Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis.
ABSTRACT: The metabolic side effects of second-generation antipsychotics (SGA) are serious and have not been compared head to head in a meta-analysis. We conducted a meta-analysis of studies comparing the metabolic side effects of the following SGAs head-to-head: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine.We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE and EMBASE (last search January 2009) for randomized, blinded studies comparing the above mentioned SGA in the treatment of schizophrenia or related disorders. At least three reviewers extracted the data independently. The primary outcome was weight change. We also assessed changes of cholesterol and glucose. The results were combined in a meta-analysis.We included 48 studies with 105 relevant arms. Olanzapine produced more weight gain than all other second-generation antipsychotics except for clozapine where no difference was found. Clozapine produced more weight gain than risperidone, risperidone more than amisulpride, and sertindole more than risperidone. Olanzapine produced more cholesterol increase than aripiprazole, risperidone and ziprasidone. (No differences with amisulpride, clozapine and quetiapine were found). Quetiapine produced more cholesterol increase than risperidone and ziprasidone. Olanzapine produced more increase in glucose than amisulpride, aripiprazole, quetiapine, risperidone and ziprasidone; no difference was found with clozapine.Some SGAs lead to substantially more metabolic side effects than other SGAs. When choosing an SGA for an individual patient these side effects with their potential cause of secondary diseases must be weighed against efficacy and characteristics of the individual patient.
Project description:While all second-generation antipsychotics (SGAs) are promoted for having a low risk of extrapyramidal side effects (EPS), clinical observations suggest differences between the various agents. Nevertheless, this question has never been examined in a systematic review and meta-analysis of head-to-head comparisons.We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE (last search July 2009) for randomized, blinded studies comparing the following SGAs in the treatment of schizophrenia or related disorders: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, and zotepine. At least 3 reviewers extracted the data independently. The primary outcome was "use of antiparkinson medication." The results were combined in a meta-analysis.We included 54 studies with 116 arms. Risperidone was associated with more use of antiparkinson medication than clozapine, olanzapine, quetiapine, and ziprasidone. Ziprasidone showed more use of antiparkinson medication than olanzapine and quetiapine and zotepine more than clozapine. There was no significant difference between amisulpride and its comparators (olanzapine, risperidone, or ziprasidone). Quetiapine showed significantly less use of antiparkinson medication than the 3 other SGAs it was compared with (olanzapine, risperidone, and ziprasidone). Scale-derived data (Barnes Akathisia Scale and Simpson Angus Scale) were limited.Our meta-analysis demonstrates that there are differences between the SGAs in their ability to induce EPS that clinicians consider warrant treatment with antimuscarinic drugs. Even though the differences were relatively small, they might be important for individual patients and should be taken into account in drug choice.
Project description:Because early treatment choice is critical in first-episode schizophrenia-spectrum disorders (FES), this meta-analysis compared efficacy and tolerability of individual second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) in FES. We conducted systematic literature search (until 12 December 2010) and meta-analysis of acute, randomized trials with ?1 FGA vs. SGA comparison; patients in their first episode of psychosis and diagnosed with schizophrenia-spectrum disorders; available data for psychopathology change, treatment response, treatment discontinuation, adverse effects, or cognition. Across 13 trials (n = 2509), olanzapine (seven trials) and amisulpride (one trial) outperformed FGAs (haloperidol: 9/13 trials) in 9/13 and 8/13 efficacy outcomes, respectively, risperidone (eight trials) in 4/13, quetiapine (one trial) in 3/13 and clozapine (two trials) and ziprasidone (one trial) in 1/13, each. Compared to FGAs, extrapyramidal symptom (EPS)-related outcomes were less frequent with olanzapine, risperidone and clozapine, but weight gain was greater with clozapine, olanzapine and risperidone. Pooled SGAs were similar to FGAs regarding total psychopathology change, depression, treatment response and metabolic changes. SGAs significantly outperformed FGAs regarding lower treatment discontinuation, irrespective of cause, negative symptoms, global cognition and less EPS and akathisia, while SGAs increased weight more (p < 0.05-0.01). Results were not affected by FGA dose or publication bias, but industry-sponsored studies favoured SGAs more than federally funded studies. To summarize, in FES, olanzapine, amisulpride and, less so, risperidone and quetiapine showed superior efficacy, greater treatment persistence and less EPS than FGAs. However, weight increase with olanzapine, risperidone and clozapine and metabolic changes with olanzapine were greater. Additional FES studies including broader-based SGAs and FGAs are needed.
