Search

Background The role of duration of untreated psychosis (DUP) as an early detection and intervention target to improve outcomes for individuals with first-episode psychosis is unknown. Study Design PRISMA/MOOSE-compliant systematic review to identify studies until February 1, 2023, with an intervention and a control group, reporting DUP in both groups. Random effects meta-analysis to evaluate (1) differences in DUP in early detection/intervention services vs the control group, (2) the efficacy of early detection strategies regarding eight real-world outcomes at baseline (service entry), and (3) the efficacy of early intervention strategies on ten real-world outcomes at follow-up. We conducted quality assessment, heterogeneity, publication bias, and meta-regression analyses (PROSPERO: CRD42020163640). Study Results From 6229 citations, 33 intervention studies were retrieved. The intervention group achieved a small DUP reduction (Hedges' g  = 0.168, 95% CI = 0.055–0.283) vs the control group. The early detection group had better functioning levels (g  = 0.281, 95% CI = 0.073–0.488) at baseline. Both groups did not differ regarding total psychopathology, admission rates, quality of life, positive/negative/depressive symptoms, and employment rates (P  > .05). Early interventions improved quality of life (g  = 0.600, 95% CI = 0.408–0.791), employment rates (g  = 0.427, 95% CI = 0.135–0.718), negative symptoms (g  = 0.417, 95% CI = 0.153–0.682), relapse rates (g  = 0.364, 95% CI = 0.117–0.612), admissions rates (g  = 0.335, 95% CI = 0.198–0.468), total psychopathology (g  = 0.298, 95% CI = 0.014–0.582), depressive symptoms (g  = 0.268, 95% CI = 0.008–0.528), and functioning (g  = 0.180, 95% CI = 0.065–0.295) at follow-up but not positive symptoms or remission (P  > .05). Conclusions Comparing interventions targeting DUP and control groups, the impact of early detection strategies on DUP and other correlates is limited. However, the impact of early intervention was significant regarding relevant outcomes, underscoring the importance of supporting early intervention services worldwide. [ABSTRACT FROM AUTHOR]

Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.

Duration of untreated psychosis (DUP) has been associated with poor mental health outcomes. We aimed to meta-analytically estimate the mean and median DUP worldwide, evaluating also the influence of several moderating factors. This PRISMA/MOOSE-compliant meta-analysis searched for non-overlapping individual studies from inception until 9/12/2022, reporting mean ± s.d. or median DUP in patients with first episode psychosis (FEP), without language restrictions. We conducted random-effect meta-analyses, stratified analyses, heterogeneity analyses, meta-regression analyses, and quality assessment (PROSPERO:CRD42020163640). From 12 461 citations, 369 studies were included. The mean DUP was 42.6 weeks (95% confidence interval (CI) 40.6–44.6, k = 283, n = 41 320), varying significantly across continents (p < 0.001). DUP was (in descending order) 70.0 weeks (95% CI 51.6–88.4, k = 11, n = 1508) in Africa; 48.8 weeks (95% CI 43.8–53.9, k = 73, n = 12 223) in Asia; 48.7 weeks (95% CI 43.0–54.4, k = 36, n = 5838) in North America; 38.6 weeks (95% CI 36.0–41.3, k = 145, n = 19 389) in Europe; 34.9 weeks (95% CI 23.0–46.9, k = 11, n = 1159) in South America and 28.0 weeks (95% CI 20.9–35.0, k = 6, n = 1203) in Australasia. There were differences depending on the income of countries: DUP was 48.4 weeks (95% CI 43.0–48.4, k = 58, n = 5635) in middle-low income countries and 41.2 weeks (95% CI 39.0–43.4, k = 222, n = 35 685) in high income countries. Longer DUP was significantly associated with older age (β = 0.836, p < 0.001), older publication year (β = 0.404, p = 0.038) and higher proportion of non-White FEP patients (β = 0.232, p < 0.001). Median DUP was 14 weeks (Interquartile range = 8.8–28.0, k = 206, n = 37 215). In conclusion, DUP is high throughout the world, with marked variation. Efforts to identify and intervene sooner in patients with FEP, and to promote global mental health and access to early intervention services (EIS) are critical, especially in developing countries. [ABSTRACT FROM AUTHOR]

Background: Early-onset psychosis (EOP) refers to the development of a first episode of psychosis before 18 years of age. Individuals at clinical high risk for psychosis (CHR-P) include adolescents and young adults, although most evidence has focused on adults. Negative symptoms are important prognostic indicators in psychosis. However, research focusing on children and adolescents is limited. Aims: To provide meta-analytical evidence and a comprehensive review of the status and advances in the diagnosis, prognosis and treatment of negative symptoms in children and adolescents with EOP and at CHR-P. Method: PRISMA/MOOSE-compliant systematic review (PROSPERO: CRD42022360925) from inception to 18 August 2022, in any language, to identify individual studies conducted in EOP/CHR-P children and adolescents (mean age <18 years) providing findings on negative symptoms. Findings were systematically appraised. Random-effects meta-analyses were performed on the prevalence of negative symptoms, carrying out sensitivity analyses, heterogeneity analyses, publication bias assessment and quality assessment using the Newcastle–Ottawa Scale. Results: Of 3289 articles, 133 were included (n = 6776 EOP, mean age 15.3 years (s.d. = 1.6), males = 56.1%; n = 2138 CHR-P, mean age 16.1 years (s.d. = 1.0), males = 48.6%). There were negative symptoms in 60.8% (95% CI 46.4%–75.2%) of the children and adolescents with EOP and 79.6% (95% CI 66.3–92.9%) of those at CHR-P. Prevalence and severity of negative symptoms were associated with poor clinical, functional and intervention outcomes in both groups. Different interventions were piloted, with variable results requiring further replication. Conclusions: Negative symptoms are common in children and adolescents at early stages of psychosis, particularly in those at CHR-P, and are associated with poor outcomes. Future intervention research is required so that evidence-based treatments will become available. [ABSTRACT FROM AUTHOR]

Background: Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use as monotherapy and adjunctive therapy. Methods: A systematic review and a meta-analysis were conducted on randomized placebo-controlled trials (RCTs) that reported on the efficacy and safety/tolerability of antipsychotics for the treatment of adults with MDD. Data of both monotherapy and adjunctive antipsychotic use were extracted, but analyzed separately using a random-effects model. Co-primary outcomes were study-defined-treatment response and intolerability-related discontinuation. We also illustrated the risk/benefit balance of antipsychotics for MDD, using two-dimensional graphs representing the primary efficacy and safety/tolerability outcome. Secondary outcomes included psychopathology, remission, all-cause-discontinuation, inefficacy-related discontinuation, and adverse events. Results: Forty-five RCTs with 12 724 patients were included in the analysis. In monotherapy (studies = 13, n = 4375), amisulpride [1.99 (1.55–2.55)], sulpiride [1.50 (1.03–2.17)], and quetiapine [1.48 (1.23–1.78)] were significantly superior to placebo regarding treatment response. However, intolerability-related discontinuations were significantly higher compared to placebo with amisulpride and quetiapine. In adjunctive therapy (studies = 32, n = 8349), ziprasidone [1.80 (1.07–3.04)], risperidone [1.59 (1.19–2.14)], aripiprazole [1.54 (1.35–1.76)], brexpiprazole [1.41 (1.21–1.66)], cariprazine [1.27 (1.07–1.52)], and quetiapine [1.23 (1.08–1.41)] were significantly superior to placebo regarding treatment response. However, of these antipsychotics that were superior to placebo, only risperidone was equivalent to placebo regarding discontinuation due to intolerability, while the other antipsychotics were inferior. Conclusion: Results suggest that there are significant differences regarding the risk/benefit ratio among antipsychotics for MDD, which should inform clinical care. [ABSTRACT FROM AUTHOR]

Background: Serious mental illness (SMI) reduces life expectancy, primarily due to somatic comorbidity linked to obesity. Meta-analyses have found beneficial effects of lifestyle interventions in people with SMI and recommended their implementation to manage obesity.Objective: The objective of this systematic review was to assess the benefits and harms of individualized lifestyle interventions for weight in people diagnosed with SMI and to explore potential mediators and moderators of the effect.Methods: The protocol was registered at PROSPERO (CRD42016049093). Randomized clinical trials (RCTs) assessing the effect of individualized lifestyle interventions on weight management in people with SMI were included. Primary outcomes were differences in endpoint body mass index (BMI) and the proportion achieving clinically relevant weight loss (≥5%). Secondary outcomes included quality of life, cardiometabolic risk factors, and adverse effects.Results: We included 41 RCTs (n = 4,267). All trials were at high risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. The experimental interventions reduced the mean difference in BMI by -0.63 kg/m2 (95% confidence interval [CI] = -1.02 to -0.23; p = 0.002; I2 = 70.7%) compared to the control groups. At postintervention follow-up (17 RCTs), the effect size remained similar but was no longer significant (BMI = -0.63 kg/m2; 95% CI = -1.30 to 0.04; p = 0.07; I2 = 48.8%). The risk ratio for losing ≥5% of baseline weight was 1.51 (95% CI = 1.07-2.13; p = 0.02) compared to the control groups. GRADE showed very low or low quality of evidence.Conclusion: There is a statistically significant, but clinically insignificant, mean effect of individualized lifestyle interventions for weight reduction in people with SMI. [ABSTRACT FROM AUTHOR]

