clozapine and Substance-Withdrawal-Syndrome

Clozapine is a potent antipsychotic medication with a complex receptor profile. It is reserved for treatment-resistant schizophrenia. We systematically reviewed studies of non-psychosis symptoms of clozapine withdrawal.. CINAHL, Medline, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews were searched using the keywords 'clozapine,' and 'withdrawal,' or 'supersensitivity,' 'cessation,' 'rebound,' or 'discontinuation'. Studies related to non-psychosis symptoms after clozapine withdrawal were included.. Five original studies and 63 case reports / series were included in analysis. In 195 patients included in the five original studies, approximately 20% experienced non-psychosis symptoms following discontinuation of clozapine. In 89 patients in four of the studies, 27 experienced cholinergic rebound, 13 exhibited extrapyramidal symptoms (including tardive dyskinesia), and three had catatonia. In 63 case reports / series included, 72 patients with non-psychosis symptoms were reported, which were catatonia (n=30), dystonia or dyskinesia (n=17), cholinergic rebound (n=11), serotonin syndrome (n=4), mania (n=3), insomnia (n=3), neuroleptic malignant syndrome (NMS) [n=3, one of them had both catatonia and NMS], and de novo obsessive compulsive symptoms (n=2). Restarting clozapine appeared to be the most effective treatment.. Non-psychosis symptoms following clozapine withdrawal have important clinical implications. Clinicians should be aware of the possible presentations of symptoms to ensure early recognition and management. Further research is warranted to better characterise the prevalence, risk factors, prognosis, and optimal drug dosing for each withdrawal symptom.

Topics: Antipsychotic Agents; Catatonia; Cholinergic Agents; Clozapine; Humans; Schizophrenia; Substance Withdrawal Syndrome

Withdrawal symptoms are common upon discontinuation of psychiatric medications. Catatonia, a neuropsychiatric condition proposed to be associated with gamma-aminobutyric acid (GABA) hypoactivity due to its robust response to benzodiazepines, has been described as a withdrawal syndrome in case reports but is not a well-recognized phenomenon. The authors undertook a review of withdrawal catatonia with an aim to understand its presentation as well as the medications and psychoactive substances it is associated with. The review identified 55 cases of withdrawal catatonia, the majority of which occurred upon discontinuation of benzodiazepines (24 cases) and discontinuation of clozapine (20 cases). No other antipsychotic medications were identified as having been associated with the onset of a catatonic episode within 2 weeks following their discontinuation. Increasing GABA activity and resultant GABA receptor adaptations with prolonged use is postulated as a shared pharmacological mechanism between clozapine and benzodiazepines that underlie their association with withdrawal catatonia. The existing evidence for clozapine's activity on the GABA system is reviewed. The clinical presentations of benzodiazepine withdrawal catatonia and clozapine withdrawal catatonia appear to differ and reasons for this are explored. One reason is that benzodiazepines act directly on GABA

Topics: Benzodiazepines; Catatonia; Clozapine; GABA Antagonists; Humans; Substance Withdrawal Syndrome

Clozapine is associated with various haematological adverse effects, including leukopenia, neutropenia, agarnulocytosis, leukocytosis, anaemia, eosinophilia, thrombocytopenia and thrombocythaemia. Recognition and treatment of clozapine-related seizures also will become increasingly important as clozapine use grows in the 1990s. The decision to stop clozapine as a result of haematological adverse effects or seizures is a frustrating one for the clinician, and frequently disastrous for the patient. Cessation of treatment results in relapse. In case that patient is unresponsive to other antipsychotic, restarting clozapine should be consider, despite the risk involved. As the risk of a second agranulocytosis is much higher in those patients, various methods of militating against repeat blood dyscrasias have been treated, including granulocyte colony-stimulating factor and lithium. The decision to restart clozapine should be taken on case-by-case basis and should take into account the likely risks and benefits of restarting. Prior response to clozapine and magnitude of patient deterioration on stopping treatment are important factors to take into this consideration. Clozapine-related seizures did not preclude successful treatment with clozapine. A strategy that has been proposed to reduce the occurrence of seizures is the addition of an anticonvulsant agent. However, clozapine does induce a variety of adverse effects, most of which are of limited duration and either preventable or manageable if a number of simple clinical procedures are followed. With careful haematologyc control, the risk of agranulocytosis can be minimized and in case of clozapine related seizures recommendations include dose reduction, electroencephalogram (EEG), plasma-level monitoring and prophylactic antiepileptic treatment. Re-exposure to clozapine may rarely be attempted where there are facilities for very close and frequent monitoring.

Topics: Adult; Agranulocytosis; Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsy; Female; Humans; Leukopenia; Lithium Carbonate; Psychotic Disorders; Recurrence; Risk Factors; Schizophrenia; Substance Withdrawal Syndrome; Thrombocytopenia

The high rates of co-morbidity of drug addiction with depression may be attributable to shared neurobiology. Here, we discuss shared neurobiological substrates in drug withdrawal and depression, with an emphasis on changes in brain reward circuitry that may underlie anhedonia, a core symptom of depression and drug withdrawal. We explored experimentally whether clinical antidepressant medications or other treatments would reverse the anhedonia observed in rats undergoing spontaneous nicotine or amphetamine withdrawal, defined operationally as elevated brain reward thresholds. The co-administration of selective serotonin reuptake inhibitors with a serotonin-1A receptor antagonist, or the tricyclic antidepressant desipramine, or the atypical antidepressant bupropion ameliorated nicotine or amphetamine withdrawal in rats. Thus, increases in monoaminergic neurotransmission, or neuroadaptations induced by increased monoaminergic neurotransmission, ameliorated depression-like aspects of drug withdrawal. Further, chronic pretreatment with the atypical antipsychotic clozapine, that has some efficacy in the treatment of the depression-like symptoms of schizophrenia, attenuated nicotine and amphetamine withdrawal. Finally, a metabotropic glutamate 2/3 receptor antagonist reversed threshold elevations associated with nicotine withdrawal. The effects of these pharmacological manipulations are consistent with the altered neurobiology observed in drug withdrawal and depression. Thus, these data support the hypothesis of common substrates mediating the depressive symptoms of drug withdrawal and those seen in psychiatric patients. Accordingly, the anhedonic state associated with drug withdrawal can be used to study the neurobiology of anhedonia, and thus contribute to the identification of novel targets for the treatment of depression-like symptoms seen in various psychiatric and neurological disorders.

Topics: Adrenergic Uptake Inhibitors; Animals; Antipsychotic Agents; Central Nervous System Stimulants; Clozapine; Depressive Disorder; Dopamine Agents; Glutamic Acid; Humans; Norepinephrine; Selective Serotonin Reuptake Inhibitors; Substance Withdrawal Syndrome; Substance-Related Disorders

To examine the evidence that discontinuation of long-term antipsychotic medication, including clozapine, may provoke a psychotic episode.. Databases were searched and citations scrutinised.. Evidence for a rapid onset psychosis (supersensitivity psychosis) following clozapine withdrawal was found and weaker evidence that this might occur with some other antipsychotic drugs. Some cases were reported in people without a psychiatric history. It appears that the psychosis may be a feature of drug withdrawal rather than the re-emergence of an underlying illness, at least in some patients. Meta-analyses of withdrawal studies have suggested that antipsychotic discontinuation may also increase the risk of relapse over and above the risk because of the underlying disorder, but not all individual studies show this effect. Mechanisms may relate to brain adaptations to long-term drug use but data are sparse.. These effects require further urgent research. Interventions to reduce morbidity after drug withdrawal need to be developed.

Topics: Antipsychotic Agents; Clozapine; Humans; Long-Term Care; Psychoses, Substance-Induced; Psychotic Disorders; Recurrence; Risk Factors; Substance Withdrawal Syndrome

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 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

Withdrawal symptoms for typical antipsychotics are generally mild, self-limited and do not include development of psychotic symptoms. In contrast, withdrawal symptoms for clozapine can be severe with rapid onset of agitation, abnormal movements, and psychotic symptoms. Different pathophysiologic etiologies have been suggested for these severe symptoms, including dopaminergic supersensitivity and rebound.. Three case reports of clozapine withdrawal symptoms are presented. A review of previous case reports and discussion of the etiology of withdrawal symptoms of typical antipsychotics and clozapine are provided.. These three patients developed delirium with psychotic symptoms that resolved rapidly and completely upon resumption of low doses of clozapine.. The severe agitation and psychotic symptoms after clozapine withdrawal in these three patients were due to delirium, perhaps the result of central cholinergic rebound. The withdrawal symptoms and delirium resolved rapidly with resumption of low doses of clozapine. Severe withdrawal symptoms can probably be avoided by slowly tapering clozapine and/or simultaneously substituting another psychotropic with high anticholinergic activity, such as thioridazine.

Topics: Adult; Clozapine; Delirium; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Middle Aged; Psychoses, Substance-Induced; Psychotic Disorders; Receptors, Dopamine; Recurrence; Schizophrenia; Schizophrenia, Paranoid; Substance Withdrawal Syndrome; Thioridazine

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

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

The side-effect profile of Clozapine (Leponex) plays a major role both from a negative and a positive perspective. Prevention and management of the most important and most frequent side-effects, of interest in daily patient practice, are primordial concerns. Additionally, attention is also paid to the question treatment and to potential problems with medication discontinuation.

