clozapine and Dyskinesia--Drug-Induced

It is commonly recommended that a switch to clozapine be implemented in the face of tardive dyskinesia, even if current treatment involves another "atypical" agent. However, reports do indicate clozapine carries a liability for tardive dyskinesia.. This review sought to evaluate clozapine in relation to tardive dyskinesia in the context of available evidence.. Medline, Embase, and PsycINFO databases were searched for studies published in English, using the keywords:. In total, 513 unique citations were identified and 29 reports met the inclusion criteria. Thirteen studies suggest clozapine reduces dyskinetic symptoms over time (. Research to date supports switching to clozapine for the purpose of reducing tardive dyskinesia risk and/or treating existing tardive dyskinesia, but prospective randomized controlled trials are necessary if we are to substantiate existing recommendations.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Schizophrenia

Topics: Animals; Antipsychotic Agents; Clozapine; Drug Administration Routes; Dyskinesia, Drug-Induced; Humans; Paliperidone Palmitate; Psychotic Disorders

Tardive syndromes (TS) arise from long term exposure to dopamine receptor blocking agents. Clozapine has been considered to have low risk of causing new onset TS and is considered as a treatment option in patients with TS.. This review evaluates the usefulness of clozapine in patients with TS and occasional reports of clozapine causing TS.. Electronic searches were carried out using the search engines of PUBMED, Science direct and Google Scholar databases. All reports describing use of clozapine in management of TS, monitoring of TS while on clozapine and onset of TS after initiation of clozapine were identified.. Fifteen trials and 28 case series/case reports describe the use of clozapine in TS. Most of these reports show that clozapine is useful in patients with TS, in the dose range of 200-300 mg/day and the beneficial effect is seen within 4-12 weeks of initiation. One case series and two case reports described clozapine withdrawal emergent dyskinesias suggesting a masking role of clozapine. One trial, three case series and two case reports describe beneficial effects of clozapine on long standing neurological syndromes. There is relatively less literature (2 trials and 15 case series/reports) describing the emergence of TS with clozapine.. Evidence of beneficial effects of clozapine in TS is greater than its role in causation/worsening of TS. Hence, clozapine should be considered in symptomatic patients who develop TS while receiving other antipsychotics. Further research on mechanism of TS and clozapine effect on TS is required.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Psychotic Disorders

Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Evidence-Based Medicine; Humans; Long-Term Care; Metabolic Clearance Rate; Parkinsonian Disorders; Precision Medicine; Psychiatric Status Rating Scales; Research; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Brain; Cardiomyopathies; Child; Clozapine; Dyskinesia, Drug-Induced; Energy Metabolism; Feeding Behavior; Female; Gene Expression; Genetic Association Studies; Humans; Male; Myocarditis; Olanzapine; Pericarditis; Risperidone; Tourette Syndrome; Twin Studies as Topic; Weight Gain

The present review focuses on atypical antipsychotics and tardive dyskinesia.. We have known for many years that clozapine has a diminished risk of tardive dyskinesia compared with typical antipsychotics. The last decade has seen the introduction of a number of other atypical antipsychotics, allowing us to begin evaluating whether they too share this attribute. In addition, the opportunity to use these drugs as first-line treatment permits a more precise means of establishing risk. While longer-term data are required, the limited evidence available clearly indicates that the atypical antipsychotics have a decreased liability of tardive dyskinesia, approximately 1% compared with 5% for typical agents annually. Like clozapine, the other atypical antipsychotics also demonstrate antidyskinetic properties in individuals with preexisting tardive dyskinesia. The underlying mechanisms remain unclear, and without such information it is not possible to say what clinical conditions, if any, might diminish or even eliminate these advantages.. An update is provided regarding the atypical antipsychotics and tardive dyskinesia. This information is critical in our decision-making regarding choice of antipsychotic and optimal use in the clinical setting.

Topics: Antipsychotic Agents; Brain; Clozapine; Drug-Related Side Effects and Adverse Reactions; Dyskinesia, Drug-Induced; Evidence-Based Medicine; Humans; Neurologic Examination; Product Surveillance, Postmarketing; Risk

Atypical antipsychotics are frequently used as augmentation agents in clozapine-resistant schizophrenic patients. Risperidone (RIS) is the one most studied as a clozapine (CLZ) adjunct. The aim of this study is to critically review all published studies regarding the efficacy and safety of RIS as an adjunctive agent in CLZ-resistant schizophrenic or schizoaffective patients.. A MEDLINE search from January 1988 to June 2005 was conducted. Identified papers were examined against several clinical, pharmacological and methodological parameters.. A total of 15 studies were found (2 randomized controlled trials, 3 open-label trials (OTs) and 8 case-studies (CSs)) comprising 86 schizophrenic or schizoaffective patients (mean age 38.4 years). Mean CLZ dosage during the combined treatment was 474.2 mg/day. Plasma CLZ levels were assessed in 62 patients (72.1%). RIS was added at a mean dosage of 4.6 mg/day for a mean of 7.9 weeks. Significant improvement in psychopathology was reported for 37 patients (43%). A lower RIS dosage and a longer duration of the trial seemed to be associated with a better outcome. Main side effects reported were: extrapyramidal symptoms or akathisia (9.3%), sedation (7%) and hypersalivation (5.8%).. Existing evidence encourages the use of RIS as an adjunctive agent in CLZ-resistant schizophrenic or schizoaffective patients.

Topics: Antipsychotic Agents; Clozapine; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Schizophrenic Psychology; Sialorrhea; Treatment Outcome

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Cognition Disorders; Drug Tolerance; Dyskinesia, Drug-Induced; Haloperidol; Humans; Olanzapine; Piperazines; Quinolones; Risperidone; Schizophrenia; Sulpiride; Time Factors

Tardive dyskinesia (TD), the principal adverse effect of long-term conventional antipsychotic treatment, can be debilitating and, in many cases, persistent. We sought to explore the incidence and management of TD in the era of atypical antipsychotics because it remains an important iatrogenic adverse effect.. We conducted a review of TD incidence and management literature from January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia, management, therapy, neuroleptics, antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Additional articles were obtained by searching the bibliographies of relevant references. We considered articles that contributed to the current understanding of both the incidence of TD with atypical antipsychotics and management strategies for TD.. The incidence of TD is significantly lower with atypical, compared with typical, antipsychotics, but cases of de novo TD have been identified. Evidence suggests that atypical antipsychotic therapy ameliorates long-standing TD. This paper outlines management strategies for TD in patients with schizophrenia.. The literature supports the recommendation that atypical antipsychotics should be the first antipsychotics used in patients who have experienced TD as a result of treatment with conventional antipsychotic agents. The other management strategies discussed may prove useful in certain patients.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Dyskinesia, Drug-Induced; Humans; Incidence; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Thiazoles

Rabbit syndrome is an antipsychotic-induced rhythmic motion of the mouth/lips, resembling the chewing movements of a rabbit. The movement consists of a vertical-only motion, at about 5Hz, with no involvement of the tongue. Usually, the involuntary movements associated with rabbit syndrome appear after a long period (in most cases months or years) of antipsychotic treatment; however, a few patients with the syndrome have had treatment histories with no antipsychotic involvement. The reported prevalence of rabbit syndrome ranges from 2.3 to 4.4% of patients treated with typical antipsychotics. There have been isolated reports of rabbit syndrome in patients treated with the atypical agents risperidone and clozapine. Patients with rabbit syndrome are most often misdiagnosed as having oral tardive dyskinesia. In such cases the key for correct diagnosis is the involvement of tardive tongue movements, which does not occur in rabbit syndrome. The treatment of rabbit syndrome is empirical, reflecting poor understanding of its neuropathology. The first step is to reduce the amount of antipsychotic treatment as much as possible. However, since, in most cases, full withdrawal of antipsychotic treatment is impossible, the syndrome cannot be completely abolished without additional measures. The next stage of treatment involves specific drugs that aim to control the syndrome. Anticholinergic drugs are the best known treatment. Rabbit syndrome does not respond to treatment with levodopa or dopamine agonists. The most striking aspect of this syndrome is its specificity. Rabbit syndrome affects only the buccal region, and within this area it involves a highly stereotyped involuntary movement. This immediately focuses attention on the basal ganglia, in particular the substantia nigra pars reticulata, which is also implicated in oral dyskinesia. Continuing neurophysiological and pharmacological research of the basal ganglia holds the key to better understanding and treatment of this syndrome in the coming years.

Topics: Animals; Antipsychotic Agents; Clozapine; Diagnosis, Differential; Dyskinesia, Drug-Induced; Humans; Rabbits; Risperidone

Tardive dyskinesia is a chronic drug-induced movement disorder that tends to be persistent in older adults who are treated with antipsychotics. Tardive dyskinesia can affect older patients both physically and psychologically, leading to frequent falls, difficulty eating, and depression. While atypical antipsychotics may cause tardive dyskinesia, the percentage is usually significantly lower than with conventional antipsychotics. Using atypical antipsychotics, particularly at lower doses, may aid in preventing symptoms of tardive dyskinesia in older adults.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Incidence; Middle Aged; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia

Central criteria for the definition of atypical antipsychotics are antipsychotic efficacy and minimal or none extrapyramidal symptoms (EPS). This last criterium is of importance in the differentiation with the traditional antipsychotics. Of the four atypical antipsychotics which are discussed here, clozapine is the most atypical. The best proof is its good efficacy in the treatment of Parkinson psychosis with minimal adverse effects on motor function. Clozapine is the best choice for this indication. At this moment there is not enough evidence available concerning quetiapine. Risperidon and olanzapine give more Dopamine2-occupancy with higher doses and can evoke EPS, but this is still less compared to the traditional antipsychotics. All four atypical drugs cause less tardive dyskinesia. Atypical antipsychotics are not well studied in the treatment of elderly patients with functional psychosis. However the available information and the literature on the treatment of young adults makes it probable that the atypical antipsychotics are at least as effective in the elderly as the traditional antipsychotics. The median daily doses are lower for elderly than for younger patients. Risperidon has been proven effective in the treatment of agressive behaviour in dementia. Atypical antipsychotics have their 'own' adverse effects. Those which have the most impact in the elderly are discussed.

Topics: Aged; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Male; Parkinson Disease; Psychotic Disorders; Receptors, Dopamine D2; Treatment Outcome

Pharmacogenetics uses genetic information to tailor drug treatment to the individual, maximizing clinical response and minimizing side effects. Failure to respond to medication and adverse side effects are common problems in psychiatry. Intolerable side effects can lead to discontinuation of medication. Individual genetic differences can determine both clinical responses to medications and the adverse side effects experienced. To fully predict clinical response to psychotropic drug treatment we must consider social, demographic and clinical factors such as compliance, social support and history of birth trauma, in addition to genetic influence on susceptibility and etiology.

Topics: Antipsychotic Agents; Clozapine; Cytochrome P-450 Enzyme System; Drug Resistance; Dyskinesia, Drug-Induced; Haloperidol; Humans; Pharmacogenetics; Polymorphism, Genetic; Schizophrenia; Weight Gain

Data from clinical trials reviewed in this article fulfill predictions based on preclinical findings that atypical antipsychotic drugs are associated with a reduced potential for inducing extrapyramidal symptoms (EPS) and other movement disorders. Atypical drugs have been shown to reduce all subtypes of acute EPS, the frequency of EPS-related patient dropouts, and the need for concomitant antiparkinsonian drug use. Clozapine remains superior to other atypicals in treating psychosis without worsening motor symptoms in patients with Parkinson's disease. Atypicals may be selectively advantageous in treating schizophrenic patients with a predisposition to catatonia. Although the risk of developing lethal neuroleptic malignant syndrome may be diminished with atypical drugs, clinicians must remain alert to the signs of this disorder. Atypicals have reduced liability for inducing tardive dyskinesia (TD) and show antidyskinetic properties in patients with preexisting TD. Passive resolution of TD may be facilitated in some patients by the use of these agents. Thus, the risk of movement disorders has become only one of several considerations in choosing among antipsychotic drugs.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Humans; Neuroleptic Malignant Syndrome; Neurotoxicity Syndromes; Olanzapine; Pirenzepine; Risperidone

Currently, tardive dyskinesia (TD) remains an important clinical problem. The average prevalence is estimated at 30%. The appearance of antipsychotics has opened new paths. The extrapyramidal profile of these molecules is more favorable than that of conventional neuroleptics. In order to assess their prophylactic as well as curative potential, we reviewed the literature concerning four of these atypical antipsychotics: clozapine, risperidone olanzapine and amisulpride. Clozapine seems to induce fewer cases of TD than the conventional neuroleptics, and has a specific therapeutic effect. However, the risk of agranulocytosis reduces the possibility of utilisation. Risperidone appears to be an effective therapy, but several authors report cases of TD during treatment. Furthermore, larger studies and longer follow-ups are necessary to confirm the efficiency of olanzapine and amisulpride. Further studies and observations are still necessary before drawing any conclusion for these new atypical antipsychotic actions. They are doubtlessly promising, but we cannot ignore the notion of risk-benefit; regular monitoring and listening to the subjective experience of the patients must remain uppermost in the choice of therapy.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Humans; Olanzapine; Pirenzepine; Prevalence; Psychotic Disorders; Risperidone; Sulpiride

Four new antipsychotic medications--clozapine, risperidone, olanzapine, and quetiapine--have been introduced in the United States during the past decade. These new medications now account for the majority of antipsychotic prescriptions. The author reviews specific issues related to the use of traditional antipsychotic medications and then highlights the emerging clinical research data regarding the new medications, which have all been shown to be efficacious in the treatment of schizophrenia. Clinical research data indicate that they are also more useful for a broader array of symptoms associated with schizophrenia than traditional compounds. Furthermore, movement disorder side effects are substantially decreased--a property that leads to higher acceptability. Surprisingly, there has been little relationship between the pivotal trials designed for FDA approval and current dosing strategies in broader clinical settings. These dosing issues are described. New uses, including treatment of mood disorders and conduct disorder, are also discussed. These medicines offer substantial hope for improved treatment of schizophrenia.

Topics: Agranulocytosis; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Humans; Olanzapine; Pirenzepine; Prolactin; Quetiapine Fumarate; Risperidone; Schizophrenia

Given the problematic nature of tardive dyskinesia in persons taking conventional antipsychotics, evaluation of newer atypical antipsychotic agents should include a systematic assessment of tardive dyskinesia liability. Results of a prospective double-blind, randomized study of schizophrenic patients who participated in 3 preclinical olanzapine studies and were treated with 5 to 20 mg/day of olanzapine (N = 1192) or haloperidol (N = 522) recently indicated a significantly lower risk of development of tardive dyskinesia with olanzapine treatment than haloperidol treatment. This article discusses the known effects of atypical antipsychotic medications on tardive dyskinesia movements (both withdrawal and persistent) and the incidence rate of tardive dyskinesia among schizophrenic patients undergoing long-term treatment with olanzapine or haloperidol.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Drug Administration Schedule; Dyskinesia, Drug-Induced; Haloperidol; Humans; Incidence; Molindone; Olanzapine; Pirenzepine; Prospective Studies; Risk Factors; Risperidone; Schizophrenia; Substance Withdrawal Syndrome; Survival Analysis

The enthusiasm produced by the introduction of antipsychotic medication in the 1950s gave way to a certain frustration in the 1970s and 1980s. Despite the development of a large number of new drugs, little progress was made in treatment because these new agents were, in essence, therapeutically equivalent. This lack of progress was perhaps also related to an emphasis on tardive dyskinesia in the 1970s, i.e., the preoccupation with a negative effect of treatment. The reverse is taking place today. Clozapine and the other atypical antipsychotics are associated in people's minds with fewer or absent extrapyramidal symptoms and less tardive dyskinesia than the older typical agents. As a result, a certain amount of complacency exists. Tardive dyskinesia not only may be painful and disfiguring, but it also predicts poor outcome in patients with schizophrenia. Although many treatments have been tried, none have proven completely efficacious. The best treatment for tardive dyskinesia and dystonia is prevention, which is a function of medication choice. Pharmacologic interventions for tardive dyskinesia include clozapine and the other atypical antipsychotics. If typical antipsychotics must be used, they should be started at the lowest possible levels. Studies of risperidone suggest that it, too, should be used at very low doses to minimize the risk of tardive dyskinesia. It is also possible that schizophrenic patients taking atypical antipsychotics may experience fewer spontaneous dyskinesias, although further study is warranted.

Topics: Adult; Akathisia, Drug-Induced; Algorithms; Antipsychotic Agents; Benzodiazepines; Clozapine; Decision Trees; Drug Administration Schedule; Dyskinesia, Drug-Induced; Dystonia; Female; Humans; Male; Olanzapine; Pirenzepine; Probability; Reserpine; Risperidone; Schizophrenia; Substance Withdrawal Syndrome; Tetrabenazine; Treatment Outcome; Vitamin E

The results of controlled studies of the efficacy of the new atypical neuroleptics in treating negative symptoms show that these antipsychotics have a more pronounced effect on negative symptoms in acute schizophrenic patients than the classical neuroleptics. Supplementary complex statistical analyses substantiate that the increased efficacy of the atypical neuroleptics in treating negative symptoms can only partially be explained by indirect effects of better extrapyramidal tolerability, better effects on productive psychotic symptoms, etc. Instead, it is due largely to the stronger direct effect of these atypical neuroleptics. Clinical studies to evaluate their efficacy in chronic schizophrenic patients with stable, predominantly negative symptoms are still mostly lacking. First results support the presumption that atypical neuroleptics have a direct effect. Parallel to the evaluation of the new atypical neuroleptics, important progress has been made in the methodology of clinical studies in this area.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Double-Blind Method; Dyskinesia, Drug-Induced; Humans; Imidazoles; Indoles; Neurotransmitter Agents; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Schizophrenic Psychology; Sulpiride; Thiazoles

Elderly patients with schizophrenia and dementia patients with agitation are frequently candidates for antipsychotic treatment. Conventional neuroleptics have relatively little effect on negative symptoms and may cause considerable side effects, especially in elderly patients. The authors have found a 29% cumulative annual incidence of tardive dyskinesia (TD) in middle-aged and elderly outpatients treated with relatively low doses of conventional neuroleptics Newer antipsychotics are less likely to cause extrapyramidal symptoms and may be associated with a lower risk of TD. They are generally effective for both positive and negative symptoms and may also improve some aspects of cognition, but these drugs have their own side effects. Dosing requirements for elderly patients tend to be much lower than those for younger adults.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Dementia; Dibenzothiazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia

The past 5 years have witnessed an intense period of change in the pharmacotherapy of schizophrenia. Several new antipsychotic agents have become available for clinical use, and more are likely to appear over the next few years. The new agents require that clinicians treating patients with schizophrenia adopt new ways of thinking regarding the pharmacotherapy of this illness. Longer drug trials than have traditionally been used may be required to determine response to the newer agents, and response should be measured across negative symptoms, cognitive symptoms, and broader rehabilitative dimensions. Clozapine has an established role in treatment-resistant schizophrenia. Other new antipsychotics are being used with broader clinical indications. The relative efficacy of these agents, particularly in treatment-refractory patients, remains to be determined. The availability of the newer agents may represent an opportunity to reduce the incidence of tardive dyskinesia and to gain better management of comorbid substance abuse and aggression among schizophrenic patients. Significant cost savings could accrue from more effective disease management.

Topics: Aggression; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Comorbidity; Cost-Benefit Analysis; Drug Costs; Dyskinesia, Drug-Induced; Health Care Costs; Humans; Schizophrenia; Schizophrenic Psychology; Substance-Related Disorders; Treatment Outcome

Typical antipsychotic agents produce central nervous system effects, especially extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Nearly every patient who receives neuroleptic therapy has one or more identifiable risk factors for TD, among the most significant of which are older age, female gender, presence of EPS, diabetes mellitus, affective disorders, and certain parameters of neuroleptic exposure (i.e. dose and duration of therapy). The typical course of TD is a gradual onset after several years of drug therapy, followed by slow improvement or remission, but a large number of patients have persistent TD with irreversible symptoms. In the management of TD, the patient's mental status is of primary concern. Currently, no uniformly safe and effective therapies for TD exist, though a variety of therapeutic agents, including some of the atypical neuroleptics, have been reported to treat TD successfully in some patients. Because TD liability is so much lower with novel antipsychotic therapy, all patients who have TD or are at risk for TD, as well as EPS, should be considered candidates for switching to these new drugs.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Sex Factors

Antipsychotic medications are among the most widely prescribed class of medications for elderly patients. Despite their high use, few studies document the efficacy, safety, and tolerability of these agents in this patient population. This is unfortunate because, as a group, the elderly are exceptionally sensitive to the adverse effects associated with antipsychotics, in particular, the extrapyramidal side effects (EPS). The atypical antipsychotics with their lower propensity to cause EPS and lower need for augmenting anticholinergic medication have introduced new options for elderly patients who need antipsychotic therapy for a number of psychiatric and neurologic disorders with psychotic manifestations. This review covers the pharmacologic, clinical, and regulatory issues involving antipsychotic use in elderly patients that warrant consideration by the practicing psychiatrist.

Topics: Accidental Falls; Age Factors; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Drug Costs; Drug Interactions; Dyskinesia, Drug-Induced; Humans; Hyperprolactinemia; Osteoporosis; Psychotic Disorders; Weight Gain

In addition to their neurochemical effects, antipsychotic (neuroleptic) drugs produce structural brain changes. This property is relevant not only for understanding the drugs' mode of action, but because it complicates morphological studies of schizophrenia. Here the histological neuropathological effects of antipsychotics are reviewed, together with brief mention of those produced by other treatments sometimes used in schizophrenia (electroconvulsive shock, lithium and antidepressants). Most data come from drug-treated rats, though there are also some human post-mortem studies with broadly congruent findings. The main alteration associated with antipsychotic medication concerns the ultrastructure and proportion of synaptic subpopulations in the caudate nucleus. In rats, synapses and dendrites in lamina VI of the prefrontal cortex are also affected. The changes are indicative of a drug-induced synaptic plasticity, although the underlying mechanisms are poorly understood. Similarly, it is unclear whether the neuropathological features relate primarily to the therapeutic action of antipsychotics or, more likely, to their predisposition to cause tardive dyskinesia and other motor side-effects. Clozapine seems to cause lesser and somewhat different alterations than do typical antipsychotics, albeit based on few data. There is no good evidence that antipsychotics cause neuronal loss or gliosis, nor that they promote neurofibrillary tangle formation or other features of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Caudate Nucleus; Clozapine; Dyskinesia, Drug-Induced; Humans; Neuronal Plasticity; Rats; Schizophrenia

Suicide is the major cause of premature death in patients with schizophrenia. Among these patients, 40% report suicidal thoughts, 20% to 40% make unsuccessful suicide attempts, and 9% to 13% end their lives by suicide. Traditional antipsychotic drugs undertreat many schizophrenic patients and can produce serious side effects, such as tardive dyskinesia. Clozapine is the only antipsychotic drug that has been shown in controlled clinical trials to be effective in reducing both positive and negative symptoms in schizophrenic patients who fail to respond to typical neuroleptic drugs. The potential decrease in suicide among schizophrenic patients treated with clozapine is estimated to be as high as 85%. Treatment with clozapine is cost-effective, and the significant decrease in the risk of suicide far outweighs the very low risk of mortality from agranulocytosis. Clozapine should be considered for treatment of both neuroleptic-resistant and neuroleptic-responsive schizophrenic patients who have persistent suicidal thoughts or behavior.

