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Many articles suggest that clozapine was strongly associated with a higher incidence of new-onset diabetes mellitus, and the issue has remained unsettled. Many articles have compared clozapine with FGAs, but few have compared clozapine with SGAs. We aimed to compare the risk of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine and other SGAs. We conducted a comprehensive search of databases from their inception up until August 26, 2023. The specific databases include PubMed, Embase and others. We included non-randomized controlled trials involving the use of SGAs such as clozapine, olanzapine, risperidone, quetiapine, amisulpride, and zotepine, with a focus on new-onset diabetes mellitus as an outcome. We utilized odds ratio with 95 % credible intervals (95 % CI) as our effect size measures. The study protocol is registered with PROSPERO, number CRD42024511280. We included 7 studies with sufficient data to include in the meta-analysis. A total of eight studies with 641,48 participants met the eligibility criteria. The OR of the incidence rates of new-onset diabetes between clozapine and olanzapine was 0.95 (95 % CI:[0.82–1.09]), between clozapine and risperidone was 1.25 (95 % CI: [1.09–1.44]), between clozapine and quetiapine was 1.44 (95 % CI: [0.92–2.25]). In patients with schizophrenia, clozapine has been found to have a higher rate of new-onset diabetes mellitus compared to risperidone. However, there was no significant difference in incidence rate between clozapine versus olanzapine and quetiapine. These findings can assist clinicians in balancing the risks and benefits of those drugs. • Differences in the incidence of new-onset diabetes caused by second-generation antipsychotics were compared. • Clozapine and olanzapine cause a similar incidence of new-onset diabetes. • Clozapine is more likely to cause new-onset diabetes than risperidone. • Explored relationship between therapy duration and incidence [ABSTRACT FROM AUTHOR]

The review of the literature by He and colleagues (Association of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine versus patients treated with olanzapine, risperidone, or quetiapine: a systematic review and meta-analysis) found that in patients with schizophrenia, clozapine is associated with a higher rate of new-onset diabetes mellitus compared to risperidone, but not in comparison to olanzapine or quetiapine, pointing to the importance of balancing risks and benefits in using these drugs. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the impact of quetiapine treatment on central set point of thyroid homeostasis in patients with acute phase schizophrenia.Methods: During Jan. 2016 to Dec. 2018, we conducted a retrospective cohort study in "the Second Affiliated Hospital of Xinxiang Medical University". All patients admitted for treatment of schizophrenia being euthyroid at admission and reevaluated for thyroid function during hospitalization were recruited and followed until discharge. Patients treated with mood stabilizers during hospitalization were excluded. Quetiapine use was the exposure measure. The primary outcomes were the parameters of central set point of thyroid homeostasis measured by "thyroid-stimulating hormone (TSH) index" and "thyroid feedback quantile-based index (TFQI)". Multiple regression models were used to estimate the association between quetiapine exposure and outcomes.Results: A total of 1302 patients were enrolled in this study. Quetiapine exposure was associated with a more significant decline in the TSH index and TFQI, and the adjusted β and 95% confidence interval (CI) were -0.12 (-0.22, -0.01) and -0.10 (-0.15, -0.05), respectively. A dose-response association between quetiapine exposure and decline in TSH index and TFQI was observed (P < 0.05). Sensitivity analyses restricting to patients under mono-atypical antipsychotic therapy, or selecting patients in the non-quetiapine group matched to quetiapine group yielded similar results.Conclusion: Quetiapine was associated with TSH index and TFQI reduction in a dose-response pattern, suggesting that impaired central set point may be involved in the mechanism by which quetiapine affects hypothalamus-pituitary-thyroid axis in acute phase schizophrenia patients. [ABSTRACT FROM AUTHOR]

Lipid core nanocapsules (LNC) have been extensively studied as a new treatment strategy to improve therapeutic effects of antipsychotic drugs. We investigated the efficacy of quetiapine LNCs (QLNCs) on the poly(i:c) model of schizophrenia in both male and female rats using the pre-pulse inhibition of startle response (PPI) test paradigm after evaluating the outcomes of three different poly(i:c) doses administered to pregnant damns at GD15 on neurodevelopmental outcomes of maternal immune activation (MIA) in adult offspring. QTP solution was not capable of producing a reversal in the sensorimotor gating-disruptive effect caused by the prenatal poly(i:c) exposure. The same dose of QTP given as QLNCs significantly improved PPI-impairment. This is the first study reporting the restoration of the PPI deficits in a neurodevelopmental model of SCZ using LNCs. This is a promising delivery system strategy to improve antipsychotic effects contributing to the development of better SCZ pharmacological treatments. [ABSTRACT FROM AUTHOR]

Rationale: This prospective study is the first to measure and correlate quetiapine concentrations in maternal blood, amniotic fluid and umbilical cord blood to account for the distribution of quetiapine.Methods: Concentrations of quetiapine are quantified in seven mother infant pairs at the time of delivery. Data are provided as median values, first (Q1) and third (Q3) quartiles and ranges. To account for the penetration ratio, the concentration of quetiapine in amniotic fluid and cord blood was divided by maternal concentrations. Correlations between daily dosage, maternal serum and umbilical cord blood concentrations were computed for seven patients while calculations for amniotic fluid were only available for six mother-infant pairs.Results: The median daily dosage of quetiapine was 300mg (Q1: 300mg, Q3: 600mg, range 200-800mg). There was a strong and significant correlation between maternal serum and cord blood concentrations (r=0.893, p=0.007). The median penetration ratio into fetal circulation was 0.18 (Q1: 0.16, Q3: 0.32; range 0.13-0.42), suggesting a low penetration. The median penetration ratio into amniotic fluid was 0.44 (Q1: 0.15, Q3: 0.96; range 0.09-1.70).Conclusions: Quetiapine concentrations in amniotic fluid and cord blood give evidence that quetiapine is constantly accessible to the fetus with a relatively low penetration ratio. A high correlation between maternal serum and umbilical cord blood concentrations highlights a predictive role of quantifying drug concentrations in maternal serum for assessing drug concentrations in fetal circulation. Findings support the important role of therapeutic drug monitoring in supporting the efficacy and safety of psychopharmacological treatment strategies in highly vulnerable populations. [ABSTRACT FROM AUTHOR]

Rationale: Hyperprolactinemia is considered a troubling adverse effect of antipsychotics. Direct comparisons among second generation antipsychotics are scant in clinical practice. We hypothesize prolactin-sparing second-generation antipsychotics may have differential effects on prolactin levels and that they may be influenced by sex.Objectives: To explore the differential effect of three widely used prolactin-sparing antipsychotics, aripiprazole, quetiapine and ziprasidone, on prolactin plasma levels in first episode non-affective psychosis during a 1year of treatment.Method: From October 2005 to January 2011 a prospective, randomized, open-label study was undertaken. 141 patients who were randomly allocated to aripiprazole (N=56), quetiapine (N=36) or ziprasidone (N=49) were analyzed. The main outcome was differences in prolactin plasma levels over 1year follow-up among the three antipsychotics. Prolactin levels had a skewed distribution and therefore they were log-transformed before statistical analyses.Results: Male patients on aripiprazole had a lower risk of suffering an increase on prolactin plasma levels (N=71; F=12.645; p<0.001). There was a gender effect with smaller changes in mean prolactin values only in males. Aripiprazole had a reduced risk of hyperprolactinemia (aripiprazole 19.6%) compared to quetiapine (44.4%) and ziprasidone (32.7%) (p=0.038); and quite similar findings were found when investigating males (p=0.040). No significant differences were found in females. The percentages of mild prolactin excess were: 14.3% on aripiprazole, 36.1% on quetiapine and 18.4% on ziprasidone (χ2=6.611 p=0.037).Conclusions: Our findings provide additional evidence of differential effects of three sparing-prolactin antipsychotics on prolactin release and may help clinicians to decide among therapeutic options. [ABSTRACT FROM AUTHOR]

