Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review

doi:10.1016/S0140-6736(03)12599-8

The Lancet

Volume 361, Issue 9358, 22 February 2003, Pages 653-661

https://doi.org/10.1016/S0140-6736(03)12599-8 Get rights and content

Summary

Background

Antidepressant drugs can promote remission from acute depressive episodes. Our aim was to establish how long such treatments should be continued to prevent relapse.

Method

We did a systematic overview of evidence from randomised trials of continuing treatment with antidepressants in patients with depressive disorders who have responded to acute treatment. Medline, Embase, Cinahl, PsycLIT, Psyndex, and Lilacs were searched.

Findings

Data were pooled from 31 randomised trials (4410 participants). Continuing treatment with antidepressants reduced the odds of relapse by 70% (95% CI 62–78; 2p<0·00001) compared with treatment discontinuation. The average rate of relapse on placebo was 41% compared with 18% on active treatment. The treatment effect seemed to persist for up to 36 months, although most trials were of 12 months' duration, and so the evidence on longer-term treatment requires confirmation. Significantly more participants allocated antidepressants withdrew from the trials than did those allocated to placebo (18% vs 15%, respectively; odds ratio 1·30, 95% CI 1·07–1·59): the treatment effect could be even greater in adherent patients. The two-thirds reduction in risk of depressive relapse seemed to be largely independent of the underlying risk of relapse, the duration of treatment before randomisation, or the duration of the randomly allocated therapy.

Interpretation

Antidepressants reduce the risk of relapse in depressive disorder, and continued treatment with antidepressants would benefit many patients with recurrent depressive disorder. The treatment benefit for an individual patient will depend on their absolute risk of relapse with greater absolute benefits in those at higher risk. Further trials are needed to establish the optimum length of therapy and should include patients who were not well represented in these trials, including those at low risk of relapse.

Introduction

Neuropsychiatric illnesses in general and unipolar depressive disorder in particular are among the most important causes of death and disability worldwide, in both developing and developed countries.1, 2 Short-term and medium-term therapy with antidepressant drugs is already standard treatment for acute episodes of depression.³ However, because of the long-term nature of depressive disorder, with many patients at substantial risk of later recurrence, there is a considerable need to establish how long, in general, such patients should stay on antidepressants. Clinical guidelines recommend that treatment should be continued for 4–6 months after the acute episode (panel). However, there is considerable variation in practice, suggesting that many patients do not receive optimum treatment.⁸

We aimed systematically to review evidence from randomised trials to determine whether continuing treatment with antidepressants reduces the risk of relapse (ie, a return of symptoms during a period of remission or partial remission) or recurrence (ie, a new episode during a period of recovery) of depressive symptoms. In addition, we assessed whether the magnitude of this benefit varies according to the length of previous treatment, length of continuing treatment, and the underlying level of risk of relapse.

Section snippets

Data acquisition

The aim of this systematic review was to identify all randomised trials, published or unpublished, available for review by August, 2000, in which continued antidepressant drug therapy was compared with placebo in patients who had responded to acute treatment with antidepressants. Trials in which patients were randomly allocated treatment after acute treatment response were included, along with those in which patients were randomised after a variable period of continuing therapy.

Selection of trials

The search

Results

122 reports and posters were identified as possibly satisfying the inclusion criteria. 33 studies, described in 40 publications, were excluded. Of these, ten were not randomised controlled trials, 21 were not of continuation versus discontinuation design, one was a crossover study with no useable data, and in the remaining trial, participants had postpsychotic depression rather than a primary depressive disorder.

37 trials, described in 82 publications, satisfied the inclusion criteria (table).13

Discussion

On the basis of pooled results of 31 randomised trials that included 4410 patients, continuing treatment with antidepressants reduced the odds of depressive relapse by around two-thirds, which is approximately equivalent to a halving of the absolute risk. The treatment effect was similar across different classes of antidepressant. We are not aware of any previous methodologically satisfactory meta-analyses of these trials, although workers in a previous quantitative review of long-term

Search strategy

Electronic databases The Cochrane collaboration depression, anxiety, and neurosis controlled trials register (CCDANCTR), which incorporates results of group searches of Medline (1966, to April, 2000); Embase (1980, to April, 2000); Cinahl (1982, to April, 2000); PsycLIT (1974, to April, 2000); Psyndex (1977, to December, 1999); and Lilacs (1982, to December, 1999) were searched with the following terms: #45 (diagnosis field)=depression* or depressive-disorder or dysthymi* and (maintenance* or

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Currently, antidepressants are recommended as the first-line treatment strategy for patients with depression, and maintenance antidepressants are the mainstay approach for preventing relapse/recurrence (Cain, 2007). After aggressive medical treatment during an acute episode, continuous medical treatment can reduce depressive relapse/recurrence (Geddes et al., 2003). However, clinical results showed that only 22 %–40 % of patients recovered gradually with medication alone (Anthes, 2014).
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ArticlesRelapse prevention with antidepressant drug treatment in depressive disorders: a systematic review

Summary

Background

Method

Findings

Interpretation

Introduction

Section snippets

Data acquisition

Selection of trials

Results

Discussion

Search strategy

Lancet

Lancet

J Affect Disord

Lancet

J Affect Disord

Lancet

Recognition and management of depression in general practice: consensus statement

BMJ

Depression in Primary Care: volume 2 treatment of major depression

Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines

J Psychopharmacol

Practice guideline for the treatment of patients with major depressive disorder (revision)

Am J Psychiatry

The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression

JAMA

Can we individualize the number needed to treat (NNT)? An empirical study of summary effect measures in meta-analyses

Int J Epidemiol

Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients

BMJ

Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction, and side-effects from 33 randomized controlled trials

Eur Heart J

Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence

Arch Gen Psychiatry

Executive dysfunction and long-term outcomes of geriatric depression

Arch Gen Psychiatry

Recurrence of depression after discontinuation of long-term amitriptyline treatment

Am J Psychiatry

Continuation therapy with amitriptyline in depression

Br J Psychiatry

Use of phenelzine in continuation therapy

Neuropsychobiology

Sertraline in the prevention of depression

Br J Psychiatry

A prospective double-blind comparative multi-centre study of paroxetine in preventing recurrent major depressive episodes

Biol Psychiatry

Double-blind, placebo-substitution study of nefazodone in the prevention of relapse during continuation treatment of outpatients with major depression

Int Clin Psychopharmacol

Three-year outcomes for maintenance therapies in recurrent depression

Arch Gen Psychiatry

A placebo-controlled comparison of nortriptyline and phenelzine in maintenance therapy of elderly depressed patients

Arch Gen Psychiatry

Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, double-blind, controlled trial

Psychol Med

Phenelzine for chronic depression: a study of continuation treatment

J Clin Psychiatry

Articles
Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review