Kidney360 Publish Ahead of Print, published on January 7, 2021 as doi:10.34067/KID.0003142020

The Effectiveness of Depression Treatment for Adults with End-Stage Kidney Disease: A Systematic

Review

Pavan Chopra,1 Chelsea K. Ayers,2 Jennifer R. Antick,3,4 Devan Kansagara,1,2,5 Karli Kondo2,6

1Department of Medicine, Oregon Health & Science University, Portland, Oregon; 2Evidence Synthesis

Program, VA Portland Health Care System, Portland, Oregon; 3School of Graduate Psychology, Pacific

University, Hillsboro, Oregon; 4Legacy Good Samaritan Medical Center, Portland, Oregon; 5Center to

Improve Veteran Involvement in Care, VA Portland Health Care System, Portland, Oregon; 6Research

Integrity Office, Oregon Health & Science University, Portland, Oregon

Correspondence: Karli K. Kondo, PhD

VA Portland Health Care System, Mail Code R&D 71

3710 SW US Veterans Hospital Road

Portland, OR 97239-2999

(503) 220-8262 ext. 51837; [email protected]

1

Copyright 2021 by American Society of Nephrology. ABSTRACT

Adults with dialysis-dependent end-stage kidney disease (ESKD) experience higher rates of depression than the general population, yet efficacy of depression treatments in this population is not well understood. We conducted a systematic review of the benefits and harms of depression treatment in adults with ESKD. We searched multiple data sources through June 2020 for English-language controlled trials that compared interventions for depression in adults with ESKD to another intervention, placebo, or usual care, and reported depression treatment-related outcomes. Observational studies were included for harms. Two investigators independently screened all studies using pre-specified criteria. One reviewer abstracted data on study design, interventions, implementation characteristics, and outcomes, and a second reviewer confirmed. Two reviewers independently assessed study quality and resolved any discords through discussion or a third reviewer. Strength of evidence (SOE) was assessed and agreed upon by review team consensus. We qualitatively analyzed the data and present syntheses in text and tables. We included 26 RCTs and 3 observational studies. SSRIs were the most studied type of drug and the evidence was largely insufficient.

We found moderate SOE that long-term, high-dose Vitamin D3 is ineffective for reducing depression severity. Cognitive behavioral therapy (CBT) is more effective than (undefined) psychotherapy and placebo for depression improvement and quality of life (low SOE), and acupressure is more effective than usual care or sham acupressure to reduce depression severity (low SOE). There is limited research evaluating treatment for depression in adults with ESKD, and existing studies may not be generalizable to adults in the US.

Studies suffer from limitations related to methodological quality or reporting. More research replicating studies of promising interventions in U.S. populations with larger samples is needed.

Systematic Review Registration: PROSPERO: CRD42020140227

2 INTRODUCTION

The incidence and prevalence of end-stage kidney disease (ESKD) in the United States (U.S.) have increased steadily over the past four decades.1 Psychiatric and mental health disorders are more common in adults with ESKD, and include issues such as depression, dementia, delirium, substance abuse, psychoses, anxiety and personality disorders.2-4 Adults with ESKD experience major depressive disorder (MDD) at anywhere from three to over six times that of the general U.S. population depending on the method of assessment, and depression is the most common mental health issue in this population.5,6

The effect of depression can be extremely detrimental for a wide range of ESKD patient outcomes.

For instance, adults with ESKD who have depressive symptoms have a 12% higher rate of hospitalization than those without,7 and those with ESKD and psychiatric issues have a 40-50% increased risk of all-cause mortality.8 Comorbid depression is associated with increased emergency department (ED) visits, hospitalizations, hospital length-of-stay, suicide, and treatment nonadherence, as well as decreased quality of life (QoL), and sleep.8-13

There are no established guidelines for treating depression in adults with ESKD. Less than 25% of those on dialysis diagnosed with moderate or severe depression actually undergo treatment.12,14,15 There are few studies of treatment efficacy in this population, and while some studies include only participants with clinical depression, others include any adults with ESKD. Psychosocial treatments and cognitive behavioral therapy (CBT) are commonly used; however, interventions vary widely, the evidence is limited, and findings may vary based on the presence and severity of depression.

Given the wide variation in depression treatment options for adults with ESKD, it is vital to understand the depression treatment-related outcomes for those in this population suffering from clinical depression. The purpose of this review is to better understand the benefits and harms of treatment for depression in these adults.

3 METHODS

Topic Development

This systematic review was part of a larger review commissioned by the Veterans Health

Administration (VHA).16 A protocol describing the review plan was posted to PROSPERO, a systematic review registry, before study initiation (CRD42020140227). Our methods and reporting follow PRISMA guidelines.17 See supplement Table S1 for systematic review scope and parameters.

Data Sources and Searches

To identify trials examining the treatment of depression in adults with ESKD, we searched Ovid

MEDLINE, PsycINFO, Elsevier EMBASE, and Ovid EBM Reviews Cochrane Database of Systematic

Reviews (CDSR, DARE, HTA, Cochrane CENTRAL, etc.) from database inception through June 2020. We reviewed the bibliographies of systematic reviews and other relevant articles and contacted experts to identify additional studies. To identify unpublished literature, we searched the VHA Health Services Research and

Development (HSR&D) website, ClinicalTrials.gov, and the World Health Organization (WHO)

International Clinical Trials Registry Platform (ICTRP). Search strategies were developed in consultation with a research librarian and peer reviewed by another research librarian using the instrument for Peer

Review of Search Strategies (PRESS; see supplement, Item S1).18

Study Selection

Studies were eligible if they: 1) included adults with dialysis-dependent ESKD not slated for transplant and depression defined by established thresholds for chronically ill populations;19-23 2) directly compared any pharmacological or non-pharmacological treatments for depression to placebo, waitlist control, other intervention; 3) were randomized or non-randomized controlled trials in any setting (for harms outcomes, we also included observational studies); 4) assessed patient outcomes of interest (e.g., depression symptom severity, suicidal ideation, QoL, etc.); and 5) were published in English. We excluded studies examining adults with acute kidney injury (AKI), or with chronic kidney disease (CKD) stages 1-4. See supplement Item S2 and Table S1 for complete selection criteria. All studies were reviewed for inclusion by

4 two independent reviewers at the title/abstract and full text levels. Discords were resolved through consensus or consultation with a third reviewer.

Data Abstraction and Quality Assessment

From included studies, we abstracted details on study design, sample size, setting, population characteristics, participant selection criteria, and intervention details including the dosage, timing, and administration methods, duration of treatment and follow-up, outcomes, and relevant harms. Data from studies meeting inclusion criteria were abstracted by one reviewer and confirmed by an additional reviewer.

Two reviewers independently assessed the methodological quality of each study using criteria established by the U.S. Preventive Services Taskforce and adapted for depression interventions (see Table 4, for quality ratings and criteria).24-26 Disagreements were resolved by consensus or a third reviewer.

Data Synthesis and Analysis

We qualitatively synthesized the evidence for each treatment category and outcome of interest. We were unable to quantitatively synthesize the evidence because there were too few studies examining the same intervention and reporting the same outcome measure.27

We assessed the overall strength of evidence (SOE) for each intervention using an established method by Berkman et al.,28 that considers study limitations, directness, consistency, precision, and reporting bias to classify the SOE for each outcome independently as high, moderate, low, or insufficient, as well as separate guidance for the applicability (external validity) of the evidence to the clinical question29 (see Table 3).

Supplement Table S2 describes SOE domains and grading in more detail.

RESULTS

We reviewed 8,050 titles and abstracts, 192 of which qualified for full-text review. Of those, we included a total of 26 RCTs, nine examining pharmacological interventions and 17 of nonpharmacologic interventions for the treatment of depression in adults with ESKD. We also included three observational

5 studies reporting harms of selective serotonin reuptake inhibitors (SSRIs; see Figure 1 for literature flow, and

Table 1 for study characteristics).

Pharmacological treatments

SSRIs

SSRIs versus placebo

Three studies comparing SSRIs to placebo report conflicting findings and provide insufficient evidence to draw conclusions about their effectiveness in treating depression in adults with ESKD (see Table

3 for SOE ratings). Two small U.S. RCTs (one eight-week, poor-quality trial of fluoxetine [N=14]30 and one recent fair-quality, six-month trial of sertraline [A Study of Sertraline in Dialysis; ASSertID; N=30]31) found no difference in depressive symptom reduction between those assigned to SSRIs or placebo. One fair-quality,

12-week, Iranian RCT (N=50)32 found that participants who received sertraline reported a significant reduction in depressive symptoms compared to placebo (see Table 2 for study results). Small sample sizes, and differences in depression assessment tools and statistical analyses detracted from the quality of these studies (see Table 4 for quality ratings).

SSRIs versus active comparators

SSRIs versus CBT. A recent fair-quality, multi-site U.S. head-to-head RCT (N=120), “A Trial of

Sertraline vs. Cognitive Behavioral Therapy for End-stage Kidney Disease Adults with Depression”

(ASCEND)33 provides low-strength evidence that sertraline and CBT are similar when used for the reduction of depressive symptoms (Tables 3 and 4). Over the 12-week study period, both groups improved significantly. Participants who received sertraline experienced significantly greater improvement (effect estimate: -1.85 [95% CI: -3.55 to -0.16]; Table 2), when assessed by a clinician (Quick Inventory of

Depressive Symptomatology [QIDS-C]). There was no difference between groups in self-reported symptoms

(i.e., BDI-II; effect estimate: -2.9 [95% CI: -6.7 to 0.8]; Table 2).

SSRIs versus psychological training. A small (N=44), three-month, poor-quality RCT34 conducted in

Iran provides insufficient evidence for the comparison of citalopram to “psychological training” in depressed

6 participants with ESKD (Tables 3 and 4). Although both arms reported a reduction in depressive symptoms, there was no difference between groups (Table 2).

Harms of SSRIs

Adverse events (AEs) reported in the included trials of SSRIs in adults with depression and ESKD were similar in type and frequency to those reported by the general population on SSRIs.35 One trial reported a higher rate of dropout due to AEs associated with sertraline (33% versus 0%; P=0.04).31 Across all four trials,30-33 a wide range of AEs (e.g., nausea, headaches, dizziness) were reported by participants in both treatment and control groups, but they were not consistently nor uniformly reported (Table 5).

Additionally, three observational studies focused specifically on potential harms related to SSRIs in adults with ESKD and depression (Table 6). Two examined Medicare beneficiaries who received SSRIs that were included in the US Renal Data System registry. A case control study (N=54,032) found that SSRIs increased the risk of hip fracture regardless of dose or duration,36 and the second,37 a retrospective cohort study (N=65,654), found that adults, especially older adults and women, taking SSRIs with higher QT- prolonging potential (i.e., citalopram and escitalopram) were at higher risk for sudden cardiac death (Adj

HR=1.18; 95% CI [1.05 to 1.31]). The final study was a follow-up to the ASSertID RCT31 that examined

SSRI practice patterns in adults with ESKD, and included participants who were already on SSRIs at baseline

(N=41). Findings suggest poor medication management and both under- and over-treatment.38

Supplements versus placebo

High-dose Vitamin D3

A large (N=746), fair-quality, 52-week RCT39 provides moderate-strength evidence that long-term, high-dose vitamin D3 does not reduce depression severity in adults with ESKD (Tables 3 and 4). In addition, no differences were reported by age, gender, body mass index (BMI), or plasma albumin level. Although overall differences in depressive symptom reduction between groups were not significant, a subgroup of

7 participants with vascular depression (but not those with MDD) receiving vitamin D3 did report significantly greater reduction in depressive symptoms at one year (Table 2).

Harms of Vitamin D3

Adverse events associated with high-dose vitamin D3, including joint pain, diarrhea, nausea, and vomiting resulted in study withdrawal of five participants. No statistical analyses of AEs or withdrawals due to AEs were reported.39

Omega-3 Fatty Acids

A single, poor-quality RCT (N=54),40 conducted in Iran, provides insufficient evidence to form conclusions about the effect of omega-3 fatty acids versus placebo on depression severity in adults with

ESKD (Tables 3 and 4). At 16 weeks, the omega-3 fatty acids group reported a significantly greater reduction in depressive symptoms compared to both placebo and their own baseline. No differences were identified by age, gender, baseline depression severity, or length of time on hemodialysis (Table 2). No serious AEs

(SAEs) were reported in this trial.

Synbiotic and Probiotic Supplements

One good-quality 12-week RCT (N=49)41 provides insufficient evidence for the use of synbiotic or probiotic supplements versus placebo on depression severity in Iranian adults with ESKD and HADS-D scores ≥8 (Tables 3 and 4). HADS-D scores at end-of-treatment were significantly lower in adults receiving synbiotics than those receiving placebo (P<0.001) and probiotics (P=0.011). HADS-D scores were also significantly reduced from baseline in the symbiotic compared to placebo (P<0.001) groups, but not in the other comparisons (Table 2). AEs reported were few and mild (Table 5).

Radix Bupleuri Herbal Supplement

A poor-quality, three-month RCT (N=160)42 of Radix Bupleuri root powder supplements compared to placebo provides insufficient evidence for its use for depression in adults with ESKD (Tables 3 and 4).

Participants who were being treated with antidepressant medications (about half of each group) continued on

8 those treatments concurrently during this trial. Participants taking Radix Bupleuri experienced significantly more reduction in MADRS scores compared to the placebo group (P=0.02; Table 2). They also experienced improvement in QoL (measured by RAND-36) compared to the placebo group (P=0.04). The trial did not report on AEs.

Non-pharmacological treatments

Cognitive Behavioral Therapy

CBT versus psychotherapy

One fair-quality RCT43 (N=90) provides low-strength evidence that small-group CBT is more effective than brief individualized psychotherapy for reducing depression severity in participants with ESKD

(Tables 3 and 4). Depressive symptoms improved significantly in both groups. Participants receiving CBT also experienced a significant within-group decrease in suicide risk and improved on several quality-of-life domains (i.e., burden of kidney disease, quality of social interaction, sleep, overall health, and mental health) over the study period (Table 2). No study dropouts from SAEs were reported.

CBT versus psychoeducation

A poor-quality RCT44 conducted in Jordan provides insufficient evidence to form conclusions about the comparison of CBT to psychoeducation (Tables 3 and 4). Participants receiving CBT reported a significantly greater reduction in depressive symptoms (both groups reported significant improvement; Table

2).

CBT versus Sertraline

A head-to-head RCT33 provides low-strength evidence that sertraline and CBT are similar when used for the reduction of depressive symptoms in participants with depression and ESKD. See the section, “SSRIs versus CBT” above and Tables 2, 3 and 4 for more detail.

CBT versus control

9 Two fair-quality RCTs45,46 provide low-strength evidence that CBT is more effective than waitlist control for reducing depression severity and improving QoL in participants with ESKD (Tables 3 and 4).

There is insufficient evidence to form conclusions about the benefit of CBT on fluid adherence.45

One study compared outcomes (depressive symptoms, QoL, and fluid adherence) based on the timing of the intervention (treatment first or after 90-day waitlist). Results indicated that participants receiving CBT experienced significantly greater benefit across all outcomes in both phases. However, findings suggest a sequence effect for depressive symptom reduction (the treatment-first group experienced greater benefit than the waitlist group), but none for QoL or fluid compliance (Table 2).45

Acupressure

We found low-strength evidence that acupressure is more effective than both usual care and sham acupressure for reducing depression severity in participants with ESKD (Table 3). There is insufficient evidence to form conclusions about the comparison of acupressure to Transcutaneous Electrical Acupoints

Stimulation (TEAS) for the reduction of depressive symptom severity, fatigue, or sleep quality improvement.

A fair-quality, three-arm RCT (N= 96)47 compared acupressure to sham acupressure (i.e., pressure applied one centimeter from the acupressure point) and usual care. Participants receiving acupressure reported a significantly greater reduction in depression symptoms than those receiving sham acupressure or usual care

(there was no difference between sham and usual care). A second three-arm RCT (poor-quality; N=108)48 compared acupressure to both TEAS and to usual care. Participants in both the acupressure and the TEAS groups reported greater reductions in depressive symptoms and fatigue, and better-quality sleep than those who received usual care (Tables 2 and 4).

Intensive Nursing

Three poor-quality RCTs49-51 provide insufficient evidence for the effect of intensive nursing interventions—compared to less-intensive nursing—for improving depressive symptoms in adults with

ESKD (Tables 3 and 4). One study in China (N=72) compared home nursing visits to telephone follow-up for adults on peritoneal dialysis.49 While both groups’ Zung Self-Rating Depression Scale (SDS) scores were

10 improved from baseline (P<0.001), the home nursing group’s depression scores were significantly lower than the control group after intervention (P<0.001). Another Chinese study of a comprehensive nursing intervention compared with usual care (N=128)50 in adults on hemodialysis found that the intervention group had significantly greater reduction in SDS scores from baseline (P=0.041), and those scores were significantly better after intervention compared to the control group (P=0.048). An Iranian RCT (N=60) using the DASS found that telenursing follow-ups compared to usual care (no telephone follow-ups) resulted in significantly lower depression scores (Table 2).51 These studies did not report on AEs.

Exercise

There was insufficient evidence from two poor-quality studies52,53 of exercise training for depression in adults with ESKD (Tables 3 and 4). One study (N=50)53 examined the effect of four months of endurance and resistance training four times weekly in Tunisian male participants. Training sessions were on off- dialysis days and the exercise group significantly improved on HADS-D scores compared to sedentary controls. The other, a Greek RCT (N=50)52 examined intradialytic exercise (during hemodialysis cycling and strength training) three times per week for a year and found significant improvement on both the BDI-II and

HADS-D with exercise compared to sedentary controls (Table 2). AEs were not reported.

Other treatments

We included RCTs of six other therapies: Benson Relaxation Technique,54 guided imagery,55 hope therapy,56 Latihan Pasrah Diri (LPD),57 Mindfulness-based Stress Reduction (MBSR),58 and Quran readings for Muslim participants.59 All were small, single trials with methodological challenges, and the evidence is insufficient for all interventions Tables 2, 3 and 4). Two of these (LPD57 and MBSR58) reported no AEs, while the others did not report on AEs.

11 DISCUSSION

In this systematic review, we examined nine RCTs of pharmacological interventions and 17 of nonpharmacologic interventions for comorbid depression in adults with ESKD. We also found three observational studies that contributed to the evidence on harms of SSRIs. We found moderate-strength evidence that long-term, high-dose vitamin D3 is ineffective for reducing depressive symptoms, and low- strength evidence that both sertraline and CBT were similar for improving depressive symptoms. We also found low-strength evidence that CBT is more effective than both standard psychotherapy and waitlist controls, and that acupressure is more effective than usual care. We found insufficient evidence to draw conclusions about all other interventions. Overall, we found limited evidence for each intervention, sample sizes were small, and nearly all studies were hampered by methodological flaws.

