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Sulforaphane has been reported to possibly improve core symptoms associated with autism spectrum disorders from mostly small size studies. Here we present results of a larger randomized clinical trial (N = 108) in China. There were no significant changes in caregiver rated scales between sulforaphane and placebo groups. However, clinician rated scales showed a significant improvement in the sulforaphane group, and one third of participants showed at least a 30% decrease in score by 12 weeks treatment. The effects of sulforaphane were seen across the full range of intelligence and greater in participants over 10 years. Sulforaphane was safe and well-tolerated even for young children. The inconsistent results between caregiver and clinician rated scales suggest more clinical trials are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia. Study Design We conducted a systematic review and meta-analysis of randomized-controlled-trials (RCTs) comparing the second-generation long-acting injectable antipsychotics (SGA-LAIs) olanzapine, risperidone, paliperidone, and aripiprazole with placebo or their oral counterparts in acutely ill patients with schizophrenia. We analyzed 23 efficacy and tolerability outcomes, with the primary outcome being overall symptoms of schizophrenia. The results were obtained through random effects, pairwise meta-analyses, and subgroup tests. The study quality was assessed using the Cochrane-Risk-of-Bias-Tool version-1. Study Results Sixty-six studies with 16 457 participants were included in the analysis. Eleven studies compared second-generation long-acting injectable antipsychotics (SGA-LAIs) with a placebo, 54 compared second-generation oral antipsychotics (SGA-orals) with a placebo, and one compared an SGA-LAI (aripiprazole) with its oral formulation. All 4 SGA-LAIs reduced overall symptoms more than placebo, with mean standardized differences of −0.66 (95% CI: −0.90; −0.43) for olanzapine, −0.64 (−0.80; −0.48) for aripiprazole, −0.62 (−0.76; −0.48) for risperidone and −0.42 (−0.53; −0.31) for paliperidone. The side-effect profiles of the LAIs corresponded to the patterns known from the oral formulations. In subgroup tests compared to placebo, some side effects were less pronounced under LAIs than under their oral formulations. Conclusions SGA-LAIs effectively treat acute schizophrenia. Some side effects may be less frequent than under oral drugs, but due to the indirect nature of the comparisons, this finding must be confirmed by RCTs comparing LAIs and orals head-to-head. [ABSTRACT FROM AUTHOR]

Background and Hypothesis This analysis examined the relationship between cannabis use, compliance with antipsychotics and risk for relapse in patients in remission following a first episode of schizophrenia, schizophreniform, or schizoaffective disorder. Study Design Analyses were performed on data from a large European study on first episode of schizophrenia, schizophreniform, or schizoaffective disorder (OPTiMiSE). After 10 weeks of antipsychotic treatment, 282/446 patients (63%) met criteria for symptomatic remission; of whom 134/282 (47.5%) then completed a 1-year follow-up. Cross-lagged models and mediation models investigated the temporal relationships between cannabis use, compliance with antipsychotics, social functioning, and symptomatic worsening/relapse. Study Results Compared to nonusers, cannabis use increased risk for relapse, adjusted hazard ratio (HR) = 3.03 (SE  = 0.32), P  < .001, even in patients who were compliant with antipsychotic medication, adjusted HR  = 2.89, (SE  = 0.32), P  < .001. Cannabis use preceded symptomatic worsening and was followed by worsening of Positive and Negative Syndrome Scale total score at the 1-year end-point (standardized β  = 0.62, SE  = 0.19, P  = .001) and by worsening of social functioning (coef = −0.66, P ≤.001). Conclusions In patients in remission from their first episode of schizophrenia, schizophreniform, or schizoaffective disorder, cannabis use increases the rate of relapse in both compliant and noncompliant individuals. Importantly, the temporal relationship between cannabis and relapse was that cannabis use preceded later relapse, noncompliance, and decrease in social functioning, and not that patients began to relapse, then used cannabis. Further research with a precision psychiatry approach might identify those patients in particular danger of relapse when using cannabis. [ABSTRACT FROM AUTHOR]

The article discusses the challenges of implementing research evidence into clinical practice, particularly in the context of choosing antipsychotics for schizophrenia treatment. It highlights the difficulty for clinicians to keep up with the vast amount of scientific literature and the complex jargon used in scientific journals. To address this gap, the article introduces the Shared Decision-Making Assistant (SDMA), a digital tool that visualizes high-quality evidence on the efficacy and side effects of antipsychotics in a simple and interactive format. The SDMA allows physicians and patients to make informed decisions by considering individual preferences and sorting results based on specific outcomes. The article also mentions other similar tools and emphasizes the importance of digital tools in supporting evidence-based treatment and shared decision making. [Extracted from the article]

Background and Hypothesis Antipsychotic-induced weight gain is associated with alterations to the composition of the gut microbiota. The purpose of this study was to determine the effect of probiotics plus dietary fiber on antipsychotic-induced weight gain. Study Design Two sequential, randomized clinical trials were conducted. In Study 1, 90 drug-naïve, first-episode schizophrenia patients were randomized to receive either olanzapine plus probiotics or olanzapine monotherapy for 12 weeks. In Study 2, 60 drug-naïve, first-episode schizophrenia patients were randomly assigned to receive either olanzapine plus probiotics and dietary fiber or olanzapine monotherapy for 12 weeks. Study Results In Study 1, no significant differences in weight gain were observed between the two groups. The insulin resistance index (IRI) was lower in the olanzapine plus probiotics group compared with the olanzapine monotherapy group at week 12 (estimated mean difference, −0.65, [95% confidence interval (CI), −1.10 to −0.20]; p =.005). In Study 2, weight gain was lower in the probiotics plus dietary fiber group than in the olanzapine monotherapy group at week 12 (estimated mean difference −3.45 kg, [95% CI, −5.91 to −1.00]; p =.007). At week 12, IRI increased significantly in the olanzapine monotherapy group (mean, 1.74; standard deviation (SD) = 1.11, p <.001), but not in the olanzapine plus probiotics and dietary fiber group (mean 0.47, SD = 2.16, p =.35) with an estimated mean difference of −0.95 between the two groups [95% CI, −1.77 to −0.14]; p =.022). Conclusions These results provide support for the efficacy and safety of probiotics plus dietary fiber in attenuating antipsychotic-induced weight gain in drug-naïve, first-episode schizophrenia patients. [ABSTRACT FROM AUTHOR]

