Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program 

Evidence Synthesis for Determining 

the Responsiveness of Depression 

Questionnaires and

Optimal Treatment Duration

for Antidepressant Medications

Department of Veterans Affairs

Health Services Research & Development Service

October 2009

Investigators:

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

Monica Nora Slubicki, MD

Resident in Psychiatry, 

VA Administrative Chief Resident 

2009-2010, 

Duke University Medical Center

Durham, NC

Damon S. Tweedy, MD

Medical Director, Primary-Care Mental 

Health Integration, Durham VA Medical 

Center

Consulting Associate, Duke University 

Medical Center

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

Daniel W. Bradford, MD, MPH

Assistant Professor of Psychiatry, 

Durham VA Medical Center and Duke 

University Medical Center

Director, Psychosocial Rehabilitation and 

Recovery Center, Durham VAMC

Durham, NC

Ranak B. Trivedi, PhD

AHRQ Postdoctoral Fellow in Health 

Services Research, 

Durham VA Medical Center and Duke 

University

Durham, NC

Dana Baker, MS

Clinical Research Coordinator

Duke University

Durham, NC
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Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

PREFACE

VA’s Health Services Research and Development (HSR&D) Service 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 healthcare 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 provides funding for four ESP Centers. Each Center has an active and publicly 

acknowledged VA affiliation and also serves as an Evidence Based Practice Center (EPC) 

supported by the Agency for Healthcare Research and Quality (AHRQ). The Centers will each 

generate three evidence syntheses annually on clinical practice topics of key importance to VHA 

leadership and policymakers. A planning committee with representation from HSR&D, Patient 

Care Services (PCS), Quality Enhancement Research Initiative (QUERI), Office of Quality 

and Performance (OQP), and the VISN Clinical and Quality Management Officers, has been 

established to identify priority topics and key stakeholder concerns 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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Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications 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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Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

EXECUTIVE SUMMARY

BACKGROUND

According to projections from the World Health Organization, depression will be the second 

leading cause of disability in the developed world by 2020. Primary care clinicians care for approximately two thirds of depressed individuals. In 2000, the U.S. economic burden of depressive disorders was estimated to be 83.1 billion dollars. This included 31% direct medical costs, 

7% suicide-related mortality costs, and 62% workplace costs. A variety of strategies have been 

tested to improve patient outcomes. Among these, integrated care models have emerged as both 

effective and cost effective. A recent systematic review identifies symptom monitoring as a key 

element of these integrated care models. However, the review did not identify the standardized 

depression scales that are responsive to clinically important change. 

A separate but important issue raised by Veterans Administration (VA) Stakeholders is how 

long to continue antidepressant medication for patients who respond to acute phase treatment. 

Clinical guidelines recommend continuation treatment for 4-6 months for uncomplicated 

major depression and some national performance measures are linked to these guidelines. 

However, clinical guidelines for longer-term maintenance phase treatment are more variable and 

performance indicators (e.g., Healthcare Effectiveness Data and Information Set, HEDIS) do 

not address maintenance phase treatment. A better understanding of the evidence for long-term 

treatment efficacy with antidepressants would inform guidelines and performance measurement. 

The Key Questions (KQ) were:

KQ1: In patients with major depressive disorder treated in primary care settings, what 

assessment tools are responsive to change? This review should specifically address 

instruments that are feasible for the primary care setting.

KQ2: In primary care patients with major depressive disorder who remit with antidepressant 

medication, what is the minimum treatment duration to decrease the risk of relapse or 

recurrence? This review will focus on patients without comorbid substance abuse, PTSD, 

psychosis or other conditions where guidelines would recommend specialty based care.

METHODS

We searched PubMed from 1950-2009 using standard search terms; PsychInfo was also 

searched for key question one (KQ1). Additional citations were identified from reference lists. 

Titles, abstracts, and articles were reviewed in duplicate by physicians trained in the critical 

analysis of literature. For KQ1, we included primary literature comparing one of the 6 eligible 

depression symptom questionnaires to an interview-based reference standard. For key question 

two (KQ2), we searched for and identified a high quality systematic review, then searched for 

relevant randomized trials published since the original review (2007-2009). For eligible articles, 

data were extracted in duplicate. We evaluated study quality for the primary literature and 

the systematic review. All data were summarized narratively. An overall strength of evidence 

“GRADE” was assigned to the body of evidence for each key question.
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Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

RESULTS

For KQ1, we screened 743 titles, rejected 661, and performed a more detailed review on 82 

articles. From these, we identified 3 unduplicated observational studies meeting eligibility 

criteria. For KQ2, we screened 154 titles, rejected 139, and performed a more detailed review 

on 15 articles. From these, we identified 1 recent high quality systematic review and 3 relevant 

randomized controlled trials (RCTs).

