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Second-Generation Antipsychotic Drugs for Patients with Schizophrenia: Systematic Literature Review and Meta-analysis of Metabolic and Cardiovascular Side Effects.
Rognoni, C, Bertolani, A, Jommi, C
Clinical drug investigation. 2021;(4):303-319
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Abstract
BACKGROUND AND OBJECTIVES Second-generation antipsychotics (SGAs) for schizophrenia show different risk profiles, whose evidence has been evaluated through comparative reviews on randomized controlled trials (RCTs) and observational studies. METHODS We performed a systematic review and meta-analysis of weight gains, metabolic and cardiovascular side effects of SGAs, relying on both RCTs and observational studies, by comparing variations between the start of treatment and the end of follow-up. The systematic review refers to papers published from June 2009 to November 2020. PRISMA criteria were followed. No restrictions on heterogeneity level have been considered for meta-analysis. A test for the summary effect measure and heterogeneity (I2 metric) was used. RESULTS Seventy-nine papers were selected from 3076 studies (61% RCTs, 39% observational studies). Olanzapine and risperidone reported the greatest weight gain and olanzapine the largest BMI increase. Paliperidone showed the highest increase in total cholesterol, but is the only drug reporting an increase in the HDL cholesterol. Quetiapine XR showed the highest decrease in fasting glucose. Lurasidone showed the lowest increase in body weight and a reduction in BMI and was also the only treatment reporting a decrease in total cholesterol and triglycerides. The highest increase in systolic and diastolic blood pressure was reported by quetiapine XR. CONCLUSIONS Despite some limitations (differences in the mean dosages per patient and other side effects not included) this paper provides the first complete meta-analysis on SGAs in variations on metabolic risk profile between start of treatment and end of follow-up, with useful results for clinical practice and possibly for future economic evaluation studies.
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The genome-wide supported CACNA1C gene polymorphisms and the risk of schizophrenia: an updated meta-analysis.
Liu, YP, Wu, X, Xia, X, Yao, J, Wang, BJ
BMC medical genetics. 2020;(1):159
Abstract
BACKGROUND The CACNA1C gene was defined as a risk gene for schizophrenia in a large genome-wide association study of European ancestry performed by the Psychiatric Genomics Consortium. Previous meta-analyses focused on the association between the CACNA1C gene rs1006737 and schizophrenia. The present study focused on whether there was an ancestral difference in the effect of the CACNA1C gene rs1006737 on schizophrenia. rs2007044 and rs4765905 were analyzed for their effect on the risk of schizophrenia. METHODS Pooled, subgroup, sensitivity, and publication bias analysis were conducted. RESULTS A total of 18 studies met the inclusion criteria, including fourteen rs1006737 studies (15,213 cases, 19,412 controls), three rs2007044 studies (6007 cases, 6518 controls), and two rs4765905 studies (2435 cases, 2639 controls). An allele model study also related rs2007044 and rs4765905 to schizophrenia. The overall meta-analysis for rs1006737, which included the allele contrast, dominant, recessive, codominance, and complete overdominance models, showed significant differences between rs1006737 and schizophrenia. However, the ancestral-based subgroup analysis for rs1006737 found that the genotypes GG and GG + GA were only protective factors for schizophrenia in Europeans. In contrast, the rs1006737 GA genotype only reduced the risk of schizophrenia in Asians. CONCLUSIONS Rs1006737, rs2007044, and rs4765905 of the CACNA1C gene were associated with susceptibility to schizophrenia. However, the influence model for rs1006737 on schizophrenia in Asians and Europeans demonstrated both similarities and differences between the two ancestors.
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From probiotics to psychobiotics - the gut-brain axis in psychiatric disorders.
Zagórska, A, Marcinkowska, M, Jamrozik, M, Wiśniowska, B, Paśko, P
Beneficial microbes. 2020;(8):717-732
Abstract
This review aims to present a comprehensive state-of-the-art analysis of the bidirectional crosstalk between gut microbiota and the central nervous system (CNS). The literature concerning the potential effects of gut microbiota on psychiatric disorders through neural pathways comprising the 'gut-brain axis' were gathered. In addition, the influence of probiotics and prebiotics and dairy-rich diets combined with the intake of probiotics and prebiotics on gut microbiota and the subsequent relationship with brain function was reviewed. However, a meta-analysis on the effectiveness of probiotic supplementation in psychiatric disorders is lacking. Therefore, a systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases from January 1969 to December 2019 was conducted. It led to the identification of a total of 844 research articles. Of these, a total of 23 studies met the meta-analysis criteria. Statistical analysis revealed that there was no significant difference in the symptoms of schizophrenia, stress, and anxiety between probiotic and placebo groups, post-intervention. Probiotic administration reduced depressive symptoms among patients with depression in a statistically significant manner (standardised mean difference (SMD) = -0.87; 95% confidence interval (95% confidence interval): -1.66, -0.99; P=0.03). Further evidence from larger and more rigorous studies with longer duration of probiotic administration, as well as well-defined populations, homogenous probiotic intervention and outcome measures, are needed to clarify the potential therapeutic effects of probiotics on psychiatric symptoms. Based on the current literature, it seems that not all probiotic-/prebiotic-/dairy-rich diet-based treatments exhibited a psychobiotic effect on the CNS. Among the parameters determining the success of the given treatment, the most significant were probiotic composition (multi-strain formulation), the quantity of ingested psychobiotics and the duration of the study.