Background Matrix metalloproteinase 9 (MMP-9), an extracellular network protease implicated in glutamatergic signaling, may be part of the pathophysiology of schizophrenia spectrum disorders (SSD). Methods We performed a systematic review in PubMed/Embase until July 15, 2020, conducting a random-effects meta-analysis of studies comparing MMP-9 blood levels in SSD vs healthy controls (HCs) and psychiatric controls (PCs), calculating between-group differences in standardized mean differences (SMDs) ± 95% confidence intervals (CIs). Meta-regression analyses included sex, age, illness duration, antipsychotic dose, and Positive and Negative Syndrome Scale (PANSS) total/subscales. Subgroup analyses included first-episode patients (FEP) vs non-FEP, each vs HCs and vs PCs, and blood sample type. Study quality was assessed using the Newcastle-Ottawa scale. Results Four, five, and two trials were rated as high, fair, and low quality. In 11 studies (n = 1443), 643 patients (age = 36.7 ± 14.1 years, females = 42.9%) were compared with HCs (n = 631), with 4 studies including also 169 PCs. MMP-9 levels were higher in SSD vs HCs (SMD = 0.52, 95%CI = 0.20–0.85, P =.002), but not in PCs vs HCs (n = 132, after removing one implausible outlier [SMD = 0.33, 95%CI = −0.16 to 0.85, P =.082]). MMP-9 differences between SSD and HCs were associated with higher PANSS total (coefficient = 0.02, 95%CI = 0.01–0.02, P <.001), PANSS positive (coefficient = 0.08, 95%CI = 0.02–0.13, P =.006), and PANSS general scores (coefficient = 0.02, 95%CI = 0.01–0.03, P <.001). MMP-9 level differences vs HCs did not vary significantly between FEP (n = 103, SMD = 0.44, 95%CI = 0.15–0.72, P =.71) and non-FEP patients (n = 466, SMD = 0.59, 95%CI = 0.38–0.80; P =.34) (FEP vs non-FEP: P =.39). In four high-quality studies, MMP-9 levels remained significantly higher in SSD vs HCs (SMD = 0.82, 95%CI = 0.03–1.61). Conclusions Findings suggest MMP-9 upregulation in SSD, requiring further validation and understanding of related pathways. [ABSTRACT FROM AUTHOR]

Objective Obesity and adverse metabolic outcomes in patients with severe mental illness are clinically significant but potentially preventable. Importantly, the evidence for switching to antipsychotics to reduce cardiometabolic burden is unclear. Method PubMED, Embase, PsycINFO, and Cochrane were searched from inception to March 8, 2020. Articles reporting weight and metabolic changes after antipsychotic switching vs staying on the previous antipsychotic were meta-analyzed both across and within group. Results Of 61 identified studies, 59 were meta-analyzed (40% rated high quality). In the switch-vs-stay pairwise meta-analyses, only aripiprazole significantly reduced weight (−5.52 kg, 95% CI −10.63, −0.42, P =.03), while olanzapine significantly increased weight (2.46 kg, 95% CI 0.34, 4.57, P =.02). Switching to aripiprazole also significantly improved fasting glucose (−3.99 mg/dl, 95% CI −7.34, −0.64, P =.02) and triglycerides (−31.03 mg/dl, 95% CI −48.73, −13.34, P =.0001). Dropout and psychosis ratings did not differ between switch and stay groups for aripiprazole and olanzapine. In before-to-after switch meta-analyses, aripiprazole (−1.96 kg, 95% CI −3.07, −0.85, P <.001) and ziprasidone (−2.22 kg, 95% CI −3.84, −0.60, P =.007) were associated with weight loss, whereas olanzapine (2.71 kg, 95% CI 1.87, 3.55, P <.001), and clozapine (2.80 kg, 95% CI 0.26, 5.34, P =.03) were associated with weight gain. No significant weight or other cardiometabolic changes were observed when switching to amisulpride, paliperidone/risperidone, quetiapine, or lurasidone. Conclusions Switching antipsychotics to agents with lower weight gain potential, notably to aripiprazole and ziprasidone, can improve weight profile and other cardiometabolic outcomes. When choosing switch agents, both the weight gain potential of the pre- and post-switch antipsychotic must be considered. Antipsychotic switching in psychiatrically stable patients must be weighed against the risk of psychiatric worsening. [ABSTRACT FROM AUTHOR]

Background: The clinical high‐risk state for psychosis (CHR‐P) paradigm has facilitated the implementation of psychosis prevention into clinical practice; however, advancements in adolescent CHR‐P populations are less established. Methods: We performed a PRISMA/MOOSE‐compliant systematic review of the Web of Science database, from inception until 7 October 2019, to identify original studies conducted in CHR‐P children and adolescents (mean age <18 years). Findings were systematically appraised around core themes: detection, prognosis and intervention. We performed meta‐analyses (employing Q statistics and I2 test) regarding the proportion of CHR‐P subgroups, the prevalence of baseline comorbid mental disorders, the risk of psychosis onset and the type of interventions received at baseline. Quality assessment and publication bias were also analysed. Results: Eighty‐seven articles were included (n = 4,667 CHR‐P individuals). Quality of studies ranged from 3.5 to 8 (median 5.5) on a modified Newcastle–Ottawa scale. Detection: Individuals were aged 15.6 ± 1.2 years (51.5% males), mostly (83%) presenting with attenuated positive psychotic symptoms. CHR‐P psychometric accuracy improved when caregivers served as additional informants. Comorbid mood (46.4%) and anxiety (31.4%) disorders were highly prevalent. Functioning and cognition were impaired. Neurobiological studies were inconclusive. Prognosis: Risk for psychosis was 10.4% (95%CI: 5.8%–18.1%) at 6 months, 20% (95%CI: 15%–26%) at 12 months, 23% (95%CI: 18%–29%) at 24 months and 23.3% (95%CI: 17.3%–30.7%) at ≥36 months. Interventions: There was not enough evidence to recommend one specific treatment (including cognitive behavioural therapy) over the others (including control conditions) to prevent the transition to psychosis in this population. Randomised controlled trials suggested that family interventions, cognitive remediation and fish oil supplementation may improve cognition, symptoms and functioning. At baseline, 30% of CHR‐P adolescents were prescribed antipsychotics and 60% received psychotherapy. Conclusions: It is possible to detect and formulate a group‐level prognosis in adolescents at risk for psychosis. Future interventional research is required. [ABSTRACT FROM AUTHOR]

Objective: To investigate oxidative stress markers and antioxidants in bipolar disorder (BD). Methods: Electronic MEDLINE/PubMed/Cochrane‐Library/Scopus/TripDatabase search until 06/30/2019 for studies comparing antioxidant or oxidative stress markers between BD and healthy controls (HCs). Standardized mean differences (SMD) and 95% confidence intervals (CIs) were calculated for ≥3 studies. Results: Forty‐four studies (n = 3,767: BD = 1,979; HCs = 1,788) reported on oxidative stress markers malondialdehyde (MDA), thiobarbituric acid reactive substances (TBARS), and total nitrites; antioxidants glutathione (GSH), uric acid, and zinc; or antioxidantenhancing enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and GSH‐transferase (GST). Compared with HCs, BD was associated with higher GST (P =.01), CAT (P =.02), nitrites (P <.0001), TBARS (P <.0001), MDA (P =.01), uric acid (P <.0001), and lower GSH (P =.006), without differences in SOD, GPX, and zinc. Compared to HCs, levels were higher in BD‐mania for TBARS (P <.0001) and uric acid (P <.0001); in BD‐depression for TBARS (P =.02); and BD‐euthymia for uric acid (P =.03). Uric acid levels were higher in BD‐mania vs BD‐depression (P =.002), but not vs BD euthymia. TBARS did not differ between BD‐mania and BD‐depression. Medication‐free BD‐mania patients had higher SOD (P =.02) and lower GPX (P <.0001) than HCs. After treatment, BD did not differ from HCs regarding SOD and GPX. Conclusions: Beyond a single biomarker of oxidative stress, the combination of several parameters appears to be more informative for BD in general and taking into account illness polarity. BD is associated with an imbalance in oxidative stress with some phase‐specificity for uric acid and TBARS and possible treatment benefits for SOD and GPX. Future studies should take into account confounding factors that can modify oxidative stress status and simultaneously measure oxidative stress markers and antioxidants including different blood sources. [ABSTRACT FROM AUTHOR]

Background: Determining the best latent structure of negative symptoms in schizophrenia could benefit assessment tools, neurobiological research, and targeted interventions. However, no review systematically evaluated studies that assessed and validated latent models of negative symptoms. Objective: To identify and evaluate existing latent structure models in the literature of negative symptoms and to determine the best model. Method: Systematic search of MEDLINE, EMBASE, and Scopus on July 19, 2020, for confirmatory factor analysis models of negative symptoms in patients with schizophrenia. The available evidence was assessed through 2 sets of criteria: (1) study design quality--based on negative symptoms assessment and modeling strategy and (2) psychometric quality and model fit--based on fit indices and factor definition quality. Results: In total, 22 studies (n = 17 086) from 9 countries were included. Studies differed greatly regarding symptom scales, setting, and sample size (range = 86-6889). Dimensional models included 2-6 factors (median = 4). Twelve studies evaluated competing models and adopted appropriate instruments to assess the latent structure of negative symptoms. The 5-factor and hierarchical models outperformed unitary, 2-factor, and 3-factor models on all direct comparisons, and most of the analyses derived from the Brief Negative Symptom Scale. Considering the quality criteria proposed, 5-factor and hierarchical models achieved excellent fit in just one study. Conclusions: Our review points out that the 5-factor and hierarchical models represent the best latent structure of negative symptoms, but the immaturity of the relevant current literature may affect the robustness of this conclusion. Future studies should address current limitations regarding psychometric properties and also address biological and clinical validity to refine available models. [ABSTRACT FROM AUTHOR]

