Conceived and designed the experiments: AM MR KM JC MS RZ SP DS PdJ BT. Performed the experiments: AM MR KM EA AL BT. Analyzed the data: AM BT. Wrote the paper: AM BT. Critical revision of manuscript: AM MR KM JC MS RZ SP DS PdJ BT EA AL. Statistical analyses: AM BT EA. Obtained funding: BT.
The authors have read the journal‘s policy and have the following conflicts: one co-author, Dr. Stewart, is a consultant for the Depression Global Advisory Board for Eli Lilly, and the Cymbalta Pregnancy Registry, and was a consultant for the Depression Advisory Board for Wyeth until 2009. All other authors have declared that no competing interests exist. This does not alter the authors‘ adherence to all the PLoS ONE policies on sharing data and materials.
Several practice guidelines recommend screening for depression in cancer care, but no systematic reviews have examined whether there is evidence that depression screening benefits cancer patients. The objective was to evaluate the potential benefits of depression screening in cancer patients by assessing the (1) accuracy of depression screening tools; (2) effectiveness of depression treatment; and (3) effect of depression screening, either alone or in the context of comprehensive depression care, on depression outcomes.
Data sources were CINAHL, Cochrane, EMBASE, ISI, MEDLINE, PsycINFO and SCOPUS databases through January 24, 2011; manual journal searches; reference lists; citation tracking; trial registry reviews. Articles on cancer patients were included if they (1) compared a depression screening instrument to a valid criterion for major depressive disorder (MDD); (2) compared depression treatment with placebo or usual care in a randomized controlled trial (RCT); (3) assessed the effect of screening on depression outcomes in a RCT.
There were 19 studies of screening accuracy, 1 MDD treatment RCT, but no RCTs that investigated effects of screening on depression outcomes. Screening accuracy studies generally had small sample sizes (median = 17 depression cases) and used exploratory methods to set sample-specific cutoff scores that varied substantially across studies. A nurse-delivered intervention for MDD reduced depressive symptoms moderately (effect size = 0.37).
The one treatment study reviewed reported modest improvement in depressive symptoms, but no evidence was found on whether or not depression screening in cancer patients, either alone or in the context of optimal depression care, improves depression outcomes compared to usual care. Depression screening in cancer should be evaluated in a RCT in which all patients identified as depressed, either through screening or via physician recognition and referral in a control group, have access to comprehensive depression care.
Over 40% of people will be diagnosed with cancer in their lifetime with two-thirds living at least 5 years
Many cancer patients report that their psychosocial needs are not addressed adequately, and improving supportive and palliative care has been prioritized
The term
No systematic reviews have specifically evaluated the effects of screening for MDD in cancer patients on depression outcomes. Thus, the objective of this systematic review was to evaluate whether evidence supports recommendations for systematic screening for depression in cancer care. We used the US Preventive Services Task Force (USPSTF)
The CINAHL, Cochrane, EMBASE, ISI, MEDLINE, PsycINFO and SCOPUS databases were searched through January 24, 2011. One search was conducted to identify articles that compared a screening instrument with a valid MDD criterion standard (Key Question #1) or that assessed outcomes from depression screening, either alone or in the context of enhanced depression care (Key Question #3). A second search was done for depression treatment studies (Key Question #2). See
Eligible articles included studies in any language on cancer patients with any type of malignancy at any disease stage that reported original data, excluding case series or case reports. Translators assisted reviewers to evaluate titles/abstracts and articles for languages not covered by investigators, who were able to independently review material in English, Dutch, French, and Spanish. Multiple articles on the same cohort were treated as a single study. Studies with mixed populations were included if cancer data were reported separately.
