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 

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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 

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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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TABLE OF CONTENTS

Executive Summary

Background.....................................................................................................................................1

Methods ..........................................................................................................................................1

Results.............................................................................................................................................1

Summary.........................................................................................................................................3

Evidence Report

Introduction.....................................................................................................................................4

Background.....................................................................................................................................4

Methods

Topic Development.........................................................................................................................6

Search Strategy ...............................................................................................................................6

Study Selection ...............................................................................................................................6

Data Abstraction .............................................................................................................................7

Quality Assessment.........................................................................................................................7

Data Synthesis.................................................................................................................................7

Peer Review ....................................................................................................................................7

Results

Literature Flow... ...........................................................................................................................8

Sample Characteristics....................................................................................................................8

Study Design and Interventions....................................................................................................10

Study Results ................................................................................................................................12

Summary and Discussion

Summary and Discussion..............................................................................................................16

Limitations....................................................................................................................................17

Future Research ...................................................................................................................................18
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Tables

Table 1...............................................................................................................9 

Table 2.............................................................................................................10

Table 3.............................................................................................................11

Table 4...........................................................................................................................................15

Evidence tables of RCT’s ................................................................... ...................25

Figures

Figure 1.........................................................................................................................................21

Figure 2.........................................................................................................................................21

Appendix A. Search strategy ............................................................................................................19

Appendix B. Peer review.....................................................................................................................22

Appendix C. Evidence Tables ............................................................................................................25 

References ..............................................................................................................................................31
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EVIDENCE REPORT

INTRODUCTION

Major depressive disorder (MDD) is one of the leading causes of disability worldwide. 1 

The lifetime prevalence of MDD in the general population is estimated at 13%2, of which 

approximately 20% will experience chronic depression and 60-85% will experience recurrence 

and relapse.3 This number is even higher in the VA medical system, where an estimated one 

third of veterans experience MDD.4 MDD is associated with greater health care utilization, 

greater functional impairment, and increased mortality.2 In addition, subclinical symptoms of 

depression can reduce quality of life, worsen disability, and adversely affect co-existing chronic 

medical conditions.5-8 Both antidepressant medications and depression-specific psychotherapies 

are effective as first-line treatments for MDD. In primary care settings, most patients with 

MDD are treated with antidepressant medications, but a substantial proportion of patients fail to 

recover with this initial treatment. This evidence synthesis was requested to evaluate the efficacy 

of psychological treatments as step-2 treatment for patients with MDD who do not achieve 

remission with an initial course of antidepressant medication. 

BACKGROUND

Antidepressant medications are the most commonly prescribed treatment modality in MDD.9

The most recent American Psychiatric Association (APA) guidelines10 suggest the use of 

antidepressants for mild, moderate or severe depressive disorders, a position that has remained 

consistent in the more recent “guideline watch” by Fochtmann & Gelenberg (2008).11 The 

efficacy and effectiveness of antidepressant treatment in primary care have been demonstrated 

in multiple large scale studies and systematic reviews.12-16 Several classes and types of 

antidepressants exist which do not substantially differ in their efficacy or effectiveness for 

treating MDD.17 Therefore, primary care physicians have a wide array of antidepressant options 

that they may prescribe depending on suitability to patient, patient preference, affordability, side 

effect profile, and the targeted physiological system.17

In addition, a sizeable body of literature has examined the efficacy and effectiveness of 

psychotherapy as acute phase treatment for MDD, either as monotherapy or in combination 

with antidepressant treatment. Psychotherapy is a heterogeneous class of treatments in which 

the therapist utilizes interpersonal strategies with the intention of alleviating mental or emotion 

distress.18 Cognitive therapy (CT) is the most widely studied form of psychotherapy for depression, 

although many other psychotherapeutic modalities exist that are depression-specific, empirically 

validated, and accessible through referral or adoption by the primary care team. Recent reviews and 

meta-analyses of acute phase treatment for depression have shown that psychotherapy may be as 

effective as antidepressant treatment and more effective than usual care in treating mild, moderate, 

and severe MDD.19-23 When MDD is severe, chronic or recurrent, the combination of medication 

and psychotherapy as initial treatment appears to be indicated.17 Combination of psychotherapy 

with an antidepressant has demonstrated greater treatment gains, lower relapse rates, and increased 

adherence to treatment when compared to usual care or antidepressant monotherapy.24-27 Therefore, 

current evidence suggests that antidepressants and psychotherapy may both form effective first line 

treatments in patients with MDD, individually or in combination. 
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However, response to initial treatment for MDD remains poor even when treatment 

recommendations are rigorously followed.28, 29 Fewer than 50% of patients fully remit after 

an adequate trial of antidepressant medication or psychotherapy.30, 31 Patients who do not fully 

remit are often considered “treatment resistant” or “treatment refractory.” Treatment resistant 

depression (TRD) is typically defined as an inadequate response to at least one 6-week or 

longer trial of an antidepressant at an adequate dose.32 TRD does not include patients who did 

not adhere to initial treatment recommendations. Clinical factors associated with treatment 

resistant depression (TRD) include comorbid generalized anxiety and other Axis I disorders (e.g., 

phobias), early onset of MDD, previous suicide attempts, number of prior depressive episodes, 

older age, and unemployment.33-36 In primary care settings, these findings may help physicians a 

priori determine patients who may be most at-risk for TRD. 

