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The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5-1.5 mg kg(-1) i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+ 171.0%) and 240 min (+ 211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg(-1) i.p.), resulted in a smaller, transient increase in NA levels (+ 72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg(-1) i.p.) nor olanzapine (1.0 mg kg(-1) i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg(-1) i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of + 354.3%), whilst local infusion of nisoxetine (1-100 microM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.
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This study is limited by the naturalistic design, the relatively small samples in the first two groups, the lack of information on the duration of the atypicals and their relatively recent introduction to the market (ziprasidone and aripiprazole were introduced to the market in the middle of the study). This study raises the question that new TD studies need to establish whether decades of treatment with atypical antipsychotics make a difference.
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Fifty-seven sites participated, including academic sites and treatment mental health facilities representative of the community.
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Scientific researchers and regulators are focusing attention on trace quantities of pharmaceuticals in wastewater effluents and surface waters, resulting in an increased level of concern regarding the potential environmental impact of these compounds. The current European regulatory guideline requires evaluation of the chronic effects of active pharmaceutical ingredients on Daphniamagna. Based on the life cycle of D. magna, chronic studies to establish survival and reproductive endpoints require a 21 d exposure period. A similar organism, Ceriodaphniadubia, has a shorter life cycle and therefore survival and reproductive endpoints may be established following 7d of exposure. No observed effect concentrations and lowest observed effect concentrations for survival and reproduction were obtained for D. magna and C. dubia following exposure to six human pharmaceuticals and two metabolites (i.e. celecoxib, linezolid, varenicline, sunitinib, Compound A, ziprasidone and the M1 and M4 metabolites of torcetrapib). These data were evaluated to determine whether one organism may be considered more sensitive. Survival and reproduction data obtained from the C. dubia study provide similar outcomes to D. magna when determining the predicted environmental concentration/predicted no effect concentration (PEC/PNEC) ratios for surface water. Based on these data, C. dubia may be used as a cost-effective alternative and representative invertebrate species when assessing the potential risk of human pharmaceuticals.
To evaluate the effects of olanzapine compared to other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis.
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A PubMed search was conducted to identify literature on the subject of this review, supported by additional articles based on the author's clinical knowledge and experience.
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Intramuscular ziprasidone may be helpful for agitation but often caused oversedation. Safety data, including ECGs, is needed in controlled prospective studies.
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The data from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) were used in this analysis. The cross-sectional data included 371 patients receiving risperidone, olanzapine, or ziprasidone, who had completed the Drug Attitude Inventory (DAI-10) at six months and provided plasma antipsychotic concentrations. Samples were analyzed to examine the relationship between DAI-10 total scores and estimated D2 occupancy using Spearman's rank correlations, followed by multiple regression analysis. In addition, to elucidate the relationship between changes in DAI-10 scores and estimated D2 occupancy, the longitudinal data from 45 patients who experienced an increase in antipsychotic dosage between six and 12months were analyzed. Mean peak and trough D2 occupancy levels were estimated from plasma antipsychotic concentrations using a population pharmacokinetic approach.
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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 to olanzapine.Other important outcomes such as service use, cognitive functioning, satisfaction with care or quality of life were rarely reported.
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Geodon for injection (ziprasidone mesylate), 20 mg/mL, was diluted to 2.5 mg/mL in a commercially available sugar-free and alcohol-free, flavored syrup and stored at room temperature under ambient fluorescent light illumination, at room temperature in darkness, and under refrigeration. The ziprasidone content was measured in samples at various time intervals using a stability-indicating high-performance liquid chromatographic method.
The aim of the present study was to compare the effects of several antipsychotics on weight gain and reproductive function in juvenile (aged 7 weeks) female hooded Lister rats.
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Future studies are needed to test whether the lack of a decrease in AGRP levels during weight gain in patients treated with olanzapine could perpetuate adverse metabolic long-term effects.
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There are no direct comparisons of paliperidone extended-release (ER), aripiprazole and ziprasidone in efficacy and metabolic influence in patients with first-episode schizophrenia.