Project description:<h4>Introduction</h4>To assess the risk of occurrence and potential determinants of metabolic disorders in adult patients treated with second-generation antipsychotics (SGAs) under real-world practice conditions.<h4>Methods</h4>MEDLINE, EMBASE, and PsycInfo were searched in July 2019 from database inception. We included population-based, longitudinal, comparative studies that report the results of the outcomes of interest for adult participants, including diabetes, ketoacidosis, hyperosmolar hyperglycemic state, weight gain/obesity, dyslipidemia, hypertension, and metabolic syndrome. Two reviewers independently extracted data on the study design, study quality, and study outcomes.<h4>Results</h4>We included 40 studies. Most studies showed that clozapine and olanzapine were associated with an increased likelihood of developing diabetes, while the results for risperidone and quetiapine were mixed. Although less well studied, ziprasidone and aripiprazole appeared to not be associated with the occurrence of diabetes. Information on antipsychotic-induced weight gain/obesity is extremely scarce. Regarding dyslipidemia, aripiprazole was not associated with an increased likelihood of developing dyslipidemia, clozapine was associated with an increased likelihood of developing dyslipidemia, and risperidone, olanzapine, quetiapine, and ziprasidone showed mixed results. Two studies suggested an association between ziprasidone and the occurrence of hypertension. Several studies found that the occurrence of a metabolic disorder acted as a risk factor for the development of other metabolic disorders. We did not find information on brexpiprazole, cariprazine, or lurasidone, and data on any long-acting SGA were lacking.<h4>Conclusion</h4>Although there are relevant differences among SGAs concerning the risk of metabolic disorders, it appears that none of the SGAs included in our review are fully devoid of these disturbances.
Project description:BACKGROUND:In many countries of the industrialised world second generation (atypical) antipsychotics have become first line drug treatments for people with schizophrenia. The question as to whether, and if so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examine how the efficacy and tolerability of amisulpride differs from that of other second generation antipsychotics. OBJECTIVES:To evaluate the effects of amisulpride compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY:We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CINAHL, EMBASE, MEDLINE and PsycINFO. SELECTION CRITERIA:We included randomised, at least single-blind, trials comparing oral amisulpride with oral forms of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS:We extracted data independently. For continuous data we calculated weighted mean differences (MD), for dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. MAIN RESULTS:The review currently includes ten short to medium term trials with 1549 participants on three comparisons: amisulpride versus olanzapine, risperidone and ziprasidone. The overall attrition rate was considerable (34.7%) with no significant difference between groups. Amisulpride was similarly effective as olanzapine and risperidone and more effective than ziprasidone (leaving the study early due to inefficacy: n=123, 1 RCT, RR 0.21 CI 0.05 to 0.94, NNT 8 CI 5 to 50). Amisulpride induced less weight gain than risperidone (n=585, 3 RCTs, MD -0.99 CI -1.61 to -0.37) or olanzapine (n=671, 3 RCTs, MD -2.11 CI -2.94 to -1.29). Olanzapine was also associated with a higher increase of glucose (n=406, 2 RCTs, MD -7.30 CI -7.62 to -6.99). There was no difference in terms of cardiac effects and extra pyramidal symptoms (EPS) compared with olanzapine (akathisia: n= 587, 2 RCTs, RR 0.66 CI 0.36 to 1.21), compared with risperidone (akathisia: n=586, 3 RCTs, RR 0.80 CI 0.58 to 1.11) and compared with ziprasidone (akathisia: n=123, 1 RCT, RR 0.63, CI 0.11 to 3.67). AUTHORS' CONCLUSIONS:There is little randomised evidence comparing amisulpride with other second generation antipsychotic drugs. We could only find trials comparing amisulpride with olanzapine, risperidone and ziprasidone. We found amisulpride may be somewhat more effective than ziprasidone, and more tolerable in terms of weight gain and other associated problems than olanzapine and risperidone. These data, however, are based on only ten short to medium term studies and therefore too limited to allow for firm conclusions.
