Bipolar Medications in Children and Adolescents: Mood Stabilizers

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 oflithium(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 carbonatehas 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 acidorsodium divalproex,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.

碳酸锂是有效的在大约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,来piramate) 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),risperidone (Risperdal)may be considered first-line alternatives to lithium, valproate, or carbamazepine. Pediatric studies withziprasidone (Geodon)andaripiprazole (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.

一个重要的考虑与非典型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, 来xic 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.

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Benzodiazepines and Antidepressants for Treating Bipolar Symptoms

Benzodiazepines, such as clonazepam and lorazepam, generally are avoided, but they may be temporarily useful in restoring sleep or in modulating irritability or agitation not caused by psychosis. Because of the slow-on and slow-off action ofclonazepam (Klonopin), the risk of abuse is lower with this drug than with fast-acting benzodiazepines such aslorazepam (Ativan)and alprazolam (Xanax). In the outpatient setting, clonazepam may be preferred because of the efficacy and the lowered risks of abuse by the patient or others. Clonazepam can be dosed in the range of 0.01-0.04 mg/kg/d, and it is often administered once per day at bedtime or twice per day. Lorazepam is dosed to 0.04-0.09 mg/kg/d and administered 3 times per day because of its short half-life.

When a patient with bipolar disorder is having a depressive episode, the use of an antidepressant may be considered after a mood stabilizer or atypical antipsychotic agent has been started and after a therapeutic response or level is achieved. Caution must be exercised in starting an antidepressant in a person with bipolar disorder because it may precipitate mania. An antidepressant with a potentially lowered risk of inducing mania isbupropion (Wellbutrin).

Selective serotonin reuptake inhibitors (SSRIs) may also be used. However, because of the risk of mania, doses should be low and titration should be slow. The only SSRI currently FDA approved for the management of unipolar depression in adolescents is fluoxetine (Prozac). However, this agent should be used carefully in patients with bipolar disorder because of its long half-life and because of its potential to exacerbate manic symptoms when not coadministered with an antimanic or mood-stabilizing agent.

All medications used in pediatric bipolar disorder pose a risk of adverse effects or interactions with other medications. These risks should be clearly discussed with patients and families and weighed against the potential benefits. Medication should be started only after informed consent is obtained.

Drug Category:Mood stabilizers-- Indicated for control of manic episodes occurring in bipolar disorder. Mood stabilizers include lithium carbonate, valproic acid or sodium divalproex, and carbamazepine. These medications are considered first-line agents in managing bipolar disorder in pediatric patients.

Drug Name	锂(Lithotabs碳酸锂,之类Lithane Eskalith)-- Used to manage and prevent acute manic episodes. Influences reuptake of serotonin and/or norepinephrine at cell membrane.
Adult Dose	300-600 PO tid/qid in divided doses Maintenance: 2.4 g/d or 450-900 mg bid of SR dosage form
Pediatric Dose	10-30 mg/kg/d PO divided bid/tid; titrate upward gradually from lower range while monitoring serum levels and patient response
Contraindications	Documented hypersensitivity; severe cardiovascular or renal disease
Interactions	Thiazide diuretics, haloperidol, phenothiazines, neuromuscular blockers, carbamazepine, fluoxetine, and ACE inhibitors may decrease elimination and increase toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Toxicity is closely related to serum levels and can occur at therapeutic doses; caution in hypothyroidism, cardiovascular or renal compromise, and diabetes insipidus; decreased intake of sodium may cause increased lithium levels

Drug Name	Valproic acid (Depakote, Depakene, Depacon)-- Although mechanism of action is not established, activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate also may potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membrane-stabilizing effect. Has proven effectiveness in treating and preventing mania. Classified as a mood stabilizer and can be used alone or in combination with lithium. Useful in treating patients with rapid-cycling bipolar disorders and has been used to treat aggressive or behavioral disorders. A combination of valproic acid and valproate (ie, divalproex [Depakote]) has been effective in treating persons in manic phase, with a success rate of 49%.
Adult Dose	10-20 mg/kg/d PO divided bid; may gradually titrate upward by 5-10 mg/kg/d at weekly intervals; not to exceed 30-60 mg/kg/d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hepatic disease or dysfunction
Interactions	Coadministration with cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce valproate levels; in pediatric patients, protein binding and metabolism of valproate decrease when taken concomitantly with salicylates; coadministration with carbamazepine may result in variable changes of carbamazepine concentrations; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in patients with HIV
Pregnancy	D - Unsafe in pregnancy
Precautions	Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; before initiating therapy, at periodic intervals, and prior to surgery, determine platelet counts and bleeding time; reduce dose or discontinue therapy if hemorrhage, bruising, or a hemostasis or coagulation disorder occurs; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness

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Drug Name	Carbamazepine (Tegretol)-- Effective in patients who have not responded to lithium therapy. Also can act to inhibit seizures induced through the kindling effect, which is thought to occur by way of repeated limbic stimulation. Has been effective in treating patients who have rapid-cycling bipolar disorder or those who have not been responsive to lithium therapy.
Adult Dose	200 mg PO bid (100 mg PO qid if susp) May increase at weekly intervals by no more than 200 mg/d tid/qid (bid with ER) until best response obtained; not to exceed 1600 mg/d
Pediatric Dose	10-20 mg/kg/d PO divided bid (qid with susp)
Contraindications	Documented hypersensitivity; history of bone marrow depression; administration of MAOIs within last 14 d
Interactions	Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not administer concurrently with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; carbamazepine may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels)
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution with increased intraocular pressure; obtain CBCs and serum-iron baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Drug Name	Risperidone (Risperdal)-- Binds dopamine D2-receptor with 20 times lower affinity than for 5-HT2-receptor. Indicated for short-term (3-wk) treatment of acute mania associated with bipolar disorder. May use alone or combined with lithium or valproate.
Adult Dose	2-3 mg PO qd up to 3 wk; may increase by 1 mg/d at 24-h intervals, not to exceed 6 mg/d
Pediatric Dose	Data limited; 0.25 mg PO bid or 0.5 mg qhs initially; titrate as tolerated to target dosage of 2-4 mg/d; not to exceed 6 mg/d
Contraindications	Documented hypersensitivity
Interactions	Coadministration with carbamazepine may decrease effects; may inhibit effects of levodopa; clozapine may increase levels; PO solution not compatible with cola or tea
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause extrapyramidal reactions, hypotension, tachycardia, and arrhythmias; hyperglycemia (some cases extreme) may occur, resulting in ketoacidosis, hyperosmolar coma, or death; do not split or chew PO disintegrating tablets

Drug Name	Quetiapine (Seroquel)-- May act by antagonizing dopamine and serotonin effects. Newer antipsychotic used for long-term management. Improvements over earlier antipsychotics include fewer anticholinergic effects and less dystonia, parkinsonism, and tardive dyskinesia.
Adult Dose	Initial: 25 mg PO bid/tid; increase by 25-50 mg bid/tid on day 2 or 3 to achieve range 300-400 mg divided bid/tid by day 4; adjust as needed at intervals of>2 d with adjustments of 25-50 mg bid Maintenance: 150-750 mg/d PO; not to exceed 800 mg/d
Pediatric Dose	Data limited; 50 mg PO bid initially; titrate as tolerated to target dosage of 400-600 mg/d
Contraindications	Documented hypersensitivity
Interactions	可能对抗左旋多巴和多巴胺受体激动剂;板式换热器nytoin, thioridazine, and other liver enzyme inducers may reduce levels; cytochrome P450 (CYP) 3A inhibitors (eg, ketoconazole, fluconazole, erythromycin) increase serum concentration
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May induce orthostatic hypotension associated with dizziness, tachycardia, and syncope; has been associated with NMS and tardive dyskinesia; hyperglycemia (some cases extreme) may occur, resulting in ketoacidosis, hyperosmolar coma, or death; caution in hepatic impairment (decrease dose)

Drug Name	Olanzapine (Zyprexa)-- Mechanism of action for acute manic episodes associated with bipolar I disorder unknown. Available as tab, PO disintegrating tab (Zyprexa, Zydis), and IM dosage forms.
Adult Dose	10-15 mg PO qd; adjust by 5 mg/d at intervals >24 h; not to exceed 20 mg/d Agitation associated with bipolar mania: 10 mg IM once; may repeat after 2 h; not to exceed 30 mg/24 h Geriatric or debilitated individuals: 2.5-5 mg IM/dose
Pediatric Dose	Data limited; 2.5-5 mg PO qhs initially; titrate as tolerated to target dosage of 10-20 mg/d
Contraindications	Documented hypersensitivity
Interactions	Fluvoxamine may increase effects; antihypertensives may increase risk of hypotension and orthostatic hypotension; levodopa, pergolide, bromocriptine, charcoal, carbamazepine, omeprazole, rifampin, and cigarette smoking may decrease effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in narrow-angle glaucoma, cardiovascular disease, cerebrovascular disease, prostatic hypertrophy, seizure disorders, hypovolemia, and dehydration; hyperglycemia (some cases extreme) may occur, resulting in ketoacidosis, hyperosmolar coma, or death; administration of>1 IM injection associated with substantial orthostatic hypotension (33%), maintain patient in recumbent position and monitor blood pressure before repeating IM doses

Sources:

• Kowatch RA, Bucci JP. Mood stabilizers and anticonvulsants. Pediatr Clin North Am. Oct 1998;45(5):1173-86, ix-x.
• Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. Mar 2005;44(3):213-35.
• Medication information listed in tables is from package inserts for each medication.

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