clozapine and Seizures

Seizures are suspected to be side effects of antipsychotics. To examine a possible causal relationship, we compared the risk of seizures on second-generation antipsychotics to the risk on placebo in randomized controlled clinical trials (RCTs) across diagnostic groups. The primary outcome was any seizure reported as International Conference on Harmonisation-Good Clinical Practice (ICH-GCP)-defined serious adverse event (SAEs). The risk ratio (RR) with antipsychotics versus placebo was synthesized in a pairwise common effects Mantel-Haenszel meta-analysis. For 314 of 597 idenitified placebo-controlled RCTs information about all SAEs could be retrieved from publications, original investigators, pharmaceutical companies and the European Medical Agency. In those, 37 seizures occurred in 42,600 participants on antipsychotics (0.09%) and 28 in 25,042 participants on placebo (0.11%). The meta-analytic results (RR 0,68; 95% Confidence Interval 0.41-1.12) indicated a reduced risk on antipsychotics with a confidence interval including no difference (i.e. RR=1). Neither in sensitivity analyses (excluding events in the safety-follow-up of trials or first-generation antipsychotics; using odds ratios) nor in subgroup analyses (on specific antipsychotics, drug combinations, diagnostic categories, age groups, and study duration) there was evidence for an increased risk on antipsychotics, except for some weak indications of an increased risk on antipsychotics in older and/or demented participants (RRs 1.11 and 1.48, respectively, but with 95% CIs of 0.35-3.49 and 0.41-5.26 including no difference and subgroup tests with p=0.54 and p=0.66 not indicating differences between age groups or diagnostic categories). Consequently, there are no indications that second-generation antipsychotics cause seizures in middle-aged adults and children in most diagnostic groups; rather our results provide some weak evidence for a protective effect. However, there was no data on SAEs available for clozapine, for which observational studies provide the strongest associations with increased seizure rates, and for older and/or demented patients a small additional risk on antipsychotics cannot be excluded.

Topics: Adult; Aged; Antipsychotic Agents; Child; Clozapine; Humans; Middle Aged; Randomized Controlled Trials as Topic; Seizures

Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs.. PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized in evidence tables corresponding to each of six major ADE domains; two authors reviewed all citations for each ADE domain and summarized their content by consensus in the corresponding evidence table. This study was conducted in accordance with PRISMA principles.. Primary and secondary searches identified a total of 305 unique reports, of which 152 were included in the qualitative synthesis. Most clozapine ADEs emerge within 3 months, and almost all appear within 6 months, after initiation. Notable exceptions are weight gain, diabetic ketoacidosis (DKA), severe clozapine-induced gastrointestinal hypomotility (CIGH), clozapine-induced cardiomyopathy (CICM), seizures, and clozapine-induced neutropenia (CIN). Most clozapine ADEs subside gradually or respond to dose reduction; those that prompt discontinuation generally do not preclude rechallenge. Rechallenge is generally inadvisable for clozapine-induced myocarditis (CIM), CICM, and clozapine-induced agranulocytosis (CIA). Clozapine plasma levels >600-1000 μg/L appear more likely to cause certain ADEs (e.g., seizures) and, although there is no clear toxicity threshold, risk/benefit ratios are generally unfavorable above 1000 μg/L.. Clozapine ADEs rarely require discontinuation.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Myocarditis; Neutropenia; Seizures

Psychiatric comorbidities in patients with epilepsy are common. A bidirectional relationship has been well described where not only patients with epilepsy have a higher prevalence of psychiatric comorbidities but also patients with primary psychiatric disorders are at an increased risk of developing seizures. The aim of this review is to highlight the complex relationship between epilepsy and common psychiatric disorders and to answer the question whether psychotropic medications are proconvulsant by reviewing the preclinical and clinical literature. The evidence shows that the majority of psychotropic medications are not proconvulsant when used in therapeutic doses with the exception of a subset of medications, mainly bupropion IR and certain antipsychotic drugs such as clozapine. An effective treatment of psychiatric comorbidities in patients with epilepsy must consider not only the potential therapeutic effect of the drug, but also its potential iatrogenic effects on the seizure disorder.

Topics: Antipsychotic Agents; Clozapine; Epilepsy; Humans; Psychotropic Drugs; Seizures

Clozapine (CLZ) is the superior drug in treatment of schizophrenia. Serum concentration of CLZ is associated with clinical response and dose-dependents side effects, where generalized tonic-clonic seizures are most critical. Thus, therapeutic drug monitoring (TDM) of CLZ may guide individual dosing to reach target exposure and prevent dose-dependent side effects. However, current TDM methods are not capable of predicting the risk of agranulocytosis, which is a dose-. The article provides an overview of clinical, pharmacological, and toxicological aspects of CLZ, and the role of TDM as a tool for dose titration and follow-up in patients with TRS. Main focus is on current challenges and strategies in CLZ TDM, including future perspectives on potential identification/analysis of CLZ metabolite biomarkers reflecting the risk of granulocyte toxicity.. The association between CLZ serum concentration, clinical response and risk of seizures is indisputable. TDM should therefore always guide CLZ dose titration. Development of advanced TDM methods, including biomarkers predicting the risk of granulocyte toxicity might extend TDM to be a tool for deciding which patients that can be treated safely with CLZ, potentially increasing its utility beyond TRS.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance; Humans; Schizophrenia; Seizures

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization's (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Cardiotoxicity; Clozapine; Connexin 43; Humans; Pneumonia; Schizophrenia; Seizures; Signal Transduction; Treatment Outcome

Clozapine is the first second generation antipsychotic with different receptor profile of action. Clozapine is the most efficacious drug for the treatment of psychotic disorder and is the drug of choice in treatment resistant schizophrenia. Clozapine is used in elderly patients infrequently owing to its adverse effects profile and tolerability. There is paucity of literature with respect to clozapine use in late life. In this narrative review, we discuss clozapine use in elderly and challenges associated with its use.

Topics: Aged; Aging; Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Cognitive Dysfunction; Humans; Metabolic Diseases; Schizophrenia; Seizures

Seizures are a known adverse effect of clozapine therapy. The literature varies on incidence rates of seizures, secondary to varying time frames in which each seizure occurred. Tonic-clonic seizures comprise the majority of seizures experienced secondary to clozapine use, but it is imperative to recognize the potential variety of seizure presentation. The exact etiology of clozapine-induced seizure is unknown. Conflicting reports regarding total oral dose, serum concentration, dose titration, and concomitant medications make it difficult to identify a single cause contributing to seizure risk. Following seizure occurrence, it may be in the best interests of the patient to continue clozapine treatment. In this clinical situation, the use of an antiepileptic drug (AED) for seizure prophylaxis may be required. The AED of choice appears to be valproate, but several successful case reports also support the use of lamotrigine, gabapentin and topiramate. Well-designed clinical trials regarding clozapine seizure prophylaxis are lacking. Given clozapine's strong evidence for efficacy in the treatment of schizophrenia and schizoaffective disorder, every attempt to manage side effects, including seizure, should be implemented to allow for therapeutic continuation.

Topics: Anticonvulsants; Antipsychotic Agents; Clozapine; Humans; Incidence; Seizures

The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures.. A systematic review of English-language MEDLINE articles was undertaken.. Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug-drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician's choice should consider drug-drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided.

Topics: Anticonvulsants; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Interactions; Humans; Risk; Seizures

Clozapine is, and will remain in the coming years, an irreplaceable drug in psychiatry which has elective indication in treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. Unfortunately, the drug is largely underused for many and serious side effects. Only a good knowledge of these side effects and of the main strategies to prevent their occurrence or minimize their impact can allow overcoming the underutilization of this valuable therapy. The article describes the clinical and epidemiological features of the non-motor side effects of clozapine including blood dyscrasias, constipation, diabetes, enuresis, fever, hepatitis, hypersalivation, ileus, myocarditis, nephritis, priapism, seizures, serositis, weight gain and metabolic syndrome. The paper suggests several strategies, supported by scientific evidence, in the management of these side effects. The neuropsychiatric side effects of clozapine are not discussed in this review.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Electroencephalography; Humans; Leptin; Metabolic Syndrome; Paraproteinemias; Receptor, Serotonin, 5-HT2C; Seizures; Weight Gain

Although the role of clozapine is well established for treatment-resistant schizophrenia, it is rarely used in pediatric populations, mainly due to its potentially serious adverse effects.. To summarize practical aspects of use of clozapine in treating children with schizophrenia and management of associated adverse effects.. Available studies in the literature using clozapine in the pediatric population are summarized and the NIMH experience in treating refractory childhood-onset schizophrenia cases with clozapine is discussed.. Despite a higher incidence of adverse effects in children, clozapine appears to be a uniquely beneficial second-line agent for treating children with refractory schizophrenia.