Antipsychotics may confer long term benefits and risks, including cardiovascular disease (CVD) risk. Several studies using routine clinical data have reported associations between antipsychotics and CVD but potential confounding factors and unclear classification of drug exposure limits their interpretation.Method: We used data from The Health Improvement Network, a large UK primary care database to determine relative risks of (CVD) comparing similar groups of people only prescribed olanzapine versus either risperidone or quetiapine. We included participants over 18 between 1995 and 2011. To assess confounding factors we created propensity scores for being prescribed each antipsychotic. We used propensity score matching and Poisson regression to calculate the CVD incidence rate ratios for olanzapine versus the other two drugs.Results: We identified 18,319 people who received a single antipsychotic during follow-up (n=5090 risperidone, 7797 olanzapine and 4613 quetiapine). In unmatched analyses, the CVD incidence rate ratio (IRR) for olanzapine versus risperidone was 0.63 (0.51-0.77) but the propensity score matched IRR was 0.78 (0.61-1.02). In the unmatched olanzapine versus quetiapine analysis the IRR adjusted for age and sex for olanzapine was 1.52 (1.16-1.98) but the propensity score matched analysis gave an IRR of 1.08 (0.79-1.46).Conclusions: After propensity score matching, we found no statistical differences in CVD incidence between olanzapine and either risperidone or quetiapine. Analyses which did not account for confounding factors produced very different results. Researchers must address confounding factors when designing observational studies to assess adverse outcomes of drugs, including antipsychotics. [ABSTRACT FROM AUTHOR]

We previously reported that treatment with 160 mg/d of lurasidone improved cognitive performance in a manner superior to placebo, quetiapine XR 600 mg/d, and lurasidone 80 mg/d, based on a 6-week randomized trial of patients with an acute exacerbation of schizophrenia. The objective of this post-hoc analysis was to explore the cognitive and functional performance of patients whose final doses of lurasidone were 40/80 mg/d, 120 mg/d, and 160 mg/d compared to quetiapine XR 200-800 mg/d (QXR) during a 6-month, double-blind continuation study that followed a short-term trial. Subjects who received final doses of lurasidone 120 mg/d (n = 77) and 160 mg/d (n = 49) showed significantly greater improvement in overall cognitive performance compared to QXR (n = 85) at week 32 (month 6 of the extension study), while those on last doses of 40/80 mg/d (n = 25) showed a trend towards significance at week 32. Mean changes in neurocognitive composite z-score from pre-treatment baseline were significant for the 3 lurasidone final dose groups at both weeks 19 and 32, with composite change scores of z = 1.53, z = 1.43, and z = 1.34 for the lurasidone 40/80 mg/d, 120 mg/d, and 160 mg/d, respectively, at week 32. In contrast, the composite change score was not statistically significant in the overall quetiapine group (z = 0.46), with none of the individual quetiapine doses showing any significant improvement. Functional capacity scores improved in all treatment groups. Our findings indicate improved cognitive performance in patients treated with each of the flexible doses of lurasidone 40–160 mg/d, compared to quetiapine XR 200–800 mg/d. All doses of lurasidone were superior to all doses of quetiapine for cognitive performance. [ABSTRACT FROM AUTHOR]

Objectives To assess daytime cognitive performance, sedation and treatment satisfaction in patients with schizophrenia receiving quetiapine extended release (XR) versus quetiapine immediate release (IR). Methods Phase IV prospective, double-blind, crossover study ( NCT01213836 ). Patients (N = 66) with stable schizophrenia, treated with XR or IR before study start, were randomised (1:1) to treatment with XR followed by IR, or IR followed by XR, at the dose received before enrolment (400–750 mg). After 10–16 days on formulation 1, patients switched to formulation 2. Assessments from three post-dose visits (≥ 5 days following treatment on each formulation) were analysed. Cognitive performance was measured by CogState Cognition testing. Sedation, treatment satisfaction and safety were also assessed. Results 65 patients received treatment (69.2% male; mean age 37.8 years). Daytime cognitive functioning was similar for both groups; adjusted mean difference in Attentional Composite Score in XR and IR patients was 0.005 (p = 0.907). Patients receiving XR were less sedated than those receiving IR, (Bond–Lader visual analogue scale score, mean [SD]: 23.5 [19.0] vs 28.6 [21.4]); estimated overall treatment difference: 5.2 (95% CI: 2.3, 8.2; p < 0.0009). Patients receiving XR reported feeling less sedated than those on IR (Stanford Sleepiness Scale, mean [SD]: 2.4 [0.9] vs 2.6 [1.0]); estimated overall treatment difference: 0.28 (95% CI: 0.12, 0.43; p < 0.0008). Patients reported improved overall treatment satisfaction (p = 0.0417) and milder side effects (p = 0.0035) with XR. Safety profile was similar in both groups. Conclusion Daytime cognitive performance was similar for both groups. XR was associated with less daytime sedation and improved patient satisfaction than IR. [ABSTRACT FROM AUTHOR]

Background The comparative antidepressant effects of clozapine and other atypical antipsychotics for schizophrenia remain elusive, leading us to examine this question using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness phase 2E. Methods Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone because of inadequate efficacy were randomly assigned to open-label treatment with clozapine (n = 49) or double-blind treatment with another atypical antipsychotic not previously received in the trial (olanzapine [n = 19], quetiapine [n = 15], or risperidone [n = 16]). The primary outcome was the Calgary Depression Scale for Schizophrenia (CDSS) total score. Antidepressant effects of clozapine and the other atypical antipsychotics were compared in patients with chronic schizophrenia and those with a major depressive episode (MDE) at baseline (i.e. ≥ 6 on the CDSS), using mixed models. Results No differences in the baseline CDSS total scores were found between the treatment groups regardless of presence of an MDE. Clozapine was more effective than quetiapine in antidepressant effects for chronic schizophrenia (p < .01 for the whole sample and p = .01 for those with an MDE), and comparable to olanzapine and risperidone. Conclusion The present findings suggest that clozapine demonstrates superior antidepressant effects to quetiapine and comparable effects to olanzapine and risperidone in chronic schizophrenia regardless of presence of MDE. Given the indication of clozapine for treatment-resistant schizophrenia (TRS) and the negative impacts of depressive symptoms on clinical outcomes in schizophrenia, further research is warranted to investigate antidepressant effects of clozapine in TRS with an MDE. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4–7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n = 139), perphenazine (n = 78), quetiapine (n = 14), risperidone (n = 143), and ziprasidone (n = 90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p = 0.002), perphenazine (best p = 0.01), quetiapine (best p = 0.008), risperidone (best p = 0.02), and ziprasidone (best p = 0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu 260 ] allele) was associated with better response to olanzapine (p = 0.002), and risperidone (p = 0.006), and worse response to perphenazine (p = .03), and ziprasidone (p = 0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser 168 ] allele) was associated with better response to perphenazine (p = 0.001) and worse response to olanzapine (p = .02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response. [ABSTRACT FROM AUTHOR]

