clozapine and zotepine

In many countries of the industrialised world, second generation (atypical) antipsychotic drugs have become first line treatment for people with schizophrenia. The question as to whether the effects of various second generation antipsychotic drugs differ is a matter of debate. In this review we examined how the efficacy and tolerability of zotepine differs from that of other second generation antipsychotic drugs.. To evaluate the effects of zotepine compared with other second generation antipsychotic drugs for people with schizophrenia and schizophrenia-like psychoses.. We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL CINAHL, EMBASE, MEDLINE and PsycINFO.. We included all randomised trials comparing oral zotepine with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole or ziprasidone in people with schizophrenia or schizophrenia-like psychoses.. We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (MD) again based on a random effects model.. The review currently includes data from two short term, ill reported trials (total n=109). Both studies compared zotepine with clozapine. 34% of people left early but there was no significant difference between groups. Zotepine was less effective than clozapine (no clinically significant response: n=59, 1 RCT, RR 8.23 CI 1.14 to 59.17, NNH 3 CI 2 to 8; average score (BPRS total) at endpoint (n=59, 1 RCT, MD 6.00 CI 2.17 to 9.83). Zotepine induced more movement disorders than clozapine (use of antiparkinson medication: n=59, 1 RCT, RR 18.75 CI 1.17 to 301.08, NNH 3 CI 2 to 5) and higher prolactin levels (n=59, 1 RCT, MD 33.40 CI 14.87 to 51.93). Data on important other outcomes such as other adverse events, service use or satisfaction with care were not available.. Zotepine may be less effective than clozapine and associated with more movement disorders and higher prolactin levels, but the evidence base is too small and prone to bias, making any practical recommendations impossible. There is no randomised evidence on the effects of zotepine compared to second generation antipsychotic drugs other than clozapine. More studies are possible to justify.

Topics: Antipsychotic Agents; Clozapine; Dibenzothiepins; Humans; Randomized Controlled Trials as Topic; Schizophrenia

In many parts of the world, particularly in industrialised countries, second generation (atypical) antipsychotic drugs have become first line treatment for people suffering from schizophrenia. The question as to whether the effects of various second generation antipsychotic drugs differ is a matter of debate.. To evaluate the effects of zotepine compared with other second generation antipsychotic drugs for people suffering from schizophrenia and schizophrenia-like psychoses.. We searched the Cochrane Schizophrenia Group Trials Register (November 2009), inspected references of all identified studies for further trials and contacted authors of trials for additional information.. We included only randomised clinical controlled trials that compared zotepine with any forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole or ziprasidone in people suffering from only schizophrenia or schizophrenia-like psychoses.. SS and KK extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated weighted mean differences (MD) again based on a random-effects model.. We included three studies (total n=289; 2 RCTs zotepine vs clozapine; 1 RCT zotepine vs clozapine vs risperidone (at 4 mg, 8 mg doses) vs remoxipride. All studies were of limited methodological quality. When zotepine was compared with clozapine, it was clozapine that was found to be more effective in terms of global state (n=59, 1 RCT, RR No clinically significant response 8.23 CI 1.14 to 59.17). Mental state scores also favoured clozapine (n=59, 1 RCT, MD average score (BPRS total, high = poor) 6.00 CI 2.17 to 9.83) and there was less use of antiparkinson medication in the clozapine group (n=116, 2 RCTs, RR 20.96 CI 2.89 to 151.90). In the comparison of zotepine and risperidone, mental state scoring found no significant difference between the groups (vs 4 mg: n=40, 1 RCT, MD average endpoint score (BPRS total, high=poor) 1.40 CI -9.82 to 12.62; vs 8 mg: n=40, 1 RCT, MD -1.30 CI -12.95 to 10.35) and use of antiparkinson medication was equivocal (vs 4 mg: n=40, 1 RCT, MD 1.80 CI -0.64 to 4.24; vs 8 mg: n=40, 1 RCT, MD 2.50 CI -0.05 to 5.05). Finally, when zotepine was compared with remoxipride, again no effect was found for mental state (n=58, 1 RCT, MD average endpoint score (BPRS total, high=poor) 5.70 CI -4.13 to 15.53) and there was no significant difference between the two groups in terms of use of antiparkinson medication (n=49, 1 RCT, RR 0.97 CI 0.41 to 2.29).Data on important other outcomes such as other adverse events, service use or satisfaction with care, quality of life were not available.. The evidence base around zotepine is insufficient to provide firm conclusions on its absolute or relative effects. This is despite it being in use in Austria, France, Germany, Japan and the UK.

