Psychiatry Research, 44:107-l 12 Elsevier

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Clinical Picture and Long-term Course of Epileptic Seizures That Occur During Clozapine Treatment

Jarmo Liukkonen, Hannu J. Koponen, and Unto Nousiainen

Received February 24, 1992; revised version received July 1. 1992; accepted September 13. 1992.

Abstract. Clozapine is an atypical neuroleptic drug that has proved to be effective in alleviating psychotic symptoms refractory to treatment with standard neuroleptic drugs. In addition to hematological side effects, an increased susceptibility to epileptic seizures during clozapine treatment has previously been described. In this report, we describe the clinical picture and electroenceph- alographic findings of 12 schizophrenic patients who have had from one to six clozapine-associated epileptic convulsions.

Key Words. Atypical neuroleptic, side effects, electroencephalography, epileptic seizures.

Clozapine is an atypical neuroleptic, a dibenzodiazepine derivative with potent antipsychotic effect. Although the drug has proved efficacious in patients who are resistant to treatment with typical neuroleptics, it has some undesirable side effects, including a higher prevalence of seizures than is associated with traditional neuroleptics (Povlsen et al., 1985; Lindstrijm, 1988; Hailer and Binder, 1990). In addition, clozapine treatment may cause severe electroencephalographic (EEG) disturbances (Isermann and Haupt, 1976; Tiihonen et al., 1991). The basic mechanism underlying the association between the administration of clozapine and the EEG abnormalities is unclear; the clinical importance of the EEG changes has also not been demonstrated. The present study was carried out to elucidate the clinical picture and outcome of epileptic seizures associated with clozapine treatment. The EEG changes in these patients are also presented.

Methods

Subjects. Our study was carried out in Moisio Mental Hospital, Mikkeli, Finland by reviewing the records of all patients (n = 127) for whom clozapine treatment was initiated between 1983 and 1991. A clozapine-associated epileptic attack was concluded to be present if a detailed description of an epileptic attack during clozapine treatment was found in the records, and the type of the attack was myoclonic or generalized tonic-clonic seizure. Patients with epileptic attacks related to alcohol or benzodiazepine withdrawal were excluded to avoid toxic-withdrawal states.

Jarmo Liukkonen, M.D., is Staff Neurologist, Mikkeli Central Hospital, Mikkeli, Finland. Hannu J. Koponen, M.D., Ph.D., is Staff Psychiatrist, Moisio Mental Hospital, Mikkeli, Finland. Unto Nousiainen, M.D., Ph.D., is Head, Department of Clinical Neurophysiology, Vaajasalo Hospital, Kuopio, Finland. (Reprint requests to Dr. H. Koponen, Moisio Hospital, SF-50520 Mikkeli, Finland.)

0165-1781/92/$05.00 @ 1992 Elsevier Scientific Publishers Ireland Ltd.

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The diagnostic evaluation of the epileptic seizures in the patient group (n = 12) included a clinical neurological examination, laboratory screening (erythrocyte sedimentation rate, complete blood count, glucose, and electrolyte, creatinine, and hepatic enzyme measures), and serial EEG recordings. Computed tomography of the head was carried out in 10 cases.

Results

This retrospective chart analysis yielded a sample of 12 schizophrenic patients (9 males and 3 females) who had had from one to six epileptic seizures during clozapine treatment. The observed clozapine-associated seizure frequency was thus 9.4%. Subtype diagnoses, which were made on the basis of DSM-III-R criteria (American Psychiatric Association, 1987) were as follows: disorganized schizophrenia, n = 2; undifferentiated schizophrenia, n = 7; and paranoid schizophrenia, n = 3. Four patients had disorders associated with an increased risk of epileptic seizures. One patient had had febrile convulsions in infancy. One patient had had a cerebral contusion 6 years before the clozapine-associated seizure. One patient had had three seizures associated with other neuroleptics 10 years before the clozapine treatment began. One patient had had periods of alcohol abuse in the past, but not during the index hospitalization period of 18 months. The mean age of the patients at the time of the first seizure was 33 years (SD = 7; range = 20-43 years) and their psychotic symptoms had lasted 14 years (SD = 8; range = 2-28) before the seizure).

The mean daily clozapine dose at the time of the seizure was 496 mg (SD = 129; range = 300-700). One patient received 700 mg clozapine/day and the others between 300 and 600 mg/day. The clozapine treatment had lasted 32 months (SD = 32; range = l-92) before the first seizure. Three patients were on clozapine monotherapy. The remaining patients also received other antipsychotic medications with a mean daily dose of 337 mg in chlorpromazine equivalents (SD = 233; range = 100-850). There was no significant difference between the clozapine dosage given to patients receiving only clozapine (mean dose = 533 mg, SD = 153) and those patients treated with additional neuroleptics (mean dose = 483 mg, SD = 127; p = 0.58, t test). None of the patients were receiving antiepileptic or lithium treatment before the epileptic attack.