Background Weight gain is among the most important side-effects of antipsychotics. It is, however, unclear whether it is associated with antipsychotic doses. We aimed to fill this gap with a dose-response meta-analysis. Methods We searched multiple electronic databases (last update search June 2021) for all fixed-dose studies that investigated 16 second-generation antipsychotics and haloperidol in adults with acute exacerbation of schizophrenia or with negative symptoms. We estimated the dose-response curves by conducting random-effects dose-response meta-analyses. We used the restricted cubic spline to model the dose-response relationship. The primary outcome was mean weight gain in kg from baseline to endpoint, the secondary outcome was the number of patients with clinically important weight gain. Findings Ninety-seven studies with 333 dose arms (36 326 participants) provided data for meta-analyses. Most studies were short-term with median duration of 6 weeks (range 4 to 26 weeks). In patients with acute exacerbation, amisulpride, aripiprazole, brexpiprazole, cariprazine, haloperidol, lumateperone, and lurasidone produced mild weight gain in comparison to placebo (mean difference at any dose≤1 kg), while more significant weight gain was observed by all other drugs. For most drugs, dose-response curves showed an initial dose-related increase in weight which plateaued at higher doses, while for others there was no plateau and some even had bell-shaped curves, meaning less weight gain to be associated with higher doses. Interpretation Second-generation antipsychotics do not only differ in their propensity to produce weight gain, but also in the shapes of their dose-response curves. This information is important for dosing decisions in clinical practice. [ABSTRACT FROM AUTHOR]

Background The magnitude of the superiority of antipsychotics over placebo is debated. One reason is that the effect-size index which is usually used in meta-analyses is in standard deviation units. Many other indices, some of which are more intuitive, exist. Methods We explain the formulae, advantages, and limitations of 13 effect-size indices: Mean Difference (MD), Standardized-Mean-Difference (SMD), Correlation Coefficient, Ratio-of-Means (RoM, endpoint and change data), Improvement Fraction (IF), Drug-Response Fraction (DRF), Minimally-Clinically-Important-Difference-Units (MCIDU), Number-Needed-to-Treat-derived from SMD (NNT), Odds Ratio (OR), Relative Risk (RR), and Risk Difference (RD) derived from SMD, Drug-response and Placebo-response in percent. We applied these indices to meta-analyses comparing antipsychotic drugs with placebo for acute schizophrenia. Results The difference of all antipsychotics pooled vs placebo (105 trials with 22741 participants) was: MD 9.4 (95% CI 8.4,10.2) PANSS points, SMD 0.47 (0.42,0.51), Correlation coefficient 0.23 (0.21,0.25), RoM endpoint 0.83 (0.81,0.85), RoM change 1.94 (1.84,2.02), IF (%) 49 (46,51), DRF (%) 94 (84,102), MCIDU 0.63 (0.56,0.68), NNT 5 (5,6), OR 2.34 (2.14, 2.52), RR 1.67 (1.59,1.73), RD 20% (18–22), and 50% (48, 52) improved on drug compared to 30% on placebo. Results of individual drugs compared to placebo are presented, as well. Conclusions Taken together these indices show a substantial, but not a large superiority of antipsychotics compared to placebo. The general chronicity of the patients in the trials must be considered. Future meta-analyses should report other effect size indices in addition to the Standardized-Mean-Difference, in particular percentage responders in the drug and placebo groups. They can be easily derived and would enhance the interpretation of research findings. [ABSTRACT FROM AUTHOR]

Importance: The doses of antipsychotic drugs needed for relapse prevention in schizophrenia is a debated issue.Objective: To examine dose-response findings in a meta-analysis of randomized clinical trials.Data Sources: Studies were identified through the Cochrane Schizophrenia Group's Study-Based Register of Trials (March 9, 2020), PubMed (January 1, 2021), and previous reviews. First authors and/or pharmaceutical companies were contacted for additional information.Study Selection: Two reviewers independently selected randomized clinical trials that compared fixed doses of a second-generation antipsychotic, haloperidol, or fluphenazine for relapse prevention in patients with stable schizophrenia.Data Extraction and Synthesis: Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters in duplicate were extracted and frequentist dose-response random-effects meta-analyses were conducted.Main Outcomes and Measures: Study-defined relapse (primary outcome), rehospitalization, Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale total score reduction from baseline, all-cause discontinuation, and dropouts due to adverse events.Results: Evidence from 72 dose arms from 26 studies with 4776 participants was analyzed. The efficacy-related dose-response curves had a hyperbolic shape meaning that the probability to relapse decreased rapidly with doses of up to 5-mg/d risperidone equivalent (relative relapse risk, 0.43; 95% CI, 0.31-0.57; standardized mean difference for Positive and Negative Syndrome Scale total score reduction, -0.55; 95% CI, -0.68 to -0.41), but flattened thereafter. In contrast, dropouts due to adverse events continued to increase beyond this dose (relative risk at 5 mg/d, 1.38; 95% CI, 0.87-2.55; relative risk at 15 mg/d, 2.68; 95% CI, 1.49-4.62). In a subgroup analysis of patients in remission, a plateau was reached earlier, at approximately 2.5-mg/d risperidone equivalent.Conclusions and Relevance: The findings of this meta-analysis suggest that doses higher than approximately 5-mg/d risperidone equivalent may provide limited additional benefit for relapse prevention but more adverse events. For patients in remission or who are receiving high-potency first-generation antipsychotics, doses as low as 2.5-mg/d risperidone equivalent may be sufficient. However, caution is needed at this low dose end when further decreases of dose may be accompanied by a disproportionally higher relapse risk. Moreover, the observations are averages, and factors such as slow or rapid metabolism, age, illness stage, comorbidities, and drug-drug interactions suggest that individual patients will often need higher or lower doses. [ABSTRACT FROM AUTHOR]