Primary care physicians have several options when treating patients with TRD: augmenting 

treatment by adding another medication; switching to a different antidepressant; augmenting 

treatment through adding psychotherapy; and switching from medication to psychotherapy.37

However, studies of clinical practice suggest that medications are often the only active treatment 

provided by primary care providers as a second step treatment for MDD.17, 38 Several limitations 

to this approach should be noted. First, the addition of another antidepressant may increase 

the number and/or severity of side effects that patients experience. Side effects are known to 

reduce quality of life and increase the chances of non-adherence, interfering with the treatment 

of MDD.39 Second, focus on antidepressants may ignore the potential impact of psychosocial 

factors in TRD. For instance, cognitions and behaviors related to MDD may be interfering 

with the treatment regimen and may best be modified by skills training. This is especially true 

when patients are experiencing acute stressors (e.g., bereavement), where psychotherapy may 

improve patients’ long-term outcomes.23 Third, patients may simply not respond to antidepressant 

treatment or may not prefer taking medications. In all of these scenarios, the addition or 

substitution of psychotherapy may be a preferred alternative. 

In summary, psychotherapy and pharmacotherapy appear to be equally effective as initial 

approaches to treating MDD in primary care. However, approximately half of patients do not 

remit after initial treatment even when treatment regimens are rigorously followed. Switching to 

a different antidepressant or augmenting treatment by adding a second antidepressant medication 

are both common clinical practices that are recommended in current guidelines as second step 

treatment strategies. However, the addition or substitution of psychotherapy is not addressed as a 

step-2 treatment for MDD in published guidelines. 

Therefore, the focus of the current review is two-fold: 

To review literature examining the use of psychotherapy as a second line treatment for patients 

with depression who do not remit with initial antidepressant medication; and, 

To determine the applicability of these studies to VA patients treated in primary care settings. 

The purpose of this review was to generate guidelines that would help determine whether the use 

of psychotherapy, either as an augmentation or a switch strategy, would lead to better outcomes 

in patients who had not responded to initial adequate antidepressant treatment. 
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Evidence Synthesis for Determining the Efficacy of 

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METHODS

Topic Development

The Veterans Health Administration (VHA) uses quality improvement strategies, including 

clinical practice guidelines, clinical reminders in the electronic medical record, and performance 

measurement to improve care processes. For veterans with depression and other mental illnesses 

managed in primary care settings, the VHA has recently made major investments in integrated 

primary care-mental health programs. This project was nominated by Ira Katz, Deputy Chief, 

Patient Care Services for Mental Health, and Carla Cassidy and Joe Francis, Office of Quality 

and Performance, with input from a technical expert panel. The overall goal was to synthesize 

data on the efficacy of psychotherapy in patients who do not fully remit with adequate 

antidepressant treatment. 

Therefore, the key question was as follows: 

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? 

For the purposes of this review, cognitive therapy (CT), interpersonal therapy (IPT), problemsolving therapy, dialectical behavior therapy (DBT), acceptance and commitment therapy 

(ACT), and mindfulness based cognitive therapy (MBCT) were considered as empirically based 

psychotherapies.

Search Strategy

We searched PubMed between 1950 and February 26, 2009 using standard search terms. 

Appendix A provides details of the search terms. Our strategy was twofold. First, we attempted 

to identify a good quality, relevant systematic review that would summarize the extant literature. 

If identified, our strategy would be to search for randomized clinical trials since the original 

review. No such systematic review was identified. Consequently, we searched PubMed for 

relevant randomized clinical trials (RCT). Titles, abstracts and full text articles were reviewed in 

duplicate. Data were extracted in duplicate from articles meeting all inclusion criteria. We then 

rated the overall quality of each study, assigned a grade, and summarized the data in narrative. 

Eligible articles were imported into an electronic reference database (EndNote® XI). 

Study Selection

Two trained researchers independently reviewed the titles and/or abstracts of citations identified 

through the PubMed literature search. If articles did not clearly meet the inclusion criteria, 

they were excluded at the title and abstract level. The remaining articles were identified for full 

text review, at which stage those that did not meet inclusion criteria were excluded. In case of 

disagreement, the two reviewers met to identify and resolve the disagreement. To be eligible, the 

articles had to be published in English, and include: 
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• English-speaking adult outpatients from general medical settings.

• Randomized clinical trial involving at least one of the following psychotherapy modalities: 

cognitive behavior therapy (CBT), interpersonal therapy (IPT), problem-solving therapy, 

dialectical behavior therapy (DBT), acceptance and commitment therapy (ACT), or 

mindfulness based cognitive therapy (MBCT).

• Patients with resistant MDD, defined as a sample consisting of at least 80% with either no 

remission or partial remission after being treated with adequate dose of an antidepressant for 

at least six weeks.

• Articles were excluded if patients were receiving psychotherapy at the time of recruitment, 

and/or if patients had comorbid psychiatric conditions that required specialty psychiatric 

care. These included, but were not limited to, active suicidal or parasuicidal ideation, severe 

substance abuse, or borderline personality disorder.