Topics: Clozapine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Humans; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

In light of the efficacy of newer antipsychotic agents and the possibility that drug withdrawal may negatively affect subsequent drug response, concern has arisen that the use of placebo in schizophrenia research may be unethical. This study examines the effect size of symptom exacerbation during drug washout with placebo and the effects of drug washout on the efficacy of subsequent drug treatment.. Fifty patients with treatment-resistant schizophrenia hospitalized on a research unit participated in a double-blind longitudinal study of the effects of drug washout after chronic treatment with a typical antipsychotic and before prospective treatment with clozapine. Brief Psychiatric Rating Scale (BPRS) scores were analyzed to examine drug effects and effect sizes for baseline treatment with a typical antipsychotic (>6 months treatment), drug washout with placebo (mean=34 days), early treatment with clozapine (mean=42 days, mean dose=345.0 mg/day), and optimal clozapine treatment (mean=83 days, mean dose=450.5 mg/day).. Patients' BPRS total, positive, and negative symptom scores significantly increased during placebo washout, compared with baseline treatment, and significantly decreased with administration of clozapine, compared with placebo washout and baseline treatment. However, 30% of patients showed some symptom improvement during placebo washout. The effect sizes for the BPRS total score were 0.63 for baseline treatment versus placebo washout, 1.10 for optimal clozapine treatment versus placebo washout, and 0.82 for optimal clozapine treatment versus baseline treatment.. Symptom exacerbation induced by drug withdrawal in patients with treatment-resistant schizophrenia did not impede subsequent responsiveness to clozapine. The effect size for clozapine, compared with typical antipsychotics, suggests that the drug-washout longitudinal design is useful for establishing a drug-free baseline and for investigating drug response, while requiring relatively few subjects.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Data Interpretation, Statistical; Double-Blind Method; Drug Resistance; Female; Humans; Longitudinal Studies; Male; Research Design; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; Treatment Outcome

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 abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double-blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (< 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5-day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Substance Withdrawal Syndrome

Topics: Clozapine; Dopamine; Humans; Receptors, Dopamine; Receptors, Serotonin; Recurrence; Schizophrenia; Serotonin; Substance Withdrawal Syndrome

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients with neuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64 neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.

Topics: Adult; Antipsychotic Agents; Clozapine; Cyproheptadine; Female; Humans; Male; Perphenazine; Schizophrenia; Serotonin Antagonists; Substance Withdrawal Syndrome

Following the conduct of a 28-day inpatient bioequivalence study of clozapine in schizophrenia patients, withdrawal effects after abrupt discontinuation from clozapine were assessed. Thirty patients who met DSM-III-R criteria for schizophrenia, residual type, or schizophrenia in remission were enrolled in the study. Patients were evaluated for symptoms of withdrawal effects for 7 days after clozapine 200 mg/day was abruptly withdrawn. Of 28 patients who completed the study, 11 had no withdrawal symptoms; 12 had mild withdrawal adverse events of agitation, headache, or nausea; four patients experienced moderate withdrawal adverse events of nausea, vomiting, or diarrhea; and one patient experienced a rapid-onset psychotic episode requiring hospitalization. Cholinergic rebound is a likely explanation for the mild to moderate withdrawal symptoms and is easily treated with an anticholinergic agent. Mesolimbic supersensitivity, as well as specific properties of clozapine, are discussed as likely causes for rapidonset psychosis. Our findings are consistent with previous reports of withdrawal reactions associated with clozapine, further reminding clinicians to monitor patients closely following abrupt discontinuation of clozapine.

Topics: Adolescent; Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Clozapine; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Nausea; Neurologic Examination; Psychoses, Substance-Induced; Receptors, Cholinergic; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; Vomiting

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

Clozapine is the only antipsychotic that is effective in treatment-resistant schizophrenia. However, in certain clinical situations, such as the emergence of serious adverse effects, it is necessary to discontinue clozapine. Stopping clozapine treatment poses a particular challenge due to the risk of psychotic relapse, as well as the development of withdrawal symptoms. Despite these challenges for the clinician, there is currently no formal guidance on how to safely to discontinue clozapine. We assessed the feasibility of developing evidence-based recommendations for (1) minimizing the risk of withdrawal symptoms, (2) managing withdrawal phenomena, and (3) commencing alternatives treatment when clozapine is discontinued. We then evaluated the recommendations against the Appraisal of Guidelines for Research and Evaluation (AGREE) II criteria. We produced 19 recommendations. The majority of these recommendation were evidence-based, although the strength of some recommendations was limited by a reliance of studies of medium to low quality. We discuss next steps in the refinement and validation of an evidence-based guideline for stopping clozapine and identify key outstanding questions.

Topics: Adult; Antipsychotic Agents; Clinical Protocols; Clozapine; Drug Substitution; Evidence-Based Medicine; Feasibility Studies; Humans; Practice Guidelines as Topic; Schizophrenia; Schizophrenia, Treatment-Resistant; Substance Withdrawal Syndrome; Symptom Flare Up; Time Factors

Drug addiction is a chronic disorder characterized by compulsive drug seeking, and involves repetitive cycles of compulsive drug use, abstinence, and relapse. In both human and animal models of addiction, chronic food restriction increases rates of relapse. Our laboratory has reported a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated controls. Recently, we reported that activation of the paraventricular nucleus of the thalamus (PVT) abolished heroin seeking in chronically food-restricted rats. However, the precise inputs and outputs of the PVT that mediate this effect remain elusive. The goal of the current study was to determine the role of corticothalamic and thalamo-accumbens projections in the augmentation of heroin seeking induced by chronic food restriction. Male Long-Evans rats were trained to self-administer heroin for 10 d. Next, rats were removed from the self-administration chambers and were subjected to a 14 d withdrawal period while sated (unlimited access to food) or mildly food-restricted (FDR). On day 14, rats were returned to the self-administration context for a 3 h heroin-seeking test under extinction conditions during which corticothalamic and thalamo-accumbens neural activity was altered using chemogenetics. Surprisingly, chemogenetic activation or inhibition of corticothalamic projections did not alter heroin-seeking behavior. Chemogenetic activation of thalamo-accumbens shell, but not core, projectors attenuated heroin seeking in FDR rats. The results indicate an important role for the PVT to nucleus accumbens shell projections in the augmentation of heroin seeking induced by chronic food restriction.

Topics: Animals; Behavior, Addictive; Cerebral Cortex; Clozapine; Drug-Seeking Behavior; Food Deprivation; Heroin; Heroin Dependence; Male; Motor Activity; Narcotics; Neural Pathways; Nucleus Accumbens; Rats; Rats, Long-Evans; Recurrence; Self Administration; Substance Withdrawal Syndrome; Thalamus

Topics: Antipsychotic Agents; Antisocial Personality Disorder; Catatonia; Clozapine; Humans; Male; Schizophrenia; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Catatonia; Clozapine; Humans; Intensive Care Units; Schizophrenia; Substance Withdrawal Syndrome

Aim\ To describe an uncommon side effect of sudden withdrawal of Clozapine.\ Method\ This case describes the occurrence of catatonia following the sudden discontinuation of long term Clozapine therapy.\ Results\ Symptoms resolved with treatment with benzodiazepines and IV fluids.\ Discussion\ In conclusion, catatonia can occur on sudden discontinuation of Clozapine therapy. Caution should be exercised when reducing or discontinuing this medication.

Topics: Antipsychotic Agents; Catatonia; Clozapine; Humans; Male; Middle Aged; Schizophrenia; Substance Withdrawal Syndrome

Rebound cholinergic syndrome is a rare, but well known unwanted phenomenon occurring after abrupt clozapine discontinuation. There have been previous reported cases of cholinergic rebound in the literature; however, these reports described cholinergic rebound following cessation of high doses of clozapine in patients diagnosed with schizophrenia. Here, we report a case of rebound cholinergic syndrome and catatonia in a male patient three days after abrupt discontinuation of 50 mg of clozapine prescribed for type I bipolar affective disorder.. A 66-year old male of Spanish origin, treated for type I bipolar affective disorder for 15 years and for Crohn disease, was brought to the emergency department because of a sudden onset of mutism, dysphagia and trismus. He was described catatonic and presented hypertension, tachycardia and tachypnea. His body temperature was normal and the laboratory tests were unremarkable at presentation. A head CT and an EEG were in the normal range. While reviewing his history, it appeared the he was on clozapine 50 mg a day, first introduced 2 months ago, during a previous hospitalization for a manic episode resistant to other mood stabilizers. For an unknown reason, the patient's psychiatrist stopped clozapine three days before the admission and replaced it by risperidone 5 mg and quetiapine 200 mg daily. A cholinergic rebound syndrome was then evoked. The patient's ability to speak recovered dramatically and fast after the intravenous administration of 2.5 mg of biperiden supporting the diagnosis. Risperidone and quetiapine were also stopped. The patient fully recovered in 20 days after the reintroduction of 50 mg of clozapine and 2.5 mg of biperiden daily.. This case report underscores that cholinergic rebound syndrome may occur in patients suffering from bipolar affective disorders, being on clozapine as a mood stabilizer. The low dose clozapine does not preclude severe manifestations of the phenomenon. Progressive tapering should therefore be adopted in any case.

Topics: Aged; Antipsychotic Agents; Bipolar Disorder; Catatonia; Cholinergic Agents; Clozapine; Humans; Male; Substance Withdrawal Syndrome; Withholding Treatment

Rostromedial tegmental nucleus (RMTg) GABA neurons exert a primary inhibitory drive onto midbrain dopamine neurons and are excited by a variety of aversive stimuli. There is, however, little evidence that the RMTg-ventral tegmental area (VTA)-nucleus accumbens shell (Acb) circuit plays a role in the aversive consequences of alcohol withdrawal. This study was performed in adult male Long-Evans rats at 48-h withdrawal from chronic alcohol drinking in the intermittent schedule. These rats displayed clear anhedonia and depression-like behaviors, as measured with the sucrose preference, and forced swimming tests. These aberrant behaviors were accompanied by a substantial increase in cFos expression in the VTA-projecting RMTg neurons, identified by a combination of immunohistochemistry and retrograde-tracing techniques. Pharmacological or chemogenetic inhibition of RMTg neurons mitigated the anhedonia and depression-like behaviors. Ex vivo electrophysiological data showed that chemogenetic inactivation of RMTg neurons reduced GABA release and accelerated spontaneous firings of VTA dopamine neurons. Finally, using a functional hemispheric disconnection procedure, we demonstrated that inhibition of unilateral RMTg, when combined with activation of D1 and D2 dopamine receptors in the contralateral (but not ipsilateral) Acb, mitigated the anhedonia and depression-like behaviors in alcohol-withdrawal rats. These data show that the integrity in the RMTg-VTA-Acb pathway in a single hemisphere is sufficient to elicit depression-like behavior during ethanol-withdrawal. Overall, the present results reveal that the RMTg-VTA-Acb pathway plays a crucial role in the depression-like behavior in animals undergoing alcohol withdrawal, further advocating the RMTg as a potential therapeutic target for alcoholism.