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Trace elements in schizophrenia: a systematic review and meta-analysis of 39 studies (N = 5151 participants).
Saghazadeh, A, Mahmoudi, M, Shahrokhi, S, Mojarrad, M, Dastmardi, M, Mirbeyk, M, Rezaei, N
Nutrition reviews. 2020;(4):278-303
Abstract
CONTEXT The pathogenesis of schizophrenia appears to be multifaceted. OBJECTIVE The aim of this meta-analysis of studies that investigated blood and hair concentrations of trace elements in people diagnosed with schizophrenia was to determine whether levels of trace elements in patients with schizophrenia differ from those in healthy individuals. DATA SOURCES The PubMed, Scopus, and Web of Science databases were searched to January 2018. STUDY SELECTION Studies that compared concentrations of trace elements in patients with schizophrenia with those in healthy controls, in patients with schizophrenia under different treatment regimens, or in patients with schizophrenia at different stages of disease were included. DATA EXTRACTION Data on study and sample characteristics and measures of trace elements were extracted. RESULTS Thirty-nine studies with a total of 5151 participants were included. Meta-analysis of combined plasma and serum data showed higher levels of copper, lower levels of iron, and lower levels of zinc among patients with schizophrenia vs controls without schizophrenia. Subgroup analyses confirmed the following: higher levels of copper in plasma, in users of typical antipsychotic drugs, and in males; lower levels of zinc in serum, in patients in Asia, in drug-naive/drug-free patients, and in inpatients; lower levels of iron in serum, in patients in Asia, in drug-naive/drug-free patients, in patients on antipsychotic drugs, in inpatients, in patients with acute or newly diagnosed schizophrenia, in patients with chronic or previously diagnosed schizophrenia, and in males; and lower levels of manganese in plasma and in patients with chronic or previously diagnosed schizophrenia. CONCLUSIONS This meta-analysis provides evidence of an excess of copper, along with deficiencies of zinc, iron, and manganese, in patients with schizophrenia.
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Effect of N-methyl-D-aspartate-receptor-enhancing agents on cognition in patients with schizophrenia: A systematic review and meta-analysis of double-blind randomised controlled trials.
Chang, CH, Lane, HY, Tseng, PT, Chen, SJ, Liu, CY, Lin, CH
Journal of psychopharmacology (Oxford, England). 2019;(4):436-448
Abstract
BACKGROUND Multiple N-methyl-d-aspartate (NMDA)-receptor-enhancing agents have demonstrated promising effects for cognition in schizophrenia. However, the results of studies have been conflicting. This updated meta-analysis explored the effect of NMDA-receptor-enhancing agents on cognitive function. METHODS We searched PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials and Cochrane Systematic Reviews for studies on the effect of NMDA-receptor-enhancing agents on cognitive function in patients with schizophrenia up to September 2018. Double-blind randomised placebo trials with cognition rating scales were included. We pooled studies by using a random-effect model for comparisons with add-on NMDA-receptor-enhancing agents. Cognitive function scores were compared between baseline and subsequent levels, and NMDA-receptor-positive modulators were assessed using the standardised mean difference (SMD) with 95% confidence intervals (CIs). We evaluated statistical heterogeneity through visual inspection of funnel plots and by using the I2 statistic. RESULTS We identified 25 trials with 1951 participants meeting the inclusion criteria. NMDA-receptor-enhancing agents had a small but nonsignificant effect compared with the placebo on overall cognitive function (SMD = 0.068, CI = -0.056 to 0.193, P = 0.283). We identified trials enrolling patients aged between 30 and 39 years old, which reported significant positive effects (SMD: 0.163, 95% CI: 0.016-0.310, P = 0.030). Men were associated with a smaller effect of NMDA-receptor-positive modulators on overall cognitive function. Moreover, subgroup meta-analysis of cognitive domains revealed that N-acetyl cysteine (NAC) had a significant effect on working memory ( P-value for interaction = 0.038; SMD = 0.679, CI = 0.397-0.961, P < 0.001). CONCLUSIONS Our meta-analysis revealed no significant effect of NMDA-enhancing agents on overall cognition. However, subgroup analysis suggested that NMDAR-enhancing agents may benefit young patients with schizophrenia, and NAC may have an effect on working memory. Additional trials with larger samples are suggested to evaluate these cognitive domains and ascertain the possible mechanisms.
