YPMED-04035; No of Pages 6 Preventive Medicine xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Preventive Medicine journal homepage: www.elsevier.com/locate/ypmed
Review
Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review☆ Margalida Gili a,c,⁎, Caterine Vicens b,c, Miquel Roca a,c, Phil Andersen d, Dean McMillan d a
Institut Universitari d'Investigació en Ciències de la Salut, Universitat de les Illes Balears, Carretera de Valldemossa, km 7.5, 07181 Palma de Mallorca, Spain Centro de Salud Son Serra-La Vileta, Ib-Salut, Matamusinos 22, 07013 Palma de Mallorca, Spain Red de Investigación en Actividades Preventivas y Promoción de la Salud (redIAPP), Spain d Department of Health Sciences, University of York, UK. 5, York YO10 5DD, United Kingdom b c
a r t i c l e
i n f o
a b s t r a c t
Available online xxxx
Objective: A systematic review was conducted to assess the efficacy of pharmacological and psychological interventions for preventing relapse or recurrence of depression in adults with depression in primary care. Method: Papers published from inception to January 28th 2014 were identified searching the electronic databases MEDLINE, EMBASE, PsycINFO, and CENTRAL. Randomized controlled trials of any pharmacological, psychological or psychosocial intervention or combination of interventions delivered in primary care settings were included, with relapse or recurrence of a depressive disorder as a main outcome. The Cochrane Collaboration risk of bias tool was used to assess study quality. Results: Only three studies with a small number of patients fulfilled the inclusion criteria. None of the three randomized controlled trials included in our review showed a statistically significant superiority of an intervention for the prevention of depression relapse or recurrence. Conclusions: There is limited evidence to inform relapse or recurrence prevention strategies specifically in primary care. © 2014 Elsevier Inc. All rights reserved.
Keywords: Depression Primary health care Recurrence Relapse Secondary prevention
Contents Introduction . . . . . . . . . . . Methods . . . . . . . . . . . . . Eligibility criteria . . . . . . Information sources . . . . . Search . . . . . . . . . . . Study selection . . . . . . . Data extraction . . . . . . . Risk of bias in individual studies Data synthesis . . . . . . . . Results . . . . . . . . . . . . . Risk of bias within studies . . Study outcomes . . . . . . . Discussion . . . . . . . . . . . . Main findings . . . . . . . . Strengths and limitations . . . Conclusions . . . . . . . . . . . Conflict of interest statement . . . References . . . . . . . . . . . .
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☆ Funding: The project has received funding from a Network for Prevention and Health Promotion in Primary Care (redIAPP, RD12/0005) grant and a research project grant (PI12/01914) from the Instituto de Salud Carlos III (Institute of Health Carlos III) of the Ministry of Economy and Competitiveness (Spain), co-financed with European Union ERDF funds. ⁎ Corresponding author at: Institut Universitari d' Investigació en Ciències de la Salut (IUNICS), Carretera de Valldemossa, km. 7.5, Palma de Mallorca, Spain. Tel.: +34 971 173081. E-mail addresses: [email protected] (M. Gili), [email protected] (C. Vicens), [email protected] (M. Roca), [email protected] (P. Andersen), [email protected] (D. McMillan).
http://dx.doi.org/10.1016/j.ypmed.2014.07.035 0091-7435/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
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M. Gili et al. / Preventive Medicine xxx (2014) xxx–xxx
Introduction Depression is a highly prevalent and disabling disorder and a major public health concern (Kessler et al., 2003). Psychopharmacology, psychotherapy or combined treatments are well supported by evidence in the acute management of the depressive disorders (Stewart et al., 2012; Fournier et al., 2010; Cuijpers et al., 2010; Imel et al., 2008; de Maat et al., 2007). Despite the successful acute treatment of depression, the risk of relapse or recurrence remains very high (Burcusa and Iacono, 2007; Yiend et al., 2009; Harter et al., 2007; Hardeveld et al., 2010; Gopinath et al., 2007). After a first episode of depression the probability of a further episode is approximately 50%; this rises to 70% for two episodes and 90% after a third episode (Burcusa and Iacono, 2007; Kessler et al., 1996). It also appears that with each further episode there is an increase in the severity of depressive symptoms and an increased probability that the symptoms will be resistant to treatment (Kendler et al., 2000). For these reasons it has become increasingly clear that developing interventions for the prevention of relapse or recurrence in specialized mental health care and in primary care is a major concern for longterm management of depressive patients. It is relevant to differentiate between relapse and recurrence when developing treatment strategies for depression. According to expert consensus (Frank et al., 1991; Rush et al., 2006) the term relapse should be used to describe a re-emergence of symptoms in a patient who has initially responded to treatment but who is not yet in remission. Recurrence is the appearance of a new episode of depression after full remission of a previous episode has been achieved. Despite these operational definitions, the majority of published clinical trials do not precisely define relapse or recurrence. Researchers have conflated relapse and recurrence without making a clear distinction between these terms (Beshai et al., 2011). Prevention of depression has emerged as a scientific and clinical challenge of great public significance (Muñoz et al., 2012). This has included the prevention of depressive relapse or recurrence and protection from the medical, psychosocial and economic consequences of the future episodes of depression (Reynolds, 2009). Strategies for reducing relapse can be divided into the type of treatment offered (pharmacological, psychological, combination) and when that treatment is delivered (during the acute phase, after the acute phase). There is evidence that psychological treatments, such as cognitive-behavioral therapy, delivered during the acute phase have effects that endure beyond the end of it to reduce subsequent rates of relapse (Vittengl et al., 2007). In contrast, acute-phase antidepressant medication does not confer a benefit in terms of subsequent relapse if the use of medication stops at the end of the acute phase (Thase, 2006). There is, though, evidence that the continued use of antidepressants after the end of acute phase treatment does reduce the likelihood of relapse (Geddes et al., 2003). In addition, continuation-phase CBT and other approaches specifically designed to be delivered after the end of the acute phase of treatment, such as mindfulness-based cognitive therapy (MBCT), also reduce the rate of relapse (Piet and Hougaard, 2011; Vittengl et al., 2007). Increasingly, the responsibility for initial diagnosis and long-term follow-up of mental illnesses is falling on primary care services, the patient's first point of contact with the health system in the majority of the European countries (Murphy et al., 2000). Around one out of every three primary care patients presents with clinical problems related to mental health difficulties, though the figures range from 26% to 60% (Ansseau et al., 2004; Norton et al., 2007; Roca et al., 2009). While there is evidence that both pharmacological and psychological treatments can be effective in reducing relapse, the majority of the trials were performed in secondary care settings. It is difficult to generalize from such settings to primary care. There are, for example, likely to be differences between the two populations in terms of the likelihood of a relapse and the likelihood of responding to a relapse-focused treatment.
Although there have been improvements in the clinical skills of primary care physicians to detect and treat depression, there is still a long way to go in preventing relapse and recurrence of this disabling disorder and much effort must be made to improve the early identification of depressive patients at risk. We have not found a published metaanalysis or systematic review focused on prevention of relapse or recurrence of depression in primary care settings. The aim of this review is to assess the efficacy of existing pharmacological and psychological interventions for preventing relapse or recurrence of depression in adults with depression in primary care. Methods Eligibility criteria Studies that met the following inclusion criteria were included: Participants: Studies of adult participants (aged 18+) who had an episode of depression or received treatment for depression. Studies of people diagnosed with bipolar disorder were excluded. Interventions: Any pharmacological, psychological or psychosocial intervention or combination of interventions delivered in primary care settings. Interventions delivered during the acute phase or a continuation phase were eligible for inclusion, but are considered separately in the analysis. Comparator/control: Control conditions such as treatment as usual, waiting list or placebo. Outcomes: Relapse or recurrence of a depressive disorder. Study design: Randomized controlled trials (RCTs). Information sources The primary electronic databases searched were MEDLINE/PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and PsycINFO (searched from inception to 28 January 2014). References of included studies were examined to identify other potentially eligible studies. Search Searches comprised a combination of subject terms selected from the controlled vocabulary with free-text terms. These terms were developed to capture the concepts of relapse, depression, randomized trials and primary care and were combined using the Boolean AND. Study selection Three authors independently examined the titles and abstracts of all retrieved citations against the pre-specified inclusion criteria outlined above. The full text of articles passing this first sift were retrieved and examined independently by two authors against the pre-specified inclusion criteria. Disagreements were resolved through consensus and, if consensus could not be reached, discussion with an additional reviewer. The study selection process with the number of studies included and excluded at each stage of the review is documented, detailing the reasons for exclusion, using a PRISMA flowchart diagram (Fig. 1). Data extraction Two reviewers independently extracted data from the included studies. Disagreements were resolved through the same approach as described above. For each study, authors extracted the following details: study design, intervention and control group, sample characteristics, length of follow-up, outcome (including data needed to calculate effect sizes), and study quality. Risk of bias in individual studies The Cochrane Collaboration risk of bias tool (Higgins et al., 2011) was used to assess study quality. Two authors independently rated these criteria and disagreements were resolved as described above.
Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
M. Gili et al. / Preventive Medicine xxx (2014) xxx–xxx
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Studies identified N=744
Duplicate studies N=280
Studies for analysis of titles and abstracts N=464
Studies excluded based on titles and abstracts N=441
Full text articles excluded = 20 Reasons for exclusion: No RCT = 6 No primary care setting = 5 No relapse or recurrence rate as outcome = 8 No comparator as defined in the protocol = 1
Full text publications reviewed N=23
Studies included in qualitative synthesis N=3
Fig. 1. Flow-chart diagram.
Data synthesis Relative risks with associated 95% confidence intervals were calculated for the dichotomous outcome of relapse/recurrence. Studies were grouped on the basis of the intervention (psychological vs. pharmacological) and study design (treatment delivered in the acute phase vs. continuation treatment delivered after the acute phase). A meta-analysis was considered when there were at least two studies that were sufficiently similar in terms of these characteristics. Heterogeneity was assessed using the I2 statistic, with values of over 50% taken to indicate substantial heterogeneity. There were an insufficient number of studies to conduct subgroup or sensitivity analyses.
Results The electronic database search identified 744 potential records of interest and, after duplicates were removed, 464 records remained. Screening of titles and abstracts excluded 441 studies, and, finally, 23 full text articles were assessed. Three studies were judged to be eligible for inclusion in the review. The flowchart diagram is shown in Fig. 1. The main reason for exclusion was the absence of relapse or recurrence rate as an outcome of the study. Some studies measured severity of depression at follow-up, quality of life or disability after the intervention or treatment but did not specifically assess relapse rate in those who recovered. Six studies were excluded because the study design was not a randomized controlled trial and five because they were not delivered in a primary care setting. One study was excluded because it compared two pharmacological interventions without usual care or placebo as a comparator. Table 1 summarizes the reasons for exclusion for the studies for which full text articles were retrieved. Study location, design, interventions, sample size and outcomes are summarized for each included study in Table 2.
De Graaf et al. (2011) conducted a randomized trial in 303 patients with depression and allocated them to three arms:computerized cognitive-behavioral therapy (CCBT), treatment as usual (TAU) and a combination of both (CCBT + TAU). Those patients who recovered at 3 months (35 CCBT, 33 TAU and 43 CCBT + TAU) were assessed for relapse at 6, 9 or 12 months. The main outcome was an increase of at least 9 points on the Beck Depression Inventory (BDI-II). The attrition rate of this study was 11.9%. Howell et al. (2008), in a pilot study, included 110 primary care patients with depression and conducted a cluster randomized trial to Table 1 Reasons for the exclusion of studies. Study
Reason for exclusion
van Weel-Baumgarten et al. (2000) Wade et al. (2003) Gelenberg et al. (2003) Von Korff et al. (2003) Capoccia et al. (2004) Klein et al. (2004) Rapaport et al. (2004) Gonzalez Gonzalez et al. (2006) Hunkeler et al. (2006) Lang et al. (2006) Ludman et al. (2007) Keller et al. (2007) Hardeveld et al. (2010) Christensen et al. (2010) van't Veer-Tazelaar et al. (2011) Cipriani et al. (2011) Rodgers et al. (2012) Lee et al. (2012) Marques et al. (2013) Stangier et al. (2013)
Not a randomized controlled trial No comparator as defined in the protocol Not conducted in a primary care setting No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome Not conducted in a primary care setting No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome Not conducted in a primary care setting Not a randomized controlled trial Not a randomized controlled trial No relapse or recurrence rate as outcome Not a randomized controlled trial Not a randomized controlled trial Not a randomized controlled trial Not conducted in a primary care setting Not conducted in a primary care setting
Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
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Table 2 Characteristics of the included studies. Study (yr)
Design
Intervention
Groups sample size
Age
Duration of follow-up
Outcomes
Katon et al. (2001)
RCT
194 IG 192 CG
18 to 80
12 months
SCL-20 Relapse rate
Howell et al. (2008)
Cluster RCT
Intervention 2 specialist in depression visits + 3 telephone contacts Control: Usual care KBA program Control: Usual care
62 KBA 49 C
18 to 75
12 months
De Graaf et al. (2011)
RCT
35 CCBT 43 CCBT + TAU 33 TAU
18 to 65
12 months
DASS Case notes Relapse rate BDI-II Relapse rate
Computerized CBT Computerized CBT + TAU TAU
RCT: randomized controlled trial; IG: intervention group; CG: control group; SCL-20: Symptoms Check List; DASS: Depression Anxiety Stress Scale; BDI: Beck Depression Inventory Scale; KBA: Keeping the Blues Away; CCBT: computerized cognitive behavior therapy; and TAU: treatment as usual.
compare an intervention based on the Keeping the Blues Away (KBA) program (ten steps including problem solving, coping skills and other psychosocial evidence-based strategies to reduce the severity and relapse of depression) with usual care. A trained psychologist assessed depression relapse retrospectively through blinded case-note review. The attrition rate was higher in the intervention group (24.2%) than in the control group (2%). Katon et al. (2001) recruited 386 primary care patients with recurrent major depression or dysthymia from the prescriptions database who had recovered after 8 weeks of antidepressant treatment. They were randomized to a relapse prevention program (194 patients) or usual primary care (192 patients). The intervention consisted of two primary care visits with a depression specialist and three telephone calls over a one year period aimed at enhancing adherence to antidepressant medication, recognition of prodromal symptoms and development of a written relapse prevention plan. The main outcome was the Symptoms Check List (SCL-20) (Derogatis et al., 1974) at 12 months after randomization. At 12 months of follow-up 10.3% of the intervention group and 20.8% of the control group missed interviews.
Risk of bias within studies Fig. 2 shows the risk of bias assessment. All three included studies presented adequate random sequence generation but only one reported adequate allocation concealment. Because the three interventions consisted of psychological interventions, participants and personnel could not be blinded about treatment allocation so there could be a risk of bias. Outcomes were measured in a standard and reliable way. The outcome assessment was blinded in two of the three studies and was not reported in the third study. The attrition rates were reported de Graaf 2011
Howell 2008
Katon 2001
Selective reporting (reporting bias)
+
?
+
Incomplete outcome data (attrition bias)
+
+
+
Blinding of outcome assessment (detection bias)
+
+
+
Blinding of participants and personnel (performance bias)
+
+
?
Allocation concealment (selection bias)
–
–
–
+
?
?
+
+
+
Random sequence generation (selection bias)
Other bias
Fig. 2. Risk of bias assessment.
and considered acceptable in the three studies. All studies used an intention-to-treat principle for statistical analyses. Study outcomes Two of the three studies (De Graaf et al., 2011; Howell et al., 2008) included patients with depression at the time of randomization, delivered the intervention and, in those who recovered, measured relapse outcomes at follow-up. The other study randomized patients who had recovered from a major depressive disorder and delivered an intervention to prevent relapse (Katon et al., 2001). These two designs are considered separately in the analysis. Although De Graaf et al. (2011) and Howell et al. (2008) used a similar study design, heterogeneity for these two studies was substantial (I2 = 70%), so a meta-analysis was not performed. As the two interventions compared to treatment as usual in De Graaf's study were similar (CBT vs. CBT + TAU), we analyzed both groups together to calculate the effect size. The results for these two studies are summarized in Fig. 3a. As the figure indicates relapse rates were lower, but not significantly so, in the control arm of De Graaf et al. (2011), and lower, but again not significantly so, in the intervention arm of Howell et al. (2008). Fig. 3b summarizes the results for Katon et al. (2001), which identified relapse rates following an intervention delivered after the acute phase of treatment specifically designed to reduce relapse. As the figure indicates, there were no differences between the relapse rates in the intervention and control group. Discussion Main findings The main result of this systematic review is that there are few studies examining the efficacy of prevention of relapse or recurrence interventions in primary care patients with depression. We found only three studies with a small number of patients and the data are not sufficient to recommend a particular strategy for the secondary prevention of depression. None of the three randomized controlled trials included in our review showed a statistically significant superiority of an intervention for the prevention of depression relapse or recurrence. Of the three studies included, only one (Katon et al., 2001) randomized patients with recurrent depression or dysthymia during a remission state after 8 weeks of treatment. De Graaf et al. (2011) and Howell et al. (2008) included and randomized patients with acute depression, delivered the intervention in those who recovered and measured the relapse rate during the follow-up, but no more specific interventions was delivered after the acute phase of treatment. As reported before, most pharmacological interventions are conducted in psychiatric settings and, even though we did not focus on them for the review, there are a number of meta-analyses of studies including pharmacological treatment with antidepressants to prevent
Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
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a) Relapse after acute phase treatment delivered in primary carea Intervention Study or Subgroup
Events
Control
Risk Ratio
Total Events Total
Risk Ratio
M-H, Random, 95% CI
de Graaf 2011
23
78
6
33
1.62 [0.73, 3.61]
Howell 2008
13
62
15
48
0.67 [0.35, 1.27]
M-H, Random, 95% CI
0.2 0.5 1 2 5 Favours intervention Favours control
b) Relapse after relapse intervention delivered in primary care Intervention Study or Subgroup Katon 2001
Events 68
Control
Risk Ratio
Total Events Total 194
66
192
Risk Ratio
M-H, Random, 95% CI
M-H, Random, 95% CI
1.02 [0.78, 1.34] 0.2 0.5 1 2 5 Favours intervention Favours control
Fig. 3. a: Relapse after acute phase treatment delivered in primary care. b: Relapse after relapse intervention delivered in primary care.
relapse that have found lower relapse rates in treatment groups versus placebo (Geddes et al., 2003; Kaymaz et al., 2008; Glue et al., 2010). A review of guidelines recommendations for long-term treatments did not found evidence for maintenance treatment with antidepressants in PC patients (Piek et al., 2010). In a meta-analysis of 28 studies on cognitive-behavioral therapies (CTs) to prevent relapse–recurrence of depression, among acutephase treatment responders, continuation-phase CT reduced relapse– recurrence compared with assessment only or with other active continuation treatments at the end of continuation treatment and at follow-up (Vittengl et al., 2007). In a review of empirical studies targeting the effects of psychotherapy in relapse or recurrence in depressive patients, a consistent finding has been that preventive cognitive-behavioral therapy and mindfulness-based therapies are most effective for patients with three or more previous depressive episodes (Beshai et al., 2011). Future research needs to be focused in shorter psychotherapeutical interventions to be delivered at PC centers. In a meta-analysis of the enduring effects between cognitivebehavioral therapy and continuation pharmacotherapy, acute phase CBT intervention was more effective than antidepressants drug acute treatment. Patients treated with acute CBT did not have a significantly lower risk of relapse than patients on pharmacotherapy (Cuijpers et al., 2013). This reduced number of studies can be explained for different reasons: First of all, studies analyzing the rates of relapse and specially recurrence are performed in primary and secondary care and not specifically in PC sites. Second, relapse or recurrence studies with pharmacological or psychoterapeutical treatments require long period of follow-up after remission. Third, an interventions strategy in PC with different types of psychotherapy needs a previous training or the participation of different professionals.
Strengths and limitations As a major strength, this is the only systematic review performed on pharmacological or psychological interventions for preventing relapse or recurrence in primary care depressive patients. The search strategy identified more than 400 papers in different databases and two authors extracted the data independently. Our search was performed in the major medical electronic databases but gray literature was not exhaustively reviewed and this is a limitation of the study. The review has one major limitation in the small number of published articles included. Several studies included patients from psychiatric and primary care settings in the same sample. It was impossible to obtain separate data for both groups of patients and for this reasons the papers were not included. Other excluded studies compared two pharmacological
interventions without placebo or control group or pharmacological trials delivered in psychiatric settings. Moreover, we excluded some studies recruiting patients with depression at baseline and measuring severity of depression at 12 months but that didn't include relapse or recurrence as an outcome for patients who had recovered. The quality of the included studies based on results of using the Cochrane Collaboration risk of bias tool was considered adequate. Conclusions We identified a small number of studies that had examined relapse or recurrence prevention specifically focusing on primary care samples. All of the studies had examined psychological interventions, two examining the effects of relapse of treatment delivered during the acute phase and one study examining a treatment delivered after the acute phase. None of the effect sizes for relapse were significant. There is currently, therefore, limited evidence to inform relapse prevention strategies specifically in primary care. There is a need to design specific strategies in primary care targeting the interventions to patients with established criteria of remission of the depressive episode and considering relapse or recurrence as a main outcome. Conflict of interest statement The authors declare that there are no conflicts of interests.
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Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
Contents lists available at ScienceDirect
Preventive Medicine journal homepage: www.elsevier.com/locate/ypmed
Review
Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review☆ Margalida Gili a,c,⁎, Caterine Vicens b,c, Miquel Roca a,c, Phil Andersen d, Dean McMillan d a
Institut Universitari d'Investigació en Ciències de la Salut, Universitat de les Illes Balears, Carretera de Valldemossa, km 7.5, 07181 Palma de Mallorca, Spain Centro de Salud Son Serra-La Vileta, Ib-Salut, Matamusinos 22, 07013 Palma de Mallorca, Spain Red de Investigación en Actividades Preventivas y Promoción de la Salud (redIAPP), Spain d Department of Health Sciences, University of York, UK. 5, York YO10 5DD, United Kingdom b c
a r t i c l e
i n f o
a b s t r a c t
Available online xxxx
Objective: A systematic review was conducted to assess the efficacy of pharmacological and psychological interventions for preventing relapse or recurrence of depression in adults with depression in primary care. Method: Papers published from inception to January 28th 2014 were identified searching the electronic databases MEDLINE, EMBASE, PsycINFO, and CENTRAL. Randomized controlled trials of any pharmacological, psychological or psychosocial intervention or combination of interventions delivered in primary care settings were included, with relapse or recurrence of a depressive disorder as a main outcome. The Cochrane Collaboration risk of bias tool was used to assess study quality. Results: Only three studies with a small number of patients fulfilled the inclusion criteria. None of the three randomized controlled trials included in our review showed a statistically significant superiority of an intervention for the prevention of depression relapse or recurrence. Conclusions: There is limited evidence to inform relapse or recurrence prevention strategies specifically in primary care. © 2014 Elsevier Inc. All rights reserved.
Keywords: Depression Primary health care Recurrence Relapse Secondary prevention
Contents Introduction . . . . . . . . . . . Methods . . . . . . . . . . . . . Eligibility criteria . . . . . . Information sources . . . . . Search . . . . . . . . . . . Study selection . . . . . . . Data extraction . . . . . . . Risk of bias in individual studies Data synthesis . . . . . . . . Results . . . . . . . . . . . . . Risk of bias within studies . . Study outcomes . . . . . . . Discussion . . . . . . . . . . . . Main findings . . . . . . . . Strengths and limitations . . . Conclusions . . . . . . . . . . . Conflict of interest statement . . . References . . . . . . . . . . . .
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☆ Funding: The project has received funding from a Network for Prevention and Health Promotion in Primary Care (redIAPP, RD12/0005) grant and a research project grant (PI12/01914) from the Instituto de Salud Carlos III (Institute of Health Carlos III) of the Ministry of Economy and Competitiveness (Spain), co-financed with European Union ERDF funds. ⁎ Corresponding author at: Institut Universitari d' Investigació en Ciències de la Salut (IUNICS), Carretera de Valldemossa, km. 7.5, Palma de Mallorca, Spain. Tel.: +34 971 173081. E-mail addresses: [email protected] (M. Gili), [email protected] (C. Vicens), [email protected] (M. Roca), [email protected] (P. Andersen), [email protected] (D. McMillan).
http://dx.doi.org/10.1016/j.ypmed.2014.07.035 0091-7435/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
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Introduction Depression is a highly prevalent and disabling disorder and a major public health concern (Kessler et al., 2003). Psychopharmacology, psychotherapy or combined treatments are well supported by evidence in the acute management of the depressive disorders (Stewart et al., 2012; Fournier et al., 2010; Cuijpers et al., 2010; Imel et al., 2008; de Maat et al., 2007). Despite the successful acute treatment of depression, the risk of relapse or recurrence remains very high (Burcusa and Iacono, 2007; Yiend et al., 2009; Harter et al., 2007; Hardeveld et al., 2010; Gopinath et al., 2007). After a first episode of depression the probability of a further episode is approximately 50%; this rises to 70% for two episodes and 90% after a third episode (Burcusa and Iacono, 2007; Kessler et al., 1996). It also appears that with each further episode there is an increase in the severity of depressive symptoms and an increased probability that the symptoms will be resistant to treatment (Kendler et al., 2000). For these reasons it has become increasingly clear that developing interventions for the prevention of relapse or recurrence in specialized mental health care and in primary care is a major concern for longterm management of depressive patients. It is relevant to differentiate between relapse and recurrence when developing treatment strategies for depression. According to expert consensus (Frank et al., 1991; Rush et al., 2006) the term relapse should be used to describe a re-emergence of symptoms in a patient who has initially responded to treatment but who is not yet in remission. Recurrence is the appearance of a new episode of depression after full remission of a previous episode has been achieved. Despite these operational definitions, the majority of published clinical trials do not precisely define relapse or recurrence. Researchers have conflated relapse and recurrence without making a clear distinction between these terms (Beshai et al., 2011). Prevention of depression has emerged as a scientific and clinical challenge of great public significance (Muñoz et al., 2012). This has included the prevention of depressive relapse or recurrence and protection from the medical, psychosocial and economic consequences of the future episodes of depression (Reynolds, 2009). Strategies for reducing relapse can be divided into the type of treatment offered (pharmacological, psychological, combination) and when that treatment is delivered (during the acute phase, after the acute phase). There is evidence that psychological treatments, such as cognitive-behavioral therapy, delivered during the acute phase have effects that endure beyond the end of it to reduce subsequent rates of relapse (Vittengl et al., 2007). In contrast, acute-phase antidepressant medication does not confer a benefit in terms of subsequent relapse if the use of medication stops at the end of the acute phase (Thase, 2006). There is, though, evidence that the continued use of antidepressants after the end of acute phase treatment does reduce the likelihood of relapse (Geddes et al., 2003). In addition, continuation-phase CBT and other approaches specifically designed to be delivered after the end of the acute phase of treatment, such as mindfulness-based cognitive therapy (MBCT), also reduce the rate of relapse (Piet and Hougaard, 2011; Vittengl et al., 2007). Increasingly, the responsibility for initial diagnosis and long-term follow-up of mental illnesses is falling on primary care services, the patient's first point of contact with the health system in the majority of the European countries (Murphy et al., 2000). Around one out of every three primary care patients presents with clinical problems related to mental health difficulties, though the figures range from 26% to 60% (Ansseau et al., 2004; Norton et al., 2007; Roca et al., 2009). While there is evidence that both pharmacological and psychological treatments can be effective in reducing relapse, the majority of the trials were performed in secondary care settings. It is difficult to generalize from such settings to primary care. There are, for example, likely to be differences between the two populations in terms of the likelihood of a relapse and the likelihood of responding to a relapse-focused treatment.
Although there have been improvements in the clinical skills of primary care physicians to detect and treat depression, there is still a long way to go in preventing relapse and recurrence of this disabling disorder and much effort must be made to improve the early identification of depressive patients at risk. We have not found a published metaanalysis or systematic review focused on prevention of relapse or recurrence of depression in primary care settings. The aim of this review is to assess the efficacy of existing pharmacological and psychological interventions for preventing relapse or recurrence of depression in adults with depression in primary care. Methods Eligibility criteria Studies that met the following inclusion criteria were included: Participants: Studies of adult participants (aged 18+) who had an episode of depression or received treatment for depression. Studies of people diagnosed with bipolar disorder were excluded. Interventions: Any pharmacological, psychological or psychosocial intervention or combination of interventions delivered in primary care settings. Interventions delivered during the acute phase or a continuation phase were eligible for inclusion, but are considered separately in the analysis. Comparator/control: Control conditions such as treatment as usual, waiting list or placebo. Outcomes: Relapse or recurrence of a depressive disorder. Study design: Randomized controlled trials (RCTs). Information sources The primary electronic databases searched were MEDLINE/PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and PsycINFO (searched from inception to 28 January 2014). References of included studies were examined to identify other potentially eligible studies. Search Searches comprised a combination of subject terms selected from the controlled vocabulary with free-text terms. These terms were developed to capture the concepts of relapse, depression, randomized trials and primary care and were combined using the Boolean AND. Study selection Three authors independently examined the titles and abstracts of all retrieved citations against the pre-specified inclusion criteria outlined above. The full text of articles passing this first sift were retrieved and examined independently by two authors against the pre-specified inclusion criteria. Disagreements were resolved through consensus and, if consensus could not be reached, discussion with an additional reviewer. The study selection process with the number of studies included and excluded at each stage of the review is documented, detailing the reasons for exclusion, using a PRISMA flowchart diagram (Fig. 1). Data extraction Two reviewers independently extracted data from the included studies. Disagreements were resolved through the same approach as described above. For each study, authors extracted the following details: study design, intervention and control group, sample characteristics, length of follow-up, outcome (including data needed to calculate effect sizes), and study quality. Risk of bias in individual studies The Cochrane Collaboration risk of bias tool (Higgins et al., 2011) was used to assess study quality. Two authors independently rated these criteria and disagreements were resolved as described above.
Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
M. Gili et al. / Preventive Medicine xxx (2014) xxx–xxx
3
Studies identified N=744
Duplicate studies N=280
Studies for analysis of titles and abstracts N=464
Studies excluded based on titles and abstracts N=441
Full text articles excluded = 20 Reasons for exclusion: No RCT = 6 No primary care setting = 5 No relapse or recurrence rate as outcome = 8 No comparator as defined in the protocol = 1
Full text publications reviewed N=23
Studies included in qualitative synthesis N=3
Fig. 1. Flow-chart diagram.
Data synthesis Relative risks with associated 95% confidence intervals were calculated for the dichotomous outcome of relapse/recurrence. Studies were grouped on the basis of the intervention (psychological vs. pharmacological) and study design (treatment delivered in the acute phase vs. continuation treatment delivered after the acute phase). A meta-analysis was considered when there were at least two studies that were sufficiently similar in terms of these characteristics. Heterogeneity was assessed using the I2 statistic, with values of over 50% taken to indicate substantial heterogeneity. There were an insufficient number of studies to conduct subgroup or sensitivity analyses.
Results The electronic database search identified 744 potential records of interest and, after duplicates were removed, 464 records remained. Screening of titles and abstracts excluded 441 studies, and, finally, 23 full text articles were assessed. Three studies were judged to be eligible for inclusion in the review. The flowchart diagram is shown in Fig. 1. The main reason for exclusion was the absence of relapse or recurrence rate as an outcome of the study. Some studies measured severity of depression at follow-up, quality of life or disability after the intervention or treatment but did not specifically assess relapse rate in those who recovered. Six studies were excluded because the study design was not a randomized controlled trial and five because they were not delivered in a primary care setting. One study was excluded because it compared two pharmacological interventions without usual care or placebo as a comparator. Table 1 summarizes the reasons for exclusion for the studies for which full text articles were retrieved. Study location, design, interventions, sample size and outcomes are summarized for each included study in Table 2.
De Graaf et al. (2011) conducted a randomized trial in 303 patients with depression and allocated them to three arms:computerized cognitive-behavioral therapy (CCBT), treatment as usual (TAU) and a combination of both (CCBT + TAU). Those patients who recovered at 3 months (35 CCBT, 33 TAU and 43 CCBT + TAU) were assessed for relapse at 6, 9 or 12 months. The main outcome was an increase of at least 9 points on the Beck Depression Inventory (BDI-II). The attrition rate of this study was 11.9%. Howell et al. (2008), in a pilot study, included 110 primary care patients with depression and conducted a cluster randomized trial to Table 1 Reasons for the exclusion of studies. Study
Reason for exclusion
van Weel-Baumgarten et al. (2000) Wade et al. (2003) Gelenberg et al. (2003) Von Korff et al. (2003) Capoccia et al. (2004) Klein et al. (2004) Rapaport et al. (2004) Gonzalez Gonzalez et al. (2006) Hunkeler et al. (2006) Lang et al. (2006) Ludman et al. (2007) Keller et al. (2007) Hardeveld et al. (2010) Christensen et al. (2010) van't Veer-Tazelaar et al. (2011) Cipriani et al. (2011) Rodgers et al. (2012) Lee et al. (2012) Marques et al. (2013) Stangier et al. (2013)
Not a randomized controlled trial No comparator as defined in the protocol Not conducted in a primary care setting No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome Not conducted in a primary care setting No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome No relapse or recurrence rate as outcome Not conducted in a primary care setting Not a randomized controlled trial Not a randomized controlled trial No relapse or recurrence rate as outcome Not a randomized controlled trial Not a randomized controlled trial Not a randomized controlled trial Not conducted in a primary care setting Not conducted in a primary care setting
Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
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M. Gili et al. / Preventive Medicine xxx (2014) xxx–xxx
Table 2 Characteristics of the included studies. Study (yr)
Design
Intervention
Groups sample size
Age
Duration of follow-up
Outcomes
Katon et al. (2001)
RCT
194 IG 192 CG
18 to 80
12 months
SCL-20 Relapse rate
Howell et al. (2008)
Cluster RCT
Intervention 2 specialist in depression visits + 3 telephone contacts Control: Usual care KBA program Control: Usual care
62 KBA 49 C
18 to 75
12 months
De Graaf et al. (2011)
RCT
35 CCBT 43 CCBT + TAU 33 TAU
18 to 65
12 months
DASS Case notes Relapse rate BDI-II Relapse rate
Computerized CBT Computerized CBT + TAU TAU
RCT: randomized controlled trial; IG: intervention group; CG: control group; SCL-20: Symptoms Check List; DASS: Depression Anxiety Stress Scale; BDI: Beck Depression Inventory Scale; KBA: Keeping the Blues Away; CCBT: computerized cognitive behavior therapy; and TAU: treatment as usual.
compare an intervention based on the Keeping the Blues Away (KBA) program (ten steps including problem solving, coping skills and other psychosocial evidence-based strategies to reduce the severity and relapse of depression) with usual care. A trained psychologist assessed depression relapse retrospectively through blinded case-note review. The attrition rate was higher in the intervention group (24.2%) than in the control group (2%). Katon et al. (2001) recruited 386 primary care patients with recurrent major depression or dysthymia from the prescriptions database who had recovered after 8 weeks of antidepressant treatment. They were randomized to a relapse prevention program (194 patients) or usual primary care (192 patients). The intervention consisted of two primary care visits with a depression specialist and three telephone calls over a one year period aimed at enhancing adherence to antidepressant medication, recognition of prodromal symptoms and development of a written relapse prevention plan. The main outcome was the Symptoms Check List (SCL-20) (Derogatis et al., 1974) at 12 months after randomization. At 12 months of follow-up 10.3% of the intervention group and 20.8% of the control group missed interviews.
Risk of bias within studies Fig. 2 shows the risk of bias assessment. All three included studies presented adequate random sequence generation but only one reported adequate allocation concealment. Because the three interventions consisted of psychological interventions, participants and personnel could not be blinded about treatment allocation so there could be a risk of bias. Outcomes were measured in a standard and reliable way. The outcome assessment was blinded in two of the three studies and was not reported in the third study. The attrition rates were reported de Graaf 2011
Howell 2008
Katon 2001
Selective reporting (reporting bias)
+
?
+
Incomplete outcome data (attrition bias)
+
+
+
Blinding of outcome assessment (detection bias)
+
+
+
Blinding of participants and personnel (performance bias)
+
+
?
Allocation concealment (selection bias)
–
–
–
+
?
?
+
+
+
Random sequence generation (selection bias)
Other bias
Fig. 2. Risk of bias assessment.
and considered acceptable in the three studies. All studies used an intention-to-treat principle for statistical analyses. Study outcomes Two of the three studies (De Graaf et al., 2011; Howell et al., 2008) included patients with depression at the time of randomization, delivered the intervention and, in those who recovered, measured relapse outcomes at follow-up. The other study randomized patients who had recovered from a major depressive disorder and delivered an intervention to prevent relapse (Katon et al., 2001). These two designs are considered separately in the analysis. Although De Graaf et al. (2011) and Howell et al. (2008) used a similar study design, heterogeneity for these two studies was substantial (I2 = 70%), so a meta-analysis was not performed. As the two interventions compared to treatment as usual in De Graaf's study were similar (CBT vs. CBT + TAU), we analyzed both groups together to calculate the effect size. The results for these two studies are summarized in Fig. 3a. As the figure indicates relapse rates were lower, but not significantly so, in the control arm of De Graaf et al. (2011), and lower, but again not significantly so, in the intervention arm of Howell et al. (2008). Fig. 3b summarizes the results for Katon et al. (2001), which identified relapse rates following an intervention delivered after the acute phase of treatment specifically designed to reduce relapse. As the figure indicates, there were no differences between the relapse rates in the intervention and control group. Discussion Main findings The main result of this systematic review is that there are few studies examining the efficacy of prevention of relapse or recurrence interventions in primary care patients with depression. We found only three studies with a small number of patients and the data are not sufficient to recommend a particular strategy for the secondary prevention of depression. None of the three randomized controlled trials included in our review showed a statistically significant superiority of an intervention for the prevention of depression relapse or recurrence. Of the three studies included, only one (Katon et al., 2001) randomized patients with recurrent depression or dysthymia during a remission state after 8 weeks of treatment. De Graaf et al. (2011) and Howell et al. (2008) included and randomized patients with acute depression, delivered the intervention in those who recovered and measured the relapse rate during the follow-up, but no more specific interventions was delivered after the acute phase of treatment. As reported before, most pharmacological interventions are conducted in psychiatric settings and, even though we did not focus on them for the review, there are a number of meta-analyses of studies including pharmacological treatment with antidepressants to prevent
Please cite this article as: Gili, M., et al., Interventions for preventing relapse or recurrence of depression in primary health care settings: A systematic review, Prev. Med. (2014), http://dx.doi.org/10.1016/j.ypmed.2014.07.035
M. Gili et al. / Preventive Medicine xxx (2014) xxx–xxx
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a) Relapse after acute phase treatment delivered in primary carea Intervention Study or Subgroup
Events
Control
Risk Ratio
Total Events Total
Risk Ratio
M-H, Random, 95% CI
de Graaf 2011
23
78
6
33
1.62 [0.73, 3.61]
Howell 2008
13
62
15
48
0.67 [0.35, 1.27]
M-H, Random, 95% CI
0.2 0.5 1 2 5 Favours intervention Favours control
b) Relapse after relapse intervention delivered in primary care Intervention Study or Subgroup Katon 2001
Events 68
Control
Risk Ratio
Total Events Total 194
66
192
Risk Ratio
M-H, Random, 95% CI
M-H, Random, 95% CI
1.02 [0.78, 1.34] 0.2 0.5 1 2 5 Favours intervention Favours control
Fig. 3. a: Relapse after acute phase treatment delivered in primary care. b: Relapse after relapse intervention delivered in primary care.
relapse that have found lower relapse rates in treatment groups versus placebo (Geddes et al., 2003; Kaymaz et al., 2008; Glue et al., 2010). A review of guidelines recommendations for long-term treatments did not found evidence for maintenance treatment with antidepressants in PC patients (Piek et al., 2010). In a meta-analysis of 28 studies on cognitive-behavioral therapies (CTs) to prevent relapse–recurrence of depression, among acutephase treatment responders, continuation-phase CT reduced relapse– recurrence compared with assessment only or with other active continuation treatments at the end of continuation treatment and at follow-up (Vittengl et al., 2007). In a review of empirical studies targeting the effects of psychotherapy in relapse or recurrence in depressive patients, a consistent finding has been that preventive cognitive-behavioral therapy and mindfulness-based therapies are most effective for patients with three or more previous depressive episodes (Beshai et al., 2011). Future research needs to be focused in shorter psychotherapeutical interventions to be delivered at PC centers. In a meta-analysis of the enduring effects between cognitivebehavioral therapy and continuation pharmacotherapy, acute phase CBT intervention was more effective than antidepressants drug acute treatment. Patients treated with acute CBT did not have a significantly lower risk of relapse than patients on pharmacotherapy (Cuijpers et al., 2013). This reduced number of studies can be explained for different reasons: First of all, studies analyzing the rates of relapse and specially recurrence are performed in primary and secondary care and not specifically in PC sites. Second, relapse or recurrence studies with pharmacological or psychoterapeutical treatments require long period of follow-up after remission. Third, an interventions strategy in PC with different types of psychotherapy needs a previous training or the participation of different professionals.
Strengths and limitations As a major strength, this is the only systematic review performed on pharmacological or psychological interventions for preventing relapse or recurrence in primary care depressive patients. The search strategy identified more than 400 papers in different databases and two authors extracted the data independently. Our search was performed in the major medical electronic databases but gray literature was not exhaustively reviewed and this is a limitation of the study. The review has one major limitation in the small number of published articles included. Several studies included patients from psychiatric and primary care settings in the same sample. It was impossible to obtain separate data for both groups of patients and for this reasons the papers were not included. Other excluded studies compared two pharmacological
interventions without placebo or control group or pharmacological trials delivered in psychiatric settings. Moreover, we excluded some studies recruiting patients with depression at baseline and measuring severity of depression at 12 months but that didn't include relapse or recurrence as an outcome for patients who had recovered. The quality of the included studies based on results of using the Cochrane Collaboration risk of bias tool was considered adequate. Conclusions We identified a small number of studies that had examined relapse or recurrence prevention specifically focusing on primary care samples. All of the studies had examined psychological interventions, two examining the effects of relapse of treatment delivered during the acute phase and one study examining a treatment delivered after the acute phase. None of the effect sizes for relapse were significant. There is currently, therefore, limited evidence to inform relapse prevention strategies specifically in primary care. There is a need to design specific strategies in primary care targeting the interventions to patients with established criteria of remission of the depressive episode and considering relapse or recurrence as a main outcome. Conflict of interest statement The authors declare that there are no conflicts of interests.
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