Antipsychotic Dose in Acute Schizophrenia: A Meta-analysis.
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ABSTRACT:
SUBMITTER: Takeuchi H
PROVIDER: S-EPMC7707077 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMany people with schizophrenia do not reach a satisfactory clinical response with a standard dose of an initially prescribed antipsychotic drug. In such cases, clinicians face the dilemma of increasing the antipsychotic dose in order to enhance antipsychotic efficacy.ObjectivesTo examine the efficacy of increasing antipsychotic dose compared to keeping the same dose in the treatment of people with schizophrenia who have not responded (as defined in the individual studies) to an initial antipsychotic drug trial. We also examine the adverse effects associated with such a procedure.Search methodsWe searched the Cochrane Schizophrenia Group Trials Register (10 June 2014, 6 October 2015, and 30 March 2017). We examined references of all included studies for further trials.Selection criteriaAll relevant randomised controlled trials (RCTs), reporting useable data, comparing increasing the antipsychotic dose rather than maintaining the original dose for people with schizophrenia who do not respond to their initial antipsychotic treatment.Data collection and analysisAt least two review authors independently extracted data . We analysed dichotomous data using relative risks (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their 95% CI. We assessed risk of bias for included studies and used GRADE to create a 'Summary of findings' table.Main resultsTen relevant RCTs with 675 participants are included in this review. All trials were double blind except one single blind. All studies had a run-in phase to confirm they did not respond to their initial antipsychotic treatment. The trials were published between 1980 and 2016. In most studies the methods of randomisation, allocation and blinding were poorly reported. In addition sample sizes were often small, limiting the overall quality of the evidence. Overall, no clear difference was found between groups in terms of the number of participants who showed clinically relevant response (RR 1.09, 95% CI 0.86 to 1.40, 9 RCTs, N = 533, low-quality evidence), or left the study early due to adverse effects (RR 1.63, 95% CI 0.52 to 5.07, very low quality evidence), or due to any reason (RR 1.30, 95% CI 0.89 to 1.90, 5 RCTs, N = 353, low-quality evidence). Similarly, no clear difference was found in general mental state as measured by PANSS total score change (MD -1.44, 95% CI -6.85 to 3.97, 3 RCTs, N = 258, very low quality evidence). At least one adverse effect was equivocal between groups (RR 0.91, 95% CI 0.55 to 1.50, 2 RCTs, N = 191, very low quality evidence). Data were not reported for time in hospital or quality-of-life outcomes. Finally, subgroup and sensitivity analyses did not show any effect on the primary outcome but these analyses were clearly underpowered.Authors' conclusionsCurrent data do not show any clear differences between increasing or maintaining the antipsychotic dose for people with schizophrenia who do not respond to their initial antipsychotic treatment. Adverse effect reporting was limited and poor. There is an urgent need for further trials in order to determine the optional treatment strategy in such cases.
| S-EPMC6494602 | biostudies-literature
Project description:Schizophrenia is associated with immune system dysfunction, including abnormal blood immune cell parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment following an acute exacerbation of psychosis.We identified articles by searching PubMed, PsycINFO, and Thomson Reuters (formerly ISI) Web of Knowledge and the reference lists of identified studies.Sixteen studies of blood lymphocytes met the inclusion criteria. There was insufficient data for a meta-analysis of the mononuclear phagocytic system. In cross-sectional studies, there was a significant increase in the CD4% and CD56% in acutely relapsed inpatients. Absolute levels of total lymphocytes, CD3, and CD4, and the CD4/CD8 ratio were significantly increased, and the CD3% was significantly decreased in drug-native first-episode psychosis. In longitudinal studies, the CD4/CD8 ratio appeared to be state-related markers, as it decreased following antipsychotic treatment for acute exacerbations of psychosis. Absolute CD56 levels appeared to be a trait marker, as levels significantly increased following antipsychotic treatment for relapse.Blood lymphocyte abnormalities in drug-naïve first-episode psychosis suggest an effect that may be independent of antipsychotic medications. While some parameters (CD4/CD8) may be state markers for acute exacerbations of psychosis, others (CD56) may be trait markers; however, more longitudinal studies are needed. Although these findings could provide the basis for future hypothesis testing, a relatively small number of studies and subjects, lack of correlative data with clinical features, and inadequate consideration of potential confounding factors limit the results.
| S-EPMC3816144 | biostudies-literature
Project description:Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placebo-response and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342).
