Xin-Hu Yang

Clozapine Augmentation With Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials

OBJECTIVE To meta-analyze randomized controlled trials (RCTs) for the efficacy and safety of adjunctive antiepileptic drugs (AEDs) to augment clozapine therapy for treatment-resistant schizophrenia. DATA SOURCES The search included databases in English (PubMed, PsycINFO, Embase, and Cochrane Library databases and the Cochrane Controlled Trials Register) and in Chinese (China Journal Net [CJN], WanFang, and China Biology Medicine [CBM]) and references from retrieved articles. The databases were searched using dates inclusive from their onset until January 1, 2016, for terms reflecting (a) schizophrenia, (b) clozapine, and (c) adjunctive drugs. STUDY SELECTION From 1,969 potentially relevant articles, 21 articles describing 22 RCTs were selected. DATA EXTRACTION Two independent investigators extracted data for a random-effects meta-analysis and assessed the quality of the studies using risk of bias and the Jadad scale. Standard mean difference, risk ratio (RR) ± 95% confidence intervals (CIs), and the number needed to harm (NNH) were used. RESULTS A total of 22 RCTs (N = 1,227) with 4 AEDs (topiramate [5 RCTs, n = 270], lamotrigine [8 RCTs, n = 299], sodium valproate [6 RCTs, n = 430], and magnesium valproate [3 RCTs, n = 228]) were analyzed. The means weighted by sample size were 12.1 weeks for treatment duration, 36.2 years for age, and 61% for male frequency. Significant superiority in total psychopathology was observed for topiramate (P < .0001), lamotrigine (P = .05), and sodium valproate (P = .002), compared to clozapine monotherapy. After removing outliers, the positive effect of sodium valproate remained, but the positive effect of lamotrigine disappeared (P = .40). Significantly improved efficacy in positive and general symptom severity was observed for topiramate (P = .04 and P = .02, respectively) and sodium valproate (P = .009 and P = .003, respectively). There were no significant differences regarding adverse drug reactions and all-cause discontinuations except for topiramate, which was associated with more all-cause discontinuations (RR = 1.99; 95% CI, 1.16 to 3.39; P = .01; I² = 0%; NNH = 7). CONCLUSIONS Sodium valproate augmentation was efficacious and safe. Topiramate augmentation had a too-high discontinuation rate. High-quality RCTs are needed to inform clinical recommendations.

N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials

This systematic review and meta‐analysis of randomized controlled trials (RCTs) examined the efficacy and safety of adjunctive N‐acetylcysteine (NAC), an antioxidant drug, in treating major depressive disorder (MDD), bipolar disorder, and schizophrenia.

Adjunctive raloxifene for postmenopausal women with schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials

OBJECTIVE Raloxifene, a selective estrogen receptor modulator, has been used in treating postmenopausal women with schizophrenia with inconsistent results. This meta-analysis of randomized, double-blind, placebo-controlled trials (RCTs) examined its efficacy and safety for postmenopausal women with schizophrenia. METHOD Standardized mean differences (SMDs) and risk ratio (RR) together with their 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS The meta-analysis included 5 RCTs (n = 240) comparing raloxifene (n = 125, 60 or 120 mg/day) with placebo (n = 115). Adjunctive raloxifene outperformed placebo with regard to the Positive and Negative Syndrome Scale (PANSS) total psychopathology [n = 240, SMD:-0.64 (95%CI:-0.90, -0.37), P < 0.00001; I2 = 0%], positive symptoms [n = 240, SMD:-0.49 (95%CI:-0.81, -0.16), P = 0.003; I2 = 29%], negative symptoms [n = 240, SMD:-0.43 (95%CI:-0.68, -0.17), P = 0.001; I2 = 0%], and general psychopathology scores [n = 240, SMD:-0.66 (95%CI:-0.92, -0.39), P < 0.00001; I2 = 0%]. Both groups had similar rates of adverse events and discontinuation (n = 159, RR: 1.32 (95%CI: 0.65, 2.70), P = 0.44, I2 = 0%). CONCLUSION Adjunctive raloxifene appears to be effective and safe in improving psychotic symptoms for postmenopausal women with schizophrenia. Review registration: CRD 42017059946.

