Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program 

Evidence Synthesis for Determining 

the Efficacy of Psychotherapy for 

Treatment Resistant Depression

Department of Veterans Affairs

Health Services Research & Development Service

October 2009

Investigators:

Ranak B. Trivedi, PhD

Core Investigator, Seattle VA HSR&D Center of Excellence

Research Asst. Professor, University of Washington Dept. of 

Health Services, School of Public Health

Seattle, WA

Jason A. Nieuwsma, PhD

MIRECC Postdoctoral Fellow in Psychology

Durham VA Medical Center

Durham, NC

John W. Williams Jr., MD, MHS

Professor of Medicine and Psychiatry, Durham VA Medical 

Center and Duke University

Director, Evidence-Based Practice Center

Durham, NC

Dana Baker, MS

Clinical Research Coordinator

Duke University

Durham, NC

Prepared for: 

Department of Veterans Affairs

Veterans Health Administration

Health Services Research

& Development Service

Washington, DC 20420 

Prepared by:

Durham Veterans Affairs Medical 

Center/Duke Evidence-Based 

Practice Center

Durham, NC
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Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

PREFACE

VA’s Health Services Research and Development Service (HSR&D) works to improve the cost, 

quality, and outcomes of health care for our nation’s veterans. Collaborating with VA leaders, 

managers, and policy makers, HSR&D focuses on important health care topics that are likely to 

have significant impact on quality improvement efforts. One significant collaborative effort is 

HSR&D’s Evidence-based Synthesis Program (ESP). Through this program, HSR&D provides 

timely and accurate evidence syntheses on targeted health care topics. These products will be disseminated broadly throughout VA and will: inform VA clinical policy, develop clinical practice 

guidelines, set directions for future research to address gaps in knowledge, identify the evidence 

to support VA performance measures, and rationalize drug formulary decisions.

HSR&D provided funding for the two Evidence Based Practice Centers (EPCs) supported by 

the Agency for Healthcare Research and Quality (AHRQ) that also had an active and publicly 

acknowledged VA affiliation—Southern California EPC and Portland, OR EPC—so they could 

develop evidence syntheses on requested topics for dissemination to VA policymakers. A planning committee with representation from HSR&D, Patient Care Services, Office of Quality and 

Performance, and the VISN Clinical Management Officers, has been established to identify 

priority topics and to ensure the quality of final reports. Comments on this evidence report are 

welcome and can be sent to Susan Schiffner, ESP Program Manager, at Susan.Schiffner@va.gov. 
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Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

This information is distributed solely for the purposes of pre-dissemination peer review. 

It has not been formally disseminated by the Department of Veterans Affairs. It does 

not represent and should not be construed to represent a Department of Veterans Affairs 

determination or policy.

Financial disclosure: No investigators have any affiliations or financial involvement (e.g., 

employment, consultancies, honoraria, stock ownership or options, expert testimony, grants 

or patents received or pending, or royalties) that conflict with material presented in the 

report.
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Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

EXECUTIVE SUMMARY

BACKGROUND

Major depressive disorder (MDD) is a prevalent disorder impacting an estimated 13% of the 

general population, and a third of the veteran population. Of the patients who experience at least 

one depressive episode, approximately 20% will experience chronic depression and 60-85% 

will experience recurrence and relapse. Antidepressant medications are the most commonly 

prescribed treatment modality for MDD and are often the first line of treatment in primary care 

settings. However, fewer than 50% of patients fully remit after adequate dosage of antidepressant 

treatment. Treatment options for these “treatment resistant” patients vary but typically involve 

using other psychoactive medications as augmentation (i.e., addition of another medication) 

or substitution treatment (i.e., switching medications). Less attention has been paid to using 

psychotherapy as an augmentation or substitution treatment for treatment resistant patients, 

despite psychotherapy being associated with clinical improvements in MDD comparable 

to those achieved with antidepressants. The current review will address the effectiveness of 

psychotherapeutic approaches as a second step treatment for MDD in patients who do not 

achieve remission after initial treatment with antidepressants. 

Question: In primary care patients with major depressive disorder who do not achieve remission 

with acute phase antidepressant treatment, is empirically based psychotherapy used as an 

augmentation or substitution treatment more effective than control for achieving remission?

METHODS

We searched PubMed from 1950-2009 using standard search terms. Titles, abstracts, and articles 

were reviewed in duplicate. Extant literature was initially screened for relevant systematic 

reviews. Following this, primary literature was screened for relevant randomized clinical trials 

comparing medications to psychotherapy in patients with major depressive disorder. Data were 

extracted in duplicate in articles that were included in this review. We evaluated study quality for 

the primary literature. All data were summarized in evidence tables and in narrative. 