| S-EPMC6785090 | biostudies-literature
Project description:We compared the efficacy, safety, and acceptability of lurasidone at different doses to establish the dose-response relationships of lurasidone therapeutic and adverse effects in acute schizophrenia. Included trials were 4- to 16-week, fixed-dose, randomized controlled trials of lurasidone in adults with acute schizophrenia. Different doses of lurasidone, other antipsychotics, and placebo were considered as independent treatments. Apart from all-cause dropout rates, four therapeutic and four adverse outcomes were included in the frequentist network meta-analysis (NMA). Lurasidone 160, 120, 80, 40, and 20 mg/day were studied in ten trials of 3,366 adults with schizophrenia exacerbation. Lurasidone 160 mg/day reduced Positive and Negative Syndrome Scale (PANSS) total scores significantly more than lurasidone 120, 80, 40, and 20 mg/day (mean differences = - 7.63, - 7.04, - 8.83, and - 12.25, respectively). All-cause dropout rates were significantly lower in participants receiving lurasidone 160 mg/day and 80 mg/day compared with those taking placebo. The half-maximal effective doses of lurasidone for PANSS total, PANSS positive, and MADRS score reductions were higher than 80 mg/day. The confidence of all NMA estimates was low or very low. Lurasidone 160 mg/day is currently the most efficacious and acceptable dose for acute schizophrenia. Its maximal effective doses may be higher than 160 mg/day.
| S-EPMC7946927 | biostudies-literature
Project description:Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation.We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies.Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1?, IL-6, and transforming growth factor-? (TGF-?) appeared to be state markers, as they were increased in AR and FEP (p < .001 for each) and normalized with antipsychotic treatment (p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-? (IFN-?), tumor necrosis factor-? (TNF-?), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p = .69). In the cerebrospinal fluid, IL-1? was significantly decreased in schizophrenia versus controls (p = .01).Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1?, IL-6, and TGF-?) may be state markers for acute exacerbations, others (IL-12, IFN-?, TNF-?, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking.
| S-EPMC4071300 | biostudies-literature
Project description:BackgroundImmune system dysfunction is a hypothesis in the psychopathology of schizophrenia, but the impact of antipsychotic treatment within this system is not clear. The aim of this meta-analysis was to investigate the impact of antipsychotic treatment on cytokine levels in in vivo studies on schizophrenia.MethodsAfter a systematic database search, original data were extracted with the help of certain authors. Means and SDs were extracted to calculate standardized mean differences. Cytokine levels were compared in vivo in schizophrenia patients, before and after antipsychotic treatment. Meta-regressions were performed to explore the influence of demographic and clinical variables on cytokine level standardized mean differences. Stratifications by treatment and diagnosis were also performed.ResultsForty-seven studies were included in this meta-analysis. Proinflammatory cytokine level decreases were found for interleukin-1 ? levels (P<.0001) and interferon-? (P=.01) and a statistical trend towards a decrease in interleukin-6 (P=.08) and tumor necrosis factor-? (P=.07) levels. An antiinflammatory cytokine level increase was found for soluble tumor necrosis factor-R2 (P<.001) and soluble interleukin 2-R (P=.03) levels. A meta-regression analysis found a correlation between interleukin-6 level standardized mean differences and positive schizophrenia symptom score standardized mean differences before and after treatment (P=.01). Stratification by diagnosis or treatment found a possible impact of the kinetics of cytokine levels.ConclusionsThe present meta-analysis provides evidence that antipsychotic treatment has an antiinflammatory effect and could normalize immune balance dysfunction in schizophrenia. Interleukin-6 level normalization could be a marker of illness equilibration and thus used in clinical practice.
| S-EPMC6119290 | biostudies-literature
Project description:ObjectivesWeight gain is a major side effect of antipsychotics (APs), which contributes to poor treatment adherence and significant morbidity. The mechanisms involved in AP-induced weight gain are incompletely understood. Recently, it has been proposed that changes in leptin, an cadipocyte-derived hormone exerting anorexigenic effects, may be involved in AP-induced weight gain. Thus far, studies on leptin changes during AP treatment have produced inconsistent results, prompting our group to perform a meta-analysis.MethodA search of the literature was performed using PubMed and Embase. Studies were included only if reporting peripheral levels of leptin before and after AP treatment in schizophrenia. Effect size estimates were calculated with Hedges g and were aggregated using a random effects model as results were heterogeneous (P<0.10). Meta-regression analyses were performed using study length and changes in body mass index (BMI) as moderator variables.ResultsTwenty-eight studies were retrieved, including 39 comparisons. A moderate and positive effect size was observed across studies. Olanzapine, clozapine, and quetiapine produced moderate leptin elevations, whereas haloperidol and risperidone were associated with small (nonsignificant) leptin changes. Across studies, BMI changes were significantly associated with increases in leptin levels. There was no effect of sex on AP-induced changes in leptin.ConclusionsA physiological role of leptin in AP-induced weight gain is supported because the most significant leptin increases were observed with APs inducing the most weight gain and because of the observed association between leptin increases and BMI changes. The overall increase in leptin levels suggests that leptin acts as a negative feedback signal in the event of fat increase.
