clozapine and Epilepsies--Myoclonic

Seizures are an important adverse effect of clozapine therapy; a cumulative 10% risk of tonic-clonic seizures is estimated after 3.8 years of treatment. Although the risk of seizures may be increased by rapid upward titration and higher doses, recent data do not clearly confirm the dose-dependent effect. The vast majority of clozapine-related seizures are tonic-clonic, although myoclonic seizures also occur. The role of the EEG in predicting the occurrence of clozapine-induced seizures remains uncertain. In patients with clozapine-related seizures, either reducing the dose or adding an antiepileptic medication usually allows continuation of therapy.

Topics: Anticonvulsants; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Epilepsy, Tonic-Clonic; Humans; Incidence; Risk Factors; Schizophrenia

We previously reported significant differences in force control (FC) function between schizophrenics treated with typical antipsychotic drugs (APD) and those treated with clozapine. Clozapine treatment was associated with an attenuation of the capacity for fine motor control. We now report that a test-retest study with 41 treatment-refractory patients confirms our earlier finding; the FC deficit is due primarily to clozapine treatment. An additional comparison was made with 10 patients who were administered the FC test repeatedly through the initial clozapine titration interval of 6-8 weeks. The results suggest that two distinct clozapine effects can be distinguished, an initial transient stage characterized by 'drowsiness' and a subsequent stage with dose-dependent emerging myoclonic features.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Epilepsies, Myoclonic; Female; Humans; Male; Psychomotor Performance; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsies, Myoclonic; Humans; Male; Schizophrenia; Stuttering; Tics; Valproic Acid

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Epilepsies, Myoclonic; Female; Haloperidol; Humans; Seizures

Clozapine elicits dose-dependent myoclonic jerks in partially restrained rats and induces paroxysmal electroencephalographic changes, myoclonus, and convulsive seizures in a small but significant percentage of patients. With the hypothesis that the central excitatory effects of clozapine may relate to the unique therapeutic activity of this agent, rats were administered repeated alternate day or weekly very low dose (1 mg/kg) injections of clozapine in an attempt to induce the central excitatory effect through sensitization or kindling. Although initial administrations of this dose elicited no motor response or other behavioral change, repeated administration of the same low dose on either the alternate-day or weekly schedule caused increasing numbers of myoclonic seizure-like jerks (MJs) reaching 75-110 MJs/hour by the sixth clozapine injection. Clozapine-sensitized animals exhibited a significantly different pattern of early gene expression in two subcortical sites compared with vehicle-treated controls. These findings may have importance for the treatment of psychosis.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; Epilepsies, Myoclonic; Gene Expression; Humans; Kindling, Neurologic; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Transcription, Genetic

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Generalized; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia

Clozapine is an 'atypical' neuroleptic that improves symptoms of many patients with schizophrenia whose illness is resistant to treatment with other neuroleptics. Unlike the 'typical neuroleptics (chlorpromazine, haloperidol), clozapine does not induce extrapyramidal symptoms such as Parkinsonism and tardive dyskinesia in humans or catalepsy in the rat. However, clozapine frequently causes epileptiform EEG changes and causes seizures in 3-5% of patients treated with this drug in therapeutic doses. Clozapine also induces dose dependent myoclonus in the partially restrained rat. In the experiments reported here, partially restrained rats were administered repeated alternate day or weekly low, fixed doses of clozapine (1 mg/kg). This dose initially caused no behavioral change. Following the third and subsequent administrations, the same dose elicited an increasing number of myoclonic seizure-like jerks reaching 140/h following the 15th injection in rats receiving the same low dose of clozapine on alternate days and 160/h following the 9th injection in animals that received the same dose once weekly. These effects are consistent with kindling, i.e. a progressive increase of brain excitability following repeated administration of a fixed subconvulsive dose of an excitatory agent. Clozapine kindled animals exhibited a significantly different pattern of early gene expression in ventral tegmental area, origin of the mesolimbic-mesocortical dopamine system and in the anterior thalamic nuclei, compared with saline treated controls subjected to exactly the same recording conditions. The evidence of central nervous system excitation with clozapine may be important to the unique therapeutic effect of this atypical antipsychotic in the treatment of symptoms, especially the deficit symptoms, of schizophrenia.

