Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders: A Multivariable Mendelian Randomization Analysis

Abstract

Importance: Growing evidence suggests that prescription opioid use affects depression and anxiety disorders; however, observational studies are subject to confounding, making causal inference and determining the direction of these associations difficult.

Objective: To investigate the potential bidirectional associations between the genetic liability for prescription opioid and other nonopioid pain medications and both major depressive disorder (MDD) and anxiety and stress-related disorders (ASRD) using genetically based methods.

Design, setting, and participants: We performed 2-sample mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) to assess potential associations of self-reported prescription opioid and nonopioid analgesics, including nonsteroidal anti-inflammatories (NSAIDs) and acetaminophen-like derivatives use with MDD and ASRD. The GWAS data were derived from participants of predominantly European ancestry included in observational cohorts. Data were analyzed February 20, 2020, to May 4, 2020.

Main outcomes and measures: Major depressive disorder, ASRD, and self-reported pain medications (opioids, NSAIDs, anilides, and salicylic acid).

Results: The GWAS data were derived from participants of predominantly European ancestry included in the population-based UK Biobank and Lundbeck Foundation Initiative for Integrative Psychiatric Research studies: approximately 54% of the initial UK Biobank sample and 55.6% of the Lundbeck Foundation Initiative for Integrative Psychiatric Research sample selected for the ASRD GWAS were women. In a combined sample size of 737 473 study participants, single-variable MR showed that genetic liability for increased prescription opioid use was associated with increased risk of both MDD (odds ratio [OR] per unit increase in log odds opioid use, 1.14; 95% CI, 1.06-1.22; P < .001) and ASRD (OR, 1.24; 95% CI, 1.07-1.44; P = .004). Using multivariable MR, these opioid use estimates remained after accounting for other nonopioid pain medications (MDD OR, 1.14; 95% CI, 1.04-1.25; P = .005; ASRD OR, 1.30; 95% CI, 1.08-1.46; P = .006), and in separate models, accounting for comorbid pain conditions. Bidirectional analyses showed that genetic liability for MDD but not ASRD was associated with increased prescription opioid use risk (OR, 1.18; 95% CI, 1.08-1.30; P < .001). These estimates were generally consistent across single-variable and multivariable inverse variance-weighted (MV-IVW) and MR-Egger sensitivity analyses. Pleiotropy-robust methods did not indicate bias in any MV-IVW estimates.

Conclusions and relevance: The findings of this mendelian randomization analysis suggest evidence for potential causal associations between the genetic liability for increased prescription opioid use and the risk for MDD and ASRD. While replication studies are necessary, these findings may inform prevention and intervention strategies directed toward the opioid epidemic and depression.

Figure 1.. Study Overview and Mendelian Randomization (MR) Model

All summary-level genetic associations were derived from cohorts of European ancestry. Consortium, study cohort, and author information of original genome-wide association study for each exposure, confounder, and outcome included in the study are in parentheses. B₂ is the association of interest (prescription opioid use on major depressive disorder [MDD] and anxiety and stress-related disorder [ASRD] risk), estimated by B₂ = B₁ / B₃. B₁ and B₃ are the estimated direct association of the genetic variants on the exposure (ie, prescription opioid use) and the outcomes (ie, MDD and ASRD), respectively. iPSYCH indicates The Lundbeck Foundation Initiative for Integrative Psychiatric Research; IVW, inverse variance–weighted MR; MRC-IEU, Medical Research Center-Integrative Epidemiology Center (UK Bristol); NSAID, nonsteroidal anti-inflammatory or antirheumatic drugs; PGC, Psychiatric Genomics Consortium; SNV, single-nucleotide variant; UKB, UK Biobank.

Figure 2.. Scatterplot and Leave-One-Out Analysis of Associations of Genetic Risk of Prescription Opioid Use on Risk of MDD (A and B) and ASRD (C and D)

Scatterplot of independent instrument single-nucleotide variant (SNV) exposure effects vs outcome effects from 2 independent samples augmented by the standard error of these effects on the vertical and horizontal sides (for presentation, alleles are coded so that all SNV exposure effects are positive). Solid lines are the regression slopes fitted by the primary inverse variance–weighted (IVW) and complementary mendelian randomization (MR) methods: slopes fitted by IVW MR method were very similar in direction and magnitude to slopes fitted by MR-Egger and weighted median methods for both risk of major depressive disorder (MDD) (A) and risk of anxiety and stress-related disorders (ASRD) (C). In leave-one-out sensitivity analyses, IVW MR was performed leaving out each SNV in turn to identify whether a single SNV may be driving the association, with results illustrated in plots showing that no single SNV was driving the association between genetic risk of prescription opioid use and MDD (B) or ASRD (D), respectively: the relevant comparisons would be between the overall IVW MR interval estimate ("ALL") vs each leave-one-out MR interval estimate, for MDD (B) and ASRD (D), respectively. Interval estimates are expressed as odds ratios (ORs) of risk of MDD or ASRD per unit increase in log odds of prescription opioid use. Heterogeneity tests did not indicate heterogeneity in the IVW estimates of prescription opioid use on either risk of MDD or ASRD; pleiotropy robust methods indicated no bias in the IVW estimates (eTable 15 in the Supplement).