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 

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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 

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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......................................................................................................................1

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

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

Results.............................................................................................................................................2

Introduction.................................................................................................................................6

Background ..................................................................................................................................7

Depression Questionnaires .............................................................................................................7

Measuring Responsiveness to Change............................................................................................7

Risk of Relapse or Recurrence........................................................................................................8

Methods ........................................................................................................................................9

Topic Development.........................................................................................................................9

Search Strategy ....................................................................................................9

Study Selection ..................................................................................................10

Data abstraction................................................................................. .................11

Quality Assessment..............................................................................................11

Data Synthesis....................................................................................................11

Peer Review......................................................................................................12

Results ........................................................................................................................................12

Literature Flow...................................................................................................12

Key Question #1............................................................................... ...................13

Key Question #2............................................................................... ...................17

Summary and Discussion ............................................................................................................20

Limitations........................................................................................................21

Conclusions.......................................................................................................22

Future Research.............................................................................................23
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Determining the Responsiveness of Depression Questionnaires and 

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Tables

Table 1.............................................................................................................13 

Table 2.............................................................................................................14

Table 3.............................................................................................................14

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

Table 5.............................................................................................................16

Table 6.............................................................................................................18

Table 7.............................................................................................................22

Figures & Appendices

Figure 1..............................................................................................................8

Figure 2. ...........................................................................................................24

Figure 3. ..........................................................................................................24

Figure 4. ...........................................................................................................24

 

Appendix A. Search strategy..................................................................... ...........25

Appendix B. Full text exclusions................................................................ ...........27

Appendix C. Quality ratings.................................................................................31

Appendix D. Peer review.....................................................................................33

Appendix E. Evidence Tables

Evidence Table 1.................................................................................................38 

Evidence Table 2.................................................................................................39 

Evidence Table 3.................................................................................................40 

Evidence Table 4.................................................................................................41 

Evidence Table 5.................................................................................................42 

References.......................................................................................... .......................43
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Determining the Responsiveness of Depression Questionnaires and 

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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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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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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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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.
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Evidence Report
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Determining the Responsiveness of Depression Questionnaires and 

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INTRODUCTION

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

leading cause of disability in the developed world by 2020.[1] Primary care clinicians (PCCs) 

care for approximately two thirds of depressed individuals.[2] Rates of guideline concordant 

care for depression, however, are suboptimal and patient outcomes are often poor.[3, 4] A variety 

of strategies have been tested to improve patient outcomes including: physician education, 

continuous quality improvement, and reorganizing care to integrate mental health and primary 

care. Of these approaches, integrated care models have been found to be both effective and 

cost effective.[5-7] A recent analysis using meta-regression techniques identified baseline and 

follow-up assessments of depressive symptoms with a standardized scale as critical components 

of successful integrated models.[8] Patients randomized to integrated care are more likely 

to receive an adequate trial of antidepressants and/or empirically based psychotherapies and 

are approximately twice as likely to respond to treatment compared to usual care. Much like 

serial monitoring of Hemoglobin A1c in patients with diabetes, careful symptom assessment 

through standardized depression scales may facilitate treatment changes that improve outcomes. 

However, the review did not identify the standardized scales that are responsive to clinically 

important change. 

A second issue relevant to the primary care management of depression is the optimal duration 

of antidepressant medication. For patients who remit with treatment, the benefits of sustained 

antidepressant medication to prevent relapse or recurrence must be balanced against the 

risks. Early clinical guidelines recommended 4-6 months of continuation phase treatment for 

uncomplicated major depression due to high rates of early relapse and demonstrated efficacy 

of continuation treatment. Maintenance phase treatment is recommended for patients at high 

risk for recurrence. More recently, some guidelines[9, 10] have recommended longer duration 

of continuation phase treatment despite emerging evidence about potential long-term adverse 

effects including gastrointestinal bleeding [11] and osteoporosis.[12, 13] The duration of 

antidepressant medication treatment not only has important implications for individual patients, 

but also has cost implications that include the direct cost of medication, longitudinal monitoring 

and treatment of adverse effects.

To inform recommendations for clinical guidelines and potential performance measures, this 

evidence synthesis evaluates the responsiveness of depression questionnaires feasible for 

primary care settings and data from randomized trials that examine the effects on continued 

antidepressant use to prevent relapse or recurrence.
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Determining the Responsiveness of Depression Questionnaires and 

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BACKGROUND

Depression Questionnaires

A prior systematic review identified eleven self-administered depression questionnaires that 

had been evaluated in primary care settings; most have been evaluated in VA settings.[14] 

Questionnaires ranged from 1 to 30 items; 7 had versions of ≤ 10 items. Response formats 

included “yes/no,” frequency ratings, and statements of symptom severity. Scores ranged from 

as brief as 0 to 1 for a single item, “yes/no” questionnaire to 0-100. All instruments could be 

self-administered in < 5 minutes but interview administration varied more substantially due to 

differences in length and response format. Six of the instruments were considered useful for 

monitoring severity or response but this judgment was based on scale characteristics rather 

than empirical data. A recent update of identified 3 additional questionnaires and new studies 

for existing questionnaires.[15] Brief, 2-9-item questionnaires compared comparably to longer 

questionnaires.[16] The review concluded that the Patient Health Questionnaire-9 (PHQ-9) 

had better performance characteristics and gave more information for depression diagnosis 

than other instruments. A recent National Heart, Lung, and Blood Institute working group 

recommended the PHQ-2 (whose items are contained within the PHQ-9) to screen for trial entry 

and recommended the interviewer-rated Hamilton Depression Rating Scale (HDRS) to assess 

outcomes. Interviewer-rated instruments, such as the Hamilton, are the reference standard for 

evaluating depression severity but require greater expertise, training and administration time 

than self-administered questionnaires and for this reason are not considered feasible for clinical 

purposes in the primary care setting.[17] Given the large number of validated questionnaires, we 

focused this review on brief instruments that may be more acceptable to clinicians and patients.

Brief Depression Questionnaires Validated in Primary Care Settings

Questionnaire Items Response format Literacy level

BDI Fast Screen 7 4 Statements of symptom severity Easy

CES-D 10 4 Frequency ratings: “less than 1d” to “most or 

all (5-7d)”

Easy

DEPS 10 4 Frequency ratings: “not at all” to “extremely)” Average

GDS 15 Yes or no Easy

PHQ-9 9 4 Frequency ratings: “not at all” to “nearly every 

day”

Average

SDDS-PC 5 Yes or no Easy

Abbreviations: BDI, Beck Depression Inventory; CES-D, Center for epidemiologic Studies Depression Screen; 

DEPS, Depression Scale; GDS, Geriatric Depression Scale; PHQ-9, Patient Health Questionnaire-9; SDDS-PC, 

Symptom-Driven Diagnostic System for Primary Care

Measuring Responsiveness to Change

Health status measures are typically evaluated for reliability and validity. A third characteristic, 

important for detecting clinically important change over time, is the measure’s responsiveness. 
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Responsiveness is determined by two properties: reproducibility, and the ability to register 

changes in scores when a patient’s symptom status shows clinically important improvement or 

deterioration. Although there is no universally recommended measure of responsiveness, most 

indices rely on calculation of an effect size. The effect size is a unit-free index that uses the mean 

change score in the numerator and a measure of variability in the denominator. The Standardized 

Response Mean[18] and the Responsiveness Index[19, 20] are particularly useful approaches to 

calculating effect sizes for this application because they incorporate information about the response variance into the denominator. Deyo and others argue that the issue is not just sensitivity 

to change but the ability to discriminate between those who improve and those who do not.[19, 

21] Receiver operating characteristic curves are proposed as an approach for describing how 

well various changes in scale scores can distinguish between improved and unimproved patients. 

This approach requires a valid reference standard to make these clinical classifications.

Risk of Relapse or Recurrence

The goal of depression treatment is to help patients achieve full recovery, defined as a sustained 

period where no or minimal symptoms exist and full functional status has returned. Operationally, 

this has been defined as a Hamilton Depression Rating Scale score of ≤ 7. [22] Patients with major 

depression who remit with antidepressant medication have at least a 50% lifetime risk of recurrence. Patients at particularly high risk include those with ≥ 2 prior major depressive episodes, 

chronic major depression, a family history of bipolar disorder and more severe depression. The 

1993 Agency for Health Care Policy and Research clinical guideline for depression used epidemiological data to propose three treatment phases: acute, continuation and maintenance (Figure).[23] 

Acute phase treatment describes the period of initial treatment until remission is achieved, continuation phase extends treatment for 4 to 6 months to prevent early relapse, and maintenance phase 

treatment continues for 1 or more years for selected patients at increased of recurrence. 

Figure 1. Phases of Depression Treatment

 Remission Recovery

Normal mood

Symptoms

Response Relapse Recurrence

Syndrome

Acute Continuation Maintenance

 Depression phases
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Determining the Responsiveness of Depression Questionnaires and 

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Current guidelines provide a range of recommendations for continuation and maintenance phase 

treatment. For example, the National Institute for Clinical Excellence guidelines (developed by 

the British National Health Service) recommend ≥ 2 years treatment for patients with 2 or more 

major depressive episodes accompanied by functional impairment, while the Institute for Clinical 

Systems Improvement guidelines, a US regional health care collaborative, recommend 6 -12 months 

treatment without specifying which groups should get longer duration of treatment.[9, 10] Since 

these guidelines were published, new data from randomized trials provide additional evidence on the 

benefits of antidepressant medication for preventing relapse or recurrence. In addition, systematic 

reviews provide evidence on potential long-term risks of continuing antidepressant medication.