SSRIs, compared either to placebo or an active comparator, were the best-studied pharmacological intervention. No other antidepressant categories were identified. Findings from placebo-controlled trials of

SSRIs were mixed, but sertraline at least warrants further study. Among the three trials examining sertraline, one reported benefit over placebo, and another found no difference between sertraline and CBT.33 Harms related to SSRIs were not uniformly reported. The type and rate of harms reported and/or evaluated in included RCTs suggest little to no increase in risk for adults with ESKD compared to otherwise healthy adults using SSRIs. Primary side effects were minor (e.g., nausea, fatigue, etc.). However, observational studies suggest that clinicians should consider known risks (e.g., QT-prolongation) when making prescribing decisions, and coordinate care to avoid over or under treatment.

Vitamin D3 is an interesting intervention for adults with ESKD, due to the associated risks of hypercalcemia and hyperphosphatemia.60 Five adults withdrew from the study due to treatment-related AEs.

Though not attributed to hyperphosphatemia, the reported AEs (i.e., joint pain, diarrhea, nausea and vomiting) may be related. The negative finding regarding vitamin D3, along with its risks, suggests that clinicians should not recommend its use as a depression treatment in this population. Given the large size and length of the trial the SOE for this finding is moderate, and future studies are unlikely to change conclusions.

12 Very few non-pharmacological studies reported harms; however, most interventions presented minimal risk. Differences by subpopulation (i.e., demographic, clinical) were also reported in very few studies, and reported differences were insufficient to form conclusions. Future research should uniformly report harms and examine these subgroups.

Many of the studies were hampered by small sample sizes, posing challenges related to group comparability and statistical power. The duration of treatment and follow-up varied widely across studies, making it more challenging to compare results. For instance, between two studies of sertraline, one was twice as long as the other (three versus six months). The methods used to screen for and diagnose depression were heterogeneous, as was the implementation of interventions (e.g., timing, doses, comparators, modes of delivery). For example, among CBT studies, while all of them met in-person, half of the studies utilized private sessions, while sessions were conducted in groups in the other studies. Session lengths varied, and in one study CBT was delivered while the participants were receiving HD. Given the association with hemodialysis and somatic complaints, hemodynamic changes, and alterations in mental acuity, treatments

(particularly psychological ones) that are administered during hemodialysis may be confronted with these challenges, although treating adults outside of HD sessions has its own challenges, including the increased time burden and physical and mental fatigue. Among other psychological treatments, some were applied in- person, while others were practices expected to be followed at home. In addition to these issues, the lack of methodological detail reported in many of the studies resulted in poor quality ratings, and uncertainty about study processes.

Another important limitation to the current evidence base is that most of the studies were conducted outside of the U.S. and examined participants and health systems that differ greatly from the general U.S. population. These differences may be reflected in both the patient demographics and medical disease burden, as well as how care is delivered, particularly because the majority of U.S. dialysis adults receive their care from large dialysis organizations in coordination with their nephrology provider.

13 This is the only systematic review to date that examines both pharmacological and non- pharmacological treatment of depression in adults with ESKD. This review confirms and adds to a 2016

Cochrane review of antidepressants in adults with ESKD that included meta-analyses of harms reported in trials included in our report.35 Although we also included more recent trials, outcomes were not reported in a way that allowed for a quantitative synthesis of harms. Our review adds to the pharmacological evidence by including studies of dietary supplements. A Cochrane review examining psychosocial interventions for adults with ESKD was recently published;61 however, it includes studies of participants with and without clinical depression. How a participant with ESKD responds to an intervention may vary widely depending on the severity of their baseline depressive symptoms. To reduce clinical heterogeneity, we included only studies with participants meeting established depression screening thresholds for chronically ill populations.19-23

Finally, additional trials included in our review, particularly the ASCEND33 and ASSertID trials,31,33 add to both the pharmacological and non-pharmacological evidence.

Future research, particularly in the U.S., is needed to better evaluate both pharmacological and non- pharmacological interventions for this population. In particular, larger replication studies of CBT, acupressure, and SSRIs such as sertraline and examination of their effects in different subgroups of adults with ESKD and depression (such as severity of depression, duration of ESKD diagnosis, peritoneal versus hemodialysis, and presence of comorbidities) will help decisionmakers to implement depression treatments that are not only evidence-based, but also the best fit for their patient population.

14 Disclosures: All authors have nothing to disclose.

Funding: This research was funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research & Development.

Acknowledgments: The authors wish to thank Robin Paynter, MLIS for developing the search strategy and running electronic searches. We also thank the members of our Technical Expert Panel for their expertise.

The findings and conclusions in this document are those of the authors who are responsible for its contents; the findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the United States government.

Author contributions: P Chopra: Conceptualization; Formal analysis; Investigation; Writing - original draft; Writing - review and editing

C Ayers: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing - original draft; Writing - review and editing

J Antick: Conceptualization; Formal analysis; Supervision; Writing - original draft

D Kansagara: Conceptualization; Formal analysis; Supervision; Writing - original draft; Writing - review and editing

K Kondo: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Supervision; Writing - original draft; Writing - review and editing

Each author contributed important intellectual content during manuscript drafting or revision, accepts personal accountability for the author’s own contributions, and agrees to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

15 SUPPLEMENTAL MATERIAL

Item S1. Search Strategies (Parent VA Review)

Item S2. Study Selection Criteria (Parent VA Review)

Table S1. PICOTS by Key Question

Table S2. Strength of Evidence Domains and Grading

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18 32. Taraz M, Khatami MR, Dashti-Khavidaki S, et al. Sertraline decreases serum level of interleukin-6 (IL-6) in hemodialysis patients with depression: results of a randomized double-blind, placebo-controlled clinical trial. Int Immunopharmacol. 2013;17(3):917- 923. 33. Mehrotra R, Cukor D, Unruh M, et al. Comparative Efficacy of Therapies for Treatment of Depression for Patients Undergoing Maintenance Hemodialysis: A Randomized Clinical Trial. Ann Intern Med. 2019;26:26. 34. Hosseini SH, Espahbodi F, Mirzadeh Goudarzi SM. Citalopram versus psychological training for depression and anxiety symptoms in hemodialysis patients. Iran J Kidney Dis. 2012;6(6):446-451. 35. Palmer SC, Natale P, Ruospo M, et al. Antidepressants for treating depression in adults with end-stage kidney disease treated with dialysis. Cochrane Database of Systematic Reviews. 2016(5):CD004541. 36. Vangala C, Niu J, Montez-Rath ME, Yan J, Navaneethan SD, Winkelmayer WC. Selective Serotonin Reuptake Inhibitor Use and Hip Fracture Risk Among Patients on Hemodialysis. Am J Kidney Dis. 2020;75(3):351-360. 37. Assimon MM, Brookhart MA, Flythe JE. Comparative Cardiac Safety of Selective Serotonin Reuptake Inhibitors among Individuals Receiving Maintenance Hemodialysis. J Am Soc Nephrol. 2019;30(4):611-623. 38. Guirguis A, Chilcot J, Almond M, Davenport A, Wellsted D, Farrington K. Antidepressant Usage in Haemodialysis Patients: Evidence of Sub-Optimal Practice Patterns. Journal of Renal Care. 2020;46(2):124-132. 39. Wang Y, Liu Y, Lian Y, Li N, Liu H, Li G. Efficacy of High-Dose Supplementation With Oral Vitamin D3 on Depressive Symptoms in Dialysis Patients With Vitamin D3 Insufficiency: A Prospective, Randomized, Double-Blind Study. J Clin Psychopharmacol. 2016;36(3):229-235. 40. Gharekhani A, Khatami MR, Dashti-Khavidaki S, et al. The effect of omega-3 fatty acids on depressive symptoms and inflammatory markers in maintenance hemodialysis patients: a randomized, placebo-controlled clinical trial. Eur J Clin Pharmacol. 2014;70(6):655-665. 41. Haghighat N, Rajabi S, Mohammadshahi M. Effect of synbiotic and probiotic supplementation on serum brain-derived neurotrophic factor level, depression and anxiety symptoms in hemodialysis patients: a randomized, double-blinded, clinical trial. Nutr Neurosci. 2019:1-10. 42. Wang X, Feng Q, Xiao Y, Li P. Radix Bupleuri ameliorates depression by increasing nerve growth factor and brain-derived neurotrophic factor. Int J Clin Exp Med. 2015;8(6):9205-9217. 43. Duarte PS, Miyazaki MC, Blay SL, Sesso R. Cognitive-behavioral group therapy is an effective treatment for major depression in hemodialysis patients. Kidney Int. 2009;76(4):414-421. 44. Al Saraireh FA, Aloush SM, Al Azzam M, Al Bashtawy M. The Effectiveness of Cognitive Behavioral Therapy versus Psychoeducation in the Management of Depression among Patients Undergoing Haemodialysis. Issues Ment Health Nurs. 2018;39(6):514- 518.

19 45. Cukor D, Ver Halen N, Asher DR, et al. Psychosocial intervention improves depression, quality of life, and fluid adherence in hemodialysis. J Am Soc Nephrol. 2014;25(1):196- 206. 46. Lerma A, Perez-Grovas H, Bermudez L, Peralta-Pedrero ML, Robles-Garcia R, Lerma C. Brief cognitive behavioural intervention for depression and anxiety symptoms improves quality of life in chronic haemodialysis patients. Psychology & Psychotherapy: Theory, Research & Practice. 2017;90(1):105-123. 47. Kalani L, Aghababaeian H, Majidipour N, et al. The effects of acupressure on severity of depression in hemodialysis patients: a randomized controlled trial. Journal of Advanced Pharmacy Education & Research. 2019;9(S2):67-72. 48. Tsay SL, Cho YC, Chen ML. Acupressure and Transcutaneous Electrical Acupoint Stimulation in improving fatigue, sleep quality and depression in hemodialysis patients. Am J Chin Med. 2004;32(3):407-416. 49. Li F, Han W, Chen W. The effects of continuous home nursing visits on patients with chronic renal failure and peritoneal dialysis. Int J Clin Exp Med. 2020;13(2):540-548. 50. Liao B, Zhao L, Peng Y, Chen J, Chen W, Wang X. Effect of comprehensive nursing intervention on negative emotion, quality of life and renal function of hemodialysis patients. Int J Clin Exp Med. 2020;13(2):949-957. 51. Kargar Jahromi M, Javadpour S, Taheri L, Poorgholami F. Effect of Nurse-Led Telephone Follow ups (Tele-Nursing) on Depression, Anxiety and Stress in Hemodialysis Patients. Global Journal of Health Science. 2015;8(3):168-173. 52. Kouidi E, Karagiannis V, Grekas D, et al. Depression, heart rate variability, and exercise training in dialysis patients. Eur J Cardiovasc Prev Rehabil. 2010;17(2):160-167. 53. Frih B, Jaafar H, Mkacher W, Ben Salah Z, Hammami M, Frih A. The Effect of Interdialytic Combined Resistance and Aerobic Exercise Training on Health Related Outcomes in Chronic Hemodialysis Patients: The Tunisian Randomized Controlled Study. Front Physiol. 2017;8:288. 54. Heshmatifar N, Sadeghi H, Mahdavi A, Shegarf Nakhaie MR, Rakhshani MH. The effect of benson relaxation technique on depression in patients undergoing hemodialysis. J Babol Univ Med Sci. 2015;17(8):34. 55. Beizaee Y, Rejeh N, Heravi-Karimooi M, Tadrisi SD, Griffiths P, Vaismoradi M. The effect of guided imagery on anxiety, depression and vital signs in patients on hemodialysis. Complement Ther Clin Pract. 2018;33:184-190. 56. Rahimipour M, Shahgholian N, Yazdani M. Effect of hope therapy on depression, anxiety, and stress among the patients undergoing hemodialysis. Iran J Nurs Midwifery Res. 2015;20(6):694-699. 57. Widyaningrum, Siswanto A, Djarwoto B. Effects of Latihan Pasrah Diri in Quality Of Life in Chronic Kidney Disease-Dialysis Patients with Depression Symptoms. Acta Interna - The Journal of Internal Medicine. 2013;3(2):16-22. 58. Thomas Z, Novak M, Platas SGT, et al. Brief Mindfulness Meditation for Depression and Anxiety Symptoms in Patients Undergoing Hemodialysis: A Pilot Feasibility Study. Clinical Journal of The American Society of Nephrology: CJASN. 2017;12(12):2008- 2015. 59. Babamohamadi H, Sotodehasl N, Koenig HG, Al Zaben F, Jahani C, Ghorbani R. The Effect of Holy Qur'an Recitation on Depressive Symptoms in Hemodialysis Patients: A Randomized Clinical Trial. Journal of Religion & Health. 2017;56(1):345-354.

20 60. Covic A, Rastogi A. Hyperphosphatemia in patients with ESRD: assessing the current evidence linking outcomes with treatment adherence. BMC Nephrol. 2013;14(1):153. 61. Natale P, Palmer SC, Ruospo M, Saglimbene VM, Rabindranath KS, Strippoli GFM. Psychosocial interventions for preventing and treating depression in dialysis patients. Cochrane Database of Systematic Reviews. 2019(12).

21 Table 1. Characteristics of randomized controlled trials of interventions for depression and studies examining harms of depression treatment in adults with ESKD

N sites, Baseline Author, year study depression N randomized, setting, Clinical characteristics/ Depression score years of Intervention/ Country/ demographics of study screening Mean (SD, enrollment comparator US region population Inclusion criteria tool(s) T vs C Pharmacological Blumenfield, Fluoxetine vs 2 sites: NR Cutoff for inclusion: HAM-D HAM-D; NR 199730 placebo Hospital score ≥16 BDI; N=14 dialysis Other inclusion criteria: age MADRS; Years: NR centers 18-70, normal liver function BSI; VAS New York, NY Friedli, 201731* Sertraline vs Multisite (5): 12% Female Cutoff for inclusion: BDI-II BDI-II; MINI; MADRS: 24.5 N=30 placebo Renal units Age: 61.7 (13.2) score ≥16; MINI mild to MADRS (4.5) vs 25.3 April 2013 - May England Race: 67% white, 13% AA, moderate MDD; MADRS (4.2) 2015 13% Asian, 7% mixed score ≥18 Other inclusion criteria: Excluded if already on SSRIs38 Gharekhani, Omega-3 fatty 2 sites: HD HD Duration: 70.7 (45.1) Cutoff for inclusion: BDI-II BDI-II 23.52 (7.49) vs 201440 acid vs placebo Centers mos score ≥16 21 (4.72) N=54 Tehran, Iran 4 hrs, 2-3x/wk Other inclusion criteria: Median/IQR: 22 Year: NR 48% Female Adults, HD 3 ≥ months and all (17, 28) vs 21 Age: 56.8 (13.09) yrs had same HD Rx (16.50, 22.75) Haghighat, Synbiotic 1 site: 52% Female Cutoff for inclusion: ≥8 HADS 9.16 (1.11) vs 201941 supplement vs hospital HD Age: 46.64 (10.69) yrs Other inclusion criteria: stable 9.77 (1.77) vs N=49 probiotic center, Iran HD pt with arteriovenous 9.20 (1.30); Year: NR supplement vs fistula, P=0.63 placebo age 30–65, HD 3x/wk 3 ≥ months Hosseini, 201234 Citalopram vs Single-site: 55% female Cutoff for inclusion: HADS≥8 HADS 9.42 (3.11) vs N=44 psych. training hospital HD Age: 52.3 (15.6) yrs Other inclusion criteria: NA 9.58 (3.47) Years NR center Iran

22 N sites, Baseline Author, year study depression N randomized, setting, Clinical characteristics/ Depression score years of Intervention/ Country/ demographics of study screening Mean (SD, enrollment comparator US region population Inclusion criteria tool(s) T vs C Mehrotra, Sertraline vs Multisite (3 Median time on dialysis Cutoff for inclusion: BDI-II BDI-II; MINI; QIDS-C mean 201933 CBT states): 41 (IQR): 31 (44) mos ≥15, then confirmed by MINI QIDS-SR; (range): SERT N=120 dialysis Mean HD session length Other inclusion criteria: age QIDS-C 10.9 (9.6 to 2017 facilities (SD): 3.9 (0.4) hrs ≥21, ESKD, On HD ≥3 12.1) vs CBT US: NM, TX, History of major depression: months 12.2 (11.0 to WA 42% 13.5) 43% Female BDI-II mean Age: 51 (13) (range): SERT Race/ethnicity: 43% white; 25.8 (23.3 to 28% Black; 28% Hispanic; 28.4) vs CBT 8% Native Amer; 12% other 26.2 (23.6 to Education: 40% ≤HS 28.8) Taraz, 201332 Sertraline vs Single site: HD for 4 hrs 3x/wk: 43% Cutoff for inclusion: BDI-II ≥16 BDI-II 29 (13) vs 23 N=50 placebo outpatient Time on HD: 42 months 59% Other inclusion criteria: age (11); P=0.243 Years NR HD clinic Female 18-80, HD ≥3 months using Tehran, Iran Age: 60 (22) arteriovenous fistula all others NR Wang, 201542 Radix Bupleuri Single-site: HD duration: 26 (13) vs 29 Cutoff for inclusion: NR MADRS 23.9 (7.8) vs N=160 herbal Dalian, NE (15) months Other inclusion criteria: aged 24.6 (7.4) 2013 supplement vs China 75% Female 30-55 yrs; no history of placebo Education: ~86% <9 yrs repeated suicidal behavior, Concurrent antidepressant severe substance abuse, medication use: 51% vs 46% severe depression impairing verbal abilities, family history of depression, or brain injury/disease Wang, 201639 Vitamin D3 vs 3 sites: 39% Female Cutoff for inclusion: BDI-II ≥16 BDI-II-II 22.7 (4.3) vs N=746 placebo Dialysis Age: 54% 18-64; 46% 65+ Other inclusion criteria: 21.9 (5.4); Years NR centers Other demographics: NR ESKD, current conventional P=0.31 HD and PD maintenance PD (3 Outpatient exchanges a day) or HD Southeast (3x/wk, 4–4.5 hrs/session) ≥3 China months, age ≥18 years, 15 to 30 ng/mL plasma 25(OH)D

23 N sites, Baseline Author, year study depression N randomized, setting, Clinical characteristics/ Depression score years of Intervention/ Country/ demographics of study screening Mean (SD, enrollment comparator US region population Inclusion criteria tool(s) T vs C Non-pharmacological Al Saraireh, CBT vs PSE Multisite: 5 Dialysis duration: NR Cutoff for inclusion: NR HAM-D PSE 19.6 (5.4) 201844 hospital ~50% Female Other inclusion criteria: vs CBT 19.5 N=130 dialysis units Age: 52 (10.7) diagnosis of chronic kidney (5.4) 2017 Jordan Education: 71% ≤ high failure; chronic dialysis ≥1 No difference: school Employment: 82% year; verbal comprehension/ t(103)=−0.13; unemployed communication P=0.89 Race/Insurance NR Babamohamadi, Quran vs TAU Single site: 42.6% Female Cutoff for inclusion: BDI-II BDI-II 33.6 (6.7) vs 201759 hospital Age: 53.3 (11.4) score ≥20 29.3 (9.0); mean N=60 dialysis ward Race: NR Other inclusion criteria: age difference: -4.3 Year NR Iran Education: 75% less than 18-65; command of Arabic; (95% CI: -8.7 to diploma HD for ≥6 months; 0.0); P=0.05 Employment: NR (55.6% hemodynamic stable "poor") Insurance: NR Beizaee, 201855 Guided Imagery Single-site: 41.25% Female Cutoff for inclusion: NR HADS 10.82 (2.70) vs N=80 vs TAU HD center Age: 47.21 (8.34) yrs Other inclusion criteria: HD 11.55 (2.29) 2015-2016 Iran Education: 46.25% 3x/wk for ≥6 months; 35-65 Secondary y/o; read/write in Farsi, intact Employment: 25% cognitive functions based on unemployed AMT Cukor, 201445 CBT vs waitlist 2 sites: 72.7% Female Cutoff for inclusion: BDI-II SCID-I; BDI- SCID-I % w/ N=65 dialysis units Age: NR score ≥10 II; HAM-D major Year NR Brooklyn, NY Race: 93.9% Black Other inclusion criteria: ESKD depression: 54.5 Education: 11.2 (3.4) yrs with HD for ≥6 months vs 42.2 Employment: 83.4% BDI-II: 25.3 (9.3) Unemployed vs 21.4 (8.9) Insurance: NR HAM-D: 15.0 (6.2) vs 13.5 (5.0)