Topics: Antipsychotic Agents; Clozapine; Dibenzothiepins; Humans; Randomized Controlled Trials as Topic; Remoxipride; Risperidone; Schizophrenia

Clozapine is an atypical antipsychotic demonstrated to be superior in the treatment of refractory schizophrenia which causes fewer movement disorders. Clozapine, however, entails a significant risk of serious blood disorders such as agranulocytosis which could be potentially fatal. Currently there are a number of newer antipsychotics which have been developed with the purpose to find both a better tolerability profile and a superior effectiveness.. To compare the clinical effects of clozapine with other atypical antipsychotics (such as amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine) in the treatment of schizophrenia and schizophrenia-like psychoses.. We searched the Cochrane Schizophrenia Groups Register (June 2007) and reference lists of all included randomised controlled trials. We also manually searched appropriate journals and conference proceedings relating to clozapine combination strategies and contacted relevant pharmaceutical companies.. All relevant randomised, at least single-blind trials, comparing clozapine with other atypical antipsychotics, any dose and oral formulations, for people with schizophrenia or related disorders.. We selected trials and extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD) again based on a random-effects model.. The review currently includes 27 blinded randomised controlled trials, which involved 3099 participants. Twelve randomised control trials compared clozapine with olanzapine, five with quetiapine, nine with risperidone, one with ziprasidone and two with zotepine. Attrition from these studies was high (overall 30.1%), leaving the interpretation of results problematic. Clozapine had a higher attrition rate due to adverse effects than olanzapine (9 RCTs, n=1674, RR 1.60 CI 1.07 to 2.40, NNT 25 CI 15 to 73) and risperidone (6 RCTs, n=627, RR 1.88 CI 1.11 to 3.21, NNT 16 CI 9 to 59). Fewer participants in the clozapine groups left the trials early due to inefficacy than risperidone (6 RCTs, n=627, RR 0.40 CI 0.23 to 0.70, NNT 11 CI 7 to 21), suggesting a certain higher efficacy of clozapine.Clozapine was more efficacious than zotepine in improving the participants general mental state (BPRS total score: 1 RCT, n=59, MD -6.00 CI -9.83 to -2.17), but not consistently more than olanzapine, quetiapine, risperidone and ziprasidone. There was no significant difference between clozapine and olanzapine or risperidone in terms of positive or negative symptoms of schizophrenia. According to two studies from China quetiapine was more efficacious for negative symptoms than clozapine (2 RCTs, n=142, MD 2.23 CI 0.99 to 3.48).Clozapine produced somewhat fewer extrapyramidal side-effects than risperidone (use of antiparkinson medication: 6 RCTs, n=304, RR 0.39 CI 0.22 to 0.68, NNT 7 CI 5 to 18) and zotepine (n=59, RR 0.05 CI 0.00 to 0.86, NNT 3 CI 2 to 5). More participants in the clozapine group showed decreased white blood cells than those taking olanzapine, more hypersalivation and sedation than those on olanzapine, risperidone and quetiapine and more seizures than people on olanzapine and risperidone. Also clozapine produced an important weight gain not seen with risperidone.Other differences in adverse effects were less documented and should be replicated, for example, clozapine did not alter prolactin levels whereas olanzapine, risperidone and zotepine did; compared with quetiapine, clozapine produced a higher incidence of electrocardiogram (ECG) alterations; and compared with quetiapine and risperidone clozapine produced a higher increase of triglyceride levels. Other findings that should be replicated were: clozapine improved social functioning less than risperidone and fewer participants in the clozapine group had to be hospitalised to avoid suicide attempts compared. Clozapine may be a little more efficacious than zotepine and risperidone but further trials are required to confirm this finding. Clozapine differs more clearly in adverse effects from other second generation antipsychotics and the side-effect profile could be key in the selection of treatment depending on the clinical situation and a patient's preferences. Data on other important outcomes such as cognitive functioning, quality of life, death or service use are currently largely missing, making further large and well-designed trials necessary. It is also important to take into account that the large number of people leaving the studies early limits the validity and interpretation of our findings.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Humans; Olanzapine; Piperazines; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Thiazoles

Topics: Amisulpride; Antipsychotic Agents; Chlorpromazine; Clozapine; Cognitive Behavioral Therapy; Dibenzothiepins; Family Therapy; Haloperidol; Humans; Patient Compliance; Risperidone; Schizophrenia; Secondary Prevention; Sulpiride; Thioridazine

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Chlorpromazine; Clozapine; Cognitive Behavioral Therapy; Dibenzothiepins; Haloperidol; Humans; Olanzapine; Patient Compliance; Perazine; Pimozide; Risperidone; Schizophrenia; Sulpiride

"Atypical" antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT2 or D4 receptors, or a more rapid dissociation from the dopamine D2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a "pharmacological shotgun" strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Dopamine Antagonists; Drug Monitoring; Haloperidol; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Dopamine D4; Risperidone; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Sulpiride; Thiazoles; Treatment Outcome

