Key PointsQuestionWhat are the optimal type, timing, and sequence of interventions for individuals at ultrahigh risk of psychosis?FindingsIn this sequential multiple assignment randomized trial including 342 individuals, a specialized psychological intervention (cognitive-behavioral case management [CBCM]) and a psychopharmacological intervention (CBCM and antidepressant medication) were not more efficacious than control conditions in improving remission and functional recovery. Relapse rates among individuals who remitted were high.MeaningThe findings of this study show that addition of sequentially more specialized psychosocial and antidepressant treatment for individuals who did not remit did not lead to superior outcomes, underscoring the need for further adaptive trials, treatment innovation, and an extended duration of care for relapse prevention.