Objective: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system.Methods: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group.Results: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine.Conclusions: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs are the mainstay of treatment of schizophrenia, and are known to reduce acute symptoms of the disorder. An original version of the current review, published in 2012, examined whether antipsychotics are effective for relapse prevention, compared to withdrawing these agents for people with schizophrenia or schizophrenia-like psychoses, based on evidence from randomized trials. The current report of the update of the review is focused on some newly investigated outcomes: rates of remission and recovery, change in social functioning and in quality of life. The updated review included 75 randomized controlled trials (RCTs) published from 1959 to 2017, involving 9145 participants. Although some potential sources of bias limited the overall quality, the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear and robust to a series of sensitivity analyses. Antipsychotic drugs were more effective than placebo in preventing relapse at 1 year (drug 24% versus placebo 61%, 30 RCTs, n = 4249, RR = 0.38, 95% CI = 0.32 to 0.45) and in reducing hospitalization (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR = 0.43, 95% CI = 0.32 to 0.57). Quality of life appeared to be better in drug‐treated participants (7 RCTs, n = 1573, SMD = −0.32, 95% CI = −0.57 to −0.07); the same for social functioning (15 RCTs, n = 3588, SMD = −0.43, 95% CI = −0.53 to −0.34). Although based on data from fewer studies, maintenance treatment apparently increased the possibility to achieve remission of symptoms (drug 53%, placebo 31%; 7 RCTs, 867 participants; RR = 1.73, 95% CI = 1.20 to 2.48) and to sustain it over 6 months (drug 36%, placebo 26%; 8 RCTs, 1807 participants; RR = 1.67, 95% CI = 1.28 to 2.19). There were no data on recovery. Antipsychotic drugs as a group were associated with more participants experiencing side effects such as movement disorders (e.g. at least one movement disorder: drug 14% versus placebo 8%, 29 RCTs, n = 5276, RR 1.52, 95% CI = 1.25 to 1.85) and weight gain (drug 9% versus placebo 6%, 19 RCTs, n = 4767, RR = 1.69, 95% CI = 1.21 to 2.35, NNTH = 25, 95% CI = 20 to 50). For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs does not only prevent relapses and rehospitalizations, but that patients also benefit in terms of quality of life, functioning and sustained remission. These positive effects must be weighed against the backdrop of the adverse effects of antipsychotics. [ABSTRACT FROM AUTHOR]

Two previous randomized controlled trials (RCTs) suggested that adjunctive aspirin is efficacious in treating schizophrenia. We conducted two 16-week double-blind randomized placebo-controlled RCTs of adjunctive 1000 mg aspirin vs placebo in schizophrenia. Study 1 included 200 patients, with Positive and Negative Syndrome Scale (PANSS) total score as the primary outcome. Study 2 included 160 patients with C-reactive protein (CRP) >1 mg/L at baseline; the primary outcome was PANSS-positive score. Dropout rates for aspirin/placebo were 12% in study 1 and 20% in study 2. Differences in outcome between aspirin and placebo were calculated with linear regression, adjusting for the baseline value of the outcome. No statistically significant between-group differences were found in primary or secondary outcomes in either study. Study 1: mean difference in PANSS at 16 weeks was −3.9 (95% CI: −8.4 to 0.5, P =.10, effect size (ES) = −0.25) and at 8 weeks was −3.5 (95% CI: −7.5 to 0.5, P =.11, ES = −0.22). Study 2: mean difference in PANSS at 16 weeks was 0.3 (95% CI: −4.1 to 4.7, P =.90, ES = 0.02) and in positive PANSS was 0.5 (95% CI: −1.0 to 2.1, P =.50, ES = 0.11). A meta-analysis of these data with the existing studies, excluding one with large baseline differences in total PANSS, found that the overall estimate of the effect of adjunctive aspirin on the PANSS total score comparing group means at the end of the study was −2.9 (95% CI: −6.6 to 0.7; P =.21), favoring aspirin. Our studies and meta-analysis failed to find a statistically significant improvement in the symptoms of schizophrenia from adjunctive aspirin therapy in comparison to placebo in schizophrenia. Trial registration: study 1: Clinicaltrials.gov: NCT01320982; study 2 (high CRP): EudraCT Number: 2014-000757-36. [ABSTRACT FROM AUTHOR]

Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. It is an important drug in psychiatry because of its use in treatment resistant patients and there are many unanswered questions, such as what is its optimal dose [[2]], should it already be used after the failure of one antipsychotic, etc. [Extracted from the article]

Background: Comparisons of antipsychotics with placebo can be biased by unblinding due to side effects. Therefore, this meta-analysis compared the efficacy of antipsychotics for acute schizophrenia in trials using barbiturates or benzodiazepines as active placebos. Methods: Randomized controlled trials (RCTs) in acute schizophrenia with at least 3 weeks duration and comparing any antipsychotic with barbiturates or benzodiazepines were eligible. ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, PubMed, WHO-ICTRP as well as previous reviews were searched up to 9 January 2018. Two separate meta-analyses, one for barbiturates and one for benzodiazepines, were conducted using random-effects models. The primary outcome was response to treatment, and mean values of schizophrenia rating scales and dropouts were analyzed as secondary outcomes. This study is registered with PROSPERO (CRD42018086263). Results: Seven barbiturate-RCTs (number of participants n = 1736), and two benzodiazepine-RCTs (n = 76) were included in the analysis. The studies were published between 1960 and 1968 and involved mainly chronically ill patients. More patients on antipsychotics in comparison to barbiturates achieved a 'good' response (36.2% v. 16.8%; RR 2.15; 95% CI 1.36–3.41; I2 = 48.9) and 'any' response (57.4% v. 27.8%; RR 2.07; 95% CI 1.35–3.18; I2 = 68.2). In a single small trial (n = 60), there was no difference between antipsychotics and benzodiazepines on 'any' response (74.7% v. 65%; RR 1.15; 95% CI 0.82–1.62). Conclusions: Antipsychotic drugs were more efficacious than barbiturates, based on a large sample size. Response ratios were similar to those observed in placebo-controlled trials. The results on benzodiazepines were inconclusive due to the small number of studies and participants. [ABSTRACT FROM AUTHOR]

Should "typical", first-generation antipsychotics no longer be generally used in the treatment of schizophrenia? Since the reintroduction of clozapine in many countries after the landmark trial by Kane et al. in 1988 [[1]], there are, to date, 16 second-generation, "atypical" antipsychotics in the United States and/or in Europe. The most notable exception is haloperidol which was the gold-standard comparator in trials on second-generation antipsychotics and is, therefore, among the best examined antipsychotics. [Extracted from the article]

