quetiapine-fumarate and sertindole

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses.. A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.. Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.. In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Topics: Acute Disease; Administration, Oral; Antipsychotic Agents; Aripiprazole; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Haloperidol; Humans; Imidazoles; Indoles; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Thiophenes

In many countries of the industrialised world second-generation ("atypical") antipsychotics (SGAs) have become the first line drug treatment for people with schizophrenia. The question as to whether and if so how much the effects of the various SGAs differ is a matter of debate. In this review we examined how the efficacy and tolerability of risperidone differs from that of other SGAs.. To evaluate the effects of risperidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis.. 1. Electronic searching We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.2. Reference searching We inspected the references of all identified studies for more trials.3. Personal contact We contacted the first author of each included study for missing information.4. Drug companies We contacted the manufacturers of all atypical antipsychotics included for additional data.. We included all randomised, blinded trials comparing oral risperidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.. We extracted data independently. For dichotomous data we calculated risk ratio (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 mean differences (MD), again based on a random-effects model.. The review currently includes 45 blinded RCTs with 7760 participants. The number of RCTs available for each comparison varied: four studies compared risperidone with amisulpride, two with aripiprazole, 11 with clozapine, 23 with olanzapine, eleven with quetiapine, two with sertindole, three with ziprasidone and none with zotepine. Attrition from these studies was high (46.9%), leaving the interpretation of results problematic. Furthermore, 60% were industry sponsored, which can be a source of bias.There were few significant differences in overall acceptability of treatment as measured by leaving the studies early. Risperidone was slightly less acceptable than olanzapine, and slightly more acceptable than ziprasidone in this regard.Risperidone improved the general mental state (PANSS total score) slightly less than olanzapine (15 RCTs, n = 2390, MD 1.94 CI 0.58 to 3.31), but slightly more than quetiapine (9 RCTs, n = 1953, MD -3.09 CI -5.16 to -1.01) and ziprasidone (3 RCTs, n = 1016, MD -3.91 CI -7.55 to -0.27). The comparisons with the other SGA drugs were equivocal. Risperidone was also less efficacious than olanzapine and clozapine in terms of leaving the studies early due to inefficacy, but more efficacious than ziprasidone in the same outcome.Risperidone produced somewhat more extrapyramidal side effects than a number of other SGAs (use of antiparkinson medication versus clozapine 6 RCTs, n = 304, RR 2.57 CI 1.47 to 4.48, NNH 6 CI 33 to 3; versus olanzapine 13 RCTs, n = 2599, RR 1.28 CI 1.06 to 1.55, NNH 17 CI 9 to 100; versus quetiapine 6 RCTs, n = 1715, RR 1.98 CI 1.16 to 3.39, NNH 20 CI 10 to 100; versus ziprasidone 2 RCTs, n = 822, RR 1.42 CI 1.03 to 1.96, NNH not estimable; parkinsonism versus sertindole 1 RCT, n = 321, RR 4.11 CI 1.44 to 11.73, NNH 14 CI 100 to 8). Risperidone also increased prolactin levels clearly more than all comparators, except for amisulpride and sertindole for which no data were available.Other adverse events were less consistently reported, but risperidone may well produce more weight gain and/or associated metabolic problems than amisulpride (weight gain: 3 RCTs, n = 585, MD 0.99 CI 0.37 to 1.61), aripiprazole (cholesterol increase: 1 RCT, n = 83, MD 22.30 CI 4.91 to 39.69) and ziprasidone (cholesterol increase 2 RCTs, n = 767, MD 8.58 CI 1.11 to 16.04) but less than clozapine (weight gain 3 RCTs n = 373, MD -3.30 CI -5.65 to -0.95), olanzapine (weight gain 13 RCTs, n = 2116, MD -2.61 CI -3.74 to -1.48), quetiapine (ch. Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other SGAs. It may also differ from other compounds in efficacy and in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes it difficult to draw firm conclusions. Further large trials, especially comparing risperidone with those other new drugs for which only a few RCTs are available, are needed.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Sulpiride; Thiazoles