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

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

To review systematically data relating to weight changes with atypical antipsychotics.. We conducted a Medline search on October 29 1999 and covered the period 1980-99. All recovered papers were examined for further relevant reports. In addition, we wrote to pharmaceutical manufacturers and 10 practising clinicians to ask them to provide other relevant reports known to them.. Eighty reports mentioning change in body weight were retrieved. Data relating to weight changes were of variable quality. Weight changes were indicated by a variety of measures. The majority of reports related to short-term changes.. All atypical drugs, with the exception of ziprasidone, have been associated with weight increases. Clozapine seems to have the highest risk of weight gain, followed by olanzapine and quetiapine. There is probably a lower risk with risperidone, sertindole and zotepine and a still lower risk with amisulpride. Ziprasidone appears not to be associated with weight gain. In the absence of more compelling data, these rankings must be considered approximate and preliminary. Longer, more robust trials are needed.

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Risperidone; Sulpiride; Thiazoles; Weight Gain

The introduction of conventional antipsychotics revolutionized the management of psychotic disorders in the 1950s. The use of these agents has been marked by several shortcomings, including their association with severe motor disturbances and their limited efficacy in treating the negative and cognitive symptoms of schizophrenia. Patients noncompliance has largely been the result of subjectively distressing extrapyramidal motor side-effects (EPMS). It was therefore necessary to develop antipsychotic drugs with selective pharmacological profiles, e.g. limbic selectivity. A defining characteristic of atypical neuroleptics is a higher ratio of serotonin receptor blockade to D2 receptor blockade. Their primary advantage is their superior side-effect profile. The implications of EPMS reduction touch several domains of pathology in schizophrenia such as short- and long-term movement disorders, noncompliance, relapse rate, negative symptoms and cognitive dysfunction. Novel antipsychotics may represent the second pharmacological revolution in the treatment of psychotic disorders. There is, however, still a need for a critical evaluation of the risk-benefit-ratio of differing atypical agents.

Topics: Aged; Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Controlled Clinical Trials as Topic; Dibenzothiazepines; Dibenzothiepins; Haloperidol; Humans; Imidazoles; Indoles; Multicenter Studies as Topic; Olanzapine; Piperazines; Pirenzepine; Placebos; Quetiapine Fumarate; Risperidone; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Sulpiride; Thiazoles

Clinical studies with clozapine have clearly demonstrated its superior efficacy over that of conventional antipsychotics in treatment-resistant schizophrenic patients. In comparative trials with these drugs, considerably more patients respond to treatment with clozapine than to conventional antipsychotic medication. Recently, new antipsychotics, such as olanzapine, quetiapine, risperidone, sertindole, and zotepine, have been introduced, but extensive data on their effects in treatment-resistant patients are not yet available. Published studies have drawn criticism in terms of inappropriate titration schedules, nonequivalent dosing between treatment groups, short treatment duration, and inadequate sample sizes. Further research will be needed to determine whether novel antipsychotics may substitute for clozapine in the future or whether clozapine will retain its unique role in the management of patients suffering from difficult-to-treat schizophrenic disorders.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dibenzothiepins; Double-Blind Method; Drug Resistance; Humans; Olanzapine; Pirenzepine; Placebos; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine is the most effective antipsychotic for patients with treatment-refractory schizophrenia, but many adverse effects are noted. Clinicians usually hesitate to switch from clozapine to other antipsychotics because of the risk of a re-emergence or worsening of the psychosis, although empirical studies are very limited. Zotepine, an atypical antipsychotic with a pharmacologic profile similar to clozapine, was found to be an effective treatment for patients with treatment-resistant schizophrenia in Japan. This 12-week study is the first prospective, randomized, and rater-blind study to investigate the efficacy and tolerability of switching from clozapine to zotepine. Fifty-nine patients with schizophrenia, who had taken clozapine for at least 6 months with a Clinical Global Impression-Severity score of at least 3, were randomly allocated to the zotepine and the clozapine groups. At the end of the study, 52 patients (88%) had completed the trial. The 7 withdrawal cases were all in the zotepine group. The final mean (SD) dose of zotepine and clozapine was 397.1 (75.7) versus 377.1 (62.5) mg/d, respectively. Patients in the zotepine group showed a significant increase in the Brief Psychiatric Rating Scale [mean (SD), 4.7 (8.7) vs -1.3 (6.3); P = 0.005], more general adverse effects as revealed by the Udvalg for Kliniske Undersogelser Rating Scale [mean (SD), 1.74 (3.9) vs -0.2 (2.8); P = 0.039], more extrapyramidal adverse effects as demonstrated by the Simpson and Angus Scale [mean (SD), 1.29 (3.5) vs 0.17 (2.1); P = 0.022], an increased use of propranolol (37.1% vs 0%, P < 0.0001) and anticholinergics (25.7% vs 0%, P = 0.008), and an increased level of prolactin (29.6 vs -3.8 ng/ mL, P < 0.0005), compared with the clozapine group. The results suggested that switching from clozapine to zotepine treatment should be done with caution.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Dibenzothiepins; Dose-Response Relationship, Drug; Drug Substitution; Humans; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Single-Blind Method; Treatment Outcome; Young Adult

