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<b><i>Background:</i></b> Evidence on the long-term efficacy of psychotherapeutic approaches for chronic depression is scarce. <b><i>Objective:</i></b> To evaluate the effects of the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) compared to Supportive Psychotherapy (SP) 1 year and 2 years after treatment termination. <b><i>Methods:</i></b> In this study, we present 1- and 2-year follow-up assessments of a prospective, multicenter, evaluator-blinded, randomized clinical trial of outpatients with early-onset chronic major depression (<i>n</i> = 268). The initial treatment included 32 sessions of CBASP or SP over 48 weeks. The primary outcome was the rate of “well weeks” (Longitudinal Interval Follow-Up Evaluation; no/minimal symptoms) after 1 year and 2 years. The secondary outcomes were, among others, clinician- and self-rated depressive symptoms, response/remission rates, and quality of life. <b><i>Results:</i></b> Of the 268 randomized patients, 207 (77%) participated in the follow-up. In the intention-to-treat analysis, there was no statistically significant difference between CBASP and SP patients in experiencing well weeks (CBASP: mean [SD] of 48.6 [36.9] weeks; SP: 39.0 [34.8]; rate ratio 1.26, 95% CI 0.99–1.59, <i>p</i> = 0.057, <i>d</i> = 0.18) and in remission rates (CBASP: 1 year 40%, 2 years 40.2%; SP: 1 year 28.9%, 2 years 33%) in the 2 years after treatment. Statistically significant effects were found in favor of CBASP 1 year after treatment termination regarding the rate of well weeks, self-rated depressive symptoms, and depression-related quality of life. <b><i>Conclusions:</i></b> CBASP lost its superiority over SP at some point between the first and the second year. This suggests the necessity of maintenance treatment for early-onset chronically depressed patients remitted with CBASP during the acute therapy phase, as well as the sequential integration of other treatment strategies, including medication for those who did not reach remission.

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