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Is remission of depressive symptoms in primary care a realistic goal? A meta-analysis Dawson, Marliese Y; Michalak, Erin E; Waraich, Paul; Anderson, J E; Lam, Raymond W Sep 7, 2004

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ralssBioMed CentBMC Family PracticeOpen AcceResearch articleIs remission of depressive symptoms in primary care a realistic goal? A meta-analysisMarliese Y Dawson1, Erin E Michalak1, Paul Waraich2, J Ellen Anderson3 and Raymond W Lam*1Address: 1Division of Clinical Neuroscience, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1, 2Division of Mental Health Services, Department of Psychiatry, Universityof British Columbia, 2250 Wesbrook Mall, Vancouver, BC, Canada V6T 1W6 and 3Family Physician, 6625B Sooke Road, Sooke, BC, Canada V0S 1N0Email: Marliese Y Dawson - mdawson@interchange.ubc.ca; Erin E Michalak - emichala@interchange.ubc.ca; Paul Waraich - waraich@interchange.ubc.ca; J Ellen Anderson - jeanderson@telus.net; Raymond W Lam* - r.lam@ubc.ca* Corresponding author    AbstractBackground: A primary goal of acute treatment for depression is clinical remission of symptoms.Most meta-analyses of remission rates involve randomized controlled trials (RCTs) using patientsfrom psychiatric settings, but most depressed patients are treated in primary care. The goal of thisstudy was to determine remission rates obtained in RCTs of treatment interventions for MajorDepressive Disorder (MDD) conducted in primary care settings.Methods: Potentially relevant studies were identified using computerized and manual searchstrategies up to May 2003. Criteria for inclusion included published RCTs with a clear definition ofremission using established outcome measures.Results: A total of 13 studies (N = 3202 patients) meeting inclusion criteria were identified.Overall remission rates for active interventions ranged between 50% and 67%, compared to 32%for pill placebo conditions and 35% for usual care conditions.Conclusions: Remission rates in primary care studies of depression are at least as high as for thosein psychiatric settings. It is a realistic goal for family physicians to target remission of symptoms asan optimal outcome for treatment of depression.BackgroundMajor depressive disorder (MDD) is one of the most com-mon and disabling of medical conditions [1]. The Cana-dian Community Health Survey recently reported a one-year prevalence rate of 4.5% for MDD, indicating that over1.1 million Canadians suffer significant distress andimpairment in function due to depression [2]. The eco-medical condition contributing to global burden of dis-ease, and is estimated to rise to second overall by the year2010 [4].There are many effective treatments for MDD, includingpsychotherapy and antidepressants. Traditionally, efficacyin randomized controlled trials (RCTs) for depression hasPublished: 07 September 2004BMC Family Practice 2004, 5:19 doi:10.1186/1471-2296-5-19Received: 07 April 2004Accepted: 07 September 2004This article is available from: http://www.biomedcentral.com/1471-2296/5/19© 2004 Dawson et al; licensee BioMed Central Ltd. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 6(page number not for citation purposes)nomic costs of depression are estimated at over $5 billionannually [3]. Depression is currently the fourth-rankedbeen determined on the basis of score changes in ratingscales such as the Hamilton Depression Rating ScaleBMC Family Practice 2004, 5:19 http://www.biomedcentral.com/1471-2296/5/19(HDRS) [5] or the Montgomery-Asberg Depression RatingScale (MADRS) [6]. Clinical outcome has been usuallyassessed by clinical response rates, typically defined as a50% or greater reduction from baseline scores on theserating scales [7]. Although obtaining clinical response rep-resents an important therapeutic milestone, it does notnecessarily indicate a complete recovery from MDD, sincemany patients with clinical response will still be left withsubstantial residual symptoms of depression. Studies haveshown that the presence of residual symptoms after anepisode of MDD is associated with higher risk of relapse,recurrence, chronicity, suicide, development of cardiovas-cular disease, and poor quality of life [8-10].Such findings suggest that the goals of acute