The metabolic side effects of second-generation antipsychotics (SGA) are serious and have not been compared head to head in a meta-analysis. We conducted a meta-analysis of studies comparing the metabolic side effects of the following SGAs head-to-head: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine.. We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE and EMBASE (last search January 2009) for randomized, blinded studies comparing the above mentioned SGA in the treatment of schizophrenia or related disorders. At least three reviewers extracted the data independently. The primary outcome was weight change. We also assessed changes of cholesterol and glucose. The results were combined in a meta-analysis.. We included 48 studies with 105 relevant arms. Olanzapine produced more weight gain than all other second-generation antipsychotics except for clozapine where no difference was found. Clozapine produced more weight gain than risperidone, risperidone more than amisulpride, and sertindole more than risperidone. Olanzapine produced more cholesterol increase than aripiprazole, risperidone and ziprasidone. (No differences with amisulpride, clozapine and quetiapine were found). Quetiapine produced more cholesterol increase than risperidone and ziprasidone. Olanzapine produced more increase in glucose than amisulpride, aripiprazole, quetiapine, risperidone and ziprasidone; no difference was found with clozapine.. Some SGAs lead to substantially more metabolic side effects than other SGAs. When choosing an SGA for an individual patient these side effects with their potential cause of secondary diseases must be weighed against efficacy and characteristics of the individual patient.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Cholesterol; Clinical Trials as Topic; Clozapine; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Sulpiride; Thiazoles; Weight Gain

Weight overload and obesity became these last years a major health problem. However gain weight is a frequent side effect of a large number of psychotropics. This article proposes to discuss this potential while reviewing various molecules. This reveals that the atypical antipsychotics are most likely to induce weight gain, in particular clozapine and olanzapine. The tricyclic antidepressants and mirtazapine come next, with the majority of the mood stabilizers. The old antipsychotics seem to involve less gain of weight. The SSRI make lose weight in the first weeks of treatment, but induce a moderate weight gain on the long term.

Topics: Adolescent; Adult; Amisulpride; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Body Mass Index; Child; Clozapine; Dibenzothiazepines; Double-Blind Method; Female; Fructose; Haloperidol; Humans; Imidazoles; Indoles; Male; Obesity; Olanzapine; Piperazines; Placebos; Psychotropic Drugs; Quetiapine Fumarate; Quinolones; Randomized Controlled Trials as Topic; Risperidone; Socioeconomic Factors; Sulpiride; Thiazoles; Time Factors; Topiramate; Valproic Acid; Weight Gain

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

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

During 20th century serious mental disorders were divided into two groups according symptomatology and course of disorder. Individuals with dominating disturbance of perception, thinking and cognition were basically diagnosed having schizophrenic. Individuals with mood disturbance were basically diagnosed having affective disorders. However, there were patients who did not fit neatly into either category. In 1933 Jocob Kasanin introduced the term "schizoaffective psychosis". Scientific discussions involved the possibility that schizoaffective disorder was conceptualized most accurately as following: a type of schizophrenia, a type of affective disorder, a unique disorder that was separate from both schizophrenia and bipolar disorder, an arbitrary categorization of clinical symptoms that marked a continuum between schizophrenia and affective illness, a heterogeneous collection of "interforms" between schizophrenia and affective disorders. However, diagnosis of schizoaffective disorder is included both in DSM-IV-TR and ICD-10. Schizoaffective disorder is listed in the category "schizophrenia and other psychotic disorders". The differential diagnosis includes basically either schizophrenia or affective disorder. The epidemiological status of schizoaffective disorder is somewhat uncertain compared with schizophrenia because of dilemmas related to diagnosis and classification of the disorder. Treatment of schizoaffective disorder comprises psychotropic medication, supportive psychotherapy, social care, rehabilitation. The most important groups of psychotropic medications are: antipsychotics, antidepressants and mood stabilizers. Atypical antipsychotics are the first-line medication for schizoaffective disorder due to their pharmacological properties. In the case of schizoaffective disorders combination of atypical antipsychotics with antidepressants seems to be useful. Novel antidepressants have priority for the combination mentioned above. Peculiarities of mechanism of action of antidepressant are important for combinations. Mood stabilizers seem to be useful for treatment of certain type of schizoaffective disorder as well.