Topics: Adult; Aged; Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Cost-Benefit Analysis; Dyskinesia, Drug-Induced; Female; Humans; Infant, Newborn; Male; Middle Aged; Risk Assessment; Risk Factors; Schizophrenia; Schizophrenic Psychology; Suicide; Suicide Prevention

Neuroleptics were the first modern class of pharmacotherapeutic agents available for the treatment of schizophrenia. Although they were effective in reducing florid psychotic symptoms, up to 90% of treated individuals subsequently developed extrapyramidal symptoms (EPS) (akathisia, dystonia, or parkinsonism), and about 20% developed tardive dyskinesia (TD). When clozapine became commercially available for treatment-resistant and treatment-intolerant (i.e., prone to EPS and TD) schizophrenic individuals, it became apparent that an antipsychotic need not induce motor side effects to be efficacious in reducing the symptomatology of schizophrenia. Sociodemographic, behavioral, and clinical predictors of TD are useful in identifying a subset of schizophrenic individuals who would benefit from treatment with clozapine, the prototype atypical antipsychotic whose efficacy and motor side effect profile are superior to those of chlorpromazine. This favorable motor side effect profile of clozapine contributes to improved patient outcomes by reducing noncompliance, substance abuse, and suicide, resulting in improved quality of life and savings on health care costs.

Topics: Age Factors; Aged; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Prevalence; Risk Factors; Schizophrenia; Substance-Related Disorders; Suicide; Suicide Prevention; Treatment Outcome; Treatment Refusal

Antipsychotic medications are the mainstay of treatment for schizophrenia. The recent advent of atypical antipsychotics has provided new clinical options and set higher expectations for the treatment of schizophrenia. It is not yet clear how each different drug will fit within the therapeutic armamentarium and this lack is most evident with considering patients with treatment refractory schizophrenia. On the other hand, the expectation of superior efficacy, more benign side effect profile and potential to impact the longitudinal course of schizophrenia provide a rationale for the use of novel antipsychotics as a first-line treatment of schizophrenia.

Topics: Antipsychotic Agents; Behavioral Symptoms; Benzodiazepines; Clozapine; Dibenzothiazepines; Dopamine Antagonists; Drug Resistance; Dyskinesia, Drug-Induced; Humans; Neurobehavioral Manifestations; Olanzapine; Pirenzepine; Psychopharmacology; Quetiapine Fumarate; Schizophrenia; Serotonin Antagonists

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.

Topics: Antipsychotic Agents; Binding, Competitive; Cholinergic Antagonists; Clozapine; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Resistance; Dyskinesia, Drug-Induced; Humans; Levodopa; Ligands; Limbic System; Nerve Tissue Proteins; Parkinson Disease, Secondary; Protein Binding; Psychoses, Substance-Induced; Psychotic Disorders; Radioligand Assay; Receptors, Dopamine D2; Receptors, Muscarinic; Receptors, Serotonin; Recurrence; Serotonin Antagonists; Tomography, Emission-Computed

Clozapine has been found to be superior to traditional neuroleptics in the treatment of refractory schizophrenia and is increasingly being used to treat schizophrenia, affective disorders, some neurological disorders, and aggression. For many patients, clozapine offers new hope for the successful pharmacological management of a disabling mental disorder. However, up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects, which also limit the rate at which the dose can be increased and the maximum dose that can be tolerated. This article reviews strategies for minimizing and managing the adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects. Incidence and morbidity are presented first. Then, the known or hypothesized pathophysiology of the adverse effects are described. Finally, nonpharmacological and pharmacological interventions are reviewed. Under-standing the incidence, pathophysiology, and treatments of adverse effects is essential for a positive therapeutic outcome when prescribing clozapine.

Topics: Agranulocytosis; Antipsychotic Agents; Cardiovascular Diseases; Central Nervous System Diseases; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Gastrointestinal Diseases; Humans; Schizophrenia

To review the existing literature on the efficacy and tolerability of antipsychotics for adolescent psychosis. The review focuses in particular on literature regarding adverse effects that are thought to have an increased incidence in young patients and on the possible neurobiological bases for such differential sensitivity.. Pertinent studies were sought using Medline searches, supplemented by selected bibliographies, and reviewed.. There is a relative paucity of research in this area; in particular, well-controlled trails are lacking. The existing literature suggests fairly good efficacy of both typical and atypical antipsychotics in the treatment of psychotic disorders in children and adolescents. However, the incidence of certain side effects, particularly extrapyramidal symptoms (EPS). is found to be higher in younger patients compared with adults. Positron emission tomography (PET) receptor studies in adults have demonstrated that the incidence of EPS is related to dose-dependent dopamine type-2 (D2) receptor occupancy and that there is a significant relationship between the number of these receptors and age.. Improved tolerability is leading to the increasing us of atypical antipsychotics for adolescent patients, though these new drugs to have specific adverse effects of their own. There is a need for more controlled studies of atypical antipsychotics in children and adolescents. In particular, dose-finding studies are needed to determine the optimal dose range to produce the greatest improvement with the least side effects for each of these drugs.

Topics: Adolescent; Adolescent Psychiatry; Age Factors; Antipsychotic Agents; Benzodiazepines; Cholinergic Fibers; Clozapine; Controlled Clinical Trials as Topic; Corpus Striatum; Disease Susceptibility; Dyskinesia, Drug-Induced; Humans; Olanzapine; Pirenzepine; Receptors, Dopamine D2; Risperidone; Schizophrenia; Tomography, Emission-Computed

Adverse effects of antipsychotics often lead to noncompliance. Thus, clinicians should address patients' concerns about adverse effects and attempt to choose medications that will improve their patients' quality of life as well as overall health. The side effect profiles of the atypical antipsychotics are more advantageous than those of the conventional neuroleptics. Conventional agents are associated with unwanted central nervous system effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sedation, and possible impairment of some cognitive measures, as well as cardiac effects, orthostatic hypotension, hepatic changes, anticholinergic side effects, sexual dysfunction, and weight gain. The newer atypical agents have a lower risk of EPS, but are associated in varying degrees with sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only). Since the incidence and severity of specific adverse effects differ among the various atypicals, the clinician should carefully consider which side effects are most likely to lead to the individual's dissatisfaction and noncompliance before choosing an antipsychotic for a particular patient.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Central Nervous System Diseases; Clozapine; Dibenzothiazepines; Drug Interactions; Dyskinesia, Drug-Induced; Health Status; Humans; Hypotension, Orthostatic; Olanzapine; Pirenzepine; Quality of Life; Quetiapine Fumarate; Receptors, Cholinergic; Risperidone; Schizophrenia; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Refusal; Weight Gain

The incidence of acute extrapyramidal symptoms (EPS)--akathisia, dystonia, and parkinsonism--associated with traditional antipsychotics varies, but most researchers agree that neuroleptic-induced EPS occur in 50% to 75% of patients who take conventional antipsychotics. Atypical antipsychotics were developed to widen the therapeutic index and to reduce EPS. Although the mechanisms are unclear, the risk of EPS is less with the novel antipsychotics than with conventional drugs, and agents that produce low levels of acute EPS are likely to produce less tardive dyskinesia. Nevertheless, clinicians should exercise caution when comparing data from investigations of the novel antipsychotics and, until long-term data become available, should administer the new drugs at doses below the EPS-producing level.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Dystonia; Humans; Olanzapine; Parkinson Disease, Secondary; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Schizophrenia; Substance Withdrawal Syndrome

Severe psychotic decompensation during clozapine withdrawal has been reported previously. Less attention has been paid to movement disorders following abrupt clozapine withdrawal. This report describes 4 subjects who experienced severe dystonias and dyskinesias upon abrupt clozapine withdrawal.. Current and past medical records of 4 subjects with DSM-IV schizophrenia or schizo-affective disorder were reviewed.. All subjects had a history of neuroleptic-induced extrapyramidal symptoms, 1 had a history of severe dystonias, and 1 had neuroleptic malignant syndrome. All had mild orolingual tardive dyskinesia prior to clozapine treatment. All subjects had received clozapine for several months, and 3 of the 4 subjects stopped clozapine abruptly. Two subjects experienced cholinergic rebound symptoms within hours, which resolved quickly. These subjects had severe limb-axial and neck dystonias and dyskinesias 5 to 14 days after clozapine withdrawal. Two subjects were unable to ambulate, and 1 had a lurching gait. Two gagged while eating or drinking. Two subjects were returned to clozapine, 1 was started on low-dose risperidone treatment, and 1 was started on olanzapine treatment. All experienced significant improvements in their mental state and movement disorders.. Severe movement disorders, which may be worse than the movements prior to clozapine treatment, and cholinergic rebound symptoms may occur upon abrupt clozapine withdrawal and must be recognized in addition to the severe psychotic decompensation noted in some patients. Patients, families, and caregivers must be alerted to this possibility. Where possible, a slow clozapine taper, the use of anticholinergic agents, and symptomatic treatment may help minimize these withdrawal symptoms, and reintroduction of clozapine or treatment with the newer atypical agents can help in the clinical management of these symptoms.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Dystonia; Female; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

Clozapine, the only commercially available atypical neuroleptic, is approved for the treatment of schizophrenic patients who are unresponsive to or intolerant of typical neuroleptics. It has an unusual pharmacologic profile compared with standard neuroleptics, and it follows that clinical response to this drug is also different. It has shattered the notion that a drug must be capable of inducing or worsening parkinsonism to be a potent antipsychotic. Based on these findings, it is being used increasingly by neurologists for psychiatric and nonpsychiatric problems in patients with movement disorders. The most common use for clozapine among neurologists is in the management of drug-induced psychosis in Parkinson's disease (PD). This problem has been a source of increased morbidity and mortality in PD because of a lack of adequate therapeutic intervention. At this time, because of success in numerous open trials, with improvement of > 80% of patients, clozapine therapy for psychosis in PD is becoming the standard of care. It also appears to be of value in the management of some motor features of PD, including tremors and dyskinesia and possibly even sensory symptoms such as akathisia and pain. The literature also suggests that clozapine may be of potential benefit in hyperkinetic movement disorders including essential tremor, Huntington's disease, and tardive dyskinesia. We review the current data concerning the use of clozapine in patients with these movement disorders and others.

Topics: Antiparkinson Agents; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dyskinesia, Drug-Induced; Humans; Huntington Disease; Movement Disorders; Parkinson Disease; Psychotic Disorders; Tremor

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

Tardive dyskinesia (TD) is the most feared and troublesome extrapyramidal side-effect of prolonged neuroleptic (NL) treatment. We present a review of TD. Its pathophysiology remains elusive, although extrapyramidal symptoms (EPS) increase the liability for TD. Nowadays, therefore, avoidance of all EPS remains the best preventive strategy, as it is not possible to predict which liable patients will develop TD, or of what type or severity. TD frequently includes dystonic features, and is more disabling when these dystonias are present. Clozapine (CLZ) has been reported to be effective in suppressing nearly 60% of TD syndromes, specially those with dystonic features. Based on the few reports in the literature on CLZ and TD by the early 1980s, we started to videotape the first severe TD patient treated with CLZ in 1984. We present the first three case reports of severe TD, with prominent disabling dystonic features, treated with CLZ and videotaped since pretreatment and then periodically for 12, 8 and 5 years of follow-up, respectively. The patients' current diagnosis, gender and age are: Case 1, DSM-IV Schizophrenia Residual Type, male, 39 years; Case 2, DSM-IV Polysubstance Related Disorder, Borderline Personality Disorder, female, 28 years; Case 3, DSM-IV Schizoaffective Disorder, male, 40 years. Two of them presented with a recurrence of TD because of CLZ interruption within the first 2 months of treatment, with no further breakthrough to date. The first two cases have complete remission of TD; the third case is still improving after 5 years of CLZ treatment, with only minor dystonic features persisting that constitute no impairment for work or daily routines at present. All patients, independent of their psychiatric primary diagnosis, have shown significant and progressive improvement in both motor and psychosocial aspects. None of them has been rehospitalized. Long-term treatment and follow-up is required to avoid TD recurrence and to assure full assessment of treatment effectiveness. Ideally, periodic video recording with standardized examination is advisable for long-term follow-up and outcome assessment. At present, CLZ could be regarded as the drug of choice for patients with TD, specially for those with disabling and or dystonic features and who require ongoing NL therapy. The use of novel antipsychotic agents for TD treatment and prevention, with their low EPS liability, is promising, but has yet to be tested.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Schizophrenia; Substance-Related Disorders; Videotape Recording

Treatment-resistant schizophrenia is the object of intense interest because of recent developments in its treatment and aetiology. The actual definition of treatment-resistant schizophrenia is, however, still controversial. It should reflect the legitimate and varied needs and perspectives of people with schizophrenia, their family members, mental health care givers, mental health administrators, public health officials, and those who fund the direct and indirect costs of treating schizophrenia. The most common definition of treatment-resistant schizophrenia denotes patients with schizophrenia who, despite at least two adequate trials of classical neuroleptic drugs, have persistent moderate to severe positive, or disorganisation, or negative symptoms together with poor social and work function over a prolonged period of time. This definition reflects the viewpoint of people with this illness, their family members, and mental health care givers. Approximately 30% (range 10-45%) of schizophrenic patients meet these criteria. While this definition is adequate for many purposes, it should be realised that the remaining 70% of schizophrenic patients, whose positive symptoms respond adequately to neuroleptic treatment, may also have clinically significant negative symptoms, poor social and work function, clinically significant cognitive dysfunction, poor quality of life relative to the normal population, and constitute a significant burden to family and society. The lifetime suicide rate in both treatment-resistant and responsive schizophrenic patients is 9-13%, indicating that conventional definitions of neuroleptic response do not convey lower risk of suicide. However, before defining a patient as treatment resistant, it is important to consider whether the patient has received an inadequate duration of treatment, and/or too low, or possibly too high, doses of neuroleptic drugs. Using these stringent criteria, treatment resistance may be present at the time of initial diagnosis and treatment, but if not present initially, it will usually develop subsequently-sometimes not until after multiple acute exacerbations over a period of years. During the first months and years after the diagnosis of schizophrenia has been made, clinicians should be especially alert in identifying a patient as treatment resistant in order to diminish the severe social disability and suicidality which may ensue if it is not recognised and correctly treated. Once present, treatment resi

Topics: Adolescent; Adult; Antipsychotic Agents; Child; Clinical Trials as Topic; Clozapine; Cognition; Cost-Benefit Analysis; Drug Resistance, Multiple; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Patient Compliance; Quality of Life; Schizophrenia; Treatment Outcome

The causes and the pathogenesis of tardive dyskinesia are not well understood. There is no therapy currently available that has been shown to alter the overall course. However, it is possible to influence the development or the progression of this disorder. A decision tree of feasible therapeutic choices is presented here, to prevent or treat tardive dyskinesia in patients who need long term neuroleptic therapy.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Long-Term Care; Neurologic Examination; Schizophrenia; Substance Withdrawal Syndrome

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

Standard neuroleptic medications have been augmented by the introduction of risperidone and clozapine into clinical practice. A great deal of attention has also been focused on efficacy and the lower propensity to extrapyramidal side-effects associated with the new agents. However, antipsychotic medication, both old and new, can cause a range of other adverse effects, some of which are serious, and many of which have the potential greatly to diminish the quality of life of patients who need to take medication in the long term. Of particular significance are postural hypotension, cardiotoxicity, peripheral and central anticholinergic effects, sedation, weight gain, and endocrine and haematological effects. Various antipsychotic compounds differ substantially with regard to propensity to adverse effects. Side-effects can be minimized by optimization of clinical strategies, including choice of appropriate drug, slow titration and dosage reduction. It is also vital to explain carefully to both patients and carers the nature of the side-effects which can be anticipated. The choice of antipsychotic is often determined by evaluation of the potential impact of the various adverse effects on a particular patient. New drugs, such as risperidone, are well tolerated, with fewer side-effects, and should now be considered as a first-line option.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Neurologic Examination; Patient Education as Topic; Risperidone; Schizophrenia

The neurological effects of neuroleptic drugs are well known from the very beginning of their history and are even part of the initial definition of this therapeutic class. However, these effects are not necessary for an antipsychotic efficacy as demonstrated by the fully effective "atypical" neuroleptics, which induce minimal neurological side-effects. The neurobiological mechanisms underlying this "atypicity" are not well elucidated but could involve a preferential action on mesocorticolimbic dopaminergic system. This preferential action on mesocorticolimbic dopaminergic system. This specificity of action seem especially interesting in the case of patients suffering of severe tardive dyskinesia. Hence, the absence of rebond of preexistent dyskinesia when stopping a long term treatment with clozapine suggest that the pursuit of neuroleptic with this substance in dyskinetic patients would not worsen the long term prognosis of their dyskinesia. Available data on other atypical neuroleptics are insufficient to conclude if this benefit action on tardive dyskinesia is specific of clozapine or shared with other new neuroleptics.

Topics: Antipsychotic Agents; Brain; Clozapine; Dyskinesia, Drug-Induced; Humans; Nervous System Diseases; Neurologic Examination; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Brain; Clozapine; Dyskinesia, Drug-Induced; Extrapyramidal Tracts; Humans; Isoxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, Dopamine; Receptors, Serotonin; Remoxipride; Risperidone; Schizophrenia; Schizophrenic Psychology

Although antipsychotic drugs are the mainstay of treatment in older patients with schizophrenia, much of the theoretical work underpinning their use is based on evidence gained from younger patients. With respect to dosages, there has been little work comparing plasma concentrations of antipsychotics in older patients with those of younger patients. However, there are well documented changes in the pharmacokinetics of these drugs in the elderly, particularly in their hepatic metabolism and renal excretion. There is also evidence that older patients experience more adverse effects from antipsychotics than younger patients. Such effects include extrapyramidal symptoms, postural hypotension and falls. For these reasons it is recommended that starting doses of antipsychotic drugs in older patients should be in the region of 25 to 50% of that recommended for younger patients, and should be slowly increased. Selection of a particular antipsychotic agent is best made on the basis of individual patient characteristics and the adverse effect profiles of particular drugs.

Topics: Aged; Aging; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Drug Prescriptions; Dyskinesia, Drug-Induced; Dystonia; Humans; Parkinson Disease, Secondary; Schizophrenia

Recent research on the role of clozapine in the treatment of Parkinson's disease and other movement disorders is discussed. Most clinical trials have shown resolution of or improvement in psychotic symptoms accompanying Parkinson's disease without worsening of parkinsonian symptoms. Adverse effects appear to be mild at dosages of < 100 mg/day; sedation is the most frequent problem. Most of these studies have serious limitations, however; until better studies have been completed, the decision to use clozapine for Parkinson's disease-related psychosis should be made on a case-by-case basis, with thorough evaluation of risks, benefits, and other therapeutic options. Some patients with Parkinson's disease have shown improvement in tremor and other abnormal movements when given clozapine. Clozapine cannot be recommended for treating tardive dyskinesia on the basis of the research done so far; some trials show dramatic resolution of symptoms, others no benefit. Anticholinergics or dopamine-reuptake inhibitors should be considered before clozapine is given to patients with tardive dyskinesia because of clozapine's potential for serious adverse effects. A few patients with Huntington's disease have responded to clozapine, but again no conclusions can be drawn. Clozapine appears to offer no real advantage over haloperidol for treating choreiform movements in Huntington's disease. The frequency of tics in Tourette's syndrome does not seem to be reduced by clozapine. Clozapine has shown some efficacy as a treatment for psychosis and abnormal movements in Parkinson's disease. Results have been less promising for other movement disorders. Further study in larger populations is needed before any definitive conclusions about clozapine's place in movement disorder therapy can be made.

Topics: Clinical Trials as Topic; Clozapine; Dyskinesia, Drug-Induced; Humans; Huntington Disease; Movement Disorders; Neurocognitive Disorders; Parkinson Disease; Tourette Syndrome

The introduction of neuroleptics over 40 years ago was a landmark in medical history. Although effective, antipsychotics have many side-effects, some severe. Because of the great needs in this therapeutic area, there has been a risk of viewing the introduction of new agents such as clozapine as panaceas. The true advantages of the new atypical neuroleptics need to be assessed realistically, by critically evaluating their effects on positive and negative symptomatology, potential adverse effects and cost benefit. Due in part to the toxic effects of neuroleptics, obtaining consent to treatment is fraught with complexities of a legal and ethical nature. However, despite the many burdensome aspects of this disease, including the high risk of suicide among patients, clinicians should foster patients insight and a collaborative approach to coping with schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Ethics, Medical; Humans; Informed Consent; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

A number of new agents to treat schizophrenia have been, or will soon be, introduced that address the limitations of traditional neuroleptics. The new class of atypical neuroleptics promises better efficacy and/or side-effects profiles, leading to improved overall clinical outcomes. However, in order to assess the potential clinical value of these new therapies, it is important not only to study the results of various clinical trials, but also to analyze the methodology and design of the trials themselves. An understanding of the relevant patient-related issues, outcome measures, pharmacological and non-pharmacological factors is necessary to apply the findings of clinical trials to daily clinical practice.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Dyskinesia, Drug-Induced; Humans; Isoxazoles; Neurologic Examination; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Since the introduction of chlorpromazine in the 1950s, neuroleptic medications have been the mainstay of treatment of schizophrenia and other psychotic disorders. These medications do not always lead to complete remission of symptoms but they have allowed many patients to lead more productive and satisfying lives away from the restrictions of chronic hospitalisation. However, neuroleptics are associated with a number of adverse effects that can compromise their effectiveness. Extrapyramidal adverse effects include acute dystonic reactions, neuroleptic-induced Parkinsonism and akathisia. They can often be treated with neuroleptic dose reduction, addition of anticholinergic or beta-blocking agents, or medication change. Later-onset movement disorders such as tardive dyskinesia or dystonia require careful evaluation and may be treated with dose reduction or change of neuroleptic to an atypical agent. Potentially fatal reactions such as agranulocytosis and neuroleptic malignant syndrome can rarely occur and often require significant medical intervention. Clozapine offers some advantages over 'typical' neuroleptics but has a unique adverse effect profile which includes agranulocytosis.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Neuroleptic Malignant Syndrome; Parasympathetic Nervous System; Parkinson Disease, Secondary

The pharmacologic treatment of the schizophrenic patient has remained substantively unchanged during the last 35 years. It is evident that as our knowledge of neuropharmacology has grown--the notion of schizophrenia being merely caused by a hyperdopaminergic state may be too simplistic. Multiple neurotransmitter systems may be involved in the manifestations of this illness. Conventional neuroleptics--the mainstay of antipsychotic treatment--have proved to be only partially effective and their untoward side effects have led to notorious patient noncompliance and iatrogenic morbidity. The demonstration that clozapine possesses both increased efficacy and reduced neurotoxicity, however, has forever altered the conventional wisdom that held all antipsychotics to be equally efficacious and uniformly neurotoxic. The pharmacologic legacy of clozapine promises to provide clinicians with biologic therapies that are at once safe, effective, and easy to administer.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Long-Term Care; Neurologic Examination; Schizophrenia; Schizophrenic Psychology

Essential fatty acids (EFAs) and their eicosanoid derivatives are important constituents of the brain and regulators of neuronal function. There is direct and indirect evidence of impaired metabolism of prostaglandin (PG)E1 in schizophrenia. There is also direct evidence of abnormal EFA biochemistry with plasma phospholipids from five populations and brain phospholipids from another all showing reduced levels of linoleic acid and elevated levels of 22-carbon EFAs of both n-6 and n-3 series. Clinical trials of PGE1 and of the PGE1 precursors, gamma-linolenic acid (GLA) and dihomo-gamma-linolenic acid (DGLA) have shown modest therapeutic effects. In view of lack of therapeutic process involving drugs based on the dopamine concept of schizophrenia, it is time for new approaches based on the EFA/PG concept to be evaluated thoroughly.