Studies on the accuracy of depression screening tools (Key Question #1) were included if they compared screening results to a
Eligible articles on depression treatment (Key Question #2) were RCTs comparing pharmacological, psychotherapeutic, or other interventions with placebo or usual care controls among cancer patients diagnosed with MDD based on a validated diagnostic interview and DSM or ICD criteria. We required a valid diagnostic interview because unassisted clinician diagnoses have poor reliability
Eligible articles for Key Question #3 were RCTs that compared depression outcomes between cancer patients who underwent depression screening and those who did not. We searched for both screening studies that included the provision of comprehensive depression care for patients with depression as part of the screening program and studies that screened patients, but did not provide such care. Changes in rates of depression recognition and treatment were noted, but not included as depression outcomes. This is because increased treatment without improved depression outcomes would expose patients to costs and potential harms without benefit. Screening was defined per the UK National Screening Committee's definition
Two investigators independently reviewed articles for eligibility. If either deemed an article potentially eligible based on title/abstract review, then a full-text review was completed. Disagreements after full-text review were resolved by consensus.
Two investigators independently extracted and entered data into a standardized spreadsheet (see
In studies included for Key Question #1 (diagnostic accuracy), for each screening instrument, sensitivity, specificity, positive predictive value, and negative predictive value with 95% confidence intervals (CIs)
Eligible studies for each key question were evaluated to determine whether there was sufficient clinical and methodological similarity to support pooling of results. For Key Question #1, studies were heterogeneous in terms of patient samples, screening tools and cutoffs, criterion standards, and whether they used
A review protocol was not published or registered for this study. However, a protocol was followed for searching, data extraction, and data synthesis with all methods determined
The database search for Key Questions #1 (diagnostic accuracy) and #3 (screening) generated 2,302 unique citations (
The 19 studies reviewed included 8 studies of breast cancer patients
First Author, Year | Country | Cancer Site/Description | N | Mean Age (Years) | Males (%) | N (%) Major Depression |
Akechi |
Japan | Mixed/Terminal | 209 | 61 | 66 | 14 (7%) |
Alexander |
UK | Breast/Stage I–IIb (disease-free) | 200 | 58 | 0 | 18 (9%) |
Coyne |
USA | Breast/Stage I–IV (Total Sample) |
113 | 56 | 0 | 10 (9%) |
Breast/Stage I–IV (Excluding Treated MDD/GAD) |
103 | 56 |
0 | 3 (3%) | ||
Grassi |
Italy | Mixed/Local, loco-regional, or metastatic | 79 | 57 |
24 |
14 (18%) |
Hopwood |
UK | Breast/Advanced | 81 | NR | 0 | 16 (20%) |
Houts |
USA | Mixed/NR | 42 | 55 | 26 | 17 (40%) |
Krespi Boothby |
UK | Breast/Early | 255 | 58 | 0 | 22 (9%) |
Kugaya |
Japan | Mixed/NR | 128 | 61 | 63 | 17 (13%) |
Lloyd-Williams |
UK | Mixed/Life-expectancy <6 months | 100 | 57 | 44 | 22 (22%) |
Lloyd-Williams |
UK | Mixed/Life-expectancy <6 months | 246 | 62 | 43 | 74 (30%) |
Love |
Australia | Breast/Stages I–IIb (excluding T3, N0, M0) | 303 | NR | 0 | 29 (10%) |
Love |
Australia | Breast/Stage IV | 227 | 52 | 0 | 16 (7%) |
Meyer |
UK | Mixed/Terminal | 45 | NR | 42 | 9 (20%) |
Murphy |
UK | NR/Advanced metastatic cancer in palliative care | 16 | 68 | 50 | 6 (38%) |
Özalp |
Turkey | Breast/Mixed | 204 | 51 | 0 | 17 (8%) |
Passik |
USA | Mixed/NR | 60 | 58 | 47 | 24 (40%) |
Patel |
Australia | Breast/Mixed (excluding Stage IV) | 100 | 53 | 0 | 8 (8%) |
Smith |
UK | Mixed/NR | 381 | 56 | 50 | 40 (10%) |
Walker |
UK | Mixed/Mixed | 361 | 62 | 24 | 30 (8%) |
Abbreviations: GAD = General Anxiety Disorder; MDD = Major Depressive Disorder; NR = Not reported; UK = United Kingdom; USA = United States of America.
Study reported diagnostic accuracy data for all 113 women in the study, and also after excluding women with MDD already treated with antidepressants and women with GAD already treated with antidepressants or anxiolytics (N = 103).
Mean age based on all 113 women in the study.
Demographic data are based on full study sample of 109 patients, rather than the 79 patients included in the analyses reported in the table. The authors excluded 30 patients with anxiety or adjustment disorders, but not MDD, from diagnostic accuracy analyses.