Importance: Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry.Objective: To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations.Evidence Review: Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes.Findings: In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered.Conclusions and Relevance: This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions. [ABSTRACT FROM AUTHOR]

Background: It has been proposed that the threshold of statistical significance should shift from P-value < 0.05 to P-value < 0.005, but there is concern that this move may dismiss effective, useful interventions. We aimed to assess how often medical interventions are recommended although their evidence in meta-analyses of randomized trials lies between P-value = 0.05 and P-value = 0.005.Methods: We included Cochrane systematic reviews (SRs) published from 1 January 2013 to 30 June 2014 that had at least one meta-analysis with GRADE (Grading of Recommendations Assessment, Development and Evaluation) assessment and at least one primary outcome having favourable results for efficacy at P-value < 0.05. Only comparisons of randomized trials between active versus no treatment/placebo were included. We then assessed the respective UpToDate recommendations for clinical practice from 22 May 2018 to 5 October 2018 and recorded how many treatments were recommended and what were the P-values in their meta-analysis evidence. The primary analysis was based on the first-listed outcomes.Results: Of 608 screened SRs with GRADE assessment, 113 SRs were eligible, including 143 comparisons of which 128 comparisons had first-listed primary outcomes with UpToDate coverage. Altogether, 60% (58/97) of interventions with P-values < 0.005 for their evidence were recommended versus 32% (10/31) of those with P-value 0.005-0.05. Therefore, most (58/68, 85.2%) of the recommended interventions had P-values < 0.005 for the first-listed primary outcome. Of the 10 exceptions, 4 had other primary outcomes with P-values < 0.005 and another 4 had additional extensive evidence for similar indications that would allow extrapolation for practice recommendations.Conclusions: Few interventions are recommended without their evidence from meta-analyses of randomized trials reaching P-value < 0.005. [ABSTRACT FROM AUTHOR]

Objective: Uncertainty surrounds the risks of lithium use during pregnancy in women with bipolar disorder. The authors sought to provide a critical appraisal of the evidence related to the efficacy and safety of lithium treatment during the peripartum period, focusing on women with bipolar disorder and their offspring.Methods: The authors conducted a systematic review and random-effects meta-analysis assessing case-control, cohort, and interventional studies reporting on the safety (primary outcome, any congenital anomaly) or efficacy (primary outcome, mood relapse prevention) of lithium treatment during pregnancy and the postpartum period. The Newcastle-Ottawa Scale and the Cochrane risk of bias tools were used to assess the quality of available PubMed and Scopus records through October 2018.Results: Twenty-nine studies were included in the analyses (20 studies were of good quality, and six were of poor quality; one study had an unclear risk of bias, and two had a high risk of bias). Thirteen of the 29 studies could be included in the quantitative analysis. Lithium prescribed during pregnancy was associated with higher odds of any congenital anomaly (N=23,300, k=11; prevalence=4.1%, k=11; odds ratio=1.81, 95% CI=1.35-2.41; number needed to harm (NNH)=33, 95% CI=22-77) and of cardiac anomalies (N=1,348,475, k=12; prevalence=1.2%, k=9; odds ratio=1.86, 95% CI=1.16-2.96; NNH=71, 95% CI=48-167). Lithium exposure during the first trimester was associated with higher odds of spontaneous abortion (N=1,289, k=3, prevalence=8.1%; odds ratio=3.77, 95% CI=1.15-12.39; NNH=15, 95% CI=8-111). Comparing lithium-exposed with unexposed pregnancies, significance remained for any malformation (exposure during any pregnancy period or the first trimester) and cardiac malformations (exposure during the first trimester), but not for spontaneous abortion (exposure during the first trimester) and cardiac malformations (exposure during any pregnancy period). Lithium was more effective than no lithium in preventing postpartum relapse (N=48, k=2; odds ratio=0.16, 95% CI=0.03-0.89; number needed to treat=3, 95% CI=1-12). The qualitative synthesis showed that mothers with serum lithium levels <0.64 mEq/L and dosages <600 mg/day had more reactive newborns without an increased risk of cardiac malformations.Conclusions: The risk associated with lithium exposure at any time during pregnancy is low, and the risk is higher for first-trimester or higher-dosage exposure. Ideally, pregnancy should be planned during remission from bipolar disorder and lithium prescribed within the lowest therapeutic range throughout pregnancy, particularly during the first trimester and the days immediately preceding delivery, balancing the safety and efficacy profile for the individual patient. [ABSTRACT FROM AUTHOR]

Importance: Antidepressant use is increasing worldwide. Yet, contrasting evidence on the safety of antidepressants is available from meta-analyses, and the credibility of these findings has not been quantified.Objective: To grade the evidence from published meta-analyses of observational studies that assessed the association between antidepressant use or exposure and adverse health outcomes.Data Sources: PubMed, Scopus, and PsycINFO were searched from database inception to April 5, 2019.Evidence Review: Only meta-analyses of observational studies with a cohort or case-control study design were eligible. Two independent reviewers recorded the data and assessed the methodological quality of the included meta-analyses. Evidence of association was ranked according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant.Results: Forty-five meta-analyses (17.9%) from 4471 studies identified and 252 full-text articles scrutinized were selected that described 120 associations, including data from 1012 individual effect size estimates. Seventy-four (61.7%) of the 120 associations were nominally statistically significant at P ≤ .05 using random-effects models. Fifty-two associations (43.4%) had large heterogeneity (I2 > 50%), whereas small-study effects were found for 17 associations (14.2%) and excess significance bias was found for 9 associations (7.5%). Convincing evidence emerged from both main and sensitivity analyses for the association between antidepressant use and risk of suicide attempt or completion among children and adolescents, autism spectrum disorders with antidepressant exposure before and during pregnancy, preterm birth, and low Apgar scores. None of these associations remained supported by convincing evidence after sensitivity analysis, which adjusted for confounding by indication.Conclusions and Relevance: This study's findings suggest that most putative adverse health outcomes associated with antidepressant use may not be supported by convincing evidence, and confounding by indication may alter the few associations with convincing evidence. Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases. No absolute contraindication to antidepressants emerged from this umbrella review. [ABSTRACT FROM AUTHOR]

Importance: Recent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine's superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice.Objective: To conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies.Data Sources: Systematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018.Study Selection: Nonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder.Data Extraction and Synthesis: Independent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data.Main Outcomes and Measures: Coprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies.Results: Of 8446 hits, 68 articles from 63 individual cohort studies (n = 109 341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; RR, 0.732; 95% CI, 0.639-0.838; P < .001; NNT, 8; 95% CI, 6-12). Associations were statistically significant for comparisons with quetiapine fumarate and aripiprazole regarding hospitalization and all NC-SGAs, except aripiprazole, for all-cause discontinuation. Clozapine was also significantly associated with better outcomes regarding overall symptoms (SMD, -0.302; 95% CI, -0.572 to -0.032; P = .03) and Clinical Global Impressions scale severity (SMD, -1.182; 95% CI, -2.243 to -0.122; P = .03). Clozapine was significantly associated with increases in body weight (MD, 1.70; 95% CI, 0.31-3.08 kg; P = .02), body mass index (MD, 0.96; 95% CI, 0.24-1.68; P = .009), and type 2 diabetes (RR, 1.777; 95% CI, 1.229-2.570; P = .002; NNH, 27; 95% CI, 13-90).Conclusions and Relevance: In cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs. [ABSTRACT FROM AUTHOR]

Introduction Patients with schizophrenia have an elevated mortality risk compared to the general population, with cardiovascular-related deaths being the leading cause. The role of clozapine use in the long-term mortality risk is unclear. While clozapine treatment may increase the risk for cardiovascular mortality, it may have protective effects regarding suicidal behavior. Methods We systematically searched EMBASE, MEDLINE, and PsycINFO and reviewed studies that used a long-term follow-up (ie, >52 weeks) and reported on mortality in adults diagnosed with schizophrenia-spectrum disorders who had received clozapine treatment. Results Altogether, 24 studies reported on 1327 deaths from any causes during 217691 patient years in patients treated with clozapine. The unadjusted mortality rate in 22 unique samples during a follow-up of 1.1–12.5 (median = 5.4) years was 6.7 (95% confidence interval [CI] = 5.4–7.9) per 1000 patient years. Long-term, crude mortality rate ratios were not significantly lower in patients ever treated with clozapine during follow-up, but significantly lower in patients continuously treated with clozapine compared to patients with other antipsychotics (mortality rate ratio = 0.56, 95% CI = 0.36–0.85, P -value =.007). Few studies reported on rates of long-term cause-specific mortality (suicide and ischemic heart disease), which showed no significant difference in patients using clozapine compared to patients using other antipsychotics. Statistical heterogeneity was high in all analyses. Discussion Continuous clozapine treatment in schizophrenia patients was associated with a significantly lower long-term all-cause mortality rate compared to other antipsychotic use. These findings, combined with the known efficacy of clozapine, give reason to re-evaluate the hesitancy to prescribe clozapine in regular care settings. Trial registration PROSPERO CRD42017069390. [ABSTRACT FROM AUTHOR]

