Relapse During SSRI Treatment for Depression


Medscape Psychiatry & Mental Health eJournal. 1996;1(5) 

In This Article

Abstract & Introduction


We surveyed 400 psychiatrists to assess depressive relapse during ongoing selective serotonin reuptake inhibitor (SSRI) treatment and the common strategies to regain remission. Among 119 respondents, most (89%) had observed re-emergent depressive symptoms after a favorable SSRI response, despite continued treatment. Depressive symptoms typically recurred in up to 25% of cases, usually within 6 months of remission. Over half of respondents eventually needed to increase SSRI dosages. Respondents associated relapse with prior depression or SSRI failure, substance abuse, and atypical depression. Dosage increases, alternative SSRIs, and non-SSRI antidepressants were typical maneuvers to regain remission. Loss of antidepressant response to SSRIs may be common in clinical practice, but appears pharmacologically surmountable by a number of tactics.


Relapses of depression after a successful response to antidepressant medication have been reported in a number of recent studies of ongoing treatment. During routine pharmacotherapy for depression, it is unknown how common it is for psychiatrists eventually to find a need to raise medication dosages after achieving a marked remission. The purpose of the current study is to determine the extent to which practicing psychiatrists who treat depression encounter relapse of depressive symptoms after initial remissions during ongoing antidepressant pharmacotherapy using selective serotonin reuptake inhibitors (SSRIs).

Numerous randomized clinical trials have demonstrated the efficacy of SSRIs in the acute treatment of depression. However, little is known about their long-term effectiveness in the maintenance treatment of depression. Because unipolar depression frequently recurs after an initial episode resolves,[1] investigators have sought to identify the optimum duration and dosage of antidepressant treatment.[2] Furthermore, it remains an open question whether relapse rates during maintenance treatment for depression are the same for different classes of medication.

Depressed patients treated with some antidepressant classes, such as monoamine oxidase inhibitors (MAOIs), have been shown to become tolerant to the antidepressant effect during long-term treatment.[3,4] The literature contains few studies examining whether a similar phenomenon, involving the loss of antidepressant efficacy after initial improvement, may also be true of SSRIs.

A mechanism to explain relapse unique to SSRI antidepressant treatment remains uncertain. Recently, McGrath and colleagues[5] proposed that relapse during SSRI maintenance may arise from the SSRI-induced depletion of dopamine in the striatum and limbic forebrain. In a preliminary open study of SSRI augmentation with the dopamine agonist bromocriptine, 6 of 12 (intent-to-treat) patients fully regained remissions from depressive symptoms.

Evidence suggests that relapse rates in depression may range from 20%[6] to as high as 44%, depending on the length of treatment, with maintained use of SSRIs.[7] In contrast, with tricyclic antidepressants (TCAs), relapse during ongoing treatment to maintain remission from depression appears relatively rare. For example, Kocsis and coworkers[8] reported 46 chronically depressed patients who fully responded to acute tricyclic antidepressant treatment, of whom only 11% of cases subsequently lost remission during continuation phases of therapy (up to 20 weeks' duration). These reports would initially suggest that relapse in major depression may occur more often with SSRIs than with TCAs.

Several open studies and case reports have described instances of successfully regaining remission, following relapse on an SSRI. Fava and associates[9] reported significant improvement after a dosage increase in 66% of depressed patients who relapsed while continuing to take fluoxetine. Cain,[6] by comparison, observed clinical improvement after lowering fluoxetine dosages when initial responders failed to sustain an initial response. We recently reported the case of a woman with major depression who failed to sustain an initial improvement while continuing an SSRI, despite a number of pharmacologic attempts to recapture her initial remission.[10]

Augmentation strategies have also been used to enhance a partial response to SSRI antidepressant therapy. These include combinations of SSRIs with TCAs,[11,12] psychostimulants,[12,13] and pindolol, a 5-HT1A partial agonist.[14,15] Systematic treatment studies for the loss of antidepressant response to an SSRI during ongoing treatment have not been described.

The current research was designed to estimate, based on the observations of a large number of practicing clinicians, the incidence of re-emergent depressive symptoms in depressed patients who initially responded and were then maintained on an SSRI. A large cohort of psychiatrists affiliated with the New York Hospital-Cornell University Medical College were surveyed regarding their experiences using SSRIs, TCAs, and other treatments for depression. Clinicians were asked about how frequently they observed breakthrough signs or symptoms of depression after achieving a marked remission, and therapeutic methods for regaining a remission.

The following specific clinical questions were addressed:


  1. How frequently do psychiatrists observe the re-emergence of depressive symptoms after remission during ongoing pharmacotherapy for depression using SSRIs?

  2. Do clinicians perceive a difference in relapse rates during ongoing SSRI versus TCA treatment for depression?

  3. Among depressed patients who experience a loss of antidepressant response to an SSRI, what factors do clinicians associate with the risk for relapse?

  4. What therapeutic maneuvers do psychiatrists view as most effective in regaining a remission of depressive symptoms after an attenuation of antidepressant response to an SSRI?