24 N sites, Baseline Author, year study depression N randomized, setting, Clinical characteristics/ Depression score years of Intervention/ Country/ demographics of study screening Mean (SD, enrollment comparator US region population Inclusion criteria tool(s) T vs C Duarte, 200943 CBT vs 2 sites: HD: 3x/wk for 4 hrs avg. Cutoff for inclusion: MDD with BDI-II; MINI BDI-II: 24.2 (9.7) N=90 psychotherapy dialysis units 63.4% Female MINI vs 27.3 (10.7); Year NR Brazil Age: 52.4 (15.9) yrs Other inclusion criteria: ESKD P=0.149 Race: 78.1% white with HD for ≥3 months MINI: 6.4 (1.3) Education: 83% ≤ primary vs 6.4 (1.2); school P=0.96 Employment/Insurance: NR Frih, 201753* Exercise Single-site: HD: 4hrs 3x/wk Cutoff for inclusion: NR HADS ~12 vs ~13 N=41 (endurance- Hospital HD duration: 72.7 (12.7) Other inclusion criteria: (exact scores 2012-2013 resistance Tunisia months excluded chronic lung NR) training) vs TAU Age: 64.2 (3.4) yrs disease, ischemic heart 0% Female disease, uncontrolled Other demographics NR arrythmias or hypertension, hemodynamically unstable or musculoskeletal disorders, regularly exercising. Heshmatifar, Benson Single site: HD: 3x/wk Cutoff for inclusion: NR BDI-II 32.46 (9.86) vs 201554 Relaxation hospital HD 18% Female Other inclusion criteria: 18-65 30.58 (9.24) N=70 Technique vs unit Age: 9% 18-35; 33% 35-45; y/o; HD 3x/wk for ≥6 months; 2013 TAU Iran 45% 45-55; 15% 55-65 regular patient of the center Race: NR Education: 94% ≤ high school Employment: 42% Unemployed Insurance: NR Jahromi, 201651 Tele-nursing vs Single site: T vs C: Cutoff for inclusion: NR DASS-21 16.60 (1.50) vs N=60 TAU hospital HD 56% vs 40% Female Other inclusion criteria: 18-65 16.72 (1.83); 2014 unit Education: 4% >HS y/o; HD 3-4hrs 3x/wk for ≥6 P=0.40 Iran Unemployed: 60% vs 44% months; no transplants, Other demographics NR hospitalizations or antidepressant Rx

25 N sites, Baseline Author, year study depression N randomized, setting, Clinical characteristics/ Depression score years of Intervention/ Country/ demographics of study screening Mean (SD, enrollment comparator US region population Inclusion criteria tool(s) T vs C Kalani, 201947 Acupressure vs 3 sites: HD 44% Female Cutoff for inclusion: BDI-II BDI-II T 27.5 (9.1) vs N=96 Sham vs TAU centers Age: 53.4 (13.9) score ≥10 Sham 25.7 (7.7) 2011 Iran Race: NR Other inclusion criteria: ESKD vs C 24.6 (8.6); Education: 31% non-literate diagnosis; Age 18+; HD for ≥3 P=NS Employment: 50% months; mental and Unemployed; 41% retired psychological ability to Insurance: NR participate Kouidi, 201052 Exercise training Single site: HD: 3x/wk for 4 hrs Cutoff for inclusion: NR BDI-II; BDI-II: 22.29 N=50 vs sedentary hospital renal 41.6% Female Other inclusion criteria: HADS (6.71) vs 22.30 Year NR control unit Age: 46.3 (11.2) ESKD; 4 hrs HD 3x/wk for ≥6 (6.81) Greece Education: 10.2 (3.4) yrs months HADS: 10.63 Employment: 16.6% (2.60) vs 10.40 Unemployed (2.50) Race/Insurance: NR Lerma, 201746 CBT vs 2 sites: HD HD: 3x/wk for 3-4hrs Cutoff for inclusion: BDI-II BDI-II 13.6 (7.6) vs N=60 waitlist units 51.6% Female score of 10–29 points 15.8 (10.0) Year NR Mexico City, Age: 41.8 (14.7) Other inclusion criteria: Mexico Education: 35.5% ESKD; literate; no psychiatric elementary illness; regular attendance of Employment: 25.8% HD sessions 3-4 hrs HD Unemployed 3x/wk for ≥6 months Race/Insurance: NR Li, 202049 Home nursing Single-site: Dialysis duration: 22.68 Cutoff for inclusion: NR Zung SDS 63.34 (6.28) vs N=72 visits vs hospital (10.25) months Other inclusion criteria: Age 64.27 (6.11); 2018–2019 telephone f/u Hainan, 44% Female 30-80; on home PD ≥3 P=0.53 China Age: 55.8 (6.2 months; Kidney Failure Education: ≤middle school 56% Liao, 202050 Comprehensive Single-site: HD duration: 43.56 (13.95) Cutoff for inclusion: NR Zung SDS 60.83 (22.67) vs N=128 nursing vs hospital mos Other inclusion criteria: Age 64.02 (28.58); 2017 conventional Hainan, 44% Female 18+, on HD ≥3 months for P=0.49 care China Age: 52.87 (10.46) CRF/ESKD Education:

26 N sites, Baseline Author, year study depression N randomized, setting, Clinical characteristics/ Depression score years of Intervention/ Country/ demographics of study screening Mean (SD, enrollment comparator US region population Inclusion criteria tool(s) T vs C Rahimipour, Hope therapy vs Multi-site: HD: 2-3x/wk for 4 hrs Cutoff for inclusion: NR DASS-21 13.36 (3) vs 201556 control hospitals 48% Female Other inclusion criteria: aged 13.64 (3.5); N=50 Iran Age: 47.82 (15.12) 18–65; HD 2-3x/wk for ≥3 P=0.76 Year NR Race/Education/Employment months; not taken medication / Insurance: NR for depression, anxiety, or stress Thomas, 201758 MBSR vs TAU Single site: 33% Female Cutoff for inclusion: PHQ-9 PHQ-9 12.7 (4.2) vs N=41 hospital HD Age: 65 (13) score ≥6 and/or GAD-7 score 11.9 (5.8) 2016 unit Race: 49% white, 51% ≥6 Montreal, nonwhite Other inclusion criteria: On Canada Education: 63% ≤ high maintenance HD; spoke school English or French Employment/Insurance: NR Tsay, 200448 Acupressure vs 4 sites: Duration HD: 50.06 (44.15) Cutoff for inclusion: BDI-II BDI-II Acupressure N=108 TEAS vs control hospital months score ≥10 20.37 (10.65) vs Year NR dialysis 66% Female Other inclusion criteria: ESKD TEAS 18.20 centers Age: 58.16 (12.19) diagnosis; Age 18+; HD for ≥3 (11.11) vs C Northern Employment: 76.1% Retired months; fatigue; PSQI score 21.61 (11.69) Taiwan or Unemployed ≥5 Race/Education: NR Widyaningrum, Latihan Pasrah Single site: HD: 2x/wk Cutoff for inclusion: BDI-II ≥16 BDI-II 23 (5.34) vs 201357 Diri vs control hospital HD 61.1 % Female Other inclusion criteria: 18-60 23.39 (5.02) N=36 unit Age: 50.06 (7.39) y/o; 2012 Java, Education: 77.8% ≤ high CKD adults on 2x/wk HD for Indonesia school ≥3 months Insurance: 5.6% uninsured Employment/Race: NR Harms only studies

27 N sites, Baseline Author, year study depression N randomized, setting, Clinical characteristics/ Depression score years of Intervention/ Country/ demographics of study screening Mean (SD, enrollment comparator US region population Inclusion criteria tool(s) T vs C Assimon, 201937 SSRIs w/ higher US Renal 52.8% Female Inclusion: New SSRI users NA NA N = 65,654 QT-prolonging Data System Age: 67.0 (17.2) who received HD during the 2007-2014 potential† vs Database Race: 35.5% AA//Black 180 days before SSRI SSRIs w/ lower Ethnicity: 19.2% Hispanic initiation and had continuous QT-prolonging Medicare Part A, B, and D potential§ coverage. Excluded: <18 years at start of baseline, dialysis vintage 90 days at the start of baseline, presence of an implantable automatic cardiac defibrillator, receipt of hospice care during the baseline period, and missing demographic data. Guirguis, SSRI Multisite: NR 37% Female ASSertID study participants BDI-II, PHQ- BDI-II: 26 (IQR 202038* observational England Age: 62 (16) who were excluded from the 9 19) N = 41 Race: 27% non-white RCT31 phase because they PHQ-9: 12 (IQR 2013-2015 were already on SSRIs 9) Vangala, 201936 SSRI vs no US Renal Cases vs controls: Inclusion: Medicare Part D, NA NA N=54,032 SSRI Data System Female: 58% vs 52% receipt of a low-income 2009-2015 Database Age: 71 (12) vs 61(14) subsidy, KRT start date, 29% vs 49% AA/Black, 22% demographic data, a Medical vs 19% Hispanic, 39% vs Evidence Report from 1995 or 25% non-Hispanic white later, > 90 days HD * Part of the larger ASSertID study † citalopram and escitalopram § fluoxetine, fluvoxamine, paroxetine, and sertraline Abbreviations: AMT=Abbreviated Mental Test; BDI-II=Beck Depression Inventory-II; BSI=Brief Symptom Inventory; C=control group; CBT=cognitive behavioral therapy; CKD=chronic kidney disease; DASS=Depression, Anxiety, and Stress Scale; DM=diabetes mellitus; DSM-IV=Diagnostic and Statistical Manual-IV; ESKD=end-stage kidney disease; GAD=Generalized Anxiety Disorder; HADS=Hospital Anxiety and Depression Scale; HAM-D =Hamilton Depression Rating Scale; HD=hemodialysis; IQR=interquartile range; KRT=Kidney Replacement Therapy; MADRS=Montgomery-Åsberg Depression Rating Scale; MAOI=Monoamine oxidase inhibitors; MBSR=Mindfulness-based Stress Reduction; hr(s)=hour(s); MDD=Major Depressive Disorder; MINI=Mini International Neuropsychiatric Interview; mo(s)=month(s); NM=New Mexico; NR=not reported; NS=not significant; NY=New York; P=p-value; PD=peritoneal

28 dialysis; PHQ-9=Patient Health Questionnaire-9; PSE=psychoeducation; PSQI=Pittsburgh Sleep Quality Index; QIDS-C=Quick Inventory of Depressive Symptomatology-Clinician; RCT=randomized controlled trial; SD=standard deviation; SDS=Self-rating Depression Scale; SERT=Sertraline; T=treatment group; TAU=treatment as usual; TEAS=Transcutaneous Electrical Acupoint Stimulation; TX=Texas; U.S.=United States; WA=Washington; wk(s)=week(s)

29 Table 2. Efficacy of interventions for depression in ESKD adults from randomized controlled trials

Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality PHARMACOLOGICAL SSRIs vs control Blumenfield, Fluoxetine: Matched Mean change from baseline (at 4 wks; at 8 NA Poor 199730 20mg/day for 8 placebo wks): 7 vs 7 weeks BDI: -12 vs -4.17 (P=0.05); -9.57 vs -8.8 Tx=8 weeks (P=0.91) F/U=8 weeks BSI: -6.29 vs 0.2 (P=0.04); -4.43 vs -3.2 (P=0.88) HAM-D: no 4 wk assessment; -9.00 vs -7.5 (P=0.72) MADRS: -7.20 vs -6.75 (P=0.93); -11.14 vs - 6.67 (P=0.45) VAS: -210.0 vs -58.3 (P=0.37); -303.0 vs - 140 (P=0.45) Electronic VAS: -262.4 vs 5.6 (P=0.05); - 389.0 vs -87.8 (P=0.13) Friedli, 201731* Sertraline: Matched MADRS between group difference at 6 NA Fair 15 vs 15 100mg/day placebo months: -0.67 (-5.7 to 4.4); NS Tx=6months (50mg/day to start. Within groups decrease significant for both F/U=6months Dose could be groups increased to max Mean change at study end at 2 and 4 months) MADRS: -14.5 (95% CI: -20.2 to -8.8) vs - 14.9 (95% CI: -18.4 to -11.5) BDI-II: -15.7 (95% CI: -24.3 to -7.1) vs -13.0 (95% CI: 19.6 to -6.4); between groups diff NS

30 Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality Taraz, 201332 Sertraline: Matched BDI-II scores (Baseline, 6 weeks, 12 weeks, NA Fair 25 vs 25 100mg/day placebo ΔBaseline to 12 weeks): Sertraline: 29 (13); Tx=12 weeks (50mg/day for 1st 2 21 (11.5); 15 (5.5); −11.3 (5.8 vs Placebo: F/U=12 weeks weeks) 23 (11); 22.5 (8.5); 22.5 (9); −0.5 (5, Comparison ΔBaseline to 12 weeks between groups (P=0.001). SSRIs vs active comparator Hosseini, 201234 Citalopram: Psychological Post-intervention HADS: 6.26 (4.18) NA Poor 22 vs 22 20mg/day training: 6 1-hr (P=0.001) vs 7.33 (4.80) after training Tx=3 months sessions on (P=0.04). No difference between groups F/U=3 months kidney disease (P=0.16). education, Between groups mean differences also NS problem (P=0.65) solving, stress management, and muscle relaxation techniques. Mehrotra, Sertraline: CBT: 10 60- QIDS-C scores: 5.9 (4.5) vs 8.1 (5.1) NA Fair 201933 200mg/day unless minute Effect estimate: −1.85 (95% CI: −3.55 to 60 vs 60 limited by AEs sessions during −0.16) Tx=12 weeks (titration began at HD for 12 BDI-II scores: 14.1 (95% CI: 11.2 to 17.0) vs F/U=12 weeks 25 mg/d and weeks, adapted 18.7 (95% CI: 15.2 to 22.2) adjusted each for Effect estimate: −2.9 (95% CI: −6.7 to 0.8) visit) maintenance HD population Supplements vs placebo Gharekhani, Omega-3 fatty Matched Mean end of study BDI-II: 13.44 (5.66) vs NA Poor 201440 acids: 1,800 placebo: 20.33 (7.56). 27 vs 27 mg/day for 4 Paraffin oil Diff: −10.08 (8.07) vs −0.88 (8.41); P=0.001

31 Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality Tx & F/U=4 months capsules Within groups: Sig decrease (P<0.001) vs months ND Haghighat, Synbiotic Matched End-of-treatment HADS-D scores: synbiotic NA Good 201941 supplement: L. placebo 6.92 (1.27) vs placebo 9.40 (1.5); P<0.001 16 vs 18 vs 15 acidophilus strain synbiotic 6.92 (1.27) vs probiotic 8.48 (1.61); Tx & F/U=12 T16, B. bifidum P=0.011 weeks strain BIA-6, B. lactis strain BIA- Mean difference (95%CI) in HADS-D scores 7, B. longum strain from baseline: symbiotic −2.24 (−3.29 to BIA-8 (2.7×107 −1.38); probiotic −1.28 (−2.05 to −0.53); CFU/g each) per placebo 0.20 (−0.43 to 0.76); P=0.001 5g sachet Synbiotic vs placebo (post-hoc): P<0.001 + prebiotics: 5g FOS + 5g GOS + 5g inulin per three 5g sachets Probiotic supplement: same as above, except prebiotics replaced with placebo Wang, 201542 Radix Bupleuri Placebo Mean (SD) MADRS scores at 3 months: QOL (RAND-36): change from Poor 80 vs 80 herbal 13.32 (8.25) vs 16.73 (9.46) baseline 14.21 vs -1.12; MD=- Tx & F/U=3 supplement: 1g Change from baseline MADRS: -11.36 vs - 4.61 (95% CI: -11.32 to 2.75); months root powder in 2.24; MD=4.72 (95% CI: 0.69 to 9.12); P=0.04 capsule daily P=0.02 Wang, 201639 High-dose oral Matched No between groups difference in delta NA Fair 373 vs 373 vitamin D3: 52- placebo values. Tx & F/U=52 week treatment of Within group BDI-II scores baseline to end weeks 50,000 IU/wk of study: 22.7 (4.3) to 19.6 (3.7); P=0.021 vs

32 Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality 21.9 (5.4) to 20.8 (5.1); P=0.033

NON-PHARMACOLOGICAL Cognitive Behavioral Therapy Al Saraireh, CBT: 7 individual Psychoeducati Post-test HAM-D scores: 15.0 (5.5) vs 11.1 NA Poor 201844 1-hr sessions on (PSE): 7 (2.3). 65 vs 65 following the individual 1-hr Between groups depression scores favored Tx=12 weeks traditional CBT sessions. PSE (t=4.68; P<0.01) over CBT. F/U=12 weeks sessions protocol Cukor, 201445 CBT: Individual Wait-list control BDI-II: Mean change score during treatment: QOL: Treatment effect=+12.0 Fair (crossover) 60-min CBT -11.7 points (SD 1.5; P,0.001) vs -4.8 points (SD 3.4; P=0.003) points vs 38 vs 27 chairside during (SD 1.4; P<0.001). +11.3 points (SD 3.7; P=0.01) Tx=3 months dialysis; Raw mean (SD) change: 24.7 (9.8) to 11.7 Raw mean (SD) score change: F/U=6 months modified for (9.8) vs 14.5 (8.5) to 9.1 (6.5) 99.5 population; 10 Mean (SD) change in BDI-II score in (27.9) to 115.3 (25.5) vs 110.6 sessions over 3 untreated group during waitlist period: -6.7 (25.1) to 119.7 (24.7); P=0.04 months (1.7) points; P<0.001 (Raw mean change: Fluid Adherence: model- 21.9 [8.9] to 14.5 [8.5]). estimated mean change score Magnitude of improvement greater in the during treatment -1.3%Δkg/d (SD intervention first group vs waitlist condition 0.3; P=0.001) vs -1.1%Δkg/d (P=0.03) (SD 0.3; P=0.001) HAM-D: The difference in mean change Raw mean (SD) change: 4.0 score between treated and untreated groups (2.0) to 2.8 (1.6) vs 3.6 (2.0) to was highly significant (P<0.001). 2.5 (2.0); P=0.002 SCID-I: Between groups not reported Duarte, 200943 CBT: Group CBT Individualized BDI-II: After 3 months 14.1 (8.7) vs 21.2 (9.), Suicide Risk Module (MINI): Fair 46 vs 44 sessions; 90 psychotherapy P=0.001; After 9 months 10.8 (8.8) vs 17.6 Baseline 2.2 (5.1) vs 1.4 (3.5), Tx= 12 weeks minutes 1x/wk for (routinely (11.2), P=0.00 P=0.287; After 3 months 1.2 F/U=9 months 12 weeks; available in MINI: the mean change from baseline (SE (4.2) vs 0.7 (1.9), P=0.433; After Followed by 6 mos dialysis unit) favored intervention. 9 months 0.6 (1.2) vs 0.6 (2.0),