Topics: Alprostadil; Brain Chemistry; Clozapine; Diabetes Complications; Dietary Fats; Dopamine; Double-Blind Method; Dyskinesia, Drug-Induced; Eicosanoids; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Linolenic Acids; Niacin; Phospholipids; Schizophrenia

One of the main advantages of clozapine is that it rarely produces extrapyramidal syndromes and tardive dyskinesia. This advantage is linked to the atypical biochemical profile of clozapine, especially its combined and low blockade of D1 and D2 receptors. The level of D2 receptor blockade is too low to induce extrapyramidal side-effects, and D1 antagonists have a lower extrapyramidal side-effect potential than traditional D2 neuroleptics, especially with respect to dystonia. The combined and balanced D1/D2 receptor blockade may prevent the development of a dysbalance between D1/D2 receptor function (in favour of D1) which otherwise might lead to tardive dyskinesia.

Topics: Animals; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Female; Haplorhini; Humans; Male; Receptors, Dopamine

Various outcome measures following clozapine administration to neuroleptic-resistant schizophrenic patients are considered. The importance of a multidimensional perspective is emphasised. There was significant improvement in positive symptoms, some negative symptoms, quality of life, some types of cognitive function (e.g. semantic memory), extrapyramidal function, and tardive dyskinesia. Readmission to hospital, and family burden were markedly reduced, which achieved significant savings in the cost of treatment. Compliance with clozapine and weekly blood testing can be achieved in the majority of treatment-resistant cases. These benefits may occur independently of each other.

Topics: Adult; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Patient Compliance; Patient Readmission; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine is a neuroleptic agent whose structure consists of a dibenzodiazepine derivative with a piperazinyl side chain. It has been classified as an atypical neuroleptic drug due to its unique neuropharmacologic profile. Clozapine has a weak binding affinity for dopamine D-1 and D-2 receptors by its slightly greater preference for D-1 receptors, as noted with a D-1:D-2 receptor binding ratio of 1.3. Other neuroreceptors are involved, as the drug has potent binding affinity for serotonin receptors 5-HT1A and 5-HT2. Clozapine also has antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties. Electrophysiologic studies show that it differs from other typical neuroleptics in that its actions appear to be specific for the cortical-limbic dopamine A-10 tract. In animal paradigms, in contrast to typical neuroleptics, clozapine did not produce catalepsy and had only transient effects in antagonizing other dopamine agonists. The drug is rapidly absorbed orally with a bioavailability of 0.27. After a single oral dose the elimination half-life was approximately 8-10 hours, but with several doses it increased to 14.1 hours. The agent is extensively metabolized by hepatic microsomal enzymes that forms the N-desmethyl and N-oxide metabolites. It is an effective neuroleptic that has been studied in short-term and long-term clinical trials, and multicenter trials. Clozapine was superior to chlorpromazine in the treatment of refractory schizophrenia that failed to respond to previous neuroleptic therapy. Reports of extrapyramidal side effects are minimal, and no case reports of tardive dyskinesia have been published. Indeed, clozapine has been used to treat tardive dyskinesia and other movement disorders. Agranulocytosis is the major adverse effect and its prevalence appears to differ among various ethnic groups. Other adverse effects that have been reported include hypersalivation, orthostatic hypotension, and constipation. Clozapine can lower the seizure threshold in a dose-dependent manner. The drug represents a significant advancement in the treatment of mental illness.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Drug Evaluation; Dyskinesia, Drug-Induced; Humans; Receptors, Dopamine; Schizophrenia

Clozapine has had a uniquely favorable motor system side effect profile since its initial evaluations. This has been convincingly corroborated by many double blind, single blind, and open studies treating acute and chronic psychosis. The acute extrapyramidal syndromes of dystonia, akathisia and parkinsonism infrequently occur, whereas these syndromes develop in up to 75% of patients receiving traditional neuroleptics. Tardive dyskinesia can be suppressed with higher doses of clozapine given over extended periods. However, an antipsychotic effect can be achieved in many patients at doses below the dyskinesia suppressing level. There is no established causative relationship between clozapine and tardive dyskinesia, but there is a theoretical basis that this may occur. Preliminary data suggest clozapine has mild antiparkinsonian effects as well as efficacy in controlling dopamine agonist-induced psychosis without aggravating parkinsonism. A much wider use of clozapine will further characterize the magnitude of differences compared to other neuroleptics, and identify additional indications for this special compound.

Topics: Basal Ganglia Diseases; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Humans

Topics: Antipsychotic Agents; Benzamides; Clinical Trials as Topic; Clozapine; Dibenzazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Haloperidol; Humans; Metoclopramide; Prospective Studies; Schizophrenia; Sulpiride; Tiapamil Hydrochloride

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Psychotic Disorders

Previous studies investigated whether prolactin (PRL) serum level was a biomarker of antipsychotic response, schizophrenia symptomatology, and tardive dyskinesia. Most of the findings support that antipsychotic drugs modulate PRL levels but PRL is not a steady indicator. Recent results suggest a genetic effect of PRL and PRL receptor (PRLR) polymorphisms in PRL levels indicating that independently of antipsychotic therapy subjects could have altered PRL levels due to their genetic background.We evaluated whether PRL and PRLR variants were associated with treatment outcome and tardive dyskinesia. We observed no association of PRL/PRLR polymorphism with treatment response (best genotypic results include PRL rs849885 and PRLR rs4703509 permuted p=0.326). Regarding tardive dyskinesia, the major allele of PRL rs37364 was nominally associated with risk for tardive dyskinesia in the European ancestry sub-sample (permuted p=0.183). Although we reported no significant associations, it is definitely worthy of investigation to see if together (genetic variants in the PRL system and PRL serum measures) could be a reliable biomarker for antipsychotic response and TD prevalence. Our results suggest that more studies in this context are required to shed light in the molecular mechanisms underlying antipsychotic response and tardive dyskinesia occurrence.

Topics: Adult; Alleles; Antipsychotic Agents; Biomarkers; Clozapine; Dyskinesia, Drug-Induced; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Prolactin; Prospective Studies; Receptors, Prolactin; Schizophrenia; Treatment Outcome; White People; Young Adult

Worldwide, conventional antipsychotic medication continues to be used extensively, and tardive dyskinesia (TD) remains a serious complication. The primary objective of the present study was to compare the efficacy of EPA versus placebo in reducing symptoms of TD.. This was a 12-week, double-blinded, randomized study of ethyl-EPA 2g/day versus placebo as supplemental medication, in patients with schizophrenia or schizoaffective disorder, with established TD.. Eighty-four subjects were randomized, of whom 77 were included in the analysis. Both the EPA and placebo groups displayed significant baseline to endpoint improvements in Extrapyramidal Symptom Rating Scale dyskinesia scores, but there were no significant between-group differences (p=0.4). Response rates (>or=30% improvement in TD symptoms) also did not differ significantly between EPA-treated subjects (45%) and placebo-treated subjects (32%) (p=0.6). However, a post-hoc linear mixed model repeated measures analysis of variance indicated an effect for treatment group and duration of TD. The EPA-treated patients had significantly greater mean reductions in dyskinesia scores initially, although this was not sustained beyond 6 weeks.. This trial failed to demonstrate an anti-dyskinetic effect for ethyl-EPA 2g/day on the primary efficacy measure. However, a modest and transient benefit is suggested in patients with more recent onset of TD. The lack of clear-cut efficacy could be explained on the basis of the dose of EPA being too low, the study being underpowered, TD being too chronic in the majority of cases, differences in dietary fatty acid intake, or that EPA lacks an anti-dyskinetic action.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Double-Blind Method; Dyskinesia, Drug-Induced; Eicosapentaenoic Acid; Female; Humans; Male; Middle Aged; Psychotic Disorders; Schizophrenia

Several case reports described neurotoxic side-effects in the course of a combined clozapine-lithium treatment. Here we report on the safety and efficacy of this combination in a sample of 44 hospital patients. Medical records were retrospectively audited and a subsample of 23 patients was re-assessed. Mean total duration of combined treatment was 23.5 months. The combination (indications: prophylaxis; treatment of affective symptoms or aggression/excitement; augmentation of neuroleptic efficacy) was rated effective in 84% and adverse events were reported in 64% of the patients. Notably, most of the adverse events were benign and transient. However, 8 patients (18%) developed transient neurological adverse events that were genuinely novel in only 3 patients (7%) and coincided with high dosage of medication or high plasma levels or serotonergic (antidepressant) co-medication. Our data suggest that combined clozapine-lithium treatment may appear to be safe and effective when administered within a moderate therapeutic dose range and without serotonergic co-medication or other substances interfering with clozapine metabolism.

Topics: Adult; Aged; Antimanic Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Lithium; Male; Middle Aged; Myoclonus; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

To investigate the efficacy and safety of clozapine in the treatment of levodopa-induced dyskinesias (LID) in patients with severe Parkinson disease (PD).. Fifty patients were randomized to treatment in this 10-week, double-blind, parallel-group, placebo-controlled, multicenter trial. The principal measure of outcome was the diurnal change in the "on" time with LID assessed using a self-evaluation of the motor performance fluctuations performed every 2 weeks. An acute levodopa challenge was also performed at the beginning and end of the study.. A reduction in the duration of "on" periods with LID was noted in favor of the clozapine group at the end of the study (placebo group day 0: 4.54 +/- 0.53 hours, end: 5.28 +/- 0.70 hours; clozapine group day 0: 5.68 +/- 0.66 hours, end: 3.98 +/- 0.57 hours; p = 0.003). The mean clozapine dosage was 39.4 +/- 4.5 (SEM) mg/day. The maximal LID score at rest during the levodopa challenge was significantly decreased under clozapine treatment, with a variation from day 0 to day 70 in the placebo group of +0.15 +/- 1.01 and in the clozapine group of -2.22 +/- 0.52 (p < 0.05). Five patients receiving clozapine and seven receiving placebo discontinued on account of adverse events. Among them, three patients in the clozapine group developed eosinophilia, which rapidly resolved after withdrawal of the drug.. Clozapine is effective in the treatment of levodopa-induced dyskinesias in severe PD.

Topics: Aged; Antiparkinson Agents; Clozapine; Double-Blind Method; Dyskinesia, Drug-Induced; Humans; Levodopa; Middle Aged; Parkinson Disease; Serotonin Receptor Agonists; Treatment Outcome

Typical antipsychotics have been reported to enlarge the caudate nucleus in schizophrenic patients. The atypical antipsychotic, clozapine, is associated with a decrease in caudate size in patients previously treated with typical antipsychotics. The present study investigates whether a change in caudate volume after switching from treatment with typical antipsychotics to treatment with clozapine is related to improvement in symptoms or tardive dyskinesia (TD). Twenty-six schizophrenic patients participated in this open study. Caudate nucleus volume and TD were assessed before discontinuing typical antipsychotics and after 24 weeks of treatment with clozapine. After discontinuing typical antipsychotics, symptoms were assessed in a 3 days drug-free period and subsequently once a month. Treatment with clozapine resulted in a decrease in caudate volume, improvement in symptoms and amelioration of TD. However, no difference in caudate volume changes was found between responders and non-responders to clozapine and no correlations were found between caudate volume changes and reduction of TD. In conclusion, this study replicates earlier findings that clozapine decreases caudate volume in patients previously treated with typical antipsychotics and suggests that this effect is unrelated to treatment response or to amelioration of TD.

Topics: Adult; Antipsychotic Agents; Caudate Nucleus; Clozapine; Disease Progression; Dyskinesia, Drug-Induced; Female; Humans; Hypertrophy; Magnetic Resonance Imaging; Male; Middle Aged; Schizophrenia; Treatment Outcome

The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptic drugs is a major challenge. Clozapine has been one treatment option; however, it is not universally effective and is limited in its use by safety concerns. With the introduction of newer agents, their performance relative to clozapine is of great clinical interest.. The primary objective of this study was to evaluate the efficacy and safety of olanzapine versus clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to demonstrate the "noninferiority" of olanzapine compared to clozapine after 18 weeks of double-blind treatment. Conclusions were based on the one-sided lower 95% confidence limit about the treatment effect observed from the primary efficacy variable (Positive and Negative Syndrome Scale [PANSS] Total).. Mean changes from baseline to end point in PANSS Total score, using a last observation carried forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the "noninferiority" of olanzapine when compared to clozapine. Overall, significantly fewer olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p =.022). Among spontaneously reported adverse events, increased salivation, constipation, dizziness, and nausea were reported significantly more often among clozapine-treated patients, whereas only dry mouth was reported more often among olanzapine-treated patients.. Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant schizophrenic patients clinically eligible for treatment with clozapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weight; Clozapine; Double-Blind Method; Drug Resistance; Dyskinesia, Drug-Induced; Female; Humans; Male; Olanzapine; Patient Compliance; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Time Factors

There is no proven effective treatment for tardive dyskinesia (TD). However, clozapine has been reported to be effective in suppressing TD symptoms. In this article, we report a TD case who received clozapine. The patient recovered from TD symptoms with a dose of 450 mg/day clozapine. At the end of the first year, clozapine was decreased to a dose of 250 mg/day and TD symptoms re-emerged.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Recurrence

Given the problematic nature of tardive dyskinesia in persons taking conventional antipsychotics, evaluation of newer atypical antipsychotic agents should include a systematic assessment of tardive dyskinesia liability. Results of a prospective double-blind, randomized study of schizophrenic patients who participated in 3 preclinical olanzapine studies and were treated with 5 to 20 mg/day of olanzapine (N = 1192) or haloperidol (N = 522) recently indicated a significantly lower risk of development of tardive dyskinesia with olanzapine treatment than haloperidol treatment. This article discusses the known effects of atypical antipsychotic medications on tardive dyskinesia movements (both withdrawal and persistent) and the incidence rate of tardive dyskinesia among schizophrenic patients undergoing long-term treatment with olanzapine or haloperidol.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Double-Blind Method; Drug Administration Schedule; Dyskinesia, Drug-Induced; Haloperidol; Humans; Incidence; Molindone; Olanzapine; Pirenzepine; Prospective Studies; Risk Factors; Risperidone; Schizophrenia; Substance Withdrawal Syndrome; Survival Analysis

Plasma homovanillic acid (HVA) changes in response to a challenge of several days with haloperidol have been found to be predictive of the therapeutic response to haloperidol over a longer period of treatment.. Twenty-six elderly women who gave informed consent were divided into two groups, with or without tardive dyskinesia, and subjected to an 80-day washout, after which both the dyskinetic and nondyskinetic group was divided, and half of each group given haloperidol or clozapine.. The nondyskinetic group had a brief rise in plasma HVA, then a decline. The dyskinetic group had no change in plasma HVA. Neither group challenged with clozapine had any change in plasma HVA.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Haloperidol; Homovanillic Acid; Humans; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

The aim of this study was to investigate the clinical efficacy of clozapine, an atypical neuroleptic, on L-dopa induced dyskinesias of Parkinson's disease.. In an open study, a group of 10 PD patients was treated with low dosage clozapine (mean 30 mg/day) for a 4-month period and L-dopa dyskinesias were evaluated in basal conditions and during clozapine treatment after the usual morning dose of clozapine. We utilized the AIMS for evaluation of dyskinesias and UPDRS for the assessment of motor performances.. Clozapine produced a significant (P<0.05) reduction of dyskinesias 1 week after the therapy onset. This effect was more pronounced at the end of the 2nd week and remained stable through the following months. We did not observe significant variations of motor performances.. A low dose of clozapine appears to be beneficial for patients with L-dopa induced dyskinesias that do not respond to other drugs and therapeutic measures.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Antiparkinson Agents; Clozapine; Dopamine Antagonists; Dyskinesia, Drug-Induced; Humans; Levodopa; Middle Aged; Parkinson Disease; Severity of Illness Index; Treatment Outcome

Tardive dyskinesia (TD) is a long-term severe complication of antipsychotic treatment, with mean prevalence of 20-35%. The aim of this study was to evaluate effects of clozapine in severe TD. In an open trial seven patients with schizophrenia and severe TD were given clozapine for 6 months. Tardive dyskinesia severity was evaluated with AIMS and ESRS and schizophrenic psychopathology with PANSS. Clozapine mean dose at the end of the study was 392.86 mg/day. A mean reduction of 52% was observed in ESRS scores for TD. Two patients also had dystonic movements, and there was 50% reduction in one of them and complete remission in the other. There was also a 27% mean reduction in PANSS scores. Clozapine seems to be an alternative in the treatment of schizophrenic patients with severe TD.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

Previous studies on the use of clozapine in neuroleptic-resistant chronic schizophrenic patients have demonstrated positive effects on tardive dyskinesia but were less conclusive about chronic akathisia and parkinsonism. The aim of the present study was to investigate the short-term (18 weeks) efficacy of clozapine in neuroleptic-resistant chronic schizophrenic patients with coexisting tardive dyskinesia, chronic akathisia, and parkinsonism.. Twenty chronic, neuroleptic-resistant schizophrenic patients with coexisting tardive dyskinesia, parkinsonism, and chronic akathisia were treated with clozapine. Assessment of tardive dyskinesia, parkinsonism, and chronic akathisia was made once weekly for 18 weeks with the Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Rating Scale for Extrapyramidal Side Effects, and Barnes Rating Scale for Drug-Induced Akathisia (BAS).. At the end of 18 weeks of clozapine treatment, improvement rates were 74% for tardive dyskinesia, 69% for parkinsonism, and 78% for chronic akathisia. A statistically significant reduction in the scores on the AIMS and Simpson-Angus Scale was achieved at Week 5 and on the BAS at Week 6 (p < .0001).. Relatively low doses of clozapine are effective for the treatment of neuroleptic-induced extrapyramidal syndromes in neuroleptic-resistant chronic schizophrenic patients. The relief of tardive dyskinesia, parkinsonism, and chronic akathisia in this group of patients occurs more rapidly than the reduction in psychotic symptoms. Disturbing, long-term extrapyramidal syndromes in chronic schizophrenic patients should be considered an indication for clozapine treatment.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Comorbidity; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Male; Parkinson Disease, Secondary; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Neuroleptic-induced extrapyramidal side effects (EPS) were evaluated in 92 patients treated with clozapine for the first time and 59 patients treated with haloperidol followed in a drug monitoring program. Side effects were measured by the Columbia University Rating Scale, the Simpson Dyskinesia Scale and the Hillside Akathisia Scale. The cumulative incidence rate for tremor was found to be 24.4% in the clozapine group and 39.3% in the haloperidol group. This did not amount to a statistically significant group difference. Bradykinesia was observed in 21.8% of the patients treated with clozapine and in 47.7% of the patients of haloperidol (P = 0.011). In the clozapine group the akathisia incidence rate was 5.6%, whereas haloperidol patients showed a higher rate of 31.7% (P = 0.005). Our results show higher incidence rates of tremor and bradykinesia during clozapine treatment than previous studies. We conclude that clozapine is not entirely free of EPS, but they are usually less severe and of a different quality than side effects induced by typical antipsychotics.

Topics: Adult; Akathisia, Drug-Induced; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Tremor

1. Supersensitivity psychosis (SSP) has emerged as a potential side effect of long-term neuroleptic therapy similar to tardive dyskinesia (TD). 2. Six schizophrenic patients with SSP, considered to be drug-resistant, were treated with risperidone, while another 5 were treated with clozapine. 3. The 6 risperidone-treated patients (all women) were rated on the Clinical Global Impression Improvement Scale as at least very much improved. Among the 5 clozapine-treated patients, all 4 men were found to have a marked response to clozapine, while the female patient was judged to be minimally improved. 4. It is hypothesized that not only TD but also SSP arise from destruction of cholinergic interneurons in the striatum as a consequence of prolonged neuroleptic administration. Thus, the drug-induced parkinsonism, which was proposed as mediating the antipsychotic effect of dopamine D2 blocking drugs, depends on the integrity of these cholinergic neurons. If these neurons are destroyed, drugs such as haloperidol lose their therapeutic effect. 5. In contrast, atypical neuroleptics like clozapine and risperidone reduce dopamine release in the striatum independently of prior production of extrapyramidal symptoms and, in this way, may be effective in psychotic illnesses unresponsive to classical anti-D2 neuroleptics. 6. In the present sample of patients, it is worth noting that schizophrenic men were good responders to clozapine. In comparison, risperidone was found to be efficacious in schizophrenic women.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Resistance; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Risperidone; Schizophrenia; Schizophrenic Psychology; Sex Characteristics

Clozapine has long been considered a useful treatment in patients who have schizophrenia with the neuroleptic-induced delayed-onset side effect tardive dyskinesia. We present data in support of the clinical impression using both an animal model of the disorder and dyskinetic patients themselves. Clozapine produces a lower rate of oral dyskinesia in laboratory rats after 6 months of chronic treatment than does haloperidol (8.6 +/- 1.3 vs. 13.6 +/- 1.4 vacuous chewing movements every 5 minutes, respectively), suggesting a lower propensity to cause tardive dyskinesia. In the human, when clozapine was compared with haloperidol in the treatment of patients with tardive dyskinesia, clozapine produced significantly greater benefit for motor symptoms after 12 months of treatment than did haloperidol (p < .001). Moreover, the dyskinesia rebound, which occurred equally in both drug groups at the beginning of the study, was sustained in the haloperidol group but lost in the clozapine-treated patients. These data suggest that dyskinetic patients lose their symptoms of tardive dyskinesia, along with dopaminergic hypersensitivity, with long-term clozapine treatment.