Project description:Sexual dysfunction is a common condition in patients taking antipsychotics, and is the most bothersome symptom and adverse drug effect, resulting in a negative effect on treatment compliance. It is known that hyperprolactinemia is a major cause of sexual dysfunction. Based on the blockade of dopamine D2 receptors, haloperidol, risperidone, and amisulpride are classed as prolactin-elevating antipsychotics, while olanzapine, clozapine, quetiapine, ziprasidone, and aripiprazole are classed as prolactin-sparing drugs. Risperidone and the other typical antipsychotics are associated with a high rate of sexual dysfunction as compared to olanzapine, clozapine, quetiapine, and aripiprazole. With regard to treatment in patients suffering from sexual dysfunction, sildenafil was associated with significantly more erections sufficient for penetration as compared to a placebo. Subsequent studies are needed in order to provide physicians with a better understanding of this problem, thereby leading toward efficacious and safe solutions.
Project description:Extensive research has been carried out on the comparative effectiveness of antipsychotic medications. Most studies, however, have been performed in Western countries. The purpose of this study was to compare the effectiveness, indicated by time to any-cause discontinuation, of antipsychotic drugs in a large number of patients with schizophrenia in South Korea. We identified 1458 patients with schizophrenia or schizophreniform disorder who were treated with antipsychotic medications using a clinical data warehouse at the Seoul National University Hospital between March 2005 and February 2014. Kaplan-Meier survival analyses were used to estimate the time to discontinuation of antipsychotic drugs. We compared the survival curves of different antipsychotics using log-rank tests. Overall, the median time to discontinuation for any cause was 133 days (95% CI, 126-147). The longest time to discontinuation was observed for clozapine, followed by aripiprazole, paliperidone, olanzapine, amisulpride, risperidone, quetiapine, ziprasidone, and haloperidol. Specifically, clozapine was significantly different from all other antipsychotic drugs (all p?<?0.001). Aripiprazole also had a significantly longer time to discontinuation than amisulpride (p?=?0.001), risperidone (p?<?0.001), quetiapine (p?<?0.001), ziprasidone (p?<?0.001), and haloperidol (p?<?0.001). In Asian patients with schizophrenia, clozapine was the most effective antipsychotic in terms of time to discontinuation, followed by aripiprazole. This study extends the findings of previous effectiveness studies from Western populations and suggests the need to develop guidelines for the pharmacotherapy of schizophrenia tailored to Asian individuals.
Project description:Movement disorders associated with antipsychotic medications are relatively common, stigmatising, and potentially disabling. Their prevalence in people with psychosis who are prescribed second-generation antipsychotics (SGAs) is uncertain, as is their level of recognition by clinicinas. We conducted meta-analyses of randomised controlled trials included in the Cochrane Database of Systematic Reviews on schizophrenia and schizophrenia-like psychoses to estimate the prevalence of new-onset dystonia, akathisia, parkinsonism, and tremor with SGAs (amisulpride, asenapine, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, L-sulpiride, and ziprasidone) approved in Canada and the UK, comparing them with haloperidol and chlorpromazine. We used a random effects model because of the heterogeneity between-studies in drug dosage and method of ascertainment of movement disorders. Our systematic search yielded 37 Cochrane systematic reviews (28 for SGAs), which generated 316 informative randomised controlled trials (243 for SGAs). With respect to SGAs, prevalence estimates ranged from 1.4% (quetiapine) to 15.3% (L-sulpiride) for dystonia, 3.3% (paliperidone) to 16.4% (L-sulpiride) for akathisia, 2.4% (asenapine) to 29.3% (L-sulpiride) for parkinsonism, and 0.2% (clozapine) to 28.2% (L-sulpiride) for tremor. Prevalence estimates were not influenced by treatment duration, the use of a flexible or fixed dosing scheme, or whether studies used validated instruments for the screening/rating of movement disorders. Overall, we found high overlap on the prevalence of new-onset movement disorders across different SGAs precribed for established psychoses. Variations in prevalence figures across antipsychotic medications were observed for the different movement disorders. Differences in pharmacological properties, such as for the dopamine D2 R association rate and serotonin 5-HT2A antagonism, could contribute to this variation.
