Valproate clozapine

Another serious side effect of clozapine is a risk of seizures. This mainly occurs at higher doses of the drug, and having a seizure is not necessarily a sufficient reason to stop clozapine permanently. If the clozapine has been especially helpful, an anticonvulsant can be added to protect against further seizures. Valproate (Depakote) may be best in this regard because it not only provides protection from seizures but also may help to relieve some of the symptoms of schizophrenia. Recently, it has become clear that two atypical antipsychotic drugs, clozapine and olanzapine, are associated with an increased risk for the development of type II diabetes. 

McElroy SL, Keck PE Jr, Pope EIG Jr, et al Valproate in primary psychiatric disorders literature review and clinical experience in a private psychiatric hospital, in Use of Anticonvulsants in Psychiatry Recent Advances. Edited by McElroy SL, Pope HG Jr. Clifton, NJ, Oxford Health Care, 1988b McElroy SL, Keck PE Jr, Pope HG Jr, et al Valproate in the treatment of rapid-cycling bipolar disorder. J Clin Psychopharmacol 8 275-279, 1988c McElroy SL, Sessain EC, Pope HG Jr, et al Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder and schizophrenia. J Clin Psychiatry 52 411-414, 1991a... 

Another use of the laboratory is for therapeutic drug monitoring (TDM) of psychotropics with defined optimal ranges, narrow therapeutic indices, or both. Although TDM is not essential for many psychotropics, it is for others, including lithium, several TCAs, valproate, and carbamazepine. It may also be helpful to optimize the use of certain antipsychotics (e.g., haloperidol, clozapine) ( 7). 

Kando JC, Tohen M, Castillo J, et al. Concurrent use of clozapine and valproate in affective and psychotic disorders. J Clin Psychiatry 1994 55 255-257. 

Dembowski C, Rechlin T. Successful antimanic treatment and mood stabilization with lamotrigine, clozapine, and valproate in a bipolar patient after lithium-induced cerebellar deterioration. A case report. Pharmacopsychiatry 2003 36(2) 83-6. 

A 57-year-old man developed severe stuttering after taking clozapine 300 mg/day and sodium valproate 600 mg/day for 8 months (59). It abated 1 week after clozapine was reduced and finally withdrawn. 

Clozapine inhibits the metabolism of valproate (277). Valproic acid has been reported to increase the sedative effects of clozapine (SEDA-20, 50) and alter serum concentrations of clozapine. 

Costello LE, Suppes T. A clinically significant interaction between clozapine and valproate. J Clin Psychopharmacol 1995 15(2) 139-41. 

Chronic valproate (600-1500 mg/day) has been associated with a slight increase in plasma clozapine concentrations and a slight fall in norclozapine concentrations (132). These changes are unlikely to be clinically significant. 

Because of the risk of orthostatic hypotension, clozapine is nsn-ally titrated more slowly than other antipsychotics, particnlarly on an outpatient basis. If a 12.5-mg test dose does not prodnce hypotension, then clozapine 25 mg at bedtime is recommended, increased to 25 mg twice a day after 3 days, and then increased in 25- to 50-mg/day increments every 3 days until a dose of at least 300 mg/day is reached. Because high doses are associated with significantly increased side effects, including seizures, a clozapine serum concentration is recommended before exceeding 600 mg/day. Althongh some clinicians add valproate when exceeding this dose to prevent the occnrrence of seizures, no evidence supports this intervention, and it is more prudent to start valproate if a seizure occurs. 

I Drug-Drug Interactions. Carbamazepine induces the hepatic cytochrome P450 isoenzymes (1A2, 3A4, 2C9/10, and 2D6), which increases the metabolism of many medications, such as anticonvulsants (i.e., lamotrigine, topiramate, and valproate), antidepressants (i.e., tricyclics and bupropion), antipsychotics (i.e., clozapine, haloperi-dol, fluphenazine, olanzapine, and thiothixene), benzodiazepines, oral contraceptives, and protease inhibitors. " Women who receive carbamazepine require higher dosages of oral contraceptives or alternative contraceptive methods." ... 

Carbamazepine is metabolized to an active 10,11-epoxide metabolite, thus medications that inhibit 3A4 isoenzymes may result in carbamazepine toxicity (e.g., cimetidine, dUtiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefa-zodone, propoxyphene, and verapamil). " When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein binding sites, thus increasing free levels." Combining clozapine and carbamazepine is not recommended because of the possibdity of bone marrow suppression with both agents. ... 

These can decrease clozapine serum levels by about 60% (carbamazepine) and 85% (phenytoin) due to hepatic cytochrome P450-inducing properties. Plasma concentrations of clozapine and its metabolites have been reported to be either slightly decreased or increased when combined with valproate. 

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. 

In cases of partial response to an SSRI, the addition of lithium has shown a beneficial response in several studies. If an SSRI fails, medication could be switched to an MAOl after an appropriate washout period. Carbamazepine, valproate, or an SCA could also be considered. Clozapine may be warranted after other treatments have failed. 

Clozapine serum levels are approximately halved by car-bamazepine and possibly by phenobarbital and phenytoin. An isolated case of fatal pancytopenia has been seen in one patient taking clozapine and carbamazepine, and neuroleptic malignant syndrome occurred in another. Sodium valproate can apparently lower serum clozapine levels, and an isolated case report su ests that lamotrigine may raise them. 

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