Topics: Adolescent; Age of Onset; Akathisia, Drug-Induced; Antipsychotic Agents; Child; Child, Preschool; Clozapine; Drug Resistance; Humans; Neutropenia; Schizophrenia; Seizures; Weight Gain

Atypical antipsychotic medications (second-generation antipsychotics) have been increasingly used in the treatment of a number of psychotic disorders since their introduction in 1988, with the newest medication introduced in 2002. Justification for their use includes claims of equal or improved antipsychotic activity over first-generation antipsychotics, increased tolerability, and decreased side effects. However, there are still significant adverse effects and toxicities with this class of medications. Toxicologic exposures and fatalities associated with atypical antipsychotics continue to increase in the United States, with 32,422 exposures and 72 deaths in 2003. There have also been Food and Drug Administration warnings in the past year about how some atypical antipsychotics have been marketed to minimize the potentially fatal risks and claiming superior safety to other atypical antipsychotics without adequate substantiation, indicating the toxicologic potential of these agents may be underestimated.. Continued research to evaluate adverse effects and tolerability of atypical antipsychotics compared with first-generation antipsychotics and each other is reviewed. This article also reviews the pharmacodynamics, pharmacokinetics, and drug interactions with these medications. New therapeutic monitoring recommendations for this class of medications have also been proposed. Finally, clinical toxicity in overdose and management are reviewed.. While new atypical antipsychotic medications may have a safer therapeutic and overdose profile than first-generation antipsychotic medications, many adverse and toxic effects still need to be considered in therapeutic monitoring and overdose management.

Topics: Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Benzodiazepines; Cardiomyopathies; Child; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Drug Interactions; Drug Overdose; Dry Eye Syndromes; Humans; Hyperlipidemias; Hypotension; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Seizures; Thiazoles

Clozapine is a distinctive antipsychotic agent, having a unique clinical profile and an idiosyncratic safety profile. More so than with other agents, the weighting of its adverse event profile is critical, in order to counterbalance its clear clinical advantages. The safety issues with clozapine are in a number of areas, some of which are considered medical emergencies and potentially life-threatening. These include haematological (neutropenia and agranulocytosis), CNS (seizures), cardiovascular (myocarditis and cardiomyopathy), metabolic (diabetes), gastrointestinal and neuromuscular. Understanding the safety profile of clozapine allows an informed use of the agent that can maximise its clear clinical benefit and minimise the known risks.

Topics: Antipsychotic Agents; Cardiomyopathies; Clozapine; Diabetes Mellitus; Humans; Muscle, Skeletal; Myocarditis; Neutropenia; Psychotic Disorders; Risk Factors; Seizures; Weight Gain

Both first-generation and second-generation antipsychotic medications can lower the seizure threshold, increasing the chances of seizure induction. This article reviews the published literature concerning the seizure-lowering effects of first- and second-generation antipsychotic medication. Unfortunately, rigorously controlled studies are relatively infrequent, and case reports form a large part of the available literature, limiting the confidence with which firm conclusions can be drawn. Of the first-generation antipsychotic medications, chlorpromazine appears to be associated with the greatest risk of seizure provocation, although other first-generation antipsychotics also lower seizure threshold. Conversely, molindone, haloperidol, fluphenazine, pimozide and trifluoperazine are associated with a lower risk of seizure induction. Clozapine is the second-generation antipsychotic most frequently associated with seizures, with risperidone appearing to confer a relatively low risk. Other factors such as history of seizure activity, concurrent use of other drugs that lower seizure threshold, rapid dose titration, slow drug metabolism, metabolic factors and drug-drug interactions appear to increase the chances of an antipsychotic medication inducing seizure activity.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Quinolones; Risperidone; Seizures; Thiazoles

Clozapine has demonstrated superior efficacy in relieving positive and negative symptoms in treatment-resistant schizophrenic patients; unlike other antipsychotics, it causes minimal extrapyramidal side effects (EPS) and has little effect on serum prolactin. Despite these benefits, the use of clozapine has been limited because of infrequent but serious side effects, the most notable being agranulocytosis. In recent years, however, mandatory blood monitoring has significantly reduced both the incidence of agranulocytosis and its associated mortality. The occurrence of seizures appears to be dose-related and can generally be managed by reduction in clozapine dosage. Less serious and more common side effects of clozapine including sedation, hypersalivation, tachycardia, hypotension, hypertension, weight gain, constipation, urinary incontinence, and fever can often be managed medically and are generally tolerated by the patient. Appropriate management of clozapine side effects facilitates a maximization of the benefits of clozapine treatment, and physicians and patients alike should be aware that there is a range of benefits to clozapine use that is wider than its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Clozapine; Drug Monitoring; Humans; Respiration Disorders; Seizures; Sialorrhea; Weight Gain

Compliance with conventional antipsychotic medication is often poor, with many patients discontinuing treatment only a few months after commencing therapy. The side effects of treatment, which are not necessarily restricted solely to motor symptoms, are often considered to be responsible for this noncompliance. In contrast to conventional antipsychotics, clozapine is associated with only minimal extrapyramidal symptoms, and in most patients, its use results in significant improvements in compliance. However, clozapine does induce a variety of adverse effects, most of which are of limited duration and either preventable or manageable if a number of simple clinical procedures are followed. Clozapine therapy is associated with a beneficial risk/benefit ratio in the majority of treatment-resistant schizophrenic patients. With careful hematologic control, the risk of agranulocytosis can be minimized. The marked increase in the well-being of patients receiving clozapine should stimulate psychiatrists to broaden its use and not limit it to severely treatment-resistant individuals.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Electroencephalography; Fatigue; Humans; Patient Compliance; Risk Assessment; Schizophrenia; Schizophrenic Psychology; Seizures; Sialorrhea; Tachycardia; Treatment Outcome

Most traditional neuroleptics have a narrow therapeutic-to-toxic index, and thus, the novel antipsychotics are the result of a search to substantially widen the distance between the dose that treats psychosis and the one that produces adverse effects. In vitro binding profiles have been created for the atypical antipsychotics that have been approved by the U.S. Food and Drug Administration (FDA)-clozapine, olanzapine, and risperidone and those that are under FDA review-quetiapine and sertindole. These profiles, which were compared with that of the typical neuroleptic haloperidol, provide guidance for predicting the adverse effects produced by these drugs. Most conventional antipsychotics have central nervous system effects, particularly extrapyramidal symptoms (EPS) and tardive dyskinesia, sedation, and dulling of cognition. Other adverse effects of the typical antipsychotics include the neuroleptic malignant syndrome, orthostatic hypotension, changes in liver function, anticholinergic and antiadrenergic side effects, sexual dysfunction, and weight gain. The newer agents have a lower incidence of EPS and tardive dyskinesia, while weight gain and changes in blood pressure and liver function tests are adverse effects that have been associated with the use of the newer agents. The favorable side effect profile of these new antipsychotics is likely to make patients more willing to continue treatment, and thus these agents represent a step forward in the treatment of patients with severe, chronic mental illness.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Haloperidol; Humans; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Receptors, Neurotransmitter; Seizures; Sleep; Weight Gain

Although neuroleptic drugs have become the mainstay of treating acute and chronic psychosis, they are substantially limited by troublesome side effects. The traditional neuroleptic drugs have a wide array of central nervous system and peripheral system side effects that often lead to problems in management or patient noncompliance. Of particular difficulty are the extrapyramidal symptoms and tardive dyskinesia. However, other side effects of seizures, sedation, neuroleptic malignant syndrome and cardiovascular, hematologic, endocrinological, and weight gain problems remain as clinical management challenges posed by existing antipsychotic drug therapy. Considerable progress has been made in improving the motor side effect profile with the advent of clozapine and risperidone. However, each of these drugs has its own dose-limiting side effect profile. Two new drugs, olanzapine and sertindole, are now added to the pharmacopeia for treating psychosis. They further improve the benefit/ risk ratio because they have even fewer EPS and other side effects. Overall, these new antipsychotic agents greatly improve the treatment of psychosis by reducing drug-induced morbidity and improving the quality of life for patients.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Humans; Imidazoles; Indoles; Neuroleptic Malignant Syndrome; Olanzapine; Pirenzepine; Psychotic Disorders; Risperidone; Schizophrenia; Seizures; Sleep; Weight Gain

The report (1) provides an overview of clozapine doses used in trials conducted in Europe and the United States, (2) compares data on efficacy, and (3) compares side effects of clozapine from recent European and U.S. investigations. The reviewed European trials used a mean dose of 283.7 mg/day, while the mean dose in the U.S. studies was 444 mg/day. Even though the mean doses used in the United States are considerably higher than those used in Europe, the response rates for the two continents are strikingly similar. The main differences in a comparison of two samples evaluated in New York and Innsbruck were found in the prevalence of seizures (Innsbruck, 0%; United States, 7.1%) and confusion (Innsbruck, 0%; United States, 14%). Excitement was less prevalent in the U.S. study. The data presented appear to suggest that a lower dose of clozapine may be as effective as a higher dose in the management of treatment-resistant schizophrenic patients and may cause fewer side effects.