Background We examined patient and study characteristics of pharmacotherapy and psychotherapy trials to establish whether the effects of these 2 treatment strategies can be compared meaningfully. Methods We inspected all randomized controlled trials included in 2 recent meta-analyses on antipsychotics and psychotherapy in patients with positive symptoms of schizophrenia, searching EMBASE, MEDLINE, PsycINFO, Cochrane Library, and ClinicalTrials.gov. Differences between psychotherapy and pharmacotherapy trials were analyzed with Wilcoxon–Mann–Whitney and chi-square tests. Results Eighty studies with 18 271 participants on antipsychotic drugs and 53 studies with 4068 participants on psychotherapy were included. Psychotherapy studies included less severely ill patients (P <.0001), with a shorter duration of illness (P =.021), lasted for a longer period (P <.0001), administered the intervention as add-on to antipsychotics (P <.0001), had higher risk of bias in some domains including blinding of outcome assessment (P <.0001), and were funded publicly more frequently (P <.0001). Antipsychotic trials had larger sample sizes (P <.0001) and more study centers (P <.0001), included more males (P =.0001), inpatients (P <.0001), and slightly older patients (P =.031), more often used diagnostic operationalized criteria (P =.006), and were sponsored by pharmaceutical companies. They did not differ in conflict of interest (P =.24). Conclusions We found key differences between the 2 groups of studies that encompass higher risk of bias in psychotherapy studies and the inclusion of more severe patients in drug trials. These differences imply that study and patient characteristics should be carefully taken into account before considering a network meta-analysis. In the interest of patients, psychopharmacologists and psychotherapists should optimize their treatments rather than seeing them in competition. [ABSTRACT FROM AUTHOR]

One previous small single-center clinical trial showed that a single intravenous administration of sodium nitroprusside added-on to antipsychotics improved a wide spectrum of schizophrenia (SCZ) symptoms more than placebo, and the improvement persisted for 4 weeks after infusion even though no additional drug was given. Our study attempted to replicate these data in a 4-week, add-on, double-blind, randomized, placebo-controlled trial on 20 patients performed in a site in Romania and a site in Moldova. This study's sample size and protocol were identical to the previous trial, including patients with a diagnosis of SCZ, within the first 5 years after diagnosis. Patients recruited needed to have a baseline total positive and negative syndrome scale (PANSS) score of 60 or above. Ten participants received a single dose of 0.5 µg/ kg/min intravenous sodium nitroprusside over 4 hours, and 10 participants received matching placebo infusion, added-on to antipsychotics. The primary outcomes were the PANSS total score and the PANSS negative subscale. There were no significant between-group differences in PANSS total scores or negative subscale scores during the infusion on daily evaluations for the next 7 days nor on weekly evaluations at weeks 2, 3, and 4. No significant differences were found between the 2 study groups in adverse events. Meta-analyses including all 5 published randomized controlled trials on the topic, representing 155 subjects, do not show a statistically significant benefit of sodium nitroprusside. We conclude that the current evidence does not support the efficacy of sodium nitroprusside in the treatment of SCZ. [ABSTRACT FROM AUTHOR]

Importance: Several lines of evidence suggest that estradiol influences the course of schizophrenia, and a previous randomized controlled trial demonstrated that transdermal estradiol improved symptoms in female patients of childbearing age. However, many initial positive findings in schizophrenia research are not later replicated.Objective: To independently replicate the results of the effect of estradiol on schizophrenia in women of childbearing age.Design, Setting, and Participants: An 8-week randomized, placebo-controlled trial performed in the Republic of Moldova between December 4, 2015, and July 29, 2016, among 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder as defined by the DSM-5.Intervention: Patients were randomized to receive a 200-μg estradiol patch or placebo patch changed twice a week added to their antipsychotic treatment.Main Outcomes and Measures: The primary outcome was the positive subscale of the Positive and Negative Syndrome Scale (PANSS; lower scores indicated fewer symptoms and higher scores indicated more symptoms), analyzed with mixed models for repeated measures on an intention-to-treat basis.Results: A total of 100 women (median age, 38 years; interquartile range, 34-42 years) were randomized to receive an estradiol patch and 100 women (median age, 38 years; interquartile range, 31-41 years) were randomized to receive a placebo patch; the median age at baseline for the entire group of 200 women was 38.0 years (range, 19.5-46.0 years). At baseline, the mean positive PANSS score was 19.6 for both groups combined; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group. Compared with placebo, participants receiving add-on estradiol patches had statistically significant improvements in the primary outcome measure, PANSS positive subscale points (-0.94; 95% CI, -1.64 to -0.24; P = .008; effect size = 0.38). Post hoc heterogeneity analyses found that this effect occurred almost entirely in 100 participants older than 38.0 years (46 in placebo group vs 54 in estradiol group; difference, -1.98 points on the PANSS positive subscale; 95% CI, -2.94 to -1.02; P < .001). Younger participants did not benefit from estradiol (difference, 0.08 points on the PANSS positive subscale; 95% CI, -0.91 to 1.07; P = .87). Breast tenderness was more common in the estradiol group (n = 15) than in the placebo group (n = 1) as was weight gain (14 in estradiol group vs 1 in placebo group).Conclusions and Relevance: The results independently replicate the finding that transdermal estradiol is an effective add-on treatment for women of childbearing age with schizophrenia and extend it, finding improvements in negative symptoms and finding that the effect could be specific to those older than 38 years. The results should be viewed in the context of the differences in the natural course of schizophrenia between females and males.Trial Registration: ClinicalTrials.gov identifier: NCT03848234. [ABSTRACT FROM AUTHOR]