Topics: Animals; Behavior, Animal; Brain; Clozapine; Dose-Response Relationship, Drug; Epilepsies, Myoclonic; Epilepsy; Gene Expression; Genes, Immediate-Early; Humans; Kindling, Neurologic; Male; Rats; Rats, Sprague-Dawley; Schizophrenia; Schizophrenic Psychology

Based on five case studies, the suggestion is that, if physiological myoclonus can be excluded, antidepressant - or neuroleptic-induced myoclonus must as a rule be presumed to be a most subtle indication of increased cerebral exitability, an epileptic fragment or, in some instances, a myoclonus epilepsy. In each of the reported cases EEG recordings reflected epilepsy-specific potentials. Whether, however, the scope of differences in the EEG recordings and the N1/P1 amplitude increase of the SSEP may be used as an additional diagnostic criterion to determine the risk of epileptic seizures, should depend on the type of myoclonus chiefly induced. This would require more extensive neurophysiological examinations which should mainly include the back-averaging to permit, beside the EEG, a better evaluation of the relatively easily obtainable SSEP findings.

Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depressive Disorder; Dose-Response Relationship, Drug; Electroencephalography; Epilepsies, Myoclonic; Evoked Potentials; Female; Humans; Male; Maprotiline; Middle Aged; Psychotic Disorders; Trimipramine

Epileptiform EEG changes, myoclonus, and seizures are reported in some patients treated with clozapine. Although these are undesirable side effects, the excitation of specific neuronal networks by clozapine and other neuroleptics may be important for the therapeutic effect of this class of agents. In these experiments, intraperitoneal clozapine 2-16 mg/kg produced dose-related myoclonic jerks in partially restrained rats. Paroxysmal slow waves and spike activity were recorded from implanted electrodes in amygdala, hippocampus, and cortex following higher doses of clozapine, but the EEG abnormalities were not correlated with the myoclonic jerks. Single doses of chlorpromazine (8 and 16 mg/kg) rarely produced myoclonic jerks but provoked generalized tonic seizures in two animals preceded by multiple myoclonic jerks in one. Myoclonus and seizures reflect increased excitability of the central nervous system. It is possible that clozapine and other neuroleptics exert a therapeutic effect by increasing excitability in critical subcortical areas of the brain.

Topics: Amygdala; Animals; Brain; Brain Mapping; Chlorpromazine; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Tonic-Clonic; Evoked Potentials; Hippocampus; Male; Rats; Rats, Sprague-Dawley; Seizures; Synaptic Transmission

Topics: Adult; Clonazepam; Clozapine; Drug Interactions; Drug Therapy, Combination; Epilepsies, Myoclonic; Fluoxetine; Humans; Lorazepam; Male; Schizophrenia, Paranoid

Topics: Adult; Brain; Clozapine; Electroencephalography; Epilepsies, Myoclonic; Female; Humans; Leg; Male; Schizophrenia

We reviewed the incidence, clinical features, and management of all clozapine-related seizures in 5,629 patients monitored by the Clozaril Patient Management System, during the first 6 months after marketing. Seventy-one patients had generalized tonic-clonic seizures yielding a frequency of 1.3%. One patient had myoclonic seizures prior to generalization. Seizures tended to occur at low doses (< 300 mg/d) during the titration phase, and at high doses (> or = 600 mg/d) during the maintenance phase. Patients with a history of seizures or epilepsy were more likely to have seizures soon after initiation of therapy, on low doses. Twenty-nine of 37 patients (78%) who had seizures and were rechallenged with clozapine were able to continue the medication with dose reduction and more-gradual dose titration, or with the addition of an antiepileptic medication.

Topics: Adolescent; Adult; Aged; Clozapine; Dose-Response Relationship, Drug; Epilepsies, Myoclonic; Epilepsy; Epilepsy, Tonic-Clonic; Female; Humans; Incidence; Life Tables; Male; Middle Aged; Retrospective Studies; Seizures; Time Factors

Topics: Adult; Clozapine; Epilepsies, Myoclonic; Epilepsy, Tonic-Clonic; Female; Humans; Schizophrenia, Paranoid

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 electroencephalographic findings of 12 schizophrenic patients who have had from one to six clozapine-associated epileptic convulsions.

Topics: Adult; Carbamazepine; Clonazepam; Clozapine; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Tonic-Clonic; Female; Follow-Up Studies; Humans; Male; Retrospective Studies; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Clozapine; Epilepsies, Myoclonic; Epilepsy, Tonic-Clonic; Humans; Male; Myoclonus; Posture; Schizophrenia; Seizures

Three adult schizophrenic patients without a previous history of epilepsy are reported who, during clozapine treatment, developed paroxysmal EEG patterns and generalized myoclonic jerks without alteration of consciousness. These seizures were phenomenologically identical to those occurring in juvenile myoclonic epilepsy and were classified as generalized epileptic seizures. We tentatively conclude that generalized myoclonic epileptic seizures may be induced by clozapine.

Topics: Adult; Cerebral Cortex; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Epilepsies, Myoclonic; Evoked Potentials; Humans; Male; Schizophrenia; Schizophrenic Psychology