Topics: Akathisia, Drug-Induced; Clozapine; Confusion; Controlled Clinical Trials as Topic; Cross-Cultural Comparison; Drug Administration Schedule; Europe; Humans; Seizures; United States

Clozapine, a novel antipsychotic agent, is an alternative to standard neuroleptic therapy for psychotic disorders. Some advantages of clozapine over neuroleptics are that it may be a more effective antipsychotic in treatment resistant patients and has a lower incidence of extrapyramidal side effects. However, seizures associated with clozapine treatment occur at a rate of about three percent. Factors which seem to increase the likelihood of seizures include high doses of clozapine, rapid dose titration, the concurrent use of other epileptogenic agents and a previous history of neurological abnormalities. A strategy that has been proposed to reduce the occurrence of seizures is the addition of an anticonvulsant agent. At present, little rigorous scientific evidence exists to establish the effectiveness of this strategy or the choice of an anticonvulsant. However, based on what evidence there is and the side effect profiles of the various anticonvulsants, the authors propose the use of valproic acid for the prophylaxis and management of clozapine related seizures.

Topics: Anticonvulsants; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Humans; Psychotic Disorders; Seizures

The arrival of clozapine has been one of the most significant developments in antipsychotic drug treatment since the advent of chlorpromazine ushered in the psychopharmacologic era. However, its utilization has been significantly limited and complicated by its potential to cause adverse effects and agranulocytosis in particular. It must be emphasized that clozapine has a side effect profile that is in many ways distinct from standard typical antipsychotic drugs. Side effects with clozapine are common and range from the benign to the potentially lethal. The most common side effects include sedation, dizziness, and sialorrhea during sleep; the most serious are agranulocytosis, seizures and respiratory depression. Although side effects from clozapine are not necessarily preventable, they are for the most part manageable. Even with the most serious adverse effects, proper knowledge of the medication's actions, clinical vigilance, and prompt intervention can prevent the occurrence of significant morbidity and mortality as a consequence of clozapine treatment.

Topics: Adult; Aged; Agranulocytosis; Blood Chemical Analysis; Central Nervous System Diseases; Clozapine; Female; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Psychotic Disorders; Seizures

Specific electroencephalogram (EEG) changes during clozapine therapy were prospectively studied in a cohort of 50 chronic state hospital patients with schizophrenia who were randomly assigned to one of three nonoverlapping clozapine serum level ranges (50-150 ng/mL, 200-300 ng/mL, and 350-450 ng/mL). EEGs were obtained before clozapine was instituted, and after 10 weeks of treatment. Fifty-three percent of patients showed EEG changes during the 10-week study period. We observed three seizures (6%), one in a patient on 900 mg (serum level 320 ng/mL) clozapine, and two in patients with lower clozapine serum levels (200-300 ng/mL) who had prior histories of seizures and inadequate valproate coverage. Thirteen percent of patients developed spikes with no relationship to dose or serum level of clozapine. Fifty-three percent of patients developed slowing on EEG. Compared to plasma levels below 300 ng/mL, a clozapine serum level between 350 and 450 ng/mL led to more frequent and more severe slowing. The EEG slowing correlated with observed sleepiness, although this factor was not sufficient to explain the severity of high-dose effects.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroencephalography; Evoked Potentials; Female; Humans; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Seizures

In the present study we tested the hypothesis that individual response to clozapine treatment and/or the occurrence of side-effects may be influenced by genetic variation in the serotonin 5-HT2C receptor. We investigated the frequency of a common Cys23Ser substitution, which is known to alter the pharmacological properties of the protein, in 152 patients treated with clozapine. Presence of the Ser23 variant was previously reported to predict a good response to clozapine. However, our results did not support an association between genetic variation of the 5-HT2C receptor and response to clozapine. This held true whether the patients were subgrouped for sex and length of treatment. Moreover, we found no consistent association with any of the observed side-effects.

Topics: Adult; Alleles; Antipsychotic Agents; Clozapine; Female; Genotype; Humans; Male; Mutation; Polymerase Chain Reaction; Psychotic Disorders; Receptors, Serotonin; Schizophrenia; Seizures; Weight Gain

Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatment-refractory. In this study, the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia.. Twenty-one patients (mean [+/-SD] age, 14.0 +/- 2.3 years) with onset of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition-defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study. Patients were randomized to a 6-week double-blind parallel comparison of clozapine (mean [+/-SD] final dose, 176 +/- 149 mg/d), or haloperidol, (16 +/- 8 mg/d).. Clozapine was superior to haloperidol on all measures of psychosis (P = .04-.002). Positive and negative symptoms of schizophrenia improved. However, neutropenia and seizures were major concerns. To date, one third of the group has discontinued using clozapine.. Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia. However, due to possibly increased toxic effects in this pediatric population, close monitoring for adverse events is essential.

Topics: Adolescent; Age Factors; Age of Onset; Child; Child, Preschool; Clozapine; Double-Blind Method; Drug Administration Schedule; Haloperidol; Humans; Neutropenia; Psychiatric Status Rating Scales; Schizophrenia, Childhood; Seizures; Severity of Illness Index; Treatment Outcome

Topics: Agranulocytosis; Clinical Trials as Topic; Clozapine; Dibenzazepines; Home Care Services; Humans; Schizophrenia; Seizures

Clozapine, a new drug for schizophrenia, was recently released for use. We have described the drug and nursing care involved for patients who are on acute inpatient unit for a trial of the drug. From our early observations, clozapine appears to be a promising drug for patients who have not responded to standard neuroleptics.

Topics: Adolescent; Adult; Agranulocytosis; Clinical Trials as Topic; Clozapine; Dibenzazepines; Female; Humans; Male; Patient Compliance; Patient Education as Topic; Professional-Family Relations; Schizophrenia; Seizures

During treatment with clozapine 59% of 127 patients showed abnormal EEGs. Remarkable are paroxysmal disturbances with sharp waves and/or SW-pattern in ca. 13%. Generalized tonic-clonic convulsive cereberal seizures were observed only twice.

Topics: Adolescent; Adult; Clinical Trials as Topic; Clozapine; Dibenzazepines; Electroencephalography; Female; Humans; Male; Middle Aged; Seizures

Among antipsychotics, clozapine is associated with a high risk of seizures. This study aimed to generate novel hypotheses regarding trends in the onset of clozapine-induced seizures using the JADER (Japanese Adverse Drug Event Report) database. Seizures were defined according to the Standardized MedDRA Queries (SMQ) for convulsions (SMQ20000079). Trends in the onset of clozapine-induced seizures were assessed using multivariate logistic regression analysis with covariates of sex, age, clozapine dose, antipsychotic polypharmacy, concomitant medications, and history of convulsive disorder. In addition, we assessed the time-to-onset of clozapine-induced seizures using the median time, interquartile range, and Weibull shape parameter. The JADER database registered 2,745 cases of adverse events with clozapine, and 1,784 cases were included in the analysis after excluding cases for which clinical information was not available. Medium (200-400 mg) and high (> 400 mg) doses of clozapine had a significantly higher reporting rate of seizures than low doses (< 200 mg) (adjusted reporting odds ratio [aROR] = 3.05, 95% confidence interval [CI]: 1.86-4.99 and aROR = 9.81, 95% CI: 6.06-15.89, respectively). Younger age, antipsychotic polypharmacy, and concomitant use of lithium were also significantly associated with reports of seizures. The time-to-onset analysis of 222 cases of clozapine-induced seizures showed that the median time was 134 (interquartile range, 72-295) days. The 95% CI of the WSP β-value for clozapine-induced seizures included 1 and was classified as a random failure type. In conclusion, the results suggest that clozapine-induced seizures are dose-dependent adverse events that should be monitored with consideration of the effects of age and concomitant medications. Further epidemiological research is needed to strengthen and validate our hypotheses.

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; East Asian People; Humans; Japan; Seizures

Expression of inhibitory designer receptors exclusively activated by designer drugs (DREADDs) on excitatory hippocampal neurons in the hippocampus represents a potential new therapeutic strategy for drug-resistant epilepsy. To overcome the limitations of the commonly used DREADD agonist clozapine, we investigated the efficacy of the novel DREADD ligand JHU37160 in chemogenetic seizure suppression in the intrahippocampal kainic acid (IHKA) mouse model for temporal lobe epilepsy (TLE). In addition, seizure-suppressing effects of chemogenetics were compared to the commonly used anti-epileptic drug (AED), levetiracetam (LEV). Therefore, an adeno-associated viral vector was injected in the sclerotic hippocampus of IHKA mice to induce expression of a tagged inhibitory DREADD hM4Di or only a tag (control) specifically in excitatory neurons using the CamKIIα promoter. Subsequently, animals were treated with LEV (800 mg/kg), clozapine (0.1 mg/kg), and DREADD ligand JHU37160 (0.1 mg/kg) and the effect on spontaneous seizures was investigated. Clozapine and JHU37160-mediated chemogenetic treatment both suppressed seizures in DREADD-expressing IHKA mice. Clozapine treatment suppressed seizures up to 34 h after treatment, and JHU37160 effects lasted for 26 h after injection. Moreover, both compounds reduced the length of seizures that did occur after treatment up to 28 h and 18 h after clozapine and JHU37160, respectively. No seizure-suppressing effects were found in control animals using these ligands. Chemogenetic seizure treatment suppressed seizures during the first 30 min after injection, and seizures remained suppressed during 8 h following treatment. Chemogenetics thus outperformed effects of levetiracetam (p < 0.001), which suppressed seizure frequency with a maximum of 55 ± 9% for up to 1.5 h (p < 0.05). Only chemogenetic and not levetiracetam treatment affected the length of seizures after treatment (p < 0.001). These results show that the chemogenetic therapeutic strategy with either clozapine or JHU37160 effectively suppresses spontaneous seizures in the IHKA mouse model, confirming JHU37160 as an effective DREADD ligand. Moreover, chemogenetic therapy outperforms the effects of levetiracetam, indicating its potential to suppress drug-resistant seizures.