Data Abstraction

The following data were abstracted on the included studies: definition of persistence; type 

of psychotherapy; type of comparison group; setting (primary care/mental health clinic); VA 

(Yes/No); sample size; study-specific inclusion/exclusion criteria; age/sex/race of sample; 

indices of MDD severity (duration of current episode; number of prior episodes; number of 

hospitalizations; number of suicide attempts); data on interviewer-rated depression severity (if 

applicable); data on self-reported depression severity (if applicable); duration of follow-up. All 

data were abstracted by one reviewer with oversight being provided by the other reviewer. All 

disagreements were resolved using discussion and consensus. 

Quality Assessment

Quality of selected articles was assessed using the quality rating tool described in Appendix C. 

We abstracted data on completeness of follow-up (<30% drop-out rate, <10% differential dropout rate); method to address incomplete data; adequacy of randomization; adequacy of allocation 

concealment; outcome assessment blind to intervention allocation; and whether there was a 

conflict of interest, either stated or implied.

Data Synthesis

We constructed evidence tables showing the study characteristics and results for all included 

articles, organized by the unique studies from which they were derived. We critically analyzed 

studies to compare characteristics, methods, and findings. We compiled a summary of findings 

and drew conclusions based on qualitative synthesis of the findings.

Peer Review

A draft version of this report was sent to three peer reviewers. Their comments and our responses 

are presented in Appendix B.
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Evidence Synthesis for Determining the Efficacy of 

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RESULTS

Literature Flow

Using the search strategy described in Appendix A, 41 systematic reviews were identified, of 

which 29 were excluded at the title and abstract level and the remaining 12 were excluded after 

conducting a full-text review (Figure 1). Reviews were excluded primarily because they did 

not apply to the question we were addressing or were not systematic; therefore, no systematic 

reviews were included in this report. 

Next, we searched for relevant randomized clinical trials. Using the search strategy described 

in Appendix B, 333 randomized clinical trials were identified for review. Of these, 290 were 

excluded at the title and abstract level, and 43 were selected for full text review. Thirty-one 

articles were excluded following full-text review, yielding 12 articles for inclusion (Figure 2). 

These 12 articles represent five unique studies, of which one of the studies (STAR*D trial) used 

both augmentation and substitution treatment modalities in separate treatment arms, each with 

a unique comparison group. These two arms were treated as separate studies in this review. 

Therefore, the evidence tables and narrative summarize six studies, with the caveat that two of 

the studies represented separate arms of the same trial. Full consensus was achieved between the 

two reviewers at each stage. 

Sample Characteristics

A total of 567 patients were evaluated across the studies. Patients were recruited from both 

mental health clinics (MHC) and primary care (PC) clinics. Three studies were conducted in the 

United States, two in Great Britain, and one in Canada. None of the studies recruited participants 

from VA clinics. Sample sizes ranged from 24 to 304 participants; two studies contributed 81% 

of the subjects.37, 40 Across all studies, participants’ average age was approximately 40-yearsold, females compromised half to three quarters of the studies’ participants, and Caucasians 

represented at least 75% of the racial makeup in studies that reported ethnicity. The average 

length of patients’ current depressive episodes ranged from 30 to 123 weeks, with the average 

number of lifetime depressive episodes ranging from 2.2 to 8.5. For all studies, depression 

severity was moderate as determined by self-report measures. These characteristics are 

summarized in Table 1 and show significant heterogeneity in depression severity and chronicity. 

Sample characteristics for the psychotherapy and the comparison groups are provided if reported.
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Evidence Synthesis for Determining the Efficacy of 

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Table 1: Sample Characteristics

Study Harley et al., 

2008

Kennedy et 

al., 2003

Scott et al., 

2000

Thase et al., 

2007 (Augmentation 

Arm)

Thase et al., 

2007 (Substitution Arm)

Blackburn 

& Moore, 

1997*†

Sample size, n

Psychotherapy

 Comparator

13

11

23

21

80

78

65

117

36

86

17

20

Age, y (M±SD)

Psychotherapy

 Comparator 41.8

40.7±12.5

37.7±11.3

43.5 ± 9.8

43.2 ±11.2

40.6 ± 11.5

39.7 ± 13.5

43.4 ± 14.7

41.5 ± 13.3

37.8 ± 13.1

40.1 ± 12.7

Female, n

 Psychotherapy

 Comparator 18 (75%)

12 (52%)

12 (57%)

37 (46%)

41 (53%)

41 (63%)

78 (67%)

22 (61%)

53 (62%)

17 (77%)*

17 (65%)*

Caucasian, n

 Psychotherapy

 Comparator 20 (83%)

_ _

52 (80%)

99 (85%)

28 (78%)

63 (73%)

_

Duration of current episode, wks 

(M±SD)

Psychotherapy

 Comparator

28.7 ± 18.8

41.8 ± 53.6

126 ± 170

120 ± 161

62.9

56.4

129 ± 214

87 ± 206

76 ± 135

115 ± 234

30.4 ± 6.1

29.9 ± 5.6

Number of prior 

MDD episodes 

(M±SD)