Importance: The value of early intervention in psychosis and allocation of public resources has long been debated because outcomes in people with schizophrenia spectrum disorders have remained suboptimal.Objective: To compare early intervention services (EIS) with treatment as usual (TAU) for early-phase psychosis.Data Sources: Systematic literature search of PubMed, PsycINFO, EMBASE, and ClinicalTrials.gov without language restrictions through June 6, 2017.Study Selection: Randomized trials comparing EIS vs TAU in first-episode psychosis or early-phase schizophrenia spectrum disorders.Data Extraction and Synthesis: This systematic review was conducted according to PRISMA guidelines. Three independent investigators extracted data for a random-effects meta-analysis and prespecified subgroup and meta-regression analyses.Main Outcomes and Measures: The coprimary outcomes were all-cause treatment discontinuation and at least 1 psychiatric hospitalization during the treatment period.Results: Across 10 randomized clinical trials (mean [SD] trial duration, 16.2 [7.4] months; range, 9-24 months) among 2176 patients (mean [SD] age, 27.5 [4.6] years; 1355 [62.3%] male), EIS was associated with better outcomes than TAU at the end of treatment for all 13 meta-analyzable outcomes. These outcomes included the following: all-cause treatment discontinuation (risk ratio [RR], 0.70; 95% CI, 0.61-0.80; P < .001), at least 1 psychiatric hospitalization (RR, 0.74; 95% CI, 0.61-0.90; P = .003), involvement in school or work (RR, 1.13; 95% CI, 1.03-1.24; P = .01), total symptom severity (standardized mean difference [SMD], -0.32; 95% CI, -0.47 to -0.17; P < .001), positive symptom severity (SMD, -0.22; 95% CI, -0.32 to -0.11; P < .001), and negative symptom severity (SMD, -0.28; 95% CI, -0.42 to -0.14; P < .001). Superiority of EIS regarding all outcomes was evident at 6, 9 to 12, and 18 to 24 months of treatment (except for general symptom severity and depressive symptom severity at 18-24 months).Conclusions and Relevance: In early-phase psychosis, EIS are superior to TAU across all meta-analyzable outcomes. These results support the need for funding and use of EIS in patients with early-phase psychosis. [ABSTRACT FROM AUTHOR]

Compared with oral antipsychotics (OAPs), long-acting injectable antipsychotics (LAIs) should improve medication adherence and reduce relapses in schizophrenia. However, meta-analyses of randomized trials and mirror-image studies yielded inconsistent results. Nonrandomized cohort studies with parallel comparisons of LAIs and OAPs offer a third design to examine this issue. We meta-analyzed cohort studies with ≥24 weeks duration and hospitalization data. Primary outcome was hospitalization rate, ie, number of hospitalizations per person-year. Secondary outcomes included hospitalization risk, ie, proportion of patients experiencing ≥1 hospitalizations, all-cause discontinuation, and total hospitalization days. Patient severity and/or chronicity at baseline was also meta-analyzed and explored as a potential effect size moderator. Altogether, 42 studies (n = 101 624; follow-up = 18.6 ± 10.0 mo) were meta-analyzed. LAIs were superior to OAPs regarding hospitalization rate (studies = 15, person-years = 68 009, rate ratio = 0.85, 95% CI = 0.78-0.93, P < .001) and all-cause discontinuations (studies = 10, n = 37 293, risk ratio = 0.78, 95% CI = 0.67-0.91, P = .001), but not regarding hospitalization risk (studies = 33, n = 51 733, risk ratio = 0.92, 95% CI = 0.84-1.00, P = .06), and hospitalization days (studies = 11, n = 21 328, Hedges' g = -0.05, 95% CI = -0.16 to 0.06, P = .39). Illness severity/chronicity was significantly greater in patients prescribed LAIs vs OAPs when all available information was pooled together (studies = 23, n = 61 806, Hedges' g = 0.15, 95% CI = 0.03-0.26, P = .01), but not when examined separately. In summary, this meta-analysis of cohort studies, which included patients that are broadly representative of clinical practice, indicates that LAIs are superior to OAPs. The lack of significant superiority of LAIs for hospitalization risk and hospital days needs to be interpreted in the context of naturalistic treatment selection with subsequently greater illness severity/chronicity in LAI-treated patients. [ABSTRACT FROM AUTHOR]

The glutamate hypothesis of schizophrenia is related to the proposed dysregulation of d-amino acid oxidase ( DAO), DAO activator ( DAOA)/ G72, and Neuregulin 1 ( NRG1) genes. Genetic studies have shown significant associations between DAO, DAOA, NRG1 single-nucleotide polymorphisms (SNPs), and schizophrenia. The systematic literature search yielded 6, 5, and 18 new studies for DAO, DAOA, and NRG1 published after 2011 and not included in the previous SchizophreniaGene (SZGene) meta-analysis. We conducted meta-analyses of 20, 23, and 48 case-control studies, respectively, to comprehensively evaluate the association of 8 DAO, 12 DAOA, and 14 NRG1 SNPs with schizophrenia. The updated meta-analyses resulted in the following findings: the C-allele of DAO rs4623951 was associated with schizophrenia across all pooled studies [Odds ratio (OR) = 0.88, 95% confidence interval (CI) = 0.79-0.98, p = 0.02, N = 3143]; however, no new reports could be included. The G-allele of DAOA rs778293 was associated with schizophrenia in Asian patients (OR = 1.17, 95% CI = 1.08-1.27, p = 0.00008, N = 6117), and the T-allele of DAOA rs3916971 was associated with schizophrenia across all studies (OR = 0.84, 95% CI = 0.73-0.96, p = 0.01, N = 1765). Again, for both SNPs, no new eligible studies were available. After adding new reports, the T-allele of NRG1 SNP8NRG241930 (rs62510682) across all studies (OR = 0.95, 95% CI = 0.91-0.997, p = 0.04, N = 22,898) and in Caucasian samples (OR = 0.95, 95% CI = 0.90-0.99, p = 0.03, N = 16,014), and the C-allele of NRG1 rs10503929 across all studies (OR = 0.89, 95% CI = 0.81-0.97, p = 0.01, N = 6844) and in Caucasian samples (OR = 0.89, 95% CI = 0.81-0.98, p = 0.01, N = 6414) were protective against schizophrenia. Our systematic meta-analysis is the most updated one for the association of DAO, DAOA, and NRG1 SNPs with schizophrenia. [ABSTRACT FROM AUTHOR]

Objectives We investigated whether catechol- O-methyltransferase (COMT) Val158Met polymorphism is associated with eating disorders (EDs). Methods We conducted a systematic literature search of studies published until 15 January 2017 and added data from the Italian ' Biobanca Veneta per i Disturbi Alimentari' biobank, performing a meta-analysis comparing COMT Val158Met genotype and allele frequencies in EDs and anorexia nervosa (AN) or bulimia nervosa (BN) patients versus controls. Results Ten studies plus Biobanca Veneta per i Disturbi Alimentari (ED: n = 920, controls: n = 261 controls) with 3541 ED patients (AN = 2388; BN = 233) and 3684 controls were included. There were no significant group differences in COMT Val158Met alleles and genotype frequencies between patients and controls, for all EDs pooled together [range of odds ratios (ORs): 0.96-1.04, p-values: 0.46-0.97, I2 = 0%] and when analysing separately patients with AN (ORs: 0.94-1.04, p-values: 0.31-0.61, I2 = 0%) or BN (ORs: 0.80-1.09, p-values: 0.28-0.64, I2 = 0-44%). Conclusions Meta-analysing data results from 11 studies and 7225 subjects show that COMT Val158Met polymorphism is not associated with EDs. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. [ABSTRACT FROM AUTHOR]

Importance: Limited treatment responses in schizophrenia prompted the testing of combining an antipsychotic drug treatment with a second psychotropic medication. A comprehensive evaluation of the efficacy of multiple medication combinations is missing.Objective: To summarize and compare the meta-analytically determined efficacy of pharmacologic combination strategies of antipsychotic drugs in adults with schizophrenia.Data Sources: Systematic search of PubMed and PsycInfo until May 13, 2016.Study Selection: Meta-analyses of randomized clinical trials comparing the efficacy of antipsychotic drugs combined with other antipsychotic or nonantipsychotic medications vs placebos or antipsychotic monotherapy among adults with schizophrenia.Data Extraction and Synthesis: Independent reviewers extracted the data and assessed the quality of the methods of the included meta-analyses using A Measurement Tool to Assess Systematic Reviews (AMSTAR), adding 6 new items to rate their quality. Effect sizes, expressed as standardized mean difference /Hedges g or risk ratio, were compared separately for combinations with any antipsychotic drug and for combinations with clozapine.Main Outcomes and Measures: The primary outcome was total symptom reduction. Secondary outcomes included positive and negative symptoms, treatment recommendations by authors, study-defined inefficacies, cognitive and depressive symptoms, discontinuation of treatment because of any cause, and inefficacies or intolerabilities.Results: Of 3397 publications, 29 meta-analyses testing 42 combination strategies in 381 individual trials and among 19 833 participants were included. For total symptom reductions, 32 strategies that augmented any antipsychotic drug and 5 strategies that augmented clozapine were examined. Fourteen combination treatments outperformed controls (standard mean difference/Hedges g, -1.27 [95% CI, -2.35 to -0.19] to -0.23 [95% CI, -0.44 to -0.02]; P = .05). No combination strategies with clozapine outperformed controls. The quality of the methods of the meta-analyses was generally high (mean score, 9 of a maximum score of 11) but the quality of the meta-analyzed studies was low (mean score, 2.8 of a maximum score of 8). Treatment recommendations correlated with the effect size (correlation coefficient, 0.22; 95% CI, 0.35-0.10; P < .001), yet effect sizes were inversely correlated with study quality (correlation coefficient, -0.06; 95% CI, 0.01 to -0.12; P = .02).Conclusions and Relevance: Meta-analyses of 21 interventions fully or partially recommended their use, with recommendations being positively correlated with the effect sizes of the pooled intervention. However, the effect sizes were inversely correlated with meta-analyzed study quality, reducing confidence in these recommendations. Higher-quality trials and patient-based meta-analyses are needed to determine whether subpopulations might benefit from combination treatment, as no single strategy can be recommended for patients with schizophrenia based on the current meta-analytic literature. [ABSTRACT FROM AUTHOR]