Topics: Animals; Clozapine; Disease Models, Animal; Kainic Acid; Levetiracetam; Ligands; Mice; Seizures

Topics: Animals; Apnea; Clozapine; Designer Drugs; Disease Models, Animal; Epilepsy; Ligands; Mice; Mice, Transgenic; NAV1.6 Voltage-Gated Sodium Channel; Oxides; Prosencephalon; Seizures; Sudden Unexpected Death in Epilepsy

Clozapine and bupropion are known to lower the seizure threshold, but little information is available regarding the risk when used in combination. It is unclear whether these agents, when used in combination, have additive seizure risk or possible synergistic effects. Bupropion should be used cautiously in patients treated with clozapine. Safer agents that do not lower the seizure threshold should be utilized whenever possible.

Topics: Antipsychotic Agents; Bupropion; Clozapine; Female; Humans; Male; Seizures; Smoking Cessation

One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons.. Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction.. In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection.. This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.

Topics: Animals; Anticonvulsants; Clozapine; Dentate Gyrus; Disease Models, Animal; Epilepsy, Temporal Lobe; Evoked Potentials; G-Protein-Coupled Receptor Kinases; Gene Editing; Hippocampus; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Receptors, Neurotransmitter; Seizures

In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.

Topics: Animals; Calcium; Clozapine; Disease Models, Animal; Electroencephalography; Epilepsy; Epilepsy, Temporal Lobe; Female; gamma-Aminobutyric Acid; Hippocampus; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Neurons; Pilocarpine; Retroviridae; Seizures

Clozapine (CZP) is an antipsychotic used in resistant psychosis, but has adverse metabolic effects and is associated with new onset or worsening of epileptic seizures (ES). There is not enough information available regarding its effect on metabolic variables and on ES in patients with epilepsy.. To describe the effect of CZP on the metabolic and hematologic profiles, and on ES in patients with epilepsy and with psychosis and/or aggressive behavior.. A case series of patients with epilepsy and psychosis and/or aggressive behavior that received CZP with an 18-week follow-up. Clinical records were assessed from 2008-2018. 30 patients with epilepsy that received CZP were included. A paired analysis (Student’s t-test or Wilcoxon signed rank test) was performed with metabolic variables (glucose, cholesterol, and triglycerides), hematologic variables, weight, body mass index (BMI), and monthly ES before and after CZP administration.. The median age to CZP initiation was 31.9 ± 16.07 years. Median CZP dosage was 193 mg/day. There were changes on BMI (p = 0.001; 3.2 kg/m2 increase, median = 3.08), triglycerides (p = 0.002) and glucose (p = 0.030). Weight increase was 7 kg (p = 0.292; median = 4 kg). Monthly ES mean was decreased from 4.9 (median = 2) to 2.04 (median = 1; p = 0.001).. This study provide information regarding the security profile of CZP in patients with epilepsy with psychosis and/or aggressive behavior. A decrease on monthly ES was observed, as well as moderate increases in triglycerides, glucose and BMI, which coincide with that described by other authors.. La clozapina (CZP) es un antipsicótico efectivo en la psicosis que no responde a otros antipsicóticos, pero tiene efectos metabólicos adversos y se relaciona con la generación de crisis epilépticas (CE). Existe poca información sobre su efecto en variables metabólicas y sobre las CE en pacientes con epilepsia.. Describir el efecto de la CZP en el perfil metabólico, el perfil hematológico y la frecuencia de CE en pacientes con epilepsia y con psicosis o agresividad.. Serie de casos de pacientes con epilepsia y psicosis o agresividad que recibieron CZP con un seguimiento de 18 semanas. Se revisaron los expedientes clínicos de 2008-2018. Se incluyeron 30 pacientes con epilepsia que recibieron CZP. Se hizo una comparación pareada (prueba t de Student o de signo y rango de Wilcoxon), antes y después del inicio de la CZP, de las variables metabólicas (glucosa, colesterol y triglicéridos) y hematológicas, el peso, el índice de masa corporal (IMC) y las CE mensuales.. La edad media al iniciar la CZP fue de 31.9 ± 16.07 años. La dosis media fue 193 mg/día. Hubo incremento en el IMC (p = 0.001; aumento de 3.2 kg/m2; mediana = 3.08), los triglicéridos (p = 0.002) y la glucosa (p = 0.030). La ganancia de peso fue de 7 ± 10.4 kg (p = 0.292; mediana = 4 kg). El promedio de CE mensuales se redujo de 4.9 (mediana = 2) a 2.04 (p = 0.001; mediana = 1).. Este estudio aporta información del perfil de seguridad del uso de CZP en pacientes con epilepsia y psicosis o agresividad. Se observó una disminución en la frecuencia mensual de CE, así como aumentos moderados de los triglicéridos, la glucosa y el IMC, que coinciden con lo descrito por otros autores.

Topics: Clozapine; Epilepsy; Humans; Metabolome; Psychotic Disorders; Seizures

More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy.. Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored.. Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals.. This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

Topics: Animals; Anticonvulsants; Clozapine; Electroencephalography; Epilepsy, Temporal Lobe; Genetic Vectors; Hippocampus; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Seizures

Topics: Adult; Antipsychotic Agents; Austria; Clozapine; Epilepsy, Tonic-Clonic; Female; Germany; Hospitals, Psychiatric; Humans; Male; Mental Disorders; Middle Aged; Pharmacovigilance; Risk; Seizures; Switzerland

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Bupropion; Clozapine; Delayed-Action Preparations; Drug Interactions; Female; Humans; Recurrence; Seizures

Topics: Antipsychotic Agents; Atrial Fibrillation; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Humans; Male; Middle Aged; Schizophrenia, Paranoid; Schizophrenic Psychology; Seizures

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Drug Resistance, Multiple; Electroconvulsive Therapy; Electroencephalography; Female; Humans; Male; Monitoring, Physiologic; Patient Selection; Retrospective Studies; Schizophrenia; Seizures; Treatment Outcome

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH

Topics: Amino Alcohols; Animals; Anticonvulsants; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Mice; Models, Molecular; Molecular Structure; Rats; Seizures; Structure-Activity Relationship

Temporal lobe epilepsy is the most common form of medically-intractable epilepsy. While seizures in TLE originate in structures such as hippocampus, amygdala, and temporal cortex, they propagate through a crucial relay: the midline/intralaminar thalamus. Prior studies have shown that pharmacological inhibition of midline thalamus attenuates limbic seizures. Here, we examined a recently developed technology, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), as a means of chemogenetic silencing to attenuate limbic seizures. Adult, male rats were electrically kindled from the amygdala, and injected with virus coding for inhibitory (hM4Di) DREADDs into the midline/intralaminar thalamus. When treated with the otherwise inert ligand Clozapine-N-Oxide (CNO) at doses of 2.5, 5, and 10mg/kg, electrographic and behavioral seizure manifestations were suppressed in comparison to vehicle. At higher doses, we found complete blockade of seizure activity in a subset of subjects. CNO displayed a sharp time-response profile, with significant seizure attenuation seen 20-30min post injection, in comparison to 10 and 40min post injection. Seizures in animals injected with a control vector (i.e., no DREADD) were unaffected by CNO administration. These data underscore the crucial role of the midline/intralaminar thalamus in the propagation of seizures, specifically in the amygdala kindling model, and provide validation of chemogenetic silencing of limbic seizures.