This randomized open-label study compared the incidence of metabolic side effects of aripiprazole, ziprasidone and quetiapine in a population of medication-naïve first-episode psychosis patients. A total of 202 subjects were enrolled. Body weight, body mass index, leptin, fasting lipids and fasting glycaemic parameters were measured at baseline and at 3 months follow-up. A hundred and sixty-six patients completed the follow-up and were included in the analyses. A high proportion of patients experienced a significant weight increase (> 7% of their baseline weight): 23% ziprasidone ( n = 12), 32% with quetiapine ( n = 16) and 45% with aripiprazole ( n = 31). Patients treated with aripiprazole gained significantly more weight than the patients in the ziprasidone group (1.2 kg [SD = 4.1] versus 4.3 kg [SD = 4.8], respectively). The increase in leptin levels was greater in women treated with aripiprazole than in those treated with ziprasidone ( p = 0.030). Mean prolactin levels significantly increased in patients treated with quetiapine and ziprasidone but not in those treated with aripiprazole. Patients treated with quetiapine and aripiprazole showed a significant increase in total cholesterol and LDL-cholesterol plasma levels. Quetiapine-treated patients resulted in a higher increase in LDL-cholesterol than patients treated with ziprasidone ( p = 0.021). No other significant differences between groups were found. No significant changes in glycaemic parameters were observed. Our results suggest that ziprasidone has a lower liability for inducing weight gain and lipid abnormalities than aripiprazole or quetiapine. [ABSTRACT FROM AUTHOR]

Abstract: Rationale: Measurement of motor cortex excitability with single and paired pulse transcranial magnetic stimulation has become an established method for in vivo characterization of the effects of central-acting drugs. The comparison of drug-free and medicated patients with schizophrenia suggests an association of neuroleptics intake and prolongation of the cortical silent period (CSP). However all available data come from cross-sectional non-randomized studies. Thus it is not clear whether the observed difference is an effect of medication or reflects differences in disease severity or both. Objectives: We aimed to investigate whether the CSP or other parameters of cortical excitability change, when cortical excitability is measured in drug-free patients with acute psychosis before and after 3week intake of the atypical neuroleptic quetiapine. Methods: Different parameters of cortical excitability were studied in 24 drug-free patients with acute psychosis before and after 3weeks of treatment with a mean dose of 352±199mg quetiapine. Results: We observed a significant prolongation of the cortical silent period (CSP) after three week treatment with quetiapine. Other parameters of cortical excitability such as motor threshold (MT), short intracortical inhibition (SICI) and intracortical facilitation (ICF) remained unaffected. There was a significant improvement in clinical parameters (PANS, GAF) but no significant correlation between clinical improvement and changes in cortical excitability. Conclusions: These longitudinal data are in line with previous reports from cross-sectional studies. The excitability changes induced by three-week intake of quetiapine in acute psychotic patients confirm the notion that neuroleptic treatment is associated with an increase in CSP. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the relationship between initiation of atypical antipsychotic agents and the risk of hyperglycemic emergencies. Method: We conducted a multicentre retrospective cohort study using administrative health data from 7 Canadian provinces and the UK Clinical Practice Research Datalink. Hospitalizations for hyperglycemic emergencies (hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state) were compared between new users of risperidone (reference), and new users of olanzapine, other atypical antipsychotics, and typical antipsychotics. We used propensity scores with inverse probability of treatment weighting and proportional hazard models to estimate the site-specific hazard ratios of hyperglycemic emergencies in the year following drug initiation separately for adults under and over age 66years. Site-level results were pooled using meta-analytic methods. Results: Among 725,489 patients, 55% were aged 66+years; 5% of younger and 19% of older patients had pre-existing diabetes. Hyperglycemic emergencies were rare (1–2 per 1000personyears), but more frequent in patients with pre-existing diabetes (6–12 per 1000personyears). We did not find a significant difference in risk of hyperglycemic emergencies with initiation of olanzapine versus risperidone; however heterogeneity existed between sites. The risk of an event was significantly lower with other atypical (99% quetiapine) compared to risperidone use in older patients [adjusted hazard ratio, 95% confidence interval (CI): 0.69, 0.53–0.90]. Conclusions: Risk for hyperglycemic emergencies is low after initiation of antipsychotics, but patients with pre-existing diabetes may be at greater risk. The risk appeared lower with the use of quetiapine in older patients, but the clinical significance of the findings requires further study. [Copyright &y& Elsevier]

Abstract: Objective: Relapse is common among patients with psychotic disorders. Identification of relapse predictors is important for decision regarding maintenance medication. Naturalistic studies often identify medication non-adherence as a dominant predictor. There are relatively few studies for predictors where adherence is already known. It is this situation i.e., discontinuation of medication that predictors will be most useful. We identify predictors for relapse in situations of (i) discontinuation and (ii) continuation of maintenance medication. Method: Analysis of relapse predictors is based on a randomized controlled study (n =178) comparing relapse rates between patients who discontinued or continued medication for at least 1year following first-episode psychosis. Demographic, clinical and neurocognitive variables were assessed at baseline as predictors of relapse within 1year. Results: Risk of relapse was 79% in the discontinuation group and 41% in the maintenance group. Predictors in the discontinuation group were diagnosis of schizophrenia, poorer semantic fluency performance, and higher blink rate. Predictors in the continuation group were disinhibition soft signs and more general psychopathology symptoms. Conclusion: Different predictors of relapse were identified for first episode psychosis patients who discontinued and continued maintenance medication. Neurocognitive dysfunctions are important predictors for both groups. While signs of frontal dysfunction and dopamine hyperactivity predict relapse in the discontinuation group, sign of cognitive disinhibition predicts relapse in the continuation group. [Copyright &y& Elsevier]

Abstract: Atypical antipsychotic medications generally maintain or increase gray matter amount and functioning. First-episode psychosis patients have lower gray matter volume in the middle frontal gyrus, as well as worse performance on spatial working memory tasks compared to controls. This study investigated the effects of short-term four- and eight-week atypical treatment on middle frontal thickness and spatial working memory in first-episode psychosis patients. Nineteen drug-naïve first-episode psychosis patients treated with risperidone or quetiapine and 26 controls completed structural magnetic resonance imaging, a spatial working memory task, and clinical assessment at three intervals (baseline, four weeks, and eight weeks; all patients and 23 controls completed all three assessments). Caudal and rostral middle frontal thicknesses were measured using the automated program Freesurfer. Positive, negative, and general symptoms of the Positive and Negative Syndrome Scale (PANSS) decreased significantly in patients, with most of the change occurring in the first four weeks of treatment. Patients demonstrated an increase in rostral middle frontal thickness over eight weeks of treatment compared to controls. There was a medium effect size relationship between reduction in negative symptoms at four and eight weeks, and a change in rostral middle frontal thickness over eight weeks. No changes were found in spatial working memory ability. Short-term atypical treatment with risperidone or quetiapine can increase prefrontal cortical thickness in psychosis. These findings are notable given the role of the rostral middle frontal region in cognition and the relationship between better cognitive functioning and better functional outcome in psychosis. [Copyright &y& Elsevier]

