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...

The idea that a longer duration of untreated psychosis (DUP) leads to poorer outcomes has contributed to extensive changes in mental health ser­vices worldwide and has attracted considerable research interest over the past 30 years. However, the strength of the evidence underlying this notion is unclear. To address this issue, we conducted an umbrella review of available meta‐analyses and performed a random‐effects meta‐analysis of primary studies. MEDLINE, Web of Science, PsycINFO and EMBASE were searched from inception to September 3, 2020 to identify relevant meta‐analyses of studies including patients with schizophrenia spectrum disorders, first‐episode psychosis, or affective and non‐affective psychosis. Thirteen meta‐analyses were included, corresponding to 129 individual studies with a total sample size of 25,657 patients. We detected potential violations of statistical assumptions in some of these meta‐analyses. We therefore conducted a new random‐effects meta‐analysis of primary studies. The association between DUP and each outcome was graded according to a standardized classification into convincing, highly suggestive, suggestive, weak, or non‐significant. At first presentation, there was suggestive evidence for a relationship between longer DUP and more severe negative symptoms (beta=–0.07, p=3.6×10–5) and higher chance of previous self‐harm (odds ratio, OR=1.89, p=1.1×10–5). At follow‐up, there was highly suggestive evidence for a relationship between longer DUP and more severe positive symptoms (beta=–0.16, p=4.5×10–8), more severe negative symptoms (beta=–0.11, p=3.5×10–10) and lower chance of remission (OR=2.16, p=3.0×10–10), and suggestive evidence for a relationship between longer DUP and poorer overall functioning (beta=–0.11, p=2.2×10–6) and more severe global psychopathology (beta=–0.16, p=4.7×10–6). Results were unchanged when analysis was restricted to prospective studies. These effect sizes are clinically meaningful, with a DUP of four weeks predicting >20% more severe symptoms at follow‐up relative to a DUP of one week. We conclude that DUP is an important prognostic factor at first presentation and predicts clinically relevant outcomes over the course of illness. We discuss conceptual issues in DUP research and methodological limitations of current evidence, and provide recommendations for future research.