KEY QUESTION 1. In patients with major depressive disorder treated in primary care settings, 

what assessment tools are responsive to change?

We identified 3 studies evaluating the responsiveness of the Patient Heath Questionnaire-9 

(PHQ-9), in primary care patients with depressive disorders; no studies for the other eligible 

questionnaires were identified. A total of 2,330 patients were evaluated, one study was limited to 

older adults and one included VA settings. 

The most relevant study to VA settings and patients was a high quality secondary analysis 

from the IMPACT study, a randomized trial comparing collaborative care to usual care. In this 

study, participants were ≥ 60 years old, had a mean of 3.8 chronic diseases and a research-based 

diagnosis of major depression or dysthymia. Three of the eighteen primary care sites were VA. 

The analysis was limited to the 434 patients in the intervention arm with complete assessments at 

baseline, 3- and 6-month follow-up. Responsiveness was reported as the standardized response 

mean (SRM) which is calculated as: Mean (time 2) - Mean (time1)/standard deviation of score 

changes.

For the cohort overall, the mean change and standardized response mean at 3 months 

was: -7.5±5.8, SRM -1.3 (95% CI -1.4 to -1.2). At 6 months, the mean change and SRM 

were: -8.0±6.1, SRM -1.3 (95% CI –1.4 to -1.2). Responsiveness equaled or exceeded the 

longer Symptom Checklist-20 (SCL-20, self-administered 20-item questionnaire measuring 

depressive symptoms) at these two time points. Results were not significantly different when 

restricted to patients with major depressive disorder (MDD). For the 317 patients with MDD, 

an independent, structured diagnostic assessment was used to classify patients at six month 

follow-up as: persistent MDD, partial- or full remission. Greater clinical improvement was 

associated with larger reductions in PHQ-9 scores. The mean change and SRM for each group 

was: persistent MDD -5.6±6.6, SRM -0.8; partial remission -8.4±6.1, SRM -1.4; full remission 

-9.8±5.9, SRM -1.7. In this analysis, the SRM was again similar for the PHQ-9 and SCL-20. An 

analysis to determine the minimum clinically important difference (MCID), estimated this value 

conservatively at 4.78, meaning a 5-point or larger decline in the PHQ-9 indicates clinically 

meaningful improvement.

Two fair quality studies, conducted with a German language version of the PHQ-9 showed 

similar results at 3- and 12-month follow-ups. Standardized response means ranged from -1.42 to 

-2.15 for patients rated as responders by a structured interview. One study conducted subgroup 

analyses and found similar responsiveness for men and women, different age groups, depression 

diagnosis and presence or absence of comorbid physical illness. 
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Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

These three studies differed in a variety of design features that could lead to heterogeneous 

results including: study quality, questionnaire language, follow-up timing, and participant 

characteristics. Despite these sources of potential variability, the overall results were consistent 

across studies. The PHQ-9 is responsive to clinically important changes in symptom status. 

Using the GRADE criteria, we judged the overall quality of evidence for this finding as 

moderate. For the finding that the minimum clinically important difference is 5, the quality of 

evidence is low based on a single, albeit, high quality studies.

A recent literature synthesis identified longitudinal assessment of depression symptoms with a 

standardized scale as a critical component of effective depression care. The PHQ-9 is the best 

validated scale in primary care populations, both for initial diagnosis and for detecting response 

to change. Its routine use for measuring response to treatment could improve patient care and 

outcomes, but logistical support to integrate the questionnaire into clinical practice would likely 

be needed to achieve successful implementation.

• The PHQ-9 is the best validated instrument for detecting clinically important response to 

treatment. Quality of Evidence = Moderate

• A 5 point change on the PHQ-9 is estimated as the minimum clinically important difference. 

Quality of Evidence = Low

KEY QUESTION 2. In primary care patients with major depressive disorder who remit with 

antidepressant medication, what is the minimum treatment duration to decrease the risk of 

relapse or recurrence?

We included 1 applicable high quality systematic review and 3 RCT’s with 4 comparisons 

published since the systematic review. A total of 9,024 patients in 26 RCT’s were evaluated. 