 Psychotherapy

 Comparator

Not 

Reported

2.1± 1.5

2.3 ± 1.4

2 (median)

2 (median)

7.3 ± 14.1

4.6 ± 5.4

8.7 ± 18.8

8.4 ± 16.0

4.1 ± 3.4

3.2 ± 2.2

Baseline HAM-Da

scores

 Psychotherapy

 Comparator

16.2 ± 4.5

18.6 ± 4.7

12.1 ± 2.2

11.6 ± 1.9

12.1 ± 2.7

12.2 ± 2.9

17.8 ± 5.7

16.0 ± 6.7

16.4 ± 6.2

16.0 ± 6.7

11.8 ± 6.3

10.6 ± 6.8

Baseline selfreport scores

 Psychotherapy

 Comparator

BDIb

27.3 ± 8.8

27.4 ± 11.7

BDI

22.7 ± 8.6

22.4 ± 10.3

BDI

21.7 ± 7.7

22.3 ± 8.0

QIDS-SRc

11.9 ± 4.3

12.0 ± 4.6

QIDS-SR

11.2 ± 4.3

12.1 ± 4.6

BDI

20.4 ± 11.1

19.7 ± 14.2

Setting MHCd MHC MHC MHC & PCe MHC & PC MHC

Location Boston, MA Canada England U.S.A. U.S.A. Scotland

*†HAM-D, BDI and QIDS-SR scores based on smaller number that enrolled in phase 2 of the study following initial treatment 

with ADM

a HAM-D=Hamiltion Depresion Scale; b

BDI=Beck Depression Inventory; bcQIDS-SR=Quick Inventory of Depressive SymptomsSelf Report; d

MHC=Mental Health Clinic; ePC=Primary Care Clinic
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Evidence Synthesis for Determining the Efficacy of 

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To determine persistence, studies used different criteria but followed similar methodology. First, 

authors ensured that patients had a MDD at baseline. Second, patients underwent antidepressant 

(AD) treatment at adequate dose as first step treatment. Third, authors ensured that patients 

continued to have residual symptoms of MDD. All studies except Harley et al. (2008) reported 

criteria used to determine initial depression diagnosis. Two studies provided 1st step AD 

treatment whereas the others relied on non-study practitioners. HAM-D scores, either singly 

or in combination with BDI scores, were used predominantly to determine residual depression 

following AD treatment. The various criteria used to determine persistence are summarized in 

Table 2. 

Table 2: Criteria to Determine Persistent Depression

Study Harley et al., 2008 Kennedy et al., 

2003 Scott et al., 2000 Thase et al., 2007 Blackburn & Moore, 1997

Criteria for 

initial depression 

diagnosis

Not Reported HAM-D=17≥16

MDD episode in previous 18 months according to DSM-III-R; 

residual symptoms 

for ≥8 weeks

Hx of MDD; HAMD≥14Unipolar MDD using 

SADSa; HAM-D≥16

1St step ADb

treatment: Type 

and Dosage

As prescribed by 

non-study psychiatrists

Moclobemide 

(300-600 mg/day) 

OR Paroxetine 

(20-40 mg/day) OR 

Sertraline (50-200 

mg/day)

OR Venlafaxine 

(75-225 mg/day)

Tricyclic antidepressant, SSRI, atypical 

AD, or MAOI; Minimum dose equivalent to 125 mg of 

amitriptyline)

Citalopram 20 mg/

day titrated to 40 

mg by week 4 if 

needed; Max. 60 

mg/day by week 6

As prescribed by 

non-study practitioners; Equivalent to 

100 mg amitryptiline 

OR 45 mg phenelzine OR 20 mg of 

Sertraline

1st Step AD 

Treatment: 

Duration

≥6 weeks 8-14 weeks

≥8 weeks (at least 4 

weeks of adequate 

dose)

14 weeks 16 weeks

Was 1st AD 

step treatment 

provided in the 

study?

No Yes No Yes No

Criteria to Determine Persistence Following 

1st Step AD 

Treatment

MDD on SCID-Ic HAM-D=8-15 HAM-D≥8 & BDI≥9 HAM-D≥14 

Moderate symptoms 

on BDI and HAMD>11

a

SADS=Schedule for Affective Disorders and Schizophrenia; bAD=Antidepressant; cSCID-I=Structured 

Clinical Interview for DSM-III-R, I

Study Design & Interventions

Four studies used true randomization whereas the two studies from the STAR*D trial used 

an equipoise stratified randomization design, allowing patients to refuse to be randomized to 

treatments that would not be acceptable. Follow-up durations ranged from 8 to 104 weeks. 

Psychotherapy was examined as an augmentation treatment with antidepressant medication in 

four studies and as a substitution treatment replacing medication in two studies. In terms of the 

modality of psychotherapy provided, one small study used DBT41 whereas all others used CT. 
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All patients in the comparison groups were taking antidepressant medications, from a wide array 

of antidepressant classes. Three of the comparison groups received medication in a maintenance 

wait list condition, and three of the comparison groups received an active systematic alteration 

to their medication regimens (including both arms of the STAR*D trial). Retention rates in the 

different conditions ranged from 25% to 91%.

