Background Antipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment.Methods We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change. FindingsOf 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with placebo ranged from −0•23 kg (95% CI −0•83 to 0•36) for haloperidol to 3•01 kg (1•78 to 4•24) for clozapine; for BMI from −0•25 kg/m² (−0•68 to 0•17) for haloperidol to 1•07 kg/m² (0•90 to 1•25) for olanzapine; for total-cholesterol from −0•09 mmol/L (-0•24 to 0•07) for cariprazine to 0•56 mmol/L (0•26-0•86) for clozapine; for LDL cholesterol from −0•13 mmol/L (−0.21 to −0•05) for cariprazine to 0•20 mmol/L (0•14 to 0•26) for olanzapine; for HDL cholesterol from 0•05 mmol/L (0•00 to 0•10) for brexpiprazole to −0•10 mmol/L (−0•33 to 0•14) for amisulpride; for triglycerides from −0•01 mmol/L (−0•10 to 0•08) for brexpiprazole to 0•98 mmol/L (0•48 to 1•49) for clozapine; for glucose from −0•29 mmol/L (−0•55 to −0•03) for lurasidone to 1•05 mmol/L (0•41 to 1•70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0•0015) and male sex (p=0•0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0•040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0•36, p=0•0021), BMI (r=0•84, p<0•0001), totalcholesterol (r=0•31, p=0•047), and LDL cholesterol (r=0•42, p=0•013), and decreases in HDL cholesterol (r=−0•35, p=0•035).Interpretation Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, caripraz...

These findings show that glucose homeostasis is altered from illness onset in schizophrenia, indicating that patients are at increased risk of diabetes as a result. This finding has implications for the monitoring and treatment choice for patients with schizophrenia.

BackgroundStudies using positron emission tomography to image striatal dopamine function, have demonstrated that individuals with schizophrenia display increases in presynaptic function. Mesolimbic dysfunction specifically, has previously been suggested to underlie psychotic symptoms. This has not been directly tested in vivo, and the precise anatomical locus of dopamine dysfunction within the striatum remains unclear. The current article investigates the magnitude of dopaminergic abnormalities in individuals with schizophrenia, and determines how the magnitude of abnormality varies across functional subdivisions of the striatum.MethodsEMBASE, PsychINFO, and MEDLINE were searched from January 1, 1960, to December 1, 2016. Inclusion criteria were molecular imaging studies that had measured presynaptic striatal dopamine functioning. Effects sizes for whole striatum and functional subdivisions were calculated separately. The magnitude of difference between functional subdivisions in patients and controls was meta-analyzed.ResultsTwenty-one eligible studies were identified, including 269 patients and 313 controls. Individuals with schizophrenia (Hedges’ g = 0.68, P < .001) demonstrated elevated presynaptic dopamine functioning compared to controls. Seven studies examined functional subdivisions. These demonstrated significant increases in patients compared to controls in associative (g = 0.73, P = .002) and sensorimotor (g = 0.54, P = .005) regions, but not limbic (g = 0.29, P = .09). The magnitude of the difference between associative and limbic subdivisions was significantly greater in patients compared to controls (g = 0.39, P = .003).ConclusionIn individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum. This is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.

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Although synaptic loss is thought to be core to the pathophysiology of schizophrenia, the nature, consistency and magnitude of synaptic protein and mRNA changes has not been systematically appraised. Our objective was thus to systematically review and meta-analyse findings. The entire PubMed database was searched for studies from inception date to the 1st of July 2017. We selected case-control postmortem studies in schizophrenia quantifying synaptic protein or mRNA levels in brain tissue. The difference in protein and mRNA levels between cases and controls was extracted and meta-analysis conducted. Among the results, we found a significant reduction in synaptophysin in schizophrenia in the hippocampus (effect size: -0.65, p<0.01), frontal (effect size: -0.36, p=0.04), and cingulate cortices (effect size: -0.54, p=0.02), but no significant changes for synaptophysin in occipital and temporal cortices, and no changes for SNAP-25, PSD-95, VAMP and syntaxin in frontal cortex. There were insufficient studies for meta-analysis of complexins, synapsins, rab3A and synaptotagmin and mRNA measures. Findings are summarised for these, which generally show reductions in SNAP-25, PSD-95, synapsin and rab3A protein levels in the hippocampus but inconsistency in other regions. Our findings of moderate-large reductions in synaptophysin in hippocampus and frontal cortical regions, and a tendency for reductions in other pre- and post-synaptic proteins in the hippocampus are consistent with models that implicate synaptic loss in schizophrenia. However, they also identify potential differences between regions and proteins, suggesting synaptic loss is not uniform in nature or extent.

Some patients with schizophrenia show poor response to first-line antipsychotic treatments and this is termed treatment-resistant schizophrenia. The differential response to first-line antipsychotic drugs may reflect a different underlying neurobiology. Indeed, a previous study found dopamine synthesis capacity was significantly lower in patients with treatment-resistant schizophrenia. However, in this study, the treatment-resistant patients were highly symptomatic, whereas the responsive patients showed no or minimal symptoms. The study could not distinguish whether this was a trait effect or reflected the difference in symptom levels. Thus, we aimed to test whether dopaminergic function is altered in patients with a history of treatment resistance to first-line drugs relative to treatment responders when both groups are matched for symptom severity levels by recruiting treatment-resistant patients currently showed low symptom severity with the clozapine treatment. Healthy controls (n=12), patients treated with clozapine (n=12) who had not responded to first-line antipsychotics, and patients who had responded to first-line antipsychotics (n=12) were recruited. Participants were matched for age and sex and symptomatic severity level in patient groups. Participants' dopamine synthesis capacity was measured by using [F]DOPA PET. We found that patients treated with clozapine show lower dopamine synthesis capacity than patients who have responded to first-line treatment (Cohen's d=0.9191 (whole striatum), 0.7781 (associative striatum), 1.0344 (limbic striatum), and 1.0189 (sensorimotor striatum) in line with the hypothesis that the dopaminergic function is linked to treatment response. This suggests that a different neurobiology may underlie treatment-resistant schizophrenia and that dopamine synthesis capacity may be a useful biomarker to predict treatment responsiveness.