Clinical interest in the so-called atypical antipsychotics currently focuses on the possibility of improving the negative symptoms of schizophrenia and the cognitive dysfunction associated with the disease. While clozapine has been shown to be effective in this respect, no data are available on zotepine. We report on a double-blind randomized study designed to evaluate the impact of zotepine and clozapine on cognitive dysfunction in schizophrenia. Cognitive function was operationalized by a maze test in which patients traversed computer-displayed mazes of increasing complexity. Passage time, route, and motor errors were evaluated. 25 schizophrenic (DSM-IIIR) patients were included in each group. After washout, they were randomized on zotepine or clozapine and given up to 450 mg of substance each. Patients were followed for six weeks and evaluated weekly. We report on a subsample of 26 patients matched for baseline BPRS, SANS, and age. 13 matched healthy persons were recruited as controls. ANOVA with group and course over time as factors was used for analysis. Both clozapine and zotepine achieved a highly significant decrease in overall symptoms (BPRS) and negative symptoms (SANS). Zotepine and clozapine were equally effective. In the maze tests, motor errors in simple mazes were stable over time and differentiated schizophrenics from controls as a "trait" marker. In passage time and maze route, schizophrenics performed worse than controls. An improvement by medication was evident in both medication groups, but was more pronounced in the zotepine-treated group. The study confirms previous results on the efficacy of clozapine and zotepine in treating negative symptoms of schizophrenia. The data presented show for the first time that zotepine is efficacious in improving cognitive dysfunction, confirming this substance's value as an atypical antipsychotic.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; Dibenzothiepins; Double-Blind Method; Female; Humans; Male; Maze Learning; Schizophrenia; Schizophrenic Psychology

In a double-blind, placebo-controlled study, the relationships between blood levels and pharmacodynamics of zotepine were investigated in 15 healthy subjects. They received randomized at weekly intervals single oral doses of 25, 50 and 100 mg zotepine and 50 mg clozapin as reference substance. Blood sampling for zotepine and prolactin plasma levels, quantitative EEG analyses, psychometry and tolerability measures were carried out at the hours 0, 1, 2, 4, 6 and 8. There was a dose-dependent increase in zotepine plasma levels with a tmax between 2-4 hours post-drug and cmax: 6.9, 14.8 and 19.6 ng/ml for the 3 doses, respectively and a slow decline thereafter. Prolactin levels also rose dose dependently, peaking in the 4th hour. Regression and correlation analyses demonstrated: the higher the zotepine plasma levels, the more delta/theta, the less alpha activity and the slower the centroid in the spectral analysed EEG and the more decrease in reaction time performance, numerical memory and CFF in psychometry. Neurophysiological changes started at 8 ng/ml, psychometric ones at 9 ng/ml. Our pharmacodynamic findings suggested zotepine to be a sedative broad-band neuroleptic, which was also reflected in the side effects.

Topics: Adult; Affect; Antipsychotic Agents; Arousal; Attention; Clozapine; Dibenzothiepins; Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; Evoked Potentials; Female; Humans; Male; Neuropsychological Tests; Psychometrics

In a double-blind, placebo-controlled study the encephalotropic and psychotropic properties of zotepine - a new tricyclic dibenzothiepine with antidopaminergic, adrenolytic and antiserotoninergic properties - were investigated utilizing quantitative EEG, psychometric and psychophysiological tests as well as clinical observations. Fifteen normal volunteers received randomized (latin square design) and at weekly intervals single oral doses of placebo, 25 mg, 50 mg and 100 mg zotepine as well as 50 mg clozapine as reference compound. Plasma samplings for blood levels, EEG recordings, and evaluation of blood pressure, pulse rate and side-effects were carried out at the hours 0, 1, 2, 4, 6 and 8, while psychometric data were recorded at the same time except the first hour. Computer-assisted spectral analysis of the EEG demonstrated after all three doses significant changes as compared with placebo characterized by an augmentation of delta and theta activity, decreased of alpha and beta activity, slowing of the centroid of the total activity and alpha activity, and decrease of the dominant frequency and its absolute and relative power. Such changes are typical for low-potency basic neuroleptics of the sedative type such as chlorpromazine. Clozapine also augmented slow activities, decreased alpha activity, the dominant frequency and the alpha centroid, but induced in contrast to zotepine a concomitant increase of fast beta activity, acceleration of the beta centroid and no slowing of the dominant frequency, while the total power was significantly attenuated. These findings confirm earlier reports about the pharmaco-EEG profile of clozapine, which has a resemblance to profiles of anticholinergic antidepressants of the amitriptyline type. Psychometric tests demonstrated after the higher doses of zotepine and clozapine a deterioration of noopsychic and thymospsychic functions which was more pronounced after the reference compound than after zotepine. The lowest dose of zotepine, 25 mg, even produced an improvement in numerical memory and complex reaction. CFF, skin conductance, pupillary diameter and pupillary response measurements decreased after both compounds. Dose-efficacy calculations showed 100 mg zotepine and clozapine to be the most CNS-effective compounds, followed by 50 mg and 25 mg zotepine, while placebo induced the least changes. Time-efficacy calculations showed neurophysiological and behavioral peak effects after zotepine at the 4th and 6th hour, as