The seizure types were grand ma1 in eight patients, grand ma1 associated with myoclonus in two patients, grand ma1 and absence in one patient, and myoclonic seizure in one patient. The neurological examination revealed no focal neurological symptoms or signs in these patients, and there were no significant abnormal hematological findings. There was no suggestion of cardiovascular origin of the seizures or, in the case of myoclonic seizure, of other nonepileptic myoclonic jerks. Computed tomographic scans of the head were normal in eight cases and showed cortical atrophy in the frontal and temporal regions in two cases.

For eight patients, a previous EEG examination had been carried out 44 months (SD = 35, range = 3-82) before the clozapine-associated epileptic seizure. Two patients had normal recordings, and six patients had mild (n = 2) or moderate (n = 4) background disturbance. Paroxysmal slow wave activity was seen in three recordings, one patient had increased beta activity, and one patient had epileptiform discharges. EEG examinations that were carried out shortly (mean = 5 days, SD = 3,

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range = 1-12) after the clozapine-associated epileptic seizures occurred showed background disturbance in 11 patients, paroxysmal slow wave activity in eight patients, and epileptiform discharges in four patients. None of the patients had the synchronous three per second spike and wave complexes often seen in petit ma1 seizures. Table 1 presents clinical information and EEG findings for the individual

patients. The patients have now been studied 35 months (SD = 33, range = 6-102) after the

first clozapine-associated seizure. Six patients have been hospitalized for the whole followup period. The other six patients have been discharged and, in those cases, the followup data are based on the mental health center reports and, in two cases, on a neurological followup. There was only one clozapine-associated seizure in five patients. Antiepileptic treatment was introduced in the remaining seven patients, who had experienced more than one epileptic attack associated with clozapine treatment. The time difference between the first and second seizures varied from 1 day to 8 months. Carbamazepine was used in five cases (mean daily dose = 490 mg, SD = 125 mg, range = 400-700 mg), and the resulting serum concentrations were within the therapeutic range. Clonazepam was used in two cases (mean daily dose = 2 mg in both cases). The antipsychotic effect of clozapine was unchanged in those patients who received anticonvulsive treatment. Clozapine doses were not changed after the epileptic seizures.

During the followup period, two patients have had epileptic seizures while using antiepileptic medication. One patient with grand ma1 and absence attacks had one grand ma1 seizure during clonazepam treatment 13 months after the first seizure. Another patient with myoclonic seizures had a myoclonic attack 4 years later during low-dose (400 mg/day) carbamazepine treatment. Clozapine treatment was continued after the epileptic seizures in all patients, but in three patients it was discontinued 2, 3, and 36 months after the seizure due to insufficient antipsychotic response. In two cases, EEG disturbance lessened significantly after the discontinuation of clozapine. The background disturbance diminished, and the epileptiform discharges and paroxysmal slow activity episodes disappeared. In the third case, both the EEG examinations after the epileptic seizure and after the discontinuation of clozapine were normal. Two male patients died 2 and 3 years after the clozapine-associated seizure while they were still being treated with clozapine. No certain causal relationship was established between death and clozapine. One patient (age 34) died from a gastric hemorrhage, and the other (age 36) suffocated. Autopsies were performed in both cases.

Discussion

Spontaneous epileptic seizures occur relatively infrequently during antipsychotic treatment, and the precise mechanism underlying neuroleptic-induced seizures is unknown. Seizures occur in approximately OS-l% of patients treated with anti- psychotic drugs (Itil and Soldatos, 1980). In addition to the individual epileptogenic potential of each drug, risk factors for seizures include structural brain diseases, polypharmacy, high doses of medication, and rapid increases in dosage (van Sweden, 1984). The prevalence of epileptic seizures is higher in patients treated with clozapine

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than in those treated with typical neuroleptic agents, and dose-dependent frequencies ranging between 0.3% and 14% have been previously reported (Povlsen et al., 1985; Lindstrom, 1988; Grohmann et al., 1989; Lieberman et al., 1989). Our results suggest that the frequency of clozapine-associated epileptic seizures may exceed the frequently proposed 1% to 5% ratio. However, the observed higher frequency may partly reflect the facts that we used higher clozapine dosages than were used in some of the previous studies and that nine patients received additional neuroleptics that may also increase the incidence of seizures.

