Nonpharmacological Interventions for Depressive Symptoms in End-Stage Renal Disease: A Systematic Review

Abstract

Depressive symptoms are common in patients with end-stage renal disease, which can affect treatment and prognosis. We aimed to evaluate the effects of nonpharmacological interventions for depressive symptoms in end-stage renal disease. Eligible studies were identified using PubMed, Web of Science, the Cochrane Library, Embase, and PsycNET (up to March 2019). We identified 24 studies including 1,376 patients. We found that psychological intervention (−0.60, 95% confidence interval [CI] = [–0.87, –0.33]), exercise (−1.13, 95% CI = [–1.56, –0.69]), and manual acupressure (−0.26, 95% CI = [–0.50, 0.03]) were associated with a significant effect on depressive symptoms. However, few studies reported adverse events, and conclusions about safety should be drawn cautiously. While the available data show that nonpharmacological interventions are potential strategies to alleviate depressive symptoms of patients with end-stage renal disease, recommendation of the most efficacious interventions for this population will require future randomized controlled trials with large-scale, long-term intervention.

Keywords

end-stage renal disease nonpharmacological interventions depressive symptoms

Chronic kidney disease (CKD) is a condition with a long pathological course and is often irreversible; during progression to the final stage (end-stage renal disease [ESRD]) of CKD, patients have to rely on substitutive therapies such as dialysis and kidney transplants for survival. A series of serious clinical issues are faced by patients, including the acknowledgment of a life-threatening diagnosis, substantial long-term treatment costs, understanding dialysis treatment techniques, coping with serious treatment side effects, and multiple complications, among other concerns (Cukor, Cohen, Peterson, & Kimmel, 2007). Therefore, patients bear considerable psychological burden and physical pain. Studies have shown that patients with ESRD develop depression at about 4 times the rate observed in the general population (Hedayati et al., 2008), and the prevalence of depression in patients with ESRD is approximately 23% to 39% (Palmer et al., 2013). Long-term depressive symptoms can cause a series of adverse outcomes, such as poor treatment adherence (Cukor, Rosenthal, Jindal, Brown, & Kimmel, 2009), increased hospitalization (Lopes et al., 2002), a decline in quality of life (Kusztal et al., 2018), and increased mortality (Chilcot et al., 2018). Therefore, health care providers and family members should work to actively treat the physical disease, while also paying attention to the psychological changes a patient may undergo, in an effort to promote the overall rehabilitation of patients.

In recent years, research into nonpharmacological interventions addressing patients’ emotional symptoms, such as psychological interventions (Pascoe, Thompson, Castle, McEvedy, & Ski, 2017), naturopathy (Kim et al., 2016), and exercise (Chung, Yeh, & Liu, 2017; Gomes Neto, de Lacerda, Lopes, Martinez, & Saquetto, 2018), has received widespread attention; Pascoe et al. (2017) examined six studies pertaining to psychosocial interventions for patients with CKD and showed that psychosocial interventions resulted in a moderate improvement effect in depressive symptoms. Kim et al. (2016) found that acupuncture and other associated interventions improved psychological conditions in patients with CKD. Both the studies of Chung et al. (2017) and Zhao et al. (2019) suggested that exercise has a significant positive effect on depressive symptoms. However, previous systematic reviews and meta-analyses included patients suffering from predialysis CKD, ESRD, and kidney transplant; this may be one reason for heterogeneity (Chung et al., 2017; Kim et al., 2016). Renal function decreases significantly in patients with ESRD, and nonpharmacological interventions may be more appropriate for the remission of depressive symptoms. Prior systematic reviews have shown that nonpharmacological interventions can reduce depressive symptoms in the general population and the risk of recurrence of depressive symptoms in adults who have been cured of depression (Clarke, Mayo-Wilson, Kenny, & Pilling, 2015; Farah et al., 2016). This is vital when considering that patients can suffer from significant depressive symptom relapse. Patients with ESRD have complicated treatment regimens, such as dietary and fluid restrictions, and studies have indicated that dialysis patients have lower compliance with the use of antidepressants (Cohen, Norris, Acquaviva, Peterson, & Kimmel, 2007; Kimmel, 2002). Furthermore, a majority of patients have stated their apprehension with the pharmacological side effects, additional renal burden of using various drugs, and an increased financial burden, among several other concerns. These findings suggest that nonpharmacological interventions may be complementary or even serve as an efficacious alternative to traditional drug therapy. Our study is an update on previous studies that have focused not only on psychosocial interventions, but also on the broader impact of other types of nonpharmacological interventions (exercise, acupressure, etc.) on depressive symptoms.

It is necessary to determine the effects of nonpharmacological interventions for depressive symptoms in patients with ESRD. Patients with ESRD are prone to weakness, fatigue, and muscle atrophy, and therefore, physical safety is a prerequisite for implementing any intervention. In this review, first, we aim to determine whether nonpharmacological interventions have significant effects on depressive symptoms in patients with ESRD; second, to determine whether these interventions induce adverse events, which would provide guidance for patients and their families, health care workers, and policy makers to formulate patient-centered treatment regimens.

