Evidence-Based Reviews

Antipsychotics and seizures: What are the risks?

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Olanzapine is a thienobenzodiazepine derivative and is chemically related to clozapine.30 The olanzapine NDA31 shows that 23 of 3,139 patients developed seizures, mainly tonic-clonic, with evidence suggesting that the seizures may have been due to confounding factors such as a history of seizures or metabolic abnormalities. There were no statistically significant differences in the rate of seizures associated with olanzapine compared with placebo or haloperidol (P = .252 and .168, respectively).

Case reports of seizures attributed to aripiprazole

A literature review for olanzapine yielded 1 case report of repetitive focal seizures and lingual dystonia,32 5 case reports of generalized tonic-clonic seizures and myoclonus,33-37 and 2 case reports of status epilepticus.38,39 Olanzapine’s clearance is 25% to 30% lower in women, and most of these case reports occurred women.40

Case reports of seizures attributed to olanzapine

Details of the above case reports are summarized in Table 1 (aripiprazole15-19), Table 2 (olanzapine32-39), and Table 3 (paliperidone,28,29 quetiapine,11-13 and risperidone22-24).

Case reports of seizures attributed to paliperidone, quetiapine, and risperidone

Ziprasidone. According to the NDA safety database, the seizure rate attributed to ziprasidone was 1.8 per 100 subject-years or 0.54% of participants (12 of 2,588).41 No additional studies have been published regarding its seizure risk.

Clozapine has a black-box warning

Frequency of clozapine-induced  seizures, by type

To the best of our knowledge, clozapine is the only antipsychotic that carries an FDA “black-box” warning regarding its risk of inducing seizures.42 Devinsky and Pacia43 reported a cumulative risk of 10% after 3.8 years of treatment. The literature has described clozapine-induced generalized tonic-clonic, myoclonic, simple and complex partial, and absence seizures.44 Table 445 lists the estimated frequency of each seizure type based on 101 cases of clozapine-induced seizures. Myoclonic seizures and drop attacks could be precursors/warning signs of grand mal tonic-clonic seizures.46,47 Seizures have been observed at all stages of treatment, but were more common during initiation of cloza­pine, which emphasizes the importance of a progressive and slow titration.43,48 The incidence of seizures was estimated to be 6% in a sample of 216 patients with schizophrenia with no history of epilepsy who were prescribed clozapine.49

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