Combination of Metformin and Lifestyle Intervention for Antipsychotic-Related Weight Gain: A Meta-Analysis of Randomized Controlled Trials

INTRODUCTION Weight gain is a common antipsychotic (AP)-related adverse drug reaction (ADR) that can increase the risk of cardiovascular diseases and premature mortality. This meta-analysis examined the efficacy and tolerability of combining metformin and lifestyle intervention for AP-related weight gain in schizophrenia. METHODS Randomized controlled trials (RCTs) with meta-analyzable data were searched and retrieved by 2 independent investigators. RevMan software (version 5.3) was used to synthesize data, and to calculate the standardized or weighted mean differences and risk ratio with their 95% confidence intervals. RESULTS Six RCTs (n=732) were included and meta-analyzed. The metformin and lifestyle combination (MLC) group had significant reduction in weight and body mass index compared with the metformin group, lifestyle group, and placebo group. There was less frequent weight gain of≥7% in the MLC group over placebo. No other group differences in ADRs, total psychopathology, and all-cause discontinuation were found. In terms of study quality, 5 RCTs were open-labelled, 1 RCT had low risk allocation concealment, and 3 RCTs specifically described randomization methods. CONCLUSION Combining metformin and lifestyle intervention shows significant effect in reducing AP-related weight gain. Higher quality and larger RCTs are needed to confirm these findings.Review registration: CRD42017059198.

Effect of adjunctive ranitidine for antipsychotic-induced weight gain: A systematic review of randomized placebo-controlled trials

This study was a meta-analysis of randomized controlled trials (RCTs) of ranitidine as an adjunct for antipsychotic-induced weight gain in patients with schizophrenia. RCTs reporting weight gain or metabolic side effects in patients with schizophrenia were included. Case reports/series, non-randomized or observational studies, reviews, and meta-analyses were excluded. The primary outcome measures were body mass index (BMI) (kg/m2) and body weight (kg). Four RCTs with five study arms were identified and analyzed. Compared with the control group, adjunctive ranitidine was associated with marginally significant reductions in BMI and body weight. After removing an outlier study for BMI, the effect of ranitidine remained significant. Adjunctive ranitidine outperformed the placebo in the negative symptom score of the Positive and Negative Syndrome Scale. Although ranitidine was associated with less frequent drowsiness, other adverse events were similar between the two groups. Adjunctive ranitidine appears to be an effective and safe option for reducing antipsychotic-induced weight gain and improving negative symptoms in patients with schizophrenia. Larger RCTs are warranted to confirm these findings. Trial registration PROSPERO: CRD42016039735

Erythropoietin for Cognitive Deficits Associated with Schizophrenia, Bipolar Disorder, and Major Depression: A Systematic Review

INTRODUCTION The purpose of this study is to systematically review the efficacy and safety of adjunctive erythropoietin (EPO) in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression based on randomized controlled trials (RCTs). METHODS Two evaluators independently and systematically searched and selected studies, extracted data, and conducted quality assessment. RESULTS Four RCTs with 144 patients (71 in the EPO group and 73 in the placebo group) met the study entry criteria. Adjunctive EPO could improve schizophrenia-related cognitive performance. In patients with bipolar disorder, EPO could also enhance sustained attention, recognition of happy faces, and speed of complex information processing across learning, attention, and executive function when compared with placebo. In addition, EPO could enhance verbal recall, recognition, and memory in patients with major depression. DISCUSSION This preliminary study found that adjunctive EPO appears to be effective in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression without major adverse effects observed. Further higher quality RCTs with larger samples are needed to confirm the findings. REVIEW REGISTRATION CRD42017058094.