Topics: 2-Amino-5-phosphonovalerate; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Behavior, Animal; Clozapine; Dopaminergic Neurons; Ethanol; gamma-Aminobutyric Acid; Male; Microinjections; Neural Inhibition; Neural Pathways; Nucleus Accumbens; Proto-Oncogene Proteins c-fos; Quinoxalines; Quinpirole; Rats; Substance Withdrawal Syndrome; Tegmentum Mesencephali; Ventral Tegmental Area

Ketamine (KET) is a non-competitive N-Methyl-d-aspartate (NMDA) receptors antagonist that intensifies sensory experiences, prompts hallucinations and delusions, exacerbates previously installed psychosis and disrupts physiological evoked potentials (AEPs). Pharmacologically, KET stimulates glutamate efflux in the medial prefrontal cortex, mainly in the prelimbic (PrL) sub-region. Efferences from this region exert a top-down regulatory control of bottom-up sensory processes either directly or indirectly. In the midbrain, the central nucleus of the inferior colliculus (CIC) plays a fundamental role in the processing of auditory ascending information related to sound localization, sensorimotor gating, and preattentive event-related potentials. Auditory hallucinations elicited during a psychotic outbreak are accompanied by CIC neural activation. Thus, it is possible that NMDA-mediated glutamate neurotransmission in the PrL indirectly modulates CIC neuronal firing. The aim of the present study was to assess the effects of KET on the latency and amplitude of AEPs elicited in the CIC of rats tested during KET effects and following withdrawal from the chronic administration. Changes on emotionally induced by KET treatment were evaluated with the use of the elevated zero maze (EZM). Unlike typical neuroleptics, the atypical antipsychotic clozapine (CLZ) potently blocks the disruption of the sensorimotor gating induced by NMDA antagonists. Therefore, the effects of KET withdrawal on AEPs were challenged with a systemic injection of CLZ. In addition, we further investigated the role of NMDA receptors of the PrL on the AEPs expression recorded in the CIC through intra-PrL infusions of NMDA itself. Our results showed that the processing of sensory information in the CIC is under indirect control of PrL. These data suggest that the long-term KET treatment disrupts the collicular auditory field potentials, possibly through influencing PrL glutamate activity on intrinsic 5-HT mechanisms in the dorsal raphe and CIC.

Topics: Animals; Clozapine; Evoked Potentials, Auditory; Excitatory Amino Acid Antagonists; Ketamine; Male; Microinjections; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Serotonin Antagonists; Substance Withdrawal Syndrome

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

Topics: Adult; Antipsychotic Agents; Catatonia; Clozapine; Diagnosis, Differential; Humans; Male; Neuroleptic Malignant Syndrome; Psychoses, Substance-Induced; Schizophrenia; Substance Withdrawal Syndrome

In this paper, we report the case of a patient, aged 26, with schizophrenia who was admitted to psychiatric emergencies for catatonia, one week after abrupt discontinuation of clozapine. An improvement was seen after only two days of the reintroduction of clozapine alone. This catatonia is reversible and it responds magnificently to the reintroduction of clozapine. And we conclude that patients and their caregivers need to be educated about the effects of abrupt cessation of clozapine administration.

Topics: Adult; Antipsychotic Agents; Catatonia; Clozapine; Humans; Male; Schizophrenia; Substance Withdrawal Syndrome; Treatment Outcome

Topics: Antipsychotic Agents; Bipolar Disorder; Clozapine; Combined Modality Therapy; Electroconvulsive Therapy; Female; Humans; Middle Aged; Recurrence; Substance Withdrawal Syndrome

We describe a case of serotonin syndrome secondary to clozapine withdrawal and concomitant use of citalopram hydrobromide, a phenomenon that has been rarely reported.. This is a case report of a 47-year-old woman admitted to an academic medical center intensive care unit with coma, hypersalivation, hyperreflexia, and stimulus-induced clonus. The patient received a diagnosis of serotonin syndrome attributed to abrupt clozapine withdrawal with concomitant use of citalopram. She improved only minimally with supportive treatment (intravenous fluids, benzodiazapines, and withdrawal of selective serotonin-reuptake inhibitor) and received cyproheptadine hydrochloride on her third day of symptoms. Four hours after she received the loading dose of cyproheptadine, she was alert and oriented and at her baseline mental status, although some clonus remained.. Serotonin syndrome can result from the abrupt withdrawal of a 5-hydroxytryptamine receptor 2A antagonist from a treatment regimen that also includes a medication that increases serotonin availability.

Topics: Benzodiazepines; Citalopram; Clozapine; Cyproheptadine; Female; Humans; Middle Aged; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Syndrome; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Clozapine; Consciousness; Diagnosis, Differential; Fever; Humans; Male; Middle Aged; Muscle Rigidity; Neuroleptic Malignant Syndrome; Schizophrenia, Paranoid; Substance Withdrawal Syndrome

Topics: Adult; Antipsychotic Agents; Catatonia; Clozapine; Disease Management; Female; GABA Modulators; Humans; Lorazepam; Remission Induction; Schizophrenia; Substance Withdrawal Syndrome; Treatment Outcome; Withholding Treatment

Despite its serious side effects, clozapine is still the golden standard in treatment of schizophrenia due to its effectiveness and lack of extrapyramidal side effects. Some studies have mentioned withdrawal symptoms, including withdrawal psychosis after stopping clozapine, and have tried to explain this severe symptom through dopamine receptor supersensitivity. This phenomenon, called supersensitivity psychosis, can be explained by the development of tolerance towards the effect of the medication. In literature, there are several cases of supersensitivity psychosis while using other neuroleptics. However, to our knowledge, there are no published cases reporting an association between clozapine and supersensitivity psychosis. The current patient, who has been diagnosed as resistant schizophrenia, responded well to the clozapine in the beginning of treatment. Due to an effective dose of clozapine, he had psychotic exacerbation with significant positive symptoms. We discuss the probable reasons causing this situation and the relationship between tolerance to the treatment effect and the dopamine supersensitivity.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Tolerance; Humans; Male; Psychoses, Substance-Induced; Receptors, Dopamine; Schizophrenia; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Clozapine; Humans; Male; Medication Adherence; Middle Aged; Schizophrenia; Substance Withdrawal Syndrome

Lack of appropriate animal models simulating core behavioural aspects of human psychosis is a major limitation in schizophrenia research. The use of drugs, that is believed to act through N-methyl d-aspartate receptor, has been demonstrated to mimic relatively broader range of behavioural symptoms in putative animal models. Our goal in this study has been to further evaluate one such drug, ketamine in mice and characterize some selective behavioural phenotypes associated with the drug dosage, treatment period and withdrawal effects to extend the understanding of this model. Our results indicate that acute treatment of ketamine (100 mg/kg, i.p.) induced hyperlocomotory response and reduced the 'transfer-latency time' in passive avoidance test but did not have any effect in the forced swim test (negative symptoms). In contrast, chronic administration of ketamine not only produced significant 'hyperactivity' response but also enhanced the immobility period in animals during the forced swim test and reduced the latency period in the passive avoidance test. Further, these behavioural alterations persisted at least for 10 days after the withdrawal of ketamine treatment. These observations were substantiated by using standard typical and atypical antipsychotic drugs, haloperidol (0.25 mg/kg, i.p.), clozapine (10 mg/kg, i.p.) and risperidone (0.025 mg/kg, i.p.). Therefore, the present study suggests that the chronic treatment with ketamine has the potential of exhibiting changes in broader range of behavioural domains than the acute treatment. Hence, animals chronically treated with ketamine might serve as a useful tool to study the underlying pathogenic mechanisms associated with some symptoms in schizophrenia and other psychiatric disorders.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Haloperidol; Ketamine; Male; Mice; Motor Activity; Psychotic Disorders; Random Allocation; Risperidone; Schizophrenia; Substance Withdrawal Syndrome; Swimming

Topics: Clozapine; Humans; Substance Withdrawal Syndrome

Topics: Adult; Antipsychotic Agents; Catatonia; Clozapine; Humans; Male; Schizophrenia; Substance Withdrawal Syndrome

Using cocaine-sensitized mice as a model for psychosis, this study investigated whether subchronic treatment with clozapine could affect the sensitized state of the animals and examined the accompanying molecular changes in the brain. To induce sensitization, ICR mice (n=44) were treated with cocaine for 5 days. After 7 days of withdrawal, sensitization was confirmed by a cocaine challenge. Then, the sensitized animals were treated with clozapine for 5 days and rechallenged with cocaine. The frontal cortices were removed from the mice (n=16) 24 h after the last challenge, and the phosphorylation status of some key signaling molecules was investigated. Compared with the sensitized mice receiving the vehicle treatment, the sensitized mice receiving subchronic clozapine showed less locomotor activity, with an activity level similar to that of non-sensitized mice. However, clozapine did not directly affect the stimulatory effect of cocaine. Clozapine also reversed some of the sensitization-induced biochemical changes, including increased phosphorylation of GSK-3beta and CREB, in the frontal cortex. Subchronic treatment with clozapine apparently de-sensitized the sensitized mice. The long-term effect of clozapine on stimulant-induced sensitization may be related to the therapeutic effect of the drug as an antipsychotic agent.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Cocaine; CREB-Binding Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Extracellular Signal-Regulated MAP Kinases; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Mice; Mice, Inbred ICR; Motor Activity; Oncogene Protein v-akt; Prefrontal Cortex; Signal Transduction; Substance Withdrawal Syndrome

Episodic memory is the capacity to recall an event in time and place (What? Where? When?). Impaired episodic memory is a debilitating cognitive symptom in schizophrenia but is poorly controlled by currently available antipsychotic drugs. Consistent with glutamatergic abnormality in schizophrenia, the NDMA receptor antagonist, phencyclidine (PCP), induces persistent 'schizophrenia-like' symptoms including memory deficits in humans and rodents and is widely used as an animal model of the disorder. However, in contrast to humans, PCP and PCP withdrawal-induced memory deficits in rodents are reversed by antipsychotic drugs such as clozapine. One possible explanation is that the memory tasks used in animal studies do not simultaneously test the What? Where? When? components that characterize episodic memory in human tasks. We investigated whether subchronic PCP withdrawal disrupts memory in rats in a task that requires simultaneous integration of memory for object, place and context. Rats learn to discriminate objects under specific spatial and contextual conditions analogous to the What? Where? When? components of human episodic memory. We found that PCP withdrawal impaired performance on this task and that the atypical antipsychotic drug clozapine did not reverse this impairment. However the acetylcholinesterase inhibitor (AChEI) donepezil, which has been shown to improve episodic memory in humans did reverse the effect of PCP. This suggests that PCP withdrawal disruption of object-place-context recognition in rats may prove to be a useful model to investigate episodic memory impairment in schizophrenia and supports the suggestion that AChEIs could prove to be a useful pharmacological strategy to specifically treat episodic memory problems in schizophrenia.