All studies used the Hamilton Depression Rating Scale (HAM-D) as their clinician administered 

diagnostic tool. Four studies used the Beck Depression Inventory (BDI) as their self-report 

measure whereas the two STAR*D trial studies used the QIDS-SR as their self-report measure. 

Mean baseline scores ranged from 11.2 to 17.3 on the HAM-D and from 20.0 to 27.3 on the BDI. 

Three trials were identified as good quality studies, two studies as fair, and one study as poor. 

Only three studies reported a sample size calculation. Study design and intervention overview is 

provided in Table 3. 

Table 3: Study Design and Interventions

Study Harley et 

al., 2008

Kennedy et 

al., 2003

Scott et al., 

2000

Thase et al., 

2007 (Augment)

Thase et al., 

2007 (Substitute)

Blackburn & 

Moore, 1997

Duration of follow up, 

wks 16 8 20 14 14 104

Study design RCT RCT RCT

Equipoise 

Stratified 

RCT

Equipoise 

Stratified RCT RCT

Augmentation with 

Medication, or Substitution?Augment Augment Augment Augment Substitute Substitute

Psychotherapy 

Intervention Used DBTa

 Group CTb CT CT CT CT

# of sessions 16 12 16 24 24 27

Comparator ADMc

Continue

Lithium 

Augment

ADM 

Continue

ADM 

Augment ADM Switch ADM Continue

Power calculation No No Yes Yes Yes No

Quality rating Fair Fair Good Good Good Poor

a

DBT=Dialectical Behavior Therapy; bCT=Cognitive Therapy; cADM=Antidepressant Medication; dNS=Not Significant
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Study Results

Results from the six studies are summarized in Table 4 and are described in detail next. The four 

studies that describe psychotherapy as augmentation treatment are described first, followed by 

the two studies that used psychotherapy as a substitute for medications. 

Psychotherapy as Augmentation to Antidepressant Medication

Harley et al. (2008) examined psychotherapy as an augmentation treatment to medication by 

randomizing 24 patients to either a DBT group (n=13) or to a wait list condition (WL; n=11).41 

Patients in the DBT condition received 16 weekly sessions of a 90-minute coping skills group in 

addition to remaining on antidepressant medication, while patients in the WL condition continued 

taking antidepressant medication and meeting with their psychiatrists and healthcare providers 

as usual. Treatment resistance in this study was defined as current depression determined by a 

structured evaluation after stable, adequate treatment with antidepressant medication for at least 

six weeks. Post treatment analyses found significant differences between the two groups for mean 

scores on the HAM-D (DBT=11.3; WL=17.1; F = 4.63, p < .05) and BDI (DBT=15.1; WL=25.9; 

F = 9.50, p < .01), such that patients in the DBT group evidenced more clinical improvement than 

those in the WL condition. The retention rate was 77% in the DBT group and 82% in the WL 

condition. Given the small sample size and confound of allowing patients to continue in non-CBT 

individual therapy, we assigned an overall quality rating of “fair” to this study.

Kennedy et al. (2003) examined psychotherapy as an augmentation treatment to medication by 

randomizing 44 patients to either cognitive therapy (CT; n=23) or lithium augmentation (LA; 

n=21).42 Patients in the CT condition received 12 psychotherapy sessions delivered over eight 

weeks and were seen every four weeks for a medication checkup, while patients in the LA 

condition had their antidepressant medication augmented with lithium carbonate (starting dose 

of 600mg/day) and were seen every two weeks for clinical management. Treatment resistance in 

this study was defined as having a HAM-D score between 8 and 15 after 8-14 weeks of treatment 

with antidepressant medication. Post treatment analyses found a significant difference between 

the two groups for mean scores on the HAM-D (CT=14.8; LA=9.2; t = 2.02, p = .04), such that 

patients in the LA condition showed a greater decrease in depressive symptoms than those in the 

CT condition. No significant post treatment difference was found between the two groups for 

mean scores on the BDI (CT=19.9; LA=15.1). The retention rate was 74% in the CT condition 

and 71% in the LA condition. One limitation of this study is that it only included “partial 

responders” to initial antidepressant medication treatment (i.e., HAM-D score from 8 to 15) and 

excluded “non-responders” (i.e., HAM-D ≥ 16). It also did not report a sample size calculation 

and probably lacked sufficient statistical power to detect clinically important differences. We 

assigned an overall quality rating of “fair” to this study.