Adjunctive melatonin for tardive dyskinesia in patients with schizophrenia: A meta-analysis

Background Tardive dyskinesia (TD) is characterized by abnormal and involuntary movements. Importantly, TD could cause considerable personal suffering and social and physical disabilities. Aims This meta-analysis based on randomized controlled trials (RCTs) systematically assessed the therapeutic effect and tolerability of melatonin for TD in schizophrenia. Methods A computerized and systematical search of both Chinese (Wanfang Data, Chinese National Knowledge Infrastructure (CNKI), SINOMED) and English (PubMed, PsycINFO, Embase, Cochrane Library databases) databases, from their inception until June 8, 2017, was conducted by two independent authors. The severity of TD symptoms were the primary outcome measure and analyzed using a random effects model by the Review Manager (RevMan) Version 5.3. Quality evaluation of included RCTs was conducted using the Cochrane risk of bias and Jadad scale. The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system recommendation grading method was used to assess the overall quality level of meta-analytic outcomes. Results Four RCTs (n=130) were identified and analyzed. Three RCTs used double blind and 1 RCT used masked assessors using the Cochrane risk of bias, and 3 RCTs were rated as high quality based on Jadad scale. Compared with the control group, adjunctive melatonin was superior in reducing the severity of TD as measured by the Abnormal Involuntary Movement Scale (AIMS) (4 RCTs, n=130, weighted mean difference (WMD): -1.52 (95% confidence intervals (CI): -3.24, 0.20), p=0.08; I2=0%) although the improvement did not reach a significant level. The overall evidence quality of the improvement of TD symptoms, according to GRADE approach, was rated as “Low”. The data on the ADRs and cognitive effect were limited. Conclusions This meta-analysis shows that melatonin has potential for improving TD symptoms in schizophrenia. Future higher quality and larger RCTs are warranted to confirm the findings.

ECT augmentation of clozapine for clozapine-resistant schizophrenia: A meta-analysis of randomized controlled trials

Treatment-resistant schizophrenia (TRS) is common and debilitating. A subgroup of patients even has clozapine-resistant schizophrenia (CRS). We aimed to evaluate the efficacy and safety of electroconvulsive therapy (ECT) augmentation of clozapine for CRS. Systematic literature search of randomized controlled trials (RCTs) reporting on ECT augmentation of clozapine in CRS. Co-primary outcomes included symptomatic improvement at post-ECT assessment and study endpoint. Eighteen RCTs (n = 1769) with 20 active treatment arms were identified and meta-analyzed. Adjunctive ECT was superior to clozapine regarding symptomatic improvement at post-ECT assessment (Standardized Mean Difference (SMD) = -0.88, 95% Confidence Interval (CI): -1.33 to -0.44; I2 = 86%, P = 0.0001) and endpoint assessment (SMD: -1.44, 95%CI: -2.05 to -0.84; I2 = 95%, P < 0.00001), separating as early as week 1-2 (SMD = -0.54, 95%CI: -0.88 to -0.20; I2 = 77%, P = 0.002). Adjunctive ECT was also superior regarding study-defined response at post-ECT assessment (53.6% vs. 25.4%, Risk Ratio (RR) = 1.94, 95%CI: 1.59-2.36; I2 = 0%, P < 0.00001, number-needed-to-treat (NNT) = 3, 95%CI: 3-5) and endpoint assessment (67.7% vs. 41.4%, RR = 1.66, 95%CI: 1.38-1.99; I2 = 47%, P < 0.00001, NNT = 4, 95%CI: 3-8), and remission at post-ECT assessment (13.3% vs. 3.7%, RR = 3.28, 95%CI: 1.80-5.99; I2 = 0%, P = 0.0001, NNT = 13, 95%CI: 6-100) and endpoint assessment (23.6% vs. 13.3%, RR = 1.80, 95%CI: 1.39 to 2.35; I2 = 5%, P < 0.0001, NNT = 14, 95%CI: 6-50). Patient-reported memory impairment (24.2% vs. 0%; RR = 16.10 (95%CI: 4.53-57.26); I2 = 0%, P < 0.0001, number-needed-to-harm (NNH) = 4, 95%CI: 2-14) and headache (14.5% vs 1.6%; RR = 4.03 (95%CI: 1.54-10.56); I2 = 0%, P = 0.005, NNH = 8, 95%CI: 4-50) occurred more frequently with adjunctive ECT. No significant group differences were found regarding discontinuation and other adverse effects. Despite increased frequency of self-reported memory impairment and headache, ECT augmentation of clozapine is a highly effective and relatively safe treatment for CRS. REGISTRATION NUMBER CRD42018089959.