Topics: Animals; Clozapine; Donepezil; Indans; Male; Memory Disorders; Memory, Episodic; Phencyclidine; Piperidines; Rats; Substance Withdrawal Syndrome

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

Topics: Catatonia; Clozapine; Family Health; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Parkinson Disease; Psychotic Disorders; Substance Withdrawal Syndrome

Topics: Akathisia, Drug-Induced; Alcoholism; Antipsychotic Agents; Aripiprazole; Clozapine; Cocaine-Related Disorders; Comorbidity; Delayed-Action Preparations; Diabetic Ketoacidosis; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Middle Aged; Molindone; Piperazines; Quinolones; Schizophrenia, Paranoid; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Catatonia; Clozapine; Electroconvulsive Therapy; Female; Humans; Long-Term Care; Medication Adherence; Middle Aged; Psychotic Disorders; Substance Withdrawal Syndrome

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

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: Aggression; Agranulocytosis; Antipsychotic Agents; Clozapine; Fatal Outcome; Humans; Intellectual Disability; Male; Middle Aged; Myelodysplastic Syndromes; Substance Withdrawal Syndrome; Time Factors

After rapid discontinuation of clozapine treatment rebound psychosis have been reported. Preexposure of D (2) receptors to clozapine may alter their affinity to endogenous dopamine. Clozapine withdrawal may also lead dysfunctional NMDA-receptors to cause dopamine release in the striatum.. We report a case of a schizophrenic patient treated with clozapine 200 mg and aripiprazole 15 mg per day. After rapid clozapine discontinuation we added quetiapine up to 700 mg daily.. No rebound psychosis occurred. Even ten weeks after switching to quetiapine the patient's condition remained stable in the Brief Psychiatric Rating Scale.. The combination of aripiprazole and quetiapine seemed to control supersensitivity effects at the D (2) receptor after clozapin withdrawal in this case.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Brain; Brief Psychiatric Rating Scale; Clozapine; Dibenzothiazepines; Drug Therapy, Combination; Humans; Male; Piperazines; Quetiapine Fumarate; Quinolones; Receptors, Dopamine D2; Schizophrenia; Secondary Prevention; Substance Withdrawal Syndrome; Treatment Outcome

Topics: Adolescent; Antipsychotic Agents; Clozapine; Female; Humans; Intellectual Disability; Mental Disorders; Ocular Motility Disorders; Substance Withdrawal Syndrome

The aims of our study were (1) to compare the dose of clozapine needed to achieve remission in patients who stopped their treatment (study group) versus patients who continued taking this medication (control group) and (2) to compare the clinical characteristics of remission between these 2 groups.. We retrospectively reviewed the medical records of all treatment-resistant schizophrenic and schizoaffective patients (according to DSM-IV criteria) who were treated with clozapine over a period of 9 years, from January 1995 through December 2003. The study group consisted of 43 patients and the control group of 12 patients. All patients' files from both groups were examined, and each patient's remission was scored twice--initially on discharge from the hospital and subsequently after final discharge for the study group, or at the end of the study for the control group.. The change of clozapine dose from the first to the last remission expressed by percentage shows a significant difference between the 43% increase in clozapine dose in the study group and the 12.5% decrease in clozapine dose in the control group (p < .001). Quality of remission assessment showed deterioration in the global remission score in the study group, while the quality of remission assessment in the control group did not show any change.. Our findings suggest that the discontinuation of clozapine treatment leads to a deterioration in the quality of remission, with a need for an increased dose of clozapine. Further prospective studies on larger samples are needed to confirm these findings.

Topics: Acute Disease; Adult; Antipsychotic Agents; Clozapine; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Patient Dropouts; Prognosis; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; Treatment Outcome

The authors report a case of a patient, who in a few days after an abrupt discontinuation of clozapine and haloperidol developed agitated and confused state resembling neuroleptic malignant syndrome (NMS) and clozapine withdrawal symptoms at the same time. Data obtained from family members led to gradual reintroduction of clozapine and to subsequent recovery. The case illustrates the importance for clinicians to be familiar with the variety of discontinuation symptoms, so they can recognize them and offer effective treatment.

Topics: Adult; Antipsychotic Agents; Clozapine; Haloperidol; Humans; Male; Neuroleptic Malignant Syndrome; Psychomotor Agitation; Substance Withdrawal Syndrome; Treatment Refusal

There is growing interest in detecting and treating schizophrenia during the "prodrome," before the symptoms are fully manifested. The objective of this study was to develop a putative model of the prodrome and study the effects of medications on it.. Rats were treated with different regimens of amphetamine to produce full sensitization (full syndrome) and partial sensitization (to model the prodromal state) and were then treated with typical and atypical antipsychotics and a D1 antagonist to mimic early intervention. After several weeks of withdrawal, locomotor activity in response to amphetamine and behavioral deficits (prepulse inhibition [PPI] and latent inhibition [LI]) were examined.. Animals that received the full sensitization showed significant increase in locomotor activity and a disruption in both PPI and LI. Animals treated with a partial regimen showed only a muted phenotype. The animals that received "early intervention" did not show progression from the prodromal to the full-blown phenotype.. The partial regimen of amphetamine injections provided a modified phenotype that could be regarded as a representative of the "prodromal" state. Early intervention, instituted once the prodromal state was already developed, prevented further progression into the full phenotype analogous to schizophrenia.

Topics: Amphetamine; Analysis of Variance; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Benzazepines; Central Nervous System Stimulants; Clozapine; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Haloperidol; Inhibition, Psychological; Male; Motor Activity; Neural Inhibition; Random Allocation; Rats; Rats, Sprague-Dawley; Reaction Time; Reflex, Startle; Schizophrenia; Substance Withdrawal Syndrome; Time Factors

Topics: Adult; Anti-Anxiety Agents; Antiparkinson Agents; Antipsychotic Agents; Bromocriptine; Clozapine; Creatine Kinase; Dose-Response Relationship, Drug; Electroconvulsive Therapy; Haloperidol; Humans; Lorazepam; Male; Neuroleptic Malignant Syndrome; Psychotic Disorders; Schizophrenia; Substance Withdrawal Syndrome

The most serious adverse effect of clozapine, agranulocytosis, was described for the first time in Finland in 1975. It caused the immediate withdrawal of clozapine from the market and immediate discontinuation of this medication in all patients. It is now known that abrupt withdrawal of clozapine may cause a rapid deterioration in psychotic symptoms.. The aim of this retrospective study was to investigate the effect of abrupt clozapine withdrawal on psychiatric patients, and to examine whether anticholinergic drugs are effective in preventing acute deterioration.. We reviewed the hospital case records from Pitkäniemi Psychiatric Hospital, Tampere, Finland, of the 28 patients with schizophrenia who had been receiving clozapine and from whom it was abruptly withdrawn due to the withdrawal of the drug from the market in the summer of 1975. We assessed the incidence of deterioration and whether or not patients in whom this occurred were receiving anticholinergic drugs.. We found a rapid deterioration after clozapine withdrawal in almost half (46.4%; n = 13) of the patients. Patients receiving anticholinergic drugs (such as antiparkinsonians, tricyclic antidepressants and antipsychotics with anticholinergic properties) were significantly less likely to deteriorate than those not receiving these drugs (21.4% vs 71.4%, p = 0.008). The condition of the patients who deteriorated was poor for up to 1 month after discontinuation, but had improved slightly by the end of 1975.. Anticholinergic medication should be considered for preventing possible symptom deterioration when clozapine is abruptly discontinued.