Pharmacogenetic (PGx) predictors of response would improve outcomes in antipsychotic treatment. Based on both biological rationale and prior evidence of an impact on Parkinson's disease, we conducted an association study for 106 SNPs in the synaptic vesicle protein 2C (SV2C) gene using genetic and treatment response data from the Clinical Trial of Antipsychotic Intervention Effectiveness (CATIE). We examined response to the atypical antipsychotics for Caucasian subjects in the blinded phases, Phases 1A, 1B, and 2, of CATIE with sample sizes as follows: olanzapine (N=134), quetiapine (N=124), risperidone (N=134), and ziprasidone (N=74). Response was defined as change in the Positive and Negative Syndrome Scale (PANSS) score using a mixed model repeat measures approach. Subjects homozygous for the T allele of rs11960832 displayed significantly worse response to olanzapine treatment, the only finding with study-wide significance (p=2.94×10−5; false discovery rate=2.18×10−2). These subjects also displayed worse response to quetiapine with nominal significance (p=4.56×10−2). While no other SNP achieved study-wide significance, one SNP (rs10214163) influencing Parkinson's disease displayed nominally significant association with olanzapine and quetiapine response, while the second such SNP (rs30196) showed a statistical trend toward correlating with olanzapine and quetiapine response. Furthermore, both coding SNPs examined (rs31244 and rs2270927) displayed nominally significant correlations with treatment response: one for olanzapine (rs227092), and one for quetiapine (rs31244). The fact that multiple SNPs in SV2C may impact response to atypical antipsychotics suggests that further evaluation of SNPs in this gene as PGx predictors of antipsychotic response is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Background: Differences among antipsychotics in terms of effectiveness have turned out to be a topic of increasing research interest, although comparisons between the different second generation antipsychotics (SGAs) are scarce. We aimed to compare the clinical effectiveness in the short-term of Aripiprazole, Ziprasidone and Quetiapine in the treatment of first-episode schizophrenia-spectrum disorders. Method: From October 2005 to January 2011, a prospective, randomized, open-label study was undertaken. 202 first-episode drug-naïve patients were randomly assigned to Aripiprazole (N=78), Ziprasidone (N=62), or Quetiapine (N=62) and followed-up for 3months. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on intention-to-treat populations was conducted in the analysis for clinical efficacy. Results: The overall dropout rate at 3months was small (13.86%). The treatment discontinuation rate differed significantly between treatment groups (Aripiprazole=23.1%, Ziprasidone=37.1% and Quetiapine=61.3%) (χ2 =21.334; p<0.001). Insufficient efficacy in the group of Quetiapine is the main reason for discontinuation rate differences (χ2 =20.223; p<0.001). The mean time to all-cause discontinuation was significantly different between groups (LogRank=23.467 p<0.001). Aripiprazole and Quetiapine were associated with a greater depressive symptoms improvement (p=0.043). The profile of side-effects varies between treatments. Patients on Quetiapine were less likely to be prescribed hypnotics. Conclusions: Patients treated with Quetiapine had a higher risk of treatment discontinuation in the short-term after a first episode due to insufficient efficacy. Establishing differences between SGAs may help clinicians in prescribing decisions for the treatment of individuals presenting with first-episode schizophrenia. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the relapse prevention efficacy of lurasidone compared with quetiapine XR (QXR) in adults patients with schizophrenia. Method: This double-blind study evaluated the relapse prevention efficacy of 12months of flexible-dose treatment with lurasidone (40–160mg/day) compared with QXR (200–800mg/day), in outpatients with an acute exacerbation of chronic schizophrenia who had recently completed a 6-week placebo-controlled trial of treatment with either lurasidone or QXR. The primary endpoint, time-to-relapse, was analyzed using a Cox proportional hazards model in this noninferiority trial. Results: The Kaplan–Meier estimate of the probability of relapse over 12months was 23.7% for subjects receiving lurasidone vs. 33.6% for QXR. The hazard ratio [95% CI] for probability of relapse was 0.728 [0.410, 1.295] (log-rank p=0.280). Since the upper limit of the hazard ratio (1.295) was smaller than the prespecified noninferiority margin (1.93), noninferiority of lurasidone compared with QXR was demonstrated in this study. The probability of hospitalization at 12months was lower for the lurasidone group compared with the QXR group (9.8% vs. 23.1%; log-rank p=0.049). A significantly higher proportion of lurasidone subjects achieved remission at study endpoint compared with the QXR group (61.9% vs. 46.3%; p=0.043). Discontinuation rates due to AEs were similar for lurasidone and QXR (7% vs. 5%). Treatment with lurasidone was not associated with clinically significant changes in weight or metabolic parameters. Conclusions: Twelve months of treatment with lurasidone met noninferiority criteria, and was associated with higher rates of remission, and reduced risk of hospitalization compared with QXR. No clinically significant effects on weight or metabolic parameters were observed during maintenance treatment with lurasidone. [Copyright &y& Elsevier]

Abstract: Purpose: This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of “hard” coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus. Method: Changes in FRS and metabolic syndrome status were compared between patients with BMI≥27 and non-HDL-C≥130mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise. Results: The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p=0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p=0.0885). Conclusion: Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations. [Copyright &y& Elsevier]

Abstract: Although second-generation antipsychotics (SGAs) are characterized by fewer prolactin (PRL)-related side effects compared with first-generation antipsychotics, the detailed effects of SGAs on the plasma PRL levels still remain unclear. We examined the differences in plasma PRL levels among 268 patients treated for schizophrenia with olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), quetiapine (QTP), or perospirone (PER). The participants had received antipsychotic monotherapy with stable doses of OLZ, RIS, ARP, QTP, or PER for ≥3weeks, and fasting blood samples were drawn to examine plasma PRL levels. The differences in median plasma PRL levels in all (P<0.001), male (P<0.001) and female patients (P<0.001) among the five SGA groups were statistically significant. A stepwise multiple regression analysis showed that ARP treatment was found to contribute to lower plasma PRL level, while female sex, RIS, OLZ and chlorpromazine equivalent dose were found to contribute to a higher plasma PRL level. The median value of plasma PRL level in the RIS group was twice as much compared with that in the OLZ group, although this was not statistically significant. In this study, OLZ had a considerable effect on plasma PRL level, similar to RIS, while PER did not affect plasma PRL levels, similar to QTP. Further studies are needed to clarify the differences in plasma PRL levels among SGAs. [Copyright &y& Elsevier]

Abstract: Background: Second-generation antipsychotics (SGAs) increase the risk of type 2 diabetes. The mechanism is thought to center on drug-induced weight gain, which starts the dysmetabolic cascade of insulin resistance, increased insulin production and pancreatic beta-cell failure. An independent effect of SGAs on insulin secretion has been suggested in animal models, but has not been demonstrated in clinical samples. Objective: To determine the post-challenge insulin secretion in patients treated with SGAs. Method: We identified 520 non-diabetic individuals treated with clozapine (N=73), olanzapine (N=190), quetiapine (N=91) or risperidone (N=166) in a consecutive, single-site cohort of 783 adult psychiatric inpatients who underwent a comprehensive metabolic assessment. Insulin secretion was measured as the area under the curve (AUCinsulin) generated by levels recorded at baseline, 30, 60 and 120min after the intake of 75g of glucose. The independent predictors of insulin secretion were determined with regression analysis in the entire sample and separately in patients with normal glucose tolerance (NGT) and prediabetes. Results: The post-challenge AUCinsulin was independently predicted by AUCglucose, waist circumference, triglyceride levels and younger age (p<0.0001); non-smoking status (p=0.0012); and treatment with clozapine (p=0.021). The model explained 33.5% of the variance in insulin secretion (p<0.0001). The clozapine effect was present in the NGT group, but not in prediabetics. Conclusions: Clozapine, but not olanzapine, quetiapine and risperidone, is an independent predictor of post-challenge insulin secretion in non-diabetics, particularly in those with normal glucose tolerance. The findings suggest that the diabetogenic risk of clozapine may persist even after weight reduction. [Copyright &y& Elsevier]