33 Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality maintenance w/ 30-50 min After 3 months: 4.5 (0.4) vs 2.1 (0.6); P=0.947 monthly mtgs 1x/wk for 12 P<0.001 Overall reduction, within group weeks; After 9 months: 4.4 (0.4) vs 2.9 (0.5); comparison: Significant reduction Followed by as- P=0.031 within T group (P=0.007) vs C needed (P=0.130) psychological QOL: CBT group significantly care for 6 improved several dimensions of months KDQOL. Between groups sig improvement in burden of kidney disease, quality of social interaction, sleep, overall health, and mental component summary dimensions. Lerma, 201746 CBT: 5 group Wait list End-of-treatment BDI-II: 10.2 (8.2) vs 15.0 Overall QOL (PLC): Fair 38 vs 22 sessions (2hrs) (10.9); P=0.084 Baseline: 99.4 (21.3) vs 91.5 Tx=5 wks 1x/wk after HD Follow-up BDI-II: 7.1 (7.2) vs 14.7 (9.7); (19.5); P=0.203 F/U=9 wks session P=0.003. After 5 weeks: 109.6 (21.1) vs Within group reduction in scores: P<0.001 94.0 (21.0); P=0.016 vs P=0.866 After 9 weeks: 112.5 (23.8) vs RR of reducing depressive symptoms 91.3 (22.5); P=0.004 (between groups)=1.7 Overall within group P=0.001 vs Adjusted RR between groups for P=0.663. Cohen's d=0.93 (large) depression=0.33 (33% clinical utility, 95% CI: 0.05 to 0.55) Nursing Interventions Jahromi, 201651 Telenursing: 30- TAU DASS-21 depression subscale after NA Poor 30 vs 30 minute telephone intervention (mean [SD]): 8.96 (1.17) vs Tx=unclear follow-up sessions 16.20 (1.60); P=0.05 F/U=30 days 30 days after dialysis shift Li, 202049 Home nursing Telephone After intervention SDS: 36.48 (5.06) vs QOL (KDQOL-36): Both groups Poor

34 Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality 36 vs 36 visits: care, follow-up: at 1-, 48.80 (5.27); P<0.001 experienced significant Tx=6 months guidance for pt 3-, and 6- Both groups experienced significant decline improvement (P<0.001). Scores F/U=6 months and family, months after in scores (P<0.001) in Tx group higher than C counseling, and discharge (P<0.001). dietary guidance. Liao, 202050 Comprehensive Conventional After intervention SDS: 51.02 (20.59) vs QOL (KDQOL-36) at 3-month f/u: Poor 64 vs 64 nursing: Health care 60.06 (28.91); P=0.048 Greater improvements from Tx=unclear, education 1-2x/wk; Improvement in scores from baseline: 9.81 baseline for physical activity, during inpatient CBT; progressive (19.32) vs 3.96 (10.79); P=0.041 mental state, burden of kidney stay relaxation, disease, symptoms of kidney F/U=3 months extended f/u care. disease and effects of kidney disease in T compared to C (all P<0.05) Acupressure Kalani, 201947 Acupressure: Sham: Same Post-test BDI-II: T 20.6 vs Sham 25.5 vs C NA Fair 32 vs 32 vs 32 Applied during 1st as acupressure 24.9 significant difference T vs Sham and C Tx=4 weeks 2hrs of HD. 3x/wk group except (P=0.001 for both); No difference between F/U=4 weeks for 4 weeks. Each pressure Sham and C (P=0.220). session lasted 20 applied 1cm minutes from acupressure points. Control: TAU Tsay, 200448 Acupressure: Control group Acupressure and TEAS are similarly Fatigue (PFS): Baseline T 5.92 Poor 36 vs 36 vs 36 applied for 15min (not described) effective, and significantly more effective (1.39) vs TEAS 5.60 (1.30) vs C Tx=4 weeks 3x/wk for 4 weeks than no intervention (P=0.009 and P=0.008 6.01 (1.60); Follow-up T 4.61 F/U=4 weeks respectively). No difference between (1.72) vs TEAS 4.70 (1.50) vs C Transcutaneous acupressure and TEAS (P=0.95) 5.70 (1.80). Post-hoc analysis Electrical Acupoint found significantly lower levels in Stimulation T (P=0.006) and TEAS (P=0.02) (TEAS): applied vs C. No diff between T and

35 Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality for 15min 3x/wk TEAS for 4 weeks Sleep quality (PSQI): Baseline T 8.85 (4.50) vs TEAS 7.12 (4.51 vs C 9.35 (3.48); Follow-up T 7.80 (4.00) vs TEAS 6.32 (4.55) vs C 9.75 (4.65). Compared to controls significantly better with T (P=0.05) and TEAS (P=0.016). No diff between T and TEAS Exercise Frih, 201753 Exercise Sedentary Favors exercise: T HADS depression scores SF-36 PCS: T significantly Poor 28 vs 22 (endurance- controls; no were not different than C before improved (P<0.01) from Tx: 4 months resistance) intervention intervention, but significantly lower than C baseline. No difference for C. No F/U: 4 months training: 60 min, after intervention (P<0.01). Within group difference between groups at 4x/wk on non- decrease also significant for T, but not C. either timepoint. dialysis days. Significant group × period interaction effect SF-36 MCS: T improved for HADS depression scores: F(1, 39)=43.91, significantly, but not C. No P<0.001 difference before, but T significantly better than C after (P<0.01). Kouidi, 201052 Exercise Training Sedentary Favors ET in both BDI-II and HADS scores Heart rate variability (HRV) Poor 25 vs 25 (ET) program control (P<0.001) Indices: SDNN, MSSD, pNN50, Tx=1 year (intradialytic): LF, HF, and LF/HF all F/U=1 year warm-up, cycling, significantly increased in strengthening, exercise group, but not controls. cool-down, 3x/wk, After intervention exercise group 60-90 min during was significantly better in all 1st 2 hrs of HD variables P<0.001 session Other interventions

36 Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality Babamohamadi, Quran: Listen to TAU Post-test BDI-II scores: 14.5 (4.8) vs 31.6 NA Poor 201759 audio of Quran (9.2); P<0.0001. 30 vs 30 recitation on Significant between-subjects treatment Tx=1 month headphones for 20 effect, independent of age (F=9.3, P=0.004, F/U=1 month minutes, Cohen’s d=0.85). beginning 5 minutes before dialysis Beizaee, 201855 Guided Imagery: TAU, nearly Post-test HADS scores: 10.02 (2.58 vs SBP: Mean Before 129.22 Fair 40 vs 40 3x/wk for 4 weeks, silent 11.65 (2.33 (12.70) vs 132.85 (13.22); After Tx=4 weeks in-person w/ environment 121.75 (12.73) vs 134.87 (12.68) F/U=4 weeks psychologist; 30 DBP: Before 82.50 (11.32) vs mins prior to HD 81.75 (8.51); After 81.00 (10.32) session vs 81.87 (8.14) Includes audio HR: Before 77.95 (6.97) vs 75. recording of 42 (8.56); After 73.75 (6.25) vs nature sounds. 77.22 (7.92) Heshmatifar, Benson relaxation TAU Only T group’s scores decreased. The NA Poor 201554 technique (BRT): difference between groups was significant 35 vs 34 Performed 20 (P=0.01). Tx=1 month minutes 2x/day for F/U=1 month 1 month. Rahimipour, Hope therapy: Control: Immediately after 8wk-intervention (t=12.75; NA Poor 201556 Sessions utilizing Listening P<0.001), and at 1-month follow-up 25 vs 25 Schneider’s session in (t=13.83; P<0.001) Tx=8 weeks hope therapy which pts could F/U=12 weeks theory talk about their 1x/wk for 8 weeks disease and 1-1.5 hr during 1st problems 2hrs of dialysis 1x/wk for 8 weeks

37 Author, year N randomized (T vs C), Duration of treatment and Findings, Treatment vs Comparator follow-up Treatment Comparator Depression Other outcomes Quality Thomas, 201758 MBSR*: guided, TAU* Change in PHQ-9: -3.0 (3.9) vs 2.0 (4.7); NA Fair 21 vs 20 chairside P=0.45 Tx=8 weeks meditative F/U=8 weeks practices 10–15 minutes 3x/wk during hemodialysis sessions Widyaningrum, Latihan pasrah diri Control group Significantly decreased BDI-II scores within QOL (KDQOL-SF36): Poor 201357 (LPD) relaxation (not described) both groups, and greater in LPD, but significantly greater change in 18 vs 18 technique and between group difference not significant sleep and overall health Tx= 3 weeks repetitive prayer (P=0.201) associated with LPD vs control. F/U= 3 weeks practice, 2x/ day No other differences were for 21 days significant. * Both treatment and control groups also received psychoeducational literature on anxiety and depression. Abbreviations: AE=adverse event; BDI-II=Beck Depression Inventory; BRT=Benson relaxation technique; BSI=; CBT=Cognitive Behavioral Therapy; CKD=chronic kidney disease; DASS=Depression, Anxiety, and Stress Scale; DBP=diastolic blood pressure; DSM=Diagnostic and Statistical Manual of Mental Disorders; ESKD=end-stage kidney disease; ET=exercise training; FLU=fluoxetine; FOS=fructo-oligosaccharides; GOS=galacto-oligosaccharides; HADS=Hospital Anxiety and Depression Scale; HAM-D=Hamilton Depression Rating Scale; HD=hemodialysis; HR=heart rate; HRV=heart rate variability; KDQOL-36=36-item Kidney Disease Quality of Life; KDQOL-SF=Kidney Disease Quality of Life Short Form; LPD=Latihan Pasrah Diri; MBSR=mindfulness- based stress reduction; MCS=mental component scale; MINI=Mini International Neuropsychiatric Interview; NR=not reported; NS=not significant; P=p-value; PBO=placebo; PCS=physical component scale; PD=peritoneal dialysis; PFS=Piper Fatigue Scale; PSE=psychoeducation; PHQ=Patient Health Questionnaire; PLC=Profile of Quality of Life in the Chronically Ill; PSQI=Pittsburgh Sleep Quality Index; QIDS-C=Quick Inventory of Depressive Symptomatology - Clinician; QOL=quality of life; RR=relative risk; RCT=randomized controlled trial; SCID-I=The Structured Clinical Interview for DSM-IV Axis I Disorders; SDS=Self-rating Depression Scale; SERT=sertraline; SF-36=36-Item Short Form Health Survey; SPB=systolic blood pressure; SSRI=Selective serotonin reuptake inhibitor; TAU=treatment as usual; TEAS=Transcutaneous Electrical Acupoint Stimulation.

38 Table 3. Summary of the evidence on interventions for depression in adults with ESKD Strength of Evidence Outcome Conclusion (Justification)* PHARMACOLOGICAL SSRIs vs controls (k=3, n=94) Fluoxetine30 No benefit (k=1, n=14) Depression severity Insufficient (NC, SLM) Sertraline31,32 Mixed findings (k=2; n=80) SSRIs vs active comparator (k=2; n=164) Sertraline vs CBT33 Low (SLM, UC) Benefit for both; no difference between groups (k=1, n=120) Depression severity Citalopram vs psychological training34 Insufficient (SLH, UC) Benefit for both; no difference between groups (k=1, n=44) Supplements vs placebo (k=4; n=986) Omega-3 Fatty Acids40 Insufficient (NP, SLH, UC) Increased benefit (k=1, n=54) High-dose Vitamin D339 Moderate (SLM, UC) No benefit (k=1, n=746) Depression severity Synbiotic or Probiotic41 Insufficient (UC) Increased benefit (k=1, n=49) Radix Bupleuri†42 Insufficient (UC, SLH) Increased benefit (k=1, n=137) Radix Bupleuri†42 QOL Insufficient (UC, SLH) Increased benefit (k=1, n=137) NON-PHARMACOLOGICAL CBT vs active comparator (k=2; n=220) CBT vs psychoeducation44 Insufficient (SLH, UC) Benefit for both, but favored psychoeducation (k=1, n=130) Depression severity CBT vs psychotherapy43 Low (SLM, UC) Benefit for both, but favored CBT (k=1, n=90) CBT vs psychotherapy43 Suicide risk Low (SLM, UC) Benefit in intervention but not control group; no difference between groups (k=1, n=90) QOL CBT vs psychotherapy43 Low (SLM, UC)

39 Strength of Evidence Outcome Conclusion (Justification)* Increased benefit for some domains of KDQOL (k=1, n=90) CBT vs control (k=2; n=125) Depression severity Increased benefit (k=2; n=125)45,46 Low (SLM) QOL Increased benefit (k=2; n=125)45,46 Low (SLM) Fluid Adherence Increased benefit (k=1; n=65)45 Insufficient (SLM, UC) Acupressure vs control (k=2; n=204) Acupressure vs TAU47,48 ‡ Increased benefit (k=2; n=204) Depression severity Low (SLM) Acupressure vs sham47 Increased benefit (k=1; n=96) Acupressure vs TAU48 Fatigue Insufficient (SLH, UC) Increased benefit (k=1, n=108) Acupressure vs TAU48 Sleep quality Insufficient (SLH, UC) Increased benefit (k=1, n=108) Acupressure vs active comparator (k=1, n=108)48 Acupressure vs TEAS Depression severity Insufficient (SLH, UC) Benefit for both; no difference between groups Acupressure vs TEAS Fatigue Insufficient (SLH, UC) Benefit for both; no difference between groups Acupressure vs TEAS Sleep quality Insufficient (SLH, UC) Benefit for both; no difference between groups Nursing Interventions: Intensive vs less-intensive nursing (k=3; n=260) Depression severity Increased benefit (k=3; n=260)49-51 Insufficient (SLH, NP) QOL Increased benefit (k=2; n=200)49,50 Insufficient (SLH, NP) Benson Relaxation Technique vs control (k=1; n=70)54 Depression severity Increased benefit Insufficient (SLH, UC) Exercise training vs control (k=2 n=100) Depression severity Increased benefit (k=2; n=100)52,53 Insufficient (SLH, UP) HRV Increased benefit (k=1; n=50)52 Insufficient (SLH, UC, UP) Guided Imagery vs TAU (k=1; n=80)55 Depression severity Unclear effect Insufficient (SLM, UC)

40 Strength of Evidence Outcome Conclusion (Justification)* Vital signs Unclear effect Insufficient (SLM, UC) Hope therapy vs active control (k=1; n=50)56 Depression severity Increased benefit Insufficient (SLH, UC, UP) LPD vs control (k=1; n=36)57 Depression severity No benefit Insufficient (SLH, UP, UC) QOL No benefit Insufficient (SLH, UP, UC) MBSR vs TAU (k=1; n=41)58 Depression severity No benefits Insufficient (SLM, UP, UC) Quran vs TAU (k=1; n=60)59 Depression severity Increased benefit Insufficient (SLH, UC, UP) *The overall strength of evidence for each outcome is based on the consistency, coherence, and applicability of the body of evidence, as well as the internal validity of individual studies. The strength of evidence is classified as follows:28 High=Further research is very unlikely to change our confidence on the estimate of effect. Moderate=Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low=Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Insufficient=Any estimate of effect is very uncertain. † Some participants were concurrently using antidepressant medications ‡ Some participants are represented more than once. Abbreviations: CBT=cognitive behavioral therapy; HRV=heartrate variability; k=number of studies; LPD=Latihan Pasrah Diri; MBSR=mindfulness-based stress reduction; n=sample size; NC=not consistent; ND=not direct; NP=not precise; SLH=study limitations high; SLM=study limitations medium; SSRI=Selective Serotonin Reuptake Inhibitor; TAU=treatment as usual; UC=unknown consistency; TEAS=Transcutaneous Electrical Acupoint Stimulation; UD=unclear directness; UP=unclear precision.

41 Table 4. Quality and applicability assessment of randomized controlled trials

Overall Rating Criteria* Quality Author, Year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Funding source Rating Applicability Al Saraireh, 2018 44 Y NR N NA Y U U N Y N Y N Y U Y NA N Investigator Poor Fair

Babamohamadi, 59 NR NR N U Y U U N Y N U N Y Y U U N NR Poor Poor 2017 Beizaee, 201855 Y Y Y Y Y Y Y N Y N Y N N U Y NA Y University Fair Fair Blumenfield, NR Y U U N U Y Y Y N N N Y U Y N N Industry grant Poor Fair 199730 Cukor, 201445 NR NR Y U Y Y Y Y Y N N Y Y U Y N N NIDDK Fair Fair Duarte, 200943 Y Y N U Y Y Y Y Y N N Y Y Y Y N N Government Fair Fair 31 Friedli, 2017 Y Y Y N Y Y Y Y Y Y N N Y U Y N N NIH grant Fair Good Frih, 201753 Y NR U Y Y Y N N Y Y N Y Y U Y N N NR Poor Fair Gharekhani, Y U Y N Y N N Y Y Y N N Y Y Y N N University Poor Good 201440 Haghighat, 201941 Ahvaz Jundishapur Y Y Y U Y Y Y Y Y U Y N Y Y Y Y N Good Fair Univ Med Sci Heshmatifar, NR NR Y U Y U U N Y N N Y Y U U N U NR Poor Fair 201554 Hosseini, 201234 U NR Y Y Y U U N Y N N Y Y U Y N N Government Poor Fair Jahromi, 2016 NR NR Y Y Y Y N Y Y N U N Y Y N U N NR Poor Fair Kalani, 201947 N U Y U Y U U U Y U Y N Y Y Y U N University Poor Fair Kouidi, 201052 NR NR Y U Y U U N Y N N Y Y U Y N N NR Poor Fair Lerma, 201746 Y NR Y U Y Y Y N Y N N N Y Y Y N N Government Fair Fair Li, 202049 Y N Y Y Y N N N N U U N Y U Y U N NR Poor Fair Liao, 202050 Y NR Y Y Y U U U Y N N N Y U Y N N NR Poor Fair Mehrotra, 201933 Government, Y Y U Y Y Y N N Y N Y N Y Y Y Y N University, NIDDK, Fair Fair DCI

42 Overall Rating Criteria* Quality Author, Year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Funding source Rating Applicability Rahimipour, 56 U NR U U Y U U U N U U U Y U Y U N NR Poor Fair 2015 Taraz, 201332 Y U Y Y Y U U Y Y N N N Y Y Y N N University grant Fair Good Thomas, 201758 Y NR N U Y Y U N Y N Y N Y Y Y N N University grant Fair Fair Tsay, 200448 NR NR Y U Y U U N Y N N Y Y U Y N N Government Poor Fair Wang, 201542 NR NR Y N Y U U Y Y Y Y N Y U Y N N NR Poor Fair Wang, 201639 Y Y Y Y Y U Y Y Y N N U Y Y Y N N NR Fair Poor Widyaningrum, 57 NR NR Y U Y U U U N U U U Y U Y U N NR Poor Poor 2013 Abbreviations: DCI = Dialysis Clinic Inc.; N = no; NA = not applicable; NIDDK = National Institute of Diabetes and Digestive and Kidney Diseases; NR = not reported; U = unclear; Y = yes *Quality Rating Criteria (Adapted from the US Preventive Services Task Force criteria26): 1. Randomization adequate? 2. Allocation concealment adequate? 3. Groups similar at baseline? 4. Maintain comparable groups? 5. Eligibility criteria specified? 6. Outcome assessors masked? 7. Care provider masked? 8. Patient masked? 9. Reporting of attrition, crossovers, adherence, and contamination? 10. Important differential loss to follow-up or overall high loss to follow-up? 11. Intention-to-treat (ITT) analysis? 12. Post-randomization exclusions? 13. Were outcomes pre-specified and defined, and ascertained using accurate methods? 14. Intervention fidelity? 15. Follow-up long enough for outcomes to occur? (minimum 4 weeks for drugs) 16. Appropriate handling of missing data? 17. Evidence of selective outcome reporting?

