exists for the efficacy of SSRIs in the treatment of separation anxiety, generalized anxiety disorder, and social phobia in children and adolescents. Thus, SSRIs are currently recommended as first-line medications in the treatment of childhood anxiety. Separation anxiety disorder, generalized anxiety disorder, and social phobia are often studied together because they so commonly coexist. A given child with one of the preceding anxiety disorders has a 60 percent chance of having a second one, and in 30 percent of cases, all three are comorbid. Alprazolam (Xanax) may be helpful in separation anxiety disorder, but randomized clinical trials are still needed. The SSRIs currently are the drugs of choice in the pharmacological treatment of depressive disorders in children and adolescents. Given the FDA placement of the “blackbox” warning on all antidepressants used in children and adolescents because of the slightly increased risk of suicidal behaviors, close monitoring of suicidal ideation and

behavior is imperative. Although most side effects of SSRIs are tolerable, anecdotal recent reports indicate occasional SSRI-induced apathy in children and adolescents. Previously, clomipramine proved effective in diminishing obsessions and compulsions in children and adolescents and was generally well tolerated. However, the SSRIs have a more favorable adverse-effect profile and appear to be as effective as clomipramine. MOOD-STABILIZING AGENTS Classic mania in children and adolescents is treated as it is treated in adults. Use of lithium in treating adolescent mania has been supported in many open trials. Divalproex is used frequently to treat bipolar disorder in children and adolescents. A recent double-blind, randomized pilot study comparing quetiapine (400 to 600 mg a day) or divalproex (serum level 80 to 120 mg/mL) in a trial lasting approximately 1 month, found that quetiapine is at least as effective as divalproex in treating acute manic symptoms. Reduction of symptoms occurred more quickly with quetiapine compared with divalproex. Lithium has been shown in multiple investigations to reduce aggression in conduct disorder, and propranolol (Inderal) has been chosen as an agent to control aggression in open trials, although no evidence supports its use in children and adolescents. Carbamazepine (Tegretol) has not been shown to be effective in controlling aggression in child and adolescent conduct disorders. Table 31.18d-4 summarizes the effects of drugs on cognitive tests of learning functions. In children with learning disorders who have attention problems, even in the absence of meeting full criteria for ADHD, methylphenidate facilitates performance on several standard cognitive, psycholinguistic, memory, and vigilance tests, but does not improve children’s academic achievement ratings or teacher ratings. Cognitive impairment from psychotropic drugs, especially antipsychotics, may be an even greater problem for persons who are mentally retarded than for those with learning disorders. Table 31.18d-4 Effects of Psychotropic Drugs on Cognitive Tests of Learning Functionsa BENZODIAZEPINES Sleep terror disorder and sleepwalking disorder occur in the transition from deep deltawave sleep (stages 3 and 4) to light sleep. Benzodiazepines may be effective in these

disorders. They work by reducing both delta-wave sleep and arousals between sleep stages. The medications should be used temporarily and only in severe cases, because tolerance to the medications develops. Cessation of these medications can lead to severe rebound worsening of the disorders, and reducing delta sleep in children may have deleterious effects; thus, behavioral approaches are preferred for these disorders. Patients with early-onset panic disorder and panic attacks have benefited from clonazepam (Klonopin) in several open trials. DESMOPRESSIN Desmopressin (DDAVP) is effective in about 50 percent of patients with intractable enuresis. Improvements with DDAVP range from diminished wetting with less urine volume, to complete cessation of bedwetting. Desmopressin has been used intranasally in dosages of 10 to 40 mg a day. When used over months, nasal discomfort can occur, and water retention is potentially a problem. Patients who respond with full dryness should continue to take the medication for several months to prevent relapses. Desmopressin is now available in oral tablets, and a controlled multicenter study found equal efficacy between intranasal and oral administration of desmopressin in the treatment of enuresis. A dose of 400 mg of oral desmopressin was the study condition associated with greater effectiveness than the lower 200 mg used. ADVERSE EFFECTS AND COMPLICATIONS Antidepressants Adverse effects related to antidepressants have diminished significantly since SSRI antidepressants have been widely accepted as first-line treatments for depressive disorders in children and adolescents. Tricyclics are rarely recommended because of the significant risks of dangerous adverse effects. The adverse effects of tricyclics for children usually are similar to those for adults and result from the drugs’ anticholinergic properties. These effects include dry mouth, constipation, palpitations, tachycardia, loss of accommodation, and sweating. The most serious adverse effects in children are cardiovascular; diastolic hypertension is more common and postural hypotension occurs more rarely than in adults. ECG changes are most likely seen in children receiving high doses. Slowed cardiac conduction (PR interval greater than 0.20 seconds or QRS interval greater than 0.12) may necessitate lowering the dosage. FDA guidelines limit dosages to a maximum of 5 mg/kg a day. The drugs can be toxic in an overdose, and in small children, ingestion of 200 to 400 mg can be fatal. When the dosage is lowered too rapidly, withdrawal effects occur, mainly gastrointestinal symptoms—cramping, nausea, and vomiting—and sometimes apathy and weakness. Antipsychotics The SGAs have generally replaced the conventional antipsychotics as first-line agents in