Abstract: Myelin and oligodendrocyte dysfunctions have been consistently found in patients with schizophrenia. The effect of antipsychotics on myelin disturbances is unknown. The present study examined the effects of quetiapine on oligodendrocyte regeneration and myelin repair in a demyelination animal model. C57BL/6 mice were fed with cuprizone (0.2% w/w) for 12weeks to induce chronic demyelination and oligodendrocyte degeneration, after which cuprizone was withdrawn to allow recovery. Quetiapine (10mg/kg/day) or vehicle (water) was administrated orally to mice for 0, 2, 3, or 4weeks after cuprizone withdrawal. Locomotor activity and Y-maze tests were used to evaluate behavioral changes in the mice. Immunohistochemical staining was used to detect morphological and biological changes in the brains. Cuprizone administration for 12weeks resulted in severe demyelination, locomotor hyperactivity, and working memory impairment in mice. Remyelination occurred when cuprizone was withdrawn. Quetiapine treatment during the recovery period significantly improved the spatial working memory and increased myelin restoration. Quetiapine treatment also enhanced the repopulation of mature oligodendrocytes in the demyelinated lesions, which was associated with down-regulation of transcription factor olig2 in the process of cell maturation. The results of this study demonstrated that quetiapine treatment during the recovery period improves spatial working memory and promotes oligodendrocyte development and remyelination. This study supports the role of oligodendrocyte dysfunction in memory deficits in a schizophrenia mouse model and suggests that quetiapine may target oligodendrocytes and improve cognitive function. [Copyright &y& Elsevier]

Abstract: Patients with schizophrenia who have predominant negative symptoms are often considered less responsive to treatment. This analysis of patients with schizophrenia or schizoaffective disorder compares changes in symptom severity between those with predominant versus merely prominent negative symptoms. Prominent negative symptoms were defined by a baseline score of ≥4 on at least 3, or ≥5 on at least 2, of the 7 Positive and Negative Syndrome Scale (PANSS) negative subscale items. Predominant negative symptoms were defined by the foregoing plus a PANSS positive score of <19, a Barnes Akathisia score of <2, a Simpson–Angus score of <4, and a Calgary Depressive Scale score of <9. Adult patients with schizophrenia (n=227) or schizoaffective disorder (n=116) received either olanzapine (10–20mg/day, n=169) or quetiapine (300–700mg/day, n=174) for up to 24weeks. Data for both medications were pooled. Of the 343 patients enrolled in the study, 34.7% met the criteria for predominant negative symptoms, the remaining 65.3% being characterized only by their prominent negative symptoms. Changes in the severity of negative symptoms in both patient types largely followed similar trajectories during treatment, as reflected both in Marder PANSS negative subscale scores and in the Scale for Assessment of Negative Symptoms total and domain scores. Patients with either predominant or prominent negative symptoms therefore appear to respond similarly to atypical antipsychotic treatment. This distinction, incorporating an evaluation of the presence of positive, affective, and extrapyramidal symptoms, may therefore not have prognostic implications for the responsiveness of patients'' negative symptoms to treatment. [Copyright &y& Elsevier]

Abstract: Acetyl-coenzyme A carboxylase α (ACACA) single-nucleotide polymorphism (SNP) (rs2229416) was significantly associated with hypertriglyceridemia, during exploration of antipsychotic direct effects on lipids. Neuropeptide Y (NPY) gene (rs1468271) and ACACB gene (rs2241220) SNPs were significantly associated with severe hypercholesterolemia. In the same sample (173 patients on olanzapine, quetiapine, chlorpromazine or mirtazapine [increasing the risk of hyperlipidemia] and 184 controls taking other antipsychotics), three (rs1266175, rs12453407 and rs9906543) of eight additional ACACA SNPs were significantly associated with hypertriglyceridemia in those taking drugs of interest, but not in controls. Five other ACACA SNPs, three additional NPY SNPs, and seven additional ACACB SNPs were not significant. [Copyright &y& Elsevier]

Abstract: Objective: Second generation antipsychotic drug (SGA) treatment is associated with detrimental effects on glucose metabolism which is often attributed to the development of obesity and insulin resistance. However, we have recently demonstrated that clozapine and quetiapine also have direct effects of glucose metabolism in animals. This study compares clozapine and quetiapine and investigates the effects of these on the development of obesity and the direct effects of these drugs on glucose metabolism compared with those caused by the obesity per se. Research design and methods: Three groups of male Sprague–Dawley rats were fed a high fat/high sugar diet to induce obesity while another three groups were fed a chow diet. One group on each diet was injected daily with vehicle, clozapine or quetiapine and effects on glucose metabolism were monitored. Results: Clozapine and quetiapine treatment did not directly cause obesity or potentiate diet induced obesity but did induce a preference for the high fat/high sugar diet. Neither drug caused a impairment in insulin tolerance over that caused by obesity but both drugs acutely induced impairments in glucose tolerance that were additive with the effects induced by the diet induced obesity. Both drugs caused increases in glucagon levels and a suppression of GLP-1. We investigated two strategies for restoring GLP-1 signalling. The DPP-IV inhibitor sitagliptin only partially restored GLP-1 levels and did not overcome the deleterious effects on glucose tolerance whereas the GLP-1 receptor agonist exendin-4 normalised both glucagon levels and glucose metabolism. Conclusions: Our findings indicate that the clozapine and quetiapine induced impairments in glucose tolerance in rats are independent of insulin resistance caused by obesity and that these defects are linked with a suppression of GLP-1 levels. These studies suggest the need to perform follow up studies in humans to determine whether clozapine and quetiapine induce acute derangements in glucose metabolism and whether GLP-1 replacement therapy might be the most appropriate therapeutic strategy for treating derangements in glucose metabolism in subjects taking these drugs. [Copyright &y& Elsevier]

Abstract: Purpose: Although olanzapine may have advantages over other second-generation antipsychotics (SGAs) regarding longer time to treatment discontinuation among chronically ill patients, little evidence has been provided for the comparative effectiveness of SGAs in the acute phase. We aimed to determine if any of four SGAs were more effective in treating newly admitted acute schizophrenic patients. We performed a rater-blinded, randomized controlled trial of four SGAs in 15 psychiatric emergency sites. Eligible patients were 18–64 years old and met diagnostic criteria for schizophrenia, acute schizophrenia-like psychotic disorder, or schizoaffective disorder. A final total of 78 patients were randomly assigned by means of sealed envelopes to receive risperidone (3–12 mg/day; n =20), olanzapine (10–20 mg/day; n =17), quetiapine (300–750 mg/day; n =20), or aripiprazole (12–30 mg/day; n =21), with follow-up at 8 weeks. The primary outcome measure was all-cause treatment discontinuation. Results: Overall, 37% (29/78) of patients discontinued the study medication before 8 weeks: 25% for risperidone; 12% for olanzapine; 55% for quetiapine; and 52% for aripiprazole. Time to treatment discontinuation for any cause was significantly longer in the olanzapine group than in the quetiapine (p =0.006) or aripiprazole (p =0.008) groups, but not compared to the risperidone group (p =0.32). Time to treatment discontinuation was significantly longer in the risperidone group than in the quetiapine group (p =0.048), but not compared to the aripiprazole group (p =0.062). However, the rate of p.r.n. intramuscular haloperidol use was significantly higher in the aripiprazole group than in other groups (p =0.029). Conclusion: Olanzapine and risperidone are superior to quetiapine and aripiprazole for the acute treatment of psychosis in hospitalized patients. [Copyright &y& Elsevier]