Project description:<h4>Background</h4>Real world evidence about antipsychotics focuses on rehospitalization. Modeling the time course of pharmacotherapy would show patients' adherence to medications and physicians' adherence to medication guidelines. We aimed to calculate the cumulative time spent in second generation antipsychotics (SGAs), gaps, antipsychotic polypharmacy, and clozapine in discharged schizophrenia patients.<h4>Methods</h4>Hospitalization and pharmacy dispensing data from 2008-2018 in Manitoba, Saskatchewan, and British Columbia were linked and an electronic cohort (<i>N</i> = 2,997) was created (mean follow-up: 49 months, SD = 38). Cohort members were required to have a minimum of 6 weeks medicated with aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.<h4>Results</h4>The multistate model predicted that schizophrenia patients accumulated 44 months in SGA monotherapy, 4 months in polypharmacy, 11 months in medication gaps and 17 days in clozapine over a 5-year period. The majority of transitions were between SGA and medication gap. Accumulated time in medication gaps was seven times as much as in clozapine. Each 10% delay in SGA initiation post-discharge was associated with a 2, 1, and 6% higher risk for polypharmacy (95% CI: 1.01-1.02), gap (95% CI: 1.01-1.01), and clozapine (95% CI: 1.04-1.08), respectively.<h4>Interpretation</h4>Schizophrenia patients accumulated more time unmedicated and in polypharmacy compared to clozapine. Either treatment guidelines for schizophrenia are not followed, or real-world challenges hamper their implementation.
Project description:AIM:To investigate whether differential influence on the QTc interval exists among four second generation antipsychotics (SGAs) in psychosis. METHODS:Data were drawn from a pragmatic, randomized head-to-head trial of the SGAs risperidone, olanzapine, quetiapine, and ziprasidone in acute admissions patients with psychosis, and with follow-up visits at discharge or maximally 6-9 wk, 3, 6, 12 and 24 mo. Electrocardiograms were recorded on all visits. To mimic clinical shared decision-making, the patients were randomized not to a single drug, but to a sequence of the SGAs under investigation. The first drug in the sequence defined the randomization group, but the patient and/or clinician could choose an SGA later in the sequence if prior negative experiences with the first one(s) in the sequence had occurred. The study focuses on the time of, and actual use of the SGAs under investigation, that is until treatment discontinuation or change, in order to capture the direct medication effects on the QTc interval. Secondary intention-to-treat (ITT) analyses were also performed. RESULTS:A total of 173 patients, with even distribution among the treatment groups, underwent ECG assessments. About 70% were males and 43% had never used antipsychotic drugs before the study. The mean antipsychotic doses in milligrams per day with standard deviations (SD) were 3.4 (1.2) for risperidone, 13.9 (4.6) for olanzapine, 325.9 (185.8) for quetiapine, and 97.2 (42.8) for ziprasidone treated groups. The time until discontinuation of the antipsychotic drug used did not differ in a statistically significant way among the groups (Log-Rank test: P = 0.171). The maximum QTc interval recorded during follow-up was 462 ms. Based on linear mixed effects analyses, the QTc interval change per day with standard error was -0.0030 (0.0280) for risperidone; -0.0099 (0.0108) for olanzapine; -0.0027 (0.0170) for quetiapine, and -0.0081 (0.0229) for ziprasidone. There were no statistically significant differences among the groups in this regard. LME analyses based on ITT groups (the randomization groups), revealed almost identical slopes with -0.0063 (0.0160) for risperidone, -0.0130 (0.0126) for olanzapine, -0.0034 (0.0168) for quetiapine, and -0.0045 (0.0225) for ziprasidone. CONCLUSION:None of the SGAs under investigation led to statistically significant QTc prolongation. No statistically significant differences among the SGAs were found.
Project description: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.