Method

Criteria for Study Inclusion

In this study, we used eligibility criteria for the inclusion of any research study in which (a) adults (aged ≥18 years) with a diagnosis of ESRD (eGFR < 15 ml/min/1.73 m²) were enrolled, where patients underwent hemodialysis and/or peritoneal dialysis; (b) a nonpharmacological intervention was compared with established traditional clinical care or no care; nonpharmacological interventions, for example, psychosocial interventions include cognitive behavioral therapy (CBT) or problem-solving therapy (PST), and so on, combined with social support components (e.g., education sessions delivered by medical professionals), exercise (e.g., aerobic exercise, resistance exercise, and a combination of aerobic and resistance exercises), physiotherapy (e.g., acupressure), and other type of nonpharmacological intervention; (c) primary outcome of this study interest was depressive symptoms (measured by depression severity scales or the number of subjects who report improvement of depressive symptoms), regardless of as primary outcome or as secondary outcome in eligible interventions, and secondary outcomes were all adverse events including renal transplantation, cardiovascular events, cardiovascular death and all-cause death, and the occurrence of other adverse events (side effects) related to any intervention; and (d) randomized controlled trials (RCTs) were performed. Subjects receiving kidney transplant were excluded.

Search Method

We used Medical Subject Headings (MeSH) and free text words to search eligible literature. We searched five databases, including PubMed, Web of Science, the Cochrane library, Embase, and PsycNET; we did not limit the language of the publication to provide more comprehensive information. The terms used to search for eligible studies included [end stage renal (kidney) disease, dialysis, hemodialysis, peritoneal dialysis], and [depression, depressive symptoms], [randomized controlled trial, clinical study]. All included studies were published prior to March 2019. We also obtained accessible literature through electronic searches for reference lists of original reports, reviews, and guidelines, and then contacted the listed corresponding author to obtain the full-text.

Study Selection and Quality Assessment

Two reviewers (X. W. and Y. W.) worked independently to identify eligible studies by screening titles, abstracts, and full-text. Endnote X8 was used to perform the process of literature screening. Disagreements were resolved by consensus or arbitrated by a third reviewer (Q.-G. Z.). We used the Cochrane Collaboration risk-of-bias tool to evaluate the quality of the included studies, which focuses on the evaluation of parallel groups and single RCTs.

Data Extraction

Data extraction was additionally completed independently by two reviewers (X.W. and Y.W.). Prescribed data collected included recruitment era, location, number of subjects, male–female ratio, and age; characteristics of interventions involved a brief summary of interventions, the form (e.g., individual or group) to deliver the interventions, time point for implementing interventions, duration of intervention and follow-up, and baseline and outcome assessment of depressive symptoms scores. Data and information not reported in the study were obtained by emailing the corresponding author or the first author.

Data Synthesis and Analyses

Continuous data were analyzed using mean difference (MD) and 95% confidence interval (CI); dichotomous data were expressed as relative risk (RR) and 95% CI. The standardized residual value of the random model was calculated by using the standardized residual method. The I² statistic was used to show the degree of heterogeneity: less than 25% is low heterogeneity, 25% to 50% is moderate heterogeneity, and >75% is high heterogeneity. A two-tailed test p < .05 represents the statistical significance of the quantitative analyses. For the heterogeneity test, if p ≥ .1, I² ≤ 50% indicate that the heterogeneity between studies is small, fixed effects model is used; if p < .1, I² > 50% indicate large interstudy heterogeneity, random effects model is used. Potential publication bias was determined through a funnel plot, Begg’s and Egger’s test, and estimation of bias is typically based on the distribution and symmetry of the studies in the funnel plot and p value of Begg’s or Egger’s test. Data statistical analyses were conducted using Review Manager (Rev Man), Version 5.3.

Results

Literature Search

We reported on the literature screening process based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. A total of 966 studies were retrieved in five databases of which 243 duplicates were removed. Thereafter 520 studies were removed after being examined at the title and abstract level according to the inclusion criteria, and the remaining 203 studies were screened for full-text. Subsequently, 183 studies were excluded, leaving 20 papers which met the inclusion criteria. An additional four studies were obtained from the reference lists of other studies. Finally, a total of 24 studies were included in this systematic review.

Characteristics of Identified Studies

The 24 studies included 1,376 patients from 12 countries: Iran (four studies), Taiwan (six studies), Greece (four studies), United States (two studies), with one study each from the remaining countries (Australia, Brazil, India, Malaysia, Mexico, Netherlands, Tunisia, and United Kingdom). Eight studies included multiple centers, 18 studies were single center, and two studies didn’t state the number of centers clearly in the design. Participants of all included studies received facility-based hemodialysis treatment. While Giannaki, Sakkas, et al. (2013) divided subjects into three groups, namely, exercise arm, dopamine agonists arm, and placebo arm without exercise training, we only secured data from the exercise and placebo arms. One study related to acupressure also had three arms, namely, an acupressure arm, sham group, and usual care arm; we acquired data from the acupressure and usual care arms only (Tsay, 2004). Furthermore, an additional study had an acupressure arm, transcutaneous electrical acupoint stimulation (TEAS) arm, and usual care group, and we extracted data from all three arms of this study because both acupressure and the TEAS arm were nonpharmacological interventions. Subjects in all identified studies were aged between 36 and 81 years (Table 1).