43 Table 5. Adverse events reported in depression treatment trials in patients with end-stage kidney disease

Blumenfield, Haghighat, Mehrotra, 199730 Friedli, 201731* 201941 201933 Taraz, 201332† FLU PBO SERT PBO Probiotic PBO CBT SERT SERT PBO Severity System Adverse Event (N=6) (N=7) (N=15) (N=15) (N=25) (N=25) (N=60) (N=60) (N=21) (N=22) Non- Autonomic Dry mouth 0 1 ------serious Cardiovascular Cardiac unspecified ------3 9 ------Hypotension 4 1 ------Palpitations ------1 0* ------Gastrointestinal Abdominal pain 1 2 ------Constipation 0 1 ------Diarrhea 1 1 ------Dyspepsia 1 0 ------6 4 Gastro-enteritis 0 2 ------Gastrointestinal ------11 22 ------unspecified Nausea 5 2 1 0* ------7 3 Vomiting 3 3 ------Musculoskeletal Myalgia 1 1 ------Neurological Dizziness 1 0 1 0* ------5 3 Headache 3 0 1 0* 1 1 ------4 2 Insomnia 2 1 1 0* ------Nervous system ------0 8 ------unspecified Sensation disturbance 1 0 ------Tremors 1 0 ------Psychiatric Abnormal thought 1 0 ------Anorexia ------2 4 Anxiety 0 1 ------Nervousness 1 1 ------

44 Blumenfield, Haghighat, Mehrotra, 199730 Friedli, 201731* 201941 201933 Taraz, 201332† FLU PBO SERT PBO Probiotic PBO CBT SERT SERT PBO Severity System Adverse Event (N=6) (N=7) (N=15) (N=15) (N=25) (N=25) (N=60) (N=60) (N=21) (N=22) Respiratory Bronchitis 1 0 ------Cough 0 2 ------Dyspnea 1 0 ------1 ------Pharyngitis 1 0 ------Rhinitis 1 0 ------Upper respiratory tract 1 0 ------infection Skin Furunculosis 1 0 ------Pruritus 1 0 ------Skin ulcer 0 1 ------Sweating ------1 0* ------Other Dehydration 0 1 ------Edema 0 1 ------Fatigue ------1 ------Flu syndrome 1 0 ------Hair Loss ------1 1 Other unspecified ------3 17 ------Sexual dysfunction ------2 1 Tooth infection 1 0 ------Severe Gastrointestinal Gastrointestinal ------1 1 ------unspecified Cardiovascular Cardiac unspecified ------4 4 ------Other Death ------1 0 ------2 0 ------Major bleeding ------1 2 ------Other unspecified ------2 9 ------*The events reported in this table are only those that resulted in study dropout. There were other adverse events reported narratively, but it was not clear from the text which category or study arm they occurred in, so they are not recorded in this table. †It is unclear whether the events of study dropouts were included in these totals. There was one death in each group and some attrition due to AEs, but the dropouts were not analyzed in this per-protocol study.

45 Abbreviations: FLU = Fluoxetine; PBO = Placebo; SERT = Sertraline

46

Table 6. Adverse events reported in observational studies of adults with ESKD and depression

Author, year N Years Treatment vs Outcomes of Source Comparator Interest Findings Assimon, 201937 SSRIs w/ higher QT- 1-year sudden Compared to SSRIs with lower QT-prolonging potential, those with higher N=65,654 prolonging potential† vs cardiac death QT-prolonging potential were associated with higher risk of sudden cardiac 2007-2014 SSRIs w/ lower QT- death (AHR=1.18, 95% CI [1.05 to 1.31]). Medicare Recipients in prolonging potential§ the US Renal Data This association was more pronounced among older adults (AHR=1.19, System Database 95% CI [1.05 to 1.35]), women (AHR=1.23, 95% CI [1.06 to 1.44]), patients with conduction disorders (AHR.=1.47, 95% CI [1.05 to 2.06]), and those treated with other non-SSRI QT-prolonging medications (AHR=1.29, 95% CI [1.10 to 1.50]). Guirguis, 202038 Antidepressants Antidepressant  At baseline, 30 pts had BDI‐II scores ≥16, and 22 remained high at N=41 (no comparator) management follow‐up. 2013-2015 practices related  At baseline, 11 pts had BDI‐II scores < 16. Five of 11 were ≥16 on follow‐ ASSertID Study to NICE up to. guidelines  27 of the 41 pts (66%) either deteriorated or failed to improve  16 pts (39%) had no review of antidepressant medication  A significant proportion of patients were taking agents cautioned against or with no available prescribing information in HD patients or taking doses that might be considered sub‐therapeutic.  15% had no evidence of ever having had MDD over their lifetime according to the MINI, in spite of their being on antidepressants. Vangala, 201936 SSRI vs no SSRI Hip fracture Any SSRI use was associated with increased hip fracture risk (AOR = 1.25, N=54,032 95% CI [1.17-1.35]). Risk for fracture was estimated for low (AOR = 1.20, 2009-2015 95% CI [1.08-1.32]), moderate (AOR = 1.31, 95% CI [1.18-1.43]), and high Medicare Recipients in SSRI use (AOR = 1.26, 95% CI [1.12-1.41]). the US Renal Data System Database The relationship between hip fracture events and SSRI use was also seen in the examination of new short-term use (AOR = 1.43, 95% CI [1.23- 1.67]).

No significant interaction with age, sex, BMI, race, or ethnicity was discovered in the short-term analysis

47 † citalopram and escitalopram § fluoxetine, fluvoxamine, paroxetine, and sertraline Abbreviations: AHR=adjusted hazard ratio; AOR= adjusted odds ratio; BDI-II=Beck Depression Inventory-II; BMI=body mass index; CI=confidence interval; NICE= National Institute for Health and Care Excellence; pts= participants; SSRI=selective serotonin reuptake inhibitor

48 Figure 1. Flow Diagram of Literature Review Process

8,050 Citations identified from electronic database searches*: 4,872 from PubMed/Ovid MEDLINE June 24, 2020 2,466 from EMBASE June 24, 2020 330 from PsycINFO June 24, 2020 271 from Ovid EBM Reviews (CDSR, DARE, HTA, Cochrane CENTRAL) June 24, 2020 86 from ClinicalTrials.gov June 24, 2020 25 from WHO ICTRP June 24, 2020 0 from VA HSR&D June 24, 2020

3 Citations identified from reference lists of relevant articles and reviews, key experts, and other sources

8,053 Citations compiled for review of titles and abstracts

7,861 Titles and abstracts excluded for lack of relevance

192 Potentially relevant articles for full text review 163 Excluded publications: 9 Articles unavailable 4 No English language publication 78 Excluded population 41 Excluded study design or publication type 15 No comparator of interest 16 Diagnostic accuracy studies included in parent VA review (not intervention studies) 29 Total included studies

Observational RCTs: studies 26 (harms only): 3

Legend: *after deduplication

49 The Effectiveness of Depression Treatment for Patients with End-Stage Kidney Disease: A Systematic Review Supplemental Material

Contents:

Item S1. Search Strategies (Parent VA Review) ...... 2 Item S2. Study Selection Criteria (Parent VA Review) ...... 8 Table S1. PICOTS by Key Question ...... 10 Table S2. Strength of Evidence Domains and Grading ...... 11 References ...... 12

1

Item S1. Search Strategies (Parent VA Review)

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to June 24, 2020 Date searched: June 24, 2020 # Searches 1 Kidney Failure, Chronic/ 2 (((chronic or endstage or end-stage or endstate or end-state or failure or long-term or maintenance) adj2 (kidney or renal)) or ESKD or ESKF or ESRD or ESRF).ti,ab,kf. 3 Renal Dialysis/ or Hemofiltration/ or Hemodiafiltration/ or Hemodialysis, Home/ or Peritoneal Dialysis/ or Peritoneal Dialysis, Continuous Ambulatory/ 4 (dialysis or haemodiafiltration or hemodiafiltration or haemo-diafiltration or hemo-diafiltration or haemofiltration or hemofiltration or haemo-filtration or hemo-filtration or haemodialysis or hemodialysis or haemo-dialysis or hemo-dialysis).ti,ab,kf. 5 or/1-4 6 Depression/ or Depressive Disorder/ or Depressive Disorder, Major/ or Depressive Disorder, Treatment- Resistant/ 7 (depressed or depressive or depression* or suicidal or suicide or suicides).ti,ab,kf. 8 or/6-7 9 and/5,8 10 Brief Psychiatric Rating Scale/ or Diagnostic Self Evaluation/ or "Diagnostic Techniques and Procedures"/ or Mental Status Schedule/ or Neuropsychological Tests/ or Patient Health Questionnaire/ or Psychiatric Status Rating Scales/ or exp Psychological Tests/ or exp "Surveys and Questionnaires"/ 11 (checklist* or check-list* or questionnaire or questionnaires or instrument or instruments or inventory or inventories or scale or scales or schedule or schedules or screen or screened or screening or "Beck Depression" or BDI or BDI2 or "geriatric depression scale" or GDS or "Hamilton Rating Scale for Depression" or "Hospital Anxiety and Depression Scale" or HADS or "Kidney Disease Quality of Life" or KDQOL or "Medical Outcomes Study Short Form Health Survey 36" or MOS-SF36 or "Minnesota Multiphasic Personality Inventory" or MMPI or "Multiple Affect Adjective Check List" or MAACL or "Patient Health Questionnaire" or PHQ2 or PHQ- 2 or PHQ9 or PHQ-9 or "PRIME-MD" or "Epidemiologic Studies Depression Scale" or CED or CESD or BREF or DASS21 or IDID or "Quick Inventory of Depressive Symptomatology Self-Report" or QIDS-SR or "RAND 36‐ Item Health Survey" or RAND-36 or "short form 36" or SF-36 or "Structured Clinical Interview" or SCID or "self- rating depression scale" or SDS or "Short Form Health Survey 36" or SF36).ti,ab,kf. 12 exp Behavior Therapy/ or exp Cognitive Behavioral Therapy/ or exp Mental Health Services/ or exp Psychotherapy/ or Psychosocial Support Systems/ or Social Support/ or Motivational Interviewing/ or Patient Participation/ 13 (cognitive-behavior* or cognitive-behaviour* or intervention or interventions or nondrug or non-drug or nonpharmac* or non-pharmac* or pharmac* or program* or psych* or psychosocial or psycho-social or rehabilitation or therapy or therapies or treat*).ti,ab,kf. 14 Antidepressive Agents/ or Antidepressive Agents, Second-generation/ or Serotonin Uptake Inhibitors/ or "Serotonin and Noradrenaline Reuptake Inhibitors"/ or Adrenergic Uptake Inhibitors/ or 5-hydroxytryptophan/ or Amisulpride/ or Bupropion/ or Citalopram/ or Fluoxetine/ or Fluvoxamine/ or Maprotiline/ or Mianserin/ or Paroxetine/ or Quipazine/ or Ritanserin/ or Sulpiride/ or Trazodone/ or Tryptophan/ or Venlafaxine Hydrochloride/ or Viloxazine/ 15 (antidepress* or anti-depress* or 5-hydroxytryptophan or Amisulpride or Bupropion or Citalopram or Escitalopram or Fluoxetine or Fluvoxamine or Maprotiline or Mianserin or Paroxetine or Quipazine or Ritanserin or Sulpiride or Trazodone or Tryptophan or Venlafaxine Hydrochloride or Viloxazine or SSRI or SSRIs or "selective serotonin reuptake" or "selective serotonin re-uptake" or SNRI or SNRIs or "Serotonin and Noradrenaline Reuptake Inhibitor" or "Serotonin and Noradrenaline Reuptake Inhibitors" or NRI or NRIs or "norepinephrine reuptake inhibitor" or "norepinephrine reuptake inhibitors").ti,ab,kf.

2

16 Antidepressive Agents, Tricyclic/ or Amitriptyline/ or Amoxapine/ or Clomipramine/ or Desipramine/ or Dothiepin/ or Doxepin/ or Imipramine/ or Iprindole/ or Lofepramine/ or Nortriptyline/ or Opipramol/ or Protriptyline/ or Trimipramine/ 17 (Amitriptyline or Amoxapine or Clomipramine or Desipramine or Dothiepin or Doxepin or Imipramine or Iprindole or Lofepramine or Nortriptyline or Opipramol or Protriptyline or Trimipramine or Gabapentin or Sildenafil or Vardenafil).ti,ab,kf,nm. 18 (nondrug or non-drug or nonpharmacolog* or non-pharmacolog*).ti,ab,kf. 19 Exercise Therapy/ or Resistance Training/ 20 (((aerobic or resistance) adj2 (exercis* or program* or therap* or train*)) or (exercise adj2 (program* or therap* or train*)) or cross-training).ti,ab,kf. 21 Music Therapy/ 22 music therapy.ti,ab,kf. 23 or/10-22 24 and/9,23 25 limit 24 to english language

PsycINFO 1806 to June 2019 Date searched: June 24, 2020 Searches 1 Kidney Diseases/ 2 (((chronic or endstage or end-stage or endstate or end-state or failure or long-term or maintenance) adj2 (kidney or renal)) or ESKD or ESKF or ESRD or ESRF).ti,ab. 3 Dialysis/ or Hemodialysis/ 4 (dialysis or haemodiafiltration or hemodiafiltration or haemo-diafiltration or hemo-diafiltration or haemofiltration or hemofiltration or haemo-filtration or hemo-filtration or haemodialysis or hemodialysis or haemo-dialysis or hemo-dialysis).ti,ab. 5 or/1-4 6 "Depression (Emotion)"/ or Major Depression/ or Reactive Depression/ or Recurrent Depression/ or Treatment Resistant Depression/ 7 (depressed or depressive or depression* or suicidal or suicide or suicides).ti,ab. 8 or/6-7 9 and/5,8 10 exp Measurement/ or exp Attitude Measures/ or exp "Checklist (Testing)"/ or exp Inventories/ or exp Psychological Assessment/ or exp Questionnaires/ or exp Rating Scales/ or exp Screening/ or exp Screening Tests/ or exp Standardized Tests/ or exp "Stress and Coping Measures"/ or exp Testing/ 11 (checklist* or check-list* or questionnaire or questionnaires or instrument or instruments or inventory or inventories or scale or scales or schedule or schedules or screen or screened or screening or "Beck Depression" or BDI or BDI2 or "geriatric depression scale" or GDS or "Hamilton Rating Scale for Depression" or "Hospital Anxiety and Depression Scale" or HADS or "Kidney Disease Quality of Life" or KDQOL or "Medical Outcomes Study Short Form Health Survey 36" or MOS-SF36 or "Minnesota Multiphasic Personality Inventory" or MMPI or "Multiple Affect Adjective Check List" or MAACL or "Patient Health Questionnaire" or PHQ2 or PHQ- 2 or PHQ9 or PHQ-9 or "PRIME-MD" or "Epidemiologic Studies Depression Scale" or CED or CESD or BREF or DASS21 or IDID or "Quick Inventory of Depressive Symptomatology Self-Report" or QIDS-SR or "RAND 36‐ Item Health Survey" or RAND-36 or "short form 36" or SF-36 or "Structured Clinical Interview" or SCID or "self- rating depression scale" or SDS or "Short Form Health Survey 36" or SF36).ti,ab. 12 ("Beck Depression" or BDI or BDI2 or "geriatric depression scale" or GDS or "Hamilton Rating Scale for Depression" or "Hospital Anxiety and Depression Scale" or HADS or "Kidney Disease Quality of Life" or KDQOL or "Medical Outcomes Study Short Form Health Survey 36" or MOS-SF36 or "Minnesota Multiphasic 3

Personality Inventory" or MMPI or "Multiple Affect Adjective Check List" or MAACL or "Patient Health Questionnaire" or PHQ2 or PHQ-2 or PHQ9 or PHQ-9 or PHQ-ADS or "PRIME-MD" or "Epidemiologic Studies Depression Scale" or CED or CESD or BREF or DASS21 or IDID or "Quick Inventory of Depressive Symptomatology Self-Report" or QIDS-SR or "RAND 36‐Item Health Survey" or RAND-36 or "short form 36" or SF-36 or "Structured Clinical Interview" or SCID or "self-rating depression scale" or SDS or "Short Form Health Survey 36" or SF36).tm. 13 exp Treatment/ 14 exp Behavior Modification/ or exp Behavior Therapy/ or Biofeedback Training/ or Contingency Management/ or Self-management/ or Anxiety Management/ or Cognitive Therapy/ or Readiness to Change/ or Relaxation Therapy/ or Self-help Techniques/ or Self-monitoring/ or Stress Management/ 15 (cognitive-behavior* or cognitive-behaviour* or intervention or interventions or nondrug or non-drug or nonpharmac* or non-pharmac* or pharmac* or program* or psych* or psychosocial or psycho-social or rehabilitation or therapy or therapies or treat*).ti,ab. 16 Antidepressant Drugs/ or Serotonin Norepinephrine Reuptake Inhibitors/ or Serotonin Reuptake Inhibitors/ or Tricyclic Antidepressant Drugs/ or Bupropion/ or Citalopram/ or Fluoxetine/ or Fluvoxamine/ or "Hydroxytryptophan (5-)"/ or MAPROTILINE/ or Mianserin/ or Paroxetine/ or RITANSERIN/ or Sulpiride/ or Trazodone/ or Tryptophan/ or Venlafaxine/ 17 (antidepress* or anti-depress* or 5-hydroxytryptophan or Amisulpride or Bupropion or Citalopram or Escitalopram or Fluoxetine or Fluvoxamine or Maprotiline or Mianserin or Paroxetine or Quipazine or Ritanserin or Sulpiride or Trazodone or Tryptophan or Venlafaxine Hydrochloride or Viloxazine or SSRI or SSRIs or "selective serotonin reuptake" or "selective serotonin re-uptake" or SNRI or SNRIs or "Serotonin and Noradrenaline Reuptake Inhibitor" or "Serotonin and Noradrenaline Reuptake Inhibitors" or NRI or NRIs or "norepinephrine reuptake inhibitor" or "norepinephrine reuptake inhibitors").ti,ab. 18 (Amitriptyline or Amoxapine or Clomipramine or Desipramine or Dothiepin or Doxepin or Imipramine or Iprindole or Lofepramine or Nortriptyline or Opipramol or Protriptyline or Trimipramine or Gabapentin or Sildenafil or Vardenafil).ti,ab. 19 (nondrug or non-drug or nonpharmacolog* or non-pharmacolog* or coping or psychosocial* or psycho-social* or "social support" or "social work*" or stress).ti,ab. 20 exp Exercise/ 21 (((aerobic or resistance) adj2 (exercis* or program* or therap* or train*)) or (exercise adj2 (program* or therap* or train*)) or cross-training).ti,ab. 22 Music Therapy/ 23 music therapy.ti,ab. 24 or/10-23 25 and/9,24 26 limit 25 to english language

