Comorbidity of substance misuse with anxiety-related and depressive disorders: A genetically informative population study of 3 million individuals in Sweden

Abstract

Importance: Substance misuse and anxiety-related and depressive disorders (ADs) are among the most common psychiatric conditions and often co-occur. Despite adversities associated with the comorbidity, its causes remain unclear. Objective: We used Swedish nationwide register data aiming to (1) estimate associations of substance misuse and ADs in the population, (2) investigate gender differences in comorbidity, and (3) test the associations while accounting for genetic and shared environmental factors in stratified analyses within twin pairs and siblings. Design, Setting, and Participants: Individuals born in Sweden between January 1968 and December 1997 (n=2,996,403) were followed-up with register-based data for 1997-2013. Main Outcomes and Measures Substance misuse was defined using ICD-10 diagnoses of substance use disorders (F10-F16, F18-F19) and drug-related criminal convictions. ADs included anxiety (F40-F43) and depressive disorders (F32-F34, F38-F39). Confounding by sex, birth year, personality disorders (F60.0-F60.9), socioeconomic covariates, and parental history of psychopathology was adjusted for. Results: Risk of ADs was substantially increased in individuals with substance misuse (Risk Ratios (RR): 2.5-4.5). Of the AD diagnosis clusters derived from exploratory factor analysis, generalized anxiety/depression had the strongest association with substance misuse (RR=4.46, 95% CI 4.42- 4.50). Similarly, those with substance misuse had a 4.6-fold (95% CI: 4.52-4.60) risk of generalized anxiety/depression and a 4.7-fold (95% CI: 4.65-4.84) risk of panic disorder/social phobia as compared to those without substance misuse. The associations were stronger in women than in men, and were attenuated in within-family analyses. However, elevated risks were found even among MZ twins suggesting the comorbidity was not fully explained by familial factors. Conclusions and Relevance: Risk of ADs is elevated in individuals with substance misuse, and vice versa, and these associations are partially confounded by familial liabilities. However, the results are also compatible with a partially causal relationship between substance misuse and ADs.