Topics: Amygdala; Analysis of Variance; Animals; Anticonvulsants; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Evoked Potentials; Intralaminar Thalamic Nuclei; Kindling, Neurologic; Male; Maze Learning; Midline Thalamic Nuclei; Rats; Rats, Sprague-Dawley; Seizures

Antipsychotic drugs (APs) are of great benefit in several psychiatric disorders, but they can be associated with various adverse effects, including seizures. To investigate the effects of chronic antipsychotic treatment on seizure susceptibility in genetically epilepsy-prone rats, some APs were administered for 7 weeks, and seizure susceptibility (audiogenic seizures) was evaluated once a week during treatment and for 5 weeks after drug withdrawal. Furthermore, acute and subchronic (5-day treatment) effects were also measured. Rats received haloperidol (0.2-1.0 mg/kg), clozapine (1-5 mg/kg), risperidone (0.03-0.50 mg/kg), quetiapine (2-10 mg/kg), aripriprazole (0.2-1.0 mg/kg), and olanzapine (0.13-0.66 mg/kg), and tested according to treatment duration. Acute administration of APs had no effect on seizures, whereas, after regular treatment, aripiprazole reduced seizure severity; haloperidol had no effects and all other APs increased seizure severity. In chronically treated rats, clozapine showed the most marked proconvulsant effects, followed by risperidone and olanzapine. Quetiapine and haloperidol had only modest effects, and aripiprazole was anticonvulsant. Finally, the proconvulsant effects lasted at least 2-3 weeks after treatment suspension; for aripiprazole, a proconvulsant rebound effect was observed. Taken together, these results indicate and confirm that APs might have the potential to increase the severity of audiogenic seizures but that aripiprazole may exert anticonvulsant effects. The use of APs in patients, particularly in patients with epilepsy, should be monitored for seizure occurrence, including during the time after cessation of therapy. Further studies will determine whether aripiprazole really has a potential as an anticonvulsant drug and might also be clinically relevant for epileptic patients with psychiatric comorbidities.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Disease Models, Animal; Epilepsy; Haloperidol; Mental Disorders; Olanzapine; Quetiapine Fumarate; Rats; Risperidone; Seizures

Topics: Adult; Antidepressive Agents, Second-Generation; Bupropion; Clozapine; Drug Therapy, Combination; Electroencephalography; Hallucinations; Humans; Male; Occipital Lobe; Schizophrenia; Seizures

Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples.. To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia.. We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group).. Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine.. Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; DiGeorge Syndrome; Dose-Response Relationship, Drug; Drug Substitution; Female; Hospitalization; Humans; Male; Middle Aged; Myocarditis; Neutropenia; Schizophrenia; Seizures; Treatment Outcome; Young Adult

To study the prevalence and incidence of seizures in patients prescribed clozapine.. The treatment records of 222 patients commenced on clozapine were retrospectively reviewed during the period of January 2007 to June 2014 to evaluate the prevalence of seizures before and after starting clozapine.. The majority of patients commenced on clozapine were male (65%), single (65%), and unemployed (57%). The mean (± standard deviation) dose of clozapine was 277.9 ± 102.5 mg/day. A history of seizure was present in 6 patients who were also prescribed antiepileptic medication; of these 6 patients, only 1 case had recurrence of seizure while taking clozapine due to poor compliance with ongoing antiepileptic medication. The incidence rate of new-onset seizure with clozapine was 6% (12/216). Most patients who developed seizures were male, aged between 24 and 41 years, and had a long duration of illness (≥ 10 years). The risk of seizure was associated with the dose of clozapine used: 3% (5/159) with dose up to 300 mg/day, 8% (4/49) with 325 to 500 mg/day, and 38% (3/8) in those receiving > 500 mg/day. More than half of the patients (7/12) who developed seizures while prescribed clozapine were managed with reduction in the dose of clozapine. In one-third of cases (4/12) an antiepileptic medication was added and in 1 case, clozapine was stopped. All patients who continued on clozapine remained seizure-free at follow-up that ranged from 6 months to 4 years.. The incidence of seizures with clozapine was 6% and the risk of seizures increased with higher doses.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Risk Factors; Schizophrenia; Seizures; Young Adult

Topics: Amisulpride; Antipsychotic Agents; Clozapine; Humans; Male; Middle Aged; Neuroleptic Malignant Syndrome; Pancreatitis; Schizophrenia; Seizures

Topics: Adult; Antipsychotic Agents; Clozapine; Electroconvulsive Therapy; Female; Humans; Schizophrenia; Seizures; Treatment Outcome

A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT₁A, 5-HT₆ and 5-HT₇b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT₁A receptors (Ki=24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.

Topics: Administration, Oral; Animals; Anticonvulsants; Drug Evaluation, Preclinical; Electroshock; Half-Life; Kinetics; Piperazine; Piperazines; Protein Binding; Rats; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Seizures; Xanthones

To evaluate the safety and effectiveness of the combination of electroconvulsive therapy (ECT) and clozapine compared to ECT with other antipsychotics or benzodiazepines in a sample of adolescents diagnosed with schizophrenia spectrum disorders.. Data regarding 28 adolescent subjects aged 13 to 18 with diagnoses of schizophrenia spectrum disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision and treated with ECT were retrospectively collected. Twelve subjects were also treated with clozapine and 16 with other antipsychotics or benzodiazepines during ECT course and follow-up. Electroconvulsive therapy parameters and adverse effects were assessed using a systematic protocol. Positive and Negative Syndrome Scale and Clinical Global Impression scores before ECT and after acute ECT, and rate of rehospitalization during 1-year follow-up were used to assess effectiveness. Response was defined as a 20% decrease in Positive and Negative Syndrome Scale scores.. No differences were observed in the mean charge needed to induce seizure and electroencephalographic duration, but there was a slight difference in the current used. The nonclozapine group showed greater restlessness and agitation, although no differences were found in other adverse effects. The percentage of responders was similar: 66.7% in the clozapine group and 68.8% in the nonclozapine group. However, the rate of rehospitalization was lower in the patients treated with clozapine during 1-year follow-up (7.1%) compared to that of the nonclozapine group (58.3%) (P = 0.009).. The main findings of this study were that combining ECT with clozapine, compared to ECT with other antipsychotics or benzodiazepines, was safe and that both treatments were equally effective. Charges needed to induce seizure were similar in both groups. Patients treated with clozapine during 1-year follow-up had a lower rate of rehospitalization.

Topics: Adolescent; Antipsychotic Agents; Clozapine; Combined Modality Therapy; Electrocardiography; Electroconvulsive Therapy; Female; Follow-Up Studies; Hospitalization; Humans; Male; Retrospective Studies; Schizophrenia; Seizures; Treatment Outcome

To investigate the effect of a complete smoking ban on a group of psychiatric inpatients maintained on the antipsychotic medication clozapine.. Retrospective data on clozapine dose and plasma levels were collected from a three month period before and a six month period after the introduction of the smoking ban.. Before the ban only 4.2% of patients who smoked had a plasma clozapine level > or =1000 microg/l but after the ban this increased to 41.7% of the sample within the six month period following the ban despite dose reductions.. Abrupt cessation of smoking is associated with a potentially serious risk of toxicity in patients taking clozapine. Plasma clozapine levels must be monitored closely and adjustments made in dosage, if necessary, for at least six months after cessation.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Interactions; England; Follow-Up Studies; Hospitals, Psychiatric; Humans; Metabolic Clearance Rate; Myoclonus; Psychotic Disorders; Retrospective Studies; Risk Factors; Seizures; Smoking Cessation

Topics: Antipsychotic Agents; Clozapine; Histamine Agonists; Histamine H1 Antagonists; Humans; Leptin; Psychotic Disorders; Receptors, Histamine H1; Seizures; Treatment Outcome

A 58-year-old man was in a period of 3 weeks twice admitted to a general hospital with symptoms of clozapine intoxication, i.e. loss of consciousness. We are of the opinion that the patient developed clozapine intoxication because he had been prescribed clozapine (300 mg/day) and at the same time had suddenly stopped smoking. The link is confirmed in the literature. We therefore recommend that clozapine-dosage be adjusted to a patient's smoking behaviour.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Middle Aged; Schizophrenia; Seizures; Smoking Cessation

Topics: Adolescent; Adult; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Infant; Internet; Pertussis Vaccine; Safety; Seizures; Selective Serotonin Reuptake Inhibitors; Spasms, Infantile; Suicide

Phenytoin is a first-line drug for the treatment of status epilepticus. We report a case of phenytoin intoxication after intravenous phenytoin loading in a patient with clozapine-related seizures. To our knowledge, this is the first description of phenytoin intoxication due to CYP2C9 inhibition by clozapine. This case report is important because it supports the use of a lower intravenous loading dose of phenytoin in patients with clozapine-related status epilepticus.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Interactions; Female; Humans; Phenytoin; Schizophrenia; Seizures

To document and measure various parameters and outcomes in patients prescribed clozapine in a forensic psychiatric setting.. A retrospective file review was conducted on patients prescribed clozapine. Parameters and outcomes were recorded and compared against a group prescribed other antipsychotics, matched for sex and diagnosis.. Patients prescribed clozapine had higher rates of substance misuse syndromes and comorbidity when compared to patients prescribed other antipsychotics. Clozapine was found to be effective in treatment of psychosis. High rates of adverse effects were noted. Discontinuation of clozapine for a variety of reasons was common.. Patients identified as treatment resistant who are prescribed clozapine are often more complex in the pattern of illness and subsequent needs. Clozapine is effective in the treatment of psychosis in this forensic service. Its benefits need to be balanced against the potential for adverse effects and problems ensuring adherence. Regular, objective monitoring of clinical and adverse effects would aid patient safety, clinical decision-making and future research.

Topics: Adult; Antipsychotic Agents; Clozapine; Crime; Diagnosis, Dual (Psychiatry); Drug Monitoring; Drug Resistance; Forensic Psychiatry; Health Status; Hospitals; Humans; Incidence; Male; Middle Aged; Neutropenia; New South Wales; Patient Dropouts; Prisoners; Psychotic Disorders; Retrospective Studies; Risk Factors; Schizophrenia; Schizophrenic Psychology; Seizures; Substance-Related Disorders

The antipsychotic agent clozapine (ClozarilE) is reserved for the treatment of refractory psychosis. Clozapine has allowed many schizophrenic patients to lead more independent and productive lives, but its use is restricted by side effects. Clozapine has been shown to lower seizure threshold and produce significant EEG changes. Although not a commonly used drug, both clinical neurophysiology technologists and interpreting electroencephalographers need to be aware of the effects of clozapine on the EEG. We review the findings of two patients who developed neurological symptoms and EEG abnormalities that resolved following reduction of clozapine therapy.