Rationale: There are many psychotropic drugs available for treatment of schizophrenia. The clinician's choice of the most effective first-line antipsychotic treatment for patients with schizophrenia should balance considerations of differential efficacy of antipsychotics against the relative risk of different side effects.Method: We reviewed recent studies using meta-analytic techniques and additional studies of new antipsychotics which quantitatively evaluate the efficacy of side effects of first- and second-generation antipsychotics and studies of the efficacy on add-on secondary medications. We present an integrated summary of these results to guide a clinician's decision-making.Results: Recent meta-analyses have suggested that antipsychotics are not equivalent in efficacy. Clozapine (effect size [SMD] 0.88 vs. placebo), amisulpride (effect size 0.6 vs placebo), olanzapine (effect size 0.59 vs. placebo), and risperidone (effect size 0.56 vs placebo) show small but statistically significant differences compared to a number of other antipsychotics on measures of overall efficacy (effect sizes 0.33-0.50). However, increasing placebo response remains a concern in interpreting these data. Amisulpride (effect size 0.47 vs placebo) and cariprazine (effect size in one trial compared to risperidone 0.29) have the strongest evidence indicating greater efficacy for treating primary negative symptoms relative to other antipsychotics. In terms of side effects, clozapine and olanzapine have among the highest weight gain potential and sertindole and amisulpride have more effects on QTc prolongation than other commonly used antipsychotics. Prolactin elevation is highest with paliperidone, risperidone, and amisulpride. Adjunctive treatment with an antidepressant drug may improve response in patients with schizophrenia who also have severe depressive or negative symptoms. For multi-episode patients with an inadequate response to an adequate dose and duration of the initial antipsychotic choice, switching to another antipsychotic, with a different receptor profile, may improve response, although evidence is very limited. In first-episode patients, a recent study on switching to another antipsychotic, with a different receptor profile after 4 weeks demonstrated no beneficial effects. There is little evidence to support using doses above the therapeutic range other than in exceptional circumstances.Conclusions: Our review of recent studies using meta-analytic techniques has provided evidence that all antipsychotics are not equal in the severity of different side effects and in some measures of clinical efficacy. Comparative analysis and rankings from network meta-analyses can provide guidance to clinicians in choosing the most appropriate antipsychotic for first-line treatment, if used in conjunction with available information of the patient's history of previous clinical response or higher risks for specific side effects. [ABSTRACT FROM AUTHOR]

Rationale: Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics.Method: We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales.Results: In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients.Conclusions: These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use. [ABSTRACT FROM AUTHOR]

The article discusses the introduction of antipsychotic agents in 1950s and their apparent efficacy was shortly followed by a tremendous reduction of institutionalized patients with schizophrenia. It mentions that the established efficacy in treating acute exacerbations of schizophrenia and preventing relapses, and there is also more recent evidence on their efficacy in patients with predominant negative symptoms.

Objective: Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences.Method: The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression.Results: The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time.Conclusions: Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients. [ABSTRACT FROM AUTHOR]

This means that doses should be reduced in a hyperbolic pattern (ie, reductions by smaller and smaller amounts) if any changes are made, because the safest course is typically to maintain a standard dose.[4] Moreover, the hyperbolic shape of the dose-response curve speaks against an average minimum effective antipsychotic dose, unless one defines the amount of efficacy by an arbitrary threshold. Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials. What dose-response meta-analysis adds is the shape of the dose response curve. [Extracted from the article]

Importance: Antipsychotic drugs constitute the mainstay in the treatment of schizophrenia, and their efficacy is well established in hundreds of randomized clinical trials. However, it is not known whether they are effective or how effective they are across the wide range of baseline symptom severity.Objective: To examine the influence of baseline severity of schizophrenia on the efficacy of antipsychotic drugs.Design, Setting, and Participants: Meta-analysis of participant-level data from 3 pivotal randomized trials of acute schizophrenia (n = 611) and 3 pivotal trials in patients with predominantly negative symptoms of schizophrenia (n = 475).Interventions: Olanzapine or risperidone vs placebo, and amisulpride vs placebo.Main Outcomes and Measures: Change scores on the Positive and Negative Syndrome Scale (PANSS; score range, 30-210) and the Scale for the Assessment of Negative Symptoms (SANS; score range, 0-125) up to 6 weeks after baseline. The relationship between baseline and change scores for the drug and placebo groups was examined with 8 competing mixed-effects models for repeated measures.Results: The best-fitting models showed that, for both types of patients, the interactions between baseline symptom severity and treatment were statistically significant (P < .01). The greater the baseline severity was, the greater the magnitude of the differences was between active treatment and placebo. In acute treatment, the mean differences in PANSS change scores were 9.5 points for patients who were mildly ill at baseline (baseline PANSS score of 58), 13.7 for moderately ill patients (baseline PANSS score of 75), 18.8 for markedly ill patients (baseline PANSS score of 95), and 24.0 for severely ill patients (baseline PANSS score of 116). In treatment of predominantly negative symptoms, the mean differences in SANS change scores were 1.7 for those who were moderately ill (baseline SANS score of 55), 5.7 for markedly ill patients (baseline SANS score of 70), and 9.7 for severely ill patients (baseline SANS score of 85).Conclusions and Relevance: We can expect benefits of antipsychotic drugs for the full spectrum of patients likely to be treated for acute schizophrenia and for highly symptomatic patients with predominantly negative symptoms. Toward the mildest end of the spectrum, clinicians need to be aware that patients benefit less in terms of symptom improvement but may experience full adverse effects of antipsychotics. Clinicians also need to be aware that in addition to the treatment of active symptoms, which was the focus of this study, antipsychotics have another important action, namely to prevent relapses among patients in remission. [ABSTRACT FROM AUTHOR]

There is a debate about long-term treatment of schizophrenia with antipsychotic drugs, with some experts suggesting that these drugs should be discontinued. In this issue, Takeuchi et al demonstrated by a meta-analysis of 11 trials that antipsychotic drugs maintained their efficacy for relapse prevention for 1 year, whereas patients on placebo kept getting worse. We consider these findings in the light of the current discussion about possible dose-related brain volume loss, supersensitivity psychosis, the high variability of results in long-term follow-up studies and recent approaches to discontinue antipsychotics in patients with a first-episode. The new findings speak in favour of continuing antipsychotics at the same dose, at least in patients whose condition is chronic, but the topic is complex. [ABSTRACT FROM AUTHOR]

