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Cover of Treatment for Depression After Unsatisfactory Response to SSRIs

Treatment for Depression After Unsatisfactory Response to SSRIs

Comparative Effectiveness Reviews, No. 62

Investigators: , BScPT, PhD, , MD, FRCPC, PhD, , BSN, PhD, , MD, FRCPC, FISPE, , BSc, MSc, PhD, and , BSc, PhD.

Author Information
Rockville (MD): Agency for Healthcare Research and Quality (US); .
Report No.: 12-EHC050-EF

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.


Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services1, Contract No. 290-2007-10060-I, Prepared by: McMaster University Evidence-based Practice Center, Hamilton, ON, Canada

Suggested citation:

Santaguida P, MacQueen G, Keshavarz H, Levine M, Beyene J, Raina P. Treatment for Depression After Unsatisfactory Response to SSRIs. Comparative Effectiveness Review No. 62. (Prepared by McMaster University Evidence-based Practice Center under Contract No. HHSA 290 2007 10060 I.) AHRQ Publication No.12-EHC050-EF. Rockville, MD: Agency for Healthcare Research and Quality; April 2012.

This report is based on research conducted by the McMaster University Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA 290 2007 10060 I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report.


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Bookshelf ID: NBK97406PMID: 22696777


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