First Author, Year | Country | Major Depression Criterion Standard | Instrument/Cutoff | Derivation of Cutoff | Sensitivity % (95% CI) | Specificity % (95% CI) | Positive Predictive Value % (95% CI) | Negative Predictive Value % (95% CI) |
Akechi |
Japan | SCID | 1 item, “Depressed? |
NA | 79 (52–92) | 92 (87–95) | 41 (25–59) | 98 (95–99) |
1 item, “Lost interest?” |
NA | 93 (68–99) | 92 (87–95) | 45 (28–62) | 99 (97–100) | |||
1 item, “Depressed” or “Lost Interest?” |
NA | 100 (78–100) | 86 (81–90) | 34 (22–49) | 100 (98–100) | |||
HADS ≥17 | Exploratory | 71 (45–88) | 77 (71–83) | 19 (10–31) | 97 (93–99) | |||
HADS-D ≥9 | Exploratory | 86 (60–96) | 69 (62–75) | 17 (10–27) | 99 (95–100) | |||
Alexander |
UK | SCID | EPDS ≥13 | Literature | 72 (49–88) | 90 (85–94) | 42 (26–59) | 97 (93–99) |
HADS-D ≥11 | Literature | 50 (29–71) | 97 (94–99) | 64 (39–84) | 95 (91–97) | |||
Coyne |
USA | SCID | HSCL-25 ≥44 |
Literature | 70 (40–89) | 75 (66–82) | 21 (11–38) | 96 (90–99) |
HSCL-25 ≥44 |
Literature | 67 (21–94) | 74 (65–82) | 7 (2–23) | 99 (93–100) | |||
Grassi |
Italy | CIDI | DT ≥5 | Exploratory | 79 (52–92) | 83 (72–90) | 50 (31–69) | 95 (86–98) |
HADS ≥15 | Exploratory | 86 (60–96) | 95 (87–98) | 80 (55–93) | 97 (89–99) | |||
Hopwood |
UK | CIS | HADS-D ≥11 | Exploratory | 75 (51–90) | 75 (64–84) | 43 (27–61) | 92 (82–97) |
Houts |
USA | SCID | PCM Acute Distress Scale ≥61 | Exploratory | 100 (82–100) | 84 (65–94) | 81 (60–92) | 100 (85–100) |
PCM Despair Scale ≥63 | Exploratory | 94 (73–99) | 84 (65–94) | 80 (58–92) | 95 (78–99) | |||
Krespi Boothby |
UK | SADS | HADS-D ≥7 | Exploratory | 77 (57–90) | 87 (82–91) | 36 (24–50) | 98 (95–99) |
GHQ-12 ≥4 | Exploratory | 77 (57–90) | 82 (77–86) | 29 (19–41) | 97 (94–99) | |||
Kugaya |
Japan | SCID | HADS ≥20 | Exploratory | 82 (59–94) | 96 (91–99) | 78 (55–91) | 97 (92–99) |
HADS-D ≥11 | Exploratory | 82 (59–94) | 96 (90–98) | 74 (51–88) | 97 (92–99) | |||
HADS-A ≥8 | Exploratory | 94 (73–99) | 88 (80–92) | 53 (36–70) | 99 (94–100) | |||
Lloyd-Williams |
UK | PSE | HADS ≥19 | Exploratory | 68 (47–84) | 67 (56–76) | 37 (24–52) | 88 (77–94) |
HADS-D ≥11 | Exploratory | 55 (35–73) | 74 (64–83) | 38 (23–55) | 85 (75–92) | |||
HADS-A ≥10 | Exploratory | 59 (39–77) | 68 (57–77) | 34 (21–50) | 85 (75–92) | |||
EPDS ≥13 | Exploratory | 82 (61–93) | 79 (69–87) | 53 (37–69) | 94 (85–98) | |||
Lloyd-Williams |
UK | PSE | EPDS ≥12 | Exploratory | 72 (60–81) | 74 (67–80) | 54 (44–64) | 86 (79–91) |
Brief EPDS ≥6 | Exploratory | 72 (60–81) | 83 (77–88) | 65 (54–74) | 87 (81–91) | |||
Love |
Australia | MILP | HADS-D ≥11 | Literature | 7 (2–22) | 98 (95–99) | 25 (7–59) | 91 (87–94) |
Love |