Table 1.

Characteristics of Included Studies.

First Author/Location	Number	Male:Female	Age (year)	Intervention	Duration
Mehrabi (2017)^a Iran	E: 25 C: 25	NA	NA	E: Fordyce’s happiness program (CBT), six 20-min weekly group sessions. C: usual care	T: 6 weeks F: 1 month
Lerma (2017)^b Mexico	E: 31 C: 18	E15:16 C8:10	E: 41.8 ± 14.7 C: 1.7 ± 15.1	E: CBT, five 2-hr weekly group sessions. C: none	T: 5 weeks F: 4 weeks
Valsaraj (2016)^a India	E: 33 C: 34	E23:10 C24:10	43-65	E: CBT, ten 50- to 60-min weekly individual sessions. C: usual care	T: 10 weeks F: 6 months
Espahbodi (2015)^a Iran	E: 27 C: 28	NA	E: 49.14 ± 14.54 C: 52.2 ± 15.58	E: psychoeducation, three 1-hr group sessions, every other day before dialysis. C: none	T: 1 month F: 1 month
Erdley (2014)^a United States	E: 15 C: 18	E10:5 C11:7	73.9 ± 7.26	E: PST, six 1-hr weekly group sessions. C: usual care	T: 6 weeks F: 6 weeks
Cukor (2014)^b United States	E: 33 C: 26	E11:27 C7:20	NA	E: CBT, ten 60-min weekly individual sessions. C: usual care	T: 3 months F: 6 months
Chen (2011)^a Taiwan	E: 37 C: 35	E17:20 C13:22	58 ± 11	E: CBT + sleep hygiene education, eighteen 30-min triweekly group sessions. C: usual care	T: 6 weeks F: 6 weeks
Duarte (2009)^b Brazil	E: 41 C: 44	E15:26 C20:24	E: 52.4 ± 15.9 C: 54.0 ± 12.7	E: CBT, twelve 1.5-hr weekly group sessions. C: usual care	T: 3 months F: 9 months
Lii (2007)^b Taiwan	E: 20 C: 28	E10:10 C13:15	NA	E: CBT, eight 2-hr weekly group sessions. C: usual care	T: 2 months F: 1 month
Tsay (2005)^b Taiwan	E: 30 C: 27	E14:16 C13:14	50.72 ± 14.10	E: ATP (CBT), eight 2-hr weekly group sessions. C: usual care	T: 8 weeks F: 1 month
Sharp (2005)^b United Kingdom	E: 29 C: 27	E18:11 C20:7	E: 56.05 ± 12.73 C: 52.52 ± 12.70	E: CBT, four 1-hr weekly group sessions. C: standard care	T: 4 weeks F: 10 weeks
Rahimimoghadam (2017)^a Iran	E: 25 C: 25	E21:4 C20:5	E: 39.1 ± 2.2 C: 38.4 ± 1.8	E: Pilates exercise, 45-min, 3 times/week in nondialysis days. C: routine care	T: 8 weeks F: 1 week
Frih (2017)^a Tunisia	E: 21 C: 20	All males	E: 64.2 ± 3.4 C: 65.2 ± 3.1	E: endurance-resistance training, 60 min, 4 times/week in nondialysis days. C: none	T: 4 months F: none
Rezaei (2015)^a Iran	E: 25 C: 26	E21:4 C14:12	43.27 ± 12.94	E: low-intensity aerobic exercise, 35 min, 3 times/week at home. C: usual care	T: 10 weeks F: 10 weeks
Giannaki (2013)^a Greece	E: 15 C₁: 7 C₂: 7	E11:4 C₁5:2 C₂4:3	E: 56.4 ± 12.5 C₁: 56.8 ± 16.5 C₂: 55.7 ± 10.4	E: aerobic exercise, 45 min, 3 times/week in dialysis days. C₁: usual care (placebo group) C₂: received the classical RLS treatment with dopamine agonist.	T: 6 months T: none
Kouidi (2010)^a Greece	E: 24 C: 20	E14:10 C12:8	E: 46.3 ± 11 C: 45.8 ± 10.9	E: cycling + strengthening training, 60-90 min, 3 times/week in dialysis days. C: none	T: 1 year F: 1 year
Ouzouni (2009) Greece	E: 19 C: 14	E14:5 C13:1	48.8 ± 13.9	E: cycling + strengthening + flexibility exercises, 60-90 min, 3 times/week in dialysis days. C: none	T: 10 months F: 10 months
van Vilsteren (2005)^a Netherlands	E: 53 C: 43	E33:20 C30:13	E: 52 ± 15 C: 58 ± 16	E: strength training + cycling + exercise counseling, 20-30 min, 2-3 times/week in dialysis days. C: none	T: 12 weeks F: 12 weeks
Kouidi (1997)^a Greece	E: 20 C: 11	E11:9 C4:7	E: 49.6 ± 12.1 C: 52.8 ± 10.2	E: cycling, walking or jogging, calisthenics, aerobics exercise, 90 min, 3-4 times/week in nondialysis days. C: usual care	T: 6 months F: none
Cheema (2007)^a Australia	E: 24 C: 25	E17:7 C17:8	E: 60.0 ± 15.3 C: 65.0 ± 12.9	E: high-intensity, progressive resistance training, 2-3 times/week in dialysis days. C: usual care	T: 12 weeks F: none
Hmwe (2015)^b Malaysia	E: 54 C: 54	E30:24 C32:22	58.08 ± 11.4	E: acupressure massage, 15 min, 2-3 times/week in dialysis days. C: usual care	T: 4 weeks F: none
Tsay (2004a)^b Taiwan	E₁: 35 C₁: 35 C₂: 36	36:70	58.16 ± 12.19	E₁: acupressure massage + usual care, 15 min, 2-3 times/week in dialysis days. E₂: sham acupressure massage + usual care C: usual care	T: 4 weeks F: 1 week
Tsay (2004b) Taiwan	E₁: 36 E₂: 36 C: 36	36:70	58.16 ± 12.19	E₁: manual acupressure + usual care, 15 min, 2-3 times/week in dialysis days. E₂: TEAS + routine care C: routine care	T: 4 weeks F: 4 weeks
Cho (2004)^a Taiwan	E: 28 C: 30	E8:20 C17:13	49.5 ± 10	E: acupressure massage, 15 min, 2-3 times/week in dialysis days. C: routine care	T: 4 weeks F: 4 weeks