Between group comparisons revealed that those with social anxiety did indeed have worse social functioning, particularly in the domains of interpersonal communication (t(45) = 2.28, P = .025) and engagement (in conversations; t(45) = 2.89, P = .000). Participants with high social anxiety also had more difficulties in recognizing neutral emotional faces, compared to individuals with schizophrenia without social anxiety (t(31) = 2.19, P = .036).Although not specific to social anxiety, results on the facial emotional tasks were correlated with specific social functioning domains (e.g., those with poor facial recognition overall had fewer recreational (r = −.49) and social activities, r = −.56). The results were not linked to negative symptoms of schizophrenia or to psychiatric symptoms (BPRS). In the role-play, individuals with social anxiety were better than those without social anxiety at recognizing 2/4 of the emotions targeted (joy and anger, χ 2 = 3.58, P = .05). Conclusion: These findings suggest that specific comorbidities, such as social anxiety, might affect facial emotional recognition, particularly for neutral emotions. More studies are warranted in order to determine whether social anxiety brings an attentional bias, therefore making individuals more prone to seeing emotions (even when not present). This study did confirm that social anxiety and facial emotional recognition have an important impact on social functioning and should be targeted in treatments. IMPAIRED GLUCOSE HOMEOSTASIS IN FIRST-EPISODE SCHIZOPHRENIA:A META-ANALYSIS Toby Pillinger*, Katherine Beck, Cristian Gobjila, Jacek Donocik, Sameer Jauhar, and Oliver Howes King's College London Background: Schizophrenia is associated with an increased risk of type 2 diabetes mellitus. However, it is not clear whether schizophrenia confers an inherent risk for glucose dysregulation in the absence of the effects of chronic illness and long-term treatment. Our objective was to conduct a meta-analysis examining whether individuals with first-episode schizophrenia already exhibit alterations in glucose homeostasis compared with controls. Methods: The Embase, Medline and PsycINFO databases were systematically searched for studies examining measures of glucose homeostasis in drug-naive individuals with first-episode schizophrenia compared to controls. Of 3660 citations retrieved, 16 case-control studies comprising 15 samples met inclusion criteria. The overall sample included 731 patients and 614 controls. Standardized mean differences in fasting plasma glucose, plasma glucose post-OGTT, fasting plasma insulin, insulin resistance, and HbA1c were calculated. Results: Fasting plasma glucose (g = 0.199 (95% CI 0.022-0.376, P = .028)), plasma glucose post-OGTT (g = 0.605 (95% CI 0.163-1.047, P = .007)), fasting plasma insulin (g = 0.409 (95% CI 0.093-0.724, P = .011)) and insulin resistance (HOMA-IR; g = 0.334 (95% CI 0.135-0.534, P = .001)) were all significantly elevated in patients compared with controls. However, HbA1c levels (g = −0.08 (CI −0.340 to 0.18...

Background Approximately 188 million people use cannabis yearly worldwide, and it has recently been legalised in 11 US states, Canada, and Uruguay for recreational use. The potential for increased cannabis use highlights the need to better understand its risks, including the acute induction of psychotic and other psychiatric symptoms. We aimed to investigate the effect of the cannabis constituent Δ⁹-tetrahydrocannabinol (THC) alone and in combination with cannabidiol (CBD) compared with placebo on psychiatric symptoms in healthy people.Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO for studies published in English between database inception and May 21, 2019, with a within-person, crossover design. Inclusion criteria were studies reporting symptoms using psychiatric scales (the Brief Psychiatric Rating Scale [BPRS] and the Positive and Negative Syndrome Scale [PANSS]) following the acute administration of intravenous, oral, or nasal THC, CBD, and placebo in healthy participants, and presenting data that allowed calculation of standardised mean change (SMC) scores for positive (including delusions and hallucinations), negative (such as blunted affect and amotivation), and general (including depression and anxiety) symptoms. We did a random-effects meta-analysis to assess the main outcomes of the effect sizes for total, positive, and negative PANSS and BPRS scores measured in healthy participants following THC administration versus placebo. Because the number of studies to do a meta-analysis on CBD's moderating effects was insufficient, this outcome was only systematically reviewed. This study is registered with PROSPERO, CRD42019136674.Findings 15 eligible studies involving the acute administration of THC and four studies on CBD plus THC administration were identified. Compared with placebo, THC significantly increased total symptom severity with a large effect size (assessed in nine studies, with ten independent samples, involving 196 participants: SMC 1•10 [95% CI 0•92-1•28], p<0•0001); positive symptom severity (assessed in 14 studies, with 15 independent samples, involving 324 participants: SMC 0•91 [95% CI 0•68-1•14], p<0•0001); and negative symptom severity with a large effect size (assessed in 12 studies, with 13 independent samples, involving 267 participants: SMC 0•78 [95% CI 0•59-0•97], p<0•0001). In the systematic review, of the four studies evaluating CBD's effects on THC-induced symptoms, only one identified a significant reduction in symptoms.Interpretation A single THC administration induces psychotic, negative, and other psychiatric symptoms with large effect sizes. There is no consistent evidence that CBD induces symptoms or moderates the effects of THC. These findings highlight the potential risks associated with the use of cannabis and other cannabinoids that contain THC for recreational or therapeutic purposes.