Embase.com Date search: June 24, 2020 # Search #26 #25 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) #25 #9 AND #23 AND [english]/lim #24 #9 AND #23 #23 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 #22 'music therapy':ti,ab,kw #21 'music therapy'/de #20 (((aerobic OR resistance) NEAR/2 (exercis* OR program* OR therap* OR train*)):ti,ab,kw) OR ((exercise NEAR/2 (program* OR therap* OR train*)):ti,ab,kw) OR 'cross training':ti,ab,kw #19 'kinesiotherapy'/de OR 'resistance training'/de #18 nondrug:ti,ab,kw OR 'non drug':ti,ab,kw OR nonpharmacolog*:ti,ab,kw OR 'non pharmacolog*':ti,ab,kw 4

#17 amitriptyline:ti,ab,kw OR amoxapine:ti,ab,kw OR clomipramine:ti,ab,kw OR desipramine:ti,ab,kw OR dothiepin:ti,ab,kw OR doxepin:ti,ab,kw OR imipramine:ti,ab,kw OR iprindole:ti,ab,kw OR lofepramine:ti,ab,kw OR nortriptyline:ti,ab,kw OR opipramol:ti,ab,kw OR protriptyline:ti,ab,kw OR trimipramine:ti,ab,kw OR gabapentin:ti,ab,kw OR sildenafil:ti,ab,kw OR vardenafil:ti,ab,kw #16 'tricyclic antidepressant agent'/de OR 'amitriptyline'/de OR 'clomipramine'/de OR 'desipramine'/de OR 'dosulepin'/de OR 'doxepin'/de OR 'imipramine'/de OR 'iprindole'/de OR 'lofepramine'/de OR 'nortriptyline'/de OR 'opipramol'/de OR 'protriptyline'/de OR 'trimipramine'/de #15 ((antidepress*:ti,ab,kw OR 'anti depress*':ti,ab,kw OR '5 hydroxytryptophan':ti,ab,kw OR amisulpride:ti,ab,kw OR bupropion:ti,ab,kw OR citalopram:ti,ab,kw OR escitalopram:ti,ab,kw OR fluoxetine:ti,ab,kw OR fluvoxamine:ti,ab,kw OR maprotiline:ti,ab,kw OR mianserin:ti,ab,kw OR paroxetine:ti,ab,kw OR quipazine:ti,ab,kw OR ritanserin:ti,ab,kw OR sulpiride:ti,ab,kw OR trazodone:ti,ab,kw OR tryptophan:ti,ab,kw OR 'venlafaxine hydrochloride':ti,ab,kw OR viloxazine:ti,ab,kw OR ssri:ti,ab,kw OR ssris:ti,ab,kw OR 'selective serotonin reuptake':ti,ab,kw OR 'selective serotonin re-uptake':ti,ab,kw OR snri:ti,ab,kw OR snris:ti,ab,kw OR serotonin:ti,ab,kw) AND 'noradrenaline reuptake inhibitor':ti,ab,kw OR serotonin:ti,ab,kw) AND 'noradrenaline reuptake inhibitors':ti,ab,kw OR nri:ti,ab,kw OR nris:ti,ab,kw OR 'norepinephrine reuptake inhibitor':ti,ab,kw OR 'norepinephrine reuptake inhibitors':ti,ab,kw #14 'antidepressant agent'/de OR 'serotonin uptake inhibitor'/de OR 'serotonin noradrenalin reuptake inhibitor'/de OR 'adrenergic receptor affecting agent'/de OR '5 hydroxytryptophan'/de OR 'amisulpride'/de OR 'amfebutamone'/de OR 'citalopram'/de OR 'fluoxetine'/de OR 'fluvoxamine'/de OR 'maprotiline'/de OR 'mianserin'/de OR 'paroxetine'/de OR 'quipazine'/de OR 'ritanserin'/de OR 'sulpiride'/de OR 'trazodone'/de OR 'tryptophan'/de OR 'venlafaxine'/de OR 'viloxazine'/de #13 'cognitive behavior*':ti,ab,kw OR 'cognitive behaviour*':ti,ab,kw OR intervention:ti,ab,kw OR interventions:ti,ab,kw OR nondrug:ti,ab,kw OR 'non drug':ti,ab,kw OR nonpharmac*:ti,ab,kw OR 'non pharmac*':ti,ab,kw OR pharmac*:ti,ab,kw OR program*:ti,ab,kw OR psych*:ti,ab,kw OR psychosocial:ti,ab,kw OR 'psycho social':ti,ab,kw OR rehabilitation:ti,ab,kw OR therapy:ti,ab,kw OR therapies:ti,ab,kw OR treat*:ti,ab,kw #12 'behavior therapy'/de OR 'cognitive behavioral therapy'/de OR 'mental health service'/de OR 'psychotherapy'/de OR 'psychosocial care'/de OR 'social support'/de OR 'motivational interviewing'/de OR 'patient participation'/de #11 (checklist*:ti,ab,kw OR 'check list*':ti,ab,kw OR questionnaire:ti,ab,kw OR questionnaires:ti,ab,kw OR instrument:ti,ab,kw OR instruments:ti,ab,kw OR inventory:ti,ab,kw OR inventories:ti,ab,kw OR scale:ti,ab,kw OR scales:ti,ab,kw OR schedule:ti,ab,kw OR schedules:ti,ab,kw OR screen:ti,ab,kw OR screened:ti,ab,kw OR screening:ti,ab,kw OR 'beck depression':ti,ab,kw OR bdi:ti,ab,kw OR bdi2:ti,ab,kw OR 'geriatric depression scale':ti,ab,kw OR gds:ti,ab,kw OR 'hamilton rating scale for depression':ti,ab,kw OR 'hospital anxiety':ti,ab,kw) AND 'depression scale':ti,ab,kw OR hads:ti,ab,kw OR 'kidney disease quality of life':ti,ab,kw OR kdqol:ti,ab,kw OR 'medical outcomes study short form health survey 36':ti,ab,kw OR 'mos sf36':ti,ab,kw OR 'minnesota multiphasic personality inventory':ti,ab,kw OR mmpi:ti,ab,kw OR 'multiple affect adjective check list':ti,ab,kw OR maacl:ti,ab,kw OR 'patient health questionnaire':ti,ab,kw OR phq2:ti,ab,kw OR 'phq 2':ti,ab,kw OR phq9:ti,ab,kw OR 'phq 9':ti,ab,kw OR 'prime-md':ti,ab,kw OR 'epidemiologic studies depression scale':ti,ab,kw OR ced:ti,ab,kw OR cesd:ti,ab,kw OR bref:ti,ab,kw OR dass21:ti,ab,kw OR idid:ti,ab,kw OR 'quick inventory of depressive symptomatology self-report':ti,ab,kw OR 'qids sr':ti,ab,kw OR 'rand 36‐item health survey':ti,ab,kw OR 'rand 36':ti,ab,kw OR 'short form 36':ti,ab,kw OR 'sf 36':ti,ab,kw OR 'structured clinical interview':ti,ab,kw OR scid:ti,ab,kw OR 'self-rating depression scale':ti,ab,kw OR sds:ti,ab,kw OR 'short form health survey 36':ti,ab,kw OR sf36:ti,ab,kw #10 'brief psychiatric rating scale'/de OR 'diagnostic procedure'/de OR 'neuropsychological test'/de OR 'patient health questionnaire'/de OR 'psychological rating scale'/de OR 'psychologic test'/de OR 'questionnaire'/de #9 #5 AND #8 #8 #6 OR #7 #7 depressed:ti,ab,kw OR depressive:ti,ab,kw OR depression*:ti,ab,kw OR suicidal:ti,ab,kw OR suicide:ti,ab,kw OR suicides:ti,ab,kw #6 'depression'/exp #5 #1 OR #2 OR #3 OR #4 #4 dialysis:ti,ab,kw OR haemodiafiltration:ti,ab,kw OR hemodiafiltration:ti,ab,kw OR 'haemo diafiltration':ti,ab,kw OR 'hemo diafiltration':ti,ab,kw OR haemofiltration:ti,ab,kw OR hemofiltration:ti,ab,kw OR 'haemo filtration':ti,ab,kw OR 'hemo filtration':ti,ab,kw OR haemodialysis:ti,ab,kw OR hemodialysis:ti,ab,kw OR 'haemo dialysis':ti,ab,kw OR 'hemo dialysis':ti,ab,kw 5

#3 'hemodialysis'/exp OR 'hemofiltration'/exp OR 'hemodiafiltration'/exp OR 'peritoneal dialysis'/exp #2 (((chronic OR endstage OR 'end stage' OR endstate OR 'end state' OR failure OR 'long term' OR maintenance) NEAR/2 (kidney OR renal)):ti,ab,kw) OR eskd:ti,ab,kw OR eskf:ti,ab,kw OR esrd:ti,ab,kw OR esrf:ti,ab,kw #1 'chronic kidney failure'/exp

EBM Reviews: Cochrane Central Register of Controlled Trials June 2020 Cochrane Database of Systematic Reviews 2005 to June 24, 2020 Database of Abstracts of Reviews of Effects 1st Quarter 2016 Health Technology Assessment 4th Quarter 2016 Date searched: June 24, 2020 # Searches 1 (((chronic or endstage or end-stage or endstate or end-state or failure or long-term or maintenance) adj2 (kidney or renal)) or ESKD or ESKF or ESRD or ESRF).ti,ab. 2 (dialysis or haemodiafiltration or hemodiafiltration or haemo-diafiltration or hemo-diafiltration or haemofiltration or hemofiltration or haemo-filtration or hemo-filtration or haemodialysis or hemodialysis or haemo-dialysis or hemo-dialysis).ti,ab. 3 or/1-2 4 (depressed or depressive or depression* or suicidal or suicide or suicides).ti,ab. 5 and/3-4 6 (checklist* or check-list* or questionnaire or questionnaires or instrument or instruments or inventory or inventories or scale or scales or schedule or schedules or screen or screened or screening or "Beck Depression" or BDI or BDI2 or "geriatric depression scale" or GDS or "Hamilton Rating Scale for Depression" or "Hospital Anxiety and Depression Scale" or HADS or "Kidney Disease Quality of Life" or KDQOL or "Medical Outcomes Study Short Form Health Survey 36" or MOS-SF36 or "Minnesota Multiphasic Personality Inventory" or MMPI or "Multiple Affect Adjective Check List" or MAACL or "Patient Health Questionnaire" or PHQ2 or PHQ- 2 or PHQ9 or PHQ-9 or "PRIME-MD" or "Epidemiologic Studies Depression Scale" or CED or CESD or BREF or DASS21 or IDID or "Quick Inventory of Depressive Symptomatology Self-Report" or QIDS-SR or "RAND 36‐ Item Health Survey" or RAND-36 or "short form 36" or SF-36 or "Structured Clinical Interview" or SCID or "self- rating depression scale" or SDS or "Short Form Health Survey 36" or SF36).ti,ab. 7 (cognitive-behavior* or cognitive-behaviour* or intervention or interventions or nondrug or non-drug or nonpharmac* or non-pharmac* or pharmac* or program* or psych* or psychosocial or psycho-social or rehabilitation or therapy or therapies or treat*).ti,ab. 8 (antidepress* or anti-depress* or 5-hydroxytryptophan or Amisulpride or Bupropion or Citalopram or Escitalopram or Fluoxetine or Fluvoxamine or Maprotiline or Mianserin or Paroxetine or Quipazine or Ritanserin or Sulpiride or Trazodone or Tryptophan or Venlafaxine Hydrochloride or Viloxazine or SSRI or SSRIs or "selective serotonin reuptake" or "selective serotonin re-uptake" or SNRI or SNRIs or "Serotonin and Noradrenaline Reuptake Inhibitor" or "Serotonin and Noradrenaline Reuptake Inhibitors" or NRI or NRIs or "norepinephrine reuptake inhibitor" or "norepinephrine reuptake inhibitors").ti,ab. 9 (Amitriptyline or Amoxapine or Clomipramine or Desipramine or Dothiepin or Doxepin or Imipramine or Iprindole or Lofepramine or Nortriptyline or Opipramol or Protriptyline or Trimipramine or Gabapentin or Sildenafil or Vardenafil).ti,ab. 10 (nondrug or non-drug or nonpharmacolog* or non-pharmacolog*).ti,ab. 11 (((aerobic or resistance) adj2 (exercis* or program* or therap* or train*)) or (exercise adj2 (program* or therap* or train*)) or cross-training).ti,ab. 12 music therapy.ti,ab. 13 or/6-12 14 and/5,13

6

ClinicalTrials.gov Date searched: June 24, 2020 ( depressed OR depressive OR depression* OR suicidal OR suicide OR suicides ) AND INFLECT EXACT ( "Active, not recruiting" OR "Completed" OR "Suspended" OR "Terminated" OR "Withdrawn" OR "Unknown status" ) [OVERALL-STATUS] AND ( ( chronic OR endstage OR end-stage OR failure ) AND ( kidney OR renal ) OR ESKD OR ESKF OR ESRD OR ESRF OR dialysis OR haemodiafiltration OR hemodiafiltration OR haemo-diafiltration OR hemo-diafiltration OR haemofiltration OR hemofiltration OR haemo-fi ) [DISEASE]

WHO ICTRP Date searched: June 24, 2020 (((chronic OR endstage OR end-stage OR failure) AND (kidney OR renal)) OR ESKD OR ESKF OR ESRD OR ESRF) AND (depress* OR suicid*)

VA HSR&D https://www.hsrd.research.va.gov/research/ Date searched: June 24, 2020 Separately searched terms: kidney and renal. Reviewed result lists

7

Item S2. Study Selection Criteria (Parent VA Review)

Inclusion/Exclusion Criteria for Full Text Review 1. Language: Is the full text of the article in English? Yes...... …...... ……...... …...... Proceed to #2 No ...... ………...... …………….………………Code X1. STOP

2. Population: Does the study include adults with ESRD or CKD (or CKF, CRF) undergoing maintenance dialysis? Yes …………………………………………………….………………………….Proceed to #3 No ……Code X2. Add code B (example: X2 – B) if retaining for background/discussion. STOP

3. Population: Does the study include adults screened, diagnosed with, or treated for depression? Yes………………...... ……………...... …...... Proceed to #4 No… ……………………..Code X2. Add code B if retaining for background/discussion. STOP

4. KQ1: Does the study examine screening tool(s) for depression? Yes………………...... ……………...... …...... Proceed to Q5 No ………………………………………………………...……...Code 0 for KQ1. Proceed to Q6

5. KQ1: Does the study compare a screening tool against the gold standard (e.g., clinical interview – e.g., SCID) or another validated depression assessment tool? Yes, gold standard (e.g., clinician interview/SCID)…Code I for "I or X Code" and 1 for KQ1. STOP Yes, another depression tool…………...Code I for "I or X Code" and 1 - Tool for KQ1. STOP No ………………………………………………………...…Proceed to Q6 (and code 0 for KQ1)

6. Study Design: Is the study original quantitative research, a systematic review (SR) or meta- analysis (MA; exclude other literature reviews, editorials, qualitative research, etc.)? Yes………………...... ……………...... …. If SR or MA code X3 - PEARL. If other quantitative, Proceed to Q7 No…….Code X3. Add code B (example: X3 – B) if retaining for background/discussion. Code 0 for all KQs. STOP

7. Comparator: The study has a comparison group (other screening tool, no screening, other intervention, waitlist controls, etc.). Pre-post studies are excluded. Yes …………………………………………………….…………………………. Proceed to Q8 No...…Code X4. Add code B if retaining for background/discussion. Code 0 for all KQs STOP

8. Outcomes: Does the study report 1 or more of the following outcomes specifically for the population of interest (ESRD/CKD maintenance dialysis) Diagnostic test performance: sensitivity, specificity, positive predictive value, and negative predictive value; Therapeutic impact: timing, setting, or type of treatment.; Intermediate and Patient outcomes: depressive symptoms, mortality, suicide attempts or completion, hospitalization, ED/urgent care utilization, patient satisfaction, adherence to dialysis, medication, or treatment, pain medication reduction, BP/metabolic control, quality of life, other outcomes (e.g., employment); Adverse effects or unintended consequences. Prevalence and correlational studies are excluded. Yes …………………………………………………….……………….……………Proceed to Q9 No.……Code X5. Add code B if retaining for background/discussion. Code 0 for all KQs STOP 8

9. Does the article or main study (from which the data were gathered) examine the impact of screening or the effectiveness of treatment for depression (including subgroup differences or harms)? Yes, screening ……………………………………………………………………..Proceed to Q10 Yes, treatment: Is depression an inclusion criterion, or is the average depression score of participants equivalent to at least moderate depression? (Cutoffs: PHQ-9 ≥ 10;1 CES-D ≥ 18;2 HAM- D ≥ 12;3 BDI-II ≥ 16;2,3 BDI-II ≥ 13;3 HADS ≥ 84,5) No…………………………………………………………………………………Code X2 Yes…………………………………………………………………………Proceed to Q10 No ………………………….Code X5. Add code B if retaining for background/discussion. STOP

10. Harms: Does the article examine the harms of screening or treatment? Yes………………………………….Code I for "I or X Code" and 1 for KQ4. Proceed to Q11. No………………………………………………………………Code 0 for KQ4. Proceed to Q11.

11. Study Design: Does the article describe data collected as part of an RCT or NRCT? Yes…………………………………………………….………………………….Proceed to Q12. No………………………………………………………..Code X3. Code 0 for KQs 2, 3. STOP.

12. KQs 2 and 3: Does the study examine the impact of screening or treatment? Yes………………………………Code I for "I or X Code" and 1 for KQ2 if screening and/or 1 for KQ3 if treatment. Code 0 for KQ 2 or 3 if NA. STOP. No…………………………………………………….…………Code 0 for KQs 2 and 3. STOP. All articles should have at least 1 code. If not, re-review. Be sure that all articles are coded 0 for all KQs that are not relevant.