Topics: Adolescent; Adult; Antipsychotic Agents; Cholinergic Antagonists; Clozapine; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; Treatment Outcome

There is an increasing awareness that a psychosis, similar to that of schizophrenic psychosis, can be derived from cocaine addiction. Thus, the prototypical atypical antipsychotic medication, clozapine, a 5-HT(2)/DA(2) antagonist, was studied for its effects on cocaine-induced dopamine (DA) and serotonin (5-HT) release in nucleus accumbens (NAcc) of behaving male Sprague-Dawley laboratory rats with In Vivo Microvoltammetry, while animals' locomotor (forward ambulations), an A(10) behavior, was monitored at the same time with infrared photobeams. Release mechanisms for monoamines were determined by using a depolarization blocker, gamma-butyrolactone (gammaBL). BRODERICK PROBE microelectrodes selectively detected release of DA and 5-HT within seconds and sequentially in A(10) nerve terminals, NAcc. Acute and subacute studies were performed for each treatment group. Acute studies are defined as single injection of drug(s) after a stable baseline of each monoamine and locomotor behavior has been achieved. Subacute studies are defined as 24-h follow-up studies on each monoamine and locomotor behavior, in the same animal at which time, no further drug was administered. Results showed that (1) acute administration of cocaine (10 mg/kg ip) (n=5) significantly increased both DA and 5-HT release above baseline (P<.001) while locomotion was also significantly increased above baseline (P<.001). In subacute studies, DA release decreased significantly below baseline (P<.001) and significant decreases in 5-HT release occurred at the 15-min mark and at each time point during the second part of the hour (P<.05); the maximum decrease in 5-HT was 40% below baseline. Locomotor behavior, on the other hand, increased significantly above baseline (P<.05). (2) Acute administration of clozapine/cocaine (20 and 10 mg/kg ip, respectively; n=6) produced a significant block of the cocaine-induced increase in DA (P<.001) and 5-HT release (P<.001). Cocaine-induced locomotion was blocked simultaneously with each monoamine by clozapine as well (P<.001). In subacute studies, DA release continued to be blocked presumably via clozapine by exhibiting a statistically significant decrease (P<.001), but 5-HT release increased significantly (P<.001), while cocaine-induced locomotor activity also continued to be antagonized by clozapine, i.e., locomotor activity exhibited no difference from baseline (P>.05). In summary, acute studies (a) support previous data from this laboratory and others that

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Brain Chemistry; Central Nervous System Stimulants; Clozapine; Cocaine; Dopamine; Dopamine Uptake Inhibitors; Electrophysiology; Male; Microelectrodes; Motor Activity; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Serotonin; Substance Withdrawal Syndrome

We consider the reasons underlying clozapine withdrawal in a group of hospitalised schizophrenic inpatients and review clinical outcome following clozapine withdrawal. A retrospective case note study was undertaken of all patients (n=41) registered at the State Hospital, Carstairs, with the Clozaril Patient Monitoring Service between 1990 and 2001 whose clozapine therapy had either been withdrawn or never initiated following registration. Twelve patients refused to commence clozapine following registration: twenty-nine patients were subsequently studied. Thirteen patients stopped clozapine owing to non-compliance, whereas seven had clozapine withdrawn due to a clinically inadequate response. Eleven patients were withdrawn primarily because of an unacceptable side-effect burden, although only four had a 'red alert'. In twenty patients, abrupt clozapine withdrawal resulted in a marked, immediate deterioration in their mental state. Twenty-three patients remained at the State Hospital at a mean follow-up period of 75 months. The study highlights the relevance of psychoeducation for clozapine patients in the maintenance phase of treatment, the importance of minimising the side-effect burden by clozapine monotherapy, the effectiveness of clozapine serum level monitoring and the evidence base for adjuvant treatment.

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Hospitals, Psychiatric; Hospitals, State; Humans; Institutionalization; Northern Ireland; Retrospective Studies; Schizophrenia; Scotland; Substance Withdrawal Syndrome; Surveys and Questionnaires; Time Factors; Treatment Outcome; Treatment Refusal

Based on the phenomenologic similarity between symptoms of drug withdrawal and the negative symptoms of schizophrenia (e.g., anhedonia), we hypothesized that treatment with clozapine may be effective against nicotine and amphetamine withdrawal.. A rate-independent discrete-trial threshold procedure was used to assess brain stimulation reward in rats prepared with electrodes in the lateral hypothalamus. Somatic signs of nicotine withdrawal were also assessed.. Clozapine administration (.75 or 1.5 mg/kg) during nicotine or amphetamine withdrawal did not affect the threshold elevations associated with drug withdrawal. The.75 mg/kg clozapine dose reversed the increased number of somatic signs of nicotine withdrawal. Ten days of clozapine treatment (3 mg/kg/b.i.d.) before exposure to nicotine prevented the threshold elevations in a subset of rats and the increases in somatic signs in all subjects. Fourteen-day pretreatment with clozapine (6 mg/kg/day) decreased the duration of amphetamine withdrawal.. Correlational analyses indicated that the ability of clozapine to prevent the affective aspects of drug withdrawal depended on low sensitivity to acute clozapine under baseline conditions. The results are consistent with the clinical situation where clozapine is partially effective against the negative symptoms of schizophrenia and more effective in some individuals than others. These results indicate that lack of sensitivity to the initial negative effects of clozapine may predict its a subsequent therapeutic response. Finally, the data suggest that there may be commonalities in the neurosubstrates mediating affective aspects of drug withdrawal and the negative symptoms of schizophrenia.

Topics: Affective Symptoms; Amphetamine; Animals; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Male; Nicotine; Rats; Rats, Wistar; Reward; Substance Withdrawal Syndrome

Antipsychotic drugs have been reported to increase the expression of subunits of the NMDA receptor at the level of mRNA but it is not clear whether such effects are apparent at the level of the radioligand binding or receptor protein. Therefore, we examined the effect of treatment of, and withdrawal from, haloperidol, chlorpromazine, olanzapine or clozapine on the binding of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP ) to the open ion channel of the NMDA receptor in rat caudate-putamen, hippocampus and frontal cortex. [3H]TCP binding was not significantly different in the caudate-putamen, hippocampus and cortex after three months of treatment with any antipsychotic drug. There were significant decreases in [3H]TCP binding in rat caudate-putamen and cortex, but not hippocampus, one month after ceasing treatment. Decreases in the caudate-putamen were detected in rats previously treated with chlorpromazine (0.1 mg/kg/day) and clozapine (0.1 and 1.0 mg/kg/day). In the cortex, decreases in [3H]TCP binding were also detected in rats previously treated with olanzapine (0.1 mg/kg/day) for three months. These data suggest that changes in the NMDA receptor associated ion channels occur following antipsychotic drug withdrawal.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Brain; Chlorpromazine; Clozapine; Haloperidol; Ion Channels; Male; Olanzapine; Phencyclidine; Pirenzepine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

Male Sprague-Dawley rats were given two separate sensitizing regimens of cocaine (7 days on, 7 days off, 7 days on at 40 mg/kg/day, s.c.) or saline injections. Half of the animals also received a drug with 5-hydroxytryptamine-2 (5-HT2) receptor antagonist properties (clozapine, 3 mg/kg; mianserin 6 mg/kg; ketanserin 1 mg/kg, all s.c.) or saline during the second cocaine dosing regimen in the acute withdrawal period, 3.5 h after each cocaine injection. On day 10 of withdrawal animals were challenged with cocaine (7.5 mg/kg, i.p.) and assessed by a behavioral rating scale and locomotor activity monitoring. The 5-HT2 receptor antagonists, but not saline, reversed behavioral sensitization and had little effect on behavior in the control animals. 5-HT2 receptor antagonists, therefore, may be a useful treatment for cocaine addicts that have undergone previous sensitization periods. The pharmacological profile of these antagonists suggests that the 5-HT2A receptor subtype may mediate this effect.

Topics: Animals; Behavior, Animal; Clozapine; Cocaine; Injections; Ketanserin; Male; Mianserin; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Substance Withdrawal Syndrome

Abrupt clozapine withdrawal can cause rebound psychosis and severe somatic symptoms in psychiatric patients. We report on the case of an advanced Parkinson's disease patient who developed myoclonus, tremor, rigidity, hyperreflexia, and stupor after abrupt clozapine withdrawal. The patient's symptoms resolved with treatment with cyproheptadine. This clinical picture suggests serotonergic rebound as an explanation for the patient's symptoms, although other pharmacological mechanisms are possible. Clozapine should be gradually withdrawn over a period of 1 to 2 weeks when possible, and abruptly discontinued only when necessary.

Topics: Aged; Antipsychotic Agents; Carbidopa; Clozapine; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Hallucinations; Humans; Levodopa; Male; Neurologic Examination; Parkinson Disease; Parkinson Disease, Secondary; Substance Withdrawal Syndrome

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

Latent inhibition (LI) is a behavioral phenomenon whereby repeated exposure to a non-reinforced stimulus retards subsequent conditioning to that stimulus. Deficits in LI may reflect an inability to ignore irrelevant stimuli and are studied as a model of the cognitive/attentional abnormalities found in schizophrenia. We recently determined that pretreatment with escalating doses of the indirect dopamine agonist amphetamine (AMPH; 3 daily injections ip, 1-5 mg/kg, over 6 days) disrupts LI in rats tested in a 2-way active avoidance paradigm during withdrawal. In the present study, we evaluated the effects of the atypical neuroleptic clozapine and the typical neuroleptic haloperidol on the expression of LI on day 4 of AMPH withdrawal. Neuroleptic injections were given either 45 min prior to each of two tone preexposure sessions and a subsequent tone-shock avoidance test session, or only prior to the test session. As expected, saline-injected control groups showed LI during the test session, as reflected by significantly reduced avoidance in tone preexposed vs. non-preexposed rats. In contrast, animals pretreated with escalating doses of AMPH did not show LI, due to the improved avoidance of the preexposed animals. Both haloperidol (0.03 mg/kg) and clozapine (5 mg/kg) largely reversed the disruptive influence of AMPH on LI regardless of whether these drugs were administered prior to both preexposure and test sessions or only prior to the test session. These results provide pharmacological validation for an AMPH withdrawal model of schizophrenic symptoms.