Multiple articles were identified for a study that examined psychotherapy as an augmentation 

treatment to medication.40, 43-46 Data were primarily extracted from Scott et al. (2000).40 In this 

good quality study, 158 patients were randomized to either CT (n=80) or clinical management 

(CM; n=78). An analysis of the pre-set sample size of 160 gave 80% power to detect a reduction 

in relapse rates from 40% in one group to 20% in the other at p = .05. Patients in the CT condition 
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received 16 psychotherapy sessions over 20 weeks in addition to continuing on antidepressant 

medication, while patients in the CM condition continued on antidepressant treatment and were 

seen every four weeks for 30-minite medication management appointments. Treatment resistance 

in this study was defined as having a HAM-D score ≥ 8 and BDI score ≥ 9 after at least eight weeks 

of adequate treatment with an antidepressant medication. Participants had an average age of 43 and 

49% were female. The average duration of participants’ current depressive episode was 60 weeks 

(CT=63; CM=56), with both groups having a median of two lifetime episodes of depression. While 

participants in both conditions improved, post treatment analyses found no significant differences 

between the two groups for mean scores on the HAM-D (CT=8.7; CM=9.4) or BDI (CT=13.8; 

CM=16.1). Retention was measured as staying in until relapse or until the end of the study at 68 

weeks, resulting in a 76% retention rate in the CT condition and an 85% retention rate in the CM 

condition. A limitation of this study is that it allowed for patients with partially remitted depressive 

symptoms and no diagnosis of current major depression to participate. 

The STAR*D trial32, 37, 47, 48 was a multistage, multicenter trial that examined both psychotherapy 

and medication as either augmentation or substitution treatments to initial treatment with 

citalopram. Treatment resistance in the STAR*D trial was defined as having a HAM-D score ≥ 

14 after 14 weeks of treatment with citalopram. The equipoise-stratified randomization design 

employed in this study allowed patients to refuse randomization to treatment strategies that they 

found unacceptable, which resulted in asymmetrical sample sizes for different treatment arms. 

Less than one third of participants agreed to true randomization, which is a significant limitation 

of the study in terms of internal validity. Analyses conducted prior to data collection indicate that 

too few patients were randomized to the different treatment conditions to achieve the originally 

desired power. However, this study represents the best external validity given that they accounted 

for patient preferences, which is similar to what may be expected in primary care settings. We 

assigned an overall quality rating of “good” to both the augmentation and substitution arms of 

this study. Data are presented separately below, first examining psychotherapy and medication as 

an augmentation to citalopram and then examining psychotherapy and medication as substitution 

treatments to replace citalopram. Data were primarily extracted from Thase et al. (2007).37 

In the augmentation arm, 182 patients were assigned to either augmentation cognitive therapy 

(A-CT; n=65) or augmentation antidepressant medication (A-ADM; n=117). Patients in the 

A-CT condition received 16 psychotherapy sessions over 12 weeks in addition to continuing on 

citalopram, while patients in the A-ADM condition had their treatment with citalopram augmented 

with either bupropion or buspirone. Participants had an average age of 40, 65% were female, and 

83% were Caucasian. The average duration of participants’ current depressive episode was 102 

weeks (A-CT=129; A-ADM=87), with a mean of 5.6 lifetime episodes of depression (A-CT=7.3; 

A-ADM=4.6). There were no significant between-group differences in mean baseline depression 

scores on the HAM-D (A-CT=17.8; A-ADM=16.0) or QIDS-C (A-CT=11.9; A-ADM=12.0). 

While participants in both conditions evidenced significant improvement, post treatment analyses 

found no significant differences between the two groups for percent remitted on the HAM-D 

(A-CT=23.1%; A-ADM=33.3%) or for mean scores on the QIDS-C (A-CT=8.2; A-ADM=8.2). 

However, participants in the A-ADM condition did demonstrate quicker benefit than participants 

in the A-CT condition. The retention rate was 91% in the A-CT condition (although only 27% of 

patients completed at least 16 sessions) and 81% in the A-ADM condition.
14

Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

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

antidepressant medication with 16 to 24 sessions of cognitive therapy and from active 

management of depression with medication, whereas a small fair quality study showed greater 

benefit from lithium augmentation than cognitive therapy augmentation. A single fair quality 

trial showed short-term benefit from 16 sessions of DBT. Because study populations and designs 

were conceptually heterogeneous, a summary estimate of effect was not calculated.

Psychotherapy as Step-2 Substitution for Antidepressant Medication

In the substitution arm of STAR*D, 122 patients were randomized using an equipoise-stratified 

randomization design to either substitution cognitive therapy (S-CT; n=36) or substitution 

antidepressant medication (S-ADM; n=86). Patients in the S-CT condition discontinued 

treatment with citalopram and received 16 psychotherapy sessions over 12 weeks, while patients 

in the S-ADM condition discontinued citalopram and switched to treatment with bupropion, 

sertraline, or venlafaxine. Participants had an average age of 42, 61% were female, and 75% 

were Caucasian. The average duration of participants’ current depressive episode was 103 

weeks (S-CT=76; S-ADM=115), with a mean of 8.5 lifetime episodes of depression (S-CT=8.7; 

S-ADM=8.4). There were no significant between-group differences in mean baseline depression 

scores on the HAM-D (S-CT=16.4; S-ADM=16.0) or QID-S (S-CT=11.2; S-ADM=12.1). While 

participants in both conditions evidenced significant improvement, post treatment analyses 

found no significant differences between the two groups for percent remitted on the HAM-D (SCT=25.0%; S-ADM=27.9%) or for mean scores on the QID-S (S-CT=9.1; S-ADM=9.1). The 

retention rate was 83% in the S-CT condition (although only 35% completed at least 16 sessions) 

and 73% in the S-ADM condition.