Note. E = experimental group; C = control group; NA = not available; CBT = cognitive behavioral therapy; F = follow-up after intervention; Age = M ± SD or median [interquartile range] or age range; PST = problem-solving therapy; ATP = adaptation training program; RLS = restless legs syndrome; TEAS = transcutaneous electrical acupoint stimulation; Duration: I = duration of intervention.

Single center.

Multiple centers.

A total of seven measurement scales were used to assess the depressive symptoms of patients (Table 2). The most frequently used scales were the Beck Depression Inventory (BDI; 765 patients, 13 studies) and Hospital Anxiety and Depression Scale (HADS; 266 patients, five studies). Less frequently used questionnaires included the Depression Anxiety Stress Scale–21 (DASS-21; 158 patients, two studies), the General Health Questionnaire–28 (GHQ-28; 158 patients, two studies), Self-Rating Depression Scale (SDS; 118 patients, two studies), Beck Depression Inventory–II (BDI-II; 59 patients, one study), and Geriatric Depression Scale (GDS; 49 patients, one study). The majority of participants in the included studies had mild or moderate depressive symptoms, whereas four studies recruited participants with severe symptoms (Cukor et al., 2014; Duarte, Miyazaki, Blay, & Sesso, 2009; Kouidi et al., 2010; Rezaei, Abdi, Rezaei, Heydarnezhadian, & Jalali, 2015). This was determined via baseline depression scores of the participants. Two studies did not specify the severity of depression at baseline (Table 2).

Table 2.

Baseline and Outcome Score for Depressive Symptoms.

First Author	Measurement Tool	Baseline Scores				Outcome Scores
		Intervention Group		Control Group		Intervention Group		Control Group
		M	SD	M	SD	M	SD	M	SD
Mehrabi (2017)	DASS-21	9.2	4.4	9.04	5.2	3.8	3.1	9.1	4.7
Lerma (2017)	BDI	13.6	7.6	15.8	10.0	7.1	7.2	14.7	9.7
Valsaraj (2016)	HADS	11.85	2.15	11.21	2.53	6.73	1.53	9.74	2.71
Espahbodi (2015)	HADS	10.22	3.40	10.07	3.39	8.33	3.72	10.11	3.39
Erdley (2014)	BDI	15.7	8.0	10.7	6	9.3	3.1	11.3	7.4
Cukor (2014)	BDI-II	24.7	9.8	21.9	8.9	9.9	8.5	9.1	6.5
Chen (2011)	BDI	16.8	8.8	15.7	13.2	13.8	11.5	16.1	14.2
Duarte (2009)	BDI	24.2	9.7	27.3	10.7	10.8	8.8	17.6	11.2
Lii (2007)	BDI	15.90	9.89	12.18	8.92	12.85	6.64	21.39	15.10
Tsay (2005)	BDI	21.07	11.54	12.07	9.18	13.28	6.03	21.56	15.37
Sharp (2005)	HADS	6.66	3.06	7.07	4.67	6.27	3.00	6.91	3.83
Frih (2017)	HADS	14.9	2.1	15.1	2.1	8.8	1.7	13	1.2
Rahimimoghadam (2017)	GHQ-28	11.7	3.5	11.7	6.6	8.6	3.06	10.4	2.4
Rezaei (2015)	BDI	23.80	10.29	19.23	12.98	12.64	11.07	26.11	13.72
Giannaki (2013)	SDS	43.45	8.06	37.85	12.15	35.84	6.38	43.71	11.17
Kouidi (2010)	BDI	22.29	6.71	22.30	6.81	14.61	4.15	22.1	6.24
Ouzouni (2009)	BDI	19.3	4.9	19.2	3.3	11.7	3.6	19.4	4
Cheema (2007)	GDS	7.2	7.1	8.1	6.4	6.9	3.6	9.1	2.9
van Vilsteren (2005)	SDS	36.2	7.8	39.0	8.7	37.2	8.3	41.4	9.6
Kouidi (1997)	BDI	21.0	10.4	21.7	10.4	13.7	9.5	21.3	11.9
Hmwe (2015)	DASS-21	11.59	8.62	10.26	8.13	9.48	7.64	10.41	8.38
Tsay (2004a)	BDI	E¹: NA E²: NA		NA		E¹: 20.37 E²: 18.20	10.65 11.11	21.61	11.69
Tsay (2004b)	BDI	E¹: NA E²: NA		NA		E¹: 13.52 E²: 12.62	8.82 7.55	18.88	9.55
Cho (2004)	BDI	13.0	7.1	12.4	8.0	10.1	9.3	14.9	7.3