Topics: Adolescent; Amisulpride; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Carbamazepine; Child; Diagnosis, Differential; Dibenzothiazepines; Dogs; Female; Humans; Imidazoles; Indoles; Lithium Carbonate; Male; Mianserin; Middle Aged; Mirtazapine; Olanzapine; Piperazines; Pirenzepine; Placebos; Prognosis; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Sulpiride; Thiazoles; Time Factors

"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

A comprehensive evaluation of atypical antipsychotics for the treatment of schizophrenia involves documentation of clinical effectiveness, quality of life and medical cost outcomes. The results of pharmacoeconomic studies assist psychiatrists, and other healthcare decision-makers, in identifying pharmacotherapies that provide the greatest benefit to patients at the most acceptable cost. The cost-effectiveness of the newer atypical antipsychotics has been examined using clinical decision-modeling studies and randomized clinical trials. The research evidence suggests that clozapine is a cost-effective treatment for neuroleptic refractory schizophrenia. Olanzapine and risperidone may be cost-neutral or, at best, slightly cost-saving compared with conventional antipsychotics, although they do improve clinical symptoms and quality of life outcomes. There is insufficient published data on pharmacoeconomic outcomes for sertindole, quetiapine and ziprasidone to make any conclusions about their cost-effectiveness in treating schizophrenia.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cost-Benefit Analysis; Dibenzothiazepines; Health Care Costs; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone

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

To develop an evidence base for recommendations on the use of atypical antipsychotics for patients with schizophrenia.. Systematic overview and meta-regression analyses of randomised controlled trials, as a basis for formal development of guidelines.. 12 649 patients in 52 randomised trials comparing atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone, and sertindole) with conventional antipsychotics (usually haloperidol or chlorpromazine) or alternative atypical antipsychotics.. Overall symptom scores. Rate of drop out (as a proxy for tolerability) and of side effects, notably extrapyramidal side effects.. For both symptom reduction and drop out, there was substantial heterogeneity between the results of trials, including those evaluating the same atypical antipsychotic and comparator drugs. Meta-regression suggested that dose of conventional antipsychotic explained the heterogeneity. When the dose was

Topics: Amisulpride; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Drug Costs; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Quetiapine Fumarate; Regression Analysis; Risperidone; Schizophrenia; Sulpiride

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

The objective of this meta-analysis is to summarize the efficacy and tolerability of the new antipsychotics risperidone, olanzapine, sertindole and quetiapine in schizophrenia compared to placebo and conventional antipsychotics. The main results are: (1) All of the 4 new drugs are more effective than placebo, but the magnitude of the effect is only moderate [mean effect size, r, of all antipsychotics vs. placebo = 0.25, with a 95% confidence interval (CI) = 0.22-0.28, n = 2477]. (2) According to the studies published to date, sertindole and quetiapine are as effective as haloperidol, and risperidone and olanzapine are slightly more effective than haloperidol in the treatment of global schizophrenic symptomatology. (3) With respect to negative symptoms, all new antipsychotics are more effective than placebo. However, contrary to widespread opinion, so is the 'conventional' antipsychotic haloperidol. Risperidone and olanzapine are slightly superior, sertindole is as effective and--according to the only study fully published to date--quetiapine is even slightly less effective than haloperidol in this regard. (4) All new antipsychotics are associated with less frequent use of antiparkinson medication than haloperidol, with risperidone appearing to have a slightly less favourable EPS-profile than the other new antipsychotics. The methodological limitations of this review, the generalizability of the results and expectations from future research are discussed.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Dibenzothiazepines; Double-Blind Method; Haloperidol; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia

Soon after the introduction of antipsychotic drugs into clinical practice, these agents were observed to be capable of producing not only acute extrapyramidal ("parkinsonian") side effects, but also later occurring abnormal involuntary movements that came to be called tardive dyskinesia. Since antipsychotic drugs are used in a variety of conditions that include psychotic features, studies have attempted to determine whether specific diagnostic subgroups may experience different degrees of vulnerability to drug-induced movement disorders. This issue is important not only to inform clinical practice, but also to provide clues to pathophysiology. A number of studies suggest that patients with affective disorders are at greater risk for developing tardive dyskinesia (controlling, to the extent possible, for other relevant variables such as age, sex, length of treatment). Encouraging preliminary data with new antipsychotic drugs such as olanzapine suggest that the risk of tardive dyskinesia associated with long-term antipsychotic drug use may be substantially reduced. This would go a long way toward improving the benefit-to-risk ratio of antipsychotic drug treatment, particularly in patients with affective disorders.