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

substitution treatment to replace antidepressant medication by randomizing 37 patients to either 

CT (n=17) or antidepressant medication (ADM; n=20).49 Patients in the CT condition received 

27 psychotherapy sessions over 104 weeks, while patients in the ADM condition continued on 

an antidepressant medication of their prescriber’s choice (prescribers were also free to switch 

medications) and were seen by their providers about every three weeks. Treatment resistance 

was not specifically defined in this study, but after 16 weeks of treatment with an antidepressant 

medication, patients continued to have depressive symptoms at a level comparable to that of the 

other patient populations included in this review (see Table 1). Post treatment analyses found 

no significant differences between the two groups for mean scores on the HAM-D (CT=8.6; 

ADM=9.3) or BDI (CT=14.2; ADM=18.1). The retention rate was 35% in the CT condition and 

was 25% in the ADM condition. The “poor” quality rating was based on the poor retention rate, 

lack of statistical power, unorthodox length of CT treatment protocol, and lack of operational 

definition for treatment resistance.

In summary, a moderate-sized, good quality study and a small, poor quality study found equal 

benefit from substituting cognitive therapy for antidepressant treatment and from continuing 

management of depression with medication in patients with treatment resistant MDD.
15

Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

Table 4: Results of the Psychotherapy Intervention

Study Harley et al., 

2008

Kennedy et 

al., 2003

Scott et al., 

2000

Thase et al., 

2007 (Augmentation)

Thase et 

al., 2007 

(Substitution)

Blackburn & 

Moore, 1997

Retention rate, n

 Psychotherapy

 Comparator

10 (77%)

9 (82%)

17 (74%)

15 (71%)

61 (76%)

66 (85%)

59 (91%)

95 (81%)

30 (83%)

63 (73%)

6 (35%)

5 (25%)

Post-treatment 

HAM-D Scores 

(M±SD)

 Psychotherapy

 Comparator

Effect Size

11.3 ± 5.3

17.1 ± 6.2 

d=1.45

14.8 ± 9.9

9.2 ± 6.7 

d=.32

8.7±5.3

9.4 ± 5.3 NSa

Remission:

23.1%

33.3% 

NS

Remission:

25.0%

27.9% 

NS

8.6±5.6

9.3±7.2 

NS

Post-treatment

BDI Scores 

(M±SD)

 Psychotherapy

 Comparator

Effect Size

15.1 ±12.1

25.9±16.3 

d=1.31

19.9 ± 10.3

15.1 ±11.4 

NS

13.8 ±9.6

16.1 ± 10.0 

NS

8.2 ±5.1

8.2 ± 4.8 NS*

9.1 ± 5.4

9.1 ± 5.0 

NS*

14.2 ± 9.9

18.1 ± 13.1 

NS

Quality rating Fair Fair Good Good Good Poor

a NS=Not significant at p<.05; *Results are for QIDS-C
16

Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

SUMMARY AND DISCUSSION

The key observation that emerges from review of the literature is that current evidence 

examining the effect of psychotherapy as augmentation or substitute therapy in resistant 

depression is sparse and reveals mixed results. Of the six studies reviewed, four studies 

examined psychotherapy as augmentation to antidepressant treatment37, 40-42 and two studies 

examined psychotherapy as substitution treatment.37, 49 The STAR*D trial reflects the greatest 

ecological validity of the studies reviewed, because it accounted for patient preference in 

randomization and is most reflective of treatment provided in primary care settings. One study 

suggested that psychotherapy used as augmentation had better impact on clinical symptoms of 

MDD than medication alone41 whereas Kennedy et al. found the opposite effect.42 The remaining 

studies did not detect any difference between psychotherapy augmentation and continuation 

on antidepressant treatment.37, 40 Substitution of antidepressant therapy with psychotherapy 

appeared to have the same benefit as substituting another antidepressant37 or continuing previous 

medication.49 While each of the studies included in this review addressed at least a portion of 

the initial key research question, none of the studies provides a complete answer to the initial 

question nor does an amalgamated consideration of the studies provide an entirely sufficient 

answer to the initial question. Most studies appeared to be underpowered to detect moderately 

large treatment effects, and conclusions are tempered by the heterogeneity in study designs 

and patient populations and limited number of good quality trials. We conclude that although 

current trials do not support favoring psychotherapy over antidepressant medication for mid-life 

adults with treatment resistant MDD, 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. Veterans 

are on average older and have high rates of psychiatric and medical co-morbidity, clinical 

characteristics that were not well described in the studies reviewed.

