BACKGROUND: Depression is often comorbid with alcohol use problems, and sex differences may further complicate this interplay.

METHODS: We conducted a longitudinal study using a large European adolescent cohort assessed at ages 14 (baseline, BL), 16 (follow-up 1, FU1), 19 (follow-up 2, FU2), and 23 (follow-up 3, FU3). Depression and alcohol use were measured using standardized behavioral scales. Cross-lagged analysis, improved Mendelian randomization (MR) analysis, and mediation analysis were conducted to infer the causal interplay.

RESULTS: 2110 adolescents were included at baseline (49% male). Depression and alcohol consumption demonstrated a significant positive correlation ( = 0.094,  = 1.58E-05, 95% CI = [0.052, 0.137]), which gradually diminished over time and eventually became significantly negative. Depression and alcohol use problems remained strongly correlated across three timepoints ( > 0.074,  < 6.76E-03). Cross-lagged analysis suggested that depression predicted future alcohol use problems:  = 0.058,  = 0.021, 95% CI = [0.009, 0.108];  = 0.142,  = 8.34E-07, 95% CI = [0.113, 0.263]. MR analyses confirmed this causal interplay ( = 0.043, longitudinal  < 0.001). Interestingly, MR analyses also indicated that alcohol consumption might alleviate depression ( = -0.022, longitudinal  = 0.043), particularly in females at FU3, of which the anxiety status and the personality trait neuroticism largely mediated the effect. These findings were validated in an independent matched sample (N = 562) from Human Connectome Project.

CONCLUSIONS: Depression may predict future alcohol use problems, whereas moderate alcohol consumption might alleviate depressive symptoms, especially in females.