Isotretinoin treatment for acne can reduce adverse psychiatric outcomes in adults, but there has been little investigation of the incidence of psychiatric outcomes in treated adolescents. This retrospective cohort study using the Rochester Epidemiology Project identified 606 patients aged 12-18 prescribed isotretinoin over a 10-year period between January 1, 2008 and December 31, 2017. Medical records were reviewed to identify psychiatric diagnoses before and during isotretinoin therapy, as well as psychiatric symptoms not captured by formal diagnoses and changes to isotretinoin dosing because of psychiatric diagnoses or symptoms. One hundred seventy-seven (29.2%) had a psychiatric diagnosis prior to isotretinoin initiation, but 98 (16.2%) had a new psychiatric diagnosis or psychiatric symptom while taking isotretinoin. Patients with a psychiatric history were no more likely than those without to receive a new psychiatric diagnosis during treatment (4.5% vs. 3.7%; p = .650), but did experience more psychiatric symptoms, primarily low mood and mood swings (23.7% vs. 7.7%; p < .001). Only 25.5% of the 98 with a new psychiatric diagnosis or psychiatric symptom had a subsequent dose change. A dose change was more likely if patients received a new psychiatric diagnosis (41.7% vs. 20.3%; p = .037) or patients did not have a psychosocial explanation for psychiatric symptoms (34.4% vs. 10.8%; p = .009). A substantial proportion of adolescent patients prescribed isotretinoin had a prior psychiatric diagnosis.This predicts more psychiatric symptoms during isotretinoin treatment. Adolescents with a psychiatric history who have worsening symptoms and those with new-onset psychiatric symptoms would benefit from close monitoring while taking isotretinoin.