Topics: Amphetamine; Animals; Antipsychotic Agents; Avoidance Learning; Central Nervous System Stimulants; Clozapine; Haloperidol; Inhibition, Psychological; Male; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Phencyclidine (PCP) reduced social behavior (SB) in a dose- and time-dependent fashion. However, no such SB deficit was observed on repeated treatment with methamphetamine for 14 days. The SB deficit produced by treatment with PCP (10 mg/kg/day) for 14 days, which persisted for 28 days after withdrawal, was attenuated by clozapine (10 mg/kg/day) given for 7 days, whereas haloperidol for 7 days had no effect. Clozapine, but not haloperidol, alone at the same treatment dose increased SB in saline-treated mice. These results suggest that the proposed PCP model in mice will provide a tool to test beneficial effects of atypical antipsychotics on social dysfunction in schizophrenia, and contribute to our understanding of the mechanisms by which clozapine improves SB deficit.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Hallucinogens; Haloperidol; Male; Mice; Models, Animal; Phencyclidine; Schizophrenia; Social Behavior; Substance Withdrawal Syndrome

To report on the possible development of serotonin syndrome in a patient receiving clomipramine after clozapine was withdrawn from the treatment regimen.. A 44-year-old white man with a 23-year history of undifferentiated schizophrenia and obsessive-compulsive behavior had been treated with clozapine and clomipramine for several years. He tolerated both agents together well, with the exception of experiencing chronic constipation. Clomipramine was tapered and reduced to 50 mg over a period of 10 days. A worsening of ritualistic behavior was noted, and the clomipramine dosage was increased to 150 mg/d over 14 days. Simultaneously with the clomipramine dosage increase, clozapine was tapered and stopped ever a period of 19 days. The day after clozapine was stopped, while he was still receiving clomipramine 150 mg/d, he began behaving oddly, started sweating profusely, shivering, and became tremulous, agitated, and confused. He was diagnosed with possible serotonin syndrome; his symptoms resolved after clomipramine was stopped but before clozapine was restarted eight days later.. There are similarities in symptoms between serotonin syndrome and clozapine withdrawal. This article discusses the reasons why this case may represent serotonin syndrome rather than clozapine withdrawal and the possible pharmacologic mechanisms involved.. Clinicians should be aware that removing a serotonin-2a (S-HT2a) antagonist 1mm a treatment regimen including an agent that increases serotonin in the synaptic cleft may worsen clozapine withdrawal or potentially result in serious adverse drug reactions, such as serotonin syndrome.

Topics: Adult; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Clomipramine; Clozapine; Humans; Male; Obsessive-Compulsive Disorder; Schizophrenia; Serotonin Syndrome; Substance Withdrawal Syndrome

Topics: Animals; Clomipramine; Clozapine; Humans; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Syndrome; Substance Withdrawal Syndrome

A 30-year-old male patient with paranoid schizophrenia was on clozapine therapy for more than five years. Discontinuation of clozapine and an attempt to change his medication to sertindole has led to serious psychotic and somatic symptoms. After readministration of clozapine the psychotic symptoms rapidly disappeared. The patient was monitored by BPRS and PANSS positive and negative scale. Also clinical and labor parameters of the patient were monitored. The change of his medication from clozapine to sertindole was unsuccessful. This case report suggests that although atypical antipsychotics may be generally different from the classical neuroleptic drugs, there are also significant differences among the atypical antipsychotic drugs in their effects on the receptors of the central nervous system. Therefore the change of clozapine to another atypical antipsychotic medication in the clinical practice should be cross-tapered and the symptoms of withdrawal closely monitored.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Imidazoles; Indoles; Male; Psychiatric Status Rating Scales; Schizophrenia, Paranoid; Schizophrenic Psychology; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Clozapine; Humans; Substance Withdrawal Syndrome

A direct comparison of the effects of clozapine and haloperidol upon naloxone-induced withdrawal jumping was investigated in morphine-dependent mice, as this syndrome may provide a behavioral baseline to differentiate between the two neuroleptics. Neither clozapine ((0.03-3.0 mg/kg s.c., n=9-10) nor haloperidol (0.01-04).1 mg/kg s.c., n=9-10) affected withdrawal jumping precipitated by 0.1 or 15.0 mg/kg i.p. naloxone in morphine-dependent mice. Measurement of locomotor activity immediately prior to naloxone administration revealed a dose-dependent reduction in activity by both compounds, indicating pharmacological effects at the time of naloxone-induced withdrawal. Clonidine (0.02-0.5 mg/kg s.c., n=9-10) also had no affect upon withdrawal jumping, although reductions in locomotor activity prior to naloxone administration were detected. There is no difference in the effects of acutely administered clozapine and haloperidol upon naloxone-precipitated withdrawal jumping in morphine-dependent mice.

Topics: Analgesics; Animals; Antipsychotic Agents; Clonidine; Clozapine; Haloperidol; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome

In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chronic treatment.. The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temperature measures.. Two groups of 15 female Wistar rats were treated chronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 days prior to cessation of drug treatment, withdrawal being studied over 4 consecutive days. Body temperatures were assessed daily throughout the study.. Acutely, clozapine induced dose-related hypothermia, to which complete tolerance developed in both groups, the development of tolerance being more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per injection of clozapine showed rapid onset significant hyperthermia. This dissipated progressively over days, and was completely absent after 4 days of withdrawal.. Clozapine induced a clear somatic withdrawal sign after chronic treatment. It is suggested that, in future research in both humans and animals, it is important to attempt to differentiate between clozapine withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in animals; to establish the neurochemical mechanisms involved in such withdrawal; and to determine which novel antipsychotics are most efficacious in inducing clozapine-like withdrawal effects, in suppressing clozapine withdrawal, and in preventing relapse to psychosis in patients being transferred from clozapine to novel atypical antipsychotic drugs.

Topics: Animals; Antipsychotic Agents; Body Temperature; Clozapine; Dose-Response Relationship, Drug; Drug Tolerance; Female; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Substance-Related Disorders

In an attempt to understand the basis of early relapse after antipsychotic withdrawal, the objective of this study was to determine whether the low occupancy of dopamine D2 receptors by clozapine and by quetiapine, as seen by brain imaging, could arise from a rapid release of some of the D2-bound clozapine or quetiapine by the brain imaging compounds and by the action of a physiological concentration of dopamine.. Human cloned D2 receptors were first pre-equilibrated with the [3H]antipsychotic drug, after which raclopride, iodobenzamide, or dopamine (at the physiological concentration in the synapse) was added, and the time course of release of the [3H]antipsychotic from the D2 receptor was measured.. Within 5 minutes, low concentrations of raclopride and iodobenzamide displaced appreciable amounts of [3H]clozapine and [3H]quetiapine from the D2 receptors but, during the course of 1 hour, did not displace any of the other antipsychotic [[3H]ligands. [3H]Clozapine and [3H]quetiapine, moreover, were displaced by dopamine (100 nM) at least 100 times faster than the other antipsychotic [3H]ligands.. Clozapine and quetiapine are loosely bound to the D2 receptor, and the injected radioactive ligand at its peak concentration may displace some of the D2-bound antipsychotic drug, resulting in apparently low D2 occupancies. Therefore, under clinical brain imaging conditions with [11C]raclopride, D2 occupancies by clozapine and by quetiapine may be higher than currently estimated. These considerations may result in high levels of the D2 receptors being occupied by therapeutic doses of clozapine or quetiapine. The rapid release of clozapine and quetiapine from D2 receptors by endogenous dopamine may contribute to low D2 receptor occupancy and to early clinical relapse upon withdrawal of these medications.

Topics: Animals; Antipsychotic Agents; Benzamides; Brain; Carbon Radioisotopes; Cloning, Molecular; Clozapine; Dibenzothiazepines; Dopamine; Dose-Response Relationship, Drug; Humans; Iodine Radioisotopes; Mice; Pyrrolidines; Quetiapine Fumarate; Raclopride; Radionuclide Imaging; Receptors, Dopamine D2; Salicylamides; Spodoptera; Substance Withdrawal Syndrome; Tritium

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

Withdrawal symptoms associated with switch between two typical antipsychotics are generally rare and mild. In contrast, switching from clozapine to risperidone can be lead to severe withdrawal symptoms. Different pathophysiologic aetiologies have been suggested for explaining these severe symptoms, including cholinergic supersensitivity and rebound. Theoretically, the switch from clozapine to olanzapine should not lead to any problems because those two agents have the same affinity in vitro for muscarinic receptors.. This study reports two cases of switches from clozapine to olanzapine, in refractory schizophrenic patients, which were associated with severe withdrawal symptoms.. After the switch, the two patients developed diaphoresis, hypersialorrhea, bronchial obstruction, agitation, anxiety and enuresis. The symptoms were treated with anticholinergic medication and by an increase in dose of olanzapine to 20 mg/day. For one of the patients this treatment led to normalization of secretion. For the other patient, a superinfection leading to a bilateral pneumopathy which required emergency hospitalization in a general hospital was observed.. The symptomatology and the response to treatment lead to the hypothesis of a muscarinic from abrupt weaning. The withdrawal symptoms disappeared rapidly with an increase in olanzapine dosage and with anticholinergic started at the beginning of the switch. We recommend slow clozapine weaning over 3 weeks or more with concurrent anticholinergic treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Receptors, Muscarinic; Schizophrenia; Substance Withdrawal Syndrome

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Substance Withdrawal Syndrome; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fluoxetine; Humans; Male; Middle Aged; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Syndrome; Substance Withdrawal Syndrome

Clozapine is an "atypical" antipsychotic agent for treating previously resistant schizophrenic patients. Its main advantages over "typical" neuroleptics are low incidence of extrapyramidal side effects and its capacity to induce therapeutic response in previously treated refractory patients. However, withdrawal from clozapine has been observed to lead to "atypical" clinical characteristics or a "rebound phenomenon," manifested in two interwoven clinical forms: (1) psychotic exacerbation, and (2) cholinergic rebound. The underlying pathophysiological mechanism of this phenomenon is postulated to be a result of cholinergic supersensitivity. In this paper, the "rebound phenomenon" will be discussed and exemplified by three case histories in which abrupt cessation of clozapine led to serious deterioration and psychotic exacerbation, and one case in which gradual titration from the drug was employed in order to preempt this hazardous occurrence.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Schizophrenia; Substance Withdrawal Syndrome

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Male; Phenobarbital; Substance Withdrawal Syndrome

Both clozapine (CLZ) and caffeine are CYP1A2 substrates. This study raises the hypothesis of whether caffeine withdrawal from the diet alters the metabolism and/or clinical status of patients receiving CLZ. Seven schizophrenic patients (six men and one woman) receiving monotherapy with CLZ at 271+/-102 mg/day (3.73+/-1.4 mg/kg) participated in the study. CLZ, norclozapine (NOR), and clozapine-N-oxide (NOX) were assayed in plasma by high-performance liquid chromatography at three different time points: A, with concomitant intake of caffeine from the diet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was determined by means of a urinary caffeine test. After a caffeine-free diet for 5 days, CLZ concentrations relative to time point A decreased from 486 to 306 ng/mL (-47%) (p < 0.02), NOX levels decreased from 66 to 49 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increased from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to initial figures at time point C. The NOR/CLZ ratio was significantly correlated to the CYP1A2 index (rs = 0.96, p < 0.0005). In conclusion, changes in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be medically supervised, and the monitoring of CLZ and metabolite levels may be warranted. Furthermore, in those patients who receive therapy with CLZ, the NOR/CLZ ratio may provide an additional and valuable estimate of CYP1A2 activity.

