A.C. Viguera, R.J. Baldessarini, J. Friedberg, Discontinuing antidepressant treatment in major depression, Harv Rev Psychiatry 1998 Mar-Apr; 5(6):293-306

This is an interesting paper, producing useful and important results. It seeks to define more precisely the benefits of long-term antidepressant treatment in major depression and the risks of discontinuing medication at various times after clinical recovery from acute depression. The authors reviewed results of 27 studies, involving 3037 depressive patients treated for 5.78 (0-48) months and then followed for 16.6 (5-66) months with antidepressants either continued (1851 pts) or withdrawn (1186 pts).

The overall picture was much as would be expected: "Compared with patients whose antidepressants were discontinued, those with continued treatment showed much lower relapse rates (1.85 vs. 6.24%/month), longer time to 50% relapse (48.0 vs. 14.2 months), and lower 12-month relapse risk (19.5 vs. 44.8%) (all p < 0.001)."   Implicitly, the authors acknowledge possible differences between the stressful effects of drug withdrawal and "relapse" - not that this distinction appears to have been made in the studies themselves. Nevertheless, detailed analyses yielded some notable, sometimes surprising results:

1. Diagnostic criteria for depression did not appear to influence crude relapse rates for patients who either continued or discontinued drug treatment.

2. There was no significant difference in time to relapse, with medication continued or not, between studies involving newer (eg SSRIs) and older antidepressants (eg tricyclic, MAOIs)

3. Even after withdrawal from treatment, "substantial proportions of patients remained stable for 1 or 2 years" - just over one half and one-third respectively.

4. Contrary to expectation, the length of treatment before drug withdrawal did not affect the risk of relapse

5. Contrary to expectation, relapse rates following withdrawal of medication did not differ significantly between studies involving rapid and more gradual drug discontinuation (dose-tapering or use of long-acting agents). "Overall survival analysis indicated that 12-month survival was actually 16.3% higher after more rapid discontinuation …"

6. Differences in relapse risk decrease over time. The risk of relapse (off versus on drug) was found to be 3.5-times higher within 3 month of drug withdrawal - compared with less than 1.5-times higher, after 4-5 years.

7. Past history of previous episodes of depression "showed no apparent effect on response to continued antidepressant treatment" - but "revealed striking and highly significant differences in relapse rates over time after treatment was stopped". After two years, patients with at least three episodes (or a chronic course) of depression, were near 5-times more likely to relapse without drug treatment. In contrast, there was no significant difference, on or off drug, in 2-year survival rates in patients with only one or more past episodes - i.e. "a past history of severe and frequently recurring depressive episodes is a plausible clinical predictor of increased recurrence risk after discontinuation of treatment."

Authors emphasise that further studies are needed to address questions raised in this review - but they do not specifically question whether this markedly increased vulnerability to relapse (point 7) might be a function of drug sensitisation, rather than numbers of previous depressive episodes. Is this heightened susceptibility to relapse related more to past experience of depression - or to past exposure to antidepressant drugs?


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