Topics: Adult; Antipsychotic Agents; Artifacts; Clozapine; Electroencephalography; Humans; Male; Middle Aged; Seizures

22q11.2 deletion is the most common microdeletion in humans and one of the most important risk factors for schizophrenia. Nevertheless, case reports of children or adolescents with 22q11.2 deletion and schizophrenia are very rare. After a review of the current knowledge about physical, developmental, behavioural and psychiatric problems in 22q11.2 deletion, the case of a 12;10-year-old boy with schizophrenia and the microdeletion is reported. About three years after the first symptoms, and only after medication with several neuroleptics, the patient reached his pre-morbid functioning level under treatment with risperidone. Under medication with clozapine he had experienced a single event of seizures which were due to hypocalcemia. This case report illustrates the importance of serum calcium controls at regular intervals for patients with 22q11.2 deletion and schizophrenia who are on neuroleptic medication. Ideally, children and adolescents with the deletion and co-morbid psychiatric problems should be treated in child and adolescent psychiatry units specialized in problems associated with the deletion. A good cooperation with other medical services is absolutely necessary.

Topics: Adolescent; Antipsychotic Agents; Calcium; Child; Chromosome Deletion; Chromosomes, Human, Pair 22; Clozapine; Developmental Disabilities; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Hypocalcemia; Male; Risperidone; Schizophrenia; Schizophrenic Psychology; Seizures

Topics: Administration, Oral; Adult; Antipsychotic Agents; Biological Availability; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Humans; Intestinal Absorption; Male; Schizophrenia; Seizures; Valproic Acid

Psychiatry co-morbidity with epilepsy is common and often requires the combined use of psychotropic and antiepileptic drugs (AEDs). For schizophrenic patients, the occurrence of seizures with atypical agents is highest among antipsychotics, although these agents are more effective in alleviating symptoms (including negative symptoms) and are associated with fewer extrapiramidal effects. The indol alkaloid alstonine is the major component of plants used by traditional Nigerian psychiatrists as anti-dementia drugs. The alkaloid presents an experimental profile very similar to the atypical antipsychotic clozapine. This study aimed to compare the pro-convulsant activity of these two antipsychotic compounds. Through repetitive administration over a 30-day period in a kindling paradigm, it is shown that, unlike clozapine, alstonine does not possess pro-convulsant activity. The data adds to previous suggestions that alstonine deserves to be scrutinized as a model for the development of newer antipsychotics.

Topics: Animals; Anticonvulsants; Antipsychotic Agents; Apocynaceae; Clozapine; Male; Mice; Mice, Inbred Strains; Phytotherapy; Plant Extracts; Secologanin Tryptamine Alkaloids; Seizures

In most patients diagnosed with psychotic depression or schizophrenia and treated with electroconvulsive therapy, parallelly administered antipsychotic medication cannot be stopped. Antipsychotic drugs can influence both seizure threshold and seizure activity in different ways.. The present study processes the data of 77 patients treated parallelly with electroconvulsive therapy and antipsychotic drugs. Oral doses of the antipsychotic medication administered the day before the electroconvulsive therapy, stimulus intensity, seizure durations, and impedance were analysed from session to session.. One group of antipsychotics (haloperidol, fluphenazine, risperidone, sulpirid) was not found to influence seizure activity: there was no significant difference in EEG and EMG registered seizure duration or in stimulus intensity between the treated and non-treated group. However, significant difference was found between the next treated and non-treated groups in 40% of the sessions in case of olanzapine, in 50% of the sessions in case of clozapine and in 57% of the sessions in case of zuclopenthixol in EEG or EMG registered seizure duration as well as in stimulus intensity. In the third group (quetiapine) there was a significant difference in each session (2nd session: EMG, p=0.02; 5th session: EEG, p=0.05, EMG, p=0.04). Most of the antipsychotics (olanzapine, clozapine, zuclopenthixol) have been shown to possess epileptogenic properties; only quetiapine reduces seizure activity.. In the clinical use of olanzapine, clozopine and zuclopenthixol seems epileptogenic, whereas in the case of quetiapine seizure reducing properties must be taken into account. Together with the consideration of the accompanying somatic and neurologic disturbances and with the concomitant medications this can influence the treatment of choice.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Brain; Clopenthixol; Clozapine; Dibenzothiazepines; Electric Impedance; Electroconvulsive Therapy; Electroencephalography; Electromyography; Female; Fluphenazine; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Risperidone; Seizures; Sulpiride

Six patients with epilepsy and severe psychosis were treated with the atypical antipsychotic clozapine. The use of clozapine might be complicated in epileptic patients because of an increased risk of seizures. However, none of the reported patients had an increase of their seizure frequency, in contrast, three patients had a substantial reduction of seizures. One patient had a reduction of non-epileptic seizures as well. In the second part of this paper, combinations of clozapine with newer and older anticonvulsants as well as their interactions and associated risks are discussed.

Topics: Adult; Aged; Anticonvulsants; Antipsychotic Agents; Clozapine; Epilepsy; Female; Humans; Male; Psychotic Disorders; Seizures; Treatment Outcome

Topics: Adult; Clozapine; Electroencephalography; Humans; Male; Schizophrenia, Paranoid; Seizures; Stuttering

1. Several neuroleptics inhibited the 3 microM gamma-aminobutyric acid induced-chloride current (GABA-current) on dissociated rat dorsal root ganglion neurons in whole-cell patch-clamp investigations. 2. The IC(50) for clozapine, zotepine, olanzapine, risperidone and chlorpromazine were 6.95, 18.26, 20.30, 106.01 and 114.56 microM, respectively. The values for the inhibitory effects of neuroleptics on the GABA (3 microM)-current, which were calculated by the fitting Hill's equations where the concentrations represent the mean therapeutic blood concentrations, were ranked clozapine>zotepine>chlorpromazine>olanzapine>risperidone. These inhibitory effects, weighted with the therapeutic concentrations of neuroleptics, were correlated with the clinical incidences of seizure during treatment with neuroleptics. 3. Clozapine reduced the picrotoxin-inhibiton, and may compete with a ligand of the t-butylbicyclophosphorothionate (TBPS) binding site. 4. Haloperidol and quetiapine did not affect the peak amplitude of the GABA (3 microM)-current. However, haloperidol reduced the clozapine-inhibition, and may antagonize ligand binding to TBPS binding site. 5. Neuroleptics including haloperidol and quetiapine enhanced the desensitization of the GABA (3 microM)-current. However, haloperidol and quetiapine at 100 microM inhibited the desensitization at the beginning of application. 6. Blonanserin (AD-5423) at 30 and 50 microM potentiated the GABA (3 microM)-current to 170.1+/-6.9 and 192.0+/-10.6% of the control current, respectively. Blonanserin shifted GABA concentration-response curve leftward. Blonanserin only partly negatively interacted with diazepam. The blonanserin-potentiation was not reversed by flumazenil. Blonanserin is not a benzodiazepine receptor agonist. 7. The various effects of neuroleptics on the GABA-current may be related to the clinical effects including modifying the seizure threshold.

Topics: Animals; Antipsychotic Agents; Cells, Cultured; Chloride Channel Agonists; Chloride Channels; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Synergism; gamma-Aminobutyric Acid; Ganglia, Spinal; Haloperidol; Incidence; Membrane Potentials; Piperazines; Piperidines; Quetiapine Fumarate; Rats; Rats, Wistar; Seizures

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

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Epilepsy, Tonic-Clonic; Female; Fructose; Humans; Schizophrenia, Paranoid; Seizures; Topiramate; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Schizophrenia; Seizures

Topics: Acetates; Aged; Amines; Antimanic Agents; Antipsychotic Agents; Clozapine; Cyclohexanecarboxylic Acids; Female; Gabapentin; gamma-Aminobutyric Acid; Humans; Schizophrenia, Paranoid; Seizures

Topics: Adult; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Liver Diseases; Male; Seizures

Topics: Aged; Antipsychotic Agents; Clozapine; Conscious Sedation; Drug Overdose; Female; Humans; Pneumonia, Aspiration; Seizures

Topics: Adult; Anti-Anxiety Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Electroencephalography; Humans; Lorazepam; Male; Risperidone; Schizophrenia; Seizures; Substance Withdrawal Syndrome

A 35-year-old man with schizophrenia was successfully treated with clozapine at a daily oral dose of 700-725 mg for more than 7 consecutive years. Two weeks after abrupt cessation of chronic heavy cigarette smoking, he suddenly developed tonic clonic seizures followed by stupor and coma. After 2 days of intensive care, the patient recovered completely but could not recall the episode. Clozapine therapy was reinstituted and could be carried out successfully at 425 mg daily, i.e., at an approximately 40% reduction of the daily dose before he stopped smoking. The sudden cessation of smoking most likely caused a rise in plasma concentrations of clozapine and/or clozapine metabolites resulting in the seizure episode. A likely mechanism is that the heavy smoking had induced cytochrome P450-1A2, the main enzyme involved in the metabolism of clozapine.