Topics: Adult; Affective Disorders, Psychotic; Anticonvulsants; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Carbamazepine; Controlled Clinical Trials as Topic; Dibenzothiazepines; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Imidazoles; Indoles; Male; Olanzapine; Piperazines; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Risk Assessment; Risk Factors; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome

The introduction of the atypical antipsychotics clozapine, risperidone, olanzapine, quetiapine and sertindole for the treatment of schizophrenia has coincided with an increased awareness of the potential of drug-drug interactions, particularly involving the cytochrome P450 (CYP) enzymes. The current literature describing the pharmacokinetics of the metabolism of these agents, including their potential to influence the metabolism of other medications, is reviewed. Clozapine appears to be metabolized primarily by CYP1A2 and CYP3A4, with additional contributions by CYP2C19 and CYP2D6. In addition, clozapine may inhibit the activity of CYP2C9 and CYP2C19, and induce CYP1A, CYP2B and CYP3A. Risperidone is metabolized by CYP2D6, and possibly CYP3A4. In vitro data indicate that olanzapine is metabolized by CYP1A2 and CYP2D6. Quetiapine is metabolised by CYP3A4 and sertindole by CYP2D6. There is, however, a general paucity of in vivo data regarding the metabolism of the atypical antipsychotics, indicating a need for further research in this area.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cytochrome P-450 Enzyme System; Dibenzothiazepines; Drug Interactions; Humans; Imidazoles; Indoles; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Schizophrenia

Since the discovery of the neuroleptics in 1952, french psychiatrists have proposed a classification of neuroleptics taking into account the pharmalogical and therapeutic differences between these drugs. They distinguished three different clinical effects of neuroleptics: sedative effects, effects on the positive symptoms of schizophrenia and effects on the negative symptoms. However these agents have many side effects including the extrapyramidal syndrome (EPS), akathisia, dystonia and parkinsonism. These side effects occur in up to 75% of patients receiving typical neuroleptics and are the main cause of non-compliance. Since the eighties, clozapine was introduced for use in refractory patients because it has a better efficacy (than haloperidol) specifically on negative symptoms, a better tolerance and fewer effects. After clozapine, several new antipsychotic agents are now available, such as risperidone, olanzapine, sertindole, quietapine, ziprasidone ... Their therapeutical effects are probably linked with a dual antagonist effect on 5HT2 and D2 receptors. The present article reviews the evolution of the use of these new agents, their real efficacy, their adverse effects and their expanding indications. Future research will more clearly establish appropriate treatment guidelines for their use. These new antipsychotics should add a positive modification in schizophrenia care and in some mood disorders. The approach consisting on individualizing dimensions and clusters analysis might be useful to test the efficiency of each antipsychotic on a syndromic dimension.

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

Topics: Antipsychotic Agents; Benzodiazepines; Benzothiazoles; Clinical Trials as Topic; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Pirenzepine; Pramipexole; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Thiazoles

New neuroleptic drugs are being developed for the treatment of schizophrenia and other psychoses. Clozapine and risperidone are available for general use. Sertindole and olanzapine are nearing release. Seroquel and ziprazidone are in the final stages of study. This generation of drugs will provide advantages in the area of lower motor side effects and probably in improved negative symptom treatment.

Topics: Antipsychotic Agents; Benzodiazepines; Dibenzothiazepines; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Pirenzepine; Quetiapine Fumarate; Schizophrenia; Thiazoles

