Depression among caregivers of cancer patients: Updated systematic review and meta‐analysis

Abstract Background It is imperative to provide care for patients with terminal illnesses such as cancer, though it demands time, financial resources and other unmet needs. Subsequently, caregivers might be exposed to psychological stress and other mental health problems. Previous meta‐analysis finding shows caregivers of cancer patient suffer from depression. During the past 4 years, there has been a considerable increase in the number of newly studies, and we therefore intended to update this finding and provide current global prevalence of depression among caregivers of Cancer patients. Methods We searched PubMed, SCOPUS, CINAHIL, Embase, and PsychINFO to identify peer‐reviewed studies which reported the prevalence of depression among caregivers of cancer patients using pre‐defined eligibility criteria. Studies were pooled to estimate the global prevalence of depression using a random‐effect meta‐analysis model. Heterogeneity was assessed using Cochran's Q and I 2 statistics. Funnel plot asymmetry and Egger's regression tests were used to check for publication bias. Result Our search identified 4375 studies, of which 35 studies with 11,396 participants were included in the meta‐analysis. In the current review, the pooled prevalence of depression among caregivers of Cancer patients was 42.08% (95% CI: 34.71–49.45). The pooled prevalence of depression was higher in the studies that used cross‐sectional data (42%, 95% CI: 31–52) than longitudinal data (34%, 95% CI: 18–50). We also observed a higher rate of depression among female caregivers when compared to their male counterparts (57.6%) (95% CI: 29.5–81.5). Conclusion Globally, around two in five cancer patient caregivers screened positive for depression, which needs due attention. Routine screening of depressive symptoms and providing psychosocial support for caregivers is crucial.


| BACKGROUND
Globally, Cancer is the leading cause of mortality, accounting for approximately 10 million deaths in 2020. 1 Caregivers of cancer patients play an essential role in reducing mortality of cancer patients through effective palliative care and supporting clinical management. 2 More than 90% of individuals living with Cancer have a caregiver (a friend or family member) who can provide care throughout their disease and treatment. 3 Caregivers play a leading role in community-based models of cancer care, 4 and their position can extend for several years. 5 Even though some caregivers recognize their role positively, 6 the health impact of caring is substantial. 7 But some caregivers consider the role as an obligation, perceiving they don't have other options. 2 Despite caregivers' critical but demanding role, they are not getting enough support. 4,8,9 As a result, caregivers experience unmet needs, 10 leading to psychological distress. 11 Besides, the diagnosis of Cancer itself can also have an adverse impact on the mental health of a family caregiver. 12 Caregivers of terminal cancer patients may suffer an even higher burden as the patient's health condition deteriorates, leading caregivers to be physically and emotionally exhausted. 13 Studies demonstrate that the caregiver's burden might increase because of the unmet need of the patient. 14 The burden caregivers of cancer patients experience is strongly linked with the patient's well-being. 15 If the unmet needs of caregivers of cancer patients are not addressed, it will affect the psychological well-being of caregivers 16 and the health outcomes of cancer patients. 17 Epidemiological studies reported a higher rate of depression (12%-59%) 18 and anxiety (30%-50%) 15,18 among caregivers of cancer patients. A study conducted on family caregivers of home-based palliative care patients (n = 300), found that around half of the caregivers (50%) met the criteria for psychological distress. 19 A global level systematic review and meta-analysis reported a pooled prevalence of 42.3% depression and 46.55% anxiety among caregivers of Cancer patients. 20 Surprisingly, this high burden of mental health problems among caregivers didn't get attention and is sub- sequently not yet addressed clinically. 21 Caregivers' mental health can be enhanced by providing routine psychosocial support. 22

| Eligibility criteria
In the current review, we have included observational studies reporting the prevalence of depression among caregivers of Cancer patients and published in English language. Eligible studies included for this review had to fulfil the following criteria: first, the type of study has to be observational (cross-sectional, nested case-control, or follow-up studies). Follow-up studies are longitudinal studies that employed continuous or repeated measures to follow individual Caregivers of cancer patients over time. Second, the study participants should be adults (whose age is greater than or equal to 18 years). Third, the measurement of depression has to be a diagnostic or validated screening tool.
Studies that reported the pooled prevalence of depression, RCTs (Randomised Controlled Trials) had a poor quality score on the New Castle Ottawa Scale (NOS), duplicate studies, conference proceedings, commentaries, abstracts, reports, short communications and letters to editors were excluded.

| Data extraction and study quality assessment
Data were extracted using a specific form developed by authors. The data extraction form included the following information: Name of the author, year of publication, country, study design, sample size, tools used to assess depression, the number of positive cases for depression, the prevalence of depression, stage of cancer, a primary site of cancer, and the relationship of caregivers with the patient. AB conducted the primary data extraction, and then BD assessed the extracted data independently. Any disagreements and discrepancies were resolved through discussion with the third author GD.
The methodological qualities of each included article were assessed by using a modified version of the Newcastle-Ottawa Scale. 28 The methodological quality and eligibility of the identified articles were evaluated by two reviewers (AB and GD), and disagreements among reviewers were resolved through discussion with the third Author (BD). Finally, studies with a scale of ≥5 out of 10 were included in the current meta-analysis.

| Data analysis
The prevalence report extracted from all the included primary studies were meta-analyzed. We have examined publication bias by visual inspection of a funnel plot and Egger's regression test. 29,30 A p-value <0.05 was used to declare the statistical significance of publication bias. Studies were pooled to estimate pooled prevalence and 95% CI using a random-effect model. 31 We have assessed heterogeneity using Cochran's Q and I 2 statistics. 32 I 2 statistics is used to quantify the percentage of the total variation in the study estimate due to heterogeneity. Due to the presence of significant heterogeneity, we have conducted a subgroup analysis based on the study design, gender of participants, and the type of tool used to detect depression. All the extracted data were analyzed using STATA 16.

| Identification of studies
We retrieved a total of 4375 records via bibliographic databases searching. After removing duplicates, 3056 records were contained for title screening. Then, after removing 2311 records because of the irrelevance of the topic to the review criteria, 745 studies were retrieved for abstract screening. Seven hundred articles were excluded during the abstract screening because of the discrepancy between the study results and our review objective. Subsequently, the remaining 45 full-text articles were assessed for eligibility. Of these screened full-text articles (n = 45), 14 new articles, together with four articles identified through reference searching fulfilled the criteria for our meta-analysis. Then, together with 17 studies from the previous review, 16 a total of 35 articles were included in the current updated systematic review and meta-analysis ( Figure 1). Table 1 has summarized the key characteristics of the studies included in this systematic review and meta-analysis. The sample size of study participants who completed a study ranged from 41 33 up to 2743 participants. 34 The studies included in this review were available online between the year 1998 35 and 2018. 36 Seven studies were conducted using a prospective longitudinal study design [37][38][39][40][41][42][43] whereas the remaining twenty eight studies used a cross-sectional study design to examine depression among caregivers of cancer patients.

| Characteristics of included studies
Of the thirty five studies included, ten studies were from USA, 33,35,37,38,[44][45][46] four studies from South Korea, and two studies each from Canada, Australia, Denmark, China, Taiwan and Turkey.

| The quality of studies included in the review
The methodological quality of studies included in this review was assessed by the modified version of the Newcastle-Ottawa Scale. 28 Of the total thirty-five studies checked for methodological quality, twenty-two (64.5%), nine (19.4%), and four studies (12.9%) were of high (NOS score ≥8), moderate (NOS score 6-7) and low methodologic quality, respectively (Table 1).

| Meta-analysis
Globally, the pooled prevalence of depression among caregivers of  Table 2 has presented the findings of subgroup analysis. The prevalence of depression that was noted in this review was diverse by the methodological designs the studies followed, the tools the studies used to measure depression, the stages of cancer, and the gender of participants.

| Subgroup analysis and publication bias
The pooled prevalence of depression among caregivers of cancer patients differed when the methodological designs of the studies varied. For example, the pooled prevalence of depression in the studies that used a cross-sectional study design (42.2%) was higher than those studies that have followed a longitudinal study design (33.6%).    The pooled prevalence in the current review was comparable with a pooled prevalence reported by a previous systematic review and meta-analysis (42.3%) conducted before 4 years. 20 However, the pooled prevalence of depression in the current study was remarkably higher than the prevalence of depression cases among a general population reported in 2015 (9%). 67 This high prevalence of depression among caregivers of cancer patients might be due to providing care for the patient for long hours per day without getting enough support. 4,8,9 Besides, those caring for terminal cancer patients may suffer from an even higher burden as the patient's health condition deteriorates, leading caregivers to be physically and emotionally exhausted. 13 Our review also indicated caregivers included in 12 studies (n = 6168) care for terminally ill cancer patients. Furthermore, the unmet need of the patient can also lead caregivers to experience psychological distress. 14 The subgroup analysis conducted using the study design as a moderator demonstrated that the pooled prevalence of depression in the studies that used a cross-sectional study design (42%) was higher than studies which followed a longitudinal study design (34%).
The possible reason for a higher prevalence of depression among cross-sectional studies might be due to the effect of decreasing participation rates over time on longitudinal studies. 68 Participant non-response is higher among the most vulnerable members of society, such as those with young age, economically poor and poor health conditions. Therefore the absence of these individuals from longitudinal studies might lower the prevalence of depression, as these individuals are most likely to experience poor mental health. whereas the lowest pooled prevalence was observed in the study that used DSM-IV (5%). This might be due to many studies included in the current meta-analysis used CES-D (i.e., 19 out of 35 studies (54.3%)) and BDI (i.e., 4 out of 31 studies (11.4%)) to examine depressive symptoms across studies, which is a highly sensitive screening tool compared to others, 69 suggesting the possibility of overestimation of depression rate. DASS-21 is also a screening tool for probable depressive symptoms, which is highly sensitive in case Our subgroup analysis indicated that the prevalence of depression among female caregivers (57.6%) was higher than that of males (34.4%). The higher prevalence of depression among female caregivers could be because females are highly exposed to sexual violence and have a higher rate of experiencing mental health problems such as depression than males. 70 Also, the diatheses stress model of depression indicated a preponderance of depression among female caregivers, making them more susceptible to depression when facing stressful life events. 71 Furthermore, biological theories suggest that the genetic susceptibility of depression is also higher among females compared to males. 72,73 The result suggests more emphasis should be given to female caregivers of cancer patients.

| Study limitations
The following are the limitations of our review, which need to be considered when inferring our findings. First, all the included studies were only from middle and high-income countries, which lacks representativeness of low-income countries. Second, we have included only articles published in English, which might introduce selection bias. Third, it is essential to note the difference between depression assessment tools across the studies could also be a potential limitation. Lastly, most studies included in the current review employed a cross-sectional design, which has the limitation of providing evidence of a temporal relationship between exposure and outcome.

| CONCLUSION
Our review found that, globally around two in five cancer patient caregivers screened positive for depression, which needs due attention. Early screening of depressive symptoms and targeted psychosocial intervention for caregivers of Cancer patients is highly recommended. Also, expanding on other evidence-based practices related to addressing depression among caregivers of cancer patients would be beneficial. Further studies should be conducted to examine the possible reasons for a higher prevalence of depression among caregivers of Cancer patients.

AUTHOR CONTRIBUTIONS
The author Asres Bedaso performed the search, quality appraisal, data extraction, analyses, and writing the draft of the initial manuscript. Bereket Duko and Getiye Dejenu participated in quality appraisal, and data extraction. Getiye Dejenu contributed to the consensus. All authors participated in revising the draft manuscript, and approved the final manuscript.