Topics: Adult; Antipsychotic Agents; Biological Availability; Biotransformation; Caffeine; Chromatography, High Pressure Liquid; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Substance Withdrawal Syndrome

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Psychotic Disorders; Risk Factors; Risperidone; Substance Withdrawal Syndrome

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

The purpose of this study was to compare the subchronic, low-dose effects of clozapine with those of olanzapine in a learned behavioral task previously shown to distinguish between clozapine and haloperidol with acute and subchronic treatment regimes. Rats were trained to use a single forelimb to press a force-recording operandum and simultaneously to lick water from a dipper that remained available while forelimb force exceeded a modest lower limit. Analysis of the resulting forcetime recordings provided measures of task engagement (time on task-analogous to response rate), lick rhythm, tremor, ballistic (maximum force) and tonic (hold force) forelimb force measures, as well as the durations of the individual responses. In a between-groups dosing design, five separate groups of rats received vehicle, clozapine 1.0 or 5.0 mg/kg, olanzapine 0.5 or 1.0 mg/kg daily for 27 days. A 7-day withdrawal period followed. On days 22 and 26 of antipsychotic drug treatment, all rats additionally received 0.3 mg/kg trihexyphenidyl or 1.0 mg/kg quipazine, respectively. The effects of olanzapine and clozapine were similar in that both drugs reduced time on task, increased response duration, and slowed lick rhythm. The two drugs differed in that clozapine reduced the force and tremor measures but olanzapine did not. Both tolerance and withdrawal effects, as reflected by the tremor measure, were observed for clozapine but not for olanzapine. Trihexyphenidyl further increased the duration of responses already lengthened by clozapine; in contrast, trihexyphenidyl decreased the duration lengthening effect of olanzapine. Taken together, the results indicated that olanzapine did not have the antitremor and hypotonic effects displayed by clozapine, and olanzapine did not induce tolerance and withdrawal phenomena as clozapine did.

Topics: Animals; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Tolerance; Forelimb; Male; Muscarinic Antagonists; Olanzapine; Pirenzepine; Quipazine; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Substance Withdrawal Syndrome; Tremor; Trihexyphenidyl

Catatonia as a clozapine withdrawal syndrome has not been documented. We report a case of excited catatonia with fever, autonomic instability, and delirium--a picture of malignant catatonia (lethal catatonia) after abrupt clozapine withdrawal. The use of conventional neuroleptics transformed the excited malignant catatonia into a stuporous state resembling neuroleptic malignant syndrome (NMS). Such a transformation of excited lethal catatonia into NMS has been described in the literature, providing support for the hypothesis that NMS is a variant of catatonia. Opinions, however, have been conflicting whether lethal catatonia and NMS are indistinguishable. We argue that NMS may be regarded as a neuroleptic-induced retarded (stuporous) subtype of malignant catatonia, clinically indistinguishable from nonneuroleptic retarded malignant catatonia but different from the excited form. To differentiate between the two subtypes of malignant catatonia would help resolve the controversy. The nosological status of excited catatonia, a poorly studied condition, remains unclear. The two subtypes of catatonia may differ in pathophysiology and responses to treatment. Clinicians should be alert to catatonia as a possible clozapine withdrawal phenomenon, and excited catatonia deserves more research attention.

Topics: Adult; Antipsychotic Agents; Catatonia; Clozapine; Humans; Male; Neuroleptic Malignant Syndrome; Schizophrenia; Substance Withdrawal Syndrome

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

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Schizophrenia; Substance Withdrawal Syndrome

Withdrawal effects of neuroleptics have not received much attention. Clozapine withdrawal phenomena have been attributed to psychosis arising from D2 supersensitivity, which is unlikely since it has minimal action on D2 receptors. The time course and clinical features of this phenomenon suggest that cholinergic overdrive and gamma-aminobutyric acid (GABA) supersensitivity occurs after withdrawal, since it is strongly anticholinergic and has a GABAergic action. Recently, a number of patients showed marked decompensation when they were switched from clozapine to risperidone, especially when they were rapidly tapered off clozapine. This was probably more due to withdrawal effects than the primary psychosis or a lack of efficacy of risperidone. A slow withdrawal schedule would facilitate homeostatic mechanisms; anticholinergics would be useful in clozapine withdrawal. This area has not received any attention from researchers, nor are there any guidelines for clinicians. This will be particularly important with the widespread use of atypical agents in the future.

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Humans; Male; Receptors, Dopamine; Receptors, GABA; Risperidone; Substance Withdrawal Syndrome

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Leukocyte Count; Psychiatric Status Rating Scales; Recurrence; Schizophrenia, Paranoid; Substance Withdrawal Syndrome; Suicide, Attempted

Akathisia is one of the most distressing side effects of neuroleptic treatment. It is usually managed by manipulating the neuroleptic dose and administering anti-akathisic compounds (beta-blockers, anticholinergics, serotonin antagonists). However, the pathophysiological background of withdrawal akathisia which follows the discontinuation of neuroleptic treatment remains unclear, and there is as yet no adequate treatment. We report a case of severe withdrawal akathisia associated with suicidal and autoaggressive behaviour during a gradual transition from perphenazine/trihexyphenidyl to clozapine. The akathisia was effectively managed by titration of clozapine (maximum dose 200 mg/day) Thereafter, reduction of the clozapine dose resulted in a recurrence of the akathisia, and the resumption of clozapine dose was accompanied by full amelioration of symptoms. We suggest that the antiserotonergic properties of clozapine were responsible for its anti-akathisic effect. Differences in the treatment of acute and withdrawal types of akathisia are emphasized.

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Psychomotor Agitation; Schizophrenia; Substance Withdrawal Syndrome

Rebound insomnia has been reported upon discontinuation of benzodiazepines. We describe the first case of a sleep polygraphically documented rebound insomnia with an unusual somatic fatigue syndrome after long-term use of clozapine in a 30-year-old schizophrenic male. The withdrawal symptoms occurred the first day after drug discontinuation and could be stopped by readministering clozapine. In our opinion, the sudden occurrence of the withdrawal symptoms cannot be explained by a dopaminergic hypersensitivity or a cholinergic rebound, but indicates an involvement of GABAergic and perhaps antiglutamatergic properties of clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Fatigue; Humans; Male; Polysomnography; Schizophrenia; Schizophrenic Psychology; Sleep Initiation and Maintenance Disorders; Substance Withdrawal Syndrome

Topics: Antipsychotic Agents; Clonazepam; Clozapine; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoxazoles; Lorazepam; Piperidines; Risperidone; Schizophrenia; Substance Withdrawal Syndrome

In September 1994, the National Institute of Mental Health convened a group of scientists to discuss the clinical effects of rapid clozapine discontinuation, especially in light of the introduction of risperidone for the treatment of schizophrenia. Despite concern over recent reports of clinical deterioration (psychotic exacerbations, somatic withdrawal symptoms, and extrapyramidal side effects) in a few patients abruptly discontinued from clozapine, there is currently insufficient information to determine the magnitude of the problems associated with clozapine withdrawal. However, clinicians are reminded that the withdrawal schedule for clozapine indicates a gradual tapering schedule (unless the patient is experiencing severe side effects); that switching patients from clozapine to risperidone does not mean that such tapering is unnecessary; and that the use of risperidone may not produce all of the same effects as clozapine in some treatment-refractory patients.

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome; United States; United States Food and Drug Administration

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

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dystonia; Humans; Isoxazoles; Male; Neurologic Examination; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

We have previously demonstrated that rats with neonatal excitotoxic hippocampal damage manifest abnormal dopamine (DA)-related behaviors after puberty, a phenomenon that has implications for an animal model of schizophrenia. In this study we investigated the effects of subchronic treatment with haloperidol and clozapine in these animals. The ventral hippocampus (VH) of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). Starting at PD56, rats were treated for 21 days with either vehicle (VEH), haloperidol (HAL) (0.1 mg/kg, IP), or clozapine (CLOZ) (4 mg/kg, IP). Spontaneous locomotor activity was measured 0.5 hour after the last injection. Apomorphine (APO)-induced stereotypy and locomotion were evaluated five days later. The VH lesioned rats treated with VEH expressed enhanced novelty- and apomorphine-induced hyperlocomotion, as well as potentiated apomorphine-induced stereotypic behaviors as compared to sham-lesioned counterparts. Spontaneous locomotor activity was suppressed by haloperidol but not by clozapine in the sham-operated group, whereas both drugs were effective in suppressing hyperlocomotion in the VH lesioned rats. Withdrawal supersensitivity to apomorphine was seen in the haloperidol but not in the clozapine-treated lesioned rats, and none of the drugs produced significant supersensitivity in the sham-operated animals. These results indicate that the two neuroleptics exerted differential behavioral effects in neurologically intact and hippocampally lesioned animals, and that these effects were also drug-specific.

