Clozapine-induced seizures, electroencephalography abnormalities, and clinical responses in Japanese patients with schizophrenia

Abstract

PurposeWe describe electroencephalography (EEG) abnormalities and seizures associated with clozapine treatment in Japanese patients with schizophrenia and retrospectively compare EEG results and total Positive and Negative Syndrome Scale (PANSS [T]) scores before and after treatment.MethodsTwenty-six patients with treatment-resistant schizophrenia were enrolled in this study. EEG measurements were obtained prior to clozapine treatment and every 4 weeks thereafter. EEG measurements were also obtained at the time of seizure. After seizures or EEG abnormalities were noted, additional EEGs were performed every 2 weeks. PANSS (T) scores were used to determine clozapine treatment outcome.ResultsAll 26 patients had normal baseline EEG measurements, and ten patients (38.5%) later manifested EEG abnormalities. The mean age was significantly lower than in the abnormal EEG group. Six patients (23.1%) experienced seizures. The mean dose of clozapine at the first occurrence of seizure was 383.3 mg/day. Five of six patients who experienced seizures in this study were successfully treated with valproate or lamotrigine without discontinuation of clozapine. The one patient who continued to experience seizures was successfully treated without antiepileptic drugs. The mean baseline PANSS (T) scores were not significantly different between the normal and abnormal EEG groups, but the mean score in the abnormal EEG group was significantly lower than that in the normal EEG group at the final follow-up (P=0.02).ConclusionEEG abnormalities may appear in younger patients, and our findings indicate that there is no need to discontinue clozapine when seizures occur. EEG abnormalities that appeared after clozapine treatment were associated with a good clinical response.

Low-dose Clozapine-induced Seizure: A Case Report

“…In a study of 26 patients, EEG abnormalities were observed with average 305.0±131.7 mg dose in 10 patients. Clozapine dose was 200 mg/day in 3 of these 10 patients 4). Having seizures despite low dose clozapine suggests that there may be other risk factors than dose and titration rate for seizures.…”

“…It is thought that this situation causes high epileptogenicity of clozapine 7). Other possible mechanisms are anticholinergic efficacy of clozapine (H1, Ach-Mus receptor blockade) and its effects on other receptor types such as gamma-aminobutyric acid A, nicotinic acetylcholine, glutamate N-methyl-D-aspartate, serotonin 5-HT2A, and strychnine-sensitive glycine 4,12–16). Increasing seizure threshold of clozapine is dose-dependent.…”

Control of seizures in a clozapine-treated schizophrenia patient, using valproate: a case report

“…Also, a case of schizophrenia comorbid for tetralogy of Fallot, without chromosome 22q.11.2 deletion or duplication, was treated successfully with a combination of clozapine and antiepileptic drugs [28]. It is unknown how valproic acid is effective in clozapineinduced seizures without exacerbating psychological symptoms although it alters activity of clozapine by reducing its plasma level [29]. Lamotrigine and gabapentin are other options in clozapine-induced seizures; however, carbamazepine should be avoided as there is a risk for bone marrow suppression when used in combination with clozapine [9].…”

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

“…The seizure risk during CLZ treatment has been estimated at roughly 1–7.5% [ 27 , 28 , 29 ]. A VigiBase search indicated that the relative lethality associated with seizures from CLZ (5%: 308 fatal outcomes in 6231 cases) was approximately 2.5 times higher than that associated with agranulocytosis (2%: 550 fatal outcomes in 34,931 cases) [ 23 ].…”

“…During the titration and initiation of CLZ intake was a high risk period of CLZ-induced seizures, whereas during the maintenance of the CLZ dosage (even after several years of therapy), CLZ-induced seizures were not rare [ 27 , 38 ]. Additionally, a younger age also provided a risk of seizure [ 27 , 28 ].…”