UIC, Dept. of Psychiatry

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Pediatric Mood Disorders Clinic
Teaching Rounds

Valproic Acid: Its Use in Children for the treatment of mania: PART 1

Natalie Hogan: MS-3

Valproic Acid (Valporate, Depakene) is the mood stabilizer of choice because of its favorable side effect profile and low toxicity in overdose. It is effective in bipolar disorders, impulse control/aggression, schizoaffective disorder, cyclothymia, rapid cycling and mixed state episodes. Its exact mechanism of action is unknown, but it does enhance the accumulation of GABA. So far, research has shown that valporate is effective as an antimanic agent for short tern usage, no long tern studies are available. Also, no optimum serum levels to produce a thymolytic effect have been established. The Clinical Practice of Child and Adolescent Psychopharmacology states that adolescents should begin with 250mg, if this dosage is well tolerated, it can be increased to 750mg/day (250mg TID). The daily dose should be increased over a 2-3 day period to obtain a total target dose of 1000-1250mg/day. This target dose is necessary for the patient to achieve adequate serum levels of 50-100mg/ml, shown to be the therapeutic levels needed. On the other hand, children require lower doses. Their test dose should be 100mg, if tolerated, then 200-300mg dose/day should be given. The gradual increase should end when the total daily target dose reaches 1000-1200mg/day, which should give serum levels between 50-100mg/ml. Common side effects of valproic acid include: GI distress (vomiting, diarrhea, anorexia) alleviated by taking medication with food or switching to the enteric coated Depakote form, sedation (which abates after the 1^st few weeks of treatment), ataxia, tremor, rash, alopecia, mild elevation of liver function, thrombocytopenia, hepatitis, and possibly polycystic ovarian disease in women. This later complication was reported in patients treated for epilepsy, not bipolar disorder. Valproic acid is a teratogen leading to neural tube defects, such as spina bifida and it also affects the metabolism of many drugs, like phenobarbital, by inhibiting the liver�s P450 enzyme mechanism.

Papatheodorou, George, Kutcher, Stan P. et al. The Efficacy and Safety of Divalproex Sodium in the Treatment of Acute Mania in Adolescents and Young Adults: An Open Clincial Trial, 15:110-16, 1994

Fristad M, Weller E, Weller R. Bipolar disorder in children and adolescents. Child and Adolescent Psychiatric Clinics of North America, 1:13-30, 1992

Valproic Acid and the treatment of mania in children: PART 2

Valproic Acid (Depakene)

Divalproex Sodium (Depakote)

General:

Mood stabilizer of choice because of favorable side effect profile and low toxicity in overdose
Mechanism of action: enhances GABA accumulation in the body and CSF. It is carrier-mediated into and out of CSF (exact mechanism of action is unknown)
Rapidly absorbed on an empty stomach, but delayed absorption occurs with food
Highly protein bound

Hepatic metabolized

Indications for usage:

It is effective in bipolar disorders, impulse control/aggression, schizoaffective disorder, cyclothymia, rapid cycling and mixed state episodes.

Treatment Guidelines:

Pretreatment evaluation includes physical examination, CBC, platelets, LFT�s and PT/PTT in order to establish patient�s baseline values. It usually requires 2 weeks for valporate to take its full effect and a trial of 4-6 weeks before one can evaluate efficacy. Serum levels of valporate should be obtained weekly during the 1^st month treatment.

Dosing Schedule:

So far, research has shown that valporate is effective as an antimanic agent for short tern usage, no long tern studies are available. Also, no optimum serum levels to produce a thymolytic effect have been established. The Clinical Practice of Child and Adolescent Psychopharmacology states that adolescents should begin with 250mg, if this dosage is well tolerated, it can be increased to 750mg/day (250mg TID). The daily dose should be increased over a 2-3 day period to obtain a total target dose of 1000-1250mg/day. This target dose is necessary for the patient to achieve adequate serum levels of 50-100mg/ml, shown to be the therapeutic levels needed. On the other hand, children require lower doses. Their test dose should be 100mg, if tolerated, then 200-300mg dose/day should be given. The gradual increase should end when the total daily target dose reaches 1000-1200mg/day, which should give serum levels between 50-100mg/ml.

One study used higher dosages in their subjects (aged 12-20), the dosage range was 750mg � 2,00mg/day with serum levels ranging from 642.85 +/- 183.08 millimolar/liter at the end of the study.

Side Effects:

Common side effects of valproic acid include: GI distress (vomiting, diarrhea, anorexia) alleviated by taking medication with food or switching to the enteric coated Depakote form, sedation (which abates after the 1^st few weeks of treatment), ataxia, tremor, rash, alopecia, mild elevation of liver function, thrombocytopenia, hepatitis, and possibly polycystic ovarian disease in women. This later complication was reported in patients treated for epilepsy, not bipolar disorder. Valproic acid is a teratogen leading to neural tube defects, such as spina bifida.

Drug Interactions:

There are also significant drug-drug interactions with valproate, for example, valproate affects the metabolism of many drugs, like phenobarbital, by inhibiting the liver�s P450 enzyme mechanism causing increased phenobarbital levels.