Short-term efficacy and tolerability of lurasidone in the treatment of acute schizophrenia: A meta-analysis of randomized controlled trials

BACKGROUND Lurasidone, an azapirone derivative, is a novel second generation antipsychotic with potent binding affinity for dopamine D2, serotonin 5-HT2A, 5-HT7, 5-HT1A, and noradrenaline alpha2C receptors. This updated meta-analysis of randomized controlled trials (RCTs) examined the short-term efficacy and tolerability of lurasidone in the treatment of acute schizophrenia. METHODS Double-blinded RCTs reporting on the short-term effects of lurasidone were included. Standardized mean difference (SMD) with their 95% confidence interval (CI), and number needed to harm (NNH) were computed. RESULTS The meta-analysis had 8 RCTs with 16 active arms that included 2373 patients with acute schizophrenia who were randomized to either lurasidone (20-160 mg/day; n = 1570) or placebo (n = 803) groups. Lurasidone was superior to placebo with regard to change in total psychopathology [SMD: -0.34, (95%CI: -0.48, -0.20), P<0.00001], positive symptoms [SMD: -0.47, (95%CI: -0.57, -0.36), P<0.00001], negative symptoms [SMD:-0.34, (95%CI: -0.45, -0.22), P<0.00001], and general psychopathology [SMD: -0.36, (95%CI: -0.48, -0.24), P<0.00001]. Results were consistent for total psychopathology in 11 out of the 13 subgroups. Lurasidone resulted in higher weight gain [SMD: 0.15, (95% CI: 0.06, 0.24), P = 0.001] and BMI [SMD: 0.17, (95%CI: 0.07, 0.28), P = 0.002] than placebo, but the differences were not clinically significant. Lurasidone group had less frequent inefficacy (NNH = 14) and discontinuation due to any reason (NNH = 17), but was associated with more frequent vomiting, akathisia, dystonia, parkinsonism, somnolence, dizziness, sedation, nausea, and weight gain of ≥7% of the initial weight (NNH = 11-50). CONCLUSION This meta-analysis of 8 short-term studies supported the efficacy and safety of lurasidone in the acute phase of schizophrenia, particularly at the higher dose range of 80 mg/day.

Adjunctive azapirone for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials

Azapirones, which are serotonin1A (5-HT1A) receptor partial agonists, have been used as an adjunctive treatment for schizophrenia with mixed results. This is a meta-analysis of the efficacy and tolerability of azapirones for schizophrenia based on randomized, double-blind, placebo-controlled trials (RCTs). English and Chinese databases were systematically and independently searched by two investigators. Data were extracted and analyzed using the RevMan software (version 5.3). Seven RCTs (n = 368) of azapirones (buspirone in 6 RCTs and tandospirone in 1 RCT) were identified and analyzed. Only adjunctive buspirone outperformed placebo regarding total psychopathology [standardized mean difference: -1.03 (95% confidence interval (CI): -1.91, -0.15), P = 0.02; I2 = 92%], but the significance disappeared in sensitivity analysis after removing two outlying studies, and in 10 of the 12 subgroup analyses. In 5 RCTs examining neurocognitive function of azapirones, only 2 RCTs found the superiority of buspirone in improving attention/speeded motor performance, verbal and performance intelligence. Adjunctive buspirone outperformed placebo regarding extrapyramidal symptoms [SMD:-0.51, (95%CI: -0.99, -0.02), P = 0.04; I2 = 0%]. Similar rates of discontinuation [risk ratio:1.06 (95%CI:0.54, 2.07), P = 0.86, I2 = 0%] and adverse drug reactions were found between both groups. Adjunctive buspirone and tandospirone failed to show efficacy for psychotic symptoms, but adjunctive buspirone may be associated with improvement in extrapyramidal symptoms and cognitive deficits in schizophrenia. Due to the preliminary nature of this meta-analysis, larger sample size and higher quality RCTs are needed to confirm these finding.