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Treatment for Depression After Unsatisfactory Response to SSRIs

Systematic Review ARCHIVED Apr 26, 2012
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Structured Abstract


A comparative effectiveness review was undertaken to evaluate treatment strategies in patients who failed to respond to selective serotonin reuptake inhibitors (SSRIs) as first-line treatment. The efficacy (benefits and harms) of monotherapy approaches (dose escalation, increased duration, or switch) or combined therapies were evaluated. Efficacy in the context of subgroups was also evaluated. Recommendations in Clinical Practice Guidelines (CPGs) from 2004 to April 2011 were compared.

Data Sources

MEDLINE®, Embase®, CINAHL®, PsychINFO®, AMED (Allied and Complementary Medicine), Cochrane Database of Systematic Reviews, and Cochrane Central® were searched from 1980 to April 13, 2011. An extensive grey literature search was also undertaken, including publications of drug regulatory agencies.

Review Methods

Systematic review methodology was employed. Eligibility criteria included English studies of adults (aged ≥18 years) or adolescents and children (8–18 years) with major depressive disorder, dysthymia, or subsyndromal depression, who had an inadequate response to an SSRI at entry into the study. Comparative study designs were eligible. Publications focusing only on treatment algorithms were not considered to be CPGs.


From 46,884 citations, there were 44 studies and 27 guidelines that were eligible. Key Questions 1 and 2 (KQ1-a and KQ2): Forty-one studies included adults and three studies included adolescents; all included subjects with major depressive disorder except for one with adult dysthymia and subsyndromal patients alone. A limited number of studies (n=11) evaluated monotherapy strategies and these showed no differences among approaches. Although there were more studies evaluating monotherapy relative to combined therapies (n=33), the types of add-on agents were numerous and showed no relative differences; the exception was the addition of risperidone to an SSRI. KQ 3: Seven studies evaluated the impact of disease type, disease severity, previous comorbidities, age, gender, and race on treatment outcomes and showed no clear trend. KQ4: From 18 CPGs for adults, the majority did not provide specific recommendations for monotherapy strategies; for combination therapies, although specific agents were specified, there was variability across CPGs when recommending agents and strategies. Recommendations were more consistent for the CPGs for adolescents (n=7).


There is low strength of evidence evaluating relative differences for any monotherapy or combination therapy approach. All but 2 of 44 studies showed no relative differences in response and remission rates. Two studies with limited sample sizes and using risperidone as an augmenting agent showed benefit with combined therapy. The majority of studies were not designed to assess superiority of the strategies. Inconsistency and lack of clarity for clinical actions were noted when comparing CPGs.

Project Timeline

Treatment for Depression After Unsatisfactory Response to SSRIs

Feb 10, 2010
Jun 15, 2010
Apr 26, 2012
Systematic Review Archived
Page last reviewed December 2019
Page originally created November 2017

Internet Citation: Systematic Review: Treatment for Depression After Unsatisfactory Response to SSRIs. Content last reviewed December 2019. Effective Health Care Program, Agency for Healthcare Research and Quality, Rockville, MD.

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