Australia | MILP | HADS-D ≥7 | Exploratory | 81 (57–93) | 80 (74–85) | 24 (14–36) | 98 (95–99) |
BDI-SF ≥5 | Exploratory | 94 (72–99) | 63 (56–69) | 16 (10–25) | 99 (96–100) | |||
Meyer |
UK | SCID | MEQ ≥90 | Literature | 56 (27–81) | 94 (82–98) | 71 (36–92) | 89 (76–96) |
Murphy |
UK | SCID | EPDS ≥13 | Literature |
67 (30–90) | 100 (72–100) | 100 (51–100) | 83 (55–95) |
Özalp |
Turkey | SCID | HADS ≥17 | Exploratory | 71 (47–87) | 80 (74–85) | 24 (15–38) | 97 (93–99) |
HADS-D ≥5 | Exploratory | 88 (66–97) | 59 (52–66) | 16 (10–25) | 98 (94–100) | |||
HADS-A ≥7 | Exploratory | 65 (41–83) | 69 (62–75) | 16 (9–26) | 96 (91–98) | |||
Passik |
USA | MINI | ZSDS ≥48 | Literature/ Exploratory |
67 (47–82) | 86 (71–94) | 76 (55–89) | 79 (64–89) |
BZSDS ≥22 | Literature/ Exploratory |
96 (80–99) | 42 (27–58) | 52 (38–66) | 94 (72–99) | |||
Patel |
Australia | CIDI | BC-VI ≥2 | Exploratory | 88 (53–98) | 59 (48–69) | 17 (8–30) | 98 (90–100) |
HADS-D ≥8 | Literature | 17 (3–56) | 94 (87–98) | 20 (4–62) | 93 (85–97) | |||
PSYCH-6 ≥2 | Literature | 80 (38–96) | 68 (56–78) | 15 (6–34) | 98 (89–100) | |||
Smith |
UK | SCAN / PSE | HADS-D ≥7 | Exploratory | 73 (57–84) | 64 (59–69) | 19 (14–26) | 95 (92–97) |
HADS-D minus misfitting items ≥5 | Exploratory | 70 (55–82) | 60 (55–65) | 17 (12–24) | 94 (91–97) | |||
Walker |
UK | SCID | HADS ≥15 | Exploratory | 87 (70–95) | 85 (81–88) | 34 (25–45) | 99 (96–99) |
HADS-D ≥7 | Exploratory | 90 (74–97) | 88 (84–91) | 40 (29–52) | 99 (97–100) | |||
HADS-A ≥9 | Exploratory | 87 (70–95) | 83 (79–87) | 32 (23–42) | 99 (96–99) |
Abbreviations: BC-VI = Breast Cancer - Vulnerability Index; BDI-SF = Beck Depression Inventory Short Form; BZSDS = Brief Zung Self Rating Depression Scale; CIDI = Composite International Diagnostic Interview; CIS = Clinical Interview Schedule; DT = Distress Thermometer; EPDS = Edinburgh Postnatal Depression Scale; GHQ = General Health Questionnaire; HADS = Hospital Anxiety and Depression Scale total score; HADS-A = Anxiety subscale of Hospital Anxiety and Depression Scale; HADS-D = Depression subscale of Hospital Anxiety and Depression Scale; HSCL-25 = 25-item version of the Hopkins Symptom Checklist; MILP = Monash Interview for Liaison Psychiatry; MINI = Mini-International Neuropsychiatric Interview; NA = Not applicable; PCM = Patient Care Monitor; PSE = Present State Examination; PSYCH-6 = 6-item subscale measuring symptoms of depression and anxiety from the Somatic and Psychological Health Report (SPHERE); SADS: Schedule for Affective Disorders and Schizophrenia; SCAN = Schedule for Clinical Assessment in Neuropsychiatry; SCID = Structured Clinical Interview for DSM; ZSDS = Zung Self Rating Depression Scale.