Despite the long-standing belief in the analgesic properties of alcohol, experimental studies have produced mixed results. This meta-analysis aimed to clarify whether alcohol produces a decrease in experimentally-induced pain and to determine the magnitude of any such effect. PubMed, PsycINFO, and Embase databases were searched from inception until April 21, 2016 for controlled studies examining the effect of quantified dosages of alcohol on pain response to noxious stimulation. Eighteen studies involving 404 participants were identified providing alcohol versus no-alcohol comparisons for 13 tests of pain threshold (n = 212) and 9 tests of pain intensity ratings (n = 192). Random effects meta-analysis of standardized mean difference (SMD) provided robust support for analgesic effects of alcohol. A mean blood alcohol content (BAC) of approximately .08% (3-4 standard drinks) produced a small elevation of pain threshold (SMD [95% CI] = .35 [.17-.54], P = .002), and a moderate to large reduction in pain intensity ratings (SMD [95% CI] = .64 [.37-.91], P < .0001), or equivalently, a mean reduction of 1.25 points on a 0- to 10-point pain rating scale. Furthermore, increasing BAC resulted in increasing analgesia, with each .02% BAC increment producing an increase of SMD = .11 for pain threshold and SMD = .20 for reduced pain intensity. Some evidence of publication bias emerged, but statistical correction methods suggested minimal impact on effect size. Taken together, findings suggest that alcohol is an effective analgesic that delivers clinically-relevant reductions in ratings of pain intensity, which could explain alcohol misuse in those with persistent pain despite its potential consequences for long-term health. Further research is needed to corroborate these findings for clinical pain states.Perspective: This meta-analysis provides robust evidence for the analgesic properties of alcohol, which could potentially contribute to alcohol misuse in pain patients. Strongest analgesia occurs for alcohol levels exceeding World Health Organization guidelines for low-risk drinking and suggests raising awareness of alternative, less harmful pain interventions to vulnerable patients may be beneficial. [ABSTRACT FROM AUTHOR]

Although clinical studies suggest depressed patients may be more vulnerable to pain, experimental research is equivocal. This meta-analysis aimed to clarify whether depression is associated with altered pain perception in response to noxious stimulation and to identify factors that might influence this association. A search of major electronic databases was conducted to identify experimental studies investigating pain response in depressed participants versus healthy control participants using established pain outcome measures. Random effects meta-analysis of standardized mean differences was conducted on data from 32 studies (N = 1,317). For high-intensity noxious stimulation, overall pain tolerance was similar across depressed and control groups (Hedges g = .09, P = .71, studies = 10). For low-intensity stimulation, a small, but statistically significant higher mean sensory threshold (g = .35, P = .01, studies = 9) and pain threshold (g = .32, P = .02, studies = 25) was observed in depressed participants, suggesting diminished pain. However, considerable heterogeneity in the direction and magnitude of effects was observed, indicating a likely condition-specific effect of depression on pain. Subgroup analysis found that pain threshold/tolerance was increased in depression for exteroceptive (cutaneous) stimulation but decreased for interoceptive (ischemic) stimulation, but that substantial heterogeneity remained. Overall, results provide some support for altered pain processing in depression, but suggest this link is dependent upon modality and additional, unidentified factors.Perspective: This meta-analysis of experimental studies suggests potential effects of depression on pain perception are variable and likely to depend upon multiple factors. The contrasting pattern for ischemic versus other noxious stimuli suggests that stimulus modality is a key factor, which could help explain discrepancies across clinical and experimental findings. [ABSTRACT FROM AUTHOR]

Background and Aims Cigarette smoking is associated with severe mental illness, including schizophrenia and bipolar disorder, and with morbidity and mortality, but the association with anorexia (AN), bulimia nervosa (BN) and binge eating disorder (BED) is unclear. This meta-analysis compared the odds of smoking in eating disorders (ED) (ED = AN or BN or BED) versus healthy controls (HC) and calculated the prevalence of smokers in people with ED. Methods Three independent authors searched PubMed, MEDLINE and Scopus from database inception until 31 December 2015 for studies reporting data on life-time or current smoking prevalence in BED, BN and AN with or without control group. Meta-analyses were undertaken, calculating odds ratios (ORs) of life-time smoking in BED, BN, AN versus healthy controls (HCs) or prevalence of smoking in BED, BN and AN with 95% confidence intervals (CI). Results Thirty-one studies (ED = 8517, controls = 68 335) were meta-analysed. Compared with HCs, there were significantly more smokers among people with BN (life-time OR = 2.165) and BED (life-time OR = 1.792) but not AN (life-time OR = 0.927). BED was associated with smoking the most (life-time prevalence = 47.73%) followed by BN (life-time prevalence = 39.4%) and AN (life-time prevalence = 30.8%). In BN, life-time smoking prevalence was highest in Europe. In AN, higher age moderated both life-time and current smoking prevalence, and body mass index moderated higher life-time smoking prevalence. In BN, female sex moderated higher life-time smoking prevalence. Conclusions People with binge eating disorder and bulimia nervosa are significantly more likely to be life-time smokers than healthy controls, which is not the case for anorexia nervosa. [ABSTRACT FROM AUTHOR]

Brexpiprazole, a serotonin-dopamine activity modulator, is a partial agonist at 5-HT1A and dopamine D2 receptors, and antagonist at 5-HT2A and noradrenaline α1B and α2C receptors, all at similar potency. Efficacy of brexpiprazole was evaluated in patients with acutely exacerbated schizophrenia in three short-term, randomized, double-blind, placebo-controlled studies. In a Phase 2 study, patients were randomized to brexpiprazole 0.25mg (fixed dose), 1.0±0.5mg, 2.5±0.5mg, 5.0±1mg (flexible-dose ranges), placebo, or aripiprazole 15±5mg. In two Phase 3 studies, patients were randomized to fixed-dose brexpiprazole 0.25mg, 1mg, 2mg, or 4mg, or placebo. For this review, brexpiprazole 2mg and 4mg arms from the Phase 3 studies were combined. Primary efficacy endpoint was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline at week 6; key secondary endpoint was change in Clinical Global Impression-Severity of illness (CGI-S) score at week 6. Primary outcome moderator analyses explored effects of sex, age, race, and illness duration. There were no statistically significant differences vs. placebo in the Phase 2 brexpiprazole and aripiprazole groups for primary and key secondary endpoints. Combined brexpiprazole 2mg (n=359) and 4mg (n=359) were superior to placebo (n=358) in change in PANSS total score (least square mean difference from placebo: -5.46, p=0.0004, and -6.69, p<0.0001, respectively) and CGI-S (-0.25, p=0.0035, and -0.38, p<0.0001, respectively). Changes from baseline in efficacy endpoints were minimal in the 0.25mg group, while the 1mg group exhibited suboptimal improvement. No relevant moderators were identified. Meta-analysis of the pivotal studies indicates brexpiprazole 2mg and 4mg are effective in treating acute schizophrenia. [ABSTRACT FROM AUTHOR]

Importance: Antipsychotics are used increasingly in youth for nonpsychotic and off-label indications, but cardiometabolic adverse effects and (especially) type 2 diabetes mellitus (T2DM) risk have raised additional concern.Objective: To assess T2DM risk associated with antipsychotic treatment in youth.Data Sources: Systematic literature search of PubMed and PsycINFO without language restrictions from database inception until May 4, 2015. Data analyses were performed in July 2015, and additional analyses were added in November 2015.Study Selection: Longitudinal studies reporting on T2DM incidence in youth 2 to 24 years old exposed to antipsychotics for at least 3 months.Data Extraction and Synthesis: Two independent investigators extracted study-level data for a random-effects meta-analysis and meta-regression of T2DM risk.Main Outcomes and Measures: The coprimary outcomes were study-defined T2DM, expressed as cumulative T2DM risk or as T2DM incidence rate per patient-years. Secondary outcomes included the comparison of the coprimary outcomes in antipsychotic-treated youth with psychiatric controls not receiving antipsychotics or with healthy controls.Results: Thirteen studies were included in the meta-analysis, including 185,105 youth exposed to antipsychotics and 310,438 patient-years. The mean (SD) age of patients was 14.1 (2.1) years, and 59.5% were male. The mean (SD) follow-up was 1.7 (2.3) years. Among them, 7 studies included psychiatric controls (1,342,121 patients and 2,071,135 patient-years), and 8 studies included healthy controls (298,803 patients and 463,084 patient-years). Antipsychotic-exposed youth had a cumulative T2DM risk of 5.72 (95% CI, 3.45-9.48; P < .001) per 1000 patients. The incidence rate was 3.09 (95% CI, 2.35-3.82; P < .001) cases per 1000 patient-years. Compared with healthy controls, cumulative T2DM risk (odds ratio [OR], 2.58; 95% CI, 1.56-4.24; P < .0001) and incidence rate ratio (IRR) (IRR, 3.02; 95% CI, 1.71-5.35; P < .0001) were significantly greater in antipsychotic-exposed youth. Similarly, compared with psychiatric controls, antipsychotic-exposed youth had significantly higher cumulative T2DM risk (OR, 2.09; 95% CI, 1.50-52.90; P < .0001) and IRR (IRR, 1.79; 95% CI, 1.31-2.44; P < .0001). In multivariable meta-regression analyses of 10 studies, greater cumulative T2DM risk was associated with longer follow-up (P < .001), olanzapine prescription (P < .001), and male sex (P = .002) (r(2) = 1.00, P < .001). Greater T2DM incidence was associated with second-generation antipsychotic prescription (P ≤ .050) and less autism spectrum disorder diagnosis (P = .048) (r(2) = 0.21, P = .044).Conclusions and Relevance: Although T2DM seems rare in antipsychotic-exposed youth, cumulative risk and exposure-adjusted incidences and IRRs were significantly higher than in healthy controls and psychiatric controls. Olanzapine treatment and antipsychotic exposure time were the main modifiable risk factors for T2DM development in antipsychotic-exposed youth. Antipsychotics should be used judiciously and for the shortest necessary duration, and their efficacy and safety should be monitored proactively. [ABSTRACT FROM AUTHOR]