Note. Criteria for depressive symptoms: Depression Anxiety Stress Scale–21 (DASS-21): 0-9 is normal, 10-13 is mild, 14-20 is moderate, 21-27 is severe, and >28 is extremely severe; Beck Depression Inventory (BDI): 10-16 is mild, 17-29 is moderate, >30 is severe; Hospital Anxiety and Depression Scale (HADS): 0-7 is normal, 8-10 is borderline case, 11-21 is abnormal; Beck Depression Inventory–II (BDI-II): 0-13 is normal, 14-19 is mild, 20-28 is moderate, 29-63 is severe; General Health Questionnaire–28 (GHQ-28): total score ≥ 5 is abnormal mental health status; Self-Rating Depression Scale (SDS): 53-62 is mild; 63-72 is moderate; >72 is severe; and Geriatric Depression Scale (GDS): 0-10 is normal, 11-20 is mild, 21-30 is moderate to severe. E = experimental group; C = control group.

Quality Assessment

As can be seen in Figure 1, on each evaluation criterion, the majority of RCTs were rated as having a low risk of bias, which results in the reasonable assumption of the evidence being reliable. Twelve studies were rated as having a low risk of bias in random sequence generation (Cheema et al., 2007; Chen et al., 2011; Erdley et al., 2014; Frih et al., 2017; Giannaki, Sakkas, et al., 2013; Hmwe, Subramanian, Tan, & Chong, 2015; Lerma et al., 2017; Lii, Tsay, & Wang, 2007; Mehrabi, Ghazavi, & Shahgholian, 2017; Sharp, Wild, Gumley, & Deighan, 2005; Tsay, 2004; Valsaraj, Bhat, & Latha, 2016). Three studies were rated as having a low risk of bias in allocation concealment (Cheema et al., 2007; Duarte et al., 2009; Sharp et al., 2005). Eight studies using a single-blind experimental model (Cheema et al., 2007; Cukor et al., 2014; Duarte et al., 2009; Lerma et al., 2017; Ouzouni, Kouidi, Sioulis, Grekas, & Deligiannis, 2009; Sharp et al., 2005; Tsay, Lee, & Lee, 2005; Valsaraj et al., 2016) and five using a double-blind (Frih et al., 2017; Giannaki, Sakkas, et al., 2013; Hmwe et al., 2015; Lii et al., 2007; Tsay, 2004) were rated as having a low risk of bias.

Figure 1.

Risk of bias of the included studies.

Psychological Intervention

Eleven trials (n = 631) evaluated psychological intervention compared with a control group (Chen et al., 2011; Cukor et al., 2014; Duarte et al., 2009; Erdley et al., 2014; Espahbodi, Hosseini, Mirzade, & Shafaat, 2015; Lerma et al., 2017; Lii et al., 2007; Mehrabi et al., 2017; Sharp et al., 2005; Tsay et al., 2005; Valsaraj et al., 2016). These interventions help patients improve their mental state by providing psychological methods (e.g., CBT, PST) combined with social support (e.g., educational programs). Overall, using a random effect model, psychological interventions showed an effect of relieving depressive symptoms, –0.60, 95% CI = [–0.87, –0.33], p < .01, with a moderate heterogeneity (I² = 64%; Figure 2). The psychological intervention format in this group of studies was face-to-face individual or group educational sessions. Depressive symptoms were measured using BDI in seven studies (Chen et al., 2011; Cukor et al., 2014; Duarte et al., 2009; Erdley et al., 2014; Lerma et al., 2017; Lii et al., 2007; Tsay et al., 2005), one of which used BDI-II, HADS in three studies (Espahbodi et al., 2015; Sharp et al., 2005; Valsaraj et al., 2016), and DASS-21 in one study (Mehrabi et al., 2017). Intervention duration for all studies ranged from 1 to 3 months.

Figure 2.

Forest plot comparison of psychological intervention.