Items were embedded in the diagnostic interview, and at least 1 of 2 was required for a diagnosis of major depression.
Study reported diagnostic accuracy data for all 113 women in the study (first line), and also after excluding women with MDD already treated with antidepressants and women with GAD already treated with antidepressants or anxiolytics (N = 103; second line).
A cutoff of 13 or greater on the EPDS is standard, although the authors did not indicate this explicitly.
Authors used several different cutoffs from the literature and tested to determine optimal cutoff in their sample.
There were 6 studies
As shown in
QUADAS Items |
|||||||||||
First Author, Year | #1 Patient Spectrum |
#2 Selection Criteria Clear | #4 Timing of Ref and Index Tests |
#5 Whole Sample Received Ref Test | #6 All Patients with Same Ref Test | #7 Ref Indep of Index Test | #8 Index Test Descrip | #9 Ref Test Descrip | #11 Ref Interpret Blind to Index | #13 Missing Data |
#14 Study With-drawals |
Akechi |
No | Yes | Yes | Yes | Yes | Yes (HADS) No (single item) | Yes | Yes | Unclear (HADS) No (single item) | Unclear | No |
Alexander |
No | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Yes |
Coyne |
Yes | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Unclear |
Grassi |
No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | No |
Hopwood |
No | Yes | Unclear | No | Yes | Yes | Yes | No | Yes | Unclear | Yes |
Houts |
No | No | Yes |
Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Yes |
Krespi Boothby |
No | Unclear | Yes | Yes | Yes | Yes | Yes | No | Yes | Unclear | No |
Kugaya |
No | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | No |
Lloyd-Williams |
Yes | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Yes |
Lloyd-Williams |
No | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Yes |
Love |
No | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Unclear |
Love |
No | Yes | Unclear | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Unclear |
Meyer |
No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Yes |
Murphy |
No | Unclear | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Yes |
Özalp |
No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Unclear | Yes |
Passik |
No | No | Unclear | Yes | Yes | Yes | Yes | Yes | No | Unclear | Yes |
Patel |
No | Yes | No |
Yes | Yes | Yes | Unclear | Yes | Unclear | Unclear | Yes |
Smith |
No | No | Yes | Unclear | Yes | Yes | Yes | Yes | Unclear | Unclear | Unclear |
Walker |
No | Yes | No | Yes | Yes | Yes | Yes | Yes | Unclear | Unclear | Yes |
See
Item #1 scored ‘no’ if patients with already diagnosed or treated depression were not excluded from study sample as they would not constitute newly identified cases in clinical practice. Studies were not downgraded for only sampling one type or stage of cancer.
Item #4 scored ‘yes’ if index test and reference standard were administered within 1 week of each other, ‘no’ if longer, and ‘unclear’ if not specified. Studies in which a significant number of patients received assessments more than 2 weeks apart were not included in the systematic review.
Item #13 originally was “Were uninterpretable, indeterminate or intermediate test results reported?” This item was adapted as “Were missing data on the index test handled correctly?”.
Authors clarified that most patients received the index test and reference standard on the same day and all within 5 days.
Authors clarified that 67% of interviews were conducted within one week and 93% within 2 weeks.
For Key Question #2, 2,923 unique citations were identified. As shown in
First Author,Year | Study Funding Source | Cancer Site/Description | Treatment vs. Control | Number of Patients Randomized | Mean Age (Years) | Males (%) |
Strong |
Non-Industry | Mixed/Mixed | Nurse Intervention vs. UC | Total: 200; Tx: 101; UC: 99 | Total: 57; Tx: 57; UC: 57 | Total: 30%; Tx: 31%; UC: 28% |
Abbreviations: Tx = treatment; UC = usual care.
First Author,Year | Number (%) Lost to Follow-up | Treatment Duration | Depression Outcomes |
|||
Remission: |
Response: |
Primary Outcome: Hedges's |
Secondary Outcome(s): Hedges's |
|||
Strong |
Total: 4 (2%); Tx: 0 (0%); UC: 4 (4%) | Mean of 7 sessions over 3 months | (a) Tx |
(a) Tx |
NR |
Abbreviations: CI = confidence interval; NR = not reported; RR = relative risk ratio; SCL-20 depression = depression subscale derived from the Symptom Checklist-90; Tx = treatment; UC = usual care.