The QT interval is the most widely used surrogate marker for predicting TdP; however, several alternative surrogate markers, such as Tpeak-Tend (TpTe) and a quantitative T-wave morphology combination score (MCS) have emerged. This study investigated the cardiac effects of sertindole and quetiapine using the QTc interval and newer surrogate markers. Data were derived from a 12 week randomized double-blind study comparing flexible dosage of sertindole 12-20mg and quetiapine 400-600mg in patients with schizophrenia. ECGs were recorded digitally at baseline and after 3, 6 and 12 weeks. Between group effects were compared by using a mixed effect model, whereas assessment within group was compared by using a paired t-test. Treatment with sertindole was associated with QTcF and QTcB interval prolongation and an increase in MCS, T-wave asymmetry, T-wave flatness and TpTe. The mean increase in QTcF from baseline to last observation was 12.1ms for sertindole (p<0.001) and -0.5ms for quetiapine (p=0.8). Quetiapine caused no increase in MCS, T-wave asymmetry, T-wave flatness or TpTe compared to baseline. In the categorical analysis, there were 11 patients (9.6%) receiving quetiapine who experienced more than 20ms QTcF prolongation compared with 36 patients (33.3%) in the sertindole group. Sertindole (12-20mg) was associated with moderate QTc prolongation and worsening of T-wave morphology in a study population of patients with schizophrenia. Although, quetiapine (400-600mg) did not show worsening of repolarization measures some individual patients did experience significant worsening of repolarization. Clinical Trials NCT00654706.

Topics: Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Imidazoles; Indoles; Long QT Syndrome; Male; Principal Component Analysis; Quetiapine Fumarate; Schizophrenia

Fitness to drive is an important prerequisite for the functional autonomy and thus also relevant for patients with a psychiatric illness. The efficacy of sertindole in the treatment of positive and negative schizophrenia symptoms has been shown in various studies. However, hitherto there exist no data about patients' fitness to drive under sertindole.. A non-randomized clinical study with 30 schizophrenic inpatients receiving sertindole (n=10), risperidone (n=10) or quetiapine (n=10) was conducted. Patients were tested under steady-state plasma level conditions prior to discharge to outpatient treatment. Data were collected with the computerized Act and React Testsystem (ART90) and the Wiener Determinationsgerät (WDG) measuring psychomotor skills relevant for fitness to drive.. The main findings of this study are (i) that about 26% of schizophrenic patients, -following psychopathologic stabilization and prior discharge to outpatient treatment show severe impairments with respect to driving skills. (ii) Statistically significant differences between atypical antipsychotics could neither be demonstrated on the level of the global driving ability score nor on individual functional domains essential for fitness to drive.. With respect to driving skills no differences have been found between patients treated with sertindole, risperidone or quetia-pine. However, a great proportion of schizophrenic patients partly remitted must be considered as unfit to drive, even when stabilized on treatment with atypical antipsychotics.

Topics: Adult; Antipsychotic Agents; Automobile Driving; Dibenzothiazepines; Female; Humans; Imidazoles; Indoles; Male; Middle Aged; Psychomotor Performance; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Visual Perception

This study was set out to examine the impact of atypical antipsychotic drugs: aripiprazole, clozapine, ziprasidone, olanzapine, quetiapine, sertindole and amisulpride on the activity of antioxidant defence enzymes in human erythrocytes in vitro.. Cu,Zn-superoxide dismutase (SOD1), catalase (CAT), selenium-dependent glutathione peroxidase and glutathione reductase activities were determined after drugs incubation with blood of 15 apparently healthy non-smoking male volunteers (ages 23-39) for 1 h at 37 °C.. A statistically significant increase in SOD1 activity was found in samples incubated with aripiprazole (p < 0.01) and quetiapine (p < 0.05) compared with incubated control. SOD1 activity profile following native polyacrylamide gel electrophoresis indicates that aripiprazole and quetiapine protect enzyme activity from inhibition with hydrogen peroxide. Our results showed that sertindole decreases activity of CAT comparing with control non-treated erythrocytes. Moreover, in sertindole treated erythrocytes, negative correlation between SOD1 and glutathione peroxidase activities was found. Increased amount of hydrogen peroxide in such situation may leave erythrocytes and transform their role in circulation from anti-oxidative to pro-oxidative.. Our results indicate that mechanism through sertindole could express its in vivo toxic effects and point toward possible (neuro)protective effects of aripiprazole and quetiapine.