treatment(approximately the first 8–12 weeks or so of treatment)for MDD should be clinical remission, a clinical state dis-tinguished by minimal residual symptoms, rather thanjust response [11-13]. Clinical remission is typicallydefined as a score within the normal range on a given out-come measure (e.g., 17-item HDRS score of 7 or less;MADRS score of 12 or less; Clinical Global Impression[CGI] [14] severity score of "Normal, not at all ill"),although there is still some uncertainty as to the validityof these cutoff scores for symptom remission [15]. Theachievement of remission is of considerable clinicalimportance as it predicts decreased risk of relapse andgreater psychosocial functioning than typically observedin patients who have achieved clinical response alone [16-18]. Clinical remission is now identified and promoted asa clinical target for successful management of MDD inmany clinical practice guidelines [13,19-21].Increasing numbers of treatment studies are now explic-itly reporting both clinical response and remission rates inassessment of outcome. A meta-analysis of 8 antidepres-sant studies of venlafaxine versus selective serotoninreuptake inhibitors [SSRIs] and placebo reported meanremission rates of 45%, 35%, and 25%, respectively [22].A subsequent meta-analysis of 32 RCTs comparing venla-faxine, SSRIs and other antidepressants reported a meanoverall remission rate of 42% [23]. Finally, a meta-analy-sis of 6 RCTs comparing antidepressants and psychother-apy in patients with MDD reported mean remission ratesof 46% for each treatment [24].All the studies in these systematic reviews involvedpatients in psychiatric or mixed settings. However, mostpeople suffering from MDD will be managed in the pri-mary care setting [25]. Approximately 5% to 10% of allpatients consulting a general practitioner have MDD, withprevalence estimates being two to three times higherwhen other depressive disorders (i.e., minor depression orextrapolated to primary care environments, although it isof clinical importance for primary care physicians to knowwhether obtaining remission is a realistic goal for theirpatients. There has been a recent surge in studies assessinga variety of treatment interventions for depression in pri-mary care settings, making this an opportune time to per-form a meta-analysis to address this question. Hence, theprimary objective of this study was to determine remis-sion rates obtained in RCTs of treatment interventions forMDD conducted in primary care settings.MethodsPotentially relevant studies were identified using compu-terized and manual search strategies. The computerizedsearch conducted in June, 2003 included the databases:Medline, Psych Info, Embase, Biosis, Cochrane Databaseof Systematic Reviews, and Cochrane Controlled TrialsRegister and Current Controlled Trials (1981–May 2003).The search terms used were 'depressive disorder' or'depression' combined with 'primary care' and 'remission'and/or variants. The bibliographies of relevant articleswere also manually searched. Two reviewers (MYD andRWL) collected and independently assessed abstracts forinclusion criteria. Disagreements were resolved withconsensus.Inclusion criteriaStudies were included if they were RCTs with original datacomparing one or more interventions (e.g., antidepres-sant vs. cognitive behavioral therapy) and published inEnglish. Only studies of predominantly adult popula-tions, as opposed to exclusively child or elderly patientpopulations, were included. Although the focus was prin-cipally upon patients with MDD (studies primarily deal-ing with minor depression and dysthymia were excluded),the criteria for a diagnosis of MDD was intentionallybroad in order to capture the heterogeneity of the sampleand allow the results to be as generalizable as possible.Included studies also had to use a standardized outcomemeasure (e.g., HDRS, MADRS, Beck Depression Inventory[BDI] [27]) and provide explicit criteria for remission.While the definition of remission varied among the stud-ies (Table 1), for the purpose of this meta-analysis weaccepted each study's definition of remission, which usu-ally was a score within the normal range on the outcomemeasure.Data extractionTwo independent reviewers (MYD and EEM) extracteddata from studies using a checklist