Depression outcomes were assessed at the end of the treatment period. Continuous outcomes that favored the treatment group are reported in this table as positive numbers.
Remission defined as (a) <0.75 on the SCL-20 and (b) no longer having major depression based on the SCID-IV.
Response defined as a 50% reduction in SCL-20 score from baseline.
Publication included remission and response data for 97 patients in the intervention group and 99 in the usual care group. In this table, patients lost to follow-up are counted as non-remitters and non-responders.
Publication included remission data for 96 patients in the intervention group and 98 in the usual care group. In this table, patients lost to follow-up are counted as non-remitters.
Unadjusted effect size
Cochrane Risk of Bias Tool Items |
|||||||
First Author, Year | #1 Sequence Generation | #2 Allocation Concealment | #3 Blinding | #4 Incomplete Outcome Data | #5 Selective Outcome Reporting | #6 Other Sources of Bias | #7 Overall Risk of Bias Rating |
Strong |
low | low | uncertain | low | low | low | low |
See
Of 2,302 unique titles/abstracts from the database search, 5 were selected for full-text review, and no RCTs of depression screening met review eligibility criteria (
A number of other studies (see
One of the most important functions of systematic reviews is to identify areas where there is not sufficient evidence and where clinical trials are needed
As described in well-established criteria for evaluating the potential benefit of screening programs
With respect to the accuracy of depression screening tools in cancer settings, most studies that we reviewed used exploratory methods that identify cutoff scores that maximize diagnostic accuracy in a particular sample. These methods tend to yield inflated estimates of screening accuracy that do not replicate consistently in other samples
With respect to depression treatment, we identified 1 high-quality RCT of a nurse-delivered collaborative care intervention for MDD
The nurse-delivered collaborative care intervention trial reported by Strong et al.
Depression screening is only useful to the degree that it leads to improved outcomes above and beyond existing care. Thus, to be successful, a screening program would need to identify a meaningful number of patients as depressed out of those who have opted not to utilize available psychosocial supports; successfully enroll those patients in treatment; and achieve positive treatment results. As illustrated by one study from Germany
As described in the recently updated NICE guidelines for depression care in general medical settings, it should not be assumed that screening programs would necessarily meet currently unmet care needs. The NICE guidelines noted a lack of evidence for benefit from depression screening and, therefore, rather than routine screening of all patients, recommended strategies to identify depression among high-risk groups of patients or patients otherwise identified by physicians as possibly having depression
Based on existing evidence from other patient groups, it is clear that screening without comprehensive systems for depression assessment and management does not improve depression outcomes. There are at least 11 trials in primary care
In the absence of demonstrated benefit, potential harms from depression screening for cancer patients should be considered carefully, as outlined in standard evaluative frameworks
In summary, this systematic review did not identify any RCTs that compared the benefits versus harms of depression screening in patients with cancer. In the absence of such RCTs, there currently is not evidence to support recommendations for the incorporation of routine depression screening into standard cancer care. Depression treatment appears to be as effective in cancer care as in other settings, but important limitations in the evidence base on screening tools in this population were identified, and research is needed to address these limitations. In order to inform health care providers who must decide whether or not to screen cancer patients for depression and developers of guidelines for cancer care, well-designed and executed RCTs that investigate depression screening programs are needed. Specifically, screening for depression in a cancer treatment setting should be tested in a trial where all patients identified as depressed via screening or by physician recognition and referral in a control group have access to high-quality, integrated depression care. Given the current absence of evidence on the effectiveness of screening in cancer, and the absence of positive results from any trial in other patient groups, however, recommendations for depression screening among patients with cancer are at this point premature.
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We would like to thank Ms. Yue Zhao, MSc, Concordia University, Montréal, Québec, Canada, for assistance with translation; Mr. Sietse Dijk, Interdisciplinary Center for Psychiatric Epidemiology, University Medical Center Groningen, University of Groningen, The Netherlands, for assistance with article retrieval; and Ms. Cathryn Griffiths, Jewish General Hospital, Montréal, Québec, Canada, for proofreading the manuscript. They were not compensated for their contributions.