Seizures clozapine-induced

DasGupta K, Young A Clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry 52 105-107, 1991 Davis KL, Kahn RS, Ko G, et al Dopamine in schizophrenia a review and reconceptualization. Am J Psychiatry 148 1474-1486, 1991 Devinsky O, Honigfeld G, Patin J Clozapine-related seizures. Neurology 41 369-371, 1991... 

Seizures and other neurological effects have been described in a few cases when lithium was added to clozapine (626), but in other instances the combination was beneficial in overcoming treatment resistance or attenuating clozapine-induced leukopenia. Five treatment-resistant patients were treated successfully with a combination of clozapine and lithium with no clinically significant adverse events (627). However, a 59-year-old woman developed neurotoxic symptoms 3 days after lithium was added to clozapine the symptoms resolved when both drugs were stopped and recurred with rechallenge (628). 

Several anticonvulsants have been shown to be helpful in the prevention and treatment of clozapine-induced seizures. 

Stuttering has been associated with clozapine (SEDA-22, 58). The pathogenesis of developmental stuttering, as well as acquired or neurogenic stuttering, is unclear. However, since clozapine-induced stuttering can precede a seizure (SEDA-25, 64) it may be related to an effect on the brain rather than to a dystonic syndrome, as previously suggested. 

Silvestri RC, Bromfield EB, Khoshbin S. Clozapine-induced seizures and EEG abnormalities in ambulatory psychiatric patients. Ann Pharmacother 1998 32(11) 1147-51. 

Usiskin SI, Nicolson R, Lenane M, Rapoport JL. Gabapentin prophylaxis of clozapine-induced seizures. Am J Psychiatry 2000 157(3) 482-3. 

Duggal HS, Jagadheesan K, Nizamie SH. Clozapine-induced stuttering and seizures. Am J Psychiatry 2002 159(2) 315. 

Seizures and other neurological effects have been described in a few cases when lithium was added to clozapine (204), but in other instances the combination was beneficial in overcoming treatment resistance or attenuating clozapine-induced leukopenia. 

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. 

The answer is c. (Hardman7 p 408.) Clozapine differs from other neuroleptic agents in that it can induce seizures in nonepileptic patients In patients with a history of epileptic seizures for which they are not receiving treatment, stimulation of seizures can occur following the administration of neuroleptic agents because they lower seizure threshold and cause brain discharge patterns reminiscent of epileptic seizure disorders. 

There is an increased risk of drug-induced seizures in all patients treated with antipsychotics. The highest risk for antipsychotic-induced seizures is with the use of CPZ or clozapine. Seizures are more likely with initiation of treatment and with the use of higher doses and rapid dose increases. 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Because of the risk of seizures with higher clozapine tissue concentrations, inhibition interactions with clozapine are potentially significant. In particular, fluvoxamine has been reported to increase clozapine serum concentrations by an average of two- to threefold and up to fivefold. Fluoxetine and erythromycin may increase clozapine serum concentrations in some patients, but to a lesser degree. Mean clozapine serum concentrations are reported to be 32% lower in smokers compared with nonsmokers." Carbamazepine may also induce clozapine metabolism and lead to lower serum concentrations. ... 

In a few cases, marked extrapyramidal side-effects (akathisia, dystonia, and parkinsonism) have been reported with flupbenazine, perphenazine, sulpiride, and thiothixene when fluoxetine is added to the regimen. The mechanism is speculated to be the result of fluoxetine-induced further suppression of dopaminergic activity in the nigrostriatal pathways (serotonergic stimulation leads to decreased dopamine release), in addition to increases in their plasma concentration. Fluoxetine has been shown to increase haloperidol serum levels by about 20%, presumably via inhibition of cytochrome P450 enzymes. Fluoxetine can increase the risk of seizure induction when added to clozapine due to an increase in clozapine serum levels, or by additive effects. Concomitant treatment with fluoxetine and risperidone is associated with a mean 4-fold increase in the plasma concentration of risperidone. ... 

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