Topics: Adult; Animals; Antipsychotic Agents; Clozapine; Disease Models, Animal; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Haloperidol; Humans; Male; Rats; Schizophrenia; Treatment Outcome

Two reaction time (RT) paradigms were used to study clozapine's effects on sustained and selective attention compared to fluphenazine and placebo in 25 chronic schizophrenic patients. Sensory dominance was studied via simple and choice RTs to lights and tones, and on double-stimulus trials in which the two stimuli were presented simultaneously. Although 8 of the 25 patients could not perform the RT tasks when taking placebo, there were no effects of clozapine on simple or choice RT compared to placebo or fluphenazine. Subjects on all 3 treatments showed visual dominance: faster RT to lights than to tones on choice and double-stimulus trials. However, clozapine reduced this by means of a selective increase in RT to lights. Clozapine reduced failures to respond to the tone on double-stimulus trials. This was shown to be due to reductions in hallucinations. Clozapine does not generally improve attention, but it may increase the ability of schizophrenic persons to process nondominant or unattended stimuli possibly by increasing the efficiency of resource allocation. This may be partially mediated by a reduction in hallucinations.

Topics: Adult; Attention; Auditory Perception; Clozapine; Dominance, Cerebral; Dyskinesia, Drug-Induced; Female; Fluphenazine; Hallucinations; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Reaction Time; Schizophrenia; Schizophrenic Psychology; Visual Perception

The effects of clozapine on the dopamine and serotonin systems may underlie its atypical pharmacologic and clinical profile. To examine this hypothesis, we measured dopamine and serotonin plasma and cerebrospinal (CSF) metabolites and the relationship of these values to treatment response in 19 neuroleptic refractory and intolerant schizophrenic patients. Only a small change in the CSF and plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) levels was found. However, the pretreatment CSF HVA/5HIAA ratio and, to a lesser extent, the CSF HVA level predicted treatment response. These results suggest that the modest relationship between HVA and 5-HIAA and treatment response supports the involvement of both neurotransmitters in the pathophysiology of schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Dopamine; Drug Resistance; Dyskinesia, Drug-Induced; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Psychiatric Status Rating Scales; Schizophrenia; Serotonin

In order to assess the safety and some efficacy aspects of clozapine under UK conditions, 54 in-patients with severe treatment-resistant schizophrenic disorders were evaluated using several scales before and during treatment. Of the 54 evaluated, 26 completed the 26-week study. Of these patients, 20 showed improvement in psychopathology, often to a marked degree, involving both positive and negative symptoms. Some oral-facial extrapyramidal side-effects decreased as well. Two patients developed neutropenia, but recovered on discontinuation of clozapine. The most frequent adverse event was hypersalivation, and five patients suffered from seizures. It is concluded that clozapine is worth considering for the treatment of severe treatment-resistant patients in the UK.

Topics: Adult; Chronic Disease; Clozapine; Drug Resistance; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neutropenia; Schizophrenia; Schizophrenic Psychology; Sialorrhea; Treatment Outcome; United Kingdom

Essential fatty acids (EFAs) and their eicosanoid derivatives are important constituents of the brain and regulators of neuronal function. There is direct and indirect evidence of impaired metabolism of prostaglandin (PG)E1 in schizophrenia. There is also direct evidence of abnormal EFA biochemistry with plasma phospholipids from five populations and brain phospholipids from another all showing reduced levels of linoleic acid and elevated levels of 22-carbon EFAs of both n-6 and n-3 series. Clinical trials of PGE1 and of the PGE1 precursors, gamma-linolenic acid (GLA) and dihomo-gamma-linolenic acid (DGLA) have shown modest therapeutic effects. In view of lack of therapeutic process involving drugs based on the dopamine concept of schizophrenia, it is time for new approaches based on the EFA/PG concept to be evaluated thoroughly.

Topics: Alprostadil; Brain Chemistry; Clozapine; Diabetes Complications; Dietary Fats; Dopamine; Double-Blind Method; Dyskinesia, Drug-Induced; Eicosanoids; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Linolenic Acids; Niacin; Phospholipids; Schizophrenia

Thirty-eight chronically ill psychotic patients were treated with clozapine for indications of tardive dyskinesia, severe extrapyramidal side effects caused by other neuroleptics, or treatment-resistant psychosis. Fifty-five percent of all patients and 40% of schizophrenics improved with clozapine. Abnormal involuntary movements were suppressed during treatment and, with 1 exception, returned to baseline levels after clozapine was discontinued. Our results support the conclusion that clozapine's efficacy in refractory cases and its lack of neurological side effects make it a unique neuroleptic with advantages over conventional antipsychotic agents. The drug appears to be safe when treatment is accompanied by frequent clinical and hematologic monitoring.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Outcome and Process Assessment, Health Care; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

Topics: Antipsychotic Agents; Benzamides; Clinical Trials as Topic; Clozapine; Dibenzazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Haloperidol; Humans; Metoclopramide; Prospective Studies; Schizophrenia; Sulpiride; Tiapamil Hydrochloride

Topics: Animals; Clinical Trials as Topic; Clozapine; Dibenzazepines; Drug Evaluation; Dyskinesia, Drug-Induced; Humans; Research Design

Twelve patients with abnormal involuntary movement disorders were treated with clozapine in a double-blind, placebo-controlled trial. The cohort consisted of individuals with Gilles de la Tourette's syndrome, Huntington's disease, and atypical persistent dyskinesia that was drug induced. Two subjects were dropped from the protocol due to complications. Two patients with Huntington's disease showed a marked decrease in movements; other individuals obtained no significant therapeutic benefits. Seven of the 10 patients completing the trial experienced moderate or marked side effects.

Topics: Adolescent; Adult; Child; Clinical Trials as Topic; Clozapine; Dibenzazepines; Double-Blind Method; Drug Evaluation; Dyskinesia, Drug-Induced; Female; Humans; Huntington Disease; Male; Middle Aged; Movement Disorders; Placebos; Tourette Syndrome

Fifteen schizophrenic inpatients were treated in a double-blind comparison study of clozapine versus chlorpromazine. Clozapine appeared to be at least as effective as chlorpromazine without producing any extrapyramidal reactions. Although bone marrow toxicity associated with clozapine has led to the drug's withdrawal from clinical use, data from studies of clozapine demonstrate that a drug can be effective antipsychotic without producing neurologic reactions.

Topics: Adult; Aged; Chlorpromazine; Clinical Trials as Topic; Clozapine; Dibenzazepines; Double-Blind Method; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

1. Human neuroleptogenic EPMS-disturbances are reversed by clozapine in animal experiments and in clinical use. This is consistent with the central anticholinergic efficacy of clozapine. 2. Clozapine seems to be a favourable concomitant medication when high dosage therapy of neuroleptics is applied--or at the incidence of dyskinesia.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Female; Humans; Male; Parkinson Disease; Placebos

Topics: Aged; Biperiden; Clinical Trials as Topic; Clozapine; Dibenzazepines; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Parkinson Disease, Secondary; Piperidines; Psychotic Disorders; Thioridazine

Clozapine, which has had limited clinical testing in the U.S.A., was evaluated in 12 chronic schizophrenic patients with tardive dyskinesia. Its antipsychotic activity was again demonstrated and it suppressed the symptoms of tardive dyskinesia with a marked rebound occurring in these symptoms when it was withdrawn; there was no rigidity or other Parkinsonian symptoms. However, out of a total of 12 patients, neutropenia (800 and 1120) occurred in two patients, convulsion in one patient, marked withdrawal effects in three patients, and a hypotensive collapse with atrial fibrillation in one patient. If these adverse effects are confirmed in a larger sample size, then despite the novel desirable effects of clozapine it would seem unlikely that it will gain widespread or routine use.

Topics: Adult; Clinical Trials as Topic; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Substance Withdrawal Syndrome; Time Factors

Amantadine and clozapine have proved to reduce abnormal involuntary movements (AIMs) in preclinical and clinical studies of L-DOPA-Induced Dyskinesias (LID). Even though both drugs decrease AIMs, they may have different action mechanisms by using different receptors and signaling profiles. Here we asked whether there are differences in how they modulate neuronal activity of multiple striatal neurons within the striatal microcircuit at histological level during the dose-peak of L-DOPA in ex-vivo brain slices obtained from dyskinetic mice. To answer this question, we used calcium imaging to record the activity of dozens of neurons of the dorsolateral striatum before and after drugs administration in vitro. We also developed an analysis framework to extract encoding insights from calcium imaging data by quantifying neuronal activity, identifying neuronal ensembles by linking neurons that coactivate using hierarchical cluster analysis and extracting network parameters using Graph Theory. The results show that while both drugs reduce LIDs scores behaviorally in a similar way, they have several different and specific actions on modulating the dyskinetic striatal microcircuit. The extracted features were highly accurate in separating amantadine and clozapine effects by means of principal components analysis (PCA) and support vector machine (SVM) algorithms. These results predict possible synergistic actions of amantadine and clozapine on the dyskinetic striatal microcircuit establishing a framework for a bioassay to test novel antidyskinetic drugs or treatments in vitro.

Topics: Amantadine; Animals; Antiparkinson Agents; Calcium; Clozapine; Corpus Striatum; Disease Models, Animal; Dyskinesia, Drug-Induced; Levodopa; Mice; Neurons; Oxidopamine

Tardive dyskinesia is defined as involuntary athetoid or choreiform movements that develop due to the use of neuroleptic drugs for at least a few months. Tongue, lower face, jaw, upper and lower extremities are the most affected parts of the body in tardive dyskinesia. Quality of life is negatively affected because of the low remission rates. Besides tardive dyskinesia, involuntary movements may appear after discontinuation, change or a reduction in the dose of antipsychotic medications, which is called withdrawal-emergent dyskinesia (WED). Unlike tardive dyskinesia, the involuntary movements involve mainly the neck, trunk, and limbs and regress in shorter period of time in WED. A consensus has not yet been reached for the treatment of WED. Restarting the previous antipsychotic agent with slow titration or switching to an atypical antipsychotic with low affinity for dopamine D2 receptors are among the primary options for treatment. As WED is one of the predictors of tardive dyskinesia development, early detection and treatment is believed to have positive effect on the quality of life. In this report, the case of a patient followed up for bipolar disorder type I (BD-I) and started on clozapine for WED after discontinuation of haloperidol on account of adverse effects is discussed. It is necessary for clinicians to consider these types of complications when discontinuing or changing treatment. Further research is needed in order to reach a common approach for the treatment of WED.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Quality of Life; Tardive Dyskinesia

A case of acute dyskinesia in a 42-year-old man with a history of cocaine use and schizophrenia is described. He had discontinued clozapine approximately 1 month before presenting to the emergency department displaying signs of psychosis, with generalised choreiform and dystonic movements. Urinary toxicology was positive for cocaine. Clozapine treatment was reinitiated, and within 2 weeks the dyskinesia had subsided. Review of his records revealed two previous episodes of similar dyskinesia, both of which were temporally associated with cocaine use. Dyskinesia occurring in the context of cocaine use, and clozapine withdrawal-associated dyskinesia were considered to be the main differential diagnoses. A range of differential diagnoses should be considered in patients presenting with an acute-onset movement disorder who have a history of long-term exposure to antipsychotic medication.

Topics: Adult; Antipsychotic Agents; Clozapine; Cocaine-Related Disorders; Crack Cocaine; Dyskinesia, Drug-Induced; Humans; Magnetic Resonance Imaging; Male; Neuroimaging; Schizophrenia; Substance Withdrawal Syndrome; Treatment Outcome

Tardive dyskinesia (TD) is a potentially disabling condition encompassing all delayed, persistent, and often irreversible abnormal involuntary movements arising in a fraction of subjects during long-term exposure to centrally acting dopamine receptor-blocking agents such as antipsychotic drugs and metoclopramide. However, the pathogenesis of TD has proved complex and remains elusive. To investigate the mechanism underlying the development of TD, we have chronically exposed 17 Cebus apella monkeys to typical (11) or atypical (6) antipsychotic drugs. Six additional monkeys were used as controls. Using autoradiography, Western blot and in situ hybridization techniques, we compared neurochemical components of the dopamine, serotonin, and glutamate neurotransmitter systems modulating striatal activity in monkeys chronically exposed to haloperidol and clozapine. Five (5) out of 11 monkeys treated with haloperidol develop TD, whereas none of the monkeys treated with clozapine develop TD. Haloperidol treatment significantly upregulated the levels of serotonin 5-HT

Topics: Animals; Antipsychotic Agents; Clozapine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dyskinesia, Drug-Induced; Female; Haloperidol; Haplorhini; Putamen; Tardive Dyskinesia

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients treated with antipsychotics. The first column in this series began with the case of a 76-year-old man with major depressive disorder who developed orofacial dyskinesias while being treated with aripiprazole as an antidepressant augmentation strategy. It was alleged that a higher than intended dose of aripiprazole (ie, 20 mg/d for 2 wk followed by 10 mg/d for 4 wk instead of the intended dose of 2 mg/d) was the cause of the dyskinetic movements in this man, and the authors were asked to review the case and give their opinion. The principal basis for this theory of causation was the class warning about TD in the package insert for aripiprazole. The rationale for concluding aripiprazole caused TD in the 76-year-old man led to this series of columns about aripiprazole, its potential--if any--to cause TD, and the presence of a class warning about TD in its package insert. The central point is to illustrate why class warnings exist and their implications for practice. The first column in this series focused on the historical background, incidence, prevalence, risk factors, and clinical presentations of tardive and spontaneous dyskinesias and concluded with a discussion of diagnostic considerations explaining why clinicians should avoid making a diagnosis of TD until a thorough differential diagnosis has been considered. This second column in the series reviews the pharmacology of aripiprazole and the preclinical and phase I translational human studies that suggest aripiprazole should have a low to nonexistent risk of causing TD compared with other antipsychotics. The third column in the series will review the systematic clinical trial data and "real-world" data on TD and the use of aripiprazole as adjunctive treatment with antidepressants for major depressive disorder to see whether these data support the conclusion of a low to nonexistent relationship between aripiprazole treatment and the development of TD. The fourth and final column in the series will consider the type of study that would need to be performed to avoid a specific class warning, focusing on the TD class warning as an

Topics: Aged; Antipsychotic Agents; Aripiprazole; Clinical Trials as Topic; Clozapine; Depressive Disorder, Major; Dyskinesia, Drug-Induced; History, 20th Century; Humans; Male; United States; United States Food and Drug Administration

Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.

Topics: Animals; Clozapine; Cyclic AMP; Diterpenes; Diterpenes, Clerodane; Dopamine; Dopaminergic Neurons; Dyskinesia, Drug-Induced; Ethylamines; Female; Fetal Tissue Transplantation; Gene Knock-In Techniques; Humans; Indoles; Oxidopamine; Parkinsonian Disorders; Postoperative Complications; Rats; Receptors, Serotonin

The aim of this study was to investigate a possible association between tardive dyskinesia (TD) and CYP1A2 (*1F, -163C>А, rs762551) polymorphism in Russian psychiatric inpatients.. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale (AIMS). Orofacial and limb-truncal dyskinesia were assessed with AIMS 1-4 and 5-7, respectively. Standard protocols were applied for genotyping. Analysis of covariance (ANCOVA) was used to compare the mean AIMS scores for each of the genotypic classes.. A total of 319 Caucasian patients from West Siberia with schizophrenia and 117 healthy volunteers were investigated. No significant differences between the patients and the controls in genotype frequencies were found. Analysis of covariance (ANCOVA) with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates showed that limb-truncal, but not orofacial TD, is associated with CYP1A2 (-163C>, rs762551) polymorphism (F = 3.27, P = 0.039). Patients with the C/C genotype had a higher mean AIMS 5-7 score than those with the A/C or the A/A genotype.. Our results support the hypothesis that not only with clozapine, but also with other classical and atypical antipsychotics, smoking may decrease plasma levels; this is most extensively expressed in carriers of the CYP1A2*1F (-163C> A) polymorphism.

Topics: Adult; Antipsychotic Agents; Case-Control Studies; Clozapine; Cytochrome P-450 CYP1A2; Dyskinesia, Drug-Induced; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Russia; Schizophrenia; Smoking; White People

Aripiprazole can cause irreversible tardive dystonia in some individuals, and additional intervention is sometimes needed. Here, we report the first case of aripiprazole-induced irreversible tardive dystonia in which complete recovery of motor function was achieved using the antipsychotic drug clozapine.. A 24-year-old man with bipolar disorder was treated with aripiprazole and gradually developed tardive dystonia. Thorough medical and neurological examinations were performed to rule out other possible causes of tardive dystonia. Clozapine was administered when the patient did not improve following long-term withdrawal of aripiprazole or adjuvant medications. Before administration of clozapine, the patient was experiencing severe dystonia as assessed by the Extrapyramidal Symptom Rating Scale. Dystonic symptoms began to improve about 1 month after starting administration of clozapine and were completely resolved 3 months after clozapine administration.. Clinicians should note the risk of aripiprazole-induced tardive dystonia and consider clozapine as an alternative and effective treatment modality in cases of irreversible tardive dystonia, particularly when concomitant treatment of psychotic symptoms is required.

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Movement Disorders; Neurologic Examination; Psychotic Disorders; Treatment Outcome; Young Adult

Topics: Aged; Antipsychotic Agents; Clozapine; Drug Substitution; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Electroencephalography; Female; Humans; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Tardive syndromes are among the most debilitating side effects associated with use of antipsychotics. In this case series we present 5 cases of drug induced tardive syndromes, who had not responded to many of the other therapeutic measures but responded to clozapine. The response rate with clozapine varied from 50% to 100% and the response was seen by week 3 in most cases. Over the long term follow-up of as long as 6 years the response to clozapine was sustained. In two cases clozapine could be stopped.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Psychotic Disorders; Treatment Outcome

This study aimed to examine the prevalence and clinical associated variables of tardive dyskinesia (TD) in a large sample of Chinese inpatients with schizophrenia on long-term treatment with clozapine versus typical antipsychotics. A total of 584 male inpatients with schizophrenia on long-term clozapine (n=341) or typical antipsychotic (n=243) treatment were evaluated using the Abnormal Involuntary Movement Scale (AIMS). The patient's psychopathology was assessed using the Positive and Negative Syndrome Scale. The overall prevalence of TD was 44.5%, with rates of 48.7% in the clozapine group and 38.7% in the typical antipsychotic group (P=0.017). The AIMS score was significantly lower in typical than in clozapine groups (P<0.005). A multiple regression analysis showed that the following variables were significantly associated with the AIMS score: clozapine versus typical medication (P=0.008), Positive and Negative Syndrome Scale negative subscore (P=0.017), and age (P=0.04). There are significant differences in the prevalence and clinical correlates of TD in schizophrenia treated with clozapine versus typical antipsychotics.

Topics: Adult; Age Factors; Aged; Antipsychotic Agents; Asian People; China; Clozapine; Cross-Sectional Studies; Dyskinesia, Drug-Induced; Humans; Inpatients; Male; Middle Aged; Prevalence; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Psychotic Disorders

Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects. This limitation presents a marked therapeutic challenge. The present method (21 days administration of haloperidol, 5 mg/kg, i.p.) has been established to gain deeper insight into the molecular etiology (inflammation and apoptosis) of haloperidol-induced cellular death. In the present model, besides the corresponding increase in the vacuous chewing movements (VCMs), enhanced oxidative stress, there was a significant increase in cellular markers of inflammation and apoptotic protein (caspase-3), leading to cellular death. We also suggest that this model will be effective in preclinical testing of new chemical entities for the treatment of haloperidol induced tardive dyskinesia and related symptoms.

Topics: Animals; Antipsychotic Agents; Apoptosis; Behavior, Animal; Caspase 3; Clozapine; Disease Models, Animal; Dyskinesia, Drug-Induced; Haloperidol; Humans; Male; Movement Disorders; Pregnatrienes; Rats; Rats, Wistar

Tardive dyskinesia (TD) is a devastating adverse effect of long-term antipsychotic drug treatment. Atypical antipsychotics produce less TD, and it has been shown that they may have a therapeutic effect on pre-existing TD. Here, we report a case of olanzapine-induced TD which did not improve after switching to risperidone but improved after the addition of quetiapine to risperidone regimen. We also provide a brief review of the reported cases on TD induced by atypical antipsychotics which improved after switching to another atypical agent. It is unclear whether some atypical antipsychotics are more effective than others in the treatment of TD. Differences in this property and the underlying mechanism require further study.

Topics: Adult; Anti-Dyskinesia Agents; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dyskinesia, Drug-Induced; Female; Humans; Olanzapine; Quetiapine Fumarate; Risperidone; Schizophrenia, Paranoid

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dyskinesia, Drug-Induced; Humans; Lithium Chloride; Male

Topics: Adult; Antipsychotic Agents; Aripiprazole; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Female; Humans; Piperazines; Quinolones; Schizophrenia

This case report presents a patient with tardive dyskinesia who also suffered from masticatory muscle pain and temporomandibular joint osteoarthrosis. The patient was treated with clozapine in gradually increasing doses and two injections of botulinum toxin type A one year apart. Involuntary movements of mandibular clenching and bruxing disappeared and pain was relieved to a great extent. Reappearances of dyskinetic movements and pain were observed during the follow-up period of 1.5 years.

Topics: Aged; Antipsychotic Agents; Botulinum Toxins, Type A; Bruxism; Clozapine; Dyskinesia, Drug-Induced; Facial Pain; Follow-Up Studies; GABA Antagonists; Haloperidol; Humans; Male; Muscle Contraction; Neuromuscular Agents; Osteoarthritis; Recurrence; Schizophrenia; Temporomandibular Joint Disorders

Topics: Anti-Dyskinesia Agents; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Respiration Disorders; Risperidone; Schizophrenia; Substance Withdrawal Syndrome; Treatment Outcome

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Olanzapine; Schizophrenia; Sulpiride

Tardive dyskinesia (TD) is a movement disorder observed after chronic neuroleptic treatment. Smoking is presumed to increase the prevalence of TD. The question of a cause-effect-relationship between smoking and TD, however, remains to be answered. Purpose of this study was to examine the correlation between the degree of smoking and the severity of TD with respect to differences caused by medication.. We examined 60 patients suffering from schizophrenia and TD. We compared a clozapine-treated group with a group treated with typical neuroleptics. Movement disorders were assessed using the Abnormal-Involuntary-Movement-Scale and the technical device digital image processing, providing rater independent information on perioral movements.. We found a strong correlation (.80

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Longitudinal Studies; Male; Middle Aged; Neurologic Examination; Pilot Projects; Psychiatric Status Rating Scales; Risk Factors; Schizophrenia; Smoking; Statistics as Topic

Oculogyric crisis is a distressing acute/chronic side effect of neuroleptic medications. Chronic oculogyric crisis can be considered as a tardive hyperkinetic movement disorder and it may be associated with worsening of psychotic symptoms. Treatment strategies for chronic oculogyric crisis include; high potency antipsychotics and anticholinergics drugs for immediate relief and clozapine as a long-term treatment strategy. Here we are presenting case histories of four patients with oculogyric crisis and associated worsening of psychosis, its possible etiology and various treatment strategies.