Topics: Adult; Antipsychotic Agents; Attention; Blood Pressure; Clozapine; Dibenzazepines; Dibenzothiepins; Double-Blind Method; Electroencephalography; Emotions; Female; Humans; Male; Psychometrics; Psychomotor Performance; Pulse; Random Allocation; Reaction Time; Time Factors

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzothiepins; Female; Haloperidol; Humans; Hyperglycemia; Incidence; Japan; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Schizophrenia

The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10

Topics: Acetylcholine; Aging; Animals; Antipsychotic Agents; Chlorpromazine; Cholinergic Antagonists; Clozapine; Dibenzothiepins; Male; Mental Disorders; Methotrimeprazine; Muscle Contraction; Muscle, Smooth; Olanzapine; Quetiapine Fumarate; Rats, Wistar; Urinary Bladder; Urologic Diseases

This study assessed the association between second-generation antipsychotic medications and risk of pneumonia requiring hospitalization in patients with schizophrenia because the evidence is limited in the population. We enrolled a nationwide cohort of 33,024 inpatients with schizophrenia ranged in age from 18 to 65 years, who were derived from the National Health Insurance Research Database in Taiwan from 2000 to 2008. Cases (n = 1741) were defined as patients who developed pneumonia after their first psychiatric admissions. Risk set sampling was used to match each case with 4 controls by age, sex, and the year of the first admission based on nested case-control study. Antipsychotic exposure was categorized by type, duration, and daily dose, and the association between exposure and pneumonia was assessed using conditional logistic regression. We found that current use of clozapine (adjusted risk ratio = 3.18, 95% CI: 2.62-3.86, P < .001) was associated with a dose-dependent increase in the risk. Although quetiapine, olanzapine, zotepine, and risperidone were associated with increased risk, there was no clear dose-dependent relationship. Amisulpride was associated with a low risk of pneumonia. The use of clozapine combined with another drug (olanzapine, quetiapine, zotepine, risperidone, or amisulpride), as assessed separately, was associated with increased risk for pneumonia. In addition, with the exception of amisulpride, each drug was associated with increased risk for pneumonia at the beginning of treatment. Clinicians who prescribe clozapine to patients with schizophrenia should closely monitor them for pneumonia, particularly at the start of therapy and when clozapine is combined with other antipsychotics.

Topics: Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Clozapine; Cohort Studies; Dibenzothiazepines; Dibenzothiepins; Drug Therapy, Combination; Female; Humans; Logistic Models; Male; Middle Aged; Olanzapine; Pneumonia; Quetiapine Fumarate; Risk Factors; Risperidone; Schizophrenia; Sulpiride; Taiwan

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

Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by "atypical" antipsychotics. In contrast, some findings indicate that not all of the "atypical" antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI. In our study, we evaluated the effect of four different "atypical" antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT1A,2A/2C receptors and muscarinic receptors. Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment. In summary, the four "atypical" antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.

Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiepins; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Olanzapine; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Muscarinic; Reflex, Startle; Risperidone