In cases of epileptic seizures induced by other psychotropic drugs, complete recovery can often be achieved by withdrawing or reducing the dosages of the offending drug or combination of drugs (Toone and Fenton, 1977; van Sweden, 1985). Even if a seizure seems clearly to have been evoked by clozapine, our findings suggest that it is possible to continue clozapine treatment in those patients who show a clear therapeutic response to clozapine but are refractory to other treatments. Antiepileptic medication should be initiated after the first clozapine-associated seizure only if the EEG simultaneously shows epileptic discharges. Otherwise

Table 1. Patient data and electroencephalographic findings

Waaelsex

Subtype of

schizoohrenia Clozapine

dose Other CNS-active

medications

1./21 /male Undifferentiated

2./36/male Disorganized

3.143Imale Undifferentiated

4./20/female

5/37/male

6./28/female

7.132lmale

8./37/female

9.140Ifemale

1 O./34/male

11 KWmale

l2./38/male

Paranoid

Undifferentiated

Disorganized

Undifferentiated

Undifferentiated

Undifferentiated

Undifferentiated

Paranoid

Undifferentiated

450 mg

600 mg

600 mg

400 mg

300 mg

300 mg

500 mg

400 mg

600 mg

700 mg

600 mg

500 ma

Chlorpromazine, 400 mg

Zuclopenthixol, 40 mg

Chlorpromazine, 700 mg;

levomepromazine, 200 mg;

orphenadrine, 200 mg

None

Zuclopenthizol, 25 mg;

oxazepam, 150 mg;

biperidine, 2 mg

Perphenazine, 8 mg;

chlorprothixene, 400 mg;

lorazepam, 2.5 mg

Perphenazine, 24 mg;

chlorpromazine, 150 mg;

oxazepam, 50 mg

Thioridazine, 150 mg

Haloperidol, 2 mg;

lorazepam, 3 mg

None

Chlorprothixene, 300 mg;

lorazepam, 7.5 mg

None

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antiepileptic medication should be initiated after a second seizure to avoid antiepileptic therapy in self-limited cases of clozapine-associatedseizures.

Carbamazepine has been considered to be a primary drug for the treatment of all types of epilepsy except absence seizures (Rall and Schleifer, 1990), and thus most of our patients were treated with carbamazepine. However, phenytoin and valproic acid have also proved to be effective for clozapine-associated grand ma1 seizures (Haller and Binder, 1990), and they can be regarded as better choices due to their less pronounced bone marrow toxicity as compared with carbamazepine (Rall and Schleifer, 1990). For myoclonic and absence attacks, valproic acid is the best choice as clonazepam used together with clozapine may predispose the patient to hypotonic reactions (Grohmann et al., 1989). In our series, seven patients were treated with anticonvulsive drugs. Five of them were completely seizure-free during the followup period, and in the remaining two cases, there were only occasional seizures. It is, however, possible that in some patients discontinuation of clozapine treatment may prove necessary, if antiepileptic treatment is not sufficient to control the attacks (Povlsen et al., 1985; Haller and Binder, 1990).

fYW of

seizures

Number of

seizures EEG findings Treatment

Grand mal

Grand mal

Myoclonic and

grand mal

Myoclonic and

grand mal

Grand mal

Grand mal

Grand mal

Grand mal

Grand mal

and absence

Grand mal

1

3

2

3

Paroxysmal theta-delta activity,

moderate background disturbance

Increased beta activity, moderate

background disturbance

Paroxysmal theta-delta activity, epileptiform

discharges, moderate background disturbance

Carbamazepine,

450 mg

None

Carbamazepine,

400 mg

Paroxysmal theta activity, epileptiform discharges,

severe background disturbance

Paroxysmal delta activity, epileptiform

discharges, mild background disturbance

None

Clonazepam, 2 mg

paroxysmal theta-delta activity, moderate Carbamazepine,

background disturbance 450 mg

Increased beta activity, mild background

disturbance

Carbamazepine,

700 mg

Mild background disturbance

Paroxysmal theta activity, moderate

background disturbance

Paroxysmal theta-delta activity, epileptiform

discharges, moderate background disturbance

Paroxysmal theta-delta activity, moderate

background disturbance

None

None

Clonazepam, 2 mg

Carbamazepine,

500 mg

Grand mal Normal None

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We conclude that our results are in accordance with previous suggestions that increased seizure frequency is associated with clozapine treatment. In the EEG taken after the clozapine-associated seizure, irritative discharges were observed in one- third of the patients, and paroxysmal slow wave activity was seen in two-thirds of the patients. The seizure activity was self-limited in five patients, and in the rest of the cases, it was controlled with anticonvulsive monotherapy, and clozapine treatment could be continued. Due to the leukopenic effects of carbamazepine, we regard phenytoin or valproic acid as the antiepileptic drugs of choice.

Acknowledgments. The study was supported by PIivikki and Sakari Sohlberg’s Foundation.

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