OBJECTIVES: Dermatological disorders are associated with secondary psychiatric illnesses. In particular, acne carries an increased risk of developing major depressive disorder (MDD) and other psychological comorbidities. The association between acne drug therapy and the incidence of secondary psychiatric disorders, however, remains unclear. This study evaluated the effects of drug therapies on the development of comorbid MDD in acne patients in the United States. METHODS: A longitudinal retrospective study was conducted using the 2003-2007 MarketScan Medicaid Claims dataset representing 177,333 patients with acne vulgaris. The Cox proportional-hazard survival analysis was performed to obtain the hazard ratios (HRs) of MDD development, adjusting age, race, sex, physician specialty, Charlson Comorbidiy index (CCI), and acne drug treatment. RESULTS: Patients totalling 11,131 had an MDD occurrence within the study period. White patients had the highest hazard of MDD incidence among all races (all p<0.01). Compared with adult patients, youths and children were less likely to have an MDD occurrence (HRs=0.66 and 0.22, respectively; both p<0.01). MDD was less frequent in patients seen by dermatologists, family physicians, or pediatricians (all p<0.01). Patients whose acne was treated with isotretinoin, oral antibiotics, or topical antibiotics were less likely to have an MDD occurrence (HRs=0.56, 0.41, and 0.46, respectively; all p<0.01). A unit of increase in CCI was associated with a 14% higher hazard of MDD incidence (p<0.01).  CONCLUSIONS: The likelihood of MDD occurrence in acne patients treated with drug therapy varied with age and race. Consultation with dermatologists, family physicians, or pediatricians was associated with a lower hazard of MDD. Drug treatment of acne with isotretinoin, oral antibiotics, or topical antibiotics was associated with a reduced incidence of secondary MDD in acne patients, indicating that the treatment of the primary cutaneous indication may reduce the risk of secondary psychiatric comorbidities.