Exercise

Nine trials (n = 417) evaluated exercise compared with a control group (Cheema et al., 2007; Frih et al., 2017; Giannaki, Hadjigeorgiou, et al., 2013; Kouidi et al., 1997, 2010; Ouzouni et al., 2009; Rahimimoghadam, Rahemi, Mirbagher Ajorpaz, & Sadat, 2017; Rezaei et al., 2015; van Vilsteren, de Greef, & Huisman, 2005). Overall, using a random effect model, exercise had a significant effect on depressive symptoms (−1.13, 95% CI = [–1.56, –0.69], p < .01) with high heterogeneity (I² = 75%; Figure 3). These interventions help patients improve their mental state by providing regular exercise training. One study used pilates, three studies conducted aerobic exercises, three studies implemented cycling and strengthening training, and one study used high-intensity, progressive resistance training. Two studies were conducted on nondialysis days (Kouidi et al., 1997; Rezaei et al., 2015) and the remaining seven studies were implemented on dialysis days. The subjects of one study conducted exercise interventions at home, with regular contact via telephone and an interview at the dialysis ward to ensure compliance with the exercise plan (Rezaei et al., 2015). The remaining eight studies were conducted at a dialysis center or a specialized sports laboratory. For the measurement of depressive symptoms, BDI was used in four studies (Kouidi et al., 1997, 2010; Ouzouni et al., 2009; Rezaei et al., 2015), and HADS (Frih et al., 2017), GHQ-28 (Rahimimoghadam et al., 2017), SDS (Giannaki, Sakkas, et al., 2013; van Vilsteren et al., 2005), and GDS (Cheema et al., 2007) were used in five studies each. Intervention duration for all studies ranged from 2 months to 1 year.

Figure 3.

Forest plot comparison of exercise.

Acupressure

Four trials (n = 308) evaluated acupressure compared with a control group (Cho & Tsay, 2004; Hmwe et al., 2015; Tsay, 2004; Tsay, Cho, & Chen, 2004). Acupressure is a massage technique to adjust and balance the Qi or energy of the human body, promote and sustain health, and prevent disease (Maxwell, 1997). The operator uses fingers and palms to stimulate the body’s acupuncture points and meridians with appropriate force. Overall, using a fixed effect model, acupressure had a significant effect on depressive symptoms (−0.36, 95% CI = [–0.57, –0.14], p < .01) with a moderate heterogeneity (I² = 63.8%). Four studies on manual acupressure showed positive effects (−0.26, 95% CI = [–0.50, 0.03], p = .03) with no heterogeneity (I² = 3%; Figure 4). There was only one study on TEAS, so the results are unconvincing. The manual acupressure procedure for these four studies were 3-min relaxing massage and 12-min acupoints massage for 1 month, and all four studies had this intervention conducted on dialysis days. As for the measurement of depressive symptoms, BDI was used in three studies (Cho & Tsay, 2004; Tsay, 2004; Tsay et al., 2004) and DASS-21 was used in one study (Hmwe et al., 2015). Intervention duration for all studies was 1 month.

Figure 4.

Forest plot comparison of acupressure.

Secondary Outcomes

There are two studies (Chen et al., 2011; Kouidi et al., 2010) that definitely reported that no adverse events occurred during trial; however, two studies (Cheema et al., 2007; Hmwe et al., 2015) reported adverse events related to the intervention. In the study of Hmwe et al. (2015), some subjects receiving manual acupressure had side effects, including hypotension (11 patients), palpitation (two patients), headache (one patient), and dizziness (six patients). In the progressive resistance training conducted by Cheema et al. (2007), an elderly woman experienced muscle tears during training. One subject in the intervention group in three studies (Duarte et al., 2009; Giannaki, Hadjigeorgiou, et al., 2013; Sharp et al., 2005) withdrew from the trial after renal transplantation, and one subject in each of two studies (Duarte et al., 2009; Rezaei et al., 2015) underwent kidney transplant and withdrew from the trial. Cardiovascular events and cardiovascular deaths were not clearly reported. All-cause death resulted in two (Lerma et al., 2017), one (Rezaei et al., 2015), four (Duarte et al., 2009), and three (Sharp et al., 2005) subjects in the intervention groups being withdrawn from the studies. Furthermore, in the control groups, of three studies, one (Lerma et al., 2017), four (Duarte et al., 2009), and two (Sharp et al., 2005) subjects were withdraw from the research due to all-cause death (Table 3).

Table 3.

Evaluation of Adverse Events on the Trials.