An atypical antipsychotic drug, zotepine, which is pharmacologically and clinically related to clozapine, has unique therapeutic effects on patients with schizophrenia. It has been demonstrated that clozapine blocks neurotoxicity in the rat retrosplenial cortex induced by administration of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801). We examined whether or not zotepine has the ability to block neurotoxicity in the rat retrosplenial cortex induced by administration of dizocilpine. Female Sprague-Dawley rats were injected intraperitoneally (i.p.) with vehicle (1 mg/kg), zotepine (5, 10 or 20 mg/kg) or clozapine (20 mg/kg). Fifteen minutes later, animals were injected intraperitoneally (i.p.) with vehicle (1 ml/kg) or dizocilpine (0.5 mg/kg). Neuropathological changes (neuronal vacuolization) were assessed 4 h after administration of dizocilpine. Immunohistochemical analysis of heat shock protein HSP-70, a marker of reversible neuronal injury, was performed 24 h after administration of dizocilpine. The pretreatment with zotepine (5, 10 or 20 mg/kg) significantly decreased the number of vacuolized neurons in the rat retrosplenial cortex 4 h after the administration of dizocilpine (0.5 mg/kg), in a dose-dependent manner. The potency of zotepine (20 mg/kg) for dizocilpine-induced neurotoxicity was similar to that of clozapine (20 mg/kg). Furthermore, similar to the case with clozapine (20 mg/kg, i.p.), zotepine (20 mg/kg, i.p.) significantly attenuated the expression of HSP-70 in the rat retrosplenial cortex induced by dizocilpine (0.5 mg/kg, i.p.). The present study suggests that the neuroprotective effects of zotepine- on dizocilpine-induced neurotoxicity are equipotent to those of clozapine. Based on the NMDA receptor hypofunction hypothesis of schizophrenia, the efficacy of zotepine in this study may partly contribute to the unique therapeutic effects of zotepine in patients with schizophrenia.

Topics: Animals; Antipsychotic Agents; Cerebral Cortex; Clozapine; Dibenzothiepins; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; HSP70 Heat-Shock Proteins; Immunohistochemistry; Injections, Intraperitoneal; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

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

During clinical experience with the "atypical" neuroleptic drugs clozapine, risperidone, and zotepine, some patients have shown a marked weight gain. To prove whether weight gain is a relevant side effect of atypical neuroleptics, the charts of all patients admitted with DSM-III-R diagnoses of schizophrenia, schizoaffective disorder, or delusional disorder in the years 1991 to 1995 were evaluated. A retrospective chart review was performed, which included all patients who were treated longer than 2 weeks with a single neuroleptic. The data analysis showed that weight gain must be considered as a common side effect of atypical neuroleptics (clozapine, risperidone, sulpiride, or zotepine). The mean weight gain (3.1, 1.5, 1.9, or 4.3 kg, respectively) was significantly higher than that of patients treated with "classic" neuroleptics (mean, 0.0-0.5 kg) (Kruskal-Wallis, p = 0.01). Young and not obese patients show the highest weight increase. Because weight gain occurs in the first weeks of treatment, particularly in previously untreated subjects, this side effect has to be considered in view of compliance with long-term neuroleptic medication.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Body Mass Index; Clozapine; Delusions; Dibenzothiepins; Female; Humans; Long-Term Care; Male; Middle Aged; Psychotic Disorders; Retrospective Studies; Risperidone; Schizophrenia; Sulpiride; Weight Gain

The effectiveness of antipsychotic drugs against positive psychotic symptoms has been demonstrated in many studies, but their effects on quality of life have yet to be clarified. The impact of different neuroleptic therapies on the subjective quality of life of schizophrenic patients is evaluated in a cross-sectional open study.. During a four-month period a standardised quality of life interview for schizophrenic patients was applied on day 10 after admission; 33 patients on atypical neuroleptics (AAP) were compared with 31 matched patients on conventional neuroleptics (CAP).. The AAP group had significantly higher scores in general quality of life as well as in different life domains: physical well-being, social life and everyday life. In separate comparisons of the AAP group, patients on clozapine and risperidone were found to have a higher quality of life score than patients on CAP or zotepine.. The pharmacological profile of clozapine and risperidone may provide a basis for explaining the higher subjective quality of life found in this study. The lower quality of life of the CAP group may possibly be related to intrinsic effects of the conventional antipsychotics.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Cross-Sectional Studies; Depression; Dibenzothiepins; Female; Humans; Male; Middle Aged; Quality of Life; Risperidone; Schizophrenia; Schizophrenic Psychology

We determined the affinity and/or potency of two metabolites of clozapine (clozapine-N-oxide and N-desmethylclozapine) and of five atypical neuroleptics, chemically related (olanzapine) or unrelated to clozapine (remoxipride, risperidone, thioridazine, zotepine), at H3 receptors. The specific binding of 3H-N alpha-methylhistamine to rat brain cortex homogenates was inhibited by the seven compounds; the pKi values were: N-desmethylclozapine (5.33); clozapine-N-oxide (4.18); olanzapine (5.45); thioridazine (4.91); zotepine (4.75); remoxipride (4.51) and risperidone (4.43). Three compounds were examined in a functional H3 receptor model as well. The electrically evoked tritium overflow from superfused mouse brain cortex slices, which represents quasi-physiological noradrenaline release, was not affected by N-desmethylclozapine (3.2 and 10 microM), clozapine-N-oxide (3.2-100 microM) and olanzapine (3.2-32 microM). On the other hand, the three compounds shifted to the right the concentration-response curve of histamine for its inhibitory effect on the evoked overflow; the apparent pA2 values were 5.84, 4.21 and 5.80, respectively. The present study shows that five atypical neuroleptics of different chemical classes and the two major metabolites of clozapine possess a lower affinity and/or antagonistic potency at H3 receptors than clozapine itself (pKi 6.15, pA2 6.33; Kathmann M, Schlicker E, Göthert M (1994). Psychopharmacology 116: 464-468).

