Prevention of depression in patients with cancer: A systematic review and meta-analysis of randomized controlled trials

Journal of Psychiatric Research 120 (2020) 113–123

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Prevention of depression in patients with cancer: A systematic review and meta-analysis of randomized controlled trials

T

Jawad Ahmad Zahid∗, Ole Grummedal, Michael Tvilling Madsen, Ismail Gögenur Center for Surgical Science, Department of Surgery, Zealand University Hospital, Lykkebaekvej 1, 4600, Koege, Denmark

A R T I C LE I N FO

A B S T R A C T

Keywords: Cancer Antidepressant Anxiety Depression Preventive Prophylaxis

Depression and depressive symptoms are prevalent in patients with cancer. Depression is underdiagnosed and therefore, patients often receive inadequate treatment for depression. We have assessed the evidence of primary prophylactic treatment for depression in patients with cancer. The systematic review was prospectively registered at PROSPERO and was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Five electronic databases were searched on the 31st of May 2018 and two independent reviewers screened the papers. Randomized controlled trials of adult patients with cancer treated prophylactically with an antidepressive intervention of any kind using validated assessment tools to measure depression or depressive symptoms were included. No language or publication year restrictions were applied. Seven out of eighteen studies reported a statistically significant prophylactic effect on depression. The studies were classified into three groups based on the type of intervention. The meta-analyses showed a significant difference in favour of pharmacotherapy (RR 0.34, 95% CI 0.18; 0.63), psychotherapy (SMD -0.23,95% CI -0.46; 0.00), and other interventions (SMD -0.17, 95% CI -0.31; −0.03). Only one study had overall low risk of bias and the rest had high risk of bias predominantly due to blinding, incomplete data, or allocation concealment. Preventive measures have been examined in patients with cancer, but no convincing evidence for any specific intervention is present. Depression in patients with cancer can be prevented and prophylactic treatment should be given during oncological treatment but further high quality studies testing safe interventions are still needed.

1. Introduction By the year 2030, depressive disorders are expected to be the leading cause of disability in high-income countries accompanied with a significant socio-economic burden (Chisholm et al., 2016; Mathers and Loncar, 2006). In Europe by 2010 it was estimated that 30 million people were suffering from depression with a total estimated cost of €92 billion (Wittchen et al., 2011). There is a considerable overlap between depression and cancer with a high proportion suffering from both conditions (McDaniel et al., 1995). Depression has shown to be treatable both with pharmacotherapy and psychotherapeutic interventions in adults with cancer (Hart et al., 2012; Okuyama et al., 2017; Ostuzzi et al., 2015). The prevalence of depression has been reported as high as 49% (Walker et al., 2013) and persistently been shown to be higher in cancer survivors than the general population (Maass et al., 2015). However, the reported prevalence in the studies varied greatly depending on cancer type and severity, the method of depression assessment, and

whether the patients were hospitalized or treated in an outpatient clinic (Krebber et al., 2014; Walker et al., 2013). Overall depressive symptoms peak during adjuvant treatment and rebound after completing treatment likely due to stressors such as accumulated burden of disease or treatment and diminishing social support (Li et al., 2011). Rates of depression increase with recurrence, progression of cancer, and peak in palliative care (Li et al., 2011; Walker et al., 2013). Depression in patients with cancer is both underdiagnosed and undertreated (Colleoni et al., 2000; Fallowfield et al., 2001; Sharpe et al., 2004; Suppli et al., 2017). Depressive symptoms are associated with decreased health related quality of life, treatment adherence, and poorer prognosis (Arrieta et al., 2013; Colleoni et al., 2000). The overall mortality rate is higher in cancer patients with depressive symptoms and major depression disorder (Satin et al., 2009). Some studies have also reported a higher suicide rate among patients with cancer (Hem et al., 2004; Misono et al., 2008). Treating psychiatric conditions in patients with cancer may improve not only their quality of life and prognosis but also their survival (Chan et al., 2015).

∗

Corresponding author. E-mail addresses: [email protected], [email protected] (J.A. Zahid), [email protected] (O. Grummedal), [email protected] (M.T. Madsen), [email protected] (I. Gögenur). https://doi.org/10.1016/j.jpsychires.2019.10.009 Received 17 July 2019; Received in revised form 4 October 2019; Accepted 9 October 2019 0022-3956/ © 2019 Elsevier Ltd. All rights reserved.

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of bias assessment. The information from the bias assessment was used in the overall data synthesis to characterize the quality of the included studies. The primary outcome was prevention of depression and/or depressive symptoms, regardless of whether they were assessed as a primary or exploratory outcome in the studies. Depression had to be assessed by a validated clinical-administered or self-rating questionnaire, including known and validated psychometric properties with the main focus on diagnosing or measuring depression. The interventions were categorized in three groups: pharmacological, psychotherapeutic and other types of interventions. The main analyses were performed in these groups with either incidence of depression or reduction in depressive symptoms as the outcome. The depressive symptoms in the included studies were measured by different questionnaires and in the main analyses all type of validated questionnaires were included. Furthermore, we conducted the following of exploratory analyses. Firstly, a sensitivity analysis in which depression was only measured with the depression subscale of the Hospital Anxiety and Depression Scale (HADS). Secondly, an exploratory analysis in which anxiety measured with the anxiety subscale of HADS were included. Thirdly, acceptability and tolerability analyses of the interventions were performed. Acceptability was measured as discontinuing the given intervention for any reason and tolerability was measured as discontinuing the given intervention due to adverse effects of treatment. Tolerability analysis was only possible for the pharmacological interventions as adverse effects were only found in pharmacological treatment and not in non-pharmacological interventions. Fourthly, an analysis in which only patients with breast cancer, the most common cancer form examined by the included studies, were included. The forest plots of these analyses are presented in the supplementary material. Meta-analyses were performed in Review Manager 5.3. In case depression was reported as a dichotomous outcome, the pooled effects were presented as risk ratios (RR) with 95% CIs. When depressive symptoms were reported as a continuous outcome change scores (post minus pre scores) for respective groups were applied. As depressive symptoms were assessed using varying instruments, the result has to be standardized to fit a uniform scale before they can be combined in a meta-analysis. The standardized mean difference (SMD) expresses the size of the intervention effect in each study relative to the variability observed in that study. Therefore, two or more studies using different depression questionnaires will have the same SMD if the difference in means is the same proportion of the standard deviation (Higgins et al., 2017). In the subgroup analyses with only studies reporting the HADS outcome, the effect size measure was represented as mean differences (MD) with 95% CIs. Heterogeneity was tested with the chi-squared test and I2 was used to estimate the percentage of outcome variability that can be attributed to heterogeneity across studies and was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al., 2017). In studies reporting median and interquartile range, means and standard deviations were estimated in accordance with the Cochrane Handbook (Higgins et al., 2017). In studies that included two intervention groups SMD were compared for each intervention-group comparison, and the number of subjects in the control group were evenly divided among the intervention groups to ensure that each participant was only included once in the analysis.

Due to the lack of time, training and thus maybe also confidence clinicians might not be able to identify the patients with cancer that are in risk of developing depression. Therefore, it might be beneficial to offer patients with cancer an intervention that could prevent depression as part of the routine cancer treatment. Patients with cancer are more vulnerable to depression in the first month after diagnosis and the estimated prevalence is highest during the acute phase of cancer treatment (Bergquist et al., 2007; Hammerlid et al., 1999; Krebber et al., 2014). We hypothesise that if a prophylactic treatment of depression is delivered in this phase it might prevent depression. In light of this, the current systematic review and meta-analysis aimed to investigate prophylactic treatment of depression in patients with cancer. The prophylactic interventions in this study included both pharmacological, psychotherapeutic and other kinds of interventions. 2. Material and methods This systematic review has been reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines (Liberati et al., 2009). The study was registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO) (Booth et al., 2011a, 2011b) with registration number: CRD42016053040. We used the following PICOS (P: population, I: intervention, C: control, O: outcomes, S: study design) (Liberati et al., 2009) when constructing the eligibility criteria in the search strategy. P: humans, adults, ≥18 years, diagnosed with cancer, I: antidepressive treatment of any kind, C: placebo or other active treatment, O: depression and depressive symptoms, and S: randomized controlled trials. Studies comparing any kind of treatment to prevent depression to placebo or standard of care were included. Studies were excluded if patients at baseline were diagnosed with depression or had a depression according to the questionnaire used in the study, thus securing prophylaxis. No restrictions on dose, administration, or timing of the intervention was chosen, or to other outcomes being assessed in the studies. No time or language restrictions were applied in the current review and no attempt to include ongoing trials was made. The search was carried out in PubMed, Embase, PsycINFO, CINAHL, and in the Cochrane Central Register of Controlled Clinical Trials (PubMed: 1966 – search date, Embase: 1974 - search date, PsycINFO: 1806 – search date, CINAHL: 1981 – search date, Cochrane Central Register of Controlled Clinical Trials: date of inception – search date). The search was conducted on 31st of May 2018 and the same search terms were used in the databases. The exact search terms can be seen in appendix. We utilized Covidence, a web-based review software platform as a blinded screening tool (Covidence systematic review software). After duplicate removal two reviewers (JAZ, OG) independently screened the title and abstract at first and then full-text according to the eligibility criteria. Any discrepancies in both screening phases were resolved through discussion until consensus was reached within the author group. The two authors extracted data on participant characteristics, interventions, and trial methodology into a pre-specified data spreadsheet. Reference lists of the included articles were manually scanned for further literature by the first author. When more than one publication from the same study population were found, only the most relevant publication was included and reported. Data from included studies were likewise extracted into predesigned spreadsheets and cross checked. Two authors (JAZ, OG) assessed the methodological quality of the included studies by using the Cochrane Handbook of Systematic Review of Interventions’ Risk of bias assessment tool (Higgins et al., 2011). Trial registration and information for all included studies were searched for on clinicaltrials.gov and in WHO International Clinical Trials Registry Platform. Published protocol articles were searched for in PubMed and consulted if available. Any discrepancies between the available online information and published protocol articles were used in the risk

3. Results A total of 3577 records were identified in the searched databases (PubMed: 1,445, Embase: 721, PsycINFO: 278, CINAHL: 464, the Cochrane Central Register of Controlled Clinical Trials: 669). An additional five studies were identified in the reference lists and added to the included full-text assessment. All articles had English abstracts and in case of a non-English paper, the papers were translated by fellow colleagues. Two non-English papers were screened and were not eligible for inclusion. 114

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Fig. 1. PRISMA flow diagram.

In the final qualitative synthesis 18 randomized controlled trials published between 1996 and 2017 were included (Billhult et al., 2007; Fernández-Rodríguez et al., 2017; Fukui et al., 2000, 2008; Hansen et al., 2014b; Hanser et al., 2006; Kim et al., 2013; Lydiatt et al., 2008, 2013; McArdle et al., 1996; Mehnert et al., 2011; Monga et al., 2007; Nangia et al., 2017; Pitceathly et al., 2009; Ream et al., 2015; Travier et al., 2015; Van Vulpen et al., 2016; Zhou et al., 2015) (Fig. 1). The number of included patients ranged from 21 to 465 patients, predominantly female with an age range from 47 to 69 years (Table 1). The most common cancer form was breast cancer (Fernández-Rodríguez et al., 2017; Fukui et al., 2000; Hansen et al., 2014b; Hanser et al., 2006; Kim et al., 2013; McArdle et al., 1996; Mehnert et al., 2011; Nangia et al., 2017; Travier et al., 2015; Zhou et al., 2015). Other studies had patients with head and neck cancer (Lydiatt et al., 2013, 2008), prostate cancer (Monga et al., 2007), colon cancer (Van Vulpen et al., 2016), lung cancer (Fernández-Rodríguez et al., 2017), and mixed cancer populations (Fukui et al., 2008; Pitceathly et al., 2009; Ream et al., 2015). The majority of studies administered the interventions during active oncological treatment (Table 1). Psychological assessments were conducted at baseline and at follow-up at least once, which ranged from time of discharge from hospital to more than one year after baseline. Two studies used a clinician-administered tool (Lydiatt et al., 2008; Pitceathly et al., 2009) while most studies used different self-administered questionnaires (Billhult et al., 2007; Fernández-Rodríguez et al., 2017; Fukui et al., 2000, 2008; Hansen et al., 2014b; Hanser et al., 2006; Kim et al., 2013; Lydiatt et al., 2013; McArdle et al., 1996; Mehnert et al., 2011; Monga et al., 2007; Nangia et al., 2017; Ream et al., 2015; Travier et al., 2015; Van Vulpen et al., 2016; Zhou et al., 2015). Seven out of 18 studies reported a significant prophylactic effect on depression or depressive symptoms (Fernández-Rodríguez et al., 2017; Hansen et al., 2014b; Lydiatt et al., 2013; McArdle et al., 1996; Mehnert

et al., 2011; Zhou et al., 2015), whereas the remaining 11 studies did not report any significant difference between intervention and control groups (Billhult et al., 2007; Fukui et al., 2000; Hanser et al., 2006; Kim et al., 2013; Lydiatt et al., 2008; Monga et al., 2007; Nangia et al., 2017; Pitceathly et al., 2009; Ream et al., 2015; Travier et al., 2015; Van Vulpen et al., 2016) (Table 2).

3.1. Pharmacological interventions Three studies used a pharmacological intervention and were doubleblinded, placebo-controlled trials (Hansen et al., 2014b; Lydiatt et al., 2008, 2013). One study used 6 mg melatonin as intervention for 12 weeks (Hansen et al., 2014b). Two studies used selective serotonin reuptake inhibitor (SSRI) – escitalopram and citalopram – in equipotent doses with a 1 week run-in phase (half dose) followed by a 15 week and 27 week full-dose follow-up, respectively (Lydiatt et al., 2013, 2008). Melatonin showed a lower incidence rate of depression compared to placebo (Hansen et al., 2014b) and this was also the case with escitalopram (Lydiatt et al., 2013), but the latter has yet to publish a secondary outcome. In contrast to this, the study on citalopram did not show any effect (Lydiatt et al., 2008). We found a significant treatment effect in favour of prophylactic pharmacological treatment with a RR of 0.34 (95% CI 0.18; 0.63, random effect, I2 = 0%, Fig. 2). In terms of acceptability, no significant difference between pharmacological interventions and placebo was found (RR: 0.59, 95% CI 0.14; 2.51, random effect, I2 = 67% - supplementary material: Fig. I). In terms of tolerability, no significant difference between pharmacological interventions and placebo was found (RR: 1.71, 95% CI 0.32; 9.04, random effect, I2 = 32%) (supplementary material: Fig. II).

115

116

b

b

54 148 25 50 70 465 90 68 170 39 86 102 272 58 21 182 44 204 33

Japan USA UK Spain Spain China

Sweden Japan South Korea Scotland Germany USA USA UK Netherlands Netherlands

Sample size

Denmark USA USA

Country

51.8 61.1 47.5 56.7 51.9 69.2 52.6 53.3 49.6 58.1

53.5 51.5 51.4 61.4 53.1 47

55.3 63 61

Age

CT: Chemotherapy. HT: Hormonal therapy. M: Month. OT: Oncological treatment. Preop.: Preoperative. Postop.: Postoperative. RT: Radiation therapy. Surg.: Surgery. W: Week. a Breast, lymphoma, ovary/cervix, bowel, testis, and other. b The same paper reported two trials. c Breast, colorectal, or lymphoma.

Pharmacological interventions Hansen et al. (2014b) Lydiatt et al. (2013) Lydiatt et al. (2008) Psychotherapeutic interventions Fukui et al. (2000) Hanser et al. (2006) Pitceathly et al. (2009) Fernández-Rodríguez et al., 2017 Fernández-Rodríguez et al., 2017 Zhou et al. (2015) Other interventions Billhult et al. (2007) Fukui et al. (2008) Kim et al. (2013) McArdle et al. (1996) Mehnert et al. (2011) Monga et al. (2007) Nangia et al. (2017) Ream et al. (2015) Travier et al. (2015) Van Vulpen et al., 2016

Study

Table 1 Patient and study characteristics.

0/100 40/60 0/100 0/100 0/100 100/0 0/100 39/61 0/100 64/36

0/100 0/100 31/69 81/19 0/100 0/100

0/100 80/20 48/52

Gender M/F %

Breast Breast, colorectal, and gastric Breast Breast Breast Prostate Breast Mixed cancersc Breast Colon

Breast Breast Mixed cancersa Lung Breast Breast

Breast Head and neck Head and neck

Cancer

CT Surg. RT Surg. + RT, CT, HT or a mix CT and/or RT RT CT CT CT CT

CT or no CT CT, HT, RT, or other CT, RT, or both CT CT Surg.

Surg. + RT, CT, or none Surg., RT, CT, or a mix Surg., RT, or CT

Oncological treatment

CT cycle 3 and 7 Post diagnosis W1, M: 1 and 3 Pre-RT and 6 W post-RT Postop. M: 1, 3, 6, and 12 Baseline, W10 Pre-RT and 8 W post-RT Baseline and post CT Baseline and post intervention Baseline, W: 18 and 36 Baseline, W: 18 and 36

Baseline, W6 and M6 Baseline, W6 and M3 Baseline, M: 6 and 12 4 cycles of CT and post-CT M: 3, 6, 9, and 12 6 cycles of CT and post-CT M: 3, 6, 9, and 12 Preop. and pre-discharge

1 W preop., postop. W: 2, 4, 8, and 12 Baseline, W: 2, 6, 4, 8, 10, 12, 16, 20, 24, and 28 Baseline, W: 4, 8, 12, and 16

Timing of assessment

During OT After OT During OT During or after OT After OT During OT During OT During OT During OT During OT

After OT During or after OT During or after OT During OT During OT After OT

Before and during OT During OT During OT

Administration of intervention

J.A. Zahid, et al.

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Usual care

Music therapy + progressive muscle relaxation training

Support by specialist nurses Brain Wave Vibration meditation A)Support: breast care nurse B)Support: voluntary group C)A + B A 10-week exercise program An 8-week aerobic exercise program Scalp cooling The “Beating Fatigue” intervention An 18-week exercise program An 18-week exercise program Waitlist group Usual care Usual care Usual care Usual care Usual care

Short unstructured conversation Support by standard nurses Waitlist group Usual care

Usual care

Therapy by psychologist

Massage

Usual care

Wait list group Usual care Usual care

Psychosocial intervention Music therapy Brief psychological intervention

Therapy by psychologist

Placebo Placebo Placebo

Comparison

Melatonin, 6 mg Escitalopram, 10 mg → 20 mg Citalopram, 20 mg → 40 mg

Intervention

BDI: Beck Depression Inventory. Diff.: Difference. CG: Control group. GLM: General Linear Model. HADS: Hospital Anxiety and Depression Scale. HRSD: Hamilton Rating Scale for Depression. IG: Intervention group. MDI: Major Depression Inventory. MLM: Mixed Linear Model. M: Month. QIDS-SR: Quick Inventory of Depressive Symptomatology (Self-Report). Sign.: Significant. SCID: Structured Clinical Interview for DSM–III–R. ZSDS: Zung Self-Rating Depression Scale. a The same paper reported two trials.

Mehnert et al., 2011 Monga et al., 2007 Nangia et al. (2017) Ream et al., 2015 Travier et al. (2015) Vulpen et al., 2016

Fukui et al., 2008 Kim et al., 2013 McArdle et al., 1996

Other interventions Billhult et al., 2007

Fernández-Rodríguez et al., 2017 a Fernández-Rodríguez et al., 2017 a Zhou et al. (2015)

Pharmacological interventions Hansen et al. (2014b) Lydiatt et al. (2013) Lydiatt et al. (2008) Psychotherapeutic interventions Fukui et al. (2000) Hanser et al., 2006 Pitceathly et al. (2009)

Study

Table 2 Outcome and measurements.

HADS BDI HADS HADS HADS HADS

HADS HADS HADS

HADS

ZSDS

HADS

HADS

HADS HADS SCID/HADS

MDI QIDS-SR HRSD

Depressive assessment tool

Sign. improvement in IG, p = 0.05. No sign. diff., p = 0.36. No sign. diff., p = 0.36. No sign. diff. between groups. No sign. diff. between groups. No sign. diff. between groups.

Sign. lower HADS score in IG, p = 0.03. No sign. diff., p = 0.184. Sign. lower HADS score in A, p = 0.002.

No sign. diff., p = 0.1.

Sign. improvement in IG, p = 0.009.

GLM: Sign. lower depression, p = 0.021 MLM: Sign. lower depression, p < 0.0001

No sign. diff., p = 0.26. No sign. diff. between groups. SCID: 41/311 in IG and 30/154 in CG had an incident of depression. No sign. diff., p = 0.17. HADS: Sign. lower at 2 + 4 M in IG, p = 0.045 and p = 0.007 but not at 6 + 12 M. GLM: No sign. group difference. MLM: Sign. lower depression, p = 0.03

Incident depression: IG 3/27 - CG 9/20 RR 0.25 (95% CI 0.08–0.80), p = 0.008 Incident depression: IG 6/60 - CG 16/65 RR 0.41 (95% CI 0.17–0.97), p = 0.04 Incident depression: IG 2/12 - CG 5/10 RR 0.33 (95% CI 0.08–1.36), p = 0.17

Results

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Fig. 2. Effect of pharmacological interventions on depression – CI: Confidence interval – IV: Inverse variance.

specialized support in both studies showed an overall effect of support by trained nurses (Fukui et al., 2008; McArdle et al., 1996). Other studies intervened using meditation (Kim et al., 2013), massage (Billhult et al., 2007), a scalp cooling device (Nangia et al., 2017) or a fatigue management program called “Beating Fatigue” (Ream et al., 2015) and found no statistically significant effect. In the meta-analysis we found a significant treatment effect in favour of other prophylactic interventions with a SMD of −0.17 (95% CI -0.31; −0.03, random effect, I2 = 0%, Fig. 4). Analysing the results from papers using the HADS only (Billhult et al., 2007; Fukui et al., 2008; Kim et al., 2013; McArdle et al., 1996; Mehnert et al., 2011; Nangia et al., 2017; Ream et al., 2015; Travier et al., 2015; Van Vulpen et al., 2016), we found a significant effect in favour of other prophylactic interventions on the depression score (MD: −0.61 points HADS-D, 95% CI -1.08; −0.13, random effect, I2 = 0%). We found no significant effect of other prophylactic interventions on the anxiety score (MD: −0.28 points HADS-A, 95% CI -1.08; 0.52, random effect, I2 = 49%) (supplementary material: figure VI and VII). In terms of acceptability, no significant difference between other interventions and usual care was found (RR: 0.83, 95% CI 0.59; 1.17, random effect, I2 = 0%) (supplementary material: Fig. VIII).

3.2. Psychotherapeutic interventions Two out of five papers showed significant effect of their interventions. One used psychologist delivered therapy and showed improvement when a mixed linear model was applied in both lung and breast cancer groups (Fernández-Rodríguez et al., 2017), whilst the second used combined music therapy with progressive muscle relaxation training and showed a significant improvement in the depression scores (Zhou et al., 2015). No significant effect was found using telephone (Pitceathly et al., 2009) or group (Fukui et al., 2000) delivered interventions or music therapy (Hanser et al., 2006). We found a significant difference in favour of prophylactic psychotherapeutic interventions with a SMD of −0.23 (95% CI -0.46; 0.00, random effect, I2 = 32%, Fig. 3). Analysing the results from papers using the HADS only (FernándezRodríguez et al., 2017; Fukui et al., 2000; Hanser et al., 2006), we found no significant effect of prophylactic psychotherapeutic interventions on the depression score (MD: −0.60 points HADS-D, 95% CI -1.82; 0.62, random effect, I2 = 13%) and on the anxiety score (MD: −0.25 points HADS-A, 95% CI -1.42; 0.92, random effect, I2 = 0%) (supplementary material: figure III and IV). In terms of acceptability, no significant difference between psychotherapeutic interventions and usual care was found (RR: 0.94, 95% CI 0.77; 1.14, random effect, I2 = 0%) (supplementary material: Fig. V).

3.4. Breast cancer Ten out of 18 included studies examined interventions in patients with breast cancer. We found a significant difference in favour of any kind of intervention with a SMD of −0.20 (95% CI -0.34; −0.07, random effect, I2 = 9%) (supplementary material: Fig. IX). Furthermore, in patients with breast cancer a significant difference was also found when analysing psychotherapeutic intervention but not in pharmacological or other interventions (supplementary material: Fig. IX).

3.3. Other interventions Ten studies were performed with interventions other than pharmacological or psychological. Four studies used group exercise programs as intervention (Mehnert et al., 2011; Monga et al., 2007; Travier et al., 2015; Van Vulpen et al., 2016). Only one exercise program showed a significant difference; it investigated a 10-week physical exercise rehabilitation program (Mehnert et al., 2011). An aerobic exercise program (Monga et al., 2007) and two 18-week exercise programs showed no effect on depression (Travier et al., 2015; Van Vulpen et al., 2016). The content of the four exercise programs did not differ greatly from one another. Two studies had specialized support as intervention; one with communication skill trained nurses (Fukui et al., 2008) and one with either an experienced breast cancer nurse, a voluntary support group, or both (McArdle et al., 1996). The use of

3.5. Study quality assessment Risk of bias assessment of the included studies is presented in Figs. 5 and 6. The melatonin study had an overall low risk of bias (Hansen et al., 2014b). Both SSRI studies had high risk of bias including funding bias (Lydiatt et al., 2013, 2008), attrition bias (Lydiatt et al., 2013), and unclear risk of reporting bias (Lydiatt et al., 2013). With regard to the psychotherapeutic intervention studies, no blinding of participants was

Fig. 3. Effect of psychotherapeutic interventions on depression – CI: Confidence interval – IV: Inverse variance – SD: Standard deviation. 118

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Fig. 4. Effect of other interventions on depression – CI: Confidence interval – IV: Inverse variance – SD: Standard deviation.

the general linear model (Fernández-Rodríguez et al., 2017). A brief psychological intervention had no effect on incidents of depression using The Structured Clinical Interview for DSM–III–R. It scored significantly lower on the HADS at two and four months but not at six and twelve months, which was measured as a secondary outcome (Pitceathly et al., 2009). In the studies using other types of interventions, one exercise study was limited by the fact that it did not account for the dropouts in the analysis (Mehnert et al., 2011) and both support studies were limited by methodological flaws; no informed consent (McArdle et al., 1996) and insufficient random allocation and concealment (Fukui et al., 2008). In the categories psychological and other interventions meta-analyses were performed using SMD for which the effect size is not directly applicable for clinical interpretation. Supplementary analysis on studies using the HADS-A or HADS-D showed that only the other interventions category had significant effect on the HADS-D subscale. The magnitude of the effect size was 0.61 points HADS-D, however, the clinical implication of this is currently unknown since no minimal clinically important difference (MCID) on the HADS have been established in cancer patients. MCID for the HADS have been established in patients with chronic obstructive pulmonary disease and cardiovascular disease in the magnitude of −1.5 to −1.8 points on a given subscale (Lemay et al., 2018). If we were to apply this to our results the significant findings for HADS-D are below clinical relevance. This coupled with the heterogeneity among the included studies the finding of the current meta-analysis should be interpreted with caution. Future studies should be based on standardized interventions, minimal clinical important differences for applied depression assessment tool should be established and this should be the basis of the sample size calculations. The five psychotherapeutic studies (Fernández-Rodríguez et al., 2017; Fukui et al., 2000; Hanser et al., 2006; Pitceathly et al., 2009; Zhou et al., 2015) and nine out of ten studies classified as “other interventions” (Billhult et al., 2007; Kim et al., 2013; McArdle et al., 1996; Mehnert et al., 2011; Monga et al., 2007; Nangia et al., 2017; Ream et al., 2015; Travier et al., 2015; Van Vulpen et al., 2016) had high risk of bias in blinding of participants. This was due to it not being possible to blind the participants from the intervention allocation. Patient reported outcomes in non-blinded participants has been reported to be exaggerated in randomized controlled trials, whereas, observerreported outcomes shows no exaggeration in effects with non-blinded participants (Hróbjartsson et al., 2014). Pragmatic trials aim to measure the effectiveness of a certain treatment by mimicking clinical practice. Explanatory trials aim to establish a cause and effect relation. Nonblinded pragmatic trials may be more likely to succeed than explanatory trials (Stephenson and Imrie, 1998). Efforts should be made to minimize the risk of performance bias in trials with interventions where blinding is not possible such as psychotherapy, exercise, and

possible (Fernández-Rodríguez et al., 2017; Fukui et al., 2000; Hanser et al., 2006; Pitceathly et al., 2009; Zhou et al., 2015) due to the nature of the intervention. One study had high risk of selection and detection bias (Billhult et al., 2007). Two studies had high risk of attrition bias (Hanser et al., 2006; Pitceathly et al., 2009) of which one also had high risk of reporting bias (Pitceathly et al., 2009). Out of ten studies classified as “other interventions”, only one had blinded participants (Fukui et al., 2008). Some studies had high risk of detection bias (Billhult et al., 2007; Fukui et al., 2008; Kim et al., 2013; McArdle et al., 1996; Mehnert et al., 2011; Monga et al., 2007), high or unclear risk of selection bias (Fukui et al., 2008; McArdle et al., 1996; Monga et al., 2007), and high or unclear risk of attrition bias (Billhult et al., 2007; Mehnert et al., 2011; Monga et al., 2007; Ream et al., 2015). One study had missing information on complementary treatment reported as high risk of other sources of bias (Billhult et al., 2007). When the risk of bias was unclear the corresponding authors of the relevant studies were contacted if possible and asked to elaborate and to clarify the relevant source of bias. To prevent false confirmation open-ended questions were used. One author replied and thus unclear risk of bias was changed to low risk of bias (Fernández-Rodríguez et al., 2017), which is marked with an asterisk in Fig. 5. 4. Discussion The present systematic review and meta-analyses of 18 randomized controlled trials found that prophylactic interventions could prevent depression in patients with cancer. The meta-analyses showed a statistically significant difference between treatment and placebo for pharmacotherapy with a risk ratio of 0.34 (95% CI 0.18; 0.63), for psychotherapy a standardized mean difference of −0.23 (95% CI -0.46; 0.00), and for other kinds of interventions a standardized mean difference of −0.17 (95% CI -0.31; −0.03). In patients with breast cancer, the meta-analysis showed a significant difference in favour of any kind of intervention with a standardized mean difference of −0.20 (95% CI -0.34; −0.07). These results should be interpreted with caution due to risk of bias and large heterogeneity among the included studies as they differed with regard to interventions, depression measurement tools, and cancer diagnoses. Even though we categorized intervention in to three groups, the included studies in the groups were heterogeneous and had limitations. In the pharmacological studies, the melatonin study was underpowered (Hansen et al., 2014b) and the SSRI studies were biased and did not list specific side effects experienced by the participants (Lydiatt et al., 2013, 2008). In the psychotherapeutic studies, the combined music therapy and progressive muscle relaxation training study had a short follow-up period (Zhou et al., 2015). Psychological therapy showed an effect only when a mixed linear model was applied, but no effect with 119

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of assessment varied, as some studies assessed depression 3, 6, and 12 months after baseline. The effect of an intervention might be diluted (i.e. intervention effect size larger under treatment) when measured three or six months after it has ended, thus weakening our analyses. On the contrary, the majority of the studies administered the interventions during the oncological treatment at which time point symptom levels are highest (Bergquist et al., 2007; Hammerlid et al., 1999; Krebber et al., 2014). Delivering a prophylactic intervention in this period seems to be beneficial according to our meta-analyses and it could therefore be argued that preventive treatment should start before or during oncological treatment. Furthermore, the methodological quality of the studies was poor with the majority of studies having either unclear or high risk bias in several domains. One methodological issue faced during this systematic review was the different depression measurement instruments used in the studies making cross study comparison difficult. A review on casefinding instrument for identifying depression in primary care showed that diagnostic interview was better due to the relatively low positive predictive value of a positive screening by a questionnaire (Williams et al., 2002). Two studies used clinician administered tools (Lydiatt et al., 2008; Pitceathly et al., 2009) and one could argue that these studies had more valid assessments than the studies using self-administered questionnaires. Within the self-administered questionnaires HADS was used most often in the included literature. HADS has three categories: normal, borderline and abnormal cases. When used for research purposes that requires inclusion or exclusion of patient with high probability of depression, the upper range of the borderline category is recommended (Zigmond and Snaith, 1983). Therefore, we adopted a cut-off score that indicates the abnormal category. One study confirms this cut-off score for a current major depressive episode (Hung et al., 2012). When comparing across questionnaires difficulties arise as the categorization varies, i.e. the Major Depression Inventory has four categories: No, mild, moderate and severe depression (Bech et al., 2001), and thus differs from how the HADS assess depression. Heterogeneity of cancer diagnoses in the included studies can be seen as both a strength and a limitation. The strength is that prevention of depression is possible in more than one type of cancer patients and different interventions can be utilized for this purpose. The limitation is that interventions that might work on patients with a specific cancer may have no effect on other cancer types, as seen by the analysis of patients with breast cancer (supplementary material: Fig. IX). Patients with certain types of cancer, e.g. oropharyngeal, pancreatic, and breast cancer, have higher prevalence of depression than other cancers (Massie, 2004), and in these groups, prophylactic regimens might be more relevant and warranted. 4.1. Study limitations There are methodological limitations of the current review. Firstly, the potential bias in the actual process of searching, selecting and extracting data is a limitation. In an effort to eliminate this bias, two review authors independently selected and extracted data. Likewise, two authors independently assessed the included studies for risk of bias. Disagreements were discussed within the author group, who also checked the data. Secondly, we only included randomized controlled trials to ensure that the highest level of evidence was included. Therefore, there is a risk of publication bias, meaning that negative studies may have not been published. Likewise, we did not search trial registers or registers of authorities (i.e. Food and Drug Administration and European Medicines Agency) for unpublished trials, which could potentially have resulted in literature been overlooked and leading to inflated effect sizes in our analyses. Lastly, due to the number and the heterogeneity of the studies, we were only able to perform three broad meta-analyses. As multiple calculations increase the risk of producing a statistically significant result by chance alone, the results should be interpreted with caution.

Fig. 5. Risk of bias table.

massage therapy. Such efforts should be reported in the manuscripts (Higgins et al., 2017). Minimizing performance bias in trials with nonblinded participants could be done by securing a blinded assessment of outcomes (Stephenson and Imrie, 1998) or by having a strict protocol on how to treat and monitor patients so that the risk of differential behaviour by patients is reduced (Higgins et al., 2017). Overall the current literature was limited by the fact that only four studies were designed with the primary outcome of preventing depression. Therefore, the majority of the psychotherapeutic interventions and the other kinds of interventions were not created or targeted to prevent depression. This weakens the conclusion that can be drawn from these analyses and there is a gap in the literature investigating prevention of depression in patients with cancer. Likewise, the timing 120

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Fig. 6. Risk of bias graph.

4.2. Future directions

Appendix A. Supplementary data

In the future, trials examining the prevention of depression in patients with cancer should consider the efficacy and side effect of the intervention and how to minimize bias. The use of prophylactic SSRI treatment is questionable due to common adverse effects and some studies show a decreased effect of anti-cancer treatment (Desmarais and Looper, 2009) or no improvement symptoms, wellbeing or survival for cancer patients (Stockler et al., 2007). Based on current evidence, prophylactic treatment with SSRIs in patients with cancer cannot be recommended. An alternative could be melatonin, which has shown a significant effect against depression (Hansen et al., 2014b) and on improving sleep in women with breast cancer (Hansen et al., 2014a; Madsen et al., 2016) and survivors thereof with no apparent adverse effects (Chen et al., 2014; Schernhammer et al., 2012). Future studies should be undertaken with great consideration and with harms and adverse effects as central outcomes.

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