Clozapine Seizures: Risk, Dose, and What Happens After One

The Clozaril label estimates that seizures occur at a cumulative incidence of about 5% at one year of clozapine treatment. The estimate is based on 61 of 1,743 patients who had one or more seizures during clinical testing before US marketing, a crude rate of 3.5%.¹ In randomized trials against other antipsychotics, clozapine increased the risk of seizures, with a risk ratio of 3.61 (95% CI 1.80 to 7.95) and a prevalence of 3.1%.²

In two reviews, 31 of 41 patients and 29 of 37 rechallenged patients continued clozapine after a seizure.^{3, 4} A seizure means emergency care and a call to the prescriber, who decides what happens to the dose.

How common seizures are on clozapine

A 1991 review covered 1,418 patients treated in the United States between 1972 and 1988. Forty-one (2.8%) had generalized tonic-clonic seizures, and life-table analysis predicted a cumulative 10% risk after 3.8 years of treatment.³ A 1994 review covered 5,629 patients during the first 6 months after marketing. Seventy-one had generalized tonic-clonic seizures, a frequency of 1.3%.⁴

In a state hospital, 10 of 100 sequential patients had at least one seizure over a year of follow-up. Of 12 patients with a history of seizures, 4 (33%) had a seizure while taking clozapine and anticonvulsants, compared with 5 of 79 (6.3%) who had no seizure disorder or head trauma.⁵ The label lists a history of seizures, head trauma or other CNS pathology, medications that lower the seizure threshold, and alcohol abuse as reasons for caution.¹

Dose and seizure risk: the label and the later data

The label states that the risk of seizure is dose-related and tells prescribers to start at 12.5 mg, titrate slowly and use divided dosing.¹

Source: Devinsky and colleagues, 1991.³ Any dose change is made by the prescriber.

Later analyses did not confirm a clear dose relationship. In 1994 the same group wrote that "recent data do not clearly confirm the dose-dependent effect".⁶ In the 5,629-patient review, seizures tended to occur at doses under 300 mg/day during titration and at 600 mg/day or more during maintenance.⁴ In the state hospital series, seizures occurred at all dose ranges, and 6 of the 10 were in the 0 to 299 mg/day range.⁵ A 2011 review found a strong relationship between clozapine dose and EEG abnormalities, while a statistically significant relationship between dose and seizures was not found.⁷

The same review could not establish a plasma level threshold because useful data were scarce. It found three case reports suggesting a very substantial risk of seizures above 1300 μg/l.⁷ Plasma levels are covered on the clozapine levels page.

Clozapine myoclonus can come before a seizure

Myoclonus on clozapine can appear as muscle jerks or as sudden, brief interruptions of motor activity that cause unexpected falls or buckling at the knee.⁸ In a Japanese hospital cohort of 106 patients, myoclonus occurred in 38.7% and seizures in 8.5%.⁹

A case report described a young man whose myoclonus during titration led to a tonic-clonic seizure, and its authors wrote that myoclonus "can herald the onset of a full seizure, even at low serum clozapine levels".⁸ In one small series cited by the 2011 review, 2 of 11 patients had myoclonus alone and 2 had myoclonus followed by a generalized seizure.⁷ New jerks or knee buckling are reported to the prescriber promptly.

Can you stay on clozapine after a seizure?

Section 5.4 of the label, which covers seizures, does not mention stopping clozapine after one.¹ In the 1991 review, 31 of 41 patients "were successfully continued on clozapine despite seizure occurrence, either with reduction of dose or addition of an antiepileptic medication".³ In the 1994 review, 29 of 37 patients (78%) who were rechallenged were able to continue with a lower dose and slower titration, or with an added antiepileptic.⁴

A 2015 review concluded that after a seizure "it may be in the best interests of the patient to continue clozapine treatment".¹⁰ That decision, and any change in dose, belongs to the prescriber once the patient has been evaluated.

Reviews disagree on preventive antiepileptics

Section 5.4 does not mention antiepileptics, and the label text does not mention valproate or lamotrigine. Section 7.1 lists carbamazepine and phenytoin among strong CYP3A4 inducers whose use with clozapine is not recommended.¹

Varma and colleagues advised considering an antiepileptic when the plasma level exceeds 500 μg/l, when the EEG shows clear epileptiform discharges, or when seizures, myoclonic jerks or speech difficulties occur. They named valproate and lamotrigine as the drugs of choice.⁷ Caetano concluded that "Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures".¹¹ Williams and Park wrote that valproate appears to be the antiepileptic of choice and that "Well-designed clinical trials regarding clozapine seizure prophylaxis are lacking".¹⁰

Clozapine and valproate: the trade-off

In a case-control study of 105 myocarditis cases and 296 controls, concomitant sodium valproate was associated with more than double the risk (odds ratio 2.59, 95% CI 1.51 to 4.42).¹² A 2022 meta-analysis of six studies found a pooled odds ratio of 3.58 (95% CI 1.81 to 7.06).¹³ The clozapine myocarditis page covers cardiac monitoring.

A register-based case-control study of 136 cases and 136 controls found that concurrent valproate was associated with neutropenia (odds ratio 2.28, 95% CI 1.27 to 4.11), with greater associations at higher doses.¹⁴ These are observational associations. The 2011 review also noted that valproate "should not normally be used in women of child-bearing age because it is an established human teratogen".⁷

Driving, swimming and other activities

Because of the seizure risk, the label tells prescribers to caution patients about "any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing)". Section 5.16, on sedation, adds a caution about operating hazardous machinery, including automobiles, until patients are reasonably certain that clozapine does not affect them adversely. The label does not mention a seizure-free interval for driving.¹

Limitations of the evidence

This evidence has limitations. First, the incidence and dose figures come from the label's pre-marketing testing and from reviews published in 1991 and 1994. Second, well-designed trials of preventive antiepileptics are lacking, and the valproate findings are observational.¹⁰ Nevertheless, most patients in the two reviews continued clozapine after a seizure, and a seizure calls for emergency care and prompt contact with the prescriber, who decides on the dose and any added medication.^{3, 4}

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

I start and manage clozapine in an outpatient practice in Chelsea, Manhattan. Details are on the schizophrenia care in NYC page. Clozapine should not be stopped, skipped, or restarted without the prescriber. This page is general information and does not replace an evaluation.

Related: Schizophrenia and psychosis treatment guide · When to start clozapine · Clozapine blood tests after the REMS ended · Clozapine side effects · Missed clozapine doses · Clozapine and suicide risk · Cannabis and psychosis · Schizoaffective vs schizophrenia · Cobenfy vs clozapine · Postpartum psychosis · Injections vs pills · Stimulants and psychosis · Drug-induced psychosis · Clozapine levels · CBT for psychosis · Clozapine myocarditis · Cannabis after psychosis · Clozapine constipation · Work and school · Clozapine drooling · Early signs in teens · Clozapine weight gain · Genetic and family risk · Who can prescribe clozapine · Schizophrenia and violence · Clozapine in teenagers · Sleepiness, bedwetting, heart rate · When clozapine isn't enough · Clozapine interactions · Benign ethnic neutropenia · Clozapine off-label uses · Starting clozapine · Clozapine and pneumonia · Clozapine in pregnancy · Clozapine rechallenge · Relative refuses treatment · Late-onset schizophrenia · Negative symptoms · First-episode psychosis · Tardive dyskinesia · Stopping antipsychotics · Schizophrenia life expectancy · Key clozapine studies