Topics: Adult; Clozapine; Humans; Male; Schizophrenia; Seizures; Smoking Cessation

Topics: Aged; Antipsychotic Agents; Clozapine; Dementia; Hallucinations; Humans; Male; Parkinson Disease; Seizures

Topics: Antipsychotic Agents; Clozapine; Female; Gastroesophageal Reflux; Humans; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Seizures

In this study, we assessed the effects of the acute (a single injection) and repeated (once daily injections for 21 days) administration of the atypical antipsychotic drug clozapine (1.5, 5, or 15 mg/kg i.p.) and the typical antipsychotic drug haloperidol (0.15, 0.5, and 1.5 mg/kg, i.p.) on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold (PNT) and the primary afterdischarge duration (ADD), respectively. A single injection of either 5 or 15 mg/kg of clozapine significantly decreased the PNT and significantly increased the primary ADD, indicating a proconvulsant action. The repeated administration of clozapine (1.5, 5, or 15 mg/kg, i.p.) produced dose-dependent, proconvulsant effects by significantly decreasing the PNT and by significantly increasing the primary ADD. In contrast to clozapine, the acute administration of haloperidol did not significantly alter the PNT or the primary ADD. The repeated administration of haloperidol (0.5 and 1.5 mg/kg, i.p.), unlike clozapine, significantly decreased the primary ADD, but did not alter the PNT. Overall, clozapine produces a greater proconvulsant action than haloperidol in an animal model of hippocampal seizures.

Topics: Animals; Antipsychotic Agents; Clozapine; Haloperidol; Hippocampus; Injections, Intraperitoneal; Kindling, Neurologic; Male; Rats; Rats, Wistar; Seizures; Time Factors

The atypical antipsychotic clozapine treatment (at high doses) has been reported to be associated with tremors. However, antitremor effects of clozapine have also been reported in Parkinsonian patients. Recently, we reported the protective effects of acute clozapine against pilocarpine-induced status epilepticus (SE). With this background, this study was designed to investigate the possible protective effect of clozapine against acute chemoconvulsions and kindling seizures produced by pentylenetetrazol (PTZ) in mice. Various doses of clozapine (1.0, 2.5, 5.0 and 7.5 mg) offered different degrees of protective effects against PTZ (80 mg) challenge, and the maximum protection was observed with the 2.5 mg dose as it delayed the onset of jerks, clonus, tonic extensor phase and reduced mortality. Animals chronically pretreated with clozapine (2.5, 7.5 and 15.0 mg) for 8 days when challenged by PTZ (50 and 80 mg) on the 8th day also showed protection. Repeated administration of PTZ at a subconvulsive dose (30 mg/kg, i.p, three times a week, for 9 weeks) produced kindled seizures in over 80% of the mice. Pretreatment with clozapine (1 or 5 mg) prevented the behavioral manifestations (motor seizures) as well as the development of kindling. The effect was compared with GABA (200 mg) and diazepam (1 mg), a known anticonvulsant drug.

Topics: Animals; Antipsychotic Agents; Clozapine; Female; gamma-Aminobutyric Acid; Kindling, Neurologic; Male; Mice; Mice, Inbred BALB C; Pentylenetetrazole; Seizures

To examine the seizure characteristics and electroencephalogram (EEG) abnormalities in psychiatric patients taking clozapine, given the estimate of a 10% cumulative risk of generalized seizures in this population.. We reviewed all consecutive EEGs of ambulatory psychiatric patients taking clozapine performed at our laboratory during 1996 and 1997.. A university-affiliated urban teaching hospital.. Twelve patients (4 F/8 M; mean age 40.1 y, range 20-63) had either presented with de novo ictal events within the first month of clozapine therapy (n = 8) or had EEGs recorded to assess seizure risk (n = 4).. According to clinical history and interictal EEG findings, the patients were subdivided as follows: three patients with generalized tonic-clonic seizures, two with generalized myoclonic jerks (1 associated with simple partial seizures), two with complex partial seizures, and one with simple partial seizures. The EEGs revealed interictal epileptiform abnormalities (IEDs) in eight patients, two of whom had not had seizures. IEDs were focal or multifocal, with a predominance of left temporal foci. One patient showed a paroxysmal response to photic stimulation.. Patients taking clozapine may be prone to partial seizures and focal EEG abnormalities as well as to generalized seizures and EEG abnormalities, as previously reported.

Topics: Adult; Antipsychotic Agents; Clozapine; Electroencephalography; Female; Humans; Male; Middle Aged; Outpatients; Psychotic Disorders; Seizures; Temporal Lobe

Topics: Clozapine; Depression, Chemical; Drug Therapy, Combination; Humans; Schizophrenia; Seizures; Valproic Acid

Topics: Brain; Clozapine; Electroconvulsive Therapy; Electroencephalography; Humans; Schizophrenia; Schizophrenic Psychology; Seizures; Synaptic Transmission

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; Clozapine; Humans; Male; Schizophrenia, Paranoid; Seizures; Smoking Cessation

Clozapine, an atypical antipsychotic drug, is widely used in refractory schizophrenia. At New Hampshire Hospital, 7 of the first 35 patients treated (20%) had convulsions. Patterns were tonic-clonic (5), complex partial (2), and myoclonic (3). Seizures were dose-related and may be anticholinergic in etiology. EEG changes are frequent with clozapine, particularly as dosage is increased. Twenty-six of 35 patients (74%) had EEG abnormalities at some time during clozapine treatment. EEG is a sensitive means of detecting clinical toxicity. When EEG abnormalities (slowing, dysrhythmia, or paroxysmal discharges) are detected, immediately lowering the dose by at least 25-50 mg per day and adjusting weekly until EEG returns to baseline can reduce the incidence of seizures.

Topics: Adult; Clozapine; Electroencephalography; Female; Humans; Male; Schizophrenia; Seizures

Topics: Ambulatory Care; Clozapine; Drug Administration Schedule; Humans; Male; Middle Aged; Schizophrenia, Paranoid; Seizures

Topics: Adult; Clozapine; Drug Interactions; Erythromycin; Humans; Male; Pharyngitis; Schizophrenia; Seizures

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; Dystonia; Female; Humans; Kindling, Neurologic; Schizophrenia, Paranoid; Seizures; Stuttering

The seizures associated with the atypical antipsychotic medication clozapine represent a serious side effect of treatment. In premarketing studies, seizures occurred at a crude rate of 3.5%. It is possible that the rate and character of seizures would vary in clinical settings because of differences in patient populations or differences in the manner in which treatment is administered. We studied the seizures that occurred during clozapine treatment in a state psychiatric hospital.. We reviewed the medical charts and pharmacy records of 100 sequential patients who were to start clozapine treatment. The review period covered 6 months pretreatment through 1 year of follow-up.. The patients were 55 men and 45 women, aged 20 to 61 years. Ten (5 men, 5 women) had at least one seizure during clozapine treatment. Seizures occurred at all dose ranges (0-299 mg/day, N = 6; 300-599 mg/day, N = 2; 600-900 mg/day, N = 2). Of 12 patients with histories of previous seizures, 4 (33%) had a seizure while taking clozapine and anticonvulsants. Of 9 patients with histories of head trauma but no seizures, 1 (11%) had a seizure. Of 79 patients without seizure disorder or a history of head trauma, 5 (6.3%) had a seizure. Nine of the patients who had a seizure continued on clozapine treatment with temporary dose reduction and/or addition of an anticonvulsant, 2 having one additional seizure.. Clozapine-associated seizures were more frequent in this group of state hospital patients than they were in premarketing studies. Clozapine-related seizures did not preclude successful treatment with clozapine.

Topics: Adult; Anticonvulsants; Clozapine; Cohort Studies; Delusions; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Hospitals, Psychiatric; Hospitals, State; Humans; Male; Middle Aged; Neurocognitive Disorders; Psychotic Disorders; Schizophrenia; Seizures; Treatment Outcome

This pharmaco-epidemiologic study was undertaken to determine if the combination of clozapine and valproate poses an increased risk of blood dyscrasias, liver function abnormalities, or other side effects and to develop dosing guidelines when the combination is utilized.. The charts of 55 patients receiving clozapine and valproate concurrently between May 8, 1989, and May 8, 1992, were reviewed to determine the indication for and length of time on each medication, abnormalities in liver function test results, blood cell dyscrasias, seizures, nausea, vomiting, sedation, sialorrhea, and enuresis. In addition, the efficacy of the combination was measured.. The combination of clozapine and valproate was efficacious and well tolerated in the majority of patients. Major adverse effects such as blood dyscrasias or seizures were not experienced by the study population. The side effect that led to discontinuation of the combination most frequently was sedation.. The combination of clozapine and valproate is safe and efficacious.