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Adjunctive memantine for major mental disorders: A systematic review and meta-analysis of randomized double-blind controlled trials.
Zheng, W, Zhu, XM, Zhang, QE, Cai, DB, Yang, XH, Zhou, YL, Ungvari, GS, Ng, CH, He, SH, Peng, XJ, et al
Schizophrenia research. 2019;:12-21
Abstract
OBJECTIVE As a non-competitive N-methyl-d-aspartate receptor antagonist, memantine has been used to treat major mental disorders including schizophrenia, bipolar disorder, and major depressive disorder (MDD). This meta-analysis systematically investigated the effectiveness and tolerability of adjunctive memantine for patients with schizophrenia, bipolar disorder, and MDD. METHODS Only randomized controlled trials (RCTs) were identified and included in the study. Data of the three disorders were separately synthesized using the RevMan 5.3 software. RESULTS Fifteen RCTs (n = 988) examining memantine (5-20 mg/day) as an adjunct treatment for schizophrenia (9 trials with 512 patients), bipolar disorder (3 trials with 319 patients), and MDD (3 trials with 157 patients) were analyzed. Memantine outperformed the comparator regarding total psychopathology with a standardized mean difference (SMD) of -0.56 [95% confidence interval (CI): -1.01, -0.11; I2 = 76%, P = 0.01] and negative symptoms with an SMD of -0.71 (95% CI: -1.09, -0.33; I2 = 74%, P = 0.0003) in schizophrenia, but no significant effects were found with regard to positive symptoms and general psychopathology in schizophrenia, or depressive and manic symptoms in bipolar disorder or depressive symptoms in MDD. Memantine outperformed the comparator in improving cognitive performance in schizophrenia with an SMD of 1.07 (95% CI: 0.53, 1.61; P < 0.0001, I2 = 29%). No group differences were found in the rates of adverse drug reactions and discontinuation due to any reason in the three major mental disorders. CONCLUSIONS Memantine as an adjunct treatment appears to have significant efficacy in improving negative symptoms in schizophrenia. The efficacy and safety of adjunctive memantine for bipolar disorder or MDD needs to be further examined. REVIEW REGISTRATION PROSPERO 42018099045.
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CACNA1C (rs1006737) may be a susceptibility gene for schizophrenia: An updated meta-analysis.
Zhu, D, Yin, J, Liang, C, Luo, X, Lv, D, Dai, Z, Xiong, S, Fu, J, Li, Y, Lin, J, et al
Brain and behavior. 2019;(6):e01292
Abstract
INTRODUCTION Schizophrenia is a serious mental illness with a genetic predisposition. Genome-wide association studies (GWAS) have identified the α-1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene as a significant risk gene for schizophrenia. However, there are inconsistent conclusions in case-control studies. METHODS We performed a comprehensive meta-analysis of all available samples from existing studies under four different genetic models (recessive model, dominant model, additive model and allele model) to further confirm whether CACNA1C rs1006737 is an authentic risk single nucleotide polymorphism (SNP) for schizophrenia. RESULTS A statistically significant difference under the four models (all p < 0.05) was observed by pooling nine Asian and European studies, including a total of 12,744 cases and 16,460 controls. For European-decent samples, a significant difference was identified between patients and controls for the four models (all p < 0.05). We observed a significant difference between patients and controls for the recessive model and allele model (GG vs. GA + AA: p < 0.00001; G vs. A: p < 0.00001) using a fixed effect model, but the dominant model (GG + GA vs. AA: OR: p = 0.15) and additive model (GG vs. AA: p = 0.11) showed no significant difference between patients and controls in the Asian samples. CONCLUSION Our findings provide important evidence for the establishment of CACNA1C as a susceptibility gene for schizophrenia across world populations, but its roles in the pathogenesis of schizophrenia need to be further investigated.
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Adjunctive use of anti-inflammatory drugs for schizophrenia: A meta-analytic investigation of randomized controlled trials.