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Atypical antipsychotics are increasingly prescribed to children and adolescents with neuropsychiatric disorders. Although their profile of potent antagonism at specific serotonin and dopamine receptors offers certain advantages compared with typical antipsychotics, their use has been associated with various adverse effects, including significant weight gain. This adverse effect is of particular concern in children and adolescents, secondary to the immediate and long-term health risks associated with weight gain, including obesity, diabetes mellitus, and hyperlipidemia. Indeed, from 1963 to 1991, the prevalence of obesity has approximately doubled in youth. Prior to selecting an atypical antipsychotic, a detailed review of the predictors of weight gain is necessary for every child and adolescent. Published data suggest that clozapine and olanzapine are associated with considerable weight gain, whereas risperidone and quetiapine have a moderate risk. Alternatively, ziprasidone and aripiprazole may exhibit a low risk for this adverse effect. Whereas behavioral and pharmacologic measures are available to manage weight gain associated with atypical antipsychotics, research is needed to establish more effective and safe interventions for this adverse effect in children and adolescents.
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Chlorpromazine, haloperidol, fluphenazine, clozapine, risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole are antipsychotics commonly used in psychiatric medicine. Approximately one third of pregnant women with psychotic symptoms use antipsychotics at least once. This review will discuss the effects of antipsychotic use during pregnancy and lactation on the fetus and infant.Although adequate and well-controlled studies have not been done in any one of these antipsychotic drugs, animal studies have revealed evidence of teratogenic or embryo/fetotoxic effects in all of them. Toxicities include skeletal malformations, central nervous system (CNS) defects, cleft palate, cardiac abnormalities, decreased fetal growth, and fetal death. For example, in pregnant women, congenital malformations and perinatal death have been reported with chlorpromazine use. Both chlorpromazine and fluphenazine in monotherapy have been shown to cause extrapyramidal symptoms and respiratory distress in infants born to mothers treated with these medications. Haloperidol use during pregnancy has been linked to severe limb reduction defects.Effects of antipsychotic use in lactating mothers are mostly unknown. However, the use of chlorpromazine has been reported to result in drowsiness and lethargy in breastfed infants. Additionally, clozapine has been reported to cause sedation, decreased suckling, restlessness, irritability, seizures, and cardiovascular instability of infants were also reported with clozapine use in lactating mother. Use of antipsychotic drugs by pregnant and lactating mother may only be justified if the potential benefit outweighs the potential risk to the fetus.
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Recent developments in psychopharmacology have lead to the introduction of several novel antipsychotic agents into clinical practice. As these agents become more commonly encountered, it is essential that forensic psychiatrists have a working knowledge of their efficacy as well as the advantages of their use. This article reviews current literature regarding the clinical efficacy and mechanisms of action of clozapine, risperidone, olanzapine, quetiapine, sertindole, and ziprasidone, with a discussion of their use in forensic psychiatry. Specifically, studies show certain advantages of the novel agents in the treatment of violent patients. Use of these medications may also reduce the risk of civil litigation. The novel antipsychotic agents offer the potential of improved patient care within forensic settings by both expediting judicial processing while providing long-term cost savings. Forensic patients represent an underserved population but must have equal access to new medications as they become available. Familiarity with these issues and the medications themselves will facilitate their use in forensic settings.
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It is well known that severe hyponatremia can cause neurologic complications such as stupor, seizures, and even coma. Hyponatremia from water intoxication (n = 28) and its correction with intravenous fluids (n = 2) may cause non-neurologic complications such as rhabdomyolysis. An explanation may lie within the calcium-sodium exchange mechanism across the skeletal myocyte or the failure of cell volume regulation secondary to extracellular hypo-osmolality. Neuroleptic medications have been linked to the development of rhabdomyolysis, with antipsychotics being the primary offenders. As of August 2005, there has been only one reported case of rhabdomyolysis related to correction of hyponatremia complicated by an atypical antipsychotic (clozapine). It is possible that ziprasidone, like clozapine, may enhance muscle cell permeability leading to rhabdomyolysis under similar conditions.
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The appeal of ketamine - in promptly ameliorating depressive symptoms even in those with non-response - has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine's potential as an option for treating depression and provide a synthesis of perspectives - derived from evidence and clinical experience - and to consider strategies for future investigations.
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Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]).
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Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects.
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Exploratory orthogonal factor analysis (varimax rotation) including both HAM-D total scores and the MRS items found different five-factor solutions for mixed and manic patients at the unmedicated baseline assessment. Confirmatory modeling indicated that these models, with some modifications, fit the data well. At the endpoint, however, a single-factor solution was found for mixed and manic groups.