Author	Adverse Event
Author	Renal Transplantation (n)	Cardiovascular Events (n)	Cardiovascular Death (n)	All-Cause Death (n)	Other (n)	Dropout (n)
Frih (2017)	NA	NA	0	0	NA	E = C = 0
Lerma (2017)	NA	NA	NA	E: 2 C: 1	NA	E: 7 C: 4
Mehrabi (2017)	NA	NA	0	0	NA	E: 3 C: 3
Rahimimoghadam (2017)	NA	NA	NA	NA	NA	E = C = 0
Valsaraj (2016)	NA	NA	NA	NA	NA	E: 7 C: 6
Espahbodi (2015)	NA	NA	NA	NA	NA	E: 3 C: 2
Hmwe (2015)	0	0	0	0	E: 2^a C: 0	E: 3 C: 3
Rezaei (2015)	E: 0 C: 1	NA	0	E: 1 C: 0	NA	E: 10 C: 9
Cukor (2014)	1	NA	NA	NA	NA	E + C = 6
Erdley (2014)	NA	NA	NA	1	NA	E: 2 C: 0
Giannaki (2013)	E: 1 C: 0	0	0	0	0	E: 1 C: 1
Chen (2011)	NA	0	0	0	0	E + C = 3
Kouidi (2010)	NA	0	0	0	NA	E: 1 C: 5
Duarte (2009)	E: 1 C: 1	NA	NA	E: 4 C: 4	NA	E: 10 C: 6
Ouzouni (2009)	0	0	0	0	NA	E: 1 C: 1
Cheema (2007)	0	0	0	0	E: 1^b C: 0	E: 4 C: 1
Lii (2007)	NA	NA	0	0	NA	E + C = 12
Tsay (2005)	NA	NA	0	0	NA	E: 3 C: 6
Sharp (2005)	E: 1 C: 0	NA	NA	E: 3 C: 2	NA	E: 6 C: 4
van Vilsteren (2005)	NA	NA	0	0	NA	E: 7 C: 0
Cho (2004)	NA	NA	0	0	NA	E: 3 C: 1
Tsay (2004a)	NA	NA	NA	NA	NA	E = C = 0
Tsay (2004b)	NA	NA	NA	NA	NA	E = C = 0
Kouidi (1997)	0	0	0	0	0	E = C = 0

Note. E = experimental group; C = control group, dizziness (six patients), palpitation (two patients), headache (one patient).

Hypotension (11 patients).

Muscle tear.

Publication Bias and Sensitivity Analysis

Among the three nonpharmacological interventions, only for psychological intervention, sufficient studies (11) were available to be included in a funnel plot analysis. As shown in Figure 5, three studies fall outside the 95% CI, and the p value of Begg’s and Egger’s test is greater than .05, indicating that this phenomenon may be due to heterogeneity between studies. To determine the stability of the three nonpharmacological interventions, sensitivity analysis revealed that after removing any of the studies there was no significant change in I².

Figure 5.

Funnel plot of the identified studies related to psychological intervention.

Discussion

This review evaluated the effects of three nonpharmacological interventions for depressive symptoms of patients with ESRD, and the results suggest that psychological intervention, exercise, and manual acupressure have significant effects on depressive symptoms in patients with ESRD. However, a few of the identified studies reported adverse events associated with intervention measure and, as such, we were unable to confirm the safety of the intervention measures.

Patients with ESRD are prone to developing significant psychological symptoms related to their disease and treatment. They often feel helpless and find it difficult to cope when confronted with the significant health-related stressors (Cukor et al., 2007). A series of studies confirmed that psychological interventions based on theoretical frameworks are effective for decreasing depressive symptoms in patients with ESRD (Cukor et al., 2014; Duarte et al., 2009; Erdley et al., 2014; Lerma et al., 2017; Mehrabi et al., 2017; Tsay et al., 2005). CBT is based on cognitive learning and behavior theory and, through strategies and techniques (e.g., behavioral activation, cognitive restructuring, problem-solving, and relaxation activities), it is used to change the mind-set and attitudes of patients with chronic diseases (White, 2002). In the current study, 11 studies used face-to-face group or individual education sessions at dialysis or renal outpatient centers provided by trained clinical psychotherapists, nephrologists, and clinical nurse specialists. Internet-based interventions have gained popularity in recent years. One study conducted Internet-delivered, CBT education lessons, researchers contacted participants via telephone and email regularly, and participants showed clinically significant improvements in depression, anxiety, and general distress (Chan, Dear, Titov, Chow, & Suranyi, 2016). Furthermore, another study conducted positive psychological interventions via teaching subjects to participate in associated activities, for instance, focusing on daily positive events, positive reappraisal of stressful events, and simple mindfulness meditation practices. Results from that study showed that the patients’ depressive symptoms were significantly improved (Hernandez et al., 2018). Internet-delivered psychological intervention may overcome some barriers associated with traditional face-to-face education sessions, such as time, distance, and mobility (Titov, 2011; Titov et al., 2015). However, the effects of psychological interventions in ESRD utilizing telemedicine still require further exploration as there remain only a limited number of single-group designed studies. Only Duarte et al. (2009) recruited hemodialysis patients who were also diagnosed with major depression symptoms, and results demonstrated that in this group also CBT could reduce severe depressive symptoms. Therefore, there remains a significant need for exploration of the effects of nonpharmacological interventions for severe depressive symptoms in ESRD.