Abstract: Objective: To examine the effect of diagnosis, mood state, and anxiety on subjective wellbeing in patients with affective and non-affective psychotic disorders treated with quetiapine IR. Methods: 2175 patients with schizophrenia-spectrum (SZ, n =1681), schizoaffective (SA, n =249), and bipolar disorder (BPD, n =245) were treated with quetiapine over 6 months and assessed with the Clinical Global Impression-Severity of illness Scale (CGI-S) and the Subjective Wellbeing under Neuroleptic Treatment Scale (SWN-K). Diagnostic group differences and effects of mood state and anxiety on subjective wellbeing were analyzed using multi-factorial linear regression analysis and mixed models repeated measures. Results: At baseline, despite similar CGI-S scores, significant SWN-K score differences between SZ (57.7 points), SA (64.1 points), and BPD (79.5 points) were detected. At baseline, depression (p <0.001) and anxiety (p <0.001) were independently associated with a worse and mania (p <0.001) with a better subjective wellbeing. Subjective wellbeing improved significantly in all groups (p <0.001; 27.6 points), and endpoint subjective wellbeing was not predicted by baseline depression or anxiety, but by endpoint depression and anxiety. Conclusion: Interventions to improve subjective wellbeing should take into account the course of mood state and anxiety. Assessment of subjective wellbeing and subjective quality of life in acute mania may need adapted tools. [Copyright &y& Elsevier]

Abstract: Background: Antipsychotic dosing used in clinical practice can differ from dosing originally recommended in product labeling. This has been reported for olanzapine and quetiapine, where higher doses are commonly used. This may be the case for ziprasidone as well. Method: To characterize changes over time in dosing for the initial and subsequent prescriptions of first-line second-generation antipsychotics used during treatment episodes for outpatients with schizophrenia and bipolar disorder, the 2001–2005 Thomson MarketScan Medicaid Database (Medicaid) and the 2001–2006 MarketScan Commercial Claims and Encounters Database (Commercial) were analyzed. Dose trends were evaluated using autoregressive time-series models. Results: Data were available for 49180 treatment episodes of schizophrenia (4683 Commercial and 44497 Medicaid) and 83289 treatment episodes of bipolar disorder (57961 Commercial and 25328 Medicaid). The initial prescription mean daily and overall mean daily doses of ziprasidone in schizophrenia episodes significantly increased across the Medicaid and Commercial populations, with similar trends observed for bipolar episodes. The first (May 2001) and last (December 2005) observed 3-month mean daily doses for ziprasidone were 112 mg/d and 138 mg/d for patients with schizophrenia and 93 mg/d and 113 mg/d for those with bipolar disorder in the Medicaid cohort, with similar findings for the Commercial cohort. Consistently significant trends in dose changes were not observed for the other medications, although quetiapine and olanzapine doses generally increased while aripiprazole and risperidone doses generally decreased. Conclusions: There remains a need for controlled randomized clinical trials that test fixed doses of antipsychotics to ascertain the dose–response relationship within the dose range used in contemporary clinical practice. [Copyright &y& Elsevier]

Abstract: Recent human studies employing new magnetic resonance imaging techniques and micro-array analyses feature schizophrenia as a brain disease with alterations in white matter (WM), which is mainly composed of oligodendrocytes (OLs) and their processes wrapping around neuronal axons. To examine the putative role of OLs in the pathophysiology and treatment of schizophrenia, animal studies are essential. In the present study, C57BL/6 mice were given 0.2% cuprizone (CPZ) in their diet for five weeks during which they drank distilled water without or with quetiapine (QTP, 10 mg/kg). The mice fed with normal chow were used as controls. CPZ is a copper chelator and has been reported to induce consistent demyelination in the brain of C57BL/6 mouse by specifically damaging OLs. QTP is an atypical antipsychotic widely used in the treatment of schizophrenia and other psychotic disorders. In accordance with previous studies, CPZ-exposed mice showed pervasive myelin breakdown and demyelination. The amount of myelin basic protein (MBP) in the cerebral cortex was decreased by CPZ-exposure as shown in Western-blot analysis. In addition, the demyelinated sites were teemed with activated microglia and astrocytes but a few myelin forming OLs. Moreover, the activity of copper-zinc superoxide dismutase decreased in the cerebral cortex of CPZ-exposed mice. However, all of these pathological changes in WM were either prevented or alleviated in CPZ-exposed mice co-administered with QTP. These results suggest that the CPZ-exposed C57BL/6 mouse is a potential animal model to study possible roles of OLs in the pathogenesis and treatment of schizophrenia. [Copyright &y& Elsevier]

Abstract: This was a randomized, flexible-dose, rater-blind, parallel-group, quasi-naturalistic trial comparing the efficacy, safety, and tolerability of quetiapine, risperidone, and olanzapine in patients with schizophrenia hospitalized for severe psychotic symptoms. Seventy-five patients were randomized to quetiapine (n =25), risperidone (n =25), or olanzapine (n =25). Mean doses at Week 8 were: 590.0 mg/day quetiapine; 5.1 mg/day risperidone; 15.1 mg/day olanzapine. Four quetiapine, five risperidone, and five olanzapine patients discontinued prior to Week 8. There were no significant differences between groups in the primary efficacy measures of improvement from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 8 in the per protocol (PP) population and the number of completers who experienced ≥ 40% improvement on the same scale. PP and intent-to-treat analyses showed significant improvement from baseline in each component of a PANSS-derived battery, without significant differences between treatments. No quetiapine patients, one risperidone, and four olanzapine patients reported an adverse event (AE) of moderate intensity; no severe AEs were reported. A linear mixed model for repeated measures showed an effect of treatment on body weight, with significant differences favoring quetiapine over risperidone and olanzapine. Simpson–Angus Scale scores were significantly worse with risperidone compared with both olanzapine and quetiapine at Week 3 and compared with quetiapine thereafter. Use of concomitant medications for anxiety or tension was significantly less frequent with quetiapine. In conclusion, quetiapine, risperidone, and olanzapine have similar efficacy in schizophrenia, but there are drug-specific differences for some AEs and in the use of concomitant medication that differentiate these agents. [Copyright &y& Elsevier]

Abstract: The goal of this study was to select some genes that may serve as good candidates for future studies of the direct effects (not explained by obesity) of some antipsychotics on hyperlipidemia. A search for single-nucleotide polymorphisms (SNPs) that may be associated with these direct effects was conducted. From a published cross-sectional sample, 357 patients on antipsychotics were genotyped using a DNA microarray with 384 SNPs. A total of 165 patients were taking olanzapine, quetiapine or chlorpromazine which may directly cause hypertriglyceridemia or hypercholesterolemia. Another 192 patients taking other antipsychotics were controls. A two-stage statistical analysis that included loglinear and logistic models was developed to select SNPs blindly. In a third stage, physiological knowledge was used to select promising SNPs. Known physiological mechanisms were supported for 3 associations found in patients taking olanzapine, quetiapine or chlorpromazine [acetyl-coenzyme A carboxylase α SNP (rs4072032) in the hypertriglyceridemia model, and for the neuropeptide Y (rs1468271) and ACCβ, (rs2241220) in the hypercholesterolemia model]. These genes may be promising candidates for studies of the direct effects of some antipsychotics on hyperlipidemia. [Copyright &y& Elsevier]