the treatment of all psychotic disorders in children and adolescents. Historically, the best-studied antipsychotics given to pediatric age groups are chlorpromazine (Thorazine) and haloperidol. High-potency and low-potency antipsychotics are thought to differ in their adverse-effect profiles. The phenothiazine derivatives (chlorpromazine and thioridazine) have the most pronounced sedative and atropinic actions, whereas the high-potency antipsychotics are commonly believed to be associated with extrapyramidal reactions, such as parkinsonian symptoms, akathisia, and acute dystonias. The risk of tardive dyskinesia in relation to antipsychotics leads to caution in the use of drugs. Tardive dyskinesia, which is characterized by persistent abnormal involuntary movements of the tongue, face, mouth, or jaw and sometimes the extremities, is a known hazard when giving antipsychotics to patients of all age groups. No known treatment is effective. Because transient choreiform movements of the extremities and trunk are common after abrupt discontinuation of antipsychotics, clinicians must distinguish these symptoms from persistent dyskinesia. REFERENCES Correll CU, Kratocvil CJ, March J. Developments in pediatric psychopharmacology: Focus on stimulants, antidepressants and antipsychotics. J Clin Psychiatry. 2011;72:655–670. Findling RL, Adeyi B, Dirks B, Babcock T, Shecner B, Lasser R, DeLeon A, Ginsberg LD. Parent-reported executive function behaviors and clinician ratings of attention-deficit/hyperactivity disorder symptoms in children treated with lisdexamfetamine. J Child Adolesc Psychopharmacol. 2013;23:28–35. Findling RL, Childress AC, Cutler AJ, Gasior M, Hamdani M, Ferreira-Cornwell MC, Squires L. Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50;395–405. Franklin ME, Sapyta J, Freeman JB, Khanna M, Compton S, Almirall D. Moore P, Choate-Summers M, Garcia A, Edson AL, Foa EB, March JS. Cognitive behavior therapy augmentation of pharmacotherapy in pediatric obsessive-compulsive disorder: The Pediatric OCD Treatment Study II (POTS II) randomized controlled trial. JAMA 2011;306:1224–1232. Ginsburg GS, Kendall PC, Sakolsky D, Compton SN, Piacentini J, Albano AM, Walkup JT, Sherrill J, Coffey KA, Rynn MA, Keeton CP, McCracken JT, Bergman L, Iyengar S, Birmaher B, March J. Remission after acute treatment in children and adolescents with anxiety disorders: findings from The CAMS. J Consult Clin Psychol. 2011;79:806–813. Greenhill, LL, Hechtman, L. Attention-deficit disorders. In: Sadock BJ, Sadock VA, & Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Vol. 2. Philadelphia. Lippincott Williams & Wilkins; 2009;3560. Hammerness PG, Perrin JM, Shelley-Abrahamson R, Wilens TE. Cardiovascular risk of stimulant treatment in pediatric attention-deficit/hyperactivity disorder: Update and clinical recommendations. J Am Acad Child Adolesc Psych. 2011;50:978–990. Hughes CW, Emslie GJ, Crimson ML, Posner K, Birmaher B, Ryan N, Jensen P, Curry J, Vitiello B, Lopez M, Shon SP, Piszka SR, Trivedi MH, and The Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder. Texas Children’s Medication Algorithm Project: Update from Texas Consensus Conference Panel on medication treatment of childhood major depressive disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:667–686. Joshi SV. Teamwork: The therapeutic alliance in pediatric pharmacotherapy. Child Adolesc Psychiatr Clin N Am. 2006;12:239. Nilsen TS, Eisemann M, Kvernmo S. Predictors and moderators of outcome in child and adolescent anxiety and depression: A systematic review of psychological treatment studies. Eur Child Adolesc Psychiatry. Feb 2013;22(2):69–87.