Regular exercise can improve mental function, reduce depression and anxiety, and improve temperament and happiness through increased growth, cortisol, and serotonin hormone release in the body (Krogh, Nordentoft, Mohammad-Nezhad, & Westrin, 2010). Our study showed that exercise could attenuate the depressive symptoms in ESRD patients. However, various measurement scales and different forms and durations of exercise were performed, which led to heterogeneity of the combined results. We found that, with the exception of the study by Cheema et al. (2007), which involved a high-intensity resistance training, all studies included in our analysis used low to moderate intensity aerobic exercise and/or strength training. Interestingly, the study by Cheema et al. (2007) was also the only study that did not observe a statistically significant improvement of depressive symptoms. This phenomenon may be due to the older age of participants (62.6 ± 14.2 years) in that study and could suggest that high-intensity training is not suitable for this demographic of ESRD patients. Only one of the included studies conducted a home-based low-intensity aerobic exercise intervention (Rezaei et al., 2015), and it showed that the intervention group secured a significant improvement in depressive symptoms. Exercises conducted in dialysis centers or sports laboratories are directly monitored by professionals, whereas home-based exercise regimes are mainly conducted by the patients themselves. This may help promote the integration of exercise training into the daily life of the patients and in forming a consistent healthy lifestyle. The effects of additional formats of physical activity, such as Qi gong and Tai Chi, on emotional symptoms in ESRD patients are still unknown and we suggest that they should be explored in future work.

Through fingers to stimulate the acupuncture points able to regulate hormonal and neurological functions, acupressure can improve sleep and general health condition, which can benefit to reduce psychological symptoms (Lane, 2009). Our review indicated that acupuncture also has a positive effect on depressive symptoms. However, it is important to note that participants in the four studies were predominantly occupied by Chinese subjects. The positive effect seen in these studies may be affected by the traditional belief in the treatment effects of acupressure among these patients. As we only retrieved four studies related to acupressure and one of the studies reported adverse events related to this intervention, caution as to the effectiveness of this intervention modality is required. More analysis on more groups is therefore needed.

Regarding adverse events, two studies reported adverse events associated with interventions. Our findings agree with previous studies which reported that acupressure can cause headache, muscle cramps, and fatigue (Harris et al., 2005). Hmwe et al. (2015) observed adverse events, including hypotension and dizziness during or after acupressure. Hypotension is one of the complications encountered during hemodialysis treatment (Chang et al., 2011; Inrig, 2010). This suggests that researchers should explore the use of acupressure on nondialysis days to mitigate adverse effects in future studies. Another reported adverse event in this study was related to resistance training (Cheema et al., 2007). Specifically, muscle tears occurred in an elderly subject during intense exercise. This indicates that there are some considerations that should be addressed in future studies related to intense exercise. The predisposing factors for the risk of injury should be identified to adjust the movements and loads in any exercise program, and preventive measures should be implemented to decrease the potential of injuring subjects.

This review has several strengths. The primary strength is that it demonstrates the effectiveness of three nonpharmacological interventions for depressive symptoms in patients with ESRD, encouraging patients to seek a variety of treatments to reduce their symptoms. Furthermore, all included studies were RCTs, so the combined results were robust. However, this review also has some limitations. First, while all eligible studies used depression severity scales to measure depression symptoms, some were excluded as they only reported data graphically, which limited our ability to examine the data further, and qualified research works were limited to electronic database searches; however, additional manual searches for specific journals and ancestral searches will be more comprehensive. Second, more than two thirds of the studies were single-center studies, and this may limit the generalization of results. In addition, the small sample size and inclusion of a majority of participants with only mild to moderate depressive symptoms likely diminished the probability of finding statistically significant results. Furthermore, most of the studies examined only had short durations of intervention and follow-up times, and adverse events were not reported. As such we could not determine whether there were adverse events in many studies, and this limited our analysis of the long-term effects and safety of the individual interventions. Moreover, this review did not conduct a subgroup analysis due to the varying durations of interventions in the various studies and the insufficient number of studies using partial scales. In addition, with regard to evaluation criterion of allocation concealment and blinding of subjects and outcome assessments, it was either unclear or we determined there was a high risk of the subjects being unblinded in many of the studies. This is due to the nature of nonpharmaceutical interventions, which are difficult to implement in a blind manner and can cause higher rates of selection and performance bias. Finally, the subjects included in the current study were all patients receiving hemodialysis; thus, the conclusions should be applied cautiously to patients on peritoneal dialysis.

Nonpharmacological interventions are a promising approach for ESRD patients with depressive symptoms. This review indicated that psychological intervention, exercise, and manual acupressure result in significant improvements of depressive symptoms in patients with ESRD. Future studies should pay special attention to the most sensitive and specific types of nonpharmacological interventions which consider the patient’s physical condition and preference, while also addressing the optimal time to conduct the intervention. Studies have shown that patients on a peritoneal dialysis regime also emerge with high levels of depressive symptoms (Yu, Yeoh, Seow, Luo, & Griva, 2012) and, as such, there is still a need to explore additional nonpharmacological interventions effective for this population. This review only included RCTs for three types of nonpharmacological interventions as other studies using additional types of nonpharmacological interventions lacked the strict design of RCTs. The effects of other types of nonpharmacological interventions for depressive symptoms of patients with ESRD remain to be explored.

Footnotes

Acknowledgements

Presenting ideas and study design, data acquisition and statistics, and article drafting were done by Xin Wen; data acquisition and statistics were done by Yu Wang and Qiuge Zhao; article drafting or revision were done by Hongrui Zhang, Huage Shi, and Mengmeng Wang; and study design and article revision were done by Pingjing Lu. Heartfelt thanks to all the authors for their efforts in this study.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Xin Wen

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