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Binding, Competitive; Clozapine; Dibenzothiepins; Dose-Response Relationship, Drug; Histamine Antagonists; Isotope Labeling; Male; Methylhistamines; Mice; Olanzapine; Pirenzepine; Rats; Rats, Wistar; Receptors, Histamine H3; Remoxipride; Risperidone; Structure-Activity Relationship; Thioridazine; Tritium

Zotepine, an atypical antipsychotic structurally similar to clozapine, is in Phase III clinical trials in the United States and Europe for the treatment and management of acute and chronic schizophrenia. Zotepine's pharmacological profile has been compared with those of the atypical antipsychotic clozapine, and the typical neuroleptics haloperidol and chlorpromazine in preclinical tests that predict antipsychotic efficacy and extrapyramidal symptoms (EPS). Because zotepine causes potent, long-lasting inhibition of dopaminergic behavioral responses in animals, it may have an efficacious prolonged antipsychotic action in humans. In contrast, it induces little catalepsy, indicating that it should cause minimal motor side effects, such as EPS. Like clozapine but unlike the typical neuroleptics, zotepine's affinities for cloned human D1 and D2 receptors are very similar. Since a stimulation imbalance favoring D1 over D2 receptors has been suggested to induce dyskinesias, zotepine's reduced EPS profile in humans may derive, in part, from balanced inhibition of these receptors.

Topics: Animals; Antipsychotic Agents; Apomorphine; Binding, Competitive; Clozapine; Dibenzothiepins; Dose-Response Relationship, Drug; Humans; Mice; Mice, Inbred Strains; Receptors, Dopamine; Time Factors

The effect of the atypical neuroleptic zotepine (CAS 26615-21-4), in comparison with clozapine, risperidone and haloperidol, on the responsiveness of different 5-hydroxytryptamine (5-HT1) receptor subtypes to their agonists was examined in rats and mice. The above antipsychotics were investigated in the following behavioural tests: 8-OH-DPAT (8-hydroxy-dipropylaminotetralin)-induced behavioural syndrome in rats, mCPP (mchlorophenylpiperazine)-induced hypothermia in mice and mCPP-induced hypoactivity measured in the open field in rats. Zotepine, clozapine and haloperidol did not affect the behavioural syndrome induced by 8-OH-DPAT (the selective agonist of 5-HT1A, receptor), only risperidone (used in higher doses) attenuated the effect of 8-OH-DPAT. The mCPP-induced hypothermia in mice (a 5-HT1B effect) was affected by neither zotepine nor clozapine, risperidone and haloperidol, all of them used in low doses which did not influence per se the body temperature of mice. All the tested antipsychotics given at high doses induced hypothermia in control mice; at the same time, zotepine, clozapine and risperidone attenuated the hypothermic effect of mCPP. mCPP decreases the exploratory activity of rats, this effect being considered to be mediated by 5-HT1C receptors. The tested antipsychotics, used in low doses, influenced neither the exploratory activity nor the hypoactivity induced by mCPP. When used at higher doses, they induced hypoactivity in control rats; the hypoactivity after joint administration of zotepine, risperidone or haloperidol and mCPP was significantly greater than after mCPP alone, whereas clozapine slightly attenuated the effect of mCPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Behavior, Animal; Body Temperature; Clozapine; Dibenzothiepins; Exploratory Behavior; Haloperidol; Isoxazoles; Male; Mice; Motor Activity; Piperazines; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Risperidone; Serotonin Antagonists; Serotonin Receptor Agonists

In the present study we compared the effects of the atypical neuroleptic zotepine to haloperidol and clozapine on stereotypies and locomotion induced in rats by the N-methyl-D-aspartate (NMDA) antagonist MK-801. Zotepine caused a dose-dependent reduction of MK-801-induced stereotypies and locomotion. Zotepine at a dosis of 2.5 mg/kg body weight showed a similar effect to 0.25 mg/kg haloperidol in reducing stereotypies and locomotion. Clozapine (5.0 mg/kg) reduced significantly locomotion and non-significantly stereotypies. These results add support to the assumption that MK-801-induced behavior provides an adequate animal model to test the potential efficacy of typical and atypical neuroleptics in the treatment of psychoses.