Topics: Adult; Antipsychotic Agents; Brain; Cholinergic Antagonists; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Eye Movements; GABA Antagonists; Humans; Male; Ocular Motility Disorders; Psychoses, Substance-Induced; Psychotic Disorders; Treatment Outcome; Young Adult

Clozapine causes few extrapyramidal symptoms and is recommended as a treatment drug for severe tardive dyskinesia (TD). However, several case reports have suggested that clozapine could also cause TD. We investigated whether clozapine used as a first-line antipsychotic drug can cause TD.. We identified 101 patients at Yanbian Socio-Mental Hospital and Yanbian Brain Hospital in China who had received clozapine as a primary antipsychotic drug since their first episode of illness and evaluated the prevalence rate, type, and severity of TD using the Extrapyramidal Symptoms Rating Scale (ESRS). The criterion for TD was a score of > or = 3 on one item or 2 on two or more items of the ESRS.. The mean age and duration of illness of the patients were 38.93+/-8.36 and 12.88+/-6.90 years, respectively. The mean duration of clozapine treatment was 12.10+/-6.26 years. The prevalence of TD was 3.96% (4/101). Compared to patients without TD, patients with TD had a long duration of illness and clozapine treatment; all had the orolingual type of TD. TD was relatively mild, with a mean score of 4.75, and tended to accentuate with an activation procedure of rapid pronation and supination of the hands.. These results suggest that clozapine may cause TD; however, the prevalence is low and the severity is relatively mild, with no or mild self-reported discomfort. Therefore, we recommend that regular examination for TD using the activation procedure should be performed in patients who use clozapine on a long-term basis.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; China; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Prevalence; Reactive Oxygen Species; Schizophrenia; Severity of Illness Index; Surveys and Questionnaires

Topics: Adult; Amisulpride; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Male; Schizophrenia, Paranoid; Sulpiride

Tardive dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures, associated with prolonged exposure to antipsychotics. We report a case of a 35-year-old patient with schizophrenia who developed a generalized form of tardive dystonia after switching of clozapine to risperidone treatment that persisted after switch to olanzapine and during the period while treatment with an antipsychotic was discontinued. It was successfully managed with reintroduction of clozapine. The case may represent the first report of generalized tardive dystonia while taking risperidone. The possible pathophysiological bases of the disorder are discussed. The goal of our report is to emphasize that an adequate trial of clozapine is a worthwhile option in the cases of tardive dystonia, even where discontinuation of antipsychotics was unsuccesful.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Dystonic Disorders; Follow-Up Studies; Hospitalization; Humans; Male; Psychiatric Status Rating Scales; Receptors, GABA; Receptors, Muscarinic; Risperidone

Clozapine has been used as an attempt to manage levodopa complications in advanced Parkinson's disease (PD). To investigate the use of clozapine in this context in a Brazilian sample, a retrospective chart review was carried out at the Movement Disorders Clinic from the Federal University of Minas Gerais. This study enrolled 43 PD patients who used or were in use of clozapine. Patients had a mean age of 64 years and a mean UPDRS score of 55. Clozapine was indicated for dyskinesias in 17 patients, for psychosis in 15 and for both reasons in 11. The average maximum dose was 70 mg/day. Twenty six patients used it for a mean of 3.5 years. Twenty nine presented an improvement of their condition, 9 remained clinically stable. Twenty subjects interrupted the use of clozapine, being 9 due to adverse effects. Clozapine may play a role in the management of motor and psychiatric complications in PD, but it is associated with low tolerability.

Topics: Adult; Aged; Antiparkinson Agents; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Psychoses, Substance-Induced; Retrospective Studies

Topics: Antipsychotic Agents; Cholinergic Antagonists; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Electroconvulsive Therapy; Female; Humans; Middle Aged; Schizophrenia

Topics: Adult; Anti-Dyskinesia Agents; Antipsychotic Agents; Clozapine; Cross-Over Studies; Dibenzothiepins; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Substance Withdrawal Syndrome; Treatment Outcome

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Brain; Chlorpromazine; Clozapine; Dopamine; Dyskinesia, Drug-Induced; Humans; Parkinson Disease, Secondary; Risk Factors; Schizophrenia

Tardive dyskinesia (TD) is still a severe side effect induced by old neuroleptic drugs as well as modern atypical ones. The treatment is inefficient and often experimental. Aim of this study was to examine the effect of pramipexole, a dopamine D3 receptor agonist, in a severe case of oro-facial TD.. The TD of a 21 year old male patient with severe oro-facial occurrence was assessed by the Simpson et al scale before starting pramipexole therapy. Reevaluation was made during therapy and when the maximum dose of 1.44 mg a day was reached. Standard therapy with clozapine, valproic acid, oxazepam, bornaprin hydrochlorid and tiapride was continued as before.. Oral dyskinesia decreased 20 % and no side effects were observed. Regarding psychopathology the patient was more interested in work and showed better concentration in therapies.. Pramipexole could be a new promising add-on therapy in severe TD. Additionally, the low plasma binding and mild side effect profile of pramipexole makes it safe in combination with antipsychotic therapy.

Topics: Adjustment Disorders; Aggression; Antipsychotic Agents; Benzothiazoles; Clozapine; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Intellectual Disability; Male; Pramipexole; Receptors, Dopamine D3; Social Behavior Disorders; Young Adult

Topics: Anticonvulsants; Antipsychotic Agents; Blepharospasm; Blinking; Clonazepam; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Psychotic Disorders

Cyproheptadine is a cheap, widely available anti-allergy drug with a broad receptor binding profile which resembles that of clozapine. In rats discriminating clozapine from vehicle cyproheptadine mimicked clozapine very closely. Acutely it induced full generalization in the absence of response suppression, as observed with clozapine. Chronic administration of clozapine and cyproheptadine induced tolerance and cross-tolerance respectively to the clozapine stimulus. This was characterized by circa 3.5-fold parallel shifts to the right in the clozapine generalization curves. Such tolerance and cross-tolerance was spontaneously reversible, suggesting that it was pharmacodynamic, and that clozapine and cyproheptadine induce similar neuroadaptations when administered chronically. Administration of chlordiazepoxide at a very high dose induced no cross-tolerance to the clozapine stimulus showing the pharmacological specificity of tolerance. The clozapine stimulus is a compound cue involving actions at various receptors, and various clozapine-like antipsychotic (APD) drugs generalize fully to it. These data demonstrate that in vivo cyproheptadine resembles clozapine both acutely and chronically. Our findings, in conjunction with other actions of cyproheptadine -- induction of weight gain, alleviation of clozapine withdrawal, anxiolytic actions, alleviation of 'typical' APD-induced motoric side effects, and some preliminary clinical findings -- suggest that further study of cyproheptadine in conjunction with a 'typical' APD for the possible treatment of schizophrenia is merited at both pre-clinical and clinical levels.

Topics: Animals; Anti-Allergic Agents; Antipsychotic Agents; Clozapine; Conditioning, Operant; Cyproheptadine; Discrimination Learning; Discrimination, Psychological; Dose-Response Relationship, Drug; Drug Tolerance; Dyskinesia, Drug-Induced; Female; Generalization, Psychological; Pharmaceutical Vehicles; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Weight Gain

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Schizophrenia

An important goal of current neuroleptic research is to develop antipsychotic compounds with the low incidence of extrapyramidal side effects. The therapeutic success and less side-effect of atypical anti-psychotics such as clozapine and risperidone has focused the attention on the role of receptor systems other than dopaminergic system in the pathophysiology of neuroleptics-associated extrapyramidal side effects. The present study compares the effect of chronic administration of typical and atypical antipsychotics on neurochemical profile in rat forebrain. The study was planned to study changes in extracellular levels of norepinephrine, dopamine and serotonin in forebrain region of brain and tried to correlate them with hyperkinetic motor activities (vacuous chewing movements (VCM's), tongue protrusions and facial jerking) in rats, hall mark of chronic extrapyramidal side-effect of neuroleptic therapy tardive dyskinesia. Chronic administration of haloperidol (1 mg/kg) and chlorpromazine (5 mg/kg) resulted in significant increase in orofacial hyperkinetic movements where as clozapine and risperidone showed less significant increase in orofacial hyperkinetic movements as compared to control. There were also significant decrease in the extracellular levels of neurotransmitters dopamine, norepinephrine and serotonin in fore-brain as measured by HPLC/ED after chronic administration of haloperidol and chlorpromazine. Chronic administration of atypical neuroleptics clozapine and risperidone resulted in the decrease in extracellular concentration of dopamine and norepinephrine but the effect was less significant as compared to typical drugs. However, treatment with atypical neuroleptics resulted in 3 fold increase in serotonin levels as compared to forebrain of control rats. Typical and atypical neuroleptics showed varying effects on neurotransmitters, especially serotonin which may account for the difference in their profile of side effects (Tardive dyskinesia).

Topics: Animals; Antipsychotic Agents; Body Weight; Chlorpromazine; Clozapine; Dopamine; Dyskinesia, Drug-Induced; Haloperidol; Male; Norepinephrine; Prosencephalon; Rats; Rats, Wistar; Risperidone; Serotonin

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Schizophrenia, Paranoid; Schizophrenic Psychology; Serotonin Antagonists

Tardive oculogyric crisis (OGC) is a dystonic syndrome that starts after long-term use of dopamine receptor antagonists. Atypical antipsychotics have reduced liability for inducing tardive dystonia and show antidystonic properties in patients with pre-existing tardive dystonia. Clozapine is an atypical antipsychotic drug, and there have been case reports that clozapine may be an effective treatment for tardive dystonia. Surprisingly, we found that three patients appeared to develop tardive OGC while taking clozapine. The relationship between tardive OGC and clozapine is still unknown. However, it is possible that the previous antipsychotic exposure could have created a sensitising or priming effect on the striatum. Also, there are some suggestions of an underlying susceptibility and possibly a genetic predisposition, at least in some patients.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Ocular Motility Disorders; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Hypothyroidism; Middle Aged; Neurologic Examination; Schizophrenia; Schizophrenic Psychology; Thyroid Function Tests; Thyroxine

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Receptors, Dopamine D2; Schizophrenia; Up-Regulation

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Clozapine; Duloxetine Hydrochloride; Dyskinesia, Drug-Induced; Female; Humans; Psychiatric Status Rating Scales; Schizophrenia, Paranoid; Thiophenes

To report a case of olanzapine-induced Pisa syndrome that improved after treatment with clozapine.. A 22-year-old male with paranoid schizophrenia presented with insidious onset tonic truncal flexion with axial rotation and difficulty in walking after exposure to olanzapine in doses up to 15 mg/day for 9 months. An objective causality assessment suggested that Pisa syndrome was probably related to olanzapine. There was improvement in his symptoms after 6 weeks of treatment with clozapine in doses gradually titrated to 350 mg/day.. Pisa syndrome is a type of dystonia that has been associated with both typical and atypical antipsychotics. Both acute and insidious onset cases have been described in the literature, which have different course and treatment response. Clozapine was found to be effective in reducing the severity of olanzapine-induced Pisa syndrome.. Clozapine may be a useful treatment option for Pisa syndrome that has been caused by olanzapine.

Topics: Adult; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Male; Olanzapine; Schizophrenia, Paranoid; Syndrome

\\Drug-induced tardive dyskinesia (TD) affects approximately 20% to 30% of schizophrenic patients. Although it is usually mild, from 1% to 8% of patients may develop severe TD. Second-generation antipsychotics have demonstrated a lower risk of inducing TD. However, despite the advances brought by second-generation antipsychotics, the treatment strategies for TD remain problematic, given both the lack of an established therapeutic choice and the need for long-term use of antipsychotics in the treatment of schizophrenia. Clozapine is an atypical antipsychotic with minimal risk of inducing TD. Furthermore, it has been suggested that clozapine might actually improve the symptoms of TD. Accordingly, we evaluated the effects of clozapine on severe TD over 5 years. Seven patients meeting Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria for chronic exacerbated schizophrenia (mean age 28.5 +/- 10.2 years) and presenting severe TD, defined as Abnormal Involuntary Movements Scale score above 13, were treated with clozapine and followed up for 5 years. Extrapyramidal Symptoms Rating Scale assessment was performed in all patients at baseline, after 6 months and 3 and 5 years. Mean Extrapyramidal Symptoms Rating Scale scores decreased 83% after 3 years and 87.5% after 5 years. Mean dose for all patients was 428 +/- 269 mg/d after 5 years. Results from this open-label study suggest that clozapine may be a further option for the treatment of TD over long term.

Topics: Adolescent; Adult; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male

Clozapine is indicated in the treatment of patients with tardive dyskinesia. However, there have been some reports of movement disorders associated with clozapine treatment in the literature. The authors report a patient who developed tardive dyskinesia 1 year after initiation of clozapine treatment.. The patient was a 65-year-old male with diagnosis of schizophrenia who had used multiple typical and atypical antipsychotics for 30 years. Clozapine treatment was initiated for his resistant symptoms. He developed buccolingual dyskinesia of moderate severity, which started 1 year after the initiation of clozapine treatment and did not ameliorate during follow-up.. This case may contribute to existing knowledge by raising the possibility that clozapine can induce dyskinesia.

Topics: Aged; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Schizophrenia; Schizophrenic Psychology

We conducted an analogue functional analysis contrasting motor tasks with varying types of social consequences for movements associated with tardive dyskinesia (TD) in 2 men who had been diagnosed with developmental disabilities and TD. Our findings suggest that TD-related movements were not a function of social reinforcement contingencies. However, motor-activation tasks decreased TD-related movements, suggesting a possible novel intervention.

Topics: Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Intellectual Disability; Male; Middle Aged

A novel method of oral drug administration was used in a neuroleptic animal study. Seventy male Sprague-Dawley rats were randomly subdivided into four groups, which were treated with clozapine, haloperidol, diazepam or a vehicle solution (5% sucrose solution). Oral drug treatment was achieved by training the rats to drink the drug of choice mixed with five percent sucrose or vehicle solution from a syringe. Within 3-4 weeks the haloperidol group developed vacuous chewing movement, which did not disappear with discontinuation of the drug. Significant weight gain was observed for all drug groups in relation to the control group, whereas only the diazepam group showed a significant increase in response latency on the disengage test of sensorimotor function, which disappeared with drug withdrawal. A novel means of testing the motivational status showed that all drug-treated groups engaged in eating chocolate before grooming (t=11.69, p<0.001), whereas the control group showed no specific tendency towards either task. Furthermore, there was a significant delay in grooming for the haloperidol group compared to the other drug groups and controls. In conclusion, a novel method of oral drug administration with minimum stress was introduced that was sufficient to cause the described changes in behavioural parameters. Additionally, the combination of tests used provided an efficient discrimination between the behavioural effects of clozapine, haloperidol and diazepam in rodents.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Behavior, Animal; Body Weight; Brain; Clozapine; Diazepam; Disease Models, Animal; Dyskinesia, Drug-Induced; Grooming; Haloperidol; Male; Mastication; Motivation; Motor Activity; Rats; Rats, Sprague-Dawley; Reaction Time

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; GABA Antagonists; Humans; Olanzapine; Patient Compliance; Schizophrenia

Topics: Adult; Basal Ganglia; Benperidol; Carbon Radioisotopes; Clozapine; Dihydroxyphenylalanine; Dyskinesia, Drug-Induced; Fluorine Radioisotopes; Humans; Male; Raclopride; Receptors, Dopamine D2; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome; Ultrasonography

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Humans; Levodopa; Randomized Controlled Trials as Topic

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus; Dyskinesia, Drug-Induced; Humans; Patient Compliance; Schizophrenia; Weight Gain

We studied whether movements associated with tardive dyskinesia (TD) served operant functions in 2 men with developmental disabilities. We found that TD-related movements occurred more frequently in the alone and attention conditions and less frequently in control and demand conditions. Our findings suggest that TD-related movements may not be maintained by social reinforcers and that decreases in TD movements are possibly a result of engagement in activities that are incompatible with TD movements.

Topics: Antipsychotic Agents; Benztropine; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Middle Aged; Observer Variation; Psychotic Disorders; Severity of Illness Index; Videotape Recording

Topics: Animals; Antipsychotic Agents; Callithrix; Clozapine; Dibenzothiazepines; Disease Models, Animal; Dyskinesia, Drug-Induced; Humans; Quetiapine Fumarate; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Fluphenazine; Haloperidol; Humans; Longitudinal Studies; Schizophrenia, Paranoid

Topics: Antipsychotic Agents; Clozapine; Diagnosis, Differential; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Schizophrenia

Clozapine is indicated for the treatment of patients intolerant of conventional antipsychotic agents. It is often used to treat those patients who have developed movement disorders while on conventional antipsychotics. We report three cases of dyskinesia associated with clozapine induction. We suggest a mechanism that might explain an underlying dopaminergic hypersensitivity during this transitional period. Further, we identify groups that might be at high risk of developing dyskinesia and suggest strategies to reduce risk especially in these groups.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Schizophrenia

The behavioral and neurochemical effects of switching from typical to atypical medications have not been evaluated in the rodent models of tardive dyskinesia. Thus, we treated rats with haloperidol-decanoate for 12 weeks, and assessed the effects of additional treatment with olanzapine, haloperidol, clozapine, or vehicle on vacuous chewing movements and expression of transcripts for dopamine receptors, tyrosine hydroxylase, delta-opioid receptor, prodynorphin, preproenkephalin, glutamic acid decarboxylase-65 (glutamic acid decarboxylase (GAD)-65) and GAD-67 and N-methyl-D-aspartate (NMDA) receptor subunits in the striatum and its efferent pathways. Haloperidol-decanoate induced vacuous chewing movements extinguished following an additional 4 weeks of treatment with vehicle, olanzapine or haloperidol, but not clozapine. Post-treatment, vacuous chewing movements in the clozapine group were significantly higher than the vehicle, olanzapine and haloperidol groups. GAD-67 mRNA expression in the globus pallidus was decreased following additional treatment with olanzapine or haloperidol, but not clozapine. Changes in expression of other transcripts were not detected. These findings demonstrate important differences in the effects of typical and atypical antipsychotics on chronic vacuous chewing movements.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Brain; Clozapine; Dyskinesia, Drug-Induced; Gene Expression; Haloperidol; In Situ Hybridization; Injections, Intramuscular; Male; Mastication; Olanzapine; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; RNA, Messenger

Our report of a patient with severe tardive dyskinesia (TD) who has been exposed to both typical antipsychotic and clozapine, olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD. Persistently high AIMS scores during all the periods of treatment with typical antipsychotics contrast strongly with the drop in scores that occurs in strict chronological sequence after switching to both clozapine (45%), olanzapine (27.8%) and quetiapine (85%). Since the reversal to haloperidol from the three atypical agents was systemically associated with a return to high AIMS scores, it seems likely that the improvement noted with clozapine, olanzapine and quetiapine represents a temporary symptomatic effect rather than a sustained resolution of the disorder. The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against TD symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific. Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect.

Topics: Amphetamine-Related Disorders; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Olanzapine; Quetiapine Fumarate; Schizophrenia, Paranoid

Topics: Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; Dystonia; Female; Humans; Piperazines; Schizophrenia; Serotonin Antagonists; Thiazoles

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Olanzapine; Pirenzepine; Schizophrenia

A series of chiral benzylpiperazinyl-1-(2,3-dihydro-indol-1-yl)ethanone derivatives were prepared and examined for their affinity at dopamine D(2) and D(4) receptors. Three compounds having D(2)/D(4) affinity ratios approximating that found for the atypical neuroleptic clozapine were further evaluated in behavioral tests of antipsychotic efficacy and motor side effects.

Topics: Amphetamine; Animals; Antipsychotic Agents; Binding, Competitive; Catalepsy; Central Nervous System Stimulants; Clozapine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Evaluation, Preclinical; Dyskinesia, Drug-Induced; Half-Life; Haloperidol; Humans; In Vitro Techniques; Indicators and Reagents; Indoles; Motor Activity; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D4; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship

Tardive dystonia is an uncommon form of chronic dystonia, which usually develops on exposure to neuroleptics. Tardive dystonia (Tdt) following lithium therapy has not been previously reported. The case of 38 year old man with bipolar affective disorder who developed tardive dystonia while on maintenance lithium treatment is described. Presentation of Tdt in this patient was fairly characteristic although there was no suggestion of recent neuroleptic exposure. Tdt known to have poor treatment response, responded very well to clozapine, a novel anti-psychotic, in this case. To conclude, Tdt may develop on exposure to drugs other than neuroleptics. An adequate trial to clozapine can prove to be a useful treatment option.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Lithium; Male

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Psychotic Disorders

Administration of typical antipsychotic drugs (APDs) is often accompanied by extrapyramidal side-effects (EPS). Treatment with atypical APDs has a lower incidence of motor side-effects and atypical APDs are superior to typical APDs in treating the negative symptoms of schizophrenia. Although typical APDs strongly induce the immediate-early gene c-fos in the striatum while atypical APDs do so only weakly, it is possible that the effects of atypical APDs are more pronounced within certain regions of the striatum. The striatum contains two histochemically defined compartments, the striosome (patch) and the matrix. These compartments have been well characterized anatomically but their functional attributes are unclear. We therefore examined the effects of typical and atypical APDs on Fos expression in the striosome and matrix of the rat. Typical and atypical APDs were distinguished by the pattern of striatal compartmental activation they induced: the striosome : matrix ratio of Fos-li neurons was greater in rats treated with atypical APDs. Pretreating animals with selective antagonists of receptors that atypical APDs target with high affinity did not increase the striosome : matrix Fos ratio of typical APD-treated rats and thus did not mimic the ratio seen in response to atypical APDs. However, pretreatment with the atypical APD clozapine did recapitulate the characteristic compartmental Fos pattern seen in response to typical APDs. These data suggest that some characteristics of atypical APDs, such as the lower EPS liability and greater reduction of negative symptoms, may be linked to the coordinate regulation of the striatal striosome and matrix.

Topics: Animals; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Haloperidol; Male; Muscarinic Antagonists; Neostriatum; Neurons; Neuropil; Proto-Oncogene Proteins c-fos; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Neurotransmitter; Serotonin Antagonists

In the present work, we investigated if an impairment of dopaminergic neurons after subchronic haloperidol treatment might be a possible physiopathologic substrate of the "early onset" vacuous chewing movements (VCMs) in rats. For this purpose, different antipsychotics were used to analyse a possible relationship between VCMs development and morphological alterations of tyrosine-hydroxylase-immunostained (TH-IM) neurons. Rats treated twice a day with haloperidol displayed a significant increase of VCMs that was both time- (2-4 weeks) and dose (0.1-1 mg/kg) dependent. Immunocytochemical analysis showed a shrinkage of TH-IM cell bodies in substantia nigra pars compacta and reticulata and a reduction of TH-immunostaining in the striatum of haloperidol treated rats with the arising of VCMs. No differences were observed in TH-IM neurons of ventral tegmental area and nucleus accumbens vs. control rats. The atypical antipsychotics risperidone (2 mg/kg, twice a day), amisulpride (20 mg/kg, twice a day) and clozapine (10 mg/kg, twice a day) did not produce any nigro-striatal morphological changes or VCMs. TH-IM nigro-striatal neuron morphological alterations and VCMs were still present after three days of withdrawal in rats treated for four weeks with haloperidol (1 mg/kg). Both the main morphological changes and the behavioural correlate disappeared after three weeks of withdrawal. These results suggest that haloperidol induces a morphological impairment of the dopaminergic nigro-striatal neurons which is directly associated with the arising, permanency and disappearance of VCMs in rats.