Objective An emerging body of evidence supports a role for dysfunctional purinergic neurotransmission in mood disorders. Adenosine agonists have been shown to have properties similar to those of dopamine antagonists; there is a well-characterized interaction between adenosine and dopamine receptors in the ventral striatum, and increasing adenosinergic transmission has been demonstrated to reduce the affinity of dopamine agonists for dopamine receptors. Allopurinol increases adenosine levels in the brain, and hence is hypothesized to reduce the symptoms of mania. Two randomized, placebo-controlled trials administering add-on allopurinol to manic patients showed significantly greater improvements in Young Mania Rating Scale ( YMRS) scores for drug compared to placebo, while a more recent, relatively small, add-on study showed negative results. Based on these data, our objective was to examine the efficacy of allopurinol as add-on treatment to mood stabilizers and/or antipsychotic agents in manic patients with bipolar disorder. Methods We performed a large, well-powered, multicenter, six-week, randomized, placebo-controlled trial of allopurinol added to mood stabilizers and/or antipsychotic agents in 180 patients with bipolar disorder in an acute manic episode. Results Both groups showed improvement on the YMRS (effect size of 1.5 for placebo and 1.6 for allopurinol), with no difference observed between groups on YMRS scores ( t = 0.28, p = 0.78). There was no difference in the proportion of patients who responded to treatment (defined as showing at least 50% improvement in YMRS score) between the two groups (p = 0.92), or in dropout rates (p = 0.84). Limitations None of our patients received lithium. However, the side effects of lithium and its narrow therapeutic index made the use of lithium less common and, therefore, our study results reflect common current clinical practice. In the present study, we used a variety of antipsychotic and/or mood stabilizing treatments, to which we added allopurinol; one might hypothesize that add-on allopurinol has a different effect in combination with different antipsychotic agents or mood stabilizers. Conclusions The findings of this large, well-powered study do not support add-on allopurinol as a treatment for acute mania. This study did not test the efficacy of allopurinol as monotherapy. [ABSTRACT FROM AUTHOR]

Background: Clinicians need to know the right antipsychotic dose for optimized treatment, and the concept of dose equivalence is important for many clinical and scientific purposes. Methods: We refined a method presented in 2003, which was based on the minimum effective doses found in fixed-dose studies. We operationalized the selection process, updated the original findings, and expanded them by systematically searching more recent literature and by including 13 second-generation antipsychotics. To qualify for the minimum effective dose, a dose had to be significantly more efficacious than placebo in the primary outcome of at least one randomized, double-blind, fixed-dose trial. In a sensitivity analysis, 2 positive trials were required. The minimum effective doses identified were subsequently used to derive olanzapine, risperidone, haloperidol, and chlorpromazine equivalents. Results: We reviewed 73 included studies. The minimum effective daily doses/olanzapine equivalents based on our primary approach were: aripiprazole 10 mg/1.33, asenapine 10 mg/1.33, clozapine 300 mg/40, haloperidol 4 mg/0.53, iloperidone 8 mg/1.07, lurasidone 40 mg/5.33, olanzapine 7.5 mg/1, paliperidone 3 mg/0.4, quetiapine 150 mg/20, risperidone 2 mg/0.27, sertindole 12 mg/1.60, and ziprasidone 40 mg/5.33. For amisulpride and zotepine, reliable estimates could not be derived. Conclusions: This method for determining antipsychotic dose equivalence entails an operationalized and evidence-based approach that can be applied to the various antipsychotic drugs. As a limitation, the results are not applicable to specific populations such as first-episode or refractory patients. We recommend that alternative methods also be updated in order to minimize further differences between the methods and risk of subsequent bias. [ABSTRACT FROM PUBLISHER]

OBJECTIVE: Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia. METHOD: Eighty-four women (ages 18-40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis. RESULTS: A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group. CONCLUSIONS: Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia. [ABSTRACT FROM AUTHOR]

The article discusses a research study on examining differences in the efficacy of long-term and mid-term use of antipsychotic medications for the treatment of schizophrenia. Selected studies were used for the data-driven study in a clinical approach where Phase 1 Clinical Antipsychotic Trials of Intervention Effectiveness results are similar to European First-Episode Schizophrenia Trial short-term efficacy studies. Conclusions indicated the importance of second-generation antipsychotics.

We describe the pharmacological treatment of schizophrenia and have arranged the manuscript as a simple algorithm which starts from the choice of an antipsychotic drug for an acutely ill patient and concludes with the most important questions about maintenance treatment. In acutely ill patients the choice of drug is mainly based on pragmatic criteria. Among many strategies used for agitated patients, haloperidol plus promethazine is the best examined one. In case of persistent depression or negative symptoms treatment includes antidepressants, and some second-generation antipsychotic drugs (SGAs) have been found somewhat superior to first-generation antipsychotic drugs (FGAs) in these domains. If an antipsychotic is suspected to be ineffective, several factors need to be checked before action is taken. Few trials have addressed strategies such as switching the drug or increasing the dose in case of non-response. Clozapine remains the gold-standard for treatment-refractory patients, while none of the numerous augmentation strategies that have been examined by randomized controlled trials can be generally recommended. Maintenance treatment with antipsychotic drugs effectively reduces relapse rates. Small, not definitive, studies have shown that withdrawing antipsychotics from patients who have been stable for up to 6 yr leads to more relapses than continuing medication. In effect, continuous treatment is more effective than intermittent strategies. The identification of optimum doses for relapse prevention with FGAs has proven difficult, and there is little randomized data on SGAs. Although the randomized evidence on a superiority of depot compared to oral treatment is not ideal, this approach suggests obvious advantages in assuring compliance. [ABSTRACT FROM AUTHOR]

Reelin is an extracellular matrix protein synthesized in cerebellar granule cells that plays an important role in Purkinje cell positioning during cerebellar development and in modulating adult synaptic function. In the cerebellum of schizophrenia (SZ) and bipolar (BP) disorder patients, there is a marked decrease (≈50%) of reelin expression. In this study we measured Purkinje neuron density in the Purkinje cell layer of cerebella of 13 SZ and 17 BP disorder patients from the McLean 66 Cohort Collection. Harvard Brain Tissue Resource Center. The mean number of Purkinje neurons (linear density, neurons per millimeter) was 20% lower in SZ and BP disorder patients compared with nonpsychiatric subjects (NPS; n = 24). This decrease of Purkinje neuron linear density was unrelated to postmortem interval, pH, drugs of abuse, or to the presence, dose, or duration of antipsychotic medications. A comparative study in the cerebella of heterozygous reeler mice (HRM). in which reelin expression is downregulated by ≈50%, showed a significant loss in the number of Purkinje cells in HRM (10-15%) compared with age-matched (3-9 months) wild-type mice. This finding suggests that lack of reelin impairs GABAergic Purkinje neUron expression and/or positioning during cerebellar development. [ABSTRACT FROM AUTHOR]