Introduction Aggression is a major concern in psychiatric inpatient care. Variations in study designs, settings, populations and data collection methods render comparisons of the prevalence of aggressive behavior in high-risk settings difficult. We proposed to estimate the pooled prevalence of aggression among inpatients with schizophrenia in China. Methods Reports on aggressive behaviour involving physical contact or risks of interpersonal violence, in schizophrenia in Chinese general psychiatric wards were retrieved by using computer-assisted searches and manual searches of the reference lists of the relevant literature. Statistical analyses were conducted using the Comprehensive Meta- Analysis V2 software. Potential sources of heterogeneity were analyzed with Cochrane's Q analysis. Results The search yielded 19 eligible studies involving a total of 3,941 schizophrenia patients. The prevalence of aggressive behavior in psychiatric wards ranged between 15.3% and 53.2%. The pooled prevalence of aggression was 35.4% (95% CI: 29.7%, 41.4%). The most commonly reported significant risk factors for aggression were positive psychotic symptoms: hostility or suspiciousness, 78.9% (15 studies); delusions, 63.2% (12 studies); disorganized behavior, 26.3% (5 studies); and auditory hallucinations, 10.5% (2 studies); together with: past history of aggression, 42.1% (8 studies); and involuntary admission, 10.5% (2 studies). Conclusions Aggressive behaviour is common in Chinese inpatients with schizophrenia. The prevalence figures indicate the need to identify reliable clinical and illness predictors for aggression in inpatient psychiatric wards and to test investigations aimed at reducing aggressive episodes and their adverse outcomes. [ABSTRACT FROM AUTHOR]

Oxidative stress markers seem to be higher in patients with anorexia nervosa (AN) than healthy controls, but the potentially beneficial effects of weight gain is not known. We calculated random effects standardised mean differences (SMDs) as effect size measures of oxidative stress marker changes after re-alimentation reported in two or more studies, summarising others descriptively. Seven longitudinal studies ( n = 104) were included. After a median follow-up period of 8 weeks, AN patients significantly increased their body mass index (15.1 ± 2.1 to 17.1 ± 2.2, p < 0.0001). This weight gain was followed by a significant increase in serum levels of the antioxidant albumin (studies = 6, SMD = 0.50, 95%CI = 0.18; 0.82, p = 0.002; I2 = 16%) and a significant decrease in the oxidative stress marker Apolipoprotein B (studies = 2, n = 19, SMD = −0.85, 95%CI = −1.53; −0.17, p = 0.01; I2 = 0). In one study, catalase and total antioxidant capacity increased, whilst superoxide dismutase significantly decreased. In conclusion, oral re-alimentation, even without full-weight normalisation, seems to improve oxidative stress in people with AN. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective In anorexia nervosa (AN), osteoporosis and osteopenia are common, which have been associated with low circulating levels of vitamin D (VitD) in other settings. We aimed to meta-analyze cross-sectional studies reporting on VitD parameters in patients with AN and healthy controls (HCs). Method Electronic PubMed search from database inception until December 31, 2013 and meta-analysis of cross-sectional studies comparing serum levels of 25-hydroxyvitamin D (25OH-D), 1,25-dihydroxyvitamin D (1,25OH-D) and dietary VitD between patients with AN and HCs, before or after VitD supplementation. We calculated random effects standardized mean differences (SMDs) ±95% confidence intervals (CIs) as effect size measures. Results Out of 1,739 initial hits, 15 studies with a total of 927 participants (AN = 408 and HCs = 519) were meta-analyzed. In the unsupplemented state, both serum 25OH-D (studies = 4; n = 168; SMD = −0.43; 95%CI: −0.83 to −0.03; p = .03) and 1,25OH-D levels (studies = 4; n = 113; SMD = −1.06; 95%CI: −1.47 to −0.66; p < .00001) were significantly lower in AN than HCs. In AN patients treated with cholecalciferol supplementation, serum 25OH-D levels were significantly higher than in HCs (studies = 5; n = 449; SMD = 0.66; 95%CI: 0.01-1.31; p = .05). Paradoxically, despite lower 25OH-D and 1,25OH-D levels, AN patients reported similar intake of VitD compared to HCs (studies = 6; n = 314; SMD = 0.33; 95%CI: −0.16, 0.81; p = .19). Discussion Although AN patients reported similar dietary VitD intake compared to HCs, AN patients had significantly lower 25OH-D and 1,25OH-D levels without supplementation. Conversely, supplementation with cholecalciferol fully normalized VitD serum levels. Future studies are needed to clarify the role of VitD supplementation in AN for improving bone health. © 2014 Wiley Periodicals, Inc. (Int J Eat Disord 2015; 48:803-813) [ABSTRACT FROM AUTHOR]

ABSTRACT Objective To systematically review and meta-analyze oxidative stress and antioxidant markers in anorexia nervosa (AN). Methods Electronic PubMed search from database inception until 12/31/2013. Out of 1062 hits, 29 studies comparing oxidative stress/antioxidant markers between patients with AN and healthy controls (HCs) with a total of 1,729 participants (AN = 895, HCs = 834) were eligible. Data about oxidative stress and antioxidant markers, independent of their source, were extracted. We calculated random effects standardized mean differences (SMDs) as effect size measures for outcomes reported in ≥5 studies; others were summarized descriptively. Results Compared to HCs, AN patients showed significantly higher apolipoprotein B (ApoB) levels (studies = 7; n = 551; SMD = 0.75; p = .0003, I2 = 74%), with higher age being associated with higher ApoB (Coefficient: 0.61 ± 0.15, p < .0001), whereas BMI ( p = .15) and measurement method ( p = .70) did not moderate the results. Serum albumin levels were similar between AN and HCs (studies = 13; n = 509; SMD =−0.19; 95%CI: −0.62 to 0.24; p = .38; I2 = 81%), with neither age ( p = .84) nor BMI ( p = .52) being significant moderators. Lower superoxide dismutase levels were reported in 2 studies, while findings for vitamin A and its metabolites were inconclusive. In single studies, patients with AN had significantly higher catalase and nitric oxide (NO) parameter levels (platelet NO, exhaled NO and nitrites), such as lower glutathione and free cysteine levels, compared to HCs. Discussion AN appears to be associated with some markers of increased oxidative stress. Additional research is needed to discern whether oxidative stress is a potential cause or effect of AN, and whether treatments improving oxidative stress could be useful in AN. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2015; 48:826-841). [ABSTRACT FROM AUTHOR]

The need to support clinical decision making and cost-effectiveness analyses in medicine, despite a dearth of head-to-head treatment comparisons, has encouraged the development of methods enabling indirect comparisons of treatment alternatives, including network meta-analysis (NMA). Valid application of NMA requires close similarity of compared trials, including their design, patient characteristics, and methods of diagnosis and symptomatic assessment. When biological or other objective measures of outcomes are not available, as is the case in psychiatric disorders, subtle differences in characteristics of trials or participants may lead to unrecognized incoherence within a network and thus to inconsistent results. By considering comparative-efficacy analyses of psychotropic drugs in major psychiatric disorders as working examples, we underscore the risks of violating the fundamental transitivity assumption in the context of NMA and suggest precautions for creating a coherent network. We conclude that with thoughtful and critical application, NMA can add useful information concerning the comparative benefits, risks, and costs of specific treatments in psychiatry. [ABSTRACT FROM AUTHOR]