developed for thisstudy, with disagreements resolved by a third reviewer(RWL). A conservative measure of remission rate was cal-culated from each study using an intent-to-treat analysisPage 2 of 6(page number not for citation purposes)dysthymia) are included [26]. It remains unclear whetherthe remission rates reported in psychiatric settings can be[28], even if this method was not used in the study. Forexample, some studies calculated remission rates usingBMC Family Practice 2004, 5:19 http://www.biomedcentral.com/1471-2296/5/19Table 1: Summary of included studies in meta-analysis of remission rates.Study Diagnostic CriteriaFollow up PeriodRemission CriteriaTotal N Intervention Intervention Remission RateRemission %Psychological Intervention OnlyDowrick et al., 2000 [31]DSM-IV criteria for MDD or Adjustment Disorder6 months No MDD detected by SCAN interview425 • PST• Usual Care•Prevention course• 58/128• 76/189• 44/108• 45• 38• 41Antidepressant Intervention OnlyBenkert et al., 2000 [32]DSM-IV criteria for MDD and HDRS ≥ 186 weeks HDRS ≤ 7 275 • Mirtazapine• Paroxetine• 52/139• 42/136• 37• 31Patris et al.,1996 [33] DSM-IIIR criteria for MDD8 weeks MADRS ≤ 12 357 • Citalopram• Fluoxetine• 114/173• 110/184• 66• 60Wade et al., 2002 [34]DSM-IV criteria for MDD8 weeks MADRS ≤ 12 380 • Escitalopram• Placebo• 92/191• 64/189• 48• 34Psychological Intervention + AntidepressantsChilvers et al., 2001 [35]Diagnosed as MDD by GP12 months RDC <4, BDI <10, or clear documentation in GP notes that patient is well103 Randomised only:• Antidepressant• Counselling• 39/51• 33/52• 76• 63Mynors-Wallis et al., 1995 [36]Diagnosed as MDD by GP12 weeks HDRS ≤ 7 or BDI ≤ 891 • PST• Amitriptyline• Placebo• 18/30• 16/31• 8/30• 60• 52• 27Mynors-Wallis et al., 2000 [37]RDC criteria for MDD12 months HDRS ≤ 8 151 • PST-group•PST-RN• Antidepressant• PST+antidepressant• 24/39• 23/41• 20/36• 23/35• 62• 56• 56• 66Schulberg et al., 1998 [38]DSM-IIIR criteria for MDD8 months HDRS ≤ 7 184 • IPT• Nortriptyline• 49/93• 52/91• 57• 53Scott et al., 1992 [39] DSM-IIIR criteria for MDD4 months HDRS ≤ 7 121 • CBT• Counselling• Amitriptyline• Usual care• 12/30• 22/30• 18/31• 14/30• 40• 73• 58• 47Program InterventionsKaton et al.,1999 [40] Diagnosed as MDD by GP6 months Presence of 0 or 1 SCID-assessed symptoms228 • Collaborative care• Usual Care• 50/114• 35/114• 44• 31Katzelnick et al., 2000 [41]Diagnosed as MDD by GP and HDRS ≥ 1512 months HDRS ≤ 7 407 • Depression management• Usual care• 92/218• 49/189• 42• 26Kutcher et al., 2002 [42]Diagnosed as MDD by GP29 weeks 8 weeks or longer with HDRS ≤ 10269 • Sertraline• Sertraline + adherence program• 84/138• 88/131• 61• 67Rost et al., 2002 [43] Diagnosed as MDD by GP24 months CES-D ≤ 16 211 • Enhanced depression care• Usual care• 85/115• 39/96• 74• 41(Abbreviations: BDI – Beck Depression Inventory, CBT – Cognitive Behavioural Therapy, CES-D – Centre for Epidemiological Studies – Depression Scale, HDRS – Hamilton Depression Rating Scale, HSCL-D-20 – 20-item Hopkins Symptom Check List, IPT-Interpersonal Psychotherapy, MADRS – Montgomery-Asberg Depression Rating Scale, MDD – Major Depressive Disorder, PST – Problem Solving Therapy, PST-PC – Problem Solving Therapy, administered by Primary Care Physician, PST-RN – Problem Solving Therapy, administered by Registered Nurse, RDC – Research Diagnostic Criteria, SCAN – Schedules of Clinical Assessment in Neuropsychiatry, SCID – Structured Clinical Interview for DSM-III-R.)Page 3 of 6(page number not for citation purposes)BMC Family Practice 2004, 5:19 http://www.biomedcentral.com/1471-2296/5/19only patients who returned for one follow-up visit post-randomization, or who had completed a course of treat-ment. The denominator used for remission rate was thetotal number of patients randomized to treatment,whether or not they were counted in the ensuing analysis.The numerator was the number of patients in remissionreported in the study, regardless of the denominator usedin the study analysis.The type of intervention was classified as placebo, "usualcare" by clinician (standard treatment by a patient's ownphysician), psychotherapy treatment only, antidepressanttreatment only, psychotherapy plus antidepressant treat-ment, or program intervention (e.g., collaborative careusing other health