T79. BALANCING EFFECTS WITH SIDE-EFFECTS: EXAMINING COMPARATIVE METABOLIC CONSEQUENCES OF 18 ANTIPSYCHOTICS IN TREATMENT OF SCHIZOPHRENIA USING NETWORK META-ANALYSIS
Authors: Pillinger Toby , McCutcheon Rob , Efthimiou Orestis , Cipriani Andrea , Howes Oliver 
Published: May 2020

Abstract

Background
Antipsychotic treatment is associated with metabolic disturbance. However, the relative degree to which metabolic alterations occur in treatment with different antipsychotics remains unclear. Furthermore, predictors of metabolic dysregulation are poorly understood, and association between metabolic-change and change in psychopathology is uncertain.

Methods
We searched Medline, EMBASE and PsychINFO from inception until June 30, 2019. We included blinded randomised controlled trials (RCTs) comparing 18 antipsychotics and placebo in acute-treatment of schizophrenia. We performed frequentist random-effects network meta-analyses (NMAs) to investigate treatment-induced changes in body weight, BMI, total/LDL/HDL-cholesterol, triglycerides, and glucose. We performed meta-regressions to examine relationships between metabolic change and age/gender/ethnicity/baseline-weight/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.

Results
Of 6532 citations, 100 RCTs met inclusion criteria, including 25,952 patients. Median treatment-duration was 6-weeks. According to our NMAs, mean differences for weight-gain compared to placebo ranged from -0.23 (95% CI: -0.83, 0.36) for best (haloperidol) to +3.01kg (1.78, 4.24) for worst (clozapine); for BMI from -0.25 (-0.68, 0.17) for best (haloperidol) to +1.07kg/m2 (0.90, 1.25) for worst (olanzapine); for total-cholesterol from -0.09 (-0.24, 0.07) for best (cariprazine) to +0.56mmol/L (0.26, 0.86) for worst (clozapine); for LDL-cholesterol from -0.13 (-0.21, -0.05) for best (cariprazine) to +0.20mmol/L (0.14, 0.26) for worst (olanzapine); for HDL-cholesterol from +0.05 (0.00, 0.10) for best (brexpiprazole) to -0.10mmol/L (-0.33, 0.14) for worst (amisulpride); for triglycerides from -0.01 (-0.10, 0.08) for best (brexpiprazole) to +0.98mmol/L (0.48, 1.49) for worst (clozapine); for glucose from -0.29 (-0.55, -0.03) for best (lurasidone) to 1.05mmol/L (0.41, 1.70) for worst (clozapine). Greater increases in glucose were predicted by higher baseline-weight (p=0.001) and male-gender (p=0.008). Non-Caucasian ethnicity was associated with greater increases in total-cholesterol (p=0.04). Improvements in symptom severity were associated with increases in weight (rho=0.36, p=0.002), BMI (rho=0.84, p&lt;0.0001), total-cholesterol (rho=0.31, p&lt;0.05), and LDL-cholesterol (rho=0.42, p=0.01), and decreases in HDL-cholesterol (rho= -0.35, p=0.04).

Discussion
There are marked differences between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles. By contrast, compared with placebo, lurasidone and cariprazine respectively reduce fasting glucose and LDL-cholesterol, while aripiprazole and brexpiprazole increase HDL-cholesterol. Baseline weight, male gender, and non-Caucasian ethnicity predict vulnerability to antipsychotic-induced metabolic change. Considering the increased prevalence of metabolic syndrome, cardiovascular disease, and cardiovascular mortality in schizophrenia, these data may be used to inform antipsychotic-prescribing, especially in those at-risk groups we have identified. However, clinical decisions to preferentially use an antipsychotic with fewer metabolic side effects should consider that clinical improvement appears to be associated with development of these side effects.