9

Table S1. PICOTS by Key Question

Key Question: KQ1: What is the effectiveness of depression KQ2: In patients with KQ3: Do the benefits or harms of treatment differ by: treatment in patients with ESRD and ESRD, what are the a. patient characteristics or other social determinants of depression: potential harms of health? a. pharmacological? treatment for depressed b. setting? b. non-pharmacological? patients? c. provider characteristics (e.g., mental health, PCP)? c. pharmacological and non-pharmacological i. pharmacological? d. other (e.g., patient engagement/ receptivity to treatment, treatments combined? ii. non-pharmacological? social support)? e. timing and type of follow up?

Population Adults with ESRD and depression (Cutoffs: PHQ-9 ≥ 10;1 CES-D ≥ 18;2 HAM-D ≥ 12;3 BDI-II ≥ 16;2,3 BDI ≥ 13;3 HADS ≥ 84,5). If study specified inclusion of subclinical or mild depression in eligibility criteria, we excluded it. Intervention Pharmacological (4+ weeks) and non-pharmacological treatments for depression Comparators Placebo, waitlist control, other intervention Outcomes Intermediate and Patient outcomes: depressive Adverse effects or Intermediate and Patient outcomes: depressive symptoms, symptoms, mortality, suicide attempts or unintended consequences mortality, suicide attempts or completion, hospitalization, completion, hospitalization, ED/urgent care ED/urgent care utilization, patient satisfaction, adherence to utilization, patient satisfaction, adherence to dialysis, medication, or treatment, pain medication dialysis, medication, or treatment, pain reduction, BP/metabolic control, quality of life, other medication reduction, BP/metabolic control, outcomes (e.g., employment) quality of life, other outcomes (e.g., employment) Timing Any Settings All settings in U.S. or international (VHA, hospital community, community mental health, ED, urgent care, other community) Study design Systematic reviews, RCTs, NRCTs Systematic reviews, RCTs, NRCTs, Observational studies Note. Subpopulations may include: Patient demographic characteristics or social determinants of health; treated by HD (home or clinic); treated by PD (home or clinic); clinical severity (ESRD or depression); setting (e.g. VHA, community hospitals, community mental health, ED, urgent care visits for mental health, home vs clinic-based dialysis); other. Abbreviations: CES-D = Center for Epidemiologic Studies Depression Scale; BDI = Beck Depression Inventory; BP = blood pressure; ED = emergency department; ESRD = End- stage Renal Disease; HADS = Hospital Anxiety and Depression Scale; HAM-D = Hamilton Depression Rating Scale; NRCT = Non-randomized controlled trial; PHQ-9 = Patient Health Questionnaire-9; RCT = Randomized controlled trial; VHA = Veterans Health Administration

10

Table S2. Strength of Evidence Domains and Grading

Strength of Evidence Domains Study Limitations Directness Consistency Precision Reporting Bias (Internal Validity) • Direct: the evidence links • Degree to which • Degree of certainty • Publication bias: • Degree to which intervention to a health outcome included studies surrounding an effect nonreporting of the full the include • Indirect: only intermediate find either the estimate with respect study studies for a outcomes are available same direction or to a given outcome • Selective outcome given outcome (e.g., lab tests) when similar magnitude based on the reporting bias: have a high outcomes of interest are of effect sufficiency of sample nonreporting or likelihood of health outcomes (e.g., • Direction of effect: size and number of incomplete reporting of adequate mortality effect sizes have events planned outcomes or protection against • Indirect: data come from proxy the same sign (are • In a meta-analysis, reporting of unplanned bias assessed respondents on the same side of consider whether the outcomes through: • Indirect: data do not come from no effect or a MID) CI crossed a • Selective analysis o Study Design head-to-head comparisons but • Magnitude of threshold for a MID reporting bias: reporting o Study Conduct from two or more bodies of effect: The range of • Consider the of one or more favorable evidence effect sizes is narrowness of analyses for a given similar (may individual study CI outcome while not Indirectness implies that more consider overlap in ranges or reporting other, less than one body of evidence is confidence significance of p- favorable analyses required to link evidence to the intervals) values in evidence most important health outcomes. base Strength of Evidence Grades Low Insufficient Moderate High We have limited confidence that the We have no evidence, we are We are moderately confident We are very confident that the estimate of effect lies close to the true unable to estimate an effect, or that the estimate of effect lies estimate of effect lies close to effect for this outcome. we have no confidence in the close to the true effect for this the true effect for this

estimate of effect for this outcome. outcome. The body of evidence has major or outcome. numerous deficiencies (or both). We The body of evidence has The body of evidence has few believe that additional evidence is No evidence is available, or the some deficiencies. We believe or no deficiencies. We believe needed before concluding either that body of evidence has that the findings are likely to that the findings are stable, the findings are stable or that the unacceptable deficiencies, be stable, but some doubt that is, another study would estimate of effect is close to the true precluding reaching a conclusion. remains. not change the conclusions. effect. Abbreviations: CI = confidence interval; MID = minimum important difference; SOE = strength of evidence Note: This table provides a summary of the elements described in Berkman and colleagues, 20156

11

References

1. Department of Veterans Affairs, Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. 2016;Verson 3.0. 2. CMS Center for Clinical Standards & Quality. Summary of Representative Clinical Depression Screening Tools. November 30, 2015. 3. Furukawa TA, Reijnders M, Kishimoto S, et al. Translating the BDI and BDI-II into the HAMD and vice versa with equipercentile linking. Epidemiol Psychiatr Sci. 2019:1-13. 4. Stafford L, Berk M, Jackson HJ. Validity of the Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9 to screen for depression in patients with coronary artery disease. Gen Hosp Psychiatry. 2007;29(5):417-424. 5. Applied Health Sciences (Mental Health). Assessing the validity of the PHQ-9, HADS, BDI-II and QIDS-SR in measuring severity of depression in a UK sample of primary care patients with a diagnosis of depression. University of Aberdeen. 2011. 6. Berkman ND, Lohr KN, Ansari MT, et al. Grading the strength of a body of evidence when assessing health care interventions: an EPC update. J Clin Epidemiol. 2015;68(11):1312-1324.

12

The Effectiveness of Depression Treatment for Patients with End-Stage Kidney Disease: A Systematic Review Supplemental Material

Contents:

Item S1. Search Strategies (Parent VA Review) ...... 2 Item S2. Study Selection Criteria (Parent VA Review) ...... 8 Table S1. PICOTS by Key Question ...... 10 Table S2. Strength of Evidence Domains and Grading ...... 11 References ...... 12

1

Item S1. Search Strategies (Parent VA Review)

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to June 24, 2020 Date searched: June 24, 2020 # Searches 1 Kidney Failure, Chronic/ 2 (((chronic or endstage or end-stage or endstate or end-state or failure or long-term or maintenance) adj2 (kidney or renal)) or ESKD or ESKF or ESRD or ESRF).ti,ab,kf. 3 Renal Dialysis/ or Hemofiltration/ or Hemodiafiltration/ or Hemodialysis, Home/ or Peritoneal Dialysis/ or Peritoneal Dialysis, Continuous Ambulatory/ 4 (dialysis or haemodiafiltration or hemodiafiltration or haemo-diafiltration or hemo-diafiltration or haemofiltration or hemofiltration or haemo-filtration or hemo-filtration or haemodialysis or hemodialysis or haemo-dialysis or hemo-dialysis).ti,ab,kf. 5 or/1-4 6 Depression/ or Depressive Disorder/ or Depressive Disorder, Major/ or Depressive Disorder, Treatment- Resistant/ 7 (depressed or depressive or depression* or suicidal or suicide or suicides).ti,ab,kf. 8 or/6-7 9 and/5,8 10 Brief Psychiatric Rating Scale/ or Diagnostic Self Evaluation/ or "Diagnostic Techniques and Procedures"/ or Mental Status Schedule/ or Neuropsychological Tests/ or Patient Health Questionnaire/ or Psychiatric Status Rating Scales/ or exp Psychological Tests/ or exp "Surveys and Questionnaires"/ 11 (checklist* or check-list* or questionnaire or questionnaires or instrument or instruments or inventory or inventories or scale or scales or schedule or schedules or screen or screened or screening or "Beck Depression" or BDI or BDI2 or "geriatric depression scale" or GDS or "Hamilton Rating Scale for Depression" or "Hospital Anxiety and Depression Scale" or HADS or "Kidney Disease Quality of Life" or KDQOL or "Medical Outcomes Study Short Form Health Survey 36" or MOS-SF36 or "Minnesota Multiphasic Personality Inventory" or MMPI or "Multiple Affect Adjective Check List" or MAACL or "Patient Health Questionnaire" or PHQ2 or PHQ- 2 or PHQ9 or PHQ-9 or "PRIME-MD" or "Epidemiologic Studies Depression Scale" or CED or CESD or BREF or DASS21 or IDID or "Quick Inventory of Depressive Symptomatology Self-Report" or QIDS-SR or "RAND 36‐ Item Health Survey" or RAND-36 or "short form 36" or SF-36 or "Structured Clinical Interview" or SCID or "self- rating depression scale" or SDS or "Short Form Health Survey 36" or SF36).ti,ab,kf. 12 exp Behavior Therapy/ or exp Cognitive Behavioral Therapy/ or exp Mental Health Services/ or exp Psychotherapy/ or Psychosocial Support Systems/ or Social Support/ or Motivational Interviewing/ or Patient Participation/ 13 (cognitive-behavior* or cognitive-behaviour* or intervention or interventions or nondrug or non-drug or nonpharmac* or non-pharmac* or pharmac* or program* or psych* or psychosocial or psycho-social or rehabilitation or therapy or therapies or treat*).ti,ab,kf. 14 Antidepressive Agents/ or Antidepressive Agents, Second-generation/ or Serotonin Uptake Inhibitors/ or "Serotonin and Noradrenaline Reuptake Inhibitors"/ or Adrenergic Uptake Inhibitors/ or 5-hydroxytryptophan/ or Amisulpride/ or Bupropion/ or Citalopram/ or Fluoxetine/ or Fluvoxamine/ or Maprotiline/ or Mianserin/ or Paroxetine/ or Quipazine/ or Ritanserin/ or Sulpiride/ or Trazodone/ or Tryptophan/ or Venlafaxine Hydrochloride/ or Viloxazine/ 15 (antidepress* or anti-depress* or 5-hydroxytryptophan or Amisulpride or Bupropion or Citalopram or Escitalopram or Fluoxetine or Fluvoxamine or Maprotiline or Mianserin or Paroxetine or Quipazine or Ritanserin or Sulpiride or Trazodone or Tryptophan or Venlafaxine Hydrochloride or Viloxazine or SSRI or SSRIs or "selective serotonin reuptake" or "selective serotonin re-uptake" or SNRI or SNRIs or "Serotonin and Noradrenaline Reuptake Inhibitor" or "Serotonin and Noradrenaline Reuptake Inhibitors" or NRI or NRIs or "norepinephrine reuptake inhibitor" or "norepinephrine reuptake inhibitors").ti,ab,kf.

2

16 Antidepressive Agents, Tricyclic/ or Amitriptyline/ or Amoxapine/ or Clomipramine/ or Desipramine/ or Dothiepin/ or Doxepin/ or Imipramine/ or Iprindole/ or Lofepramine/ or Nortriptyline/ or Opipramol/ or Protriptyline/ or Trimipramine/ 17 (Amitriptyline or Amoxapine or Clomipramine or Desipramine or Dothiepin or Doxepin or Imipramine or Iprindole or Lofepramine or Nortriptyline or Opipramol or Protriptyline or Trimipramine or Gabapentin or Sildenafil or Vardenafil).ti,ab,kf,nm. 18 (nondrug or non-drug or nonpharmacolog* or non-pharmacolog*).ti,ab,kf. 19 Exercise Therapy/ or Resistance Training/ 20 (((aerobic or resistance) adj2 (exercis* or program* or therap* or train*)) or (exercise adj2 (program* or therap* or train*)) or cross-training).ti,ab,kf. 21 Music Therapy/ 22 music therapy.ti,ab,kf. 23 or/10-22 24 and/9,23 25 limit 24 to english language

PsycINFO 1806 to June 2019 Date searched: June 24, 2020 Searches 1 Kidney Diseases/ 2 (((chronic or endstage or end-stage or endstate or end-state or failure or long-term or maintenance) adj2 (kidney or renal)) or ESKD or ESKF or ESRD or ESRF).ti,ab. 3 Dialysis/ or Hemodialysis/ 4 (dialysis or haemodiafiltration or hemodiafiltration or haemo-diafiltration or hemo-diafiltration or haemofiltration or hemofiltration or haemo-filtration or hemo-filtration or haemodialysis or hemodialysis or haemo-dialysis or hemo-dialysis).ti,ab. 5 or/1-4 6 "Depression (Emotion)"/ or Major Depression/ or Reactive Depression/ or Recurrent Depression/ or Treatment Resistant Depression/ 7 (depressed or depressive or depression* or suicidal or suicide or suicides).ti,ab. 8 or/6-7 9 and/5,8 10 exp Measurement/ or exp Attitude Measures/ or exp "Checklist (Testing)"/ or exp Inventories/ or exp Psychological Assessment/ or exp Questionnaires/ or exp Rating Scales/ or exp Screening/ or exp Screening Tests/ or exp Standardized Tests/ or exp "Stress and Coping Measures"/ or exp Testing/ 11 (checklist* or check-list* or questionnaire or questionnaires or instrument or instruments or inventory or inventories or scale or scales or schedule or schedules or screen or screened or screening or "Beck Depression" or BDI or BDI2 or "geriatric depression scale" or GDS or "Hamilton Rating Scale for Depression" or "Hospital Anxiety and Depression Scale" or HADS or "Kidney Disease Quality of Life" or KDQOL or "Medical Outcomes Study Short Form Health Survey 36" or MOS-SF36 or "Minnesota Multiphasic Personality Inventory" or MMPI or "Multiple Affect Adjective Check List" or MAACL or "Patient Health Questionnaire" or PHQ2 or PHQ- 2 or PHQ9 or PHQ-9 or "PRIME-MD" or "Epidemiologic Studies Depression Scale" or CED or CESD or BREF or DASS21 or IDID or "Quick Inventory of Depressive Symptomatology Self-Report" or QIDS-SR or "RAND 36‐ Item Health Survey" or RAND-36 or "short form 36" or SF-36 or "Structured Clinical Interview" or SCID or "self- rating depression scale" or SDS or "Short Form Health Survey 36" or SF36).ti,ab. 12 ("Beck Depression" or BDI or BDI2 or "geriatric depression scale" or GDS or "Hamilton Rating Scale for Depression" or "Hospital Anxiety and Depression Scale" or HADS or "Kidney Disease Quality of Life" or KDQOL or "Medical Outcomes Study Short Form Health Survey 36" or MOS-SF36 or "Minnesota Multiphasic 3

Personality Inventory" or MMPI or "Multiple Affect Adjective Check List" or MAACL or "Patient Health Questionnaire" or PHQ2 or PHQ-2 or PHQ9 or PHQ-9 or PHQ-ADS or "PRIME-MD" or "Epidemiologic Studies Depression Scale" or CED or CESD or BREF or DASS21 or IDID or "Quick Inventory of Depressive Symptomatology Self-Report" or QIDS-SR or "RAND 36‐Item Health Survey" or RAND-36 or "short form 36" or SF-36 or "Structured Clinical Interview" or SCID or "self-rating depression scale" or SDS or "Short Form Health Survey 36" or SF36).tm. 13 exp Treatment/ 14 exp Behavior Modification/ or exp Behavior Therapy/ or Biofeedback Training/ or Contingency Management/ or Self-management/ or Anxiety Management/ or Cognitive Therapy/ or Readiness to Change/ or Relaxation Therapy/ or Self-help Techniques/ or Self-monitoring/ or Stress Management/ 15 (cognitive-behavior* or cognitive-behaviour* or intervention or interventions or nondrug or non-drug or nonpharmac* or non-pharmac* or pharmac* or program* or psych* or psychosocial or psycho-social or rehabilitation or therapy or therapies or treat*).ti,ab. 16 Antidepressant Drugs/ or Serotonin Norepinephrine Reuptake Inhibitors/ or Serotonin Reuptake Inhibitors/ or Tricyclic Antidepressant Drugs/ or Bupropion/ or Citalopram/ or Fluoxetine/ or Fluvoxamine/ or "Hydroxytryptophan (5-)"/ or MAPROTILINE/ or Mianserin/ or Paroxetine/ or RITANSERIN/ or Sulpiride/ or Trazodone/ or Tryptophan/ or Venlafaxine/ 17 (antidepress* or anti-depress* or 5-hydroxytryptophan or Amisulpride or Bupropion or Citalopram or Escitalopram or Fluoxetine or Fluvoxamine or Maprotiline or Mianserin or Paroxetine or Quipazine or Ritanserin or Sulpiride or Trazodone or Tryptophan or Venlafaxine Hydrochloride or Viloxazine or SSRI or SSRIs or "selective serotonin reuptake" or "selective serotonin re-uptake" or SNRI or SNRIs or "Serotonin and Noradrenaline Reuptake Inhibitor" or "Serotonin and Noradrenaline Reuptake Inhibitors" or NRI or NRIs or "norepinephrine reuptake inhibitor" or "norepinephrine reuptake inhibitors").ti,ab. 18 (Amitriptyline or Amoxapine or Clomipramine or Desipramine or Dothiepin or Doxepin or Imipramine or Iprindole or Lofepramine or Nortriptyline or Opipramol or Protriptyline or Trimipramine or Gabapentin or Sildenafil or Vardenafil).ti,ab. 19 (nondrug or non-drug or nonpharmacolog* or non-pharmacolog* or coping or psychosocial* or psycho-social* or "social support" or "social work*" or stress).ti,ab. 20 exp Exercise/ 21 (((aerobic or resistance) adj2 (exercis* or program* or therap* or train*)) or (exercise adj2 (program* or therap* or train*)) or cross-training).ti,ab. 22 Music Therapy/ 23 music therapy.ti,ab. 24 or/10-23 25 and/9,24 26 limit 25 to english language

Embase.com Date search: June 24, 2020 # Search #26 #25 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) #25 #9 AND #23 AND [english]/lim #24 #9 AND #23 #23 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 #22 'music therapy':ti,ab,kw #21 'music therapy'/de #20 (((aerobic OR resistance) NEAR/2 (exercis* OR program* OR therap* OR train*)):ti,ab,kw) OR ((exercise NEAR/2 (program* OR therap* OR train*)):ti,ab,kw) OR 'cross training':ti,ab,kw #19 'kinesiotherapy'/de OR 'resistance training'/de #18 nondrug:ti,ab,kw OR 'non drug':ti,ab,kw OR nonpharmacolog*:ti,ab,kw OR 'non pharmacolog*':ti,ab,kw 4