Topics: Adult; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Incidence; Leukopenia; Liver; Liver Function Tests; Male; Middle Aged; Psychotic Disorders; Seizures; Sleep; Treatment Outcome; Valproic Acid

Topics: Adult; Clozapine; Drug Administration Schedule; Female; Humans; Myoclonus; Receptors, Serotonin; Schizophrenia; Seizures; Valproic Acid

Clozapine and haloperidol were tested for their ability to influence the acquisition of kindled seizures following electrical stimulation of the amygdala and ventral hippocampus. While haloperidol pretreatment did not alter kindling genesis from either limbic region, preexposure to clozapine delayed the rate at which kindling evolved. Analysis of the number of seizure behaviors expressed during epileptogenesis revealed that clozapine produced a relative antagonism of seizure development arresting kindling at the stage-3 level. The kindling inhibition was dependent upon the daily administration of clozapine during the kindling process and was not evident after withdrawal from a chronic schedule of clozapine exposure. A subconvulsive dose of pilocarpine (80.0 mg/kg) produced an overall enhancement of kindling rate, a finding consistent with the excitatory role of acetylcholine (ACh) in kindling. Lower doses of pilocarpine (20.0 and 40.0 mg/kg) that did not alter seizure advancement partially antagonized the clozapine-elicited inhibition of amygdaloid kindling. Pilocarpine, however, did not affect the clozapine-induced increase in the number of stage-3 behaviors exhibited during amygdaloid kindling, suggesting that other neurochemical effects of clozapine, not related to its anticholinergic properties, modulate the kindling suppression. Clozapine's unique actions on limbic system sensitization were discussed in relation to its effectiveness as an antipsychotic agent.

Topics: Acetylcholine; Amygdala; Animals; Antipsychotic Agents; Clozapine; Dopamine; Drug Interactions; Electroencephalography; Haloperidol; Hippocampus; Kindling, Neurologic; Limbic System; Male; Parasympatholytics; Pilocarpine; Rats; Rats, Wistar; Seizures; Substance Withdrawal Syndrome

In a retrospective study, 1863 EEG recordings made during clozapine treatment of 283 patients with normal pretreatment EEG evaluations were analyzed. Furthermore, they were compared to the EEGs of the same patients without clozapine (i.e., during other neuroleptic medication). Moreover, the data of all patients who had seizures during treatment with clozapine were evaluated in case reports. Classical clinical EEG evaluation criteria for normal versus abnormal were used (including diffuse slowing and grouped alterations according to Jung 1953 and Kugler 1983). Of the 283 patients investigated, 61.5% (174) showed at least one abnormal EEG under clozapine according to these criteria. Evaluating all recorded EEGs of these patients in order to get some longitudinal information, we found a rate of 53.4% abnormal EEG recordings during clozapine treatment. Most of the EEG changes were evaluated as slight (22.5%) to moderate (10.1%) diffuse slowing and some as groups of nonparoxysmal waves (39.8%) or sharp waves (16.2%) rendering the EEGs abnormal according to the above criteria. Potential signs of increased bioelectrical cerebral reagibility such as paroxysmal activity (4.3%) or severe diffuse slowing (0.2%) were rare. A nearly linear correlation with the daily dose was found in the range up to 300 mg clozapine/day for both diffuse and grouped alterations. Possibly due to selection, adaptive mechanisms/habituation, and/or other unknown factors, the rate of alterations decreased slightly at doses above 300 mg and rose again sharply for doses over 600 mg/d. Three of the clozapine-treated patients, equivalent to 1.1%, developed seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Clozapine; Electroencephalography; Female; Humans; Male; Middle Aged; Neurocognitive Disorders; Psychotic Disorders; Retrospective Studies; Schizophrenia; Seizures

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

Topics: Basal Ganglia Diseases; Clozapine; Haloperidol; Schizophrenia; Schizophrenic Psychology; Seizures

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Humans; Male; Schizophrenia, Paranoid; Seizures

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Middle Aged; Schizophrenia; Seizures

Topics: Clozapine; Delta Rhythm; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Humans; Schizophrenia; Seizures; Theta Rhythm

Clozapine is an effective antipsychotic agent with atypical neuroleptic and side effects. The risk of pathological changes in the EEG and of seizures is correlated to the dosage administered. With dosages of 300 mg/day or higher the EEG should be monitored regularly. The neurophysiological effects of this drug, known only in adults up till now, were also found in adolescents suffering from schizophrenia.

Topics: Adolescent; Cerebral Cortex; Clozapine; Dose-Response Relationship, Drug; Electroencephalography; Evoked Potentials; Female; Humans; Male; Schizophrenia; Schizophrenic Psychology; Seizures

Clozapine is an atypical antipsychotic drug with minimal extrapyramidal toxicity recently approved by the Food and Drug Administration for hard-to-treat schizophrenic patients. We reviewed information on 1,418 patients treated with clozapine in the United States between 1972 and 1988. Forty-one of 1,418 (2.8%) patients had generalized tonic-clonic seizures during treatment with clozapine. Life-table analysis predicts a cumulative 10% risk of seizures after 3.8 years of treatment. Clozapine-related seizures appear to be dose-related. High-dose therapy (greater than or equal to 600 mg/day) was associated with a greater risk of seizures (4.4%) than medium (300 to 600 mg/day; 2.7%) or low doses (less than 300 mg/day; 1.0%). Also, rapid upward titration may increase seizure risk. Thirty-one of 41 patients were successfully continued on clozapine despite seizure occurrence, either with reduction of dose or addition of an antiepileptic medication. Recognition and treatment of clozapine-related seizures will become increasingly important as its use grows in the 1990s.

Topics: Adult; Anticonvulsants; Clozapine; Dose-Response Relationship, Drug; Female; Forecasting; Humans; Life Tables; Male; Middle Aged; Risk Factors; Seizures; Time Factors

Topics: Adult; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Humans; Male; Schizophrenia, Paranoid; Seizures; Substance Withdrawal Syndrome

Clozapine is a newly released antipsychotic that is associated with a higher prevalence of seizures than traditional neuroleptics. The authors describe four patients who developed seizure activity during clozapine treatment and provide recommendations for clinical management of this problem.

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Male; Psychotic Disorders; Schizophrenia; Seizures

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from a transcription, it has been edited by Homer A. Boushey, MD, Professor of Medicine, and Nathan M. Bass, MD, PhD, Associate Professor of Medicine, under the direction of Lloyd H. Smith, Jr, MD, Professor of Medicine and Associate Dean in the School of Medicine.

Topics: Adult; Agranulocytosis; Clozapine; Dibenzazepines; Female; Humans; Male; Schizophrenia; Seizures

The long-term efficacy of clozapine therapy and its effect on health care costs were examined over a two-year period. Patients on clozapine showed marked clinical improvement as measured by the Brief Psychiatric Rating Scale. They also had significantly lower rates of rehospitalization and hospitalization costs than a comparison group of schizophrenic patients who received standard neuroleptic treatment and who were considerably less psychotic at hospital admission. By the second year of the study, savings on mental health care costs averaged $20,000 for each patient on clozapine therapy. The savings were due largely to the patients' change in residence from costly inpatient facilities to less expensive settings in the community.

Topics: Agranulocytosis; Chronic Disease; Clozapine; Cohort Studies; Cost Control; Dibenzazepines; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Patient Readmission; Schizophrenia; Schizophrenic Psychology; Seizures

A series of 3-phenyl-2-piperazinyl-5H-1-benzazepines and related compounds were synthesized and evaluated for potential neuroleptic activity. The preparation of these compounds was carried out by 2,3-dichlorination of 3-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-ones with phosphorus pentachloride followed by amination and concurrent dehydrochlorination. Compounds having the 4-chloro or 4-fluoro substituent in the 3-phenyl group were found to possess the neuroleptic-like activity. Among them, 2-(4-methyl-1-piperazinyl)-3-(4-fluorophenyl)-5H-1-benzazepine dihydrochloride (23) was comparable to chlorpromazine in inhibiting exploratory activity, conditioned avoidance response, and self-stimulation response and more potent than chlorpromazine in antagonizing apomorphine-induced emesis. These neuroleptic effects may be based on an antidopaminergic property of the compound. In causing catalepsy or ptosis, however, 23 was weaker than chlorpromazine. Therefore, this ring system is of interest as a novel class of neuroleptics. Some compounds having the 7-chloro or 7-bromo substituent showed potent anticonvulsant effects against maximal seizures induced by electroshock or pentylenetetrazole.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzazepines; Body Temperature Regulation; Brain; Electroshock; Exploratory Behavior; Homovanillic Acid; Hypothermia; Indicators and Reagents; Male; Mice; Mice, Inbred Strains; Piperazines; Rats; Rats, Inbred Strains; Reserpine; Seizures; Structure-Activity Relationship

A hyperactive mentally retarded patient receiving clozapin and other major tranquilizers had an unexpected seizure. The EEG revealed severe pathological patterns which disappeared after discontinuation of clozapin and could be reproduced as a function of clozapin medication. Other major tranquilizers had no particular effects. This study demonstrates how we determined whether clozapin or other major tranquilizers had seizure-promoting effects in a particular patient.

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzazepines; Electroencephalography; Humans; Male; Seizures