Abstract

Major depressive disorder (MDD) is highly prevalent in youth and generally characterized by psychiatric comorbidities. Secular trends in co-occurring diagnoses remain unclear, especially in healthcare settings. Using large-scale electronic health records data from a major U.S. healthcare system, we examined the prevalence of MDD diagnoses and co-occurring psychiatric conditions during adolescence (12–18 years; N = 133,753) across four generations (birth years spanning 1985 to 2002) and by sex. Then using a phenome-wide association analysis, we explored which of 67 psychiatric conditions were associated with adolescent MDD diagnosis in earlier versus recent generations. Adolescent MDD diagnosis prevalence increased (8.9 to 11.4%) over time. Over 60% with an MDD diagnosis had co-occurring psychiatric diagnoses, especially neurodevelopmental and anxiety disorders. Co-occurring diagnoses generally increased over time, especially for anxiety disorders (14 to 50%) and suicidal behaviors (6 to 23%), across both sexes. Eight comorbidities interacted with generation, showing stronger associations with MDD diagnosis in earlier (e.g., conduct disorder) versus more recent (e.g., suicidal ideation and behaviors) generations. The findings underscore the importance of assessing psychiatric complexity in adolescents diagnosed with MDD, applying transdiagnostic approaches to address co-occurring presentations, and further investigating potential causes for generational increases.