Aripiprazole Valproate

Olanzapine Zyprexa 20, 30 mg Tablets 2.5, 5, 7.5, 10, 5-20 mg/day in 1 or 2 doses combination with lithium or valproate for the acute treatment of mania or mixed states for bipolar I disorder. Olanzapine and aripiprazole are approved for relapse prevention as well as for acute therapy... 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

Until recently, lithium carbonate was the universally preferred treatment for bipolar disorder, especially in the manic phase. With the approval of valproate, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone for this indication, a smaller percentage of bipolar patients now receive lithium. This trend is reinforced by the slow onset of action of lithium, which has often been supplemented with concurrent use of antipsychotic drugs or potent benzodiazepines in severely manic patients. The overall success rate for achieving remission from the manic phase of bipolar disorder can be as high as 80% but lower among patients who require hospitalization. A similar situation applies to maintenance treatment, which is about 60% effective overall but less in severely ill patients. These considerations have led to increased use of combined treatment in severe cases. After mania is controlled, the antipsychotic drug may be stopped and benzodiazepines and lithium continued as maintenance therapy. 

Aripiprazole, olanzapine, quetiapine , risperidone, and ziprasidone are effective as monotherapy or as add-on therapy to lithium or valproate for acute mania. Prophylactic use of antipsychotics can he needed for some patients with recurrent mania or mixed states, hut the risks versus benefits must be weighed in view of long-term side effects (e.g., obesity, type 2 diabetes, hyperlipidemia, hyperprolactinemia, cardiac disease, and tardive dyskinesia). 

Thus, valproate is often used to reduce the risk for clozapine-induced seizures. Carbamazepine can potentially increase the risk for development of agranulocytosis when coadministered with clozapine, so this combination should be avoided. Carbamazepine increases renal clearance of olanzapine by about 45% and reduces its half-life by about 20%. To date, no pharmacokinetic interactions have been reported between aripiprazole and valproate. 

Valproate causes a reduction in aripiprazole levels which is not considered to be clinically signiilcant. 

Aripiprazole 30 mg daily was given to 6 healthy subjects for 5 weeks, with valproate semisodium (divalproex sodium) daily in doses to achieve a serum valproate level of 50 to 125 mg/L, for weeks 3 to 5 of the study. The mean AUC and maximum plasma concentrations of aripiprazole were found to decrease by 24% and 26%, respectively, and the time to maximum aripiprazole levels was extended by 2 hours. Since aripiprazole and valproate share the same protein binding sites, it was considered likely that the valproate displaced bound aripiprazole leading to increased... 

Vieta E, Owen R, Baudelet C, McQuade RD, Sanchez R, Marcus RN. Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lith-ium/valproate in bipolar mania a 46-week, open-label extension following a 6 week double-blind study. Curr Med Res Opin 2010 26(6) 1485-96. 

In a multicenter study, out-patients were randomly assigned to adjunctive aripiprazole (15 or 30 mg/day n = 253) or placebo ( = 131) for 6 weeks [62. They had had a manic or mixed episode (with or without psychotic features) with partial non-response to lithium/valproate monotherapy and with target serum concentrations of lithium (0.6-1.0 mmol/1) or valproate (50-125 mgA). Improvement was significantly greater with aripiprazole than with placebo. Withdrawal rates due to adverse reactions were higher with aripiprazole than with placebo (9% versus 5% respectively). Akathisia was the most frequently reported extrapyramidal symptom-related adverse reaction, and it occurred... 

Vieta E, T joen C, McQuade RD, Carson Jr. WH, Marcus RN, Sanchez R, Owen R, Nameche L. Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy a placebo-controlled study. Am J Psychiatry 2008 165(10) 1316-25. 

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