Relapse and recurrence prevention in major depression: a critical review of placebo-controlled efficacy studies with special emphasis on methodological issues

This article critically reviews the design and methodology of studies aimed at evaluating relapse and recurrence prevention in major depression. A lit erature search in MEDLINE was performed with the medical subject headings ' depression', 'recurrence', 'relapse', 'prevention' and 'study'. This search covered the period from January 1990 to July 1999. Only long-term placebo- controlled studies that included patients with non-chronic major depression were selected, Two types of design could be distinguished: randomised with drawal studies in responders/remitters (N = 11) and extension studies in re sponders without re-randomisation (N = 3). Randomised withdrawal studies are suitable for demonstrating long-term effi cacy for the duration of the study period. However, this design does not pe rmit a clear differentiation between relapse or recurrence and, therefore, is not suitable to demonstrate unequivocally relapse prevention or recurren ce prevention. Extension studies in short-term responders without randomisa tion are not even suitable to demonstrate long-term efficacy. A novel design is proposed that overcomes the weaknesses of designs employe d thus far. In essence, this design calls for a long-term randomised placeb o-controlled study in patients who are free of medication for a substantial period of time and who fulfil the criteria of major depression (recurrent) in sustained remission (e.g., HDRS < 7) as a possible option. (C) 2001 edi tions scientifiques et medicales Elsevier SAS.