professionals; educational programstargeted at quality improvement for prescribing practices).StatisticsEach set of rates was pooled based on a Bayesian approachto meta-analysis using the Fastpro software program (ver-sion 1.7) by Eddy and Hasselblad. Readers interested in amore detailed discussion of this approach should refer toEddy et al [29]. The pooled means and confidence inter-vals were calculated using Jeffrey's prior and a randomeffects model.ResultsThe initial electronic and bibliographic search found 63articles of which 47 warranted more detailed review basedon the published abstract. Of these, 34 articles wereexcluded due to methodology (not RCTs, 4 studies), lackof remission criteria (18 studies), diagnostic criteria (notMDD, 11 studies) and age criteria (geriatric, 4 studies)(some studies were excluded for multiple reasons, seeAdditional File 1). A final count of 13 studies met the fullinclusion criteria (Table 1). In total, 3202 primary careoutpatients (75% female, 25% male) were included in theanalysis. The mean age of the participants was 32.1 years(range 18–73 years). The average length of follow-up was32 weeks (range 6–104 weeks).The study interventions and methodologies were too het-erogeneous to allow for a meaningful statistical compari-son of results between treatments. Figure 1 shows meanremission rates for specific interventions. Overall remis-sion rates for active interventions, regardless of type,ranged between 50% and 67%, compared to 32% for pillplacebo conditions and 35% for usual care conditions.There were a sufficient number of antidepressant arms inthe studies to permit the summary of remission rates byduration of follow-up period. For antidepressant studieswith follow-up of 6 months or less, mean remission ratewas 51.4% (95% C.I., 43.1%–59.6%); for antidepressantDiscussionThis review of research assessing remission of depressivesymptoms in primary care populations identified 13 stud-ies meeting the inclusion criteria. Overall remission rates(regardless of type of intervention but excluding placeboor usual care arms) ranged between 50% and 67%. Theserates are equivalent to, or indeed greater than, thosereported in meta-analyses of studies examining pharma-cological or psychological interventions for depression inpsychiatric populations, in which the overall remissionrates ranged between 35% and 46% [22-24]. On the onehand, we might have predicted this finding as studies con-ducted in primary care settings tend to include morepatients with mild to moderate depression (although weexcluded studies that focused exclusively upon minordepression or dysthymia), whereas patients referred topsychiatric settings are more likely to have moderate tosevere depression. Primary care treatment trials also tendto be longer, favouring a higher remission rate; whereasthe mean follow-up period of studies included in the cur-rent analysis was 9 months, it was only 7 weeks and 10weeks in the two previous meta-analyses of pharmacolog-ical interventions for MDD [22,23], and 16 weeks in themeta-analysis of antidepressant versus psychotherapeuticinterventions [24]. Conversely, we might have predictedRemission rates for specific treatment conditions from rand-omized controlled trials (RCTs) of i erventions for depres-sion in prim ry care sett ngsFigure 1Remission rates for specific treatment conditions from rand-omized controlled trials (RCTs) of interventions for depres-sion in primary care settings. The white lines represent the mean remission rates and the boxes represent the 95% con-fidence interval. N is the number of treatment arms in the RCTs (Note: Psychotx = Psychotherapy, Antidepr = Antide-pressants, pts = patients).UsualCareN=5 arms(618 pts)020406080100PlaceboConditionsN=2 arms(219 pts)Remission Rate %PsychotxOnlyN=9 arms(551 pts)AntideprOnlyN=11 arms(1201 pts)ProgramInterventionsN=4 arms(578 pts)Psychotx+ AntideprN=1 arm(35 pts)Page 4 of 6(page number not for citation purposes)studies with greater than 6 months of follow-up, meanremission rate was 62.3% (95% C.I., 48.9%–74.8%).that we would observe lower remission rates in the currentmeta-analysis as it included a number of studies withBMC Family Practice 2004, 5:19 http://www.biomedcentral.com/1471-2296/5/19more lenient exclusion criteria than typically used in