Topics: Amisulpride; Animals; Antipsychotic Agents; Clozapine; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Haloperidol; Male; Mastication; Neostriatum; Nerve Degeneration; Neural Pathways; Neurons; Rats; Rats, Sprague-Dawley; Risperidone; Substance Withdrawal Syndrome; Substantia Nigra; Sulpiride

Topics: Adult; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Female; Humans; Olanzapine; Pirenzepine; Tongue Diseases

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.

Topics: Animals; Antipsychotic Agents; Apomorphine; Behavior, Animal; Cebus; Dibenzothiazepines; Dopamine Antagonists; Dyskinesia, Drug-Induced; Female; Male; Mice; Quetiapine Fumarate; Receptors, Dopamine D2; Stereoisomerism; Structure-Activity Relationship

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Interactions; Dyskinesia, Drug-Induced; Humans; Olanzapine; Ondansetron; Pirenzepine; Receptors, Serotonin; Serotonin Antagonists

Topics: Aged; Antipsychotic Agents; Clozapine; Dementia; Dyskinesia, Drug-Induced; Humans; Nursing Homes

Topics: Clozapine; Dopamine Antagonists; Dyskinesia, Drug-Induced; Female; Humans; Metoclopramide; Middle Aged; Nausea; Schizophrenia; Syndrome

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Hallucinations; Humans; Male; Olanzapine; Parkinson Disease; Pirenzepine

Changes in striatopallidal GABA are believed to play a significant role in the motor side effects produced by antipsychotic drugs (APDs). In the current study, we measured extracellular GABA in the globus pallidus (GP) of rats. GABA release was partially impulse- and Ca2+-dependent, as evidenced by decreased efflux following tetrodotoxin (TTX) or removal of Ca2+. In addition, GABA release was significantly increased by high K+ (100 mM KCl) stimulation. Reverse dialysis of the atypical APD, clozapine (1-100 microM), produced a concentration dependent decrease in extracellular GABA. In contrast, the typical APD, haloperidol (1-100 microM), had no significant effect on GABA levels. These results suggest that clozapine has direct actions within the GP, while the effects of haloperidol are most likely mediated through its effects in the striatum. The clozapine-induced decrease in pallidal GABA may account for its low motor side effect liability.

Topics: Animals; Antipsychotic Agents; Calcium; Clozapine; Dose-Response Relationship, Drug; Down-Regulation; Dyskinesia, Drug-Induced; Extracellular Space; Female; gamma-Aminobutyric Acid; Globus Pallidus; Haloperidol; Microdialysis; Neurons; Potassium; Rats; Rats, Sprague-Dawley; Tetrodotoxin

Converging evidence indicates that, in controlled drug trials, individuals receiving novel antipsychotic medications have fewer adverse effects than those receiving conventional antipsychotic medications. This in turn may lead to greater patient treatment satisfaction. This study examines patient satisfaction and burden of adverse effects in a county-wide epidemiologic study of first admission psychotic persons with psychosis who were receiving novel antipsychotic drugs (n = 42). Comparisons were made within this group, and between 25 of these persons and 25 others with the same diagnosis and sex, from the same epidemiologic study, who were receiving a comparable regimen of conventional antipsychotic drugs. Patients receiving novel antipsychotics were significantly more satisfied and were significantly less burdened by adverse effects than those receiving conventional antipsychotics. Among the group receiving novel antipsychotics, dosage was not related to satisfaction or burden of adverse effects. For those treated with risperidone (n = 27), there was a difference, approaching statistical significance, for greater satisfaction and less adverse effect burden among those persons with dosages less than 5 mg daily as compared to higher dosages.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Depressive Disorder, Major; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neurologic Examination; Olanzapine; Patient Satisfaction; Pirenzepine; Risperidone; Schizophrenia; Schizophrenic Psychology

Typical neuroleptic therapy often results in extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Recent reports reveal neurotoxic activity in some neuroleptics. We hypothesized that neurotoxicity might be implicated in EPS. This study aims to evaluate the neurotoxic activity of typical and atypical neuroleptics and to determine the possible role of neurotoxicity in neuroleptic-induced EPS. Perphenazine, haloperidol, clozapine, sulpiride, and risperidone (10-100 microM) were administered, either alone or combined with dopamine, to primary mouse neuronal or intact brain culture and to a human neuroblastoma (NB) cell line (SK-N-SH). Cell viability (measured by neutral red and alamar blue), DNA fragmentation (flow cytometry-NB) were determined. Neuroblastoma: perphenazine, clozapine, and haloperidol (100 microM) decreased viability by 87, 43, and 34% respectively. Sulpiride and risperidone were not toxic. At 10 microM, toxicity decreased markedly. Dopamine (125 microM) potentiated the perphenazine-induced toxicity. Flow cytometry of NB cells treated with perphenazine (2.5-40 microM) showed an increase (perphenazine 20 microM, 40 microM, 48 h) in fragmented DNA (74.7% and 95.0% vs. 8.7% in controls). Lower concentrations increased the G1 phase and decreased S phase in the cell cycle. In primary neurons, perphenazine, haloperidol, and clozapine, but not risperidone and sulpiride, induced a significant neurotoxic effect, which, in intact brain culture, was absent (haloperidol and clozapine) or lowered (perphenazine). Dopamine (0.5 mM) did not modify the effect of the drugs in the primary cultures. Neuroleptics possess differential neurotoxic activity with higher sensitivity of neoplasm tissue (NB compared to primary cultures). The order of toxicity was perphenazine > haloperidol = clozapine:sulpiride and risperidone were not toxic. Neurotoxicity is independent of dopamine and is associated with cell cycle arrest and apoptosis. With the exception of clozapine, neurotoxicity seems relevant to neuroleptic-induced EPS and TD.

Topics: Animals; Antipsychotic Agents; Basal Ganglia Diseases; Brain; Cell Cycle; Cell Survival; Clozapine; DNA Fragmentation; Dopamine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Iatrogenic Disease; Mice; Mice, Inbred ICR; Neurons; Neurotoxins; Perphenazine; Pregnancy; Risperidone; Tumor Cells, Cultured

Neuroleptic-induced tardive dyskinesia, which often appears in middle-aged and older adults early in the course of treatment with low doses of conventional antipsychotics, is 5 to 6 times more prevalent in elderly than in younger patients. In addition to age, other risk factors for tardive dyskinesia include early extrapyramidal symptoms (EPS), cumulative amounts of neuroleptics, duration of neuroleptic treatment, and history of alcohol abuse and/or dependence. The atypical antipsychotics, which have a low liability for EPS, are likely to also have low potential for tardive dyskinesia, despite the paucity of controlled studies. Starting and maintenance doses of the atypical antipsychotics should generally be lower in older than in younger adults.

Topics: Adult; Age Factors; Aged; Alzheimer Disease; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Incidence; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risk Factors; Risperidone

Clozapine therapy for 2,996 patients with treatment-refractory schizophrenia was examined over a five-year period in the Veterans Affairs health care system. Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) and the Abnormal Involuntary Movement Scale (AIMS). BPRS scores, which were available for 522 patients, indicated a significant improvement, as did AIMS scores, which were available for 252 patients. Compared with individuals who showed a modest improvement, those with a more robust response to clozapine had higher initial BPRS scores and were three times more likely to have been suicidal in the month before starting clozapine therapy.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neurologic Examination; Psychiatric Status Rating Scales; Schizophrenia; Veterans

In 200 inpatients on regular neuroleptics, point prevalence of extrapyramidal syndromes, including Parkinson syndrome, akathisia and tardive dyskinesia (TD), was studied and found to be 20, 11 and 22%, respectively. A total of 46 patients have currently, and for a longer time, (average about 3years, median over 1year) been treated with clozapine, and 127 with typical neuroleptics (NLs). Comparing both groups, higher TD scores were found in the clozapine sample. Investigating the influence of a set of seven clinical variables on the TD score with the help of multiple regression analysis, the influence of the treatment modality disappeared, whereas the age proved to be the only significant variable. Studying the role of past clozapine therapy in patients currently on typical NLs and comparing 10 matched pairs of chronic patients with and without TD in whom a complete life-time cumulative dose of NLs was identified, a relationship between TD and length of current typical NL therapy and life-time typical NL dosage could be demonstrated. On the whole, long-term relatively extensive use of clozapine has not markedly reduced the prevalence of extrapyramidal syndromes in our psychiatric inpatient population. In particular, we failed to demonstrate a beneficial effect of clozapine on prevalence of TD. There are certainly patients who suffer from TD in spite of a long-term intensive clozapine treatment.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Mental Disorders; Middle Aged; Prevalence; Time Factors

Topics: Acute Disease; Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Cost-Benefit Analysis; Dibenzothiazepines; Dibenzothiepins; Dyskinesia, Drug-Induced; Germany; Humans; Neurotransmitter Agents; Olanzapine; Patient Compliance; Pirenzepine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Sulpiride

Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapine is related to antagonism at the dopamine D(4) receptor, we investigated the effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa were used in this study. They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-Dopa/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The present results suggest that novel selective dopamine D(4) receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias.

Topics: Analysis of Variance; Animals; Antiparkinson Agents; Behavior, Animal; Benserazide; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Levodopa; Macaca fascicularis; Motor Activity; Parkinsonian Disorders

Topics: Antipsychotic Agents; Black People; Clozapine; Diabetes Mellitus, Type 2; Dyskinesia, Drug-Induced; Humans; Hyperglycemia; Netherlands Antilles; Risk Factors

Tardive dyskinesia (TD) continues to be a significant health problem and a serious limitation to neuroleptic medication treatment. Clozapine treatment may reduce the severity of TD but it is unclear wether the medication temporarily suppresses symptoms or leads to a sustain resolution of the disorder. Herein we describe two cases with severe TD which clozapine had to be discontinued. These cases suggest that clozapine provides a temporary suppression of TD rather than a permanent resolution of the disorder.

Topics: Aged; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Middle Aged; Recurrence; Serotonin Antagonists; Severity of Illness Index; Time Factors

The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2. The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to the wild-type mice (p = 0.0286), while there was a trend for the AUC of clozapine N-oxide to be greater in the CYP1A2 -/- mice (p = 0.0571). The CYP1A2 -/- mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that, in vivo, CYP1A2 is the major determinant of clozapine clearance, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation. Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures.

Topics: Animals; Antipsychotic Agents; Area Under Curve; Behavior, Animal; Biotransformation; Body Weight; Chromatography, High Pressure Liquid; Clozapine; Cytochrome P-450 CYP1A2; Dyskinesia, Drug-Induced; Half-Life; Mice; Mice, Knockout; Spectrophotometry, Ultraviolet

The present study evaluated chronic oral treatment of rats with haloperidol or clozapine. Drugs were given in the drinking water for a 23-day period. Rat behavior was analyzed once a week in an open field. Rats ingested either 1.7 mg/kg haloperidol or 40 mg/kg clozapine daily. Blood serum analysis revealed concentrations of 6 ng/ml for haloperidol and 22 ng/ml for clozapine at the end of the treatment. Haloperidol decreased overall activity from the onset of treatment. Clozapine showed similar effects only on the last test day. Control animals showed a slight habituation in exploration-related parameters. In conclusion, these results indicate that oral drug administration through the drinking water is a suitable mode of noninvasive chronic treatment that led to sufficiently high drug levels to induce specific pharmacological effects in rats.

Topics: Administration, Oral; Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Dyskinesia, Drug-Induced; Exploratory Behavior; Female; Habituation, Psychophysiologic; Haloperidol; Locomotion; Rats; Rats, Sprague-Dawley; Time Factors; Weight Gain

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Psychotic Disorders; Quetiapine Fumarate; Schizophrenia

Rats received haloperidol (1.0 mg/kg i.p.) or clozapine (10 mg/kg i.p.), twice daily for 4 weeks: vacuous chewing--recorded 26 h after the final injection--similarly increased in both groups. Three h later, the rats were challenged with dopaminomimetics, and automatically recorded jaw movements were analysed. Both apomorphine and a mixture of D1 and D2 receptor agonists (SKF 38393 resp. quinpirole) increased jaw movements in haloperidol-treated, but not clozapine-treated rats; SKF 38393 or quinpirole remained ineffective, when given alone. A fixed dose of quinpirole together with increasing doses of SKF 38393, but not a fixed dose of SKF 38393 together with increasing doses of quinpirole, produced a dose-dependent increase in jaw movements in otherwise non-treated rats, suggesting that the noted haloperidol-induced increase was due to a shift in the D1-D2 receptor balance towards a predominance of D1 receptors. This study presents a new animal model of tardive dyskinesia with predictive validity, good reliability and, especially, great efficiency.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Behavior, Animal; Clozapine; Disease Models, Animal; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dyskinesia, Drug-Induced; Haloperidol; Jaw; Male; Mastication; Quinpirole; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Serotonin Antagonists

Antipsychotic-induced extrapyramidal adverse effects continue to be a serious problem in the treatment of psychotic disorders. While the pathophysiology of these adverse effects is not well understood, much recent research has focused on improving our ability to use available pharmacotherapy in the most effective and least toxic manner. Acute dystonic reactions only occur within the first days of antipsychotic treatment. They are often distressing and frightening for the patient and may even be dangerous. However, they can be effectively prevented or reversed with anticholinergics. Furthermore, the growing use of the new atypical antipsychotics will lead to a significant decrease in the rate of acute dystonic reactions. In contrast, tardive dystonia is a long-lasting menace in the course of antipsychotic treatment, for which there is no established therapy. Tardive dystonia is sometimes disabling or disfiguring and, like other tardive disorders, is potentially irreversible. Because, in most cases, patients need to continue taking the antipsychotic that has caused the adverse effect to prevent relapse of the mental illness, preventive measures are crucial. Antipsychotics should be prescribed only for patients affected by psychotic disorders, when definitely indicated and at the lowest effective dosage. The use of clozapine and other novel antipsychotic agents is also likely to represent an important step in the prevention and treatment of tardive dystonia. Compared with traditional antipsychotics, most of the new antipsychotics are characterised by a low acute extrapyramidal adverse effects liability and they also bring the hope of reducing the risk of tardive disorders. If tardive dystonia has occurred, switching to clozapine or another atypical antipsychotic and treatment with tetrabenazine, reserpine and botulinum toxin are possible options.

Topics: Antipsychotic Agents; Cholinergic Antagonists; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Prevalence; Risk Factors; Risperidone

1. Tardive Dyskinesia (TD) can be a serious consequence of the use of antipsychotic medications to treat psychotic illness. There is evidence to suggest that the atypical antipsychotic, clozapine, is less likely to cause, and may even ameliorate TD. 2. The authors reviewed their experience regarding clozapine and TD among patients in their Clozapine Clinic, and summarize some of the recent clinical literature in this area. 3. Retrospective review of chart records for 13 patients was carried out. Comparisons of TD and symptom rating scales were made: 1) between groups (with and without TD) at baseline; 2) between individuals (self as own control) in the TD group at baseline and at the end of the follow-up period. 4. Subjects with and without TD at baseline had a significant decrease in psychiatric symptoms over the course of treatment. 5. In those with TD at baseline, mean Abnormal Involuntary Movement Scale (AIMS) score decreased by 85% over 10.3 +/- 5.5 (mean +/- S.D.) months at a dose of 358 +/- 196 mg/day of clozapine. 6. The data, and the recently published clinical literature on clozapine and TD, continue to support the striking utility of clozapine for chronically psychotic patients, and particularly those with TD.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Male; Middle Aged; Schizophrenia; Tremor

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Syndrome

Relationships between symptom profile and clozapine response were studied. Symptom scores on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms were subjected to principal component analysis (PCA) in a group of 66 treatment-resistant schizophrenic patients, 49 of whom were treated with clozapine. Factor scores were compared among responders, non-responders and partial responders. The PCA yielded a four-factor solution, with positive symptoms, negative symptoms, cognitive disorganization and behavioral disorganization components. Cognitive and behavioral disorganization syndrome scores showed significant differences across groups. Cognitive disorganization was higher in non-responders, while behavioral disorganization was higher in partial responders. The results support the possibility of using clinical profiles to predict therapeutic response to clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neurologic Examination; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Syndrome; Treatment Outcome

Whether the pathophysiology and treatment of neuroleptic-induced oral dyskinesias in rats parallel that for tardive dyskinesia in humans remains a question. To address the issue further, Sprague Dawley rats were treated for 6 months with multiple oral doses of haloperidol (1.5 and 3.0 mg/ kg/day) or clozapine (10, 20, and 30 mg/kg/day) and compared with water treated animals. The rate of oral dyskinesias was monitored at study start and monthly by trained raters who were blind to treatment group. All haloperidol-treated rats developed oral dyskinesias at a significantly higher rate than rats treated with water (p = 0.0007) or those treated with clozapine (p = 0.0017). Each dose of haloperidol produced significantly higher rates of oral dyskinesias than did any dose of clozapine and did so in an apparent dose-sensitive manner. Clozapine lacked a dose-sensitive relationship with the oral dyskinesias, and failed to show a significant difference in rate from control rats at any dose. Plasma levels of haloperidol with these doses were in the human therapeutic range; with clozapine only the highest dose produced plasma levels in the human therapeutic range. These data show little association between rat oral dyskinesias and clozapine treatment, whereas a strong association is present with haloperidol. The data are, thereby, consistent with the clinical association of tardive dyskinesia with typical neuroleptics like haloperidol but not with the atypical neuroleptic clozapine.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Haloperidol; Male; Rats; Rats, Sprague-Dawley

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydroc hlo ride) is a novel dopamine D2 family receptor agonist with a predominant action on D2 autoreceptors and with some D3 vs. D2 receptor preference. The central behavioural effects of pramipexole given subcutaneously to rats (male Wistar) and mice (Albino Swiss) are presented in this paper. Used in low doses (0.001-0.1 mg/kg), pramipexole induced locomotor hypoactivity which was antagonized by a low dose of spiperone; at higher doses (0.3, 1 mg/kg) it evoked hyperactivity which was inhibited by haloperidol, sulpiride and clozapine, but not by SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride). Pramipexole (0.1-1.0 mg/kg) antagonized the akinesia induced by combined pretreatment with reserpine (5 mg/kg) and alpha-methyl-p-tyrosine (250 mg/kg). Pramipexole (0.1-1 mg/kg) potentiated the hyperkinetic effect of L-DOPA (L-3,4-dihydroxyphenylalanine) (50 and 200 mg/kg, together with benserazide, 50 mg/kg) in naive and monoamine-depleted (reserpine + alpha-methyl-p-tyrosine) rats. The higher doses of pramipexole (1 and 3 mg/kg) evoked stereotypy which was antagonized by pretreatment with sulpiride or clozapine. The catalepsy induced by haloperidol, spiperone or fluphenazine was antagonized by pramipexole (1-3 mg/kg). Pramipexole (1 mg/kg) induced hypothermia in mice, which was antagonized by sulpiride. The obtained results indicate that pramipexole: (i) at low doses stimulates the dopamine D2 presynaptic autoreceptors; (ii) at higher doses stimulates dopamine D2 postsynaptic receptors. An effect on the dopamine D3 receptor cannot be excluded. At low doses pramipexole may have antipsychotic activity, and at higher ones antiparkinsonian activity.