Topics: Adult; Amisulpride; Antioxidants; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Catalase; Clozapine; Dibenzothiazepines; Enzyme Activation; Erythrocytes; Glutathione Peroxidase; Glutathione Reductase; Humans; Imidazoles; Indoles; Male; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Sulpiride; Superoxide Dismutase; Superoxide Dismutase-1; Thiazoles; Treatment Outcome; Young Adult

Prefrontal cortical dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. Nevertheless, the effectiveness of second-generation antipsychotic drugs in treating specific prefrontal dysfunctions remains equivocal.. To model schizophrenia-like cognitive inflexibility in rats, we evaluated the effects of repeated administration of ketamine, the noncompetitive antagonist of the N-methyl-D: -aspartate receptor, after a washout period of 14 days in the attentional set-shifting task (ASST). Next, we investigated whether the atypical antipsychotics quetiapine and sertindole would alleviate the ketamine-induced set-shifting impairment.. Ketamine (30 mg/kg) was administered intraperitoneally to rats once daily for 5 or 10 consecutive days to assess its efficacy in producing cognitive impairment. The ASST was performed 14 days following the final drug administration. Quetiapine (0.63, 1.25 or 2.5 mg/kg) or sertindole (2.5 mg/kg) was administered per os 120 min before testing.. The results of the present study demonstrate that ketamine treatment for 10 but not 5 days significantly and specifically impaired rats' performance in the extra-dimensional shift (EDs) stage of the ASST. This cognitive inflexibility was reversed by acute administration of sertindole or quetiapine. Quetiapine also promoted set-shifting in cognitively unimpaired control animals.. The data presented here show that subchronic administration of ketamine induces cognitive inflexibility after a washout period. This cognitive deficit likely reflects clinically relevant aspects of cognitive dysfunction encountered in schizophrenic patients. The beneficial effects of quetiapine on set-shifting may have therapeutic implications for the treatment of schizophrenia and other disorders associated with frontal-dependent cognitive impairments.

Topics: Animals; Antipsychotic Agents; Attention; Cognition Disorders; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Imidazoles; Indoles; Ketamine; Male; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Schizophrenia

Insomnia associated with chronic schizophrenia and after clozapine discontinuation represents a common, but mostly not predominant, complaint and often does not respond sufficiently to classical hypnotics. We report the case of a 46-year-old patient with schizophrenia who developed a rebound insomnia confirmed by polysomnography after discontinuation of long-term treatment with clozapine and changing to sertindole therapy. Zolpidem, zolpiclone and chloral hydrate only led to short-term improvement of subjective sleep quality. An add-on therapy with 300 mg quetiapine resulted in improved subjective quality of sleep regarding sleep latency and the number of nocturnal awakenings. The combination of the two neuroleptics did not lead to increased QTc intervals (normal QTc < 450 ms) or metabolic side effects. In conclusion, the combination of sertindole and quetiapine might be a safe and effective combination in therapy-refractory insomnia after clozapine discontinuation in schizophrenia.

Topics: Antipsychotic Agents; Clozapine; Dibenzothiazepines; Drug Therapy, Combination; Humans; Hypnotics and Sedatives; Imidazoles; Indoles; Male; Middle Aged; Polysomnography; Quetiapine Fumarate; Schizophrenia; Sleep; Sleep Initiation and Maintenance Disorders

The current generation of atypical antipsychotic drugs represents an improvement over traditional ("typical") antipsychotics in many respects. However, a theoretical framework and adequate preclinical models have not yet been developed to predict or explain differences among the atypical antipsychotics, a necessary component of future development.. The purpose of the present set of experiments was to identify differences between the acute and subchronic effects of several atypical antipsychotic drugs and the typical antipsychotic haloperidol on operant responding in rats.. The effects of haloperidol and the atypical antipsychotics clozapine, olanzapine, risperidone, sertindole, quetiapine, remoxipride, and thioridazine were determined in rats trained to respond for food reward under a multiple fixed ratio 30/fixed interval 60 s schedule. A profile of the acute effects of each drug on response rates, response durations, and within-session effects were determined. Next, the dose of each drug that produced 75% suppression of response rates was administered for 16 consecutive days to determine whether or not tolerance would develop to the rate-suppressing effects of that dose.. All drugs produced dose-related decreases in response rates. Only haloperidol and risperidone produced significant increases in response duration, while only haloperidol and remoxipride displayed within-session response decrements. Tolerance was evident for clozapine and to a lesser extent thioridazine.. These results illustrate that the current generation of atypical antipsychotics are a heterogeneous group and that operant procedures may be useful for identifying differences preclinically. Specifically, clozapine appears to possess properties that distinguish it from other atypical antipsychotics, particularly after repeated dosing.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Conditioning, Operant; Dibenzothiazepines; Dose-Response Relationship, Drug; Haloperidol; Imidazoles; Indoles; Male; Olanzapine; Pirenzepine; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Remoxipride; Risperidone; Thioridazine; Time Factors