Topics: Animals; Animals, Newborn; Apomorphine; Clozapine; Female; Haloperidol; Hippocampus; Ibotenic Acid; Motor Activity; Neurotoxins; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Stereotyped Behavior; Substance Withdrawal Syndrome

Topics: Adult; Clozapine; Female; Humans; Male; Schizophrenia; Substance Withdrawal Syndrome; Trihexyphenidyl

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

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

Haloperidol, a 'typical' neuroleptic, with affinity for both dopamine (DA) receptors and sigma binding sites, exacerbates morphine withdrawal in guinea-pigs. In this study, the effects of sigma ligands (+)- and (-)-SKF 10,047 (1 and 10 mg/kg s.c.), pentazocine (20 mg/kg s.c.) and DTG (1 and 10 mg/kg s.c.), non-competitive NMDA antagonists ketamine hydrochloride (20 mg/kg s.c.) and MK-801 (0.025, 0.1 and 1 mg/kg s.c.), 'atypical' neuroleptic drugs with (remoxipride 25 mg/kg s.c.) and without (raclopride 10 mg/kg s.c.; clozapine 25 mg/kg s.c.) affinity for sigma sites, and atropine sulphate (20 mg/kg s.c.), were investigated on the opiate withdrawal response induced by naloxone hydrochloride (15 mg/kg s.c.) in guinea-pigs treated 2 h before with a single dose of morphine sulphate (15 mg/kg s.c.). (+)- and (-)-SKF 10,047, pentazocine, ketamine and MK-801, given 0.5 h before naloxone, significantly attenuated the increased locomotor activity and other behaviours associated with morphine withdrawal in guinea-pigs. The selective sigma ligand DTG, and remoxipride had no effect on the withdrawal response but raclopride, clozapine, and atropine exacerbated the response. It is concluded that exacerbation of the morphine withdrawal response by neuroleptics is not related to sigma activity but to other mechanisms. Furthermore NMDA but not sigma mechanisms might play a role in the morphine withdrawal response.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Atropine; Behavior, Animal; Clozapine; Dizocilpine Maleate; Female; Guinea Pigs; Ketamine; Kinetics; Male; Morphine; Motor Activity; Naloxone; Phenazocine; Raclopride; Radioligand Assay; Receptors, sigma; Remoxipride; Salicylamides; Substance Withdrawal Syndrome

Topics: Adult; Clozapine; Drug Therapy, Combination; Humans; Lorazepam; Male; Recurrence; Schizophrenia, Paranoid; Substance Withdrawal Syndrome

This study aimed to differentiate chronically administered typical (haloperidol) and atypical (clozapine) neuroleptics in the dog using a complex temporal regulation schedule combining operant, voluntary, and involuntary motor parameters. Although clozapine and haloperidol showed some characteristics of neuroleptics, justifying their adherence to the same class of compounds, differences have also been highlighted and compared to the clinical observations. Haloperidol induced catalepsy, tremor, dystony, hyperkinesia, and stereotypy. Subjects produced anticipated responses before any stimulus. Incomplete and delayed responses were also produced. An interpretation in terms of akathisia and anhedonia has been suggested. Clozapine induced tremor, exploration, dystony, and hypersalivation. Subjects produced disinhibitory responses to the negative stimulus and incomplete responses but these latter were submitted to tolerance. The simultaneous presence of tranquilizing and disinhibitory effects has been reported on the clinical potential of clozapine both in cases of positive and negative schizophrenic symptomatologies.

Topics: Animals; Clozapine; Conditioning, Operant; Dogs; Haloperidol; Male; Motor Activity; Reinforcement Schedule; Salivation; Substance Withdrawal Syndrome

Topics: Adult; Agranulocytosis; Clozapine; Humans; Male; Neutropenia; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

The short- and long-term treatment tolerance of low-dose clozapine was retrospectively investigated in 18 psychogeriatric patients. Discontinued use of the drug because of side effects or inefficiency was required for only four patients. In the long-term treatment group leukopenia was not observed, and disturbances of liver function appeared to be very infrequent. A second group of seven severely demented psychogeriatric inpatients who were currently being treated with low-dose clozapine underwent a withdrawal study in order to evaluate the therapeutic efficacy of the drug, measured by the NOSIE and the SCAG scales. The results indicate that for patients such as these, with paranoid or socially disturbing behavior who also tend to develop severe neurological side effects with classical neuroleptics, a low-dose administration of clozapine is an acceptable alternative treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Clozapine; Dementia; Dementia, Multi-Infarct; Dose-Response Relationship, Drug; Female; Geriatric Assessment; Hospitalization; Humans; Hydrocephalus, Normal Pressure; Long-Term Care; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychotic Disorders; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Social Behavior; Substance Withdrawal Syndrome

Umespirone was compared to buspirone, diazepam and clozapine as a potential anxiolytic and antipsychotic agent. In the mouse black and white test box, umespirone was considerably more potent than diazepam or buspirone to reduce aversive responding, tolerance to its effects was not observed and sedation was absent, a chronic treatment and withdrawal was not associated with an anxiogenic profile, and umespirone prevented the behavioural consequences of withdrawal from diazepam. Umespirone also had an anxiolytic profile of action in the tests of rat social interaction and in the marmoset exposed to a human threat. Both umespirone and clozapine reduced the hyperactivity induced by the infusion of dopamine into the nucleus accumbens of rat. In radioligand binding assays umespirone demonstrated nanomolar affinity for the alpha 1-adrenoceptor and the 5-HT1A and dopamine D2 receptors. It is concluded that umespirone may present as a novel psychotropic agent with anxiolytic and antipsychotic potential.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Brain Chemistry; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Buspirone; Callithrix; Clozapine; Diazepam; Dopamine; Female; Interpersonal Relations; Limbic System; Male; Mice; Rats; Rats, Inbred Strains; Receptors, Drug; Substance Withdrawal Syndrome; Tetrahydronaphthalenes

Haloperidol and clozapine were rapidly withdrawn from a schizophrenic patient on separate occasions several months apart. Mental status changes and fluctuations in involuntary movements were carefully observed under both conditions. Although little change in either mental status or involuntary movements was observed within the 3 weeks following the withdrawal of haloperidol, marked deterioration in mental status and involuntary movements occurred within 1 week of withdrawal of clozapine. Implications of this differential response to withdrawal of antipsychotic medications are discussed.

Topics: Acute Disease; Adult; Ambulatory Care; Clozapine; Haloperidol; Hospitalization; Humans; Male; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

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

Topics: Adolescent; Bipolar Disorder; Clozapine; Female; Humans; Malignant Hyperthermia; Middle Aged; Neuroleptic Malignant Syndrome; Neurologic Examination; Paranoid Disorders; Psychiatric Status Rating Scales; Substance Withdrawal Syndrome

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Male; Middle Aged; Psychotic Disorders; Substance Withdrawal Syndrome

Topics: Clozapine; Dibenzazepines; Female; Humans; Middle Aged; Recurrence; Schizophrenia; Substance Withdrawal Syndrome

Topics: Adult; Clozapine; Dibenzazepines; Humans; Male; Psychotic Disorders; Recurrence; Schizophrenia; Substance Withdrawal Syndrome

It has been demonstrated in experiments on rats receiving chronic (16 days) treatment with haloperidol (1.0 mg/kg/day), sulpiride (50 mg/kg/day) and clozapine (10 mg/kg/day) that binding of 3H-flunitrazepam in the striatum, limbic system, and cortex is reduced at the 5th day after withdrawal of the neuroleptics. That release was determined by the diminution of the number of receptors without changing in the dissociation constant. The reduction in the density of benzodiazepine receptors (BD-receptors) after withdrawal of the neuroleptics attests to their agonistic effect on BD-receptors. Apparently these changes are not linked with a direct effect of the neuroleptics on BD-receptors, since they displace 3H-flunitrazepam in experiments in vitro only at micromolar concentrations. It is assumed that the reduction in 3H-flunitrazepam binding is mediated via the GABAergic system transsynaptically in response to increase in the number of dopamine (neuroleptic) receptors.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Flunitrazepam; Haloperidol; Humans; Male; Rats; Rats, Inbred Strains; Receptors, GABA-A; Substance Withdrawal Syndrome; Sulpiride; Time Factors

In two patients with chronic schizophrenia, who were on clozapine medication for more than 6 months, a sudden withdrawal of the drug resulted in a very pronounced deterioration of the psychosis within 24-48 h. The most prominent symptoms were auditory hallucinations and persecutory ideas and one patient tried to commit suicide. These observations are interpreted as supersensitivity psychoses induced by the very effective clozapine treatment.

Topics: Adult; Clozapine; Dibenzazepines; Female; Humans; Male; Psychotic Disorders; Schizophrenia; Substance Withdrawal Syndrome

Topics: Acetylcholine; Basal Ganglia Diseases; Chorea; Clozapine; Diagnosis, Differential; Dibenzazepines; Drug Synergism; Humans; Hyperkinesis; Long-Term Care; Male; Middle Aged; Movement Disorders; Parasympatholytics; Schizophrenia, Paranoid; Substance Withdrawal Syndrome; Tranquilizing Agents

The present study has compared the abilities of clozapine, haloperidol, chlorpromazine and loxapine to induce dopamine (DA)-receptor hypersensitivity in rats, as measured by the apomorphine response after withdrawal of the antipsychotic drugs. Haloperidose during 1-2 weeks after withdrawal. Clozapine, given prior to apomorphine, reduced the responses of the haloperidol and loxapine groups to the control level. The effects of haloperidol and clozapine were quantified in rats with unilateral striatal lesions. Biochemical investigations showed that tolerance developed to the increase in striatal homovanillic acid (HVA) after chronic treatment with haloperidol, chlorpromazine and loxapine, whereas clozapine (20 mg/kg p.o.) failed to affect the HVA content, and no tolerance developed to the increase seen at 80 mg/kg. Cross-tolerance to the rise in HVA was seen with haloperidol, chlorpromazine and loxapine, but chronicc pretreatment with clozapine failed to affect the rise in HVA induced by a singel dose of the former compounds.

Topics: Animals; Apomorphine; Chlorpromazine; Clozapine; Corpus Striatum; Dibenzazepines; Dibenzoxazepines; Disease Models, Animal; Dopamine; Drug Tolerance; Female; Haloperidol; Homovanillic Acid; Humans; Loxapine; Male; Movement Disorders; Rats; Receptors, Drug; Stereotyped Behavior; Substance Withdrawal Syndrome