Background: Cognitive deficits are recognized as a critical determinant of functional outcomes in schizophrenia; and second generation antipsychotic drugs have been touted for their potential to enhance cognitive functioning and community tenure.Objectives: The study examined the relative merits of olanzapine and quetiapine in improving cognitive deficits and enhancing psychosocial functioning in a sample of community dwelling adults previously treated with first generation antipsychotic drugs for schizophrenia.Methods: In a prospective, rater-blinded study, 86 participants were randomized to receive either olanzapine or quetiapine, and assessed at baseline and after 3, 6, 9 and 12 months. Outcome measures included, besides symptoms and side effects rating scales, the subjective scale to investigate cognition in schizophrenia (SSTICS), a computer-assisted cognitive test battery (COGLAB), the sickness impact profile (SIP), the global assessment of functioning (GAF) scale, and the drug attitude inventory (DAI).Results: Both olanzapine and quetiapine were equally effective in improving symptom severity and decreasing the neurological side effects. Quetiapine was significantly better tolerated (p=0.002), improved self-rated cognitive dysfunction (p=0.002) and subjects' performance on selected neurocognitive tasks (p=0.01). Olanzapine use was associated with greater symptom stability, fewer drop outs (p=0.01) and frequent metabolic aberrations (p=0.001). The accrued benefits of drug therapy, however, were not reflected as significant gains in daily functioning and quality of life.Conclusions: Quetiapine is noted to have specific cognition enhancing properties in schizophrenia that warrants further exploration. The observed clinical and cognitive benefits associated with quetiapine may likely be attributable to its loose binding to, and fast dissociation from the dopamine receptors. Olanzapine has proved to be a reliable antipsychotic drug with a greater liability to cause metabolic abnormalities. [ABSTRACT FROM AUTHOR]

Abstract: Following a prior Kentucky clinical practice study on metabolic syndrome, serum glucose and lipid levels were used in a new sample to determine whether after correcting for confounding factors, olanzapine hyperlipidemia risk may be higher under naturalistic non-randomized treatment. Serum glucose, total cholesterol, HDL cholesterol and triglyceride levels were assessed in 360 patients with severe mental illnesses. The initial goal was to focus on olanzapine lipid profiles, but visual data inspection indicated that quetiapine needed attention as well. Patients were divided into 3 groups: 57 (16%) on olanzapine, 105 (29%) on quetiapine, and 198 (55%) on other antipsychotics (risperidone, ziprasidone, aripiprazole or typicals). HDL and glucose levels were not significantly different across the three antipsychotic groups. When compared with other antipsychotics, olanzapine patients had a borderline significantly higher mean total serum cholesterol level (178 vs. 192 mg/dl, p =0.06) and mean triglyceride level (172 vs. 202 mg/dl, p =0.06). These differences became significant (p =0.006 and 0.03) after correcting for confounders. Quetiapine appeared overprescribed in patients with metabolic syndrome complications. When compared with other antipsychotics, quetiapine patients had a significantly higher mean total serum cholesterol level (178 vs. 194 mg/dl, p =0.004) and mean triglyceride level (172 vs. 225 mg/dl, p <0.001). These differences were significant (p =0.02 and <0.001) after correcting for confounders. This study is consistent with emerging literature that suggests that some antipsychotics may have direct and immediate effects on lipid levels beyond obesity effects. The effect sizes of olanzapine and quetiapine on hyperlipidemia were about 0.40 in this naturalistic study. [Copyright &y& Elsevier]

Abstract: Objective: This study compared the effects of atypical antipsychotics (risperidone or quetiapine) with placebo and with each other in recently exacerbated patients with schizophrenia requiring hospitalization. Methods: This international, randomized, double-blind study included a 2-week monotherapy phase followed by a 4-week additive therapy phase. Recently exacerbated patients with schizophrenia or schizoaffective disorder (DSM-IV) were randomized (2:2:1) to risperidone (n =153), quetiapine (n =156), or placebo (n =73). Target doses were 4 or 6 mg/day of risperidone and 400 or 600 mg/day of quetiapine by day 5, with the ability to increase to 600 or 800 mg/day of quetiapine on day 8. The main outcome measures were the total Positive and Negative Syndrome Scale (PANSS) and need for additional psychotropic medications. Results: Monotherapy Phase: The combined atypical antipsychotic group (n =308) reached borderline superiority to placebo (n =71) at the 2-week endpoint on mean change in total PANSS score (−24.1±1.2 and −20.2±2.0, respectively; p =0.067). The change in the atypical group was driven by the improvement with risperidone (−27.7±1.5 vs. −20.2±2.0 with placebo, p <0.01; and vs. −20.5±1.5 with quetiapine, p <0.01); the improvement with quetiapine was similar to placebo, p =0.879. Results were similar on other efficacy endpoints. Additive Therapy Phase: Additional psychotropics were prescribed to fewer (p <0.01) risperidone (36%) than quetiapine (53%) or placebo patients (59%). The overall discontinuation rate was 18%, 26%, and 38%, respectively. Risperidone, compared with placebo, was associated with more parkinsonism, akathisia, plasma prolactin changes, and weight gain; while quetiapine was associated with more somnolence, sedation, dizziness, constipation, tachycardia, thyroid dysregulation, and weight gain. Conclusion: While the combined atypical antipsychotic group did not experience greater improvements than the placebo group, risperidone, but not quetiapine, was significantly superior in all measured domains to placebo in the management of recently exacerbated hospitalized patients with schizophrenia or schizoaffective disorder, with no unexpected tolerability findings. [Copyright &y& Elsevier]

Background: The first episode of a psychotic disorder provides a unique opportunity to initiate optimal treatment but when a new medication becomes available, little data exist to guide the appropriate use in this population.Objectives: The objectives were to determine the optimal doses and titration of quetiapine for this group and to measure outcomes (including symptom response, social functioning, mood alterations, motor symptoms, metabolic parameters and cognitive functioning) over 2 years of treatment with quetiapine.Design: Thirty nine subjects with a first episode of psychosis referred to the Nova Scotia Early Psychosis Program in Halifax, Canada, were invited to participate in this study. Standardized clinical, laboratory, and neuropsychological assessments were performed at baseline and following treatment with quetiapine at intervals out to 2 years.Results: Quetiapine was effective in treating the psychotic and mood symptoms while not causing extra-pyramidal signs or symptoms (EPSS). Pre-existing motor dysfunction improved. No anticholinergic medications were required. Several domains of cognitive function also improved (sustained attention, the number of perseverative errors, visuomotor speed and sequencing, verbal fluency and verbal memory). Weight gain was observed along with increases in cholesterol levels but there was no glucose dysregulation.Conclusions: The results of this two year, naturalistic study of people with a first episode of psychosis indicated that quetiapine was well tolerated and effective for this population. Significant improvements in cognitive functioning also provided evidence for potential longer-term benefits of early and optimal treatment with this agent. However, monitoring metabolic parameters, as recommended for other atypicals, is likely prudent. [ABSTRACT FROM AUTHOR]