METHODS

Topic Development

The Veterans Health Administration (VA) 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 VA 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, and assigned to 

the Durham VA Evidence Synthesis Team. The overall goal was to synthesize data on two 

key issues – the responsiveness of depression severity instruments and minimum duration of 

treatment with antidepressants – to inform future quality improvement efforts.

The final key questions (KQ) are:

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, 

post-traumatic stress disorder, psychosis or other conditions where guidelines would 

recommend specialty based care.

Search Strategy

We conducted a search in Medline and PsychInfo for literature published from 1950 through 

February 2009. For key question one (KQ1), we searched for relevant primary literature. For key 

question two (KQ2), our search strategy was designed to identify recent high quality systematic 

reviews and any relevant randomized controlled trials published since the review. A high quality 

review was identified that included articles published through March 2007; our search for additional 
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Determining the Responsiveness of Depression Questionnaires and 

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randomized controlled trials (RCT) included articles published from January 2007 through February 

2009. Appendix A provides the search strategy in detail. We reviewed reference lists of pertinent 

studies for additional citations. All citations were imported into an electronic database (EndNote X1).

Study Selection

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

searches. Full-text articles of potentially relevant citations were retrieved for further review. 

Each article was reviewed with a brief screening form (see Appendix B) to determine eligibility 

and record reasons for exclusion. In case of disagreement, the two reviewers met to identify 

and resolve the disagreement. Eligible articles had English-language abstracts and provided 

primary data relevant to the key questions. Eligibility criteria varied depending on the question 

of interest, as described below. 

To be included in our evidence report for KQ1, a study had to: 

• Evaluate Beck Depression Fast Screen [24], Center for Epidemiologic Studies Depression 

Scale 10-item version [25], DEPS scale [26,]Geriatric Depression Scale 15 item version [27], 

the Patient Heath Questionnaire-9[28], or Symptom Driven Diagnostic System-PC [29] 

• Compare the depression questionnaire to an interview-based depression severity assessment 

such as the Hamilton Depression Rating Scale or Clinical Global Impression

• Use a longitudinal study design so that response to change could be assessed

• Be conducted in adult patients with depressive disorder followed in the outpatient setting and

• Be published in English

We restricted the depression questionnaires to those that had been identified in a previous 

systematic review[14, 15] as having adequate performance characteristics to identify patients 

with major depression in primary care settings, had a range of scores sufficient to show 

change and that were feasible for use as self- or interviewer administered instruments. Thus, 

questionnaires with a very limited scoring range (e.g. Yale, PRIME-MD) or with greater than 10 

items (e.g., 21 item Beck Depression Inventory, 21 item Center for Epidemiologic Depression 

Scale, Hopkins Symptom Checklist) were not considered. Although the Geriatric Depression 

Scale is 15 items, we included this measure because it is specifically cited as an option in the VA/

DOD Major Depression Guideline.

To be included in our evidence report for KQ2, a study had to: 

• Be a systematic review of randomized controlled trials. A review was considered systematic 

if it contained a methods section describing the search strategy and described an analytic 

approach to data synthesis.

• Focus on adult patients with major depressive disorder who remitted or improved 

substantially with antidepressant medication.

• Compared continuation or maintenance phase treatment with antidepressant medication to 

placebo.

• Report relapse and/or recurrence rates.

• Be published in English.
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We then applied quality criteria (see below) and retained the most recent high quality systematic 

review. We included newly identified studies if they were randomized controlled trials, instead 

of reviews, and if they met all other criteria described for systematic reviews

Data Abstraction

We abstracted the following data from included studies: Study Design/setting, eligibility 

criteria/method for assembling cohort, exclusion criteria, sample size, duration of follow-up, 

demographics, clinical category/baseline depression, results and conclusions. For KQ 1, we also 

abstracted information on the method of administration and version of depression questionnaire 

and on the interview-based depression evaluation. For KQ2, we also abstracted information 

on the intervention and comparator and follow-up rate. Data abstractions were completed by 

a single reviewer, then over-read for accuracy by 1-2 additional reviewers. Any disagreements 

were resolved by discussion and consensus.

Quality Assessment

To assess internal validity of studies, we used criteria appropriate to the study design (see 

Appendix C). For KQ1, we abstracted data on whether the interview-based assessment was 

performed blind to the depression questionnaire results; whether the depression questionnaire 

was performed blind to the interview-based assessment; whether the interview-based assessment 

was adequate; the completeness of follow-up; whether the analytic methods were appropriate; 

study funding; and whether a conflict of interest statement was given. 

For KQ2, we abstracted data for systematic reviews and separately for randomized controlled 

trials. For systematic reviews, we abstracted search methods and strategy; whether inclusion/

exclusion criteria were clearly defined and appropriate; whether primary studies were 

appropriately evaluated for quality; were the assessments reproducible; was there an analysis 

of variability; were results combined appropriately; was publication bias assessed; were 

clinically important outcomes, including harms and benefits, reported. For randomized trials, 

we determined whether the method of randomization and allocation concealment was adequate; 

whether intervention and control groups were similar at baseline regarding the most important 

prognostic indicators; was the outcome assessed using a valid methodology and the assessor 

blinded; was the care provider blinded; was the patient blinded; was loss to follow-up < 20% and 

differential loss between groups < 10%; were missing outcome data addressed adequately; and 

was there a conflict of interest.

Data Synthesis

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

included studies, organized by key question. We critically analyzed studies to compare their 

characteristics, methods, and findings. We compiled a summary of findings for each key 

question or clinical topic, and drew conclusions based on qualitative synthesis of the findings. 

We assigned an overall quality of evidence using the GRADE criteria.[30]
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Peer Review

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

are presented in Appendix D.

RESULTS

Literature Flow

For KQ1, the combined library contained 673 citations, of which we reviewed 82 articles at the 

full-text level (Figure 2.). Of the 82 articles, 4 studies met eligibility criteria [31-34] but two 

citations [31, 32] were derived from the same study population leaving 3 unique studies. For 

KQ2, the combined library for systematic reviews contained 106 citations, of which we reviewed 

9 articles at the full-text level (Figure 3). Of the 9 articles, we included the most recent, high 

quality review meeting eligibility criteria. [35] To identify new studies since the eligible 

systematic review was complete, we searched for relevant RCT’s from January 2007 to present. 

This search identified 48 citations, of which we reviewed 6 articles at the full-text level (Figure 

4.). Of the 6 articles, 3 studies with 4 comparisons met eligibility criteria.[36-39]
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Key Question 1 

Studies Evaluating Responsiveness

of Depression Questionnaires

We identified 3 studies that compared change scores for an eligible depression questionnaire to an 

interview based assessment of depression severity. All three studies used the PHQ-9 and one of 

these completed a separate analysis of the PHQ-2. Two studies were conducted in Germany, using 

German language versions of the questionnaire. One study was a secondary analysis from a multicenter randomized trial of care management in older adults and included three VA sites. Key features 

of the studies are summarized in the Table below and study details are contained in Appendix E.

Table 1: Characteristics of Studies Evaluating Responsiveness of the PHQ-9

Study Lowe 2004[34] Lowe 2006[33] Lowe 2004[32] and 

Lowe 2005[31]

N 434 1788 108

Primary care Yes Mixed Mixed

VA settings Yes No No

Mean age (SD) 70.9 (7.3) 50.3 (14.7) 41.1 (14.2) to 42.8 

(12.1)

Men 160 (36%) 594 (33.2%) 34 (31.5%)

Major depressive 

disorder 317 (73%) 757 (42.3%) 55 (51%)

Questionnaire PHQ-9 (English) PHQ-9 (German) PHQ-9 (German)

Comparator Structured Clinical Interview 

for DSM-IV Clinical Global Impression Structured Clinical Interview for DSM-IV

Quality Good Fair Fair

The responsiveness, or sensitivity to change of an instrument describes its ability to accurately 

detect clinically meaningful change when it occurs. There is no consensus on the best measure 

for describing responsiveness but three common methods are used in the studies reviewed: effect 

size, standardized response mean and responsiveness index. 

• Effect size: Mean (time 2)-Mean (time1)/Standard deviation (time 1) [40]

• Standardized response mean: Mean (time 2)-Mean (time1)/Standard deviation of score 

changes [18]

• Responsiveness index: Mean (time 2)-Mean (time1)/Standard deviation in unchanged 

subjects [19, 20]

The good quality study by Lowe et al [34] is the most applicable to Veterans. It evaluated the 

responsiveness of the PHQ-9 and Symptom Checklist-20 (SCL) in older adults enrolled in a 
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randomized trial comparing collaborative care to usual care. The PHQ-9 was self-administered 

or given by telephone interview. The study was conducted in 18 primary care sites, three that 

were VA. Participants were age ≥ 60 years old, had a mean of 3.8 ± 2.0 chronic diseases and 

had a research-based diagnosis of major depressive disorder or dysthymia. Among intervention 

patients, 71% had ≥ 2 prior episodes of depression, 35% screened positive for cognitive 

impairment and 28% screened positive for anxiety symptoms. Important exclusion criteria 

were: severe cognitive impairment, CAGE ≥ 2 or history of bipolar disorder or psychosis. The 

analysis was limited to patients in the intervention arm who had the depression questionnaires, 

the interview-based Structured Clinical Interview for DSM-IV and clinical assessment within 

2 weeks of each other at each scheduled assessment: baseline, 3- and 6-month follow-up. Of 

the 906 intervention patients, 434 (47.9%) had complete assessments. Study strengths were: 

independent, blind comparison of the questionnaires and interview-based assessments, an 

adequate criterion standard and appropriate analysis. A weakness was that only 48% of patients 

enrolled were analyzed, but the study sample was similar to the intervention group overall except 

for a smaller proportion of ethnic minorities. The mean change and standardized response mean 

