Seizures clozapine

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. 

Clozapine Increased clozapine serum concentrations increased risk for seizures and orthostatic hypotension... 

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 causes virtually no extrapyramidal side effects and can actually relieve tardive dyskinesia. Nevertheless, it is a difficult medication to tolerate. Its common side effects include drowsiness, weight gain, dizziness, constipation, and drooling (sialorrhea). Clozapine also increases the risk that vulnerable individuals may have seizures. 

Carbamazepine and possibly the antidepressant mirtazapine should not be coadministered with clozapine because these drugs may further increase the risk of agranulocytosis. In addition, the antidepressant bupropion should not be coprescribed with clozapine because it may increase clozapine s seizure risk. 

Quetiapine (Seroquel). Another atypical antipsychotic, quetiapine has also been approved by the FDA for the treatment of acute mania. It is usually administered twice daily at doses of 150-750mg/day. Like its counterparts, quetiapine is a well-tolerated medication. Its common side effects are drowsiness, dizziness, and headache. It causes less weight gain than olanzapine or clozapine but more than ziprasidone or aripiprazole. Quetiapine also does not cause agranulocytosis nor does it increase the risk of seizures. It can occasionally cause mild changes in liver function tests, but these usually return to normal even if the patient continues taking quetiapine. 

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. 

Care should be taken when prescribing other medications with clozapine. The mood stabilizer carbamazepine (Tegretol) and perhaps the antidepressant mirtazap-ine (Remeron) should not be taken with clozapine because they might further increase the risk of agranulocytosis. Likewise, the antidepressant bupropion (Wellbutrin, Zyban) should not be taken with clozapine because it may add to the seizure risk. 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Seizures Seizures have been associated with the use of clozapine. Dose appears to be an important predictor of seizure, with a greater likelihood at higher clozapine doses. Use caution when administering clozapine to patients having a history of seizures or other predisposing factors. Advise patients not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others. 

Neurological Extrapyramidal side effects, sedation, seizures Dopamine 2, histamine Examine for Parkinsonism, akath-isia, and abnormal involuntary movements at each visit Baseline electroencephalogram if treated with clozapine. 

Devinsky, O., Honigfeld, G., and Patin, J. (1991) Clozapine-related seizures. Neurology 41 369-371. 

Dassa D, Kaladjian A, Azorin JM, et al Clozapine in the treatment of psychotic refractory depression. Br J Psychiatry 163 822-824, 1993 Dauge V, Steimes P, Derrien M, et al CCK8 effects on motivational and emotional states of rats involve CCKA receptors of the postero-median part of the nucleus accumbens. Pharmacol Biochem Behav 34 157-163, 1989 Davidson J Seizures and bupropion a review. J Clin Psychiatry 50 256-261, 1989 Davidson J, Pelton S Eorms of atypical depression and their response to antidepressant drugs. Psychiatry Res 17 87-95, 1986 Davidson JR, Miller R, Turnbull CD, et al Atypical depression. Arch Gen Psychiatry 39 527-534, 1982... 

Most conventional antipsychotics are associated with a dose-depen-dent risk of a lowered seizure threshold, although the incidence of seizures with most of these drugs is quite small (Devinsky et al. 1991). Of all the conventional antipsychotics, molindone and fluphenazine have been shown most consistently to have the lowest potential for this side effect (ltd and Soldatos 1980 Ohver et al. 1982). The atypical antipsychotic clozapine is associated with a dose-dependent risk of seizure. 

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. 

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... 

Clozapine. Clozapine produces seizures at a greater rate than other antipsychotics, especially in the dose range of 600 to 900 mg/day. Fortunately, these levels are substantially above the usual therapeutic range of 300 to 400 mg/day, but seizures can occur on lower doses, as well. A more rapid escalation of the clozapine dose may also predispose to the development of seizures. According to the drug s manufacturer, the reported incidence of seizures, based on daily dosage, is as follows ... 

Erythromycin may increase clozapine levels, predisposing to seizures (527). 

Funderburg LG, Vertrees JE, True JE, et al. Seizure following addition of erythromycin to clozapine treatment. Am J Psychiatry 1994 151 1840-1841. 

Dibenzodiazepine Clozapine May benefit treatment-resistant patients little extrapyramidal toxicity May cause agranulocytosis in up to 2% of patients dose-related lowering of seizure threshold... 

Seizures, though recognized as a complication of chlorpromazine treatment, were so rare with the high-potency older drugs as to merit little consideration. However, de novo seizures may occur in 2-5% of patients treated with clozapine. Use of an anticonvulsant is able to control seizures in most cases. 

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