Introduction

Unlike the complexity of addressing metabolic adverse effects, seizure management is extremely successful to the extent that recent reviews comment that it should never be a reason to discontinue clozapine treatment [ 1 ]. Evidence suggests that psychiatric providers may have adopted this position, as case data on 316 new clozapine starts from 2007 to 2011 at the South London and Maudsley National Health Service Foundation Trust did not list seizures among reasons for clozapine cessation, although 20 other forms of adverse drug reactions were cited [ 2 ]. Seizures are not unique to clozapine, and antipsychotic package insert warnings in the United States consider this a class effect, although the mechanisms for this common property remain unknown. Recent reviews note rates ranging from 0.2% to 0.5% with other antipsychotics, and a 9% incidence with high-dose chlorpromazine (≥ 1000 mg/day) [ 3 ]. Experience during clinical trials led Novartis to include the following package insert warning:

The first large data set covering 1481 clozapine-treated patients was published in 1991, and reported a seizure rate of 2.8% [ 4 ]. The data also indicated a dose-dependent relationship, with a rate of 1.0% at doses < 300 mg/day, 2.7% for 300–599 mg/day, and 4.4% at doses≥ 600 mg/day [ 3 ]. Although the incidence in this group was 2.8%, the authors estimated the cumulative risk as high as 10% at 3.8 years. However, a subsequent 1994 analysis by these same authors of 5629 patients found only 71 cases of tonic–clonic seizures, or a rate of 1.3% [ 5 ]. Of relevance to the debate about dose and seizure risk, the 1994 review noted that seizures tended to occur in two patterns: at low doses (< 300 mg/day) during the titration phase, and at high doses (≥ 600 mg/day) during the maintenance phase [ 5 ]. The only other risk was a prior history of seizures or epilepsy, with seizures in those patients often occurring early in treatment at low doses. Of those who were rechallenged, 78.3% continued on clozapine.

Principles

• Seizures are not uncommon but easily managed in most patients. It should never be a reason to discontinue clozapine treatment.

• Routine EEG screening is not warranted due to the high prevalence of minor findings, and should not be used in asymptomatic patients. Seizure treatment is based on clinically evident seizure activity.

• The relationship between dose (or plasma level) and seizure induction is not clear as some develop seizures during the early titration at low doses.

• Seizures often occur shortly after a dose increase or a jump in plasma level due to addition of a cytochrome P450 inhibitor, or removal of an inducer (e.g. smoking cessation). Patients who have tolerated stable high levels for months without seizure activity do not require additional measures.

• New-onset stuttering has been observed rarely during titration or after dose increases and is hypothesized to be related to subclinical epileptiform activity. Dose reduction and slower retitration resolve the problem.

• Due to the low prevalence of seizures, prophylactic anticonvulsants should not be used as these will be unnecessary in > 90% of patients.

• When an anticonvulsant is needed, divalproex is the medication of choice as it best covers the spectrum of tonic–clonic and myoclonic events and has modest kinetic interactions with clozapine.

Although the 1994 postmarketing incidence of 1.3% is closer to that seen with other antipsychotics, subsequent case series with variable periods of exposures reported incidence rates as high as 22% [ 3 ]. Given the greater scrutiny with clozapine treatment, and the lack of systematic tracking for other antipsychotics, the true incidence and the magnitude of risk difference compared to other antipsychotics may never be known. As noted in Box 10.1 , this is one of several unresolved issues with regards to the association between clozapine treatment and seizure induction.

Box 10.1 Ongoing Debates Regarding Clozapine and Seizure Risk [ 3 ]

1. What is the relative risk of seizures for clozapine-treated patients compared to those on other antipsychotics?

2. Does rapid titration increase seizure risk?

3. Is there a well-defined dose (and plasma level) threshold for increased seizure risk?

A 2015 paper neatly sums up the issues after an extensive review of the relevant literature:

While this lack of certainty may appear daunting, the unclear relationship between many of these variables and the appearance of clinically evident seizures implies that the titration of clozapine should be made primarily with regards to the usual tolerability concerns including orthostasis and sedation. Moreover, the absence of a well-defined plasma-level relationship supports the use of clozapine at levels up to 1000 ng/ml or 3057 nmol/l if lower levels are tolerated and there is a need for greater efficacy (see Table 5.8 ) [ 6 ].

Box 10.2 General Principles Governing Clozapine Treatment and Seizure Risk

• 1. Due to the absence of a clear relationship between seizure induction and the rapidity of titration or dose, early dose adjustments should be based on other tolerability concerns (e.g. orthostasis, sedation).

• 2. Electroencephalographic (EEG) abnormalities without clinical seizure activity are not uncommon in clozapine-treated patients. Routine EEG monitoring is not recommended and should be performed only when clinically evident actions raise the suspicion of a seizure.

• 3. Patients in need of greater efficacy should not be deprived of clozapine treatment with levels as high as 1000 ng/ml or 3057 nmol/l due to concerns about seizures.

• 4. Divalproex is the anticonvulsant of choice for clozapine-related tonic–clonic, myoclonic or atonic seizures. Due to the risks of divalproex treatment (e.g. neutropenia, thrombocytopenia, weight gain, hyperammonemia), and the low incidence of clozapine-related seizures even at higher plasma clozapine levels, patients should not be placed on routine prophylactic anticonvulsant therapy.

• 5. Seizures often occur after a recent dose increase (e.g. titration phase) or an increased plasma level due to kinetic factors (addition of a CYP P450 inhibitor, removal of a CYP 450 inducer, smoking cessation). Patients who tolerate high levels without seizure activity do not require additional measures.

• 6. If a seizure occurs:

  • a. Scenario 1: After a dose adjustment or due to mitigating kinetic factors. Obtain a plasma clozapine level (ideally as a 12-hour trough), hold clozapine for 24 hours, and reduce back to the prior tolerated clozapine dose (if after a dose increase), or adjust the dose based on the expected kinetic effect. (See Chapter 5 for discussion of kinetic effects of various CYP 450 inhibitors and smoking cessation.) Recheck the plasma clozapine level at steady state. Presumably the patient will remain seizure-free at a plasma level previously tolerated. If a second seizure occurs, or higher plasma levels are anticipated due to the need for further titration, add divalproex.

  • b. Scenario 2: No recent dose adjustment or known kinetic factors. Obtain a plasma clozapine level (ideally as a 12-hour trough), check renal and hepatic function, look at medication history, hold clozapine for 24 hours and reduce the dose by 25%. If no cause can be found (e.g. benzodiazepine or alcohol withdrawal), and the plasma level is consistent with prior stable levels, add divalproex. If levels are > 30% above prior stable levels, adjust the clozapine dose, and recheck the plasma clozapine level at steady state. Presumably the patient will remain seizure-free at a plasma level previously tolerated. If a second seizure occurs, add divalproex.