Objective: Whether there are differences in efficacy among second-generation antipsychotics in the treatment of schizophrenia is a matter of heated debate. The authors conducted a systematic review and meta-analysis of blinded studies comparing second-generation antipsychotics head-to-head. Method: Searches of the Cochrane Schizophrenia Group's register (May 2007) and MEDLINE (September 2007) were conducted for randomized, blinded studies comparing two or more of nine second-generation antipsychotics in the treatment of schizophrenia. All data were extracted by at least three reviewers independently. The primary outcome measure was change in total score on the Positive and Negative Syndrome Scale; secondary outcome measures were positive and negative symptom subscores and rate of dropout due to inefficacy. The results were combined in a meta-analysis. Various sensitivity analyses and metaregressions were used to examine bias. Results: The analysis included 78 studies with 167 relevant arms and 13,558 participants. Olanzapine proved superior to aripiprazole, quetiapine, risperidone, and ziprasidone. Risperidone was more efficacious than quetiapine and ziprasidone. Cloza pine proved superior to zotepine and, in doses >400 mg/day, to risperidone. These differences were due to improvement in positive symptoms rather than negative symptoms. The results were rather robust with regard to the effects of industry sponsorship, study quality, dosages, and trial duration. Conclusions: The findings suggest that some second-generation antipsychotics may be somewhat more efficacious than others, but the limitations of meta-analysis must be considered. In tailoring drug treatment to the individual patient, small efficacy superiorities must be weighed against large differences in side effects and cost. [ABSTRACT FROM AUTHOR]

This study presents a meta-analysis of the influence of several potentially biasing factors (eg industry support, extrapyramidal side effects) on efficacy of studies comparing second-generation antipsychotic (SGA) with first-generation antipsychotic (FGA) medications. We used the dataset from our previously published meta-analysis of 124 randomized controlled trials (RCTs) comparing SGAs with FGAs, to evaluate whether certain possible biases could influence the actual outcome on the total score of the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impressions (CGI) scores. Industry sponsorship was determined by contact with authors or publication statement. We calculated whether (1) industry sponsorship, (2) study quality, (3) extrapyramidal symptoms (EPS) properties, or (4) prophylactic antiparkinsonian medications influenced SGA vs FGA efficacy for each drug and averaged overall by two Hedges and Olkin-based meta-analyses. The analysis found that none of the factors was significantly associated with a particular outcome. While industry-sponsored articles may conclude their medication to be more favorable than that of a competitor in an RCT, we found that the observed efficacy was not influenced by sponsorship. Many attribute the finding that SGAs appears to be more efficacious than FGAs to be a result of EPS-decreasing efficacy (or its measurement). We were unable to confirm that the drug's EPS properties or antiparkinsonian management altered actual efficacy.Neuropsychopharmacology (2008) 33, 971–975; doi:10.1038/sj.npp.1301493; published online 4 July 2007 [ABSTRACT FROM AUTHOR]

Scale-derived cutoff points are frequently used to define ‘response’ in antipsychotic drug trials. This procedure is useful, because responder rates can be understood more intuitively than a difference in means of rating scales. As various definitions of response have been used, we examined original participant data to assess whether the choice of the Brief Psychiatric Rating Scale-based response cutoff had an impact on the results of seven (n=1870) antipsychotic drug trials in schizophrenia. We also analyzed whether the chronicity of the illness has an impact on the question of which cutoff is most sensitive in detecting differences between drugs. The results in terms of p-values and response rate differences varied substantially in dependence on the cutoff chosen. The use of response rate ratios attenuated the variability. In contrast to a widely held belief, low response cutoffs were not more sensitive in detecting differences between drugs than higher cutoffs. In more chronic, less responsive participants, there was a trend for higher cutoffs to be less sensitive in detecting differences between drugs than lower ones. The results of clinical trials depend considerably on the response cutoff chosen. Therefore, the cutoff should never be chosen post hoc, a large range of cutoffs should be presented and the a priori choice of the primary cutoff should be based on clinical relevance. The use of ratios rather than differences attenuates the variability. Cutoffs need to be calculated on the basis of 0–6 rather than on 1–7 scoring systems. We suggest a table presenting responder rates in 25 percent steps covering the whole range up to 100% reduction from baseline, which could be displayed together with recently presented criteria for remission.Neuropsychopharmacology (2007) 32, 1903–1910; doi:10.1038/sj.npp.1301325; published online 7 February 2007 [ABSTRACT FROM AUTHOR]

Objective: In many parts of the world, second-generation antipsychotics have largely replaced typical antipsychotics as the treatment of choice for schizophrenia. Consequently, trials comparing two drugs of this class—so-called head-to-head studies—are gaining in relevance. The authors reviewed results of head-to-head studies of second-generation anti-psychotics funded by pharmaceutical companies to determine if a relationship existed between the sponsor of the trial and the drug favored in the study's overall outcome. Method: The authors identified head-to- head comparison studies of second-generation antipsychotics through a MEDLINE search for the period from 1966 to September 2003 and identified additional head-to-head studies from selected conference proceedings for the period from 1999 to February 2004. The abstracts of all studies fully or partly funded by pharmaceutical companies were modified to mask the names and doses of the drugs used in the trial, and two physicians blinded to the study sponsor reviewed the abstracts and independently rated which drug was favored by the overall outcome measures. Two authors who were not blinded to the study sponsor reviewed the entire report of each study for sources of bias that could have affected the results in favor of the sponsor's drug. Results: Of the 42 reports identified by the authors, 33 were sponsored by a pharmaceutical company. In 90.0% of the studies, the reported overall outcome was in favor of the sponsor's drug. This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared. Potential sources of bias occurred in the areas of doses and dose escalation, study entry criteria and study populations, statistics and methods, and reporting of results and wording of findings. Conclusions: Some sources of bias may limit the validity of head-to-head comparison studies of second-generation antipsychotics. Because most of the sources of bias identified in this review were subtle rather than compelling, the clinical usefulness of future trials may benefit from minor modifications to help avoid bias. The authors make a number of concrete suggestions for ways in which potential sources of bias can be addressed by study initiators, peer reviewers of studies under consideration for publication, and readers of published studies. [ABSTRACT FROM AUTHOR]

Abstract: In our opinion the best guide to prescribing antipsychotics is the clinician’s experience with his patients and in particular the patient being treated. If treatment works, stick with it. We feel it is also important for the clinician to consider the evidence from well-controlled double-blind random-assignment studies because in “evidence-based medicine,” biases both known and unknown are controlled by blinding and randomization. The purpose of this paper is to summarize and discuss the evidence on efficacy. Choice of antipsychotic, in our opinion, is probably the most important decision that the clinician makes for the psychotic patient. This involves the choice of drug, its dose, balancing efficacy, side-effects and cost. [Copyright &y& Elsevier]