psy-chiatric clinical trials. In particular, the program interven-tion studies tend to include more heterogeneous patientpopulations as they do not routinely exclude patients withpsychiatric or medical comorbidities, factors that maylessen the likelihood of obtaining remission of depressivesymptoms [30].While it was not within the scope of the current study tocompare the effectiveness of different treatment interven-tions in improving remission rates, we can report on thetrends we observed in the data. Antidepressant and psy-chotherapy interventions delivered in isolation showedsimilar remission rates (54% for both). Combinationantidepressant plus psychotherapy interventions showedsomewhat higher rates (67%), although this categoryincluded only 1 arm with only 35 patients. Program inter-ventions had a mean remission rate of 50%, and all treat-ment interventions fared better than either placebo (32%)or usual care (35%).The studies identified in our review were quite heteroge-neous in nature, ranging from those that looked solely atthe effects of a particular pharmacological agent, throughto complex program initiatives that incorporated a varietyof interventions at different levels of care. This heteroge-neity limits our ability to make broad comments aboutremission rates in primary care, but was not unexpected,as we wanted to capture the diversity of treatment inter-ventions for depression currently being tested in this set-ting. Other potential limitations of the study include thatfact that we only assessed published studies written inEnglish and that we used a conservative measure of remis-sion rate. Finally, we also used the definition of remissionas specified by each individual study. While these defini-tions were similar to those widely used in RCTs conductedin psychiatric settings, and thus are useful for comparison,there is current controversy about depression scales andwhich cutoff scores indicate true remission of symptoms[15].ConclusionsThis meta-analysis serves to answer an important clinicalquestion about the feasibility of obtaining remission ofsymptoms of MDD in primary care patients. Our resultsindicate that this is a realistic goal in this population,although further research is still required to determinewhether certain treatment modalities (or combinations oftreatment interventions) are superior to others in achiev-ing higher remission rates. Future research should alsofocus upon developing pragmatic strategies for generalpractitioners to implement evidence-based guidelinesconcerning the treatment of depression to clinicalAuthors' contributionsMYD and EEM conducted the data extraction, wrote theinitial draft of the manuscript, interpreted results, andrevised the manuscript. PW provided statistical consulta-tion and analysis, and revised the manuscript. JEA inter-preted the results and revised the manuscript. RWLconceived the initial idea, developed the method, inter-preted results, revised the manuscript, and providedfinancial resources for the study. All authors read andapproved the final manuscript.Competing interestsRWL is on advisory/speaker boards or has receivedresearch funds from: AstraZeneca, Biovail, Canadian Net-work for Mood and Anxiety Treatments, Eli Lilly, Glaxo-SmithKline, Janssen-Ortho, Litebook, Inc., Lundbeck,Merck, Organon, Roche, Shire, Servier, and Wyeth.Additional materialAcknowledgmentsDr. Michalak was supported by a Canadian Institutes of Health Research/Wyeth Canada Postdoctoral Fellowship Award.References1. Parikh SV, Lam RW: Clinical guidelines for the treatment ofdepressive disorders, I. Definitions, prevalence, and healthburden. Can J Psychiatry 2001, 46 Suppl 1:13S-20S.2. Statistics Canada : Canadian Community Health Survey: Men-tal health and well-being. www statcan ca/Daily/English/030903/d030903a htm, accessed November 9, 2003.3. Desjardins B, Laurier C: The burden of depression in Canada.Value in Health 2002, 5:229.4. 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BMJ 2002, 325:934.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-2296/5/19/prepubyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 6 of 6(page number not for citation purposes)British Medical Journal - Clinical Research 2000, 321:1450-1454.


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