Objective: To comprehensively evaluate the efficacy and safety of atomoxetine (ATX) in pediatric attention-deficit/hyperactivity disorder (ADHD). Method: Meta-analysis of all double-blind randomized controlled trials (DBRCTs) evaluating the efficacy and tolerability of ATX for ADHD. Pooled, random-effects analyses were conducted, calculating standardized mean difference (SMD), yielding effect sizes (ES), relative risk (RR), and number-needed-to-treat/harm (NNT/NNH).Moderator/mediator analyses were also conducted, including metaregression. Results: Across 25 DBRCTs (56 treatment arms, N = 3,928), ATX outperformed placebo regarding overall ADHD symptoms (ES = -0.64, 95% confidence interval [CI] = -0.56 to -0.71, p < 0.0001), hyperactivity/impulsivity (ES = -0.67, CI = -0.53 to -0.81, p < 0.0001), and inattention (ES = -0.59, CI = -0.51 to -0.67, p < 0.0001). Altogether, 44.4% versus 21.4% of patients improved by ≥40% (NNT = 4), whereas 39.9% versus 65.9% improved by <25% (NNT = 4). Oppositional defiant disorder symptoms (ES = -0.33) and quality-of-life-related outcomes (ES = -0.48 to -0.25) improved somewhat less. A higher percentage of treatment-naive patients moderated the efficacy of ATX for overall ADHD symptoms (p = 0.017). All-cause discontinuation with ATX was similar to that for placebo (p = 1.00), with lower discontinuation because of inefficacy (relative risk [RR] = 0.51, CI = 0.36-0.74, p < 0.0001, NNT = 34), but higher discontinuation because of adverse effects (AEs) (RR = 1.89, CI = 1.08-3.31, p = 0.03, NNH = 50) with ATX. At least 1 adverse effect (AE) (70.4% versus 56.1%, p < 0.01, NNH = 6) and ≥1 psychiatric AE (21.5% versus 7.4%, NNH = 7, p < 0.01) were more frequent with ATX, whereas serious AEs (1.5% versus 1.0%), aggression (7.5% versus 6.0%), and suicidal ideation (1.3% versus 0.9%) were not different from placebo. Conclusions: Short-term ATX treatment is safe and superior to placebo for overall ADHD symptoms and key secondary outcomes, with a medium ES. However, a relevant patient subgroup (40%) continues to have significant symptomatology, requiring additional clinical attention. [ABSTRACT FROM AUTHOR]

Background: While long-acting injectable antipsychotics (LAIs) are hoped to reduce high relapse rates in schizophrenia, recent randomized controlled trials (RCTs) challenged the benefits of LAIs over oral antipsychotics (OAPs). Methods: Systematic review/meta-analysis of RCTs that lasted ≥6 months comparing LAIs and OAPs. Primary outcome was study-defined relapse at the longest time point; secondary outcomes included relapse at 3, 6, 12, 18, and 24 months, all-cause discontinuation, discontinuation due to adverse events, drug inefficacy (ie, relapse + discontinuation due to inefficacy), hospitalization, and nonadherence. Results: Across 21 RCTs (n = 5176), LAIs were similar to OAPs for relapse prevention at the longest time point (studies = 21, n = 4950, relative risk [RR] = 0.93, 95% confidence interval [CI]: 0.80–1.08, P = .35). The finding was confirmed restricting the analysis to outpatient studies lasting ≥1 year (studies = 12, RR = 0.93, 95% CI:0.71–1.07, P = .31). However, studies using first-generation antipsychotic (FGA)-LAIs (studies = 10, RR = 0.82, 95% CI:0.69–0.97, P = .02) and those published ≤1991 (consisting exclusively of all 8 fluphenazine-LAI studies; RR = 0.79, 95% CI: 0.65–0.96, P = 0.02) were superior to OAPs regarding the primary outcome. Pooled LAIs also did not separate from OAPs regarding any secondary outcomes. Again, studies using FGA-LAIs and those published ≤1991 were associated with LAI superiority over OAPs, eg, hospitalization and drug inefficacy. Conclusions: In RCTs, which are less representative of real-world patients than naturalistic studies, pooled LAIs did not reduce relapse compared with OAPs in schizophrenia patients. The exceptions were FGA-LAIs, mostly consisting of fluphenazine-LAI studies, which were all conducted through 1991. Because this finding is vulnerable to a cohort bias, studies comparing FGA-LAI vs second-generation antipsychotics-LAI and LAI vs OAP RCTs in real-world patients are needed. [ABSTRACT FROM PUBLISHER]

Objective: To meta-analytically assess the efficacy and tolerability of nonsteroidal anti-inflammatory drugs (NSAIDs) vs placebo in schizophrenia. Method: Searching PubMed, PsycINFO, ISI Web of Science, and the US National Institute of Mental Health clinical trials registry from database inception to December 31, 2012, we conducted a systematic review/meta-analysis of randomized placebo-controlled studies assessing the efficacy of adjunctive NSAIDs. Primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes included change in PANSS positive and negative subscores, all-cause discontinuation, and tolerability outcomes. Random effects, pooled, standardized mean changes (Hedges’ g) and risk ratios were calculated. Results: Across 8 studies, including 3 unpublished reports (n = 774), the mean effect size for PANSS total score was −0.236 (95% CI: −0.484 to 0.012, P = .063, I2 = 60.6%), showing only trend-level superiority for NSAIDs over placebo. The mean effect sizes for the PANSS positive and negative scores were −0.189 (95% CI: −0.373 to −0.005, P = .044) and −0.026 (95% CI: −0.169 to 0.117, P = .72), respectively. The relative risk for all-cause discontinuation was 1.13 (95% CI: 0.794 to 1.599, P = .503). Significant superiority of NSAIDs over placebo regarding PANSS total scores was moderated by aspirin treatment (N = 2, P = .017), inpatient status (N = 4, P = .029), first-episode status (N = 2, P = .048), and (in meta-regression analyses) lower PANSS negative subscores (N = 6, P = .026). Interpretation: These results indicate that adjunctive NSAIDs for schizophrenia may not benefit patients treated with first-line antipsychotics judged by PANSS total score change. NSAIDs may have benefits for positive symptoms, but the effect was minimal/small. However, due to a limited database, further controlled studies are needed, especially in first-episode patients. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Objective: Patients with bipolar disorder have high levels of cardiovascular disease risk factors. The presence of metabolic syndrome significantly influences future cardiovascular disease morbidity and mortality. The authors sought to clarify the prevalence and moderators of metabolic syndrome in bipolar patients, accounting for subgroup differences. Method: The authors searched MEDLINE, PsycINFO, EMBASE, and CINAHL through April 2012 for research reporting metabolic syndrome prevalence rates in bipolar patients. Medical subject headings "metabolic syndrome" and "bipolar" were used in the title, abstract, or index term fields. Manual searches were conducted using the reference lists from identified articles. Results: The search yielded 81 articles in 37 publications (N=6,983). The overall metabolic syndrome rate was 37.3% (95% confidence interval [CI]=36.1-39.0) using any standardized metabolic syndrome criteria. Compared with general population groups, bipolar patients had higher metabolic syndrome rates (odds ratio= 1.98; 95% CI=1.74-2.25). In bipolar patients, older age had a modest effect on the metabolic syndrome rate. The strongest moderator was the region in which the study took place, with the highest rates observed in New Zealand and Australia (64.2% [95% 0=38.3-83.9]) and North America (49.3% [95% CI=29.7-69.3]). Metabolic syndrome was significantly more prevalent in patients currently treated with antipsychotics (45.3% [95% CI=39.6-50.9] than in patients who were antipsychotic free (32.4% [95% CI=27.5-37.4]; odds ratio=1.72 [95% CI=1.24-2.38]). Conclusions: These findings strongly sup- port the claim that patients with bipolar disorder are at high risk for metabolic syndrome and related cardiovascular morbidity and mortality and require regular monitoring and adequate preventive efforts and treatment for cardio-metabolic risk factors. These findings further suggest that the risk of metabolic syndrome is greater in bipolar patients taking prescribed antipsychotic medication. INSET: Clinical Guidance: High Rate of Metabolic Syndrome.... [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate the efficacy of non-pharmacological interventions for antipsychotic-associated weight gain. Methods: Systematic literature search and meta-analysis of randomized controlled trials comparing behavioral interventions with control groups to ameliorate antipsychotic-associated weight gain. Results: Across 17 studies (n=810, mean age: 38.8years, 52.7% male, 40.8% White, 85.6% with schizophrenia-spectrum disorders), non-pharmacological interventions led to a significant reduction in weight (−3.12kg; CI: −4.03, −2.21, p<0.0001) and body mass index (BMI) (−0.94kg/m2; CI: −1.45, −0.43, p=0.0003) compared with control groups. Intervention benefits extended to all secondary outcomes, except for high density-lipoprotein-cholesterol and systolic blood pressure. Compared to controls, intervention patients experienced significant decreases in waist circumference (WMD=−3.58cm, CI: −5.51, −1.66, p=0.03), percent body fat (WMD=−2.82%, CI: −5.35, −0.30, p=0.03), glucose (WMD=−5.79mg/dL, CI: −9.73, −1.86, p=0.004), insulin (WMD=−4.93uIU/mL, CI: −7.64, −2.23, p=0.0004), total cholesterol (WMD=−20.98mg/dL, CI: −33.78, −8.19; p=0.001), low density-lipoprotein-cholesterol (WMD=−22.06mg/dL, CI: −37.80, −6.32, p=0.006) and triglycerides (WMD=−61.68mg/dL, CI: −92.77, −30.59, p=0.0001), and less weight gain > 7% (29.7% vs. 61.3%; RR=−0.52, CI: −0.35, −0.78, p=0.002; number-needed-to-treat=4). Up to 12months after the intervention ended (mean=3.6months), benefits endured regarding weight (WMD=−3.48kg, CI: −6.37, −0.58, p=0.02), but not BMI (p=0.40). Subgroup analyses showed superiority of non-pharmacological interventions irrespective of treatment duration, individual or group, cognitive behavioral or nutritional interventions, or prevention versus intervention trials. However, weight and BMI were significantly improved only in outpatient trials (p<0.0001), but not in inpatient or mixed samples (p=0.09–0.96). Conclusion: Behavioral interventions effectively prevented and reduced antipsychotic-associated weight gain and cardiometabolic perturbations, at least in outpatients agreeing to participate in trials aimed at improving physical health. Effective treatments ranged from nutritional interventions to cognitive behavioral therapy. [Copyright &y& Elsevier]

The article presents a meta-analysis of antidepressant or antipsychotic monotherapy compared with combination antidepressant-antipsychotic treatment for psychotic depression. Data such as study-defined inefficacy, all-cause discontinuation, and side effects are cited to have been extracted from trials. Combination antidepressant-antipsychotic treatment is showed to have lesser study-defined inefficacy than monotherapy.