Topics: Animals; Antiparkinson Agents; Benzazepines; Benzothiazoles; Body Temperature; Catalepsy; Clozapine; Dopamine Agents; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; Haloperidol; Injections, Subcutaneous; Levodopa; Male; Mice; Motor Activity; Pramipexole; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3; Spiperone; Stereotyped Behavior; Sulpiride; Thiazoles

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Neurologic Examination; Paroxetine; Serotonin Receptor Agonists; Sumatriptan

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Haloperidol; Humans; Male; Schizophrenia; Substance Withdrawal Syndrome

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Male; Paranoid Disorders; Psychotic Disorders; Reserpine; Treatment Outcome

Topics: Benztropine; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Schizophrenia, Paranoid; Substance Withdrawal Syndrome

Topics: Adult; Antipsychotic Agents; Bromocriptine; Clozapine; Dancing; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Dystonia; Humans; Male; Psychotic Disorders; Trihexyphenidyl; Vitamin E

This study evaluates clozapine and its present role in the pharmacotherapy of schizophrenia.. Clozapine's current clinical status is reviewed, as is its position with respect to other treatment options.. Clozapine represents the prototype of "atypical" neuroleptics, with evidence of clinical efficacy in both positive and negative symptoms, as well as a diminished risk of extrapyramidal side effects. It is the only neuroleptic to date that has established itself as having little, if any, risk of tardive dyskinesia. More recent research has focused on its potential for overall savings in health care costs, as well as possible benefits in the area of neuropsychological functioning.. Evidence suggesting that the course of schizophrenia can be altered by effective treatment favours a systematic approach that optimizes treatment options. While clozapine does not represent a 1st-line agent because of its risk of agranulocytosis, it has an integral role to play in treatment-resistant schizophrenia or in individuals experiencing intolerable side effects with conventional neuroleptics.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Cost-Benefit Analysis; Dyskinesia, Drug-Induced; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Three studies were undertaken to investigate the effects of the atypical neuroleptic clozapine on the vacuous jaw movements induced by cholinergic stimulation in rats. In the first experiment, acute clozapine injections (4.0-16.0 mg/kg) produced a dose-related suppression of the vacuous jaw movements induced by 0.4 mg/kg physostigmine. In the second experiment, acute injections of clozapine (2.0-16.0 mg/kg) also suppressed vacuous jaw movements induced by 4.0 mg/kg pilocarpine in a dose-related manner. The third experiment was designed to compare the effects of acute and repeated administration of 16.0 mg/kg clozapine. In this experiment, there were three groups: one that received 4.0 mg/kg pilocarpine, a second group that received pilocarpine plus an acute injection of 16.0 mg/kg clozapine, and a third group that received injections of 16.0 mg/kg clozapine for 14 consecutive days, including the final day in which they also were injected with pilocarpine. For the third experiment, animals were assessed for the sedative effects of clozapine as well as vacuous jaw movements. The results indicated that either acute or repeated injections of 16.0 mg/kg clozapine reduced vacuous jaw movements relative to rats that received pilocarpine alone, and the two clozapine-treated groups did not differ from each other. The sedation ratings indicated that acute injections of 16.0 mg/kg clozapine produced substantial drowsiness and sedation, whereas rats that had received clozapine for 14 days did not show substantial sedation. These results indicate that clozapine can suppress cholinomimetic-induced vacuous jaw movements. The suppressive effects of clozapine on pilocarpine-induced vacuous jaw movements do not show tolerance within the 14-day period of repeated injections, whereas the sedative effects of clozapine do show tolerance. Thus, these results demonstrate that the suppression of pilocarpine-induced vacuous jaw movements by clozapine is not merely an artifact of clozapine-induced sedation. Because pilocarpine-induced vacuous jaw movements share some characteristics with human parkinsonian symptoms, the present results are consistent with previous reports indicating that repeated injections of clozapine produce anti-parkinsonian effects.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Hypnotics and Sedatives; Male; Parasympathomimetics; Physostigmine; Pilocarpine; Rats; Rats, Sprague-Dawley

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Neurologic Examination; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Male; Neurologic Examination; Schizophrenia; Schizophrenic Psychology; Vomiting

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Haloperidol; Humans; Injections, Intramuscular; Male; Neurologic Examination; Schizophrenia; Schizophrenic Psychology; Social Behavior; Substance Withdrawal Syndrome; Tourette Syndrome

This study estimated rates of eligibility for treatment with clozapine among clients in a public mental health system using criteria with various degrees of restrictiveness.. A stratified, random cluster sample of 293 clients was selected from among all clients with schizophrenic disorders known to the mental health system of the city and county of San Francisco during 1991. Data on variables associated with eligibility for clozapine were abstracted from clinical records, and eligibility was estimated using broad and stringent criteria.. An estimated 42.9 percent of the clients were eligible for clozapine using broad eligibility criteria that included a diagnosis of schizophrenia or schizoaffective disorder, two previous neuroleptic trials of at least 600 mg per day chlorpromazine equivalents for at least four weeks or tardive dyskinesia, Global Assessment of Functioning score less than 61, and no contraindications. Eliminating eligibility due to tardive dyskinesia alone, excluding persons with schizoaffective disorder, requiring six-week medication trials, and requiring three adequate medication trials instead of two resulted in substantial reductions in the rate of eligibility.. Varying interpretations of the criteria for clozapine treatment listed in the medication package insert dramatically affect patients' eligibility for clozapine. Mental health agencies should endeavor to maintain a balance between restricting use of clozapine due to cost and providing it to the full spectrum of patients who might benefit from the medication.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Eligibility Determination; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Psychotic Disorders; Public Sector; San Francisco; Schizophrenia; Schizophrenic Psychology; United States; United States Food and Drug Administration

Various types of movement disorder have been reported to occur rarely in patients treated with clozapine. This paper describes five cases in which these phenomena appeared to be clearly associated with clozapine medication and discusses possible pharmacologic mechanisms and treatment options.. Inpatients receiving clozapine were investigated for the presence of movement disorders. We present five patients with clozapine-induced myoclonus, describe their patterns, and compare clinical features.. Five patients treated with clozapine developed a similar pattern of movement disorder that can be described as myoclonus. The neurologic symptoms improved after the treatment was discontinued, the clozapine dose reduced, or concomitant carbamazepine administered.. Clozapine can induce dose-dependent myoclonus. However, these symptoms can be relieved by reducing the dose of clozapine or giving carbamazepine so that discontinuation of clozapine treatment can be avoided.

Topics: Adult; Antipsychotic Agents; Carbamazepine; Clozapine; Depressive Disorder; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Hospitalization; Humans; Male; Middle Aged; Myoclonus; Schizophrenia

Schizophrenics with a neurodevelopmental disturbance resulting in micro- and macroanatomical cortical abnormalities are supposed to form a subgroup clinically characterized by low premorbid adjustment, early onset, incomplete remission, poor outcome, male predominance and high risk for tardive dyskinesia. A small amplitude of the event-related P3 (P300) potential could be a marker of this subgroup, because the cortical neurons and their orderly laminar arrangement are crucial for the electrogenesis of P3. In a 2-year follow-up study, auditory evoked P3 was recorded in 89 stabilized schizophrenic outpatients. Patients who developed tardive dyskinesia during the follow-up had smaller P3 than matched controls. Furthermore, a small P3 was associated with low premorbid adjustment, pronounced residual symptoms, low relapse rate, and male predominance. These findings indicate that schizophrenic patients with a reduced P3 have a higher risk of developing tardive dyskinesia and correspond clinically to a schizophrenic subgroup with a supposedly neurodevelopmental disturbance.

Topics: Adult; Age of Onset; Biperiden; Clozapine; Dyskinesia, Drug-Induced; Evoked Potentials; Female; Follow-Up Studies; Humans; Male; Middle Aged; Perazine; Schizophrenia; Severity of Illness Index; Sex Factors

We report six cases of psychosis in patients with akinetic-rigid syndromes who were treated with risperidone.. Five of the six patients experienced intolerable exacerbation of parkinsonism. Four subsequently did well on clozapine therapy. One patient required nursing home placement and a feeding gastrostomy as a result of the worsening parkinsonism during risperidone treatment, but was able to return home and have the gastrostomy removed after switching from risperidone to clozapine. Two of the five patients who worsened motorically also developed encephalopathy during risperidone treatment; the encephalopathy resolved when the patients were switched to clozapine treatment. Only one patient, the youngest, did well on risperidone therapy.. We believe that risperidone is not a substitute for clozapine in treating psychosis in parkinsonian patients and should be used with caution.

Topics: Aged; Antiparkinson Agents; Clozapine; Dyskinesia, Drug-Induced; Humans; Male; Parkinson Disease; Parkinson Disease, Secondary; Psychoses, Substance-Induced; Risperidone

Topics: Antipsychotic Agents; Cholinergic Antagonists; Clozapine; Diagnosis, Differential; Dyskinesia, Drug-Induced; Humans; Terminology as Topic; Vitamin E

Most reports of clozapine in treatment-refractory patients have dealt with outpatient and/or relatively less chronic samples. This report focuses on clinical outcome in an institutionalized sample, notable for chronicity, poor functioning, and representing the extreme segment of the treatment-refractory population. We analyzed the data for 50 persistently hospitalized patients referred for clozapine treatment in open trials. Dimensions of outcome assessed at baseline and periodically thereafter included psychopathology, cognitive performance, extrapyramidal side effects (EPS), and patient satisfaction. Certain features of clozapine response in institutionalized patients have been underemphasized (e.g., reduced use of restraint and seclusion, greater social interaction, reduced cost for care). Ninety-four percent of this sample showed some form of improvement with clozapine. Improvement ranged from modest (e.g., less EPS) to remarkable (e.g., discharge). An adequate clozapine trial may require more than 6 months.

Topics: Activities of Daily Living; Adult; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Long-Term Care; Male; Middle Aged; Neurologic Examination; Neuropsychological Tests; Patient Admission; Patient Satisfaction; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Social Behavior; Treatment Outcome

A 51-year old, female patient suffering from schizophrenic disorder was treated with clozapine (Leponex). Four hours after the first parenteral, drug administration, she developed an acute dyskinesia.

Topics: Administration, Oral; Biperiden; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Infusions, Intravenous; Injections, Intramuscular; Middle Aged; Neurologic Examination; Schizophrenia, Paranoid

To investigate whether the occurrence of extrapyramidal side effects was related to D2 dopamine receptor occupancy, iodobenzamide single positron emission computed tomography was carried out in 27 schizophrenic patients and 10 controls. Eighteen patients were treated with haloperidol; 9 patients were treated with clozapine. Our data suggest a relationship between D2 receptor occupancy and extrapyramidal side effects as well as the existence of a neuroleptic threshold of a striatal:frontal cortex ratio of 1.2, below which drug-induced exptrapyramidal side effects can be expected.

Topics: Adult; Basal Ganglia Diseases; Clozapine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Extrapyramidal Tracts; Female; Haloperidol; Humans; Male; Middle Aged; Neurologic Examination; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed, Single-Photon

Among the tardive dyskinesia syndromes, dystonia can be the most difficult to treat. It may be severe to the point of being disabling, yet the patients may require antipsychotic medications for an even more disabling psychosis. Clozapine, an atypical neuroleptic drug that lacks extrapyramidal effects, may be the drug of choice for such patients. This report describes three patients with significant dystonia, previously disabled by their psychoses, who have been successfully managed with clozapine plus other agents for > 3 years.

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neurologic Examination; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Evaluation of neuroleptics should include not only the effects on symptoms but also social functioning and the quality of life. Akathisia, cognitive and emotional impairment (cognitive and emotional parkinsonism) are probably the most important reasons for lack of compliance with classical neuroleptics. Atypical neuroleptics such as clozapine and remoxipride offer an advantage because of little impairment of cognitive and emotional functioning. In 122 schizophrenic and schizoaffective therapy-resistant patients treated with clozapine for up to 17 years, the treatment was stopped in only 8 cases (7%) because of lack of compliance. In patients treated for more than 2 years, 40% were employed and functioned well socially. It is concluded that, in many schizophrenic patients, atypical neuroleptics should be preferred in long-term maintenance treatment because of a low incidence of extrapyramidal syndromes as well as cognitive and emotional parkinsonism. An "awakening" is often seen when changing from a classical neuroleptic to an atypical one.

Topics: Antipsychotic Agents; Clozapine; Cognition; Dyskinesia, Drug-Induced; Emotions; Follow-Up Studies; Humans; Neurologic Examination; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Social Adjustment; Sweden; Treatment Outcome

Akathisia is a common side effect of traditional neuroleptic drugs and is associated with medication refusal and impulsive behavior. While our previous experience indicates that clozapine is effective in treating persistent akathisia, two controlled studies indicate vastly different prevalence rates of akathisia (7% vs. 40%) in patients receiving clozapine.. We used the Barnes Rating Scale for Drug-Induced Akathisia to estimate the prevalence of akathisia in patients receiving stable doses of clozapine alone (N = 29) in a state hospital. Measurements were also made of manifest psychopathology (Brief Psychiatric Rating Scale) and tardive dyskinesia (Abnormal Involuntary Movement Scale).. Two patients (6.8%) receiving clozapine were rated as having akathisia. Only 4 (28.6%) of the 14 subjects with a history of moderate-to-severe tardive dyskinesia on traditional neuroleptic drugs continued to show current evidence of tardive dyskinesia, and in 10 patients (71.4%) there was no evidence of the syndrome (p < .002). In the 4 subjects with tardive dyskinesia there was amelioration to a milder form of the syndrome. There were no new cases of tardive dyskinesia among clozapine-treated subjects.. These data support the low prevalence of akathisia in patients receiving stable doses of clozapine monotherapy. There is further support that clozapine has an ameliorating effect on tardive dyskinesia associated with traditional neuroleptic drugs. These and other data indicate the need for a controlled trial of clozapine in patients experiencing persistent and disabling akathisia on traditional neuroleptic drugs.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Mental Disorders; Prevalence; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

Long-term experience with clozapine has shown that the agent has a motor and mental side effect profile that is distinct in many ways from classical neuroleptics. It can produce a parkinsonian-like bradykinesia and mild akathisia, but no rigidity and rarely tremor. In patients with tardive dyskinesia induced by other neuroleptics, clozapine permits the dyskinesia to disappear in about half the cases. That clozapine may induce tardive dyskinesia in extremely rare cases cannot be excluded, but it seems more likely that this tardive dyskinesia in clozapine-treated patients is due to previous treatment with classical neuroleptics. The earlier clozapine is started, the less chance for development of tardive dyskinesia. As do other neuroleptics, clozapine can elicit sedation and asthenia, but corresponding to the motoric extrapyramidal syndrome, clozapine causes emotional indifference ("mental parkinsonism"), depression, and restlessness to a significantly lesser degree, which may be of importance in the higher compliance seen with this drug.

Topics: Affective Symptoms; Akathisia, Drug-Induced; Antipsychotic Agents; Asthenia; Basal Ganglia Diseases; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Parkinson Disease, Secondary; Schizophrenia; Schizophrenic Psychology

Dyskinesias commonly appear during L-dihydroxyphenylalanine (L-DOPA) therapy of advanced Parkinson's disease (PD) and can occur in both dose-related and dose-independent patterns. Clozapine exerts a dose-related suppression of L-DOPA-induced dyskinesias by shifting the i.v. L-DOPA dose-response curve for production of dyskinesias without altering relief of parkinsonism. We report our outpatient experience with 13 patients on daily clozapine therapy (maximum dose 400 mg/day), followed for 3-21 months (median 10). Beneficial effects of clozapine, determined from twice-weekly diaries, included increased "on time" and decreased "off time" and time "on with dyskinesia." Improvements were statistically apparent by 75 mg/day and remained so through 200 mg/day. Sedation was a common problem, reflected by increased time "asleep" which was significant by 50 mg/day. Sedation was dose limiting in most patients. Orthostatic hypotension and sialorrhea were variably present. No patients had seizures, bone marrow toxicity, or detectable loss of efficacy of clozapine with chronic use. We conclude that clozapine is an effective agent for suppression of dyskinesias in PD with an effective daily dose for most patients of 100-200 mg/day.

Topics: Aged; Clozapine; Disability Evaluation; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Long-Term Care; Male; Middle Aged; Neurologic Examination; Parkinson Disease

We report a patient with severe axial tardive dystonia who has had dramatic improvement for 4 years after treatment with the atypical antipsychotic drug clozapine (625 mg/day). Clozapine differs from conventional neuroleptics in that it has higher affinity for D1 and lower affinity for D2 dopamine receptors than do conventional antipsychotics, which are relatively selective D2 antagonists. We propose that repetitive stimulation of the D1 receptor by endogenous dopamine, resulting in sensitization of the D1-mediated striatal output in the presence of D2 receptor blockade, is a fundamental mechanism mediating tardive dyskinesia, including the dystonic type. According to this hypothesis, it is primarily the D1 antagonist action of clozapine that accounts for its inability to cause tardive dyskinesia as well as its therapeutic effect in tardive dystonia. Regardless of its mechanism of action, the sustained improvement observed in this case suggests that clozapine should be tried in cases of severe refractory tardive dystonia.

Topics: Adult; Antipsychotic Agents; Clozapine; Corpus Striatum; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Dystonia; Follow-Up Studies; Humans; Long-Term Care; Male; Neurologic Examination; Psychotic Disorders; Receptors, Dopamine D1; Receptors, Dopamine D2

Acute administration of the typical neuroleptic haloperidol (HAL, 2 mg/kg) induced the immediate-early gene proteins (IEGPs) c-Fos, Fos-related antigens (FRAs), FosB, JunB, JunD and Krox24 in the striatum and nucleus accumbens of the rat brain. In contrast, acute administration of the atypical antipsychotic drug clozapine (CLOZ, 30 mg/kg) induced only FRAs, JunB and Krox24 IEGPs in the striatum, and c-Fos, FRAs, and Krox24 IEGPs in the nucleus accumbens. c-Jun was not induced by acute administration of HAL or CLOZ in the rat brain. Differential induction of IEGs by HAL and CLOZ was also observed in the lateral septal nucleus and the islands of Calleja complex of the rat brain. These differences in IEG induction by HAL and CLOZ may be related to the different clinical profiles of the two drugs. Specifically, CLOZ induces FRAs in the islands of Calleja and lateral septum and this action may be involved in its therapeutic effects on the negative symptoms of schizophrenia, whereas HAL produces a coordinate induction of Fos and JunB in striatal neurons and this dimer combination may be involved in producing the extrapyramidal side-effects of typical neuroleptics.

Topics: Animals; Caudate Nucleus; Clozapine; DNA-Binding Proteins; Dyskinesia, Drug-Induced; Early Growth Response Protein 1; Gene Expression Regulation; Genes, Immediate-Early; Haloperidol; Immediate-Early Proteins; Male; Neostriatum; Nerve Tissue Proteins; Nucleus Accumbens; Olfactory Pathways; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Putamen; Rats; Rats, Wistar; Septum Pellucidum; Transcription Factors

Topics: Adult; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Long-Term Care; Male; Neurologic Examination; Schizophrenia, Paranoid

Topics: Adult; Basal Ganglia Diseases; Benztropine; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Ocular Motility Disorders; Schizophrenia, Paranoid

The development of severe tardive dystonia after short-term use of low-dose Fluspirilen is described. A 39-year-old woman was treated with Fluspirilen IM by her family doctor for reactive depression. She did received no other neuroleptic agents and no risk factors for the development of tardive dyskinesia (e.g. old age or organic brain damage) were present. For the first time a relation between short-term monotherapy with Fluspirilen and tardive dyskinesia appears highly probable. The use of Fluspirilen for the treatment of psychogenic disturbances should therefore be considered carefully.

Topics: Adjustment Disorders; Adult; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Dystonia; Female; Fluspirilene; Humans; Neurologic Examination

Since the 1950s, the main treatment for schizophrenia has been the use of neuroleptic therapy. However, these medications may produce tardive dyskinesia in those patients who require prolonged neuroleptic treatment. With the advent of clozapine, patients with preexisting tardive dyskinesia began therapy and their symptoms did not worsen--and, in many cases, their symptoms improved dramatically. In this study, the mean Abnormal Involuntary Movement Scale (AIMS) scores from baseline to 6 months are compared for 12 patients in a private partial hospitalization program for schizophrenia. The findings reveal a drastic decrease in AIMS scores after 1 month of clozapine therapy and a steady decrease in scores throughout the 6 months of analysis.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Neurologic Examination; Schizophrenia; Schizophrenic Psychology

We gave increasing daily doses of clozapine to six patients with advanced Parkinson's disease (PD) and levodopa-induced dyskinesias. Clozapine reduced the daily dyskinesia time five-fold, increased "on" time eight-fold, and doubled the serum [DOPA] producing half-maximal dyskinesia. Parkinsonism scores after overnight DOPA withdrawal improved with increasing daily clozapine intake, and there was no clozapine dose-related shift in levodopa dose response for relief of parkinsonism. Patients experienced sedation, sialorrhea, and orthostatic hypotension. Clozapine appears to be an effective agent for suppression of levodopa-induced dyskinesias in PD.

Topics: Aged; Clozapine; Dihydroxyphenylalanine; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Dystonia; Humans; Male; Psychotic Disorders

The authors attempted to determine if chronic exposure to clozapine can cause tardive dyskinesia.. Twenty-eight schizophrenic or schizoaffective patients with no prior history of definite tardive dyskinesia were treated with clozapine for at least 1 year, and their ongoing modified Simpson Dyskinesia Scale ratings were analyzed. These data were then compared with those of another group of similarly diagnosed patients who were treated with a conventional neuroleptic for at least 1 year.. Two patients in the clozapine-treated group (both of whom had ratings of questionable tardive dyskinesia at baseline) were later rated by the modified Simpson Dyskinesia Scale as having mild tardive dyskinesia on at least two consecutive ratings 3 months apart. Although there was uncertainty about whether clozapine definitely caused the tardive dyskinesia in those two patients, a survival analysis comparing the clozapine-treated group with the neuroleptic-treated group showed a lower risk of tardive dyskinesia developing in the clozapine-treated group.. This study was unable to definitively conclude whether clozapine causes tardive dyskinesia. However, if cases do develop, the risk of tardive dyskinesia is likely to be less with clozapine than with typical neuroleptics.

Topics: Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Incidence; Male; Prospective Studies; Psychotic Disorders; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Male; Propranolol; Schizophrenia; Tetrabenazine

Studies in the literature that attempt to relate neuroleptic plasma levels to the development of tardive dyskinesia (TD) report inconsistent findings. As part of an open, long-term study, 60 schizophrenic and schizoaffective patients were started gradually on a b.i.d. schedule of the atypical antipsychotic drug clozapine. Blood samples were drawn weekly for 6 weeks and analyzed for a variety of constituents including clozapine plasma levels. Patients with higher levels of TD were found to have significantly higher levels of plasma clozapine and a higher ratio of plasma/dose than those with lower levels of TD. Our data suggests that schizophrenics with TD may have different pharmacokinetics, drug metabolism, and elimination processes than those without TD. Higher typical plasma neuroleptic levels may increase susceptibility to TD development. A second hypothesis implies that it is not the higher mean plasma level of a neuroleptic that is associated with TD but the greater fluctuations of plasma levels over time (i.e., a higher variance). This hypothesis is discussed in the context of our data.

Topics: Adult; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Psychotic Disorders; Schizophrenia

Topics: Adult; Biopterins; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Neopterin; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Animals; Antipsychotic Agents; Clozapine; Dizocilpine Maleate; Dyskinesia, Drug-Induced; Haloperidol; Ketamine; Metoclopramide; Pharynx; Rats; Rats, Inbred Strains; Stereotyped Behavior; Tongue

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Humans

Clozapine, an atypical neuroleptic, is an effective medication in a subgroup of schizophrenic patients who have either failed to respond to the typical neuroleptics or experienced intolerable side effects such as neuroleptic malignant syndrome and disabling tardive dyskinesia. Its efficacy for persistent and disabling akathisia is less clear. Akathisia, especially the chronic and disabling form, can be a treatment dilemma for the clinician and the patient.. We describe three representative case illustrations of schizophrenic patients who had severe, persistent treatment-resistant akathisia. Two of them had refractory psychoses and the third had multiple disabling side effects during treatment with typical neuroleptics. Two had tardive dyskinesia. These patients were treated with clozapine while other neuroleptics were discontinued.. During a 2-year follow-up, these patients made impressive social and vocational strides coinciding with a fairly rapid remission of akathisia (under 3 months) and a lesser though notable improvement in the psychoses. Tardive dyskinesia also remitted, though over a period of 6 to 12 months.. Our experience leads us to suggest a trial of clozapine in a subgroup of schizophrenic patients, who in addition to refractory psychoses have persistent disabling akathisia. However, given the risk of agranulocytosis with clozapine, we suggest that the usual treatment strategies for akathisia be tried before clozapine is initiated in the approved manner. Future controlled trials of clozapine that specifically investigate persistent akathisia may answer this question more conclusively.

