Suicide risk with selective serotonin reuptake inhibitors and new-generation serotonergic-noradrenergic antidepressants in adults: a systematic review and meta-analysis of observational studies

Background: There is ongoing controversy whether antidepressant use alters the suicide risk in adult routine-care patients with depression and other treatment indications. The aim of this study was thus to examine the suicide risk with antidepressants in observational studies, considering financial conflicts of interest (fCOI) and publication bias. Design: Systematic review and meta-analysis. Main outcome measures: Risk of suicide, suicide attempt and/or intentional self-harm. Data sources: We searched MEDLINE, PsycINFO, Web of Science, PsycARTICLES and SCOPUS for case-control and cohort studies published 1990-2020. Eligibility criteria for study selection: Cohort and case-control studies in adults (aged >=18 years) with depression and any unspecified condition reporting suicide risk for patients exposed to selective serotonin reuptake inhibitors (SSRI) or new-generation serotonergic-noradrenergic antidepressants (SNA) relative to unexposed patients. Data extraction and analysis: Effects were aggregated with a random-effects model and reported as relative risk estimates (RE) with 95%-confidence-intervals. We assessed heterogeneity via I2-statistics and publication bias via funnel-plot asymmetry and trim-and-fill method. Study fCOI was defined present when lead-authors' professorship was industry-sponsored, they received payments from the industry, or when the study was industry-sponsored. Results: We included 27 original studies in the meta-analysis; 19 on depression (including other affective and anxiety disorders) and 8 on any unspecified condition. Use of SSRI or SNA for depression was associated with increased suicide risk (comprising both suicide and suicide attempt), RE=1.29, 1.06-1.57. Risk estimates were significantly lower in studies with fCOI (Q=21.87, p<0.001) and the trim-and-fill method estimated that 12 studies were missing due to publication bias; the result with missing studies imputed was RE=1.61, 1.31-1.99. Use of SSRI or SNA for all conditions (including depression and any unspecified condition) was associated with increased suicide risk, RE=1.43, 1.21-1.68. Studies with fCOI reported significantly lower risk estimates (Q=34.19, p<0.001) and the trim-fill method estimated that 13 studies were missing; after imputation of missing studies the result was RE=1.72, 1.44-2.05. Quality of evidence was rated very low due to substantial inconsistency of between-study results (I2>85%). Conclusions: Exposure to new-generation antidepressants is associated with increased suicide risk in adult routine-care patients with depression and other conditions. Publication bias and fCOI contribute to systematic underestimation of risk estimates in the published literature. Registration: Open Science Framework, https://osf.io/eaqwn/