Topics: Animals; Antipsychotic Agents; Clozapine; Dibenzothiepins; Dizocilpine Maleate; Dopamine Antagonists; Dose-Response Relationship, Drug; Haloperidol; Male; Motor Activity; Rats; Rats, Wistar; Stereotyped Behavior

Topics: Animals; Antipsychotic Agents; Clozapine; Dibenzothiepins; Disease Models, Animal; Haloperidol; Humans; Rats; Schizophrenia

In vivo occupancy by typical or atypical antipsychotic drugs of dopamine D-1, D-2 and serotonin (5-HT)2 receptors in the membranes and slices of the rat brain was measured using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist at these receptor sites. In the membranes, the occupancy of D-1 receptors in the striatum by all tested drugs except cis-flupenthixol was minimal. Typical antipsychotic drugs such as chlorpromazine (10 mg/kg), haloperidol (1 mg/kg), cis-flupenthixol (1 mg/kg) and zotepine (5 mg/kg) occupied predominantly D-2 receptors in the striatum. Among atypical antipsychotic drugs, sulpiride (30 mg/kg) and amperozide (1 mg/kg) had no effect on the EEDQ-induced reduction in D-1, D-2 or 5-HT2 receptors, whereas clozapine (10 mg/kg), fluperlapine (10 mg/kg), risperidone (1 mg/kg), setoperone (0.25 mg/kg) and ORG 5222 (0.25 mg/kg) occupied mainly 5-HT2 receptors in the frontal cortex. In the slices, the occupancy by all tested drugs of D-1 receptors in the striatum, nucleus accumbens and substantia nigra was minimal with the exception of clozapine which showed about 30% occupancy in the substantia nigra. Typical antipsychotic drugs, chlorpomazine (10 mg/kg) and haloperidol (1 mg/kg) occupied predominantly D-2 receptors in the striatum and the nucleus accumbens. On the other hand, atypical antipsychotic drugs, clozapine (10 mg/kg) and risperidone (1 mg/kg), occupied mainly 5-HT2 receptors in the frontal cortex. These results suggest that there is a certain group of atypical antipsychotic drugs characterized by high occupancy of 5-HT2 receptors and low or minimum occupancy of D-2 receptors. These characteristics may be relevant to their weak potency in producing extrapyramidal side effects in man or catalepsy in rodents. Although we could find no clear regional differences in receptor occupancies by these antipsychotic drugs, further study are needed to elucidate this issue.

Topics: Animals; Antipsychotic Agents; Autoradiography; Brain; Chlorpromazine; Clozapine; Dibenzothiepins; Flupenthixol; Haloperidol; In Vitro Techniques; Isoxazoles; Male; Piperidines; Pyrimidinones; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, Serotonin; Risperidone

The effects of the atypical neuroleptic zotepine in comparison with clozapine, risperidone and haloperidol were examined in tests related to the central 5-HT2 activity. Zotepine, as well as clozapine and risperidone, were very potent inhibitors of the 5-HTP-induced head twitches (the behavior mediated by 5-HT2 receptors) in mice, with rank order of potency risperidone > zotepine > clozapine; haloperidol used in high doses only slightly reduced the effect of 5-HTP. Zotepine, clozapine, risperidone and haloperidol antagonized the stimulatory effects of mCPP on the hind limb flexor reflex in spinal rats. As the mCPP-induced stimulation is considered to be mediated by 5-HT2 receptors, the above results provide further evidence for the 5-HT2 antagonistic activity of the drugs studied. Te rank order of potency in that test was the same as in the 5-HTP-induced head twitches (risperidone > zotepine > clozapine). The effect of haloperidol was somewhat unspecific, since its active doses were very high. In the model of hind limb flexor reflex of spinal rats, the anti-alpha 2-adrenergic effect was also tested. Clonidine-induced stimulation of the hind limb flexor reflex (an alpha 2-adrenergic effect) was antagonized by zotepine, clozapine, risperidone and haloperidol. It may be concluded that zotepine, clozapine and risperidone show an alpha 2-adrenergic antagonistic activity (order of potency: zotepine = risperidone > clozapine). The effect of haloperidol may be considered unspecific, since it is observed at high (cataleptic) doses only. In conclusion, it appears that zotepine, as well as clozapine and risperidone, are strong 5-HT2 antagonists, while haloperidol is not.

Topics: Animals; Antipsychotic Agents; Clozapine; Dibenzothiepins; Haloperidol; Isoxazoles; Male; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Risperidone

Topics: Animals; Antipsychotic Agents; Body Temperature; Clozapine; Dibenzothiepins; Fenfluramine; Male; Piperazines; Rats; Rats, Inbred Strains; Spiperone