#17 amitriptyline:ti,ab,kw OR amoxapine:ti,ab,kw OR clomipramine:ti,ab,kw OR desipramine:ti,ab,kw OR dothiepin:ti,ab,kw OR doxepin:ti,ab,kw OR imipramine:ti,ab,kw OR iprindole:ti,ab,kw OR lofepramine:ti,ab,kw OR nortriptyline:ti,ab,kw OR opipramol:ti,ab,kw OR protriptyline:ti,ab,kw OR trimipramine:ti,ab,kw OR gabapentin:ti,ab,kw OR sildenafil:ti,ab,kw OR vardenafil:ti,ab,kw #16 'tricyclic antidepressant agent'/de OR 'amitriptyline'/de OR 'clomipramine'/de OR 'desipramine'/de OR 'dosulepin'/de OR 'doxepin'/de OR 'imipramine'/de OR 'iprindole'/de OR 'lofepramine'/de OR 'nortriptyline'/de OR 'opipramol'/de OR 'protriptyline'/de OR 'trimipramine'/de #15 ((antidepress*:ti,ab,kw OR 'anti depress*':ti,ab,kw OR '5 hydroxytryptophan':ti,ab,kw OR amisulpride:ti,ab,kw OR bupropion:ti,ab,kw OR citalopram:ti,ab,kw OR escitalopram:ti,ab,kw OR fluoxetine:ti,ab,kw OR fluvoxamine:ti,ab,kw OR maprotiline:ti,ab,kw OR mianserin:ti,ab,kw OR paroxetine:ti,ab,kw OR quipazine:ti,ab,kw OR ritanserin:ti,ab,kw OR sulpiride:ti,ab,kw OR trazodone:ti,ab,kw OR tryptophan:ti,ab,kw OR 'venlafaxine hydrochloride':ti,ab,kw OR viloxazine:ti,ab,kw OR ssri:ti,ab,kw OR ssris:ti,ab,kw OR 'selective serotonin reuptake':ti,ab,kw OR 'selective serotonin re-uptake':ti,ab,kw OR snri:ti,ab,kw OR snris:ti,ab,kw OR serotonin:ti,ab,kw) AND 'noradrenaline reuptake inhibitor':ti,ab,kw OR serotonin:ti,ab,kw) AND 'noradrenaline reuptake inhibitors':ti,ab,kw OR nri:ti,ab,kw OR nris:ti,ab,kw OR 'norepinephrine reuptake inhibitor':ti,ab,kw OR 'norepinephrine reuptake inhibitors':ti,ab,kw #14 'antidepressant agent'/de OR 'serotonin uptake inhibitor'/de OR 'serotonin noradrenalin reuptake inhibitor'/de OR 'adrenergic receptor affecting agent'/de OR '5 hydroxytryptophan'/de OR 'amisulpride'/de OR 'amfebutamone'/de OR 'citalopram'/de OR 'fluoxetine'/de OR 'fluvoxamine'/de OR 'maprotiline'/de OR 'mianserin'/de OR 'paroxetine'/de OR 'quipazine'/de OR 'ritanserin'/de OR 'sulpiride'/de OR 'trazodone'/de OR 'tryptophan'/de OR 'venlafaxine'/de OR 'viloxazine'/de #13 'cognitive behavior*':ti,ab,kw OR 'cognitive behaviour*':ti,ab,kw OR intervention:ti,ab,kw OR interventions:ti,ab,kw OR nondrug:ti,ab,kw OR 'non drug':ti,ab,kw OR nonpharmac*:ti,ab,kw OR 'non pharmac*':ti,ab,kw OR pharmac*:ti,ab,kw OR program*:ti,ab,kw OR psych*:ti,ab,kw OR psychosocial:ti,ab,kw OR 'psycho social':ti,ab,kw OR rehabilitation:ti,ab,kw OR therapy:ti,ab,kw OR therapies:ti,ab,kw OR treat*:ti,ab,kw #12 'behavior therapy'/de OR 'cognitive behavioral therapy'/de OR 'mental health service'/de OR 'psychotherapy'/de OR 'psychosocial care'/de OR 'social support'/de OR 'motivational interviewing'/de OR 'patient participation'/de #11 (checklist*:ti,ab,kw OR 'check list*':ti,ab,kw OR questionnaire:ti,ab,kw OR questionnaires:ti,ab,kw OR instrument:ti,ab,kw OR instruments:ti,ab,kw OR inventory:ti,ab,kw OR inventories:ti,ab,kw OR scale:ti,ab,kw OR scales:ti,ab,kw OR schedule:ti,ab,kw OR schedules:ti,ab,kw OR screen:ti,ab,kw OR screened:ti,ab,kw OR screening:ti,ab,kw OR 'beck depression':ti,ab,kw OR bdi:ti,ab,kw OR bdi2:ti,ab,kw OR 'geriatric depression scale':ti,ab,kw OR gds:ti,ab,kw OR 'hamilton rating scale for depression':ti,ab,kw OR 'hospital anxiety':ti,ab,kw) AND 'depression scale':ti,ab,kw OR hads:ti,ab,kw OR 'kidney disease quality of life':ti,ab,kw OR kdqol:ti,ab,kw OR 'medical outcomes study short form health survey 36':ti,ab,kw OR 'mos sf36':ti,ab,kw OR 'minnesota multiphasic personality inventory':ti,ab,kw OR mmpi:ti,ab,kw OR 'multiple affect adjective check list':ti,ab,kw OR maacl:ti,ab,kw OR 'patient health questionnaire':ti,ab,kw OR phq2:ti,ab,kw OR 'phq 2':ti,ab,kw OR phq9:ti,ab,kw OR 'phq 9':ti,ab,kw OR 'prime-md':ti,ab,kw OR 'epidemiologic studies depression scale':ti,ab,kw OR ced:ti,ab,kw OR cesd:ti,ab,kw OR bref:ti,ab,kw OR dass21:ti,ab,kw OR idid:ti,ab,kw OR 'quick inventory of depressive symptomatology self-report':ti,ab,kw OR 'qids sr':ti,ab,kw OR 'rand 36‐item health survey':ti,ab,kw OR 'rand 36':ti,ab,kw OR 'short form 36':ti,ab,kw OR 'sf 36':ti,ab,kw OR 'structured clinical interview':ti,ab,kw OR scid:ti,ab,kw OR 'self-rating depression scale':ti,ab,kw OR sds:ti,ab,kw OR 'short form health survey 36':ti,ab,kw OR sf36:ti,ab,kw #10 'brief psychiatric rating scale'/de OR 'diagnostic procedure'/de OR 'neuropsychological test'/de OR 'patient health questionnaire'/de OR 'psychological rating scale'/de OR 'psychologic test'/de OR 'questionnaire'/de #9 #5 AND #8 #8 #6 OR #7 #7 depressed:ti,ab,kw OR depressive:ti,ab,kw OR depression*:ti,ab,kw OR suicidal:ti,ab,kw OR suicide:ti,ab,kw OR suicides:ti,ab,kw #6 'depression'/exp #5 #1 OR #2 OR #3 OR #4 #4 dialysis:ti,ab,kw OR haemodiafiltration:ti,ab,kw OR hemodiafiltration:ti,ab,kw OR 'haemo diafiltration':ti,ab,kw OR 'hemo diafiltration':ti,ab,kw OR haemofiltration:ti,ab,kw OR hemofiltration:ti,ab,kw OR 'haemo filtration':ti,ab,kw OR 'hemo filtration':ti,ab,kw OR haemodialysis:ti,ab,kw OR hemodialysis:ti,ab,kw OR 'haemo dialysis':ti,ab,kw OR 'hemo dialysis':ti,ab,kw 5

#3 'hemodialysis'/exp OR 'hemofiltration'/exp OR 'hemodiafiltration'/exp OR 'peritoneal dialysis'/exp #2 (((chronic OR endstage OR 'end stage' OR endstate OR 'end state' OR failure OR 'long term' OR maintenance) NEAR/2 (kidney OR renal)):ti,ab,kw) OR eskd:ti,ab,kw OR eskf:ti,ab,kw OR esrd:ti,ab,kw OR esrf:ti,ab,kw #1 'chronic kidney failure'/exp

EBM Reviews: Cochrane Central Register of Controlled Trials June 2020 Cochrane Database of Systematic Reviews 2005 to June 24, 2020 Database of Abstracts of Reviews of Effects 1st Quarter 2016 Health Technology Assessment 4th Quarter 2016 Date searched: June 24, 2020 # Searches 1 (((chronic or endstage or end-stage or endstate or end-state or failure or long-term or maintenance) adj2 (kidney or renal)) or ESKD or ESKF or ESRD or ESRF).ti,ab. 2 (dialysis or haemodiafiltration or hemodiafiltration or haemo-diafiltration or hemo-diafiltration or haemofiltration or hemofiltration or haemo-filtration or hemo-filtration or haemodialysis or hemodialysis or haemo-dialysis or hemo-dialysis).ti,ab. 3 or/1-2 4 (depressed or depressive or depression* or suicidal or suicide or suicides).ti,ab. 5 and/3-4 6 (checklist* or check-list* or questionnaire or questionnaires or instrument or instruments or inventory or inventories or scale or scales or schedule or schedules or screen or screened or screening or "Beck Depression" or BDI or BDI2 or "geriatric depression scale" or GDS or "Hamilton Rating Scale for Depression" or "Hospital Anxiety and Depression Scale" or HADS or "Kidney Disease Quality of Life" or KDQOL or "Medical Outcomes Study Short Form Health Survey 36" or MOS-SF36 or "Minnesota Multiphasic Personality Inventory" or MMPI or "Multiple Affect Adjective Check List" or MAACL or "Patient Health Questionnaire" or PHQ2 or PHQ- 2 or PHQ9 or PHQ-9 or "PRIME-MD" or "Epidemiologic Studies Depression Scale" or CED or CESD or BREF or DASS21 or IDID or "Quick Inventory of Depressive Symptomatology Self-Report" or QIDS-SR or "RAND 36‐ Item Health Survey" or RAND-36 or "short form 36" or SF-36 or "Structured Clinical Interview" or SCID or "self- rating depression scale" or SDS or "Short Form Health Survey 36" or SF36).ti,ab. 7 (cognitive-behavior* or cognitive-behaviour* or intervention or interventions or nondrug or non-drug or nonpharmac* or non-pharmac* or pharmac* or program* or psych* or psychosocial or psycho-social or rehabilitation or therapy or therapies or treat*).ti,ab. 8 (antidepress* or anti-depress* or 5-hydroxytryptophan or Amisulpride or Bupropion or Citalopram or Escitalopram or Fluoxetine or Fluvoxamine or Maprotiline or Mianserin or Paroxetine or Quipazine or Ritanserin or Sulpiride or Trazodone or Tryptophan or Venlafaxine Hydrochloride or Viloxazine or SSRI or SSRIs or "selective serotonin reuptake" or "selective serotonin re-uptake" or SNRI or SNRIs or "Serotonin and Noradrenaline Reuptake Inhibitor" or "Serotonin and Noradrenaline Reuptake Inhibitors" or NRI or NRIs or "norepinephrine reuptake inhibitor" or "norepinephrine reuptake inhibitors").ti,ab. 9 (Amitriptyline or Amoxapine or Clomipramine or Desipramine or Dothiepin or Doxepin or Imipramine or Iprindole or Lofepramine or Nortriptyline or Opipramol or Protriptyline or Trimipramine or Gabapentin or Sildenafil or Vardenafil).ti,ab. 10 (nondrug or non-drug or nonpharmacolog* or non-pharmacolog*).ti,ab. 11 (((aerobic or resistance) adj2 (exercis* or program* or therap* or train*)) or (exercise adj2 (program* or therap* or train*)) or cross-training).ti,ab. 12 music therapy.ti,ab. 13 or/6-12 14 and/5,13

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ClinicalTrials.gov Date searched: June 24, 2020 ( depressed OR depressive OR depression* OR suicidal OR suicide OR suicides ) AND INFLECT EXACT ( "Active, not recruiting" OR "Completed" OR "Suspended" OR "Terminated" OR "Withdrawn" OR "Unknown status" ) [OVERALL-STATUS] AND ( ( chronic OR endstage OR end-stage OR failure ) AND ( kidney OR renal ) OR ESKD OR ESKF OR ESRD OR ESRF OR dialysis OR haemodiafiltration OR hemodiafiltration OR haemo-diafiltration OR hemo-diafiltration OR haemofiltration OR hemofiltration OR haemo-fi ) [DISEASE]

WHO ICTRP Date searched: June 24, 2020 (((chronic OR endstage OR end-stage OR failure) AND (kidney OR renal)) OR ESKD OR ESKF OR ESRD OR ESRF) AND (depress* OR suicid*)

VA HSR&D https://www.hsrd.research.va.gov/research/ Date searched: June 24, 2020 Separately searched terms: kidney and renal. Reviewed result lists

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Item S2. Study Selection Criteria (Parent VA Review)

Inclusion/Exclusion Criteria for Full Text Review 1. Language: Is the full text of the article in English? Yes...... …...... ……...... …...... Proceed to #2 No ...... ………...... …………….………………Code X1. STOP

2. Population: Does the study include adults with ESRD or CKD (or CKF, CRF) undergoing maintenance dialysis? Yes …………………………………………………….………………………….Proceed to #3 No ……Code X2. Add code B (example: X2 – B) if retaining for background/discussion. STOP

3. Population: Does the study include adults screened, diagnosed with, or treated for depression? Yes………………...... ……………...... …...... Proceed to #4 No… ……………………..Code X2. Add code B if retaining for background/discussion. STOP

4. KQ1: Does the study examine screening tool(s) for depression? Yes………………...... ……………...... …...... Proceed to Q5 No ………………………………………………………...……...Code 0 for KQ1. Proceed to Q6

5. KQ1: Does the study compare a screening tool against the gold standard (e.g., clinical interview – e.g., SCID) or another validated depression assessment tool? Yes, gold standard (e.g., clinician interview/SCID)…Code I for "I or X Code" and 1 for KQ1. STOP Yes, another depression tool…………...Code I for "I or X Code" and 1 - Tool for KQ1. STOP No ………………………………………………………...…Proceed to Q6 (and code 0 for KQ1)

6. Study Design: Is the study original quantitative research, a systematic review (SR) or meta- analysis (MA; exclude other literature reviews, editorials, qualitative research, etc.)? Yes………………...... ……………...... …. If SR or MA code X3 - PEARL. If other quantitative, Proceed to Q7 No…….Code X3. Add code B (example: X3 – B) if retaining for background/discussion. Code 0 for all KQs. STOP

7. Comparator: The study has a comparison group (other screening tool, no screening, other intervention, waitlist controls, etc.). Pre-post studies are excluded. Yes …………………………………………………….…………………………. Proceed to Q8 No...…Code X4. Add code B if retaining for background/discussion. Code 0 for all KQs STOP

8. Outcomes: Does the study report 1 or more of the following outcomes specifically for the population of interest (ESRD/CKD maintenance dialysis) Diagnostic test performance: sensitivity, specificity, positive predictive value, and negative predictive value; Therapeutic impact: timing, setting, or type of treatment.; Intermediate and Patient outcomes: depressive symptoms, mortality, suicide attempts or completion, hospitalization, ED/urgent care utilization, patient satisfaction, adherence to dialysis, medication, or treatment, pain medication reduction, BP/metabolic control, quality of life, other outcomes (e.g., employment); Adverse effects or unintended consequences. Prevalence and correlational studies are excluded. Yes …………………………………………………….……………….……………Proceed to Q9 No.……Code X5. Add code B if retaining for background/discussion. Code 0 for all KQs STOP 8

9. Does the article or main study (from which the data were gathered) examine the impact of screening or the effectiveness of treatment for depression (including subgroup differences or harms)? Yes, screening ……………………………………………………………………..Proceed to Q10 Yes, treatment: Is depression an inclusion criterion, or is the average depression score of participants equivalent to at least moderate depression? (Cutoffs: PHQ-9 ≥ 10;1 CES-D ≥ 18;2 HAM- D ≥ 12;3 BDI-II ≥ 16;2,3 BDI-II ≥ 13;3 HADS ≥ 84,5) No…………………………………………………………………………………Code X2 Yes…………………………………………………………………………Proceed to Q10 No ………………………….Code X5. Add code B if retaining for background/discussion. STOP

10. Harms: Does the article examine the harms of screening or treatment? Yes………………………………….Code I for "I or X Code" and 1 for KQ4. Proceed to Q11. No………………………………………………………………Code 0 for KQ4. Proceed to Q11.

11. Study Design: Does the article describe data collected as part of an RCT or NRCT? Yes…………………………………………………….………………………….Proceed to Q12. No………………………………………………………..Code X3. Code 0 for KQs 2, 3. STOP.

12. KQs 2 and 3: Does the study examine the impact of screening or treatment? Yes………………………………Code I for "I or X Code" and 1 for KQ2 if screening and/or 1 for KQ3 if treatment. Code 0 for KQ 2 or 3 if NA. STOP. No…………………………………………………….…………Code 0 for KQs 2 and 3. STOP. All articles should have at least 1 code. If not, re-review. Be sure that all articles are coded 0 for all KQs that are not relevant.

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Table S1. PICOTS by Key Question

Key Question: KQ1: What is the effectiveness of depression KQ2: In patients with KQ3: Do the benefits or harms of treatment differ by: treatment in patients with ESRD and ESRD, what are the a. patient characteristics or other social determinants of depression: potential harms of health? a. pharmacological? treatment for depressed b. setting? b. non-pharmacological? patients? c. provider characteristics (e.g., mental health, PCP)? c. pharmacological and non-pharmacological i. pharmacological? d. other (e.g., patient engagement/ receptivity to treatment, treatments combined? ii. non-pharmacological? social support)? e. timing and type of follow up?

Population Adults with ESRD and depression (Cutoffs: PHQ-9 ≥ 10;1 CES-D ≥ 18;2 HAM-D ≥ 12;3 BDI-II ≥ 16;2,3 BDI ≥ 13;3 HADS ≥ 84,5). If study specified inclusion of subclinical or mild depression in eligibility criteria, we excluded it. Intervention Pharmacological (4+ weeks) and non-pharmacological treatments for depression Comparators Placebo, waitlist control, other intervention Outcomes Intermediate and Patient outcomes: depressive Adverse effects or Intermediate and Patient outcomes: depressive symptoms, symptoms, mortality, suicide attempts or unintended consequences mortality, suicide attempts or completion, hospitalization, completion, hospitalization, ED/urgent care ED/urgent care utilization, patient satisfaction, adherence to utilization, patient satisfaction, adherence to dialysis, medication, or treatment, pain medication dialysis, medication, or treatment, pain reduction, BP/metabolic control, quality of life, other medication reduction, BP/metabolic control, outcomes (e.g., employment) quality of life, other outcomes (e.g., employment) Timing Any Settings All settings in U.S. or international (VHA, hospital community, community mental health, ED, urgent care, other community) Study design Systematic reviews, RCTs, NRCTs Systematic reviews, RCTs, NRCTs, Observational studies Note. Subpopulations may include: Patient demographic characteristics or social determinants of health; treated by HD (home or clinic); treated by PD (home or clinic); clinical severity (ESRD or depression); setting (e.g. VHA, community hospitals, community mental health, ED, