Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants

Depression is commonly a recurrent illness: over half of people with a diagnosis of major depression will go on to have a further episode, and the risk of future relapse rises, with 80% of those having a second episode going on to have a third.

Most clinical guidelines recommend that treatment with antidepressants should be continued for four to six months after recovery to reduce the risk of relapse (re-emergence of original symptoms) and recurrence (new episode of depression).

However, the benefits of long term or maintenance treatment are considered, particularly by clinicians, to be less certain. A systematic review included 31 randomised trials (4410 participants) investigating whether continuing treatment with antidepressants (of all classes, although most included either a tricyclic antidepressant or an SSRI) reduced the risk of relapse.
These trials were mainly discontinuation studies in which participants with depressive disorders who had responded to acute treatment were randomly assigned to continue drug treatment or receive a placebo.
Pooled results found that, compared with placebo, continuing antidepressant treatment after recovery markedly reduced the proportion of patients who relapsed over one to three years (pooled odds ratio for relapse 0.30; 95% confidence interval 0.22 to 0.38).
A re-analysis of these data, summarises the rates of relapse by length of follow-up. While the absolute risk reduction progressively increased from six to 36 months of follow-up, the relative risk reduction was stable (from 60% at six months to 58% at 36 months), suggesting that continuing antidepressant treatment more than halved the average relapse rate regardless of the duration of treatment. The absolute risk reduction was similar at six and 12 months, although the larger sample size at 12 months provides a more precise estimate. On average four patients required antidepressant treatment to prevent one additional relapse. Further systematic reviews, restricted to data on SSRIs and newer antidepressants (bupropion, mirtazapine, nefazodone, and venlafaxine), produced similar findings: a risk reduction in the proportion of patients relapsing of about 50%.
These trials also indicate that the reduction in relapse rates with prophylactic antidepressants is greater for patients with single episodes (odds ratio for relapse 0.12; 0.06 to 0.26) than for those with recurrent episodes (0.37; 0.31 to 0.44).

An evidence based approach to long term treatment with SSRIs and newer antidepressants

In adults with depression who have benefited from treatment with an antidepressant good evidence exists that they are at high risk of relapse, particularly in the first six months after recovery. Good evidence also exists that continuing antidepressant treatment reduces the absolute risk of relapse by about 50%.
The trials on which guidelines are based come predominantly from secondary care settings with follow-up limited to three years. Longer term studies that include patients from primary care with less severe illness would inform clinical practice.
Psychological treatments may augment the prophylactic effect of antidepressants, but much of the evidence for this has been inconclusive. Several studies have found that cognitive behavioural therapy combined with maintenance drug treatment significantly reduces rates of relapse compared with antidepressants alone, although whether this additional benefit is due to non-specific therapeutic effects is not clear.

In summary, after a single depressive episode in the absence of specific risk factors for relapse (see the box on risk factors) people should be advised to continue treatment with antidepressants for 12 months after recovery. Treatment should be regularly re-evaluated, with the frequency determined by the severity of the episode. Individuals with risk factors for relapse, in particular those with several previous episodes or two episodes in the recent past, should be advised to continue with treatment for at least 12 months and consider long term maintenance treatment. With long term antidepressant treatment, regular reviews should take into consideration the social consequences of relapse for the individual, concurrent physical health problems, and the development of adverse effects, as well as patient preference.

BMJ 2010;340:c1468
Steven Reid, consultant psychiatrist1, Corrado Barbui, lecturer in psychiatry2 1 Department of Liaison Psychiatry, St Mary’s Hospital, London W2 1PF, 2 Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, 37134 Verona, Italy Correspondence to: S Reid steve.reid@nhs.net