Treatment via psychotherapy continues to face numerous barriers both in primary care and 

specialty mental health settings. The first consideration is access to psychotherapy. Many Veterans 

live in underserved areas and may have to travel farther to access facilities that would offer 

psychotherapeutic interventions. This issue is exacerbated by the greater time commitment required 

to receive traditional psychotherapy, which often requires weekly or biweekly face-to-face contact 

for an hour each. A second consideration is the relative cost of delivering psychotherapy versus 

providing antidepressant medications. The baseline costs of psychotherapy are typically higher, 

especially when delivered by a mental health professional such as a psychologist.50, 51 However, 

there appears to be dispute when mid to long-term outcomes are measured. Some studies have 

demonstrated that antidepressant medications are more cost-effective within 1 year of follow-up 

for both direct and indirect costs.52, 53, whereas other studies have not found differences in direct, 

aggregate or societal costs.51, 54, 55 Studies have found psychotherapy to be superior in reducing 

costs related to missed work 56, treatment of medical comorbidities57, and relapse.45 Therefore, the 

cost-benefit ratio of antidepressant treatment versus psychotherapy remains disputed. A further 

limitation is that no current study has examined the cost-effectiveness of the two treatments in 

patients who do not respond to initial antidepressant treatment. Because TRD is both common and 

costly58, large, high quality, long-term randomized trials are needed to evaluate the effectiveness 

and cost-effectiveness of different treatment strategies for patients with TRD. 
17

Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

One strategy to increase access and cost-effectiveness of psychotherapy involves collaborative 

care. Recent research has shown that training non-mental health professionals (e.g., nurses) to 

provide brief psychotherapeutic interventions are effective in reducing depressive symptoms.59-61

Collaborative care models involving depression care managers has been shown to improve the 

quality of depression care, symptom severity, patient satisfaction, and functional impairment.50, 

62 Some of these trials59, 63 utilized empirically based psychotherapy as a step-2 treatment option 

for treatment resistant patients. These studies were conducted in older adults with MDD or 

dysthymia who are more similar to the Veteran population than most of the studies we reviewed 

in the current evidence synthesis. Unfortunately, the psychotherapy was delivered as part of 

a package of collaborative care and its unique contribution to improved outcomes cannot be 

assessed. Nevertheless, evidence suggests that training non-mental health professionals to deliver 

brief psychotherapy may improve outcomes in primary care patients without burdening resources 

within the VA system.

Prior systematic reviews 19-23 have shown that psychotherapy and antidepressant medications 

have similar benefit in acute phase treatment for MDD. For patients with chronic MDD or 

dysthymia, current evidence supports the combination of psychotherapy and antidepressant 

medication for initial treatment. Treatment resistant depression is common and a greater number 

of effective treatment options are needed. Our evidence synthesis found only limited studies that 

do not support psychotherapy as a step-2 strategy, either for augmentation or as a substitute for 

antidepressant medication. 

Limitations

Several limitations of the current literature emerged upon review. First, few RCTs exist that 

adequately address the question of resistant depression. In the future, this may be addressed in 

two ways: 1) re-analysis of existing data from trials in which patients with TRD are recruited, 

or 2) conducting studies designed to examine this question. Second, there was significant 

heterogeneity in how resistant depression was defined in the different studies. Measures 

included interviewer rated depression scales (e.g., HAM-D), self-report depression scales (e.g., 

BDI), DSM diagnostic criteria (DSM-III-R or DSM-IV), and clinical judgment. Future studies 

should consider a standardized operational definition of TRD to facilitate comparisons across 

studies. Third, all of the studies involved comparators that received active treatment. True 

placebo controlled trials may be necessary to compare the relative effects of psychotherapy and 

antidepressants as second step treatments. Fourth, none of the six studies reviewed involved 

patients from within the VA. Compared to the general population, Veterans have higher 

incidences of depression with psychiatric and medical comorbidities.4 Therefore, results of 

the current review may have limited generalizability to the VA population. Fifth, only two 

psychotherapeutic strategies have been considered in the limited literature, with the majority 

using CT. Traditionally, CT requires a minimum of 12-16 sessions and is often delivered by 

trained experts. As a result, none of the psychotherapies reviewed were likely to be administered 

within the primary care setting. This is in contrast with the larger literature, where brief therapies 

such as problem-solving therapy and interpersonal therapy have been adapted by non-mental 

health professionals with demonstrated improvements as first step treatments in primary care 

settings.50 Studies to compare the effectiveness of differing psychotherapies could inform policy.
18

Evidence Synthesis for Determining the Efficacy of 

Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

FUTURE RESEARCH

There is a pressing need to conduct RCTs examining psychotherapy as a second step treatment 

in patients who have not responded to initial antidepressant medication treatment. Studies 

conducted within the VA would provide the best evidence on how to treat veterans. As more 

OEF/OIF veterans return with significant medical and psychiatric comorbidities, this question 

will become critical in the management of MDD. 

Future investigations should also address cost-effectiveness of the different treatment options. 

To our knowledge, no current study has examined the cost-effectiveness of psychotherapy 

versus antidepressant treatment when used as second step treatment. As a first step, analyses 

using observational data from the VA depression registry may be informative. Ideally, however, 

studies designed for this purpose would involve longer follow-up, as well as measures of direct 

costs, indirect costs, and costs associated with comorbid non-psychiatric conditions. Finally, 

innovative interventions are needed that adapt validated psychotherapeutic techniques to primary 

care settings. The VA has already initiated primary care mental health integration techniques; 

however, there remains a need for trials of depression treatments to inform the specific treatments 

offered in these integrated models. This will be crucial in improving access for underserved 

veterans while simultaneously reducing the strain on the VA resources. 
31

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Psychotherapy for Treatment Resistant Depression Evidence-based Synthesis Program

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