Topics: Adult; Agranulocytosis; Akathisia, Drug-Induced; Antipsychotic Agents; Chronic Disease; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychomotor Agitation; Schizophrenia; Schizophrenic Psychology; Social Adjustment

Topics: Age Factors; Aged; Aged, 80 and over; Clozapine; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Schizophrenia, Paranoid

Topics: Acute Disease; Adult; Bulimia; Clozapine; Dyskinesia, Drug-Induced; Female; Fluoxetine; Humans; Recurrence; Schizophrenia; Thiothixene

Perforated synapses, which contain a discontinuous density along the postsynaptic membrane, can increase or decrease in numbers following various behavioral and biochemical manipulations. We have previously established that 14-day treatment with haloperidol causes an increase in the number of perforated synapses within the caudate nucleus (dorsolateral region) but not the nucleus accumbens (Meshul and Casey 1989). This effect was reversed if the animals were withdrawn from the drug for an equivalent period of time. We have now further examined the effects of haloperidol administration, which is associated with a high incidence of extrapyramidal side effects (EPS) and tardive dyskinesia (TD), and assessed the effects of clozapine, which appears to have a lower potential for inducing EPS and TD. Administration of haloperidol for 2 weeks significantly increased the percentage of perforated synapses in the caudate, but not in the nucleus accumbens or layer VI of medial prefrontal cortex (MPCx). There was an increase in specific [125I]epidepride binding to D-2 receptors in the caudate nucleus and MPCx following haloperidol. Administration of clozapine for 2 weeks did not affect the percentage of perforated synapses in any of the three dopamine (DA)-rich regions that were examined. There was an increase in specific [3H]SCH 23390 binding to D-1 receptors and in specific [125I]epidepride binding to D-2 receptors only within MPCx following clozapine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Benzazepines; Brain; Caudate Nucleus; Clozapine; Dopamine Antagonists; Dyskinesia, Drug-Induced; Frontal Lobe; Haloperidol; Male; Microscopy, Electron; Nucleus Accumbens; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Dopamine D1; Receptors, Dopamine D2; Synapses

Topics: Aged; Chlorpromazine; Chronic Disease; Clonazepam; Clozapine; Depressive Disorder; Desipramine; Diphenhydramine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Neurologic Examination

Acute and late onset movement disorders frequently complicate the treatment of psychosis with typical neuroleptic drugs like haloperidol, but not with atypical neuroleptic drugs like clozapine. Although the neural mechanisms underlying neuroleptic-induced movement disorders remain unknown, alterations in basal ganglia function are likely involved. A potential role for the endogenous opiate peptides in neuroleptic-induced movement disorders is suggested by the immunocytochemical localization of met5-enkephalin (ME) in the striatopallidal projection pathway, and by the increased levels of ME measured by radioimmunoassay in the rat caudate-putamen nuclei (CPN) following haloperidol treatment. We sought to determine whether met5-enkephalin-like immunoreactivity (MELI) in terminal fields within globus pallidus and in perikarya in CPN was differentially altered in rats chronically treated with haloperidol or clozapine. Acrolein-fixed forebrain sections were collected from cohorts of adult rats receiving 21-day oral administration of haloperidol, clozapine, or water. Sections from the three treatment groups were collectively processed for immunocytochemical labeling using varying dilutions of ME antiserum and the avidin-biotin peroxidase method. In globus pallidus, densitometry measures revealed significantly increased levels of immunoperoxidase labeling for ME in haloperidol-treated, but not in clozapine-treated animals. In CPN, optical densitometry as well as cell counting measurements also showed a significant increase in MELI only in the haloperidol-treated group. These results support the concept that alterations in endogenous opiate peptides in basal ganglia may contribute to movement disorders seen in patients receiving typical neuroleptic drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Clozapine; Corpus Striatum; Disease Models, Animal; Drug Administration Schedule; Dyskinesia, Drug-Induced; Enkephalin, Methionine; Globus Pallidus; Haloperidol; Immunoenzyme Techniques; Immunohistochemistry; Male; Models, Neurological; Organ Specificity; Rats; Rats, Inbred Strains; Water

This article reviews eight published studies that describe clozapine's effects on TD and examines the outcome of 30 patients with TD treated with clozapine for up to 36 months. These data indicate that TD response to clozapine is variable but that approximately 43% of cases, particularly those with dystonic features, improved after clozapine treatment. Methodological limitations of the studies described, however, preclude definitive conclusions, which must await appropriately controlled trials.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Neurologic Examination; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

No convincing case of tardive dyskinesia has been associated with clozapine. We briefly discuss a case of clozapine-induced reversible initial dyskinesia described in the German literature, and we report a case of jaw dyskinesia in a 49-year-old female schizophrenic. The dyskinesia appeared 2 weeks after the patient started clozapine treatment, did not respond to anticholinergic medication, and has continued for more than 1 year while the patient has remained on clozapine treatment. The patient had taken haloperidol (less than or equal to 5 mg/day) for 5 weeks before starting clozapine treatment. These are the only two cases of dyskinesia associated with clozapine use that are known to us. They raise the possibility that clozapine can induce dyskinesia.

Topics: Biperiden; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Jaw Diseases; Middle Aged; Schizophrenia

Rats were administered haloperidol, clozapine, raclopride, or no drug for 28 days or 8 months. Following a 3 week withdrawal period, in vitro autoradiography was utilized to examine receptor binding for dopamine D2 ([3H]spiperone and [3H]raclopride), dopamine D 1 ([3H]SCH23390), GABA(A) ([3H]muscimol), benzodiazepine ([3H]RO15-1788), and muscarinic ACh receptors ([3H]QNB). [3H]spiperone was elevated in striatal subregions only in haloperidol-treated rats, with the largest increases seen in the 8 month duration animals. Striatal [3H]raclopride binding was increased after both short- and long-term treatment in both haloperidol and raclopride, but not clozapine-treated animals. Clozapine-treated rats showed significant increases in [3H]SCH23390 in the nucleus accumbens after 28-day administration; otherwise no changes were seen for this ligand in any other groups. Increases in [3H]muscimol binding in the substantia nigra reticulata were seen in haloperidol-treated rats after 8 month treatment. Binding of [3H]QNB and [3H]RO151788 were not significantly different from control for any of the drug-treated groups. These data suggest that persisting alterations in receptor binding are primarily seen in dopamine D2 and GABA receptors after withdrawal from chronic administration of haloperidol but not the atypical neuroleptics, clozapine and raclopride.

Topics: Animals; Antipsychotic Agents; Brain Chemistry; Clozapine; Dyskinesia, Drug-Induced; Female; Haloperidol; Raclopride; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, GABA-A; Receptors, Muscarinic; Receptors, Neurotransmitter; Salicylamides; Up-Regulation

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Male; Motor Activity; Neurologic Examination; Psychomotor Agitation; Schizophrenia, Paranoid

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Meige Syndrome; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Cataplexy; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Schizophrenia

Topics: Agranulocytosis; Clozapine; Dyskinesia, Drug-Induced; Humans; Leukocyte Count; Mental Health Services; Schizophrenia; United States

Topics: Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Humans; Metoclopramide; Nausea; Parkinson Disease, Secondary

Rats were administered haloperidol, clozapine, raclopride, or no drug for either 28 days or 8 months and then withdrawn from drug treatment for 3 weeks. Oral movements were repeatedly recorded, both by a human observer and by a computerized video analysis system which determined mouth openings and closings, or computer-scored movelets (CSMs). Four weeks of neuroleptic administration produced no changes in CSMs in any drug-treated group. Long-term administration induced distinctively different patterns of oral activity in the three drug groups, both in number of CSMs and the form of these movements. The oral movements which developed in the haloperidol-treated rats fit a previously described syndrome of late-onset oral dyskinesias which increased upon drug withdrawal. The clozapine- and raclopride-treated rats did not show the increased oral movements seen in the haloperidol animals, but each exhibited uniquely different CSM characteristics compared to controls. The results from this rodent model imply that haloperidol, but not clozapine or raclopride, produces late-onset oral dyskinesias in rats that fit the pattern expected for tardive dyskinesia.

Topics: Animals; Behavior, Animal; Body Weight; Clozapine; Dibenzazepines; Disease Models, Animal; Drinking; Dyskinesia, Drug-Induced; Female; Fourier Analysis; Haloperidol; Raclopride; Rats; Rats, Inbred Strains; Salicylamides

Clozapine, an atypical neuroleptic, does not cause extrapyramidal symptoms of Parkinsonism and dystonia and appears to have a reduced or absent capacity to produce tardive dyskinesia. 37 subjects, most with chronic schizophrenia, were treated with clozapine and TD outcome was analyzed. A subset of these subjects underwent plasma and CSF studies. TD response was heterogenous, but a proportion of patients improved with clozapine treatment. Neurochemical data differed from published reports of classical neuroleptics with the most robust effect produced by clozapine seen in CSF norepinephrine levels. Other neurochemical data and implications for the mechanism of clozapine in TD are reviewed.

Topics: Adolescent; Adult; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Epinephrine; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Norepinephrine; Phenethylamines; Prolactin; Schizophrenia

Topics: Adolescent; Carbamazepine; Clozapine; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Haloperidol; Humans; Meclofenoxate; Neuroleptic Malignant Syndrome; Schizophrenia; Schizophrenic Psychology; Tiapamil Hydrochloride

Topics: Adult; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Female; Humans; Male

Medical charts of 387 in-patients (schizophrenia n = 284, tardive dyskinesia, TD, n = 48), were analyzed to evaluate efficacy and adverse effects of clozapine. These patients were previously treated with between two and four other neuroleptics and were either therapy resistant or had severe side effects. Schizophrenic patients were treated with clozapine for 48 +/- 35 (TD 49 +/- 40) days, dosage was 189 +/- 119 (TD 220 +/- 176) mg. Four per cent showed worsening, 13% no change, 38% slight improvement, 42% marked improvement and 3% nearly total reduction of symptoms. In TD, 44% showed marked improvement, but only in 17% the drug was superior to previous neuroleptics. Adverse effects occurred in 56% of patients. Most frequent were sedation (17%), EEG alterations (16%), increase of liver enzymes (8%), hypotension (7%), hypersalivation (5%), fever (5%), ECG alterations (4%), tachycardia (3%), gastro-intestinal (3%) and delirious states (2%). A gradual increase in dosage seems to considerably reduce the incidence of some side effects. Clozapine treatment had to be discontinued because of severe side effects in 5.9%. In none of these patients did serious complications such as agranulocytosis occur. Only EEG alterations were significantly related to clozapine dosage (P less than 0.0005). At dismissal, most patients continued to receive clozapine; only in 22% (TD 20%) was it replaced by another neuroleptic. Thus, the ratio benefit/risk of clozapine treatment seems to be satisfactory in most of the negatively selected patients. Nevertheless, a gradual increase in dosage and careful control of hematological and other variables is highly recommended.

Topics: Adult; Clozapine; Dibenzazepines; Drug Resistance; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Patient Compliance; Retrospective Studies; Schizophrenia

Topics: Antipsychotic Agents; Benzamides; Clozapine; Dibenzazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Tiapamil Hydrochloride

Based on the results of two preliminary studies, we concluded that late-developing persistent drug-induced movement disorders are pharmacologically heterogeneous, and this heterogeneity is seen between individual patients (and groups of patients) as well as within body areas of individual patients; dystonic pathology has a distinct and more consistent response to pharmacologic stimulation than does nondystonic tardive dyskinesia (TD); and, although disturbances in dopamine and acetylcholine appear to be involved in these disorders, they do not in all cases exist in functionally opposite relationships. The observed pharmacologic heterogeneity in TD response reflects the limitations of the dopamine/acetylcholine model of TD, which oversimplifies the neuroanatomy of the basal ganglia and the pathophysiology of TD. The chemical and anatomical complexity of this region suggests that other neurotransmitter systems and neuronal circuits within and extending from the basal ganglia may be disturbed in the pathogenesis of TD.

Topics: Adult; Aged; Clozapine; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Psychotic Disorders; Time Factors

After a short review of the German literature dealing with basal schizophrenic disturbances, the authors present the results of their own studies involving 135 schizophrenics. A large inventory of statistical methods is used to present the findings gained during differential neuroleptic therapy by means of the Frankfurt complaints questionnaire and the structured psychopathic assessment system (SPES-A). The studies indicate that basal schizophrenic disturbances are accessible to (differential) neuroleptic influence.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Dyskinesia, Drug-Induced; Haloperidol; Humans; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

On the basis of clinical self-assessment scales (von Zerssen) and the Frankfurt questionnaire of complaints, it is demonstrated by the comparison of three groups of schizophrenic patients with one control group which is not undergoing therapy with neuroplegics that within the "genuine" groups the psychopathological factors investigated recede, sometimes quite significantly. Cross-over design treatment involving the control group has not revealed any significance. We conclude that when treating schizophrenic psychoses, psychosocial measures must accompany biological measures.

Topics: Clozapine; Depressive Disorder; Dibenzazepines; Dyskinesia, Drug-Induced; Haloperidol; Humans; Psychiatric Status Rating Scales; Psychometrics; Schizophrenia; Schizophrenia, Paranoid; Schizophrenic Psychology

Two adult female cebus apella monkeys with persistent tardive dyskinesia (TD) were given acute i.m. injections of reference neuroleptics (chlorpromazine, haloperidol, thioridazine, and clozapine) or of potential new antipsychotic agents (MJ 13859-1 and MJ 13980-1). The drugs were assessed for their ability to modify TD symptoms or to produce acute neurologic reactions. Effects of three doses of MJ 13859-1 administered orally were also examined. At the doses used, thioridazine and clozapine had little or no effect. Chlorpromazine, haloperidol, MJ 13859-1 and MJ 13980-1 reduced or abolished TD and concomitantly produced hypokinesia, akinesia, mask expression, trembling, and reduced response to stimuli. Haloperidol also produced a mildly abnormal posture. In addition to the above effects, MJ 13859-1 also produced "slow motion" movement, sustained bizarre postures, sudden falls, and episodes of severe rigidity with trembling.

Topics: Animals; Antipsychotic Agents; Cebus; Chlorpromazine; Clozapine; Dyskinesia, Drug-Induced; Female; Haloperidol; Motor Activity; Posture; Spiro Compounds; Thioridazine

The state of health of 135 schizophrenic patients was examined during therapy with a nigrostriatal (Haloperidol) and a mesolimbic (Clozapin) neuroplegic drug, and compared with the situation during treatment without neuroplegics. Among the methods used was the state of health scale of von Zerssen; the neuroleptic threshold was tested using Haase's handwriting test. There was evidence that the patient's health was primarily affected, but individual differential treatment with neuroplegics produced a significant improvement in this important respect. Contrary to Haase, we noticed nothing to convince us of a link between the antipsychotic efficacy of the neuroplegics under investigation and the neuroleptic threshold.

Topics: Adolescent; Adult; Antipsychotic Agents; Attitude to Health; Clozapine; Dyskinesia, Drug-Induced; Haloperidol; Humans; Middle Aged; Motor Skills; Schizophrenia; Schizophrenic Psychology

Rats were treated continuously for 12 months with therapeutically equivalent doses of either haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day), or clozapine (24-27 mg/kg/day). After treatment for 3 and 12 months with haloperidol or clozapine but not sulpiride, striatal acetylcholine levels were increased. Striatal choline acetyltransferase activity was not altered by any drug treatment. Vmax for striatal acetylcholinesterase activity during the course of 12 months' treatment with haloperidol or clozapine, but not with sulpiride, tended to increase; Km was not altered by any drug treatment. Bmax for specific striatal [3H]quinuclidinyl benzilate binding was not altered by haloperidol or sulpiride treatment but was transiently elevated after 6 months of clozapine treatment, thereafter returning to control levels. Kd was not altered by any drug treatment. These findings indicate that alterations in striatal acetylcholine content caused by chronic treatment with some but not all neuroleptics are due to changes in cholinergic neuronal activity rather than neurotransmitter synthesis or destruction. The effects of haloperidol but not those of clozapine may be related to the emergence of functional striatal dopamine receptor supersensitivity. Since haloperidol (which is associated with a high prevalence of tardive dyskinesias) but not clozapine (which is not) had similar effects on striatal cholinergic function, the latter may not be related to the emergence of tardive dyskinesias during chronic therapy.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Choline O-Acetyltransferase; Clozapine; Corpus Striatum; Dibenzazepines; Dyskinesia, Drug-Induced; Haloperidol; Male; Quinuclidinyl Benzilate; Rats; Rats, Inbred Strains; Sulpiride

There have been conflicting reports as to whether clozapine, an atypical antipsychotic, will suppress symptoms of tardive dyskinesia. With this in mind, the authors present the case of a 32-year-old chronically institutionalized schizophrenic who showed a remarkable improvement in both tardive dyskinesia and psychotic symptoms following an open trial of clozapine, 900 mg daily. This effect was noted to persist throughout the 15-month observation period with no breakthrough dyskinesia. The ability of clozapine to suppress tardive dyskinesia symptoms raises the possibility that clozapine, at least at the doses used in this report, might also induce the disorder. Long-term, controlled studies are required to specifically address this issue.

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Female; Humans; Schizophrenia

Topics: Animals; Brain; Cerebral Cortex; Choline O-Acetyltransferase; Clozapine; Corpus Striatum; Dibenzazepines; Dyskinesia, Drug-Induced; Fluphenazine; Hippocampus; Male; Mice; Pilocarpine; Quinuclidinyl Benzilate; Receptors, Cholinergic; Receptors, Muscarinic

Topics: Adult; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Humans; Male; Psychoses, Substance-Induced

In squirrel monkeys that had undergone repeated treatment with haloperidol at intervals of 7--14 days, subsequent acute administration of haloperidol induced dystonia and dyskinesias. This acute effect of haloperidol was dose-related and occurred at the same doses that impaired Sidman avoidance performance. Chlorpromazine, fluphenazine, metoclopramide, tetrabenazine, and Su-23397, all of which have been associated with extrapyramidal side effects, reliably elicited dyskinesias in these monkeys. Dyskinesias were less mared after thioridazine and absent after clozapine, corresponding to the reported lower incidence of extrapyramidal side effects in the clinic. The non-neuroleptics, baclofen, and diazepam, failed to elicit dyskinesias. In contrast to the dyskinetic syndrome, the incidence of catalepsy or tremor did not accurately predict propensity to elicit extrapyramidal symptomatology. The acute dyskinetic syndrome in squirrel monkeys may therefore serve as an animal model for predicting the ability of antipsychotics to cause extrapyramidal dysfunction, and may yield insight into the mechanisms of these drug-induced motor disorders.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Baclofen; Basal Ganglia Diseases; Clozapine; Diazepam; Dyskinesia, Drug-Induced; Haloperidol; Haplorhini; Male; Saimiri

Topics: Agranulocytosis; Clozapine; Dibenzazepines; Dyskinesia, Drug-Induced; Humans; Leukemia

The authors conducted an extensive pharmacological analysis of a patient severely affected by tardive dyskinesia. No drug treatment gave lasting clinical improvement. Several agents recently recommended for this condition, dimethyl aminoethanol, clozapine, and thioridazine, failed to modify the dyskinesia. Reserpine caused a worsening of the symptoms. A paradoxical and unexpected improvement was observed with apomorphine injections and with low-dosage oral L-dopa. These two drugs may have acted by stimulating presynaptic inhibitory dopamine receptors.

Topics: Adrenergic alpha-Agonists; Adult; Amantadine; Apomorphine; Benztropine; Clozapine; Deanol; Dextroamphetamine; Dose-Response Relationship, Drug; Drug Antagonism; Drug Tolerance; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Levodopa; Physostigmine; Receptors, Dopamine; Reserpine; Stimulation, Chemical; Thioridazine

Topics: Animals; Carbachol; Catheterization; Clozapine; Corpus Striatum; Disease Models, Animal; Dyskinesia, Drug-Induced; Haloperidol; Huntington Disease; Hydrazines; Levodopa; Male; Phentolamine; Rats; Trifluoperazine; Tyramine

The effects of haloperidol, alone and in combination with atropine, were compared with the effects of clozapine, alone and in combination with physostigmine, in a variety of tests commonly used to characterize neuroleptic compounds. It was found that clozapine in combination with physostigmine did not present the profile of activity of a classical neuroleptic agent; neither did haloperidol in combination with atropine present that of clozapine. In fact, some effects of haloperidol (catalepsy) were antagonized by atropine, while others (induction of striatal DA-receptor hypersensitivity) were enhanced. It is concluded that the interaction between dopaminergic and cholinergic systems in the striatum is highly complex, and that a neuroleptic possessing both potent DA-receptor blocking and muscarinic anticholinergic activity, while being less likely to cause parkinsonism in patients, would be more likely to induce tardive dyskinesias.

Topics: Animals; Antipsychotic Agents; Atropine; Basal Ganglia Diseases; Clozapine; Corpus Striatum; Drug Interactions; Dyskinesia, Drug-Induced; Female; Haloperidol; Homovanillic Acid; Male; Parasympathetic Nervous System; Physostigmine; Rats; Receptors, Dopamine; Receptors, Muscarinic

Rhesus monkeys with a history of drinking methadone, but presently drug-free, were injected with low doses of methamphetamine (MA). They immediately developed oral dyskinesias resembling the symptoms of tardive dyskinesia in humans, a condition resulting from chronic blockade of striatal dopamine receptors by neuroleptics. Nine of 11 control monkeys failed to develop dyskinesias during prolonged MA administration. A stressful stimulus intensified the MA-elicited oral dyskinesias, an effect analogous to exacerbation of tardive dyskinesias by emotional stress. Control monkeys were then injected with methadone, chlorpromazine, haloperidol, or saline for 45 days. Ten days following this chronic treatment, MA immediately elicted oral dyskinesias in the methadone and chlorpromazine monkeys. Acute administration of the dopaminergic blocking agents chlorpromazine, spiroperidol, and clozapine eliminated MA-elicited dyskinesias, whereas the alpha-adrenergic blocker phentolamine was ineffective. Physostigmine blocked the dyskinesias in 1 of 2 cases. Sedative doses of phenobarbital and diazepam had no effect on oral dyskinesias. These data indicate that chronic treatment with methadone or other dopamine receptor blocking agents leads to receptor supersensitivity to the actions of MA.

Topics: Animals; Chlorpromazine; Clozapine; Diazepam; Dyskinesia, Drug-Induced; Haloperidol; Haplorhini; Humans; Macaca mulatta; Male; Methadone; Methamphetamine; Naloxone; Phenobarbital; Phentolamine; Physostigmine; Spiperone; Stereotyped Behavior

Eight rhesus monkeys that had drunk subdependence-producing doses of methadone daily for 10-22 months, and had subsequently been drug-free for 2-17 months, were injected with low doses of methamphetamine (MA). They immediately exhibited oral dyskinesias resembling the symptoms of tardive dyskinesia in humans, a condition resulting from chronic blockade of striatal dopamine receptors by neuroleptics. Eleven control monkeys failed to develop dyskinesias during prolonged MA administration. Control monkeys then received parenteral methadone, chlorpromazine, haloperidol, or saline for 45 days. Upon subsequent retest with MA, the methadone and chlorpromazine monkeys immediately displayed oral dyskinesias. Dopaminergic antagonists blocked MA-elicited dyskinesis, whereas neither a noradrenergic blocker nor sedative doses of phenobarbital and diazepam had any effect on dyskinesias. We suggest that receptor supersensitivity is produced by chronic treatment with methadone or other dopamine receptor blockers. Following treatment, stimulation of hypersensitive striatal receptors by the dopamine released by MA results in oral dyskinesias. The clinical implications for methadone maintenance treatment program patients are discussed.

Topics: Animals; Chlorpromazine; Clozapine; Diazepam; Drug Interactions; Dyskinesia, Drug-Induced; Haloperidol; Haplorhini; Macaca mulatta; Male; Methadone; Methamphetamine; Phenobarbital; Phentolamine; Physostigmine; Spiperone; Time Factors