Cho, M, Lee, TY, Kwak, YB, Yoon, YB, Kim, M, Kwon, JS
The Australian and New Zealand journal of psychiatry. 2019;(8):742-759
Abstract
OBJECTIVE Recent evidence suggests that adjuvant anti-inflammatory agents could improve the symptoms of patients with schizophrenia. However, the effects of the adjuvant anti-inflammatory agents on cognitive function, general functioning and side effects have not yet been systematically investigated. The present meta-analysis aimed to explore the effects of anti-inflammatory agents in patients with schizophrenia comprehensively. METHOD We performed a literature search in online databases, including PubMed, EMBASE and the Cochrane Database of Systematic Reviews. Randomized, placebo-controlled double-blind studies that investigated clinical outcomes including psychopathology, neurocognition, general functioning and extrapyramidal side effects were included. The examined anti-inflammatory agents included aspirin, celecoxib, omega-3 fatty acids, estrogen, selective estrogen receptor modulator, pregnenolone, N-acetylcysteine, minocycline, davunetide and erythropoietin. RESULTS Sixty-two double-blind randomized clinical trials studying 2914 patients with schizophrenia met the inclusion criteria for quantitative analysis. Significant overall effects were found for anti-inflammatory agents for reducing total, positive and negative symptom scores in the Positive and Negative Syndrome Scale. Cognitive improvements were significant with minocycline and pregnenolone augmentation therapy. General functioning was significantly enhanced by overall anti-inflammatory agents. There were no significant differences in side effects compared with placebo. Baseline total Positive and Negative Syndrome Scale score and illness duration were identified as moderating factors in the effects of anti-inflammatory augmentation on psychiatric symptom improvements. CONCLUSION The comparative evaluation of efficacy and safety supported the use of anti-inflammatory adjuvant therapy over the use of antipsychotics alone. However, future studies could focus on patients with homogeneous clinical profile to figure out more detailed effects of anti-inflammatory therapy.
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Treatment Strategies for Clozapine-Induced Sialorrhea: A Systematic Review and Meta-analysis.
Chen, SY, Ravindran, G, Zhang, Q, Kisely, S, Siskind, D
CNS drugs. 2019;(3):225-238
Abstract
BACKGROUND Clozapine is the most effective medication for treatment-refractory schizophrenia. However, it has a high burden of adverse events, including common adverse events such as sialorrhea. Sialorrhea can lead to severe physical complications such as aspiration pneumonia, as well as psychological complications including embarrassment and low self-esteem. Compromised adherence and treatment discontinuation can occur due to intolerability. There have been no meta-analyses examining strategies to mitigate clozapine-induced sialorrhea. METHODS We systematically searched Chinese and Western research databases for randomised controlled trials examining agents for clozapine-induced sialorrhea. No limit to language or date were applied to the search. Where sufficient data for individual agents was available, pairwise meta-analyses were conducted. Results were provided as risk ratios and number needed to treat. Sensitivity analysis was conducted by study quality. Adverse events were provided as number needed to harm. RESULTS 19 studies provided data for use in the meta-analysis. Improvement in clozapine-induced sialorrhea was seen in meta-analyses of propantheline (studies = 6, risk ratio [RR] 2.38, 95% confidence interval [CI] 1.52-3.73; number needed to treat [NNT] 3, 95% CI 1.9-2.7), diphenhydramine (studies = 5, RR 3.09, 95% CI 2.36-4.03; NNT 2, 95% CI 1.5-2.0), chlorpheniramine (studies = 2, RR 2.37, 95% CI 1.59-3.55; NNT 3, 95% CI 1.6-3.5), and benzamide derivatives (odds ratio [OR] 6.93, 95% CI 3.03-15.86). When meta-analyses were limited to high-quality studies, all these results remained significant. Single studies of benzhexol, cyproheptadine, doxepin and Kongyan Tang showed promise. Propantheline increased rates of constipation with a number needed to harm (NNH) of 9 (95% CI 4.2-204.1). CONCLUSION Clozapine-induced sialorrhea is a potentially serious adverse event. Included studies in this meta-analysis were limited by poor study quality. Diphenhydramine, chlorpheniramine and benzamide derivatives appear to have the best supporting evidence and lowest reported adverse events. Caution should be exercised when using propantheline given its increased risk of constipation.
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An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis.
Çakici, N, van Beveren, NJM, Judge-Hundal, G, Koola, MM, Sommer, IEC
Psychological medicine. 2019;(14):2307-2319
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Abstract
BACKGROUND Accumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs). METHODS PubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes. RESULTS Our search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect. CONCLUSIONS Some, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.