None of the studies included a VA setting; three were restricted to patients age ≥ 65 years old.

The systematic review evaluated 23 fair quality RCT’s comparing second-generation 

antidepressant to placebo in fully- or partially-remitted patients. Patients with comorbid 

psychiatric or serious medical conditions were generally excluded. Twelve took place in 

unspecified outpatient clinics, four in primary care and psychiatry clinics, and the remaining 

seven did not specify the setting. Relapse or recurrence was generally defined using a predefined 

score on the Hamilton Depression Rate Scale (HDRS), a validated, interview-administered 

depression severity measure. The authors stratified the studies according to treatment duration: 

less than 1 year after acute phase treatment remission (continuation) and 1 year or more 

after acute phase treatment duration (maintenance). The unadjusted frequency of relapse for 

continuation phase (12 studies) was 22% for active treatment and 42% for placebo. In a pooled 

analysis the relative risk of relapse was 0.54 (95% CI 0.46 to 0.62); heterogeneity was moderate 

(I2 =47%). The unadjusted frequency of recurrence for maintenance phase (11 studies) was 

similar to shorter duration studies, 26% with active treatment and 48% with placebo. The relative 

risk of recurrence was 0.56 (95% CI 0.48 to 0.66); heterogeneity was moderate (I2 =30%). 

Loss to follow up due to adverse events was not significantly different between antidepressant 

and placebo. Only one study out of the 23 RCT’s randomized patients in remission to varying 
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Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

durations (14, 38 or 50 weeks) of continuation phase antidepressant or placebo. In that study, 

relapse rates were significantly lower for patients on active treatment at 14 weeks (26% vs. 49%), 

and 38 weeks (9% vs. 23%) but not at 50 weeks (11% vs. 16%). In meta-regression analyses, the 

duration of treatment prior to and after randomization were not associated with the magnitude of 

treatment effect, suggesting a constant reduction in relative risk.

Of the three additional RCT’s identified, the PREVENT study was the most informative. This 

multi-phase, double-blind, placebo-controlled study evaluated 12 and 24 month treatment with 

venlafaxine ER versus placebo. It found that venlafaxine ER was associated with a statistically 

significantly lower recurrence rate at 12-month follow-up (23.1% vs. 42.0%). Using an 

expanded definition of recurrence, freedom from recurrence at 24 month follow up was 67% for 

venlafaxine vs. 41.0% for placebo. The 24 month PREVENT follow up phase did not report on 

patients lost to follow up. Another good quality RCT reported the results of a 24 week RCT of 

escitalopram (10-20mg/day) versus placebo in older adults who had responded to acute treatment 

with escitalopram for MDD. Escitalopram was associated with a significantly lower relapse rate 

compared with placebo (9% vs. 33%, p<0.001). The last RCT evaluated was a small, fair quality 

trial that did not find a significant difference between antidepressant and placebo for prevention 

of relapse.

The high quality systematic review and 2 of the most recent relevant RCT’s provide moderately 

strong evidence that continued antidepressant treatment decreases the risk of subsequent 

relapse for patients with MDD who achieve partial- or full-remission. The moderate strength of 

evidence grade is based on RCT’s with some important methodological limitations, generally 

consistent results, and a precise estimate of effect. Of note, none of these studies were performed 

in a VA population. The magnitude of risk reduction was similar for shorter- and longer-term 

trials and maintained for up to 2.5 years. However, these trials do not directly address the 

question about the minimum duration of continued antidepressant treatment since they report the 

average risk reduction over these time periods. At the individual patient level, the decision for 

how long to continue antidepressant treatment should be based on effectiveness, adverse effects 

and patient preferences. Additional studies that could include decision analyses and randomized 

trials that stratify treatment duration based on risk factors are needed to inform clinical guidelines 

and performance measures for maintenance phase treatment.

• A high quality systematic review and 2 of the most recent relevant RCT’s provide 

moderately strong evidence that continued antidepressant treatment decreases the risk of 

subsequent relapse for patients with MDD who achieve partial- or full-remission. Continued 

treatment for 1 to 2 years after achieving partial- or full-remission with second-generation 

antidepressants decreases the risk of relapse or recurrence by almost 50%. The number 

needed to treat to prevent one relapse was 5. Quality of Evidence = Moderate.

• The magnitude of risk reduction was similar for shorter- and longer-term trials and 

maintained for up to 2 years. However, these trials do not directly address the minimum 

duration of continued antidepressant treatment since they report the average risk reduction 

over these time periods.