Elizabeth A. O'Connor, PhD; Evelyn P. Whitlock, MD, MPH; Tracy L. Beil, MS; Bradley N. Gaynes, MD, MPH
In primary care settings, prevalence estimates of major depressive disorder range from 5% to 13% in all adults, with lower estimates in those older than 55 years (6% to 9%). In 2002, the U.S. Preventive Services Task Force (USPSTF) recommended screening adults for depression in clinical practices that have systems to ensure accurate diagnosis, effective treatment, and follow-up.
To conduct a targeted, updated systematic review for the U.S. Preventive Services Task Force about the benefits and harms of screening adult patients for depression in a primary care setting, the benefits of depression treatment in older adults, and the harms of depression treatment with antidepressant medications.
MEDLINE, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, PsycINFO (1998 to 2007), expert suggestions, and bibliographies of recent systematic reviews.
Fair- to good-quality randomized clinical trials or controlled clinical trials; systematic reviews; meta-analyses; and large observational studies of serious adverse events and early discontinuation due to adverse effects. All studies were published in English.
Two investigators abstracted, critically appraised, and synthesized 33 articles that met inclusion criteria.
Nine fair- or good-quality trials indicate that primary care depression screening and care management programs with staff assistance, such as case management or mental health specialist involvement, can increase depression response and remission. Benefit was not evident in screening programs without staff assistance in depression care. Seven regulatory reviews or meta-analyses and 3 large cohort studies indicate no increased risk for completed suicide deaths with antidepressant treatment. Risk for suicidal behaviors was increased in young adults (aged 18 to 29 years) who received antidepressants, particularly those who received paroxetine, but was reduced in older adults.
Examination of harms was limited to serious adverse events, and existing systematic reviews were primarily used. Additional studies published from 2007 to 2008 extend this review.
Depression screening programs without substantial staff-assisted depression care supports are unlikely to improve depression outcomes. Close monitoring of all adult patients who initiate antidepressant treatment, particularly those younger than 30 years, is important both for safety and to ensure optimal treatment.
SSRI = selective serotonin reuptake inhibitor.
KQ = key question.
* Numbers differ slightly from the full report (16) because only articles relevant to the more limited body of literature discussed in this publication are included in this figure.
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Appendix Table 6.
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Roy M. Poses
Foundation for Integrity and Responsibility in Medicine
December 30, 2009
Questions Unanswered about Screening for Depression
The US Preventive Service Task Force's (USPSTF) efforts to keep their evidence-based guidelines up to date is praiseworthy. It is understandable that practical concerns may lead to limits on specific questions addressed by new literature reviews. Nonetheless, it is disappointing that the questions addressed for the recent update of the guidelines for depression screening(1) were not broader. In particular, the narrowly defined review did not consider new evidence on the efficacy of anti-depressant treatment of depression from two recent meta-analyses which included a substantial number of clinical trials whose results were not published, and were heretofore inaccessible.
Turner et al(2) showed that results of 31% completed trials registered with the US Food and Drug Administration (FDA) for 12 anti- depressant drugs were provided to the FDA but not published. 16/23 of these unpublished trials did not show significant efficacy per FDA reviews of them. Meta-analysis of all trials, published and unpublished, showed that anti-depressant drugs were less efficacious than did previous meta- analyses of only published trials. Furthermore, Kirsch and Moore's meta- analysis of published and unpublished trials of six anti-depressants which all provided results in terms of the Hamilton Rating Scale for Depression (HRSD) showed that the drugs' effects were barely clinically significant.(3)
Thus, these two meta-analyses showed that failure to publish an important minority of "negative" trials of anti-depressants biased the published literature in favor of these drugs, and that this bias lead to the impression that the drugs may be more efficacious than they really are. If these widely touted treatments of depression are really of marginal clinical effectiveness, the rationale for screening for depression comes into question.