RESULTS

We initially screened 41 systematic reviews, of which 29 were excluded at the title/abstract 

level and the remaining 12 were excluded after full-text review. For the primary literature, 333 

titles were screened, of which 290 were excluded at the title/abstract level and 31 were excluded 

after full-text review. The remaining 12 articles reflected five unique randomized clinical trials 

examining the effect of psychotherapy in patients who had shown resistance to antidepressant 

therapy. Because one of the trials had both “substitution with psychotherapy” and “augmentation 

with psychotherapy” arms, these were treated as two different studies, resulting in a total of six 

studies reviewed. A total of 567 patients were evaluated; none of these were recruited from VA 

clinics. Psychotherapy was examined as an augmentation to antidepressant medication in four 

studies and as a substitution treatment to replace medication in two studies. The STAR*D trial 

examined psychotherapy in both conditions. Three studies-including the two STAR*D treatment 
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Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

arms- were rated as good quality, two studies were rated fair, and one was rated poor. The 

STAR*D trial used an equipoise stratified randomization design; the remaining four studies were 

true RCTs. Patients in the comparison groups were on medications in all studies.

A fair quality trial compared psychotherapy as augmentation treatment to medication by 

randomizing 24 patients to either a 16-session dialectical behavior therapy (DBT) group or to 

a wait list condition. Participants in the DBT group evidenced significantly more improvement 

than participants in the wait list condition, both on interviewer rated and self-report measures 

of depression severity. Interpretation is complicated by control participants being allowed to 

continue in individual therapy. 

Psychotherapy was also examined as an augmentation treatment to medication in a fair quality 

trial, in which 44 patients were randomized to either 12 sessions of cognitive therapy or to 

lithium augmentation. Participants in the lithium augmentation condition evidenced significantly 

more improvement than participants in the cognitive therapy condition on an interviewer rated 

measure of depression severity, but there were no between-group differences on a self-report 

measure of depression severity. One limitation was that patients must have partially responded to 

medication treatment to be eligible for inclusion. 

A moderate sized, good quality trial also used psychotherapy to augment antidepressant 

treatment. In this study, 158 patients were randomized to either 16 sessions of cognitive therapy 

(CT) or to clinical management with antidepressant medication. Participants in both conditions 

improved over time but there were no significant differences between the two treatment groups. 

The good quality STAR*D trial examined psychotherapy and medication as either augmentation 

or substitution treatments to initial treatment with citalopram. Sixteen sessions of CT were 

provided, although only a minority of enrolled participants completed all sessions. Only 

the portion of results germane to our question was considered for the review, resulting in a 

sample size of 304 participants. Patients were allowed to refuse randomization to treatment 

strategies that they found unacceptable, resulting in the two CT conditions having roughly half 

the number of participants as in the two medication conditions. While participants in all four 

conditions evidenced improvement over time, there were no significant differences between the 

conditions. However, participants who had citalopram augmented with another antidepressant 

did demonstrate quicker benefit than participants who had citalopram augmented with cognitive 

therapy. This study had excellent ecological validity given that patient preferences were taken 

into account prior to randomization. 

Finally, a poor quality study by Blackburn and Moore (1997), examined psychotherapy as a 

substitution treatment to replace antidepressant medication. There were 37 patients in this study 

who were randomized to 27 sessions of psychotherapy over two years or to clinical management 

with antidepressant medication. While participants in both conditions evidenced clinical 

improvement over time, there were no significant differences between the two conditions. 
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Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

SUMMARY

In summary, two good quality, moderate-sized trials showed equal benefit from augmenting 

antidepressant medication with CT and from active medication management, one fair quality 

small study showed lithium augmentation to be more beneficial than CT, and one fair quality trial 

showed short-term benefit from augmentation through 16 sessions of DBT. A moderate-sized, 

good quality study and a small, poor quality study found equal benefit from substituting CT for 

antidepressant treatment and from continuing management of depression with medication. There 

was significant heterogeneity in study designs, sample sizes, and comparator groups, and most 

studies were underpowered to detect moderate effect sizes. We conclude that current trials do not 

support favoring psychotherapy over antidepressant medication for mid-life adults with treatment 

resistant MDD; however, psychotherapy appears to be an equally effective treatment compared 

to antidepressant medication and is therefore a reasonable treatment option for this demographic. 

Whether these results are directly applicable to Veterans is uncertain because most study samples 

were mid-life adults, more than 50% female, and medical and psychiatric co-morbidity was 

incompletely described. The limited number of studies, mixed effects and uncertain applicability 

to Veterans suggest a need for additional trials to adequately evaluate the potential treatment 

benefit of psychotherapy for treatment resistant depression.