The effects of acute intravenous administration of several new, atypical antipsychotic drugs (APDs): olanzapine (0.05 and 1.0 mg/kg), sertindole (0.1 and 1.0 mg/kg) and quetiapine (0.25 and 2.5 mg/kg), a selective 5-HT(2A) receptor antagonist, M100907 (0.03 and 0.3 mg/kg), and an alpha(1)-adrenoceptor antagonist, prazosin (0.3 mg/kg), on regional dopamine output were examined in the two subdivisions of the nucleus accumbens (NAC), the core and shell, which seem associated with motor control and limbic functions, respectively, by using in vivo differential normal pulse voltammetry in anaesthetised, pargyline-pretreated rats. Both quetiapine and sertindole, in the two doses used, caused a more pronounced dopamine release in the shell than in the core region of the NAC. In contrast, the low dose of olanzapine increased dopamine output almost to the same extent in both regions, whereas the high dose increased dopamine output to a greater extent in the core. M100907 selectively increased dopamine output in the shell. Also, prazosin significantly increased dopamine output in the shell, but not in the core. The results indicate that both 5-HT(2A) and alpha(1)-adrenoceptor antagonism may play an important role in the preferential effect of atypical APDs on dopamine output in the shell versus the core of the NAC.

Topics: Adrenergic Antagonists; Animals; Antipsychotic Agents; Benzodiazepines; Dibenzothiazepines; Dopamine; Fluorobenzenes; Imidazoles; Indoles; Male; Nucleus Accumbens; Olanzapine; Piperidines; Pirenzepine; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Adrenergic, alpha-1; Receptors, Serotonin; Serotonin Antagonists

Topics: Aged; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials as Topic; Dibenzothiazepines; Dose-Response Relationship, Drug; Humans; Imidazoles; Indoles; Movement Disorders; Psychotic Disorders; Quetiapine Fumarate; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine; Receptors, Serotonin; Schizophrenia; Treatment Outcome

Phencyclidine (PCP) induces stereotyped behaviour and social isolation in rats; comparisons with clinical observations have suggested that these behaviours may mimic certain aspects of the positive and the negative symptoms, respectively, of an acute schizophrenic episode. Novel antipsychotics are effective in treating the positive symptoms in schizophrenic patients and have also shown some promise in treating the negative symptoms. In the present study the effects of the novel antipsychotics remoxipride (2.5-20 mg/kg), risperidone (0.02-0.63 mg/kg), sertindole (0.01-2.5 mg/kg), olanzapine (0.16-2.5 mg/kg) and quetiapine (0.16-10 mg/kg) on PCP-induced behaviours were determined. The drugs were administered daily for 3 or 21 days in combination with vehicle or 2.0 mg/kg of PCP for the last 3 days of the administration regime, and the rats were tested using the social interaction test. The antipsychotic drugs all reliably reduced the level of PCP-induced stereotyped behaviour and had distinct effects on PCP-induced social isolation. Comparison with clinical findings suggests that the PCP-induced behaviours respond to treatment with antipsychotic drugs in a manner that correlates well with clinical observations, and that this animal model of schizophrenia may be useful for evaluating novel drug candidates. However, the study also showed that additional experiments are required to determine the specificity by which antipsychotic drugs alleviate PCP-induced behaviours because most of the drugs also affected considerably the behaviour of the control animals.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Benzodiazepines; Dibenzothiazepines; Dose-Response Relationship, Drug; Hallucinogens; Imidazoles; Indoles; Interpersonal Relations; Male; Olanzapine; Phencyclidine; Pirenzepine; Quetiapine Fumarate; Rats; Rats, Wistar; Remoxipride; Social Isolation; Stereotypic Movement Disorder