The clock gene ( CLOCK) is considered to be a good candidate gene for the pathophysiology of mood disorders, including bipolar disorder (BP) and major depressive disorder (MDD). rs1801260 (T3111C) has been detected at position 3111 in the CLOCK mRNA 3' untranslated region, and was reported to be associated with a substantial delay in preferred timing for activity and sleep in a human study. As for function, rs1801260 has been speculated to affect mRNA. Therefore, the authors investigated the association between the three tagging single-nucleotide polymorphisms (SNPs) (rs3736544, rs1801260, and rs3749474) in CLOCK and risk of BP (n == 867) and MDD (n == 139) compared to controls (n == 889) in the Japanese population. In addition, we also performed an updated meta-analysis of nine published, genetic association studies investigating the relationship between rs1801260 and mood disorder risk, comprising 3321 mood disorders cases and 3574 controls. We did not detect any associations between tagging SNPs in CLOCK and BP or MDD in the allele, genotype, or haplotype analysis (global pBP == .605 and global pMDD == .211). Moreover, rs1801260 was also not associated with BP, MDD, or any mood disorders in the meta-analysis. In conclusion, these data suggest that CLOCK does not play a major role in the pathophysiology of mood disorders. (Author correspondence: ) [ABSTRACT FROM AUTHOR]

Antipsychotic-related weight gain and metabolic effects are a critical outcome for patients requiring these medications. A literature search using MEDLINE, Web of Science, PsycNET, and EMBASE for randomized, open and double-blind, placebo-controlled trials of medications targeting antipsychotic-induced weight gain was performed. Primary outcome measures were change and endpoint values in body weight and body mass index (BMI). Secondary outcomes included 7% weight gain, all-cause discontinuation, change in waist circumference, glucose and lipid metabolism parameters, and psychiatric symptoms. Sensitivity analyses were conducted to explain heterogeneity of the results. Across 32 studies including 1482 subjects, 15 different medications were tested: amantadine, dextroamphetamine, d-fenfluramine, famotidine, fluoxetine, fluvoxamine, metformin, nizatidine, orlistat, phenylpropanolamine, reboxetine, rosiglitazone, sibutramine, topiramate, and metformin+sibutramine. Compared with placebo, metformin had the greatest weight loss (N=7, n=334, −2.94 kg (confidence interval (CI:−4.89,−0.99)), followed by d-fenfluramine (N=1, n=16, −2.60 kg (CI:−5.14,−0.06)), sibutramine (N=2, n=55, −2.56 kg (CI:−3.91,−1.22)), topiramate (N=2, n=133, −2.52 kg (CI:−4.87,−0.16)), and reboxetine (N=2, n=79, −1.90 kg (CI:−3.07,−0.72)). Weight loss remained significant with metformin initiation after weight gain had occurred, but not when started concomitantly with antipsychotics. Nausea rates were not higher with any treatment compared with placebo. In all, 5 of 15 psychopharmacologic interventions aimed at ameliorating antipsychotic-induced weight gain outperformed placebo. Results were most robust for metformin, although these were modest and heterogeneous. Only one (negative) combination treatment study was available and head-to-head studies are absent. None of the agents were able to entirely reverse weight gain because of antipsychotics. At present, no treatment has sufficient evidence to recommend broad clinical usage. Antipsychotics with no or minimal cardiometabolic liability, as well as interventions that prevent or normalize adverse antipsychotic cardiometabolic effects are needed. [ABSTRACT FROM AUTHOR]

Early-onset psychosis (EOP) refers to the development of psychosis before the age of 18 years. We aimed to summarize, for the first time, the meta-analytical evidence in the field of this vulnerable population and to provide evidence-based recommendations. We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)–compliant, pre-registered (PROSPERO: CRD42022350868) systematic review of several databases and registers to identify meta-analyses of studies conducted in EOP individuals to conduct an umbrella review. Literature search, screening, data extraction, and quality assessment were carried out independently. Results were narratively reported, clustered across core domains. Quality assessment was performed with the Assessment of Multiple Systematic Reviews–2 (AMSTAR-2) tool. A total of 30 meta-analyses were included (373 individual studies, 25,983 participants, mean age 15.1 years, 38.3% female). Individuals with EOP showed more cognitive impairments compared with controls and individuals with adult/late-onset psychosis. Abnormalities were observed meta-analytically in neuroimaging markers but not in oxidative stress and inflammatory response markers. In all, 60.1% of EOP individuals had a poor prognosis. Clozapine was the antipsychotic with the highest efficacy for overall, positive, and negative symptoms. Tolerance to medication varied among the evaluated antipsychotics. The risk of discontinuation of antipsychotics for any reason or side effects was low or equal compared to placebo. EOP is associated with cognitive impairment, involuntary admissions, and poor prognosis. Antipsychotics can be efficacious in EOP, but tolerability and safety need to be taken into consideration. Clozapine should be considered in EOP individuals who are resistant to 2 non-clozapine antipsychotics. Further meta-analytical research is needed on response to psychological interventions and other prognostic factors. This umbrella review summarized the meta-analytical knowledge from 30 meta-analyses on early-onset psychosis. Early-onset psychosis refers to the development of psychosis before the age of 18 years and is associated with cognitive impairment, hospitalization, and poor prognosis. Individuals with early-onset psychosis show more cognitive impairments and abnormalities compared with controls. Clozapine was the antipsychotic with the highest efficacy for positive, negative, and overall symptoms and should be considered in individuals with early-onset psychosis. Early Onset Psychosis: Umbrella Review on Diagnosis, Prognosis and Treatment factors; https://www.crd.york.ac.uk/PROSPERO/ ; CRD42022350868. [ABSTRACT FROM AUTHOR]

Background: None of the currently available treatments are effective for negative symptoms of schizophrenia, which represent a long-lasting burden on sufferers, their families and on wider society. The gut-microbiota has been emerging as a putative novel target of intervention for negative symptoms of schizophrenia. This hypothesis has been welcomed with enthusiasm by the scientific community as showed by the growing number of commentaries and not-systematised reviews on the topic. To date, only few clinical trials tested the efficacy of interventions with the a-priori rationale of targeting the gut-microbiome in schizophrenia, with contrasting results. However, there is a number of trials that used compounds, such as antibiotics, antimicrobials, pre- and pro-biotics with a clear potential of modifying the gut-microbiome in patients. Interpreting and analysing data from these studies will help to shed light on the potential of the gut-microbiome as a therapeutic target in schizophrenia. Here we provide the first systematic review and meta-analysis on augmentation strategies targeting the gut-microbiome in schizophrenia. Methods: Following PRISMA guidelines, we searched from inception to August 2019 all the randomised double-blind controlled trials of add-on antibiotics, antimicrobics, pre/probiotics, and fecal transplant in schizophrenia. Primary outcomes were negative symptoms at end of follow-up and acceptability of treatment. Data were independently extracted by multiple observers and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Sensitivity analyses tested the robustness of the results. Results: We identified 28 placebo-controlled trials: 21 investigated antibiotics, 4 antimicrobials, 3 pre/probiotics, none faecal transplant. None of the investigated compounds were effective for treating negative symptoms of schizophrenia, with the exception of the antimicrobial Sodium benzoate. It was possible to perform individual meta-analyses on three compounds for the outcome negative symptoms: (i) D-Cycloserine vs placebo (10 studies, N=389; SMD, -0.15; 95% CI -0.39, 0.10; P=0.24; I2: 26.4%); (ii) Minocycline vs placebo (7 studies, N=713, SMD: -0.35; 95% CI -0.70, 0.00; P=0.05, I2:77.7%) (iii) Sodium benzoate vs placebo (2 studies, N=107, SMD, -0.83; 95%CI -1.12, -0.42; P<0.001; I2:0%) Acceptability of interventions was similar to placebo. Qualitative and quantitative subgroup analyses suggested that baseline severity of negative symptoms and stage of illness have the potential to influence treatment outcomes. Discussion: None of the available treatment with a putative action on the gut-microbiome are effective for the treatment of negative symptoms of schizophrenia, with limited evidence supporting the use of the antimicrobial Sodium benzoate. However, this latter finding is likely to be related to the central effect of the compound. The effect of some compounds might be beneficial if timing of intervention and clinical heterogeneity are taken into account. A more detailed characterisation of the gut microbiome and the pathophysiological path linking it with schizophrenia is needed before engaging in further trials [ABSTRACT FROM AUTHOR]

The authors reflect on the role of clozapine in the treatment of resistant schizophrenia, focusing on a study by Samara and colleagues in the March 2016 issue of the journal "JAMA Psychiatry." They explore the study which provides additional insight into the evidence of the effectiveness of clozapine as the treatment preferred for treatment-resistant schizophrenia and examine topics including treatment refractories, meta-analysis, and randomized controlled trials (RCTs).