(SRM) for the PHQ-9 and SLC-20 are shown below:

Table 2. Responsiveness in Patients with Major Depressive Disorder or Dysthymia (n=434)

Baseline 3 Month Change 6 Month Change

Instrument Mean (SD) Mean (SD) SRM (95% CI) Mean (SD) SRM (95% CI)

PHQ-9, range 0-27 13.6 (5.4) -7.5 (5.8) -1.3 (-1.4 to -1.2) -8.0 (6.1) -1.3 (-1.4 to -1.2)

SCL-20, range 0-4 1.7 (0.6) -0.6 (0.7) -0.9 (-1.0 to -0.8) -0.8 (0.7) -1.2 (-1.4 to -1.1)

At 3 months, the PHQ-9 was more responsive than the longer SCL-20; at 6-months the 

responsiveness was not significantly different. The results were unchanged when the analysis 

was restricted to subjects with MDD. In a secondary analysis, the SCID was used to categorize 

treatment response for the 317 patients with MDD as persistent MDD (≥ 5 criterion symptoms), 

partial remission (1-4 criterion symptoms) or full remission (no criterion symptoms). Using this 

classification, the mean change and standardized response mean at six months were as follows:

Table 3. Responsiveness Characteristics in Patients with Major Depressive Disorder at Six Month Follow-up 

(n=317)

PHQ-9 SCL-20

SCID category Mean change 

(SD)

Standardized 

response mean

Mean 

change (SD)

Standardized 

response mean

Persistent MDD -5.6 (6.6) -0.8 -0.3 (0.7) -0.4

Partial remission -8.4 (6.1) -1.4 -0.9 (0.6) -1.5

Full remission -9.8 (5.9) -1.7 -1.3 (0.6) -2.2

For both instruments, an independent assessment of clinical improvement is associated with 

greater reductions in symptom scores. Finally, the authors determined the minimum clinically 

important difference (MCID) in a subset of 82 patients who had the PHQ-9 administered twice, 

exactly 7 days apart at the 6-month follow-up. The MCID was calculated as the standard error 
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of measurement * 1.96. A sensitivity analysis showed the MCID ranged from 2.59 to 4.78 

consistent with prior recommendations based on cross-sectional studies.[41]

The studies by Lowe et al conducted in Germany and using a German-language version of 

the PHQ-9 are less applicable to VA settings. [31-33] German language versions of the PHQ9 may theoretically perform differently from the English language version. The larger study 

[33] enrolled 1878 patients and was conducted in the context of an open-label, post-marketing 

surveillance trial of sertraline. Patients were adults with major, minor or other depressive 

disorders beginning a course of the antidepressant sertraline. The PHQ-9 was compared to the 

Clinical Global Impression (CGI) at 3 months. Patients with a CGI of 1 (very much improved) 

or 2 (much improved) were classified as responders (n=1552, 86.8%). Study strengths were: a 

follow-up rate of 95%, and appropriate analysis and administration of the PHQ-9 blind to the 

CGI results. Study weaknesses were: the CGI criterion standard was applied with knowledge 

of the PHQ-9 results and almost 50% the raters were non-mental health professionals with 

a single training session on using the CGI rating scale. In addition the study team included 

a biostatistician from Pfizer and Pfizer funded the analysis by Lowe et al and the PHQ-9 

development suggesting a potential conflict of interest. The mean change scores and standardized 

response means are shown for CGI responders and non-responders.

Table 4. Responsiveness Characteristics at Three Month Follow-up (n=1788)

PHQ-9 (German Language Version)

CGI category Mean change (95% CI) Standardized response mean

Non-responder -4.42 (-5.0 to -3.84) -1.00

Responder -11.15 (-11.41 to -10.8) -2.15

Subgroup analyses were conducted comparing responsiveness by gender, age groups, depression 

diagnosis, and presence of comorbid physical illness. Standardized response means were similar 

for these subgroups. Because this study was an open label trial, the study population may be more 

representative of typical patients initiating antidepressants than those recruited into a randomized 

trial. 

The second German-language evaluation of the PHQ-9 followed a cohort of 167 patients with 

major depressive disorder (n=55), other depressive disorder (n=53) or no depressive disorder 

(n=59).[31, 32] Only the first two groups with depressive disorders are relevant to our study 

question and our discussion is limited to these groups. At 12-months, PHQ-9 changes scores 

were compared to clinical status as determined by the Structured Clinical Interview for DSMIV (SCID). Improved status included patients who transitioned from major depressive disorder 

to other- or no depressive disorder and patients with other depressive disorder who transitioned 

to no depressive disorder. Worse clinical status included those who transitioned from no 

depressive disorder to major depressive disorder. Study strengths include a follow-up rate > 

80%, appropriate analysis and an adequate criterion standard administered by trained raters with 

excellent inter-rater reliability. Limitations are lack of an independent, blind comparison between 

the PHQ-9 and SCID at 12-month follow-up. Results are given for both the PHQ-9 and for its 

first 2 items (PHQ-2). 
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Table 5. Responsiveness Characteristics at Twelve Month Follow-up (n=108)

PHQ-9 PHQ-2

SCID category Mean 

change (SD)

Effect 

size

Standardized 

response 

mean

Mean 

change 

(SD)

Effect 

size

Standardized 

response 

mean

Worse 3.25 (4.3) 0.62 0.75 1.0 (2.0) 0.6 0.5

Unchanged

 MDD

 Other Depression

0.24 (4.2)

-1.96 (5.28)

0.05

-0.38

0.06

-0.37

0.4 (1.3)

-0.7 (2.2)

0.3

-0.5

0.3

-0.3

Improved -6.7 (4.91) -1.33 -1.42 -2.3 (2.1) -1.4 -1.1

Across the three studies, the standardized response mean ranged from -1.0 to 0.5 for patients 

who were unchanged or worse, and -2.15 to -1.4 for those who responded or remitted. Mean 

changes in PHQ-9 showed greater variability: -5.6 to 3.25 for non-responders and -11.15 to 

-6.7 for those who responded or remitted. The three studies vary on a number important design 

factors that may explain some of the observed heterogeneity. Effect sizes were calculated 

over a range of follow-up from 3 to 12 months. Study samples differed in ways that could 

affect responsiveness, including the proportion with major depressive disorder, the mean age 

and proportion male. The PHQ-9 was administered in English and German languages. The 

interview-based comparator differed and definitions of response varied across studies. Finally, 

study quality differed importantly. Despite these sources of potential variability, the overall 

results were consistent across studies. Greater clinical improvement as determined by an 

interview based severity measure was associated with greater improvement on the PHQ-9. 

Using the GRADE criteria that incorporates study design, consistency and precision of results, 

publication bias and directness, we judge the body of evidence as moderate quality, downgrading 

for limitations in study design. 
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Key Question 2 

The selected systematic review[35] evaluated 23 fair quality RCT’s that compared a secondgeneration antidepressant to placebo in patients who achieved partial- or full remission after 

acute phase treatment. Using the quality assessment instrument described in Appendix D, 

this systematic review met all quality criteria. Included studies generally enrolled patients 

with a criteria-based diagnosis of major depressive disorder and excluded patients with 

concurrent psychiatric illness (e.g. substance abuse or anxiety disorder) or severe chronic 

medical conditions. None of the studies described a VA recruitment site. Four studies 

recruited patients from primary care and psychiatry outpatient clinics, 12 were conducted in 

unspecified outpatient clinics; the remaining seven settings were not described. Studies used 

a randomized discontinuation design, randomizing responders to continued antidepressant or 

placebo. In all trials, antidepressants were used in the acute phase of treatment; none described 

adjunctive treatment with non-pharmacological treatment. All but two[42, 43] of the 23 RCT’s 

continued the same antidepressant or antidepressants at the same dose from acute phase 

treatment to continuation and maintenance phases. Only studies evaluating second-generation 

antidepressants were included; a list of these is available in the evidence table (Appendix E). 

The primary outcomes were relapse and recurrence rates during continuation and maintenance 

phases. Relapse was generally defined as a Hamilton Depression Rating Scale score exceeding 

a specified severity level. Secondary outcomes were adverse event rates and treatment 

discontinuation due to adverse events. A separate analysis included 4 RCT’s that compared 

antidepressants to each other with regards to rates of relapse after remission; this analysis is not 

included for further discussion here because it does not relate directly to KQ2.

Because the RCT’s defined their continuation and maintenance phases differently, the authors 

of the systematic review stratified the studies by treatment duration: less than 1 year after 

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

remission (maintenance). Results stratified by continuation and maintenance phase treatment 

are summarized in Table 6. The unadjusted frequency of relapse for continuation phase (12 

studies) was 22% for active treatment and 42% for placebo. Heterogeneity among these trials 

was moderate (I2

 = 47%). The unadjusted frequency of recurrence for maintenance phase 

(11 studies) was similar to continuation phase treatment: 26% for active treatment and 48% 

placebo. Heterogeneity for these longer duration studies was also moderate (I2

=30%). Tests for 

publication bias were not statistically significant for either group of studies. Meta-regression 

analyses were conducted to evaluate heterogeneity. The duration of open-label treatment before 

random assignment of responders, the length of the post-randomization phase and type of 

second-generation antidepressant were not associated with the estimate of effect. The authors 

concluded that their results provide consistent evidence in favor of antidepressant treatment over 

placebo in both continuation and maintenance phases. 
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Table 6. Systematic Review -Summary of findings 

Unadjusted 

frequency of 

relapse/recurrence

Pooled relative 

risk of relapse/

recurrence

Number needed to treat to 

prevent 1 additional relapse/

recurrence

Continuation 

(<1yr of ongoing 

treatment)

22% antidepressant

42% placebo

0.54

(95% CI 0.46 to 0.62)

5 (95% CI 4 to 6) over a mean 

time of 8 months

Maintenance

(≥1yr ongoing 

treatment)

26% antidepressant

48% placebo

0.56

(95% CI 0.48 to 0.66)

5 (95% CI 4 to 6) over a mean 

time of 16 months

Adverse events were reported incompletely. The most common adverse events documented in 

continuation and maintenance phases were headache (weighted mean incidence 15.5%) and 

nausea (7.4%). Based on data pooled from 18 of the RCT’s, loss to follow up due to adverse 

events was not statistically significantly different between antidepressant and placebo (relative 

risk=1.42, CI = 0.92 to 2.20).

The primary limitation of this review is the lack of studies designed to specifically answer our 

study question – the minimum duration of continued treatment to prevent relapse or recurrence. 

Only one study[44] randomized patients in remission to varying durations (14, 30 or 50 weeks) 

of continuation phase antidepressant or placebo. 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%). Only 62 patients were randomized to 50 weeks treatment and 

the finding of no benefit is inconsistent with the overall body of evidence. A second limitation 

is incomplete descriptions of the study setting, recruitment approach and patient clinical and 

demographic characteristics. Careful descriptions of study populations, including risk factors for 

relapse would help decision makers apply these data. If patients included were at particularly 

high risk, then the estimates of baseline risk (from the placebo control groups) would not apply 

to patients with uncomplicated depression at low risk for relapse. Thus, the absolute benefit and 

number needed to treat (NNT) could be overstated.

Our search for additional RCT’s identified three eligible studies published since the systematic 

review. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years 

(PREVENT) was a multi-phase, double-blind, placebo-controlled study of patients with recurrent 

MDD. Analyses from two phases of this larger study[37, 39] were relevant to KQ2. In the first 

phase,[37] participants who maintained a satisfactory response or clinical remission after acute 

phase and six months continuation phase treatment were randomized to 12-month maintenance 

treatment with venlafaxine ER or placebo. Venlafaxine ER was associated with a statistically 

significantly lower recurrence rate at 12-month follow-up (23.1% vs. 42.0%). The study had 

significantly higher loss to follow-up in the placebo group, which may have underestimated 

the difference between relapse rates. In the second phase[39] patients maintaining response at 

12 months in phase 1 were re-randomized into a second 12 month course of venlafaxine ER or 

placebo. Failure to maintain response was defined as an increase in maintenance dose to 300mg/

day or recurrence (HDRS-17 score > 12 and reduction of <= 50% from acute-phase baseline). 

Kaplan-Meier probability estimates for maintaining response across the combined 2 years of 

maintenance therapy were 67% for venlafaxine ER <= 225 mg/day and 41% for placebo (P = 
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0.007). This second report from the PREVENT study was of fair quality and did not report 

an analysis of patients lost to follow up in placebo or antidepressant groups, thus limiting 

applicability of its conclusions.

A good quality RCT[38] reported the results of a 24 week randomized controlled trial of 

escitalopram (10-20 mg per day) versus placebo in older adults who responded to a 12 week 

trial of open label escitalopram for treatment of a major depressive episode. The proportion 

of patients who relapsed within 24 weeks was significantly higher in the placebo group (33%; 

50 patients) than in the escitalopram group (9%; 13 patients), (p<0.001). A small, fair quality 

RCT[36] reported the one-year follow up of 106 patients who had responded to 16 weeks of 

treatment with paroxetine, cognitive therapy, or behavioral activation. Of the 49 responders 

allocated randomly to either continued paroxetine treatment (n=28) or to placebo (n=21), relapse 

rates were 53% for antidepressant medication and 59% for placebo. 

These additional studies support the findings of the systematic review. 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%. Based on RCT’s with some important 

limitations, generally consistent results and a precise estimate of effect, we grade the overall 

strength of evidence for this finding is moderate. 
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SUMMARY AND DISCUSSION

For KQ1, we only found studies addressing the responsiveness of the PHQ-9 and PHQ-2. 

In these few studies, there was a consistent association between PHQ-9 change scores and 

interview-based assessments of clinical status. The single study comparing the PHQ-9 and 

PHQ-2 showed comparable responsiveness. One study[34] included VA settings and is 

directly applicable to VA populations. In this study, a direct comparison of PHQ-9 to a longer 

questionnaire showed comparable responsiveness. Another study conducted relevant subgroup 

analyses with the German language version of the PHQ-9 and found similar responsiveness 

for important subgroups including men and women, and patients with comorbid medical 

conditions. A single study examined the minimum clinically important difference (MCID) and 

conservatively estimated this value as a 5 point change. This finding is consistent with other 

studies that use cross-sectional analyses to infer the MCID.[41] In summary, the PHQ-9 is 

the best validated instrument for identifying depressed patients in primary care [14-16]and for 

detecting clinically important response to treatment. 

A recent literature synthesis [8] identified baseline and follow-up assessment of depression 

symptoms with a standardized scale as key features of effective depression care. The PHQ-9 

appears well suited for this purpose and has been used in large VA evaluations of depression 

care.[45] Based on a single study conducted in Germany, the PHQ-2 appears responsive to 

change but only tracks two criterion symptoms and does not include an assessment of suicidal 

ideation. Based on this limited data and concerns about inadequate clinical data, the PHQ-2 

alone cannot be recommended to monitor treatment response for clinical purposes. It may be 

useful for research studies when very brief instruments are needed. Our review was based in part 

on the assumption that questionnaires need to be brief to allow for both self-administration and 

interview administration in person or by telephone as is often done in integrated mental healthprimary care models. Other, longer instruments may be preferred if the data collection burden 

can be eased through interactive voice response, web-based applications or scanable forms and 

the instrument has superior clinical content, better responsiveness or a better defined minimum 

clinically important difference. In addition, the response burden would need to be acceptable to 

patients.

Qualitative studies show that patients favor questionnaires to measure depression severity but 

general practitioners in the UK were cautious about the validity and utility of these measures 

and skeptical about the motives behind their introduction.[46] General practitioners specifically 

valued clinical judgment more than objective assessment. Practitioners were aware of the 

potential for manipulation of indicators for economic reasons. In the U.S.A., the PHQ-9 has 

been successfully implemented into primary care and psychiatric practices as part of quality 

improvement studies[47] and pragmatic clinical trials.[48, 49] These findings suggest that 

successful implementation of the PHQ-9 (or any other measure) will need to address attitudinal 

barriers and provide logistical support to integrate PHQ-9 administration into routine clinical 

processes.

For KQ2, the high quality systematic review[35] and 2 of the most recent relevant RCT’s 

provide moderately strong evidence that continued antidepressant treatment decreases the 
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risk of subsequent relapse for patients with MDD who achieve partial- or full-remission. The 

magnitude of risk reduction was similar for shorter- and longer-term trials and maintained for up 

to 2 years. The number needed to treat to prevent one relapse over a mean time of 8 or 16 months 

was 5. However, these trials do not directly answer our question about the minimum duration of 

continued antidepressant treatment since they report the average risk reduction over these time 

periods. In the single trial randomizing patients to differing durations of continuation treatment, 

the risk reduction was similar for 14 and 38 weeks but declined by 50 weeks. More studies 

utilizing this design in patients with various risks of relapse would better address the issue of 

minimum duration. 

At the individual patient level, the decision for how long to continue antidepressant treatment 

should be based on effectiveness, adverse effects and patient preferences. These studies show 

clinically important risk reduction and adverse event rates similar to or slightly lower than acute 

phase treatment studies. A comprehensive review of adverse effects was beyond the scope of this 

study, but a careful evaluation of long-term adverse effects would be important to an accurate 

assessment of net benefit. Emerging evidence from observational studies suggest that newer 

antidepressants may increase the risk of osteoporosis[12, 13] or gastrointestinal bleeding in patients 

with concurrent non-steroidal anti-inflammatory drugs or low dose aspirin. Given the high rates of 

indicated aspirin use in the veteran population, a careful weighing of benefits and risks is needed 

and will depend in part on the patient’s baseline risk of relapse or recurrence. As baseline risk of 

relapse increases, the absolute benefit increases. Since these studies appeared to enroll patients 

primarily from mental health settings, these patients may have been at higher risk than the average 

primary care patient with major depression. However two factors argue for applicability to primary 

care. First, the trials excluded patients with concurrent psychiatric conditions that may have 

increased the risk of relapse. Second, the large primary care based study by Unutzer et al.[50] 

included VA settings and found that almost three-quarters of patients with major depression had at 

least two prior episodes, a strong predictor of relapse risk. The current APA guidelines recommend 

at least 16-20 weeks of continuation treatment after remission is achieved and a judgment about 

maintenance treatment that is individually tailored to the patient. Other guidelines recommend 

longer treatment in patients at elevated risk. A key point and one that may require increased 

attention in primary care is need for a careful assessment of relapse risk when making the decision 

about continuing antidepressants beyond the acute and continuation phase treatment. 

Limitations

Our review has a number of potential limitations. First, there are no validated search strategies 

to identify the literature for KQ1, increasing the risk that we may have missed relevant studies. 

Second, there were insufficient studies to do quantitative evaluations for publication bias or 

statistical heterogeneity. In addition, these types of studies are not typically included in clinical 

trials registries, further limiting our ability to detect publication bias. Third, we did not include 

studies that examined simple change in depression scores without a comparator to an interviewbased measure of response. These studies could provide some, although less convincing 

evidence for responsiveness. Finally, the same author (Lowe) used three separate datasets 

from different study populations to conduct the relevant analyses. Replication by multiple 

investigators could increase confidence in the results.
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Determining the Responsiveness of Depression Questionnaires and 

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For KQ2, the search strategy did not include foreign-language or articles published outside the 

Medline® database, potentially excluding relevant findings. However, the systematic review 

that was identified was recent, high quality, and addressed heterogeneity and publication 

bias. The systematic review looked to compare relapse rates for placebo and antidepressants 

during continuation and maintenance phase, but did not address directly the optimal duration 

of treatment. The two higher quality RCT’s we identified found results consistent with the 

systematic review. Finally, we did not address first-generation antidepressants.

Conclusions

Table 7. Summary of Systematic Evidence Review by Key Question

KQ Key Question Type of 

Evidence

Quality of 

Evidence Comments

1 Responsiveness of 

depression questionnaires Observational Moderate

PHQ-9 is responsive to change 

(mean change -11.2 to -6.7 

for responders; standardized 

response mean -2.15 to -1.4)

2

Minimum duration of 

continued antidepressant 

treatment in patients 

achieving remission

RCT’s Moderate

Continued antidepressant 

treatment decreases the risk of 

relapse by 0.54 to 0.56 for up to 

two years (Number needed to 

treat = 5)
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Determining the Responsiveness of Depression Questionnaires and 

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FUTURE RESEARCH

Although moderately strong evidence shows the PHQ-9 is sensitive to change, studies that 

use receiver operating characteristic analysis to determine how well specific change scores 

classify patients into improved and unchanged or worse would be useful. These studies could 

help establish the minimum clinically important difference, which currently is based on limited 

data. Since data are limited in important subgroups (e.g., medical comorbidity, psychiatric 

comorbidity), studies evaluating responsiveness in key subgroups could also strengthen validity. 

Brief depression questionnaires, such as the PHQ-9, could be used in VA for performance 

measurement. Performance indicators could include: baseline administration at diagnosis (as 

an indicator of careful diagnostic assessment), administration longitudinally (as an indicator of 

careful follow-up), change scores or proportion achieving clinical response, or linked indicators 

that examine changes in treatment matched to changes in severity scores. Studies to examine 

the feasibility, acceptability to patients and clinicians, validity and impact on process of care 

and patient outcomes could help inform policy. If undertaken, these studies should include 

provisions for evaluating any unexpected consequences of introducing these measures into 

routine practice. 

Although it is clear that continued antidepressant treatment beyond the acute phase decreases 

relapse, the optimal duration of treatment remains uncertain. Some clinical guidelines 

recommend that maintenance treatment duration should be customized based on risk factors 

for relapse, but the randomized trials we reviewed did not examine a risk factor based strategy. 

Future studies should carefully describe patient characteristics, such as number of prior 

depressive episodes that may predict relapse. These data would aid clinicians in applying these 

data and could help explain heterogeneity in treatment effects. Most importantly, analysis of 

a timeline for patients during continuation and maintenance phase would be most informative, 

documenting critical periods of increased relapse if they exist and measuring the balance 

between adverse effects and beneficial effects as patients stay on the antidepressant versus 

placebo treatment. It would also be informative to compare the different second-generation 

antidepressants, as well as compare first and second generation antidepressants.
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# Citations

594

 # excluded

 486

# full text review

82

 # excluded

 78

# included

4

 # duplicates

 1

# unique studies

1

Figure 2. Key Question #1 Literature Flow

# Citations

106

 # excluded

 97

# full text review

9

 # excluded

 8

# included

1

Figure 3. Key Question #2 Literature Flow

# Citations

48

 # excluded

 42

# full text review

6

 # excluded

 2

# included

1

Figure 4. Key Question #2 Randomized Control 

Trials Literature Flow
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Determining the Responsiveness of Depression Questionnaires and 

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APPENDIX A: SEARCH STRATEGIES

Key Question #1

Database: PubMed ® <1950 to February 2, 2009>

1 “Depressive Disorder, Major”[Mesh] OR (major AND depression) 32348

2

PHQ9 OR “Patient Health Questionnaire” OR “Beck Depression Inventory” OR BDI 

OR BDI-II OR GDS OR “Geriatric Depression Scale” OR SDDS-PC OR “symptom 

driven diagnostic system primary care” OR PRIMEMD OR “Primary care evaluation of mental disorders” OR DEPS OR “CESD” OR “CES-D” OR (“Center” AND 

Epidemiologic* AND Stud* AND Depression) OR “CESD-10”

11913

3 (change OR changes OR Improv* OR decreas*) AND (score OR scale* OR scores 

OR responsiv* OR sensitiv*) 447184

4 #1 AND #2 AND #3 522

5

(questionnaire OR psychometrics) AND (“Depressive Disorder, Major”[Mesh] OR 

(major AND depression)) AND (((responsiv*[tw] OR sensitiv*[tw]) AND (change[tw] 

OR changes[tw])) OR (clinical*[tw] AND important[tw] AND (change[tw] OR 

changes[tw])))

126

6 #4 OR #5 626

7 #6 Limits: Humans, English, All Adult: 19+ years 516

Database: PsychInfo <up to February 2, 2009>

1 major depression/ 58084

2 major depression.tw. 16118

3

(PHQ9 or “Patient Health Questionnaire” or “Beck Depression Inventory” or BDI or 

BDI-II or GDS or “Geriatric Depression Scale” OR SDDS-PC or “symptom driven 

diagnostic system primary care” or PRIMEMD or “Primary care evaluation of mental disorders” or DEPS).tw. 9324

4

((change or changes or Improv* or decreas*) and (score or scale* or scores or 

responsiv* or sensitiv*)).tw. 82044

5 #1 or #2 61641

6 #3 and #4 and #5 893

7

limit 6 to ((“followup study” or “longitudinal study” or “prospective study” or “systematic review”) AND “adulthood age 18 yrs AND older” AND “peer-reviewed journal” 

AND English AND human) 157
26

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

Key Question #2, Systematic Reviews

Database: PubMed ® <1950 to March 02, 2009>

1 (“Depressive Disorder”[Mesh] OR “major depression”) 63463

2 (antidepress* OR “Antidepressive Agents”[Mesh] OR “Antidepressive Agents 

“[Pharmacological Action]) 114617

3 (recurrence[Mesh] OR relaps* OR recurren*) 410446

4 #1 AND #2 AND #3 2073

5 #4 AND systematic[sb] 106

Key Question #2, Randomized Controlled Trials

Database: PubMed ® <1950 to March 01, 2009>

1 (“Depressive Disorder”[Mesh] OR “major depression”) 63463

2 (antidepress* OR “Antidepressive Agents”[Mesh] OR “Antidepressive Agents 

“[Pharmacological Action]) 114617

3 (recurrence[Mesh] OR relaps* OR recurren*) 410446

4 (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND 

controlled[Title/Abstract] AND trial[Title/Abstract]) 275051

5 #1 AND #2 AND #3 AND #4 428

6 Limits: Publication Date from 2007/01/01 to 2009/03/1, Humans, English, All Adult: 

19+ years 48 
27

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

APPENDIX B: FULL TEXT EXCLUSIONS

Inclusion Criteria for Key Question #1, Assessment Tools Responsive to Change

1. One of the specified instruments (PHQ-9, Beck Fast Screen, CESD-10, GDS-15, SDDS-PC, 

DEPS, PRIME MD)

2. Adults with depressive disorder: outpatient setting

3. Comparator: Comparison to an interview-based instrument

4. Study Design: Longitudinal 

5. Study Design: Sample > 50

6. English language article

General Exclusion Criteria*

Author & Ref #

NOT 1. NOT 2.NOT 3.NOT 4.NOT 5.NOT 6.

Ahava, 1998[51] X

Adler, 2004[52] X

Allard, 2004[53] X

Altamura, 1989[54] X

Amsterdam, 2008[55] X

Babyak, 2000[56] X

Baldwin, 2008[57] X

Barbosa, 2003[58] X

Berkman, 2003[59] X

Berlim, 2005[60] X

Berlim, 2007[61] X

Boyer, 1998[62] X

Brody, 2006[63] X

Brown, 2000[64] X

Brown, 2005[65] X

Cassidy, 2005[66] X

Casten, 2000[67] X

Chen, 2006[68] X

Conradi, 2007[69] X

Cook,1999[70] X

Corney, 2005[71] X

Coulehan, 1997[72] X

Dalton, 2000[73] X

Davies, 2003[74] X

DeBattista, 2003[75] X

Dori, 1999[76] X
28

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

General Exclusion Criteria*

Author & Ref #

NOT 1. NOT 2.NOT 3.NOT 4.NOT 5.NOT 6.

Dubovsky, 2001[77] X

Dunner, 1987[78] X

Einarson, 2004[79] X

Fava, 1999[80] X

Fawcett, 1987[81] X

George, 1999[82] X

George, 2008[83] X

Goodnick, 1997[84] X

Goodnick, 1998[85] X

Judd, 2004[86] X

Kates, 2002[87] X

Koivumaa-Honkanen, 2008[88] X

Koran, 1995[89] X

Kroenke, 2006[90] X

Lesperance, 2007[91] X

Lett, 2007[92] X

Levitt, 1999[93] X

Liebowitz, 2007[94] X

Lustman, 1998[95] X

Lustman, 2000[96] X

Lydiard, 1997[97] X

Mazeh, 2007[98] X

McIntyre, 2005[99] X

Mohamed, 2006[100] X

Mulrow, 1998[101] X

Mynors-Wallis, 2000[102] X

Patkar, 2006[103] X

Perez, 1999[104] X

Picardi, 2005[105] X

Pollock, 1989[106] X

Posternak, 2001[107] X

Proudfoot, 2003[108] X

Pyne, 2002[109] X

Quilty, 2008[110] X

Raskin, 2003[111] X

Raskin, 2007[112] X

Rollman, 2002[113] X
29

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

General Exclusion Criteria*

Author & Ref #

NOT 1. NOT 2.NOT 3.NOT 4.NOT 5.NOT 6.

Rush, 2005[114] X

Rutherford, 2007[115] X

Salkovskis, 2006[116] X

Shelton, 2001[117] X

Singh, 2001[118] X

Skevington, 2001[119] X

Spalletta, 2002[120] X

Stark, 1985[121] X

Szegedi, 2005[122] X

Thase, 1997[123] X

Trivedi, 2004[124] X

Tutty, 2000[125] X

van Gurp, 2002[126] X

van Marwijk, 2008[127] X

Vinkers, 2004[128] X

Wade, 2008[129] X

Wise, 2007[130] X

Items in the table (e.g. Not 1) correspond to the inclusion criteria listed above the table

Inclusion Criteria for Key Question #2, Systematic Reviews

1. Systematic review evaluating anti-depressant vs. placebo. A systematic review contains a 

methods section with search strategy and approach to synthesizing the data

2. Patients: Adults with major depressive disorder who have remitted or improved substantially 

with anti-depressant medication, English language article

3. Outcome: Relapse/recurrence

General Exclusion Criteria*

Author & Ref #

NOT 1. NOT 2.NOT 3. 

Bauer 2009[131] X

Gartlehener 2008[132] X

Quaseem 2008[133] X

Anderson 2008[134] X

Papakostas 2007[135] X

Furukawa 2007[136] X

Zimmerman 2007[137] X

Lam 2004[138] X

Items in the table (e.g. Not 1) correspond to the inclusion criteria listed above the table*
30

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

Inclusion Criteria for Key Question #2, Randomized Controlled Trials

1. Study Design: Randomized Controlled Trial

2. Patients: Adults

3. Outcome: Relapse/recurrence

4. Compares anti-depressant vs. placebo

5. Patients: Adults with major depressive disorder who have remitted or improved substantially 

with anti-depressant medication

6. English language article

General Exclusion Criteria*

Author & Ref #

NOT 1. NOT 2.NOT 3.NOT 4.NOT 5.NOT 6.

Dombrovski 2008[139] X

Keller 2007[140] X

*Items in the table (e.g. Not 1) correspond to the inclusion criteria listed above the table
31

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

APPENDIX C: QUALITY RATINGS

Quality Rating for Key Question #1, Assessment Tools Responsive

to Change

Was the criterion standard applied and interpreted blinded to the results of the depression 

questionnaire?

Was the depression questionnaire applied and interpreted blinded to the results of the criterion 

standard?

Was the interview-based criterion standard a validated measure of depression severity?

Did follow-up of the enrolled sample exceed 80%?

Was the analysis appropriate to the study question?

Was the study funded by the pharmaceutical industry?

Was a conflict of interest disclosure given? If given, was there a potential conflict of interest?

Quality Rating for Key Question #2, Systematic Reviews

Was a focused clinical question clearly stated?

Was the search for relevant studies detailed and exhaustive?

Were inclusion/exclusion criteria clearly defined and appropriate?

Were primary studies evaluated for quality and appropriateness?

Were assessments of studies reproducible?

Were analyses conducted to measure variability in effect?

Were differences in how outcomes were reported and analyzed across studies were taken into 

consideration?

Was publication bias assessed?

Were clinically important outcomes (harms and benefits) reported?

Were the conclusions supported by the data presented?
32

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

Quality Rating for Key Question #2, Randomized Controlled Trials

Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? 

Were depression outcomes assessed using a valid methodology and criteria?

Were subjects and providers blind to the intervention/exposure status of participants?

Were outcome assessors blind to exposure/intervention status?

Were incomplete outcome data adequately addressed?

Was there an important differential loss to follow-up between the compared groups (defined as ≥ 

10%)?

Was there an overall high loss to follow-up ( ≥ 20% for studies <12 months and ≥ 30% for 

studies of 12 month or longer duration)

Was there a conflict of interest?

Were the methods used for randomization adequate?

Was allocation concealment adequate? 
33

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

APPENDIX D: PEER REVIEW

Question: Are the objectives, scope, and methods for this review clearly described?

Reviewer Comment Reply

1 YES. The objectives, scope were very clear and appropriate. The methods were transparent and appropriately rigorous for a best evidence 

review, even though the types of studies sought to answer KQ1 and 

KQ2 were very different. It was helpful to have all of the information 

on search strategies, inclusion/exclusion criteria and data extraction in 

the appendices.

Acknowledged

2 The inclusion and exclusion criteria for Key Question 1 greatly diminish the synthesis’s scope. Given this limitation, I know of no additional 

studies that should have been included in the review for Key Question 

1 or 2.

In general, the Synthesis needs a strong editing (e.g. ensuring consistency in abbreviations, defining abbreviations before applying them, 

correcting punctuation and formatting) 

In addition, there were several places within the synthesis where this 

reviewer could not understand the meaning of a sentence. Specifically:

• Page 8, line 11-12 – “For the finding that the MCID is 5” would 

be best to define this as the Mean Change in Depression Score for 

MDD 

• Page 16, line 11 – “the similarity of groups similar at baseline” 

• Page 25, line 2 – “the number needed”...(number of what?)

• The Evidence Tables 1-5 are very difficult to read because of inconsistent formatting and text layout.

The inclusion/exclusion 

criteria were developed 

with the stakeholders to 

focus on the questions of 

interest.

Editing has been completed to ensure consistency

These sentences have 

been edited to clarify the 

meaning.

We did not find the Page 

25, line 2 reference; on 

page 26 we state the 

“number needed to treat 

to prevent one relapse...”

3 Yes, all of these aspects are clearly described. Acknowledged

4 a) Objectives are clearly defined.

b) Scope is also clearly defined, with the exception that the assessment 

tools that are surveyed are those immediately referable to depressive 

disorders and their symptoms (i.e., disease-specific). One could also 

perceive quality of life, functional capacities, health services utilization and costs as relevant outcomes. I agree with focusing on diseasespecific assessment, and this is clear as the manuscript goes on, but I 

would make it absolutely clear up front so as to frame the boundaries of 

this review explicitly.

c) Methods are clearly defined.

Acknowledged

Edits made to clarify 

that focus is limited to 

depression symptom 

questionnaires

Acknowledged
34

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

Question: Is there any indication of bias in our synthesis of the evidence? 

Reviewer Comment Reply

1 NO. Appropriate precautions were used to minimize bias including 1) 

having 2 researchers review the titles and/or abstracts of articles for 

potential inclusion, 2) having 1-2 reviewers over-read the data abstraction forms to assure accurate abstraction, 3) using well known criteria to 

assess the quality of the studies that included items about funding source 

and conflict of interest (Appendix C) and strength of evidence (GRADE), 

4) providing readers with enough detail to assure transparency, and 5) 

including comments from outsider reviewers in an Appendix. 

Acknowledged

2 It was not clear how this group of authors was selected to conduct the 

evidence synthesis. Was this a competitive application or were the 

authors selected based on their willingness to conduct the synthesis, their 

expertise in the area of study, or other factors?

This has been addressed 

in the topic refinement 

section

3 No, there is no indication of bias Acknowledged

4 No Acknowledged

Question: Are there any studies on responsiveness of depression questionnaires or relapse prevention trials 

related to this report that we have overlooked?

Reviewer Comment Reply

1 NO. These are difficult studies to do well and get funded appropriately 

since they require a diagnostic interview as a reference standard (KQ1) 

and have a long follow-up period (KQ2). I was not surprised that few 

studies were found.

Acknowledged

2 None

3 No, there are no responsiveness studies missed to include in the analysis. 

However, in the discussion of results, the authors refer to a UK qualitative 

study suggesting clinicians are skeptical of depression questionnaires. If 

this study is cited, the authors should also cite two recent studies showing 

US primary care physicians (Nease et al, 2008) and psychiatrists (Duffy et 

al) found the PHQ-9 clinically useful and continued to use.

Also, the authors did not include the 10-item CES-D short-form (Andresen et al, 1994). There are probably no studies testing its responsiveness, 

but I mention it simply because it does fall within the authors’ 10-item 

inclusion criteria for brief measures.

• Nease DE, Nutting PA, Dickinson WP, Bonham AJ, Graham DG, Gallagher KM, Main DS. Inducing sustainable improvement in depression 

care in primary care practices. Joint Commission Journal on Quality 

and Patient Safety 2008;34:247-255.

• Duffy FF, Chung H, Trivedi M, Rae DS, Regier DA, Katzelnick DJ. 

Systematic use of patient-rated depression severity monitoring: is 

it helpful and feasible in clinical psychiatry? Psychiatric Services 

2008;59:1148–1154.

• Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for 

depression in well older adults: evaluation of a short form of the CESD (Center for Epidemiologic Studies Depression Scale). Am J Prev 

Med. 1994; 10: 77–84.

The discussion has been 

revised and the additional 

studies referenced

The CESD-10 was not 

excluded but our search 

did not include terms 

specific to this instrument. We have updated 

the search and results. 49 

additional citations were 

identified but none met 

eligibility criteria

4 None that meet the defined criteria, to my knowledge Acknowledged
35

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

Question: Please write additional suggestions or additional comments below for this report. If applicable, 

please indicate the page and line numbers from the draft report. 

Reviewer Comment Reply

1 The target audience for this report includes administrators and policy 

makers. They would benefit from a conclusion section at the end of 

the Executive Summary that simply stated the conclusions followed 

by quality of the evidence supporting the conclusion. This could even 

be 2 bullet points. Administrators and policy makers are likely to start 

with this bottom line and read backwards if they need more detail. For 

example, you could use lines 14-16 on page 24, lines 11-15 on page 

23, and lines 44-46 and 1-4 on pages 24 and 25 after editing them. For 

KQ2, it helps to have both the RR and NNT. 

The results section in the Executive Summary was difficult to follow for KQ1, lines 31-43, page 7. The methods paragraph describes 

the standardized response mean (SRM) then the results start with the 

mean change score. I would list the mean change score and SRM for 3 

months, then for 6 months. Although you save words in the current version, it is harder to read. Also in line 41 define the abbreviation MCID 

since you use it later.

Figure 1 on page 13 is difficult to read in its current size. It would be 

good if it could be enlarged.

In Table 7 on page 26, it would be helpful to include some data in the 

comments section after the summary comment, e.g., mean change score 

expected of responders. Also, I would include the NNT with the RR.

Appendix B is important to document why studies were excluded/

include. Using “not 1,” “not 2,” etc is a bit confusing, but I could not 

think of a better way to concisely describe these criteria for the table 

headers.

In Appendix C, page 37, line 30 has a typo. I think it should read “...

evaluated for quality and appropriateness?”

The evidence tables are dense, but the details are important for transparency.

We have followed this 

suggestion

We have followed this 

suggestion

The figure has been 

enlarged

We have followed this 

suggestion

Modified to improve 

clarity

Thank you. Typo corrected

Acknowledged
36

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

2 Key Question 1

In general, this reviewer felt that Key Question 1 was not an “assessment of tools that were responsive to change”, but rather a review of 

the PHQ-9’s (and at times the PHQ-2’s) responsiveness to change. 

This apparent bias first appears in the background section in which the 

synthesis first author’s work (reference 15) concluded that the PHQ9 had better performance characteristics and gave more information 

for depression diagnosis than other instruments. Thus, from the very 

beginning, this reviewer was confused on why Key Question 1 was 

requested for a synthesis review.

Given these issues, the background on Depression Questionnaires either 

1) needs to be expanded to describe the 7 other questionnaires that have 

< 10 items, or 2) for the sake of transparency, the background section 

should clearly state in the text that the work that identified the PHQ-9 

as the optimal self reported primary care depression measure was conducted by the first author of this synthesis. 

The fact that the primary manuscripts reviewed for Key Question 1 

(references 29-32) were all conducted by the same first author (Lowe) 

should be noted in the limitations.

Since the authors note that there has been no work to date measuring 

responsiveness to change in instruments was for the PHQ-9 and was 

applied in a population greater than age 60, the Future Research section 

should also call for additional studies to identify whether or not the 

PHQ-9 (and other measures) respond to change in younger populations.

Key Question 2

Given that the number of prior episodes is a major risk for relapse, 

did any of the RCT’s reviewed for Key Question 2 address this issue? 

Though this is alluded to on page 22, lines 17-20, it should be more 

clearly stated.

We have attempted to 

strengthen the message 

that we searched for ALL 

feasible instruments, but 

only found data for the 

PHQ. The background 

has been modified to 

briefly describe the eligible questionnaires.

Discussion has been 

updated to note this issue.

No change; the PHQ9 

has been evaluated in 

mid-life and older adults

The number of prior depressive episodes was not 

systematically reported in 

the trials

3 Page 6, lines 17-36: In paragraph, authors state “Clinical guidelines 

recommend continuation treatment for 4-6 months ... However, clinical guidelines for longer-term maintenance phase treatment are more 

variable and performance indicators (e.g., HEDIS) do not address 

maintenance phase treatment.” But Key Question #2 is: “What is the 

minimum duration of continuation phase treatment to decrease risk of 

relapse?” Continuation (1st 4-9 months after remission) and maintenance (long-term treatment after continuation) phases of treatment 

have distinct meanings in some guidelines, and the authors’ going back 

and forth between these 2 terms (and in other places the vaguer phrase 

“long-term treatment” leaves the reader confused whether their review 

is focused on evidence for continuation phase treatment, maintenance 

phase, or both. Please clarify for reader.

Page 8, Lines 31-46: This section clarifies the answer to the question 

above (i.e., this review looks at both continuation and maintenance 

treatment) – this should be clarified on p. 6

This comment and the 

following comment have 

been addressed in the revision. The background 

on page 6 clarifies that 

the review addressed 

continuation and maintenance phase treatment

As above
37

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

Page 14, Lines 36-37: There is a short-form of the CES-D (10 items). 

The reference is provided under #3 above. The authors might note why 

this was not included in their search.

Page 15, Lines 7-8: The authors might add to their parenthetical examples of measures longer than 10 items the Inventory for Depressive 

Symptoms (since it was used in the landmark STAR*D trial where 40% 

of patients were from primary care) and the CES-D.

Page 18, Lines 7-9: The authors state: “In addition the study team included a biostatistician from Pfizer, and Pfizer funded the current study 

and the PHQ-9 development, suggesting a potential conflict of interest.” 

However, unlike drugs sold for profit, the PHQ-9 always has been made 

available free of charge. Thus, the potential conflict of interest is much 

weaker than if drug trials were being analyzed.

Page 24, Lines 35-42: The authors state: “Qualitative studies show that 

patients favor questionnaires to measure depression severity but general 

practitioners in the UK were cautious about the validity and utility of these 

measures and skeptical about the motives behind their introduction. General practitioners specifically valued clinical judgment more than objective 

assessment. Practitioners were aware of the potential for manipulation of 

indicators for economic reasons. If these findings hold true for VA clinicians, these barriers would need to be addressed for successful implementation of the PHQ-9 (or any other measure) for routine monitoring.”

However, two recent studies in the US showed good uptake of the 

PHQ-9 by primary care physicians (Nease et al 2008) and psychiatry 

(Duffy et al 2008).

Previously addressed

This recommendation 

was followed

This is a valid point 

about the availability 

free of charge. However, 

potential COI still exists 

as increased identification of depression may 

increase sales or related 

for-profit products. No 

change

Previously addressed

Question: Recommendations for future ESP topical areas of interest or programmatic comments may also 

be included at the end of this section. 

Reviewer Comment Reply

1 Topics: 

1. Treatment of chronic obstructive pulmonary disease

2. Palliative chemotherapy for lung, colon, and possibly other cancers

Programmatic Comments:

1. Translating evidence syntheses into policy and organizational decisions will be a difficult step. I assume the ESPs are linked to OQP, 

but there should be outreach to VISNs and medical centers.

Acknowledged

Acknowledged

2 None

3 None at this time

4 If feasible, a review of evidence-based methods and data on suicide risk 

evaluation in primary care settings would be helpful

Acknowledged
38

of Depression Questionnaires and 

Antidepressant Medications Evidence-based Synthesis Program

vidence Tables

stion #2 Systematic Review, Hansen, 2008[35]

haracteresigns

Patient Characteristics Outcomes Assessed Relative risks/other sum- mary effect measures Comments Quality Rating

udies: 23 

ontrolled 

untries:

uded US

UK, France, 

multinational

ervention: 

eneration 

ssant: bu

citalopram, 

e, escit

fluoxetine, 

ine, mir

nefazadone, 

e, sertraline, 

, venla

ettings 

ticles):

ttings: 4

nt”: 12

n: 6

22

Total no. of patients: 8241Age: Mean age range generally 40-50. Two trials w/ range 65-87Gender:Most >60% femaleMany >65% femaleDepressive Disorder:26 required MDD diagnosis, 1 required only QIDS-C-16 > 5.Severity of initial symptoms:Many used HDRS. Some had requirement for # episodes.Race/ethnicity: NG Exclusion:Use of other psychotropics, presence of comorbid psychiatric or medical disease most common

Relapse definition: most used increase in HAMD or MADRS above predefined cutoff pt. Some added clinical criteria.Treatment duration (after acute phase): Continuation: 14-72 weeksMaintenance: 36-100 weeks.12 trials: f/up <1yr (redefined as continuation)11 trials: f/up 1+ yr (redefined as maintenance)Outcomes:1) Continuation phase relapse rate compared to placebo2) Maintenance phase recurrence rate compared to placeboOther Outcomes: 4) Rates of adverse events5) Rates of loss to f/up attributed to adverse events

Relapse re-defined as relapse w/in 

1 yr continuationRecurrence re-defined as relapse w/in 1 yr maintenanceOutcomes:1) Unadjusted frequency of relapse was 22% active treatment, 42% placebo2) Unadjusted frequency of recurrence was 26% for active treatment, 48% placeboOther Outcomes: 3) Adverse events rates given for individual studies when reported (compared w/ acute-phase studies, relative incidence of most common adverse events was lower)5) Loss to f/up attributed to adverse events was 7% for active treatment and 4% for placebo (did not report significance) 

Comments: -In meta-regression, duration of follow-up did not impact effect size -Authors reported fair quality of studies included-Moderate grade evidence

Quality Rating: highFocused clinical question? YesDetailed & exhaustive search? YesInclusion/exclusion criteria clearly defined & appropriate? YesStudies evaluated for quality & appropriately? YesAssessments of studies reproducible? YesMeasured variability in effect? YesDifferences in how outcomes were reported and analyzed across studies considered? YesPublication bias assessed? Yes,Clinically important outcomes (harms & benefits) reported? YesConclusions supported by data presented? Yes
39

of Depression Questionnaires and 

Antidepressant Medications Evidence-based Synthesis Program

stion #2 Randomized Controlled Trials

ve

Patient Baseline Characteristics

Inclusion/Exclusion Criteria Outcome

Results 

Adverse Events (%) Analysis

Quality Rating 

ve:

 

s

ne 

:

ne 

y

Mean Age:Venlafaxine ER 42.0 Placebo 42.6 Sex (% female):Venlafaxine ER 69%Placebo 67%Race (% white):Venlafaxine ER 81%Placebo 88%Baseline (HDRS)Venlafaxine ER 4.3Placebo 4.9

Inclusion Criteria:

• ≥ 18 years old• MDD by DSM-IV• Depression symptoms for ≥ 1 month• ≥3 prior depressive episodes, 2 in the past 5 

years

• Two months between episodes • HDRS-17 score ≥ 20 at screening and ≥18 at 

randomization

• Response or remission of intake episode at 

end of continuation phase

Exclusion Criteria:

• Failed trial of study medications• Treatment resistant, defined as failure of 

three med trials, ECT, or psychotherapy

• Hypersensitivity to study medications• Alcohol or illicit drug use within 6 months• Seizure disorder• Other serious medical diseases• Other mental illnesses • Pregnant or lactating• ECT within 3 months• Fluoxetine or MAO-I within 30 days• Other antidepressant within 14 days• Any other psychotropic drug 7 days

Venlafaxine ER was associated with significantly lower risk of recurrence in comparison to placebo.Probability of recurrence:Month 6: Venlafaxine ER: 18.8%Placebo: 28.4%Month 12:Venlafaxine ER: 23.1%Placebo: 42%

Headache:Venlafaxine ER 25Placebo 24Upper Respiratory Infection:Venlafaxine ER 17Placebo 12Dry Mouth: Venlafaxine ER 15Placebo 11Insomnia:Venlafaxine ER 14Placebo 13Sweating:Venlafaxine ER 14Placebo 12Weight Gain:Venlafaxine ER 12Placebo 7Dizziness:Venlafaxine ER 11Placebo 21Nausea:Venlafaxine ER 11Placebo 10Sexual Problems:Venlafaxine ER 11Placebo 7

Overall Attrition Rate:Venlafaxine = 50%Placebo = 73%(p<.001)ITT Analysis:YesQuality Rating: fair?Grps similar at baseline? YesOutcomes used valid methodology & criteria?Yes, HDRS-17Subjects & providers blind to intervention status of participants? Yes

Outcome assessors blind? YesIncomplete outcome data adequately addressed? Yes, ITT>10% differential loss to f/up between grps? YesOverall >30% loss to f/up? Yes, 40%Conflict of interest? Funded by venlafaxine manufacturerAdequate randomization methods? NGAllocation concealment adequate? NG
40

of Depression Questionnaires and 

Antidepressant Medications Evidence-based Synthesis Program

stion #2 Randomized Controlled Trials

ve

Patient Baseline Characteristics

Inclusion/Exclusion Criteria Outcome

Results 

Adverse Effects Analysis

Quality Rating 

ve:

erm 

xine 

in 

ent 

:

Mean Age:Venlafaxine ER 41Placebo 43.1Sex (% female):Venlafaxine ER 73Placebo 63Race (% white):NGBaseline (HDRS)Venlafaxine 3.2Placebo 4.5

Inclusion Criteria:

• ≥18 years old• MDD by DSM-IV• Depression symptoms for ≥ 1 month• ≥ 3 prior depressive episodes, 2 in the 

past 5 years

• Two months between episodes • HDRS-17 score ≥20 at screening and 

≥18 at randomization

• Response or remission of intake episode 

at end of continuation phase

Exclusion Criteria:

• Failed trial of study medications• Treatment resistant, defined as failure of 

three med trials, ECT, or psychotherapy

• Hypersensitivity to study medications• Alcohol or illicit drug use within 6 

months

• Seizure Disorder• Others serious medical diseases• Other mental illnesses • Pregnant or Lactating• ECT within 3 months• Fluoxetine or MAO-I within 30 days• Other antidepressant within 14 days• Any other psychotropic drug 7 days

Kaplan-Meier probability estimate for not experiencing recurrence OR increasing dose to 300mg/day:67% for venlafaxine ER =< 225 mg 41% for placeboNNT of 4.5Estimated probability of not having recurrence greater in venlafaxine ER group vs. placebo (76% versus 58%) but did not reach level of statistical significance 

Not reported Overall Attrition Rate:

NGITT Analysis:Not doneQuality Rating: fair or poor?Grps similar at baseline? YesOutcomes used valid methodology & criteria?Partial, HDRS-17 & dose increase of antidepressantSubjects & providers blind to intervention status of participants? YesOutcome assessors blind? YesIncomplete outcome data adequately addressed? No, reasons not reported>10% differential loss to f/up between grps? NoOverall >30% loss to f/up? NoConflict of interest? Funded by venlafaxine manufacturerAdequate randomization methods? NGAllocation concealment adequate? NG
41

of Depression Questionnaires and 

Antidepressant Medications Evidence-based Synthesis Program

stion #2 Randomized Controlled Trials

ve

Patient Baseline Characteristics

Inclusion/Exclusion Criteria Outcome

Results 

Adverse Events (%) Analysis 

Quality Rating 

ve:

sis that 

s will 

pram 

:

nce 

ram 

 weeks 

ment

am 10-

Mean Age:Escitalopram 73Placebo 72Sex (% female):Escitalopram 78%Placebo 79% Race (% white):Escitalopram 99.7%Placebo 100%Baseline (MADRS):Escitalopram 5.1Placebo 5.1

Inclusion Criteria:

• >= 65 years old• MDD by MINI• Response to a 12 week trial of escitalopram• MADRS score >= 22• Duration of t index episode of at least 4 

weeks

• MMSE score >= 24 •Exclusion Criteria:• Current or past history of manic or hypomanic episode, psychotic disorder (including MDD with psychotic features), 

MR, or mental disorders resulting from a general medical condition

• Any substance abuse disorder, presence or history of a clinically significant 

neurologic disorder, neurodegenerative disorder, and any personality disorder.

• Significant suicide risk• Recent receipt prior to screening of the 

following treatments:

antipsychotic drugs, ECT, lithium, carbamazepine, valproate, or valpromide antidepressants, benzodiazepines, nonbenzodiazepine anxiolytics or hypnotics 

(other than zolpidem, zopiclone, or zaleplon); serotonin agonists (for example, triptans), psychotherapy

hypersensitivity to citalopram and/or 

escitalopram

resistance to two trials of antidepressants 

or resistance to citalopram or escitalopram 

Escitalopram wasfour times as effective as placebo in preventing relapse over 24 weeks in older patients with MDD who had achieved full remission Percentage who relapsed:Escitalopram: 9% (13 patients)Placebo: 33% (50 patients)

Any adverse event:Escitalopram 35.3Placebo 34.9Diarrhea:Escitalopram 3.3Placebo 2.6Dizziness:Escitalopram 4.6Placebo 3.3Nausea:Escitalopram 0Placebo 0Headache:Escitalopram 2.6Placebo 3.3

Overall Attrition Rate:Escitalopram = 15%Placebo = 8.5%(excluding relapsers)ITT Analysis:Yes

Quality Rating:

Grps similar at baseline? YesOutcomes used valid methodology & criteria?Yes, MADRSSubjects & providers blind to intervention status of participants? YesOutcome assessors blind? Yes

Incomplete outcome data adequately addressed? Yes, ITT

>10% differential loss to f/up between grps? NoOverall >30% loss to f/up? NoConflict of interest? Funded by escitalopram manufacturerAdequate randomization methods? YesAllocation concealment adequate? Yes
42

of Depression Questionnaires and 

Antidepressant Medications Evidence-based Synthesis Program

stion #2 Randomized Controlled Trials

ve

Patient Baseline Characteristics

Inclusion/Exclusion Criteria Outcome

Results 

Adverse Events (%) Analysis

Quality Rating 

ve:

e 

on, 

rapy, 

 

) to 

y:

p af

phase 

e all 

DM 

ne 

21)

Baseline characteristics of those randomized to ADM and placebo in the maintenance phase were not separately reported.For all subjects randomized to AMD or placebo:Female 78.2%Caucasian 80.0%Minority 20.0%Married 36.3%Have children 43.6%College education 63.8%

Inclusion Criteria:

• response to acute phase treatment 

for depression with 16 weeks of paroxetine

• diagnosis of MDD for index 

episode on the basis of diagnostic interviews

• 20 or above on the Beck Depression Inventory II and scores of 14 

or above on the 17-item version of the HDRS

Exclusion Criteria:Not explicitly stated in this report

Rates of relapse after 1 year follow up from Cox regression analysis:paroxetine: 53%placebo: 59%(not statistically significantly different)

Not reported Overall Attrition Rate:

ADM = 7%Placebo = 19%ITT Analysis:UnclearQuality Rating: Poor - Fair?Grps similar at baseline? NGOutcomes used valid methodology & criteria?Yes, HRSDSubjects & providers blind to intervention status of participants? YesOutcome assessors blind? YesIncomplete outcome data adequately addressed? No, reasons not reported>10% differential loss to f/up between grps? YesOverall >30% loss to f/up? NoConflict of interest? No, funded by NIMHAdequate randomization methods? YesAllocation concealment adequate? Yes
43

Determining the Responsiveness of Depression Questionnaires and 

Optimal Treatment Duration for Antidepressant Medications Evidence-based Synthesis Program

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