| S-EPMC4418620 | biostudies-literature
Project description:This systematic review and meta-analysis examined predictors of successful antipsychotic dose reduction in schizophrenia. Prospective clinical trials and randomized controlled trials (RCTs) investigating antipsychotic dose reduction in schizophrenia were selected for systematic review and meta-analysis, respectively. In total, 37 trials were identified. Only 8 studies focused on second-generation antipsychotics (SGAs); no studies investigated long-acting injectable SGAs. Of 24 studies evaluating relapse or symptom changes, 20 (83.3%) met the criteria for successful dose reduction. Factors associated with successful dose reduction were study duration < 1 year, age > 40 years, duration of illness > 10 years, and post-reduction chlorpromazine equivalent (CPZE) dose > 200 mg/day. Clinical deterioration was mostly re-stabilized by increasing the dose to the baseline level (N = 7/8, 87.5%). A meta-analysis of 18 RCTs revealed that relapse rate was significantly higher in the reduction group than the maintenance group (risk ratio [RR] = 1.96; 95% confidence interval [CI], 1.23-3.12), whereas neurocognition was significantly improved (standardized mean difference = 0.69; 95% CI, 0.25-1.12). A subgroup analysis indicated that only a post-reduction CPZE dose ≤ 200 mg/day was associated with an increased risk of relapse (RR = 2.79; 95% CI, 1.29-6.03). Thus, when reducing antipsychotic doses, clinicians should consider the long-term risk of relapse in younger patients with a relatively short illness duration and keep the final doses higher than CPZE 200 mg/day. Further studies, particularly those involving SGAs, are warranted to determine the optimal strategies for successful antipsychotic dose reduction in schizophrenia.
| S-EPMC7075912 | biostudies-literature
Project description:This meta-analysis was conducted to evaluate whether HTR1A gene polymorphisms impact the efficacy of antipsychotic drugs in patients with schizophrenia. Candidate gene studies that were published in English up to August 6, 2015 were identified by a literature search of PubMed, Web of Science, and Google scholar. Data were pooled from individual clinical trials considering overall symptoms, positive symptoms and negative symptoms, and standard mean differences were calculated by applying a random-effects model. The present meta-analysis included a total of 1281 patients from 10 studies. Three polymorphisms of HTR1A (rs6295, rs878567, and rs1423691) were selected for the analysis. In the pooled data from all studies, none of these HTR1A polymorphisms correlated significantly with either overall symptoms or positive symptoms. However, C allele carriers of the rs6295 polymorphism showed a significantly greater negative symptoms improvement than G allele carriers (P=.04, standardized mean difference =-0.14, 95％CI = 0.01 to 0.28). The results of our present analysis indicate that the HTR1A rs6295 polymorphism may impact negative symptoms improvement but not on either overall symptoms or positive symptoms improvement. However, this meta-analysis was based on a small number of studies and patients, and the effect size on negative symptoms was small. Given this limitation, the results should be confirmed by further investigations.
| S-EPMC4886666 | biostudies-literature
Project description:Determining the optimal antipsychotic target dose in acute phase treatment is of high clinical relevance. The effect of antipsychotics on negative symptoms should be taken into account because patients will often continue on the treatment received in the acute phase. Therefore, we conducted a formal dose-response meta-analysis of negative symptoms and positive symptoms based on a systematic review of fixed-dose randomized controlled trials (RCTs) that examined the effectiveness of antipsychotics for the acute exacerbation of schizophrenia. Forty RCTs included a total of 15,689 patients. The 95% effective doses per day for the 13 antipsychotics included and 3 long acting were mostly different for negative and positive symptoms: amisulpride (481 mg, 690.6 mg); aripiprazole (11.9 mg, 11 mg); asenapine (7.61 mg, 5.66 mg); brexpiprazole (2.1 mg, 4 mg); cariprazine (4 mg, 6.51 mg); haloperidol (6.34 mg, 7.36 mg); lurasidone (58.2 mg, 86.3 mg); olanzapine (15.5 mg, 9.52 mg); olanzapine long-acting injection (15.7 mg, 13.5 mg); paliperidone (7.2 mg, 7 mg); paliperidone long-acting injection (7.5 mg, 5.9 mg); quetiapine instant-release (264.2 mg, 316.5 mg); quetiapine extended-release (774 mg, 707.2 mg); risperidone (7.5 mg, 7.7 mg); risperidone long-acting injection (5.13 mg, 6.7 mg); sertindole (13.5 mg, 16.3 mg); and ziprasidone (71.6 mg, 152.6 mg). The shape of the dose-response curves varied across different drugs with most drugs showing a plateau at higher doses. Most dose-response curves suggested that the near-maximum effective doses could be in the lower-to-medium range of the licensed dose. Additional RCTs are necessary to establish the optimal dose.
| S-EPMC8438046 | biostudies-literature