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Detailed information on mood stabilizers and atypical antipsychotics for treatment of bipolar disorder in children and adolescents.

Detailed information on mood stabilizers and atypical antipsychotics for treatment of bipolar disorder in children and adolescents.Children and adolescents with bipolar disorder are treated with medications, although none of these medications, with the sole exception of lithium (in patients as young as 12 years old), have received Food and Drug Administration (FDA) approval for this application. Despite the paucity of data, pediatric treatment guidelines have evolved based on empirically derived plans. The Child Psychiatric Workgroup on Bipolar Disorder established guidelines based on the most up-to-date evidence (Kowatch, 2005). In general, these guidelines involve algorithm-based use of mood stabilizers and atypical antipsychotic agents alone or in various combinations.

Use of mood-stabilizing agents in children and adolescents has some unique considerations. Specifically, adolescents and children generally metabolize more rapidly than adults because of more efficient hepatic functions. Also, adolescents and children have faster renal clearance rates than adults. For example, lithium carbonate has an elimination half-life of 30-36 hours in an elderly patient, 24 hours in an adult, 18 hours in an adolescent, and less than 18 hours in children. Steady states also are achieved earlier in children than in adolescents and earlier in adolescents than in adults. Thus, plasma levels may be drawn and assessed earlier in children and adolescents than in adults.

Some consequences of the efficient metabolizing and clearance systems of young individuals are as follows: (1) peak drug levels may show higher plasma concentrations than anticipated in adults, and (2) trough levels may show lower plasma concentrations than anticipated in adults. Thus, children may require higher doses of medications to attain therapeutic response (measured in mg/kg/d) than adults. Special precautions must be taken when dosing psychiatric medications in the treatment of adolescents and children to achieve therapeutic effect while staying safely below toxic levels.

Although the mood stabilizers have not been established as primary treatment of bipolar disorders in adolescents or children by controlled studies, they are used clinically in this context. Mood stabilizers include lithium carbonate, valproic acid or sodium divalproex, and carbamazepine. These medications still are considered first-line agents in managing bipolar disorders in pediatric patients because case reports and limited studies have suggested that efficacy and safety are sufficiently present to benefit the patient with symptom relief and control.

Lithium carbonate is effective in approximately 60-70% of adolescents and children with bipolar disorder and remains the first line of therapy in many settings. Approximately 15% of children receiving lithium medication have enuresis, primarily nocturnal enuresis. In those who do not respond to lithium, sodium divalproex is generally the next agent of choice. As with adult patients with bipolar disorder, carbamazepine often is considered a third choice, after sodium divalproex and lithium carbonate have been tried at optimal doses for a sufficient length of time. This medication often is tried after an acute or crisis state has been stabilized and adverse effects of either sodium divalproex or lithium carbonate are intolerable.

Lamotrigine has been approved for bipolar maintenance therapy in adults, but data in pediatric patients are lacking. Other antiepileptic medications (eg, gabapentin, oxcarbazepine, topiramate) have had mixed results in adults with bipolar disorder in case reports and studies. However, limited data are available regarding the potential usefulness of these medications in pediatric patients with bipolar disorder, though a benefit may theoretically be possible.

Emerging evidence indicates that atypical antipsychotic agents may be used in pediatric patients with bipolar disorder who presents with or without psychosis. Given the antimanic properties demonstrated in adult and limited adolescent studies, olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) may be considered first-line alternatives to lithium, valproate, or carbamazepine. Pediatric studies with ziprasidone (Geodon) and aripiprazole (Abilify) are limited at this point; this limitation indicates that these agents should be considered second-line alternatives if first-line mood stabilizers or atypical antipsychotic agents are ineffective or if they result in intolerable adverse effects. Clozapine (Clozaril) may be considered only in treatment-refractory cases given its need for frequent hematologic monitoring due to the risk for agranulocytosis.

An important consideration with atypical antipsychotics is the potential for weight gain and metabolic syndrome. The patient's weight should be measured, and a fasting lipid profile and serum glucose level should be evaluated before these agents are started, and these values should be monitored periodically during treatment. Patients and families should be advised of the need to appropriately manage diet and exercise. Limited data indicate that ziprasidone and aripiprazole may have a low potential for these adverse effects and that they may be considered in patients at high risk because of a family or personal history of metabolic abnormalities. Atypical antipsychotics also pose a potential risk for extrapyramidal symptoms and tardive dyskinesia.

Common adverse effects and special concerns for mood stabilizers are listed in Table 1.

Table 1. Mood Stabilizers: Common Adverse Effects and Special Concerns

Mood Stabilizer Common Adverse Effects Doses Special Concerns
Lithium Carbonate (Eskalith CR, Lighobid) Gastrointestinal distress, lethargy or sedation, tremor,
enuresis,
weight gain,
alopecia,
cognitive blunting
10-30 mg/kg/d
Dose must be adjusted by monitoring serum level and patient response
Titrate up on bid schedule
Hypothyroidism,
diabetes insipidus,
toxic in dehydration,
polyuria,
polydipsia,
renal disease
Sodium divalproex/valproic acid (Depakote, Depakene) Sedation, platelet dysfunction, liver disease, alopecia, weight gain 15-60 mg/kg/d
Dose must be adjusted by monitoring serum levels
Titrate up on bid/tid schedule
Elevated liver enzymes or liver disease, drug-drug interactions, bone marrow suppression
Carbamazepine (Tegretol) Suppressed WBC, dizziness, drowsiness, rashes, liver toxicity (rarely) 10-20 mg/kg/d
Dose must be adjusted by monitoring serum blood levels
Titrate up on bid schedule
Drug-drug interactions, bone marrow suppression
Risperidone (Risperdal) Weight gain, sedation, orthostasis 0.25 mg bid or 0.5 mg at bedtime initially; titrate as tolerated to target dosage of 2-4 mg/d; not to exceed 6 mg/d Galactorrhea, extrapyramidal symptoms
Quetiapine (Seroquel) Sedation, orthostasis, weight gain 50 mg bid initially; titrate as tolerated to target dosage of 400-600 mg/d Decrease dosage with hepatic impairment, may cause neuroleptic malignant syndrome (NMS) or hyperglycemia
Olanzapine (Zyprexa) Weight gain, dyslipidemia, sedation, or orthostasis 2.5-5 mg at bedtime initially; titrate as tolerated to target dosage of 10-20 mg/d Metabolic syndrome, extrapyramidal symptoms

While mood stabilizers are first-line agents for patients with bipolar disorder, adjunctive medications often are used to control psychosis, agitation, or irritability and to improve sleep. Commonly, antipsychotics and benzodiazepines are used to reduce these symptoms.