Kupfer 1992.

Study characteristics
Methods	Design: multi‐phase randomised controlled trial Prerandomisation phase Phase 1: short‐term treatment with interpersonal psychotherapy (IPT) and imipramine (duration not clearly reported) Phase 2: continuation treatment with IPT and imipramine (17 weeks) Phase 3: maintenance treatment with imipramine with or without IPT (156 weeks) Duration post randomisation: 104 weeks Aim: to determine whether maintaining antidepressant medication at the dosage used to treat the acute episode beyond 3 years would continue to provide a significant prophylactic effect compared with medication discontinuation after the 3 years of effective maintenance treatment
Participants	Country: USA Setting: not reported Type of AD: imipramine Duration of antidepressant treatment prerandomisation: 173 weeks + short‐term treatment (duration not clearly reported) Duration of antidepressant treatment post stabilisation: 173 weeks Number of randomised participants: 230 entered study, 157 entered phase 2, 128 completed and responded to phase 2, 128 entered phase 3, 106 completed and responded to phase 3, 28 completed phase 3 and remained in remission Total numbers of randomised participants: 20 (9 placebo, 11 antidepressant) Primary diagnosis: recurrent depression Number of previous episodes, mean (SD): 6.4 (4.4) placebo, 6.5 (3.1) antidepressant Gender distribution (male): 50% placebo, 37.5% antidepressant Mean age, years (SD): 44.3 (9.9) placebo, 35.6 (8.2) antidepressant Severity of depressive symptoms at randomisation (SD) HDRS‐17: 3.7 (1.5) placebo, 3.0 (2.1) antidepressant HDRS‐25: 5.1 (1.6) placebo, 3.9 (2.0) antidepressant Inclusion criteria ‐ 21 to 65 years of age ‐ ≥ 3 episodes unipolar depression, immediately preceding episode ‐ < 2.5 years before onset of present episode ‐ ≥ 10 weeks remission (RDC criteria) between index episode and immediately preceding episode ‐ HDRS ≥ 15 and Raskin ≥ 7 at entry to short‐term treatment Definition of response/remission ‐ HDRS ≤ 7 and Raskin ≤ 5 for 3 weeks Exclusion criteria ‐ any other Axis I diagnosis except GAD or panic disorder ‐ antisocial or borderline personality disorder ‐ any condition considered to be incompatible with imipramine therapy
Interventions	Intervention 1 ‐ placebo Tapering scheme: reduction of 33% a week for first 3 weeks; varied slightly depending on the number of pills the patient was taking at random assignment Intervention 2 ‐ active imipramine: target dose 200 mg, at the same dose patient had been taking at the end of the 3‐year maintenance treatment Co‐interventions ‐ maintenance IPT (methods by Klerman) if patient received it during the first 3 phases of the study (13 participants). The purpose of IPT was to improve social adjustment and thus to provide additional protection against future episodes. Study authors elected IPT because of pronounced deficits in social adjustment that they had observed, even among patients who remained well for 2 years ‐ all participants received the same acute treatment consisting of a combination of imipramine and IPT. IPT treatment sessions were scheduled weekly for 12 weeks, then biweekly for 8 weeks, then monthly. If patients met the criteria for remission (at whatever point in this short‐term treatment regimen), they continued to receive combined treatment for an additional 17 weeks. IPT was conducted according to the methods described by Klerman et al. Participants met with their primary therapist for 45 to 50 minutes of IPT, after which they were joined by the physician member of the treatment team that was responsible for the pharmacotherapy. During the 17‐week continuation treatment phase (phase 2), patients continued to see their psychotherapist but with decreasing frequency in preparation for maintenance treatment. Toward the end of the 17‐week continuation treatment phase, therapists and patients discussed the possibility that psychotherapy and active medication would be discontinued, and a review of psychotherapeutic accomplishments in the short term and in continuation treatment phases was carried out. In phase 3 of the trial; participants were randomised to monthly IPT sessions or to discontinuation of IPT sessions. In the discontinuation trial, patients were randomised to receive continuation pharmacotherapy or placebo and were informed that they would continue to receive psychotherapy or monthly medication clinic visits consistent with their previous maintenance treatment phase ‐ medication clinics monthly (7 participants)
Outcomes	Primary outcome ‐ recurrence of major depression Definition of relapse/recurrence ‐ HDRS ≥ 15 and Raskin ≥ 7 on 2 occasions within 7 days by an independent clinical evaluator and confirmed by clinical evaluation of senior psychiatrist ‐ survival time
Notes	Funding: study supported by a grant from the National Institute of Mental Health COI: not reported Of the 20 patients, 13 continued to receive psychotherapy once a month, and the remaining 7 attended medication clinic NO significant difference was evident in the number of individuals receiving psychotherapy and active medication vs psychotherapy (n = 6) vs psychotherapy and placebo (n = 7)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “patients were randomly assigned” Comment: information insufficient to permit judgement
Allocation concealment (selection bias)	Unclear risk	Comment: information insufficient to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “double blind, both the patients and members of their treatment team remained blind to whether they were receiving active medication or placebo, only the research pharmacist and one physician, who had no direct care patient responsibilities, were aware of patients’ actual treatment assignments” Comment: blinding of participants and personnel ensured; unlikely that blinding could have been broken
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “the patient was seen by an independent senior psychiatrist not affiliated with the study and who was blind to the patient’s maintenance treatment assignment”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: all 20 patients accounted for. 1 in the active medication group did not complete the trial; reason given was non‐compliance with medication
Selective reporting (reporting bias)	High risk	Comment: the study report fails to include results for adverse events and withdrawal symptoms that would be expected to have been reported for such a study
Other bias	Low risk	Study appears to be free from other sources of bias