Understanding the effects of antipsychotic drugs (APDs) on social behaviors such as maternal behavior is valuable for understanding the complete spectrum of therapeutic and side-effects of antipsychotics. Although previous studies have suggested that typical antipsychotics impair maternal behavior, the effects of the atypical antipsychotics have not been systematically explored. The purpose of the present report was to examine the effects of typical (haloperidol, HAL) and several atypical (clozapine, CLZ; risperidone, RIS; quetiapine, QUE) antipsychotics on maternal behavior in female rats. Maternal behaviors were examined repeatedly over a period of 24 h after a single injection of a range of doses of HAL, CLZ, RIS or QUE on Day 6 postpartum. All antipsychotic drugs, typical or atypical, elicited a qualitatively similar disruptive effect on the active components of maternal behavior such as pup approach, pup retrieval and nest building at clinically relevant doses. However, HAL caused a prolonged disruption, whereas CLZ, RIS and QUE induced an early onset but shorter duration disruption. In addition, only the atypical antipsychotics showed some inhibitory effects on nursing behavior, possibly due to sedative side-effects shared by all atypical antipsychotics. The current generation of atypical antipsychotics shows a disruptive influence on maternal behavior similar to that of the typical antipsychotics. This effect may be intrinsic to antipsychotic activity or may be reflective of a side-effect. Since the latter is more likely, this may be an effect to avoid in the design of future antipsychotics. [ABSTRACT FROM AUTHOR]

This open-label study investigated the strategy of switching patients who had gained excessive weight on olanzapine to quetiapine, with assessments of safety and continued efficacy as well as weight change. Patients who were psychiatrically stable on olanzapine but had gained >20% in weight and had body mass index >25 mg/kg2 were switched to quetiapine over a 4-week period and followed for 6 weeks, the total study duration being 10 weeks. Assessments included weight change, antipsychotic efficacy using the Positive and Negative Symptom Syndrome Scale (PANSS), extrapyramidal adverse events using the Simpson–Angus Scale (SAS), and laboratory studies for metabolic measures. Of 16 enrolled patients, 12 completed the study. Mean weight loss was 2.25 kg (Cohen''s d=0.12; P=0.03). There were no significant changes in PANSS total scores, SAS scores, or metabolic parameters. Switching patients to quetiapine, appears to be a viable strategy for managing olanzapine-induced weight gain as indicated by this 10-week open-label study. Prospective controlled trials of longer duration and larger number of subjects are needed. [Copyright &y& Elsevier]

This short-term, single-blind, pilot trial was initiated to investigate the usefulness of quetiapine therapy in the treatment of schizophrenic patients refractory to first-generation antipsychotics. Following a neuroleptic-free period prior to study entry (at least 1 week for oral formulations and 6 weeks for depot formulations), quetiapine was started at 50 mg/day and titrated up to 500 mg/day by Day 6. This 500 mg daily dose was then maintained or increased up to a maximum of 750 mg/day, at the discretion of the treating physician, who was aware of the antipsychotic prescribed. Efficacy measures were represented by changes in total and component PANSS score from baseline to different intervals. Safety and tolerability were evaluated by monitoring the spontaneously referred moderate-to-severe adverse events, changes from baseline in SAS, BARS, and AIMS scores, supplementary use of flurazepam, lorazepam, and benztropine, clinically relevant physical changes, abnormalities in vital signs, blood chemistry, and hematology, and modifications in QTc interval and body weight. Rating scale assessments, categorization of adverse events, determination of physical examination, vital signs, and body weight were performed by a qualified physician blind to the particular antipsychotic under investigation and the aims of the study. All 12 patients completed the 4-week quetiapine treatment course. Mean total PANSS scores were significantly reduced between baseline and study endpoint (p=0.006). Five out of six PANSS subcomponent scores also showed significant decreases (p<0.05). Six patients showed a reduction of ≥20% in PANSS total score by the final day of quetiapine treatment, so were classified as responders. There were responders in all schizophrenia diagnostic subgroups (undifferentiated, paranoid, and disorganized). Two patients reported moderate adverse events. One patient received 3 days of benztropine therapy for EPS and five received flurazepam for insomnia. Weight change was minimal and mean SAS, BARS, and AIMS scores all showed nonsignificant decreases between baseline and endpoint. The 50% quetiapine response rate reported here in refractory patients is comparable with those previously reported for other atypical antipsychotics in populations of both refractory and intolerant patients. [Copyright &y& Elsevier]

With the notable exception of clozapine, there is at present insufficient information on the efficacy of atypical antipsychotic medications in patients with poorly responsive schizophrenia. The present study reports on the efficacy and tolerability of quetiapine and haloperidol in patients with schizophrenia who showed no response to treatment with fluphenazine. This study is a post hoc subanalysis of an 8-week, double-blind study of patients receiving quetiapine 600 mg/day or haloperidol 20 mg/day. The proportion of patients classified as “Clinical Global Impression responders” (defined as Clinical Global Impression Severity of Illness score of ≤3 at study end) was greater in the quetiapine group compared with the haloperidol group (51% vs. 25%; P=0.023). Overall, quetiapine was well tolerated with less extrapyramidal side-effects and reduction in prolactin when compared to haloperidol. Weight gain was modest but more apparent in quetiapine-treated patients. Quetiapine is an appropriate treatment choice in patients who do not respond to prior antipsychotic treatment. [Copyright &y& Elsevier]

Objectives: The aim of this cross-sectional study, the EIRE study, was to assess the frequency of several side effects with antipsychotics in the clinical setting. This paper addresses the adverse effect of weight gain. Method: Outpatients diagnosed of schizophrenia according to DSM-IV criteria and receiving a single antipsychotic (risperidone, olanzapine, quetiapine or haloperidol) for at least 4 weeks were consecutively recruited. Data were collected in a single visit, including data on demographic, clinical and treatment characteristics. Mean weight change was evaluated retrospectively by means of clinical charts and the weight at the time of the visit; in addition, the corresponding item of a modified version of the UKU, a Scandinavian side-effect rating scale, was used. Chi-squared test and logistic regression methods were used to analyze frequency of weight gain between treatments. Results: Out of 669 recruited, 636 evaluable patients were assessed. The treatment with the highest number of patients with weight gain as an adverse reaction on the UKU scale was olanzapine (74.5%), followed by risperidone (53.4%) and haloperidol (40.0%). The proportion of patients with clinically relevant weight gain (≥7% increase versus initial weight) was also higher with olanzapine (45.7%) than with risperidone (30.6%) and haloperidol (22.4%). Five patients (13.5%) treated with quetiapine had some degree of weight gain according to the UKU scale, although no patient showed a clinically relevant weight gain (≥7%). Treatment with olanzapine and risperidone were identified as risk factors of weight gain versus haloperidol. The risk of weight gain was higher in women (OR: 4.4), overweight patients (OR: 3.0) and in patients with ≤1 year of treatment (OR: 6.3) in the olanzapine group. A higher risk of weight gain in women (OR: 2.6) was also seen with risperidone. Conclusion: Clinically relevant weight gain is clearly associated with olanzapine, and to lesser extent, with haloperidol and risperidone. Data for quetiapine were not conclusive because of the short duration of treatment. [Copyright &y& Elsevier]