Background: Consensus panel recommendations regarding choice of an antipsychotic agent for schizophrenia differ markedly, but most consider second-generation antipsychotics (SGAs) as a homogeneous group. It has been suggested that SGAs seem falsely more efficacious than first-generation antipsychotics (FGAs) as a result of reduced efficacy due to use of a high-dose comparator, haloperidol. We performed (1) a meta-analysis of randomized efficacy trials comparing SGAs and FGAs, (2) comparisons between SGAs, (3) a dose-response analysis of FGAs and SGAs, and (4) an analysis of the effect on efficacy of an overly high dose of an FGA comparator. Methods: Literature search of clinical trials between January 1953 and May 2002 of patients with schizophrenia from electronic databases, reference lists, posters, the Food and Drug Administration, and other unpublished data. We included 124 randomized controlled trials with efficacy data on 10 SGAs vs FGAs and 18 studies of comparisons between SGAs. Two of us independently extracted the sample sizes, means, and standard deviation of the efficacy data. Results: Using the Hedges-Olkin algorithm, the effect sizes of clozapine, amisulpride, risperidone, and olanzapine were 0.49, 0.29, 0.25, and 0.21 greater than those of FGAs, with P values of 2 × 10[SUP-8], 3 × 10[SUP-7], 2 × 10[SUP-12], and 3 × 10[SUP-9], respectively. The remaining 6 SGAs were not significantly different from FGAs, although zotepine was marginally different. No efficacy difference was detected among amisul-pride, risperidone, and olanzapine. We found no evidence that the haloperidol dose (or all FGA comparators converted to haloperidol-equivalent doses) affected these results when we examined its effect by drug or in a 2-way analysis of variance model in which SGA effectiveness is entered as a second factor. Conclusion: Some SGAs are more efficacious than FGAs, and, therefore, SGAs are not a homogeneous group. [ABSTRACT FROM AUTHOR]

Reports the arguments on prescribing antipsychotic medications for treating schizophrenia in the U.S. Controversy on efficacy of antipsychotics; Evidence on the safety of ziprasidone; Concern on the reaction of patients treated with antipsychotic medications. INSETS: Antipsychotic treatment evaluated for prodromal schizophrenia.;FDA issues 'approvable letter' for aripiprazole..

Examines the minimum effective dose of haloperidol decanoate for treatment of schizophrenia. Rates of symptomatic exacerbation among the treated schizophrenics; Findings on the measures of psychopathology among the patients; Relation between the 200 milligrams per month dose of haloperidol decanoate with the lowest rate of symptomatic exacerbation.

This study is an analysis of findings of a follow-up study of 105 patients with functional psychotic illness who had participated in a random and blind 4-week trial of pimozide, lithium, both and placebo. The intention was to examine the question of whether a 4-week delay in initiating antipsychotic treatment has a detrimental effect 2.5 years later. Detailed follow-up measures included need for care over the 2.5 years, treatments required, occupational decline, police contact, substance misuse, psychopathology and cognitive function. There was no evidence at all that those initially randomized to placebo had a poorer outcome in terms of any of these variables. It is concluded that a 4-week delay in initiating active treatment in patients with functional psychosis has no long-term adverse effects. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of thiothixene in the treatment of behaviorally agitated dementia nursing home patients was studied in a double-blind, randomized, placebo-controlled clinical trial. Thirty-three subjects were randomized for thiothixene (dose range: 0.25–18 mg) or placebo treatment over an 11-week period, followed by a 6-week crossover period to assess for return of symptoms in the group crossed over to placebo and further improvement in the group crossed over to thiothixene. Thiothixene was significantly more effective than placebo in the reduction of agitation at the end of 11 weeks of treatment. Symptoms tended to return after discontinuation. There were no significant changes in the Mini-Mental State Examination (MMSE) or Activities of Daily Living (ADLs) and no significant differences in side-effects. Two placebo-treated patients died, and two patients died after being crossed over from thiothixene to placebo. The results suggest the efficacy of low doses of thiothixene for well-defined agitation in specifically selected demented nursing home patients. [ABSTRACT FROM AUTHOR]

The classification system of atypical and typical antipsychotics has created a lot of confusion and might be abandoned. Nevertheless, to say that all drugs are the same and that therefore it does not matter which drug is given is wrong. Both typical and atypical antipsychotics differ in side-effects, mechanisms of action, cost and efficacy. The available choice of antipsychotics should be adapted to individual patients in a shared decision-making process. [ABSTRACT FROM AUTHOR]

Both the new generation of antipsychotics and the more traditional antipsychotic drugs produce an important and meaningful improvement in patients with schizophrenia, but most patients are neither cured nor free of symptoms. As a consequence, it is common to switch from one drug to another in the hope of obtaining a better response. All antipsychotic drugs produce some side effects, so switching can also be a tolerance issue. There are reports in the literature on the tactics of switching: abrupt discontinuation, cross tapering, starting a patient on a new drug while continuing with the old drug until the new drug has reached a steady state, or some variation on these tactics. In this issue, Ganguli et al. have carried out a randomized switching study, the data from which indicates the tactics that might be optimal. We put this paper into context, provide a critique and describe indications for switching. [ABSTRACT FROM AUTHOR]

The author reflects on the paper by Robert A. Rosenheck published within the issue which summarizes the costs of treatment of schizophrenics in the U.S. during the National Institute of Mental Health-sponsored Clinical Antipsychotic Trials of Intervention Effectiveness study. He affirms that Rosenheck's study reassessed the outcome data to assign patients quality-adjusted life year rating. He notes that the study's important aspect is the calculation of lower costs for the drug perphenazine.

Discusses various aspects of antipsychotic drugs. Replacement of new generation of so-called atypical antipsychotics (NGAs) with conventional antipsychotics; Discussion on side-effects of new drugs; Information that all antipsychotics have the same efficacy; Importance of NGAs on in patients with schizophrenia.

The article highlights the findings of a study concerning the use of national registers in analyzing the outcomes of psychotropic drug. Topics discussed include limitations of randomized clinical trials (RCTs); comparison between the efficacy of classic mood stabilizers and antipsychotics for the prevention of rehospitalization; and mentions that the use of lithium was not associated with increased frequency of hospitalization for cardiac reasons.