Furthermore, increasing numbers of cases in which clinical research results which did not favor the interests of the commercial sponsors of the studies were suppressed suggest that we need to rethink how evidence is gathered to support evidence-based practice guidelines, and perhaps rethink how we regulate clinical research. A recent editorial in response to concerns about manipulating and suppressing evidence noted, "the current system isn't working. Worse than that, it gives a false sense of security. The system's failures have left a legacy of drug evaluations for which, in the absence of better information, we must assume ... confusion and uncertainty...."(4) Failure to consider these issues when developing evidence-based guidelines just boots the problem down the road for others to solve after it has become even more pernicious.
1. O'Connor EA, Whitlock EP, Bell TL, Gaynes BN. Screening for depression in adult patients in primary care settings: a systematic evidence review. Ann Int Med 2009; 151: 793-803.
2. Turner EH, Matthews AM, Linardatos E et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252-260.
3. Kirsch I, Moore TJ. The emperor's new drugs: an analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prevention Treatment 2002; 5:
4. Godlee F, Clarke M. Why don't we have all the evidence on oseltamivir? - the full data from drug trials must be available for scrutiny. Brit Med J 2009; 339: 1321-1322.
Evelyn P. Whitlock
The Center for Health Research, Kaiser Permanente
February 3, 2010
Response to Comment by Poses
We agree there may be trade-offs involved in conducting targeted systematic reviews to efficiently update an evidence-based recommendation, as illustrated by the writer's letter (1). We refer the reader to the USPSTF's methods workgroup/procedure manual for further clarification on their rationale and approach for conducting updates (2).
Poses's main question concerns the possibility that explicit inclusion of unpublished trials in meta-analysis would reduce current estimates of antidepressant efficacy, thus undercutting the rationale for depression screening in primary care. We do not believe an overestimate has been clearly established nor, if established, would undercut the importance of screening for several reasons. First and foremost, the rationale for screening relies most strongly on studies (Key Question 1) providing direct evidence that depression screening and care management programs increase depression response and remission, compared with usual care. This evidence does not assume any particular efficacy of antidepressants per se, although efficacious treatments are part of the care pathway. Second, in the absence of direct evidence, the USPSTF's analytic framework for screening topics requires only that one or more primary care applicable treatment(s) be effective in screen-detected disease. For depression, pharmaceuticals are only one potential effective treatment. Psychotherapy's effectiveness is not in dispute on the basis of unpublished studies. Thus, even if antidepressants overall efficacy were found to be less than estimated, it would not eliminate screening's potential value.
While we do not dispute the "file drawer problem" (publication bias wherein null studies are less likely to be published), we believe that the Turner (3) and Kirsch/Moore (4) studies cited do not, in themselves, refute the efficacy of antidepressants in major depressive disorder (the focus of our review). Turner and colleagues elegantly demonstrate not only publication bias, but also distortion and inflation in effect sizes, when they examined published vs. unpublished antidepressant trials provided to the FDA. While effectively demonstrating reporting biases that would overestimate treatment efficacy, Turner did not attempt a true meta-analysis of published and unpublished antidepressant efficacy studies. The Kirsch study has several analytic problems limiting its conclusions, particularly the likely overestimate of the proportion of drug response attributable to placebo, due to use of between-studies rather than within-studies pooling to gauge improvement.
While we do not agree that our overall review findings about depression screening should be called into question, we appreciate the letter writer's emphasis that systematic reviews rigorously consider the full range of available data and potential biases involved in study reporting.
1. Poses RR. Submitted letter to editors of Annals of Internal Medicine.
2. U.S. Preventive Services Task Force Procedure Manual. AHRQ Publication No. 08-05118-EF, July 2008 Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf08/methods/procmanual.htm
3. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252-260.
4. Kirsch I, Moore TJ. The emperor's new drugs: an analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prevention Treatment 2002: 5.
Elizabeth A. O'Connor, Evelyn P. Whitlock, Tracy L. Beil, Bradley N. Gaynes. Screening for Depression in Adult Patients in Primary Care Settings: A Systematic Evidence Review. Ann Intern Med. 2009;151:793–803. doi: 10.7326/0003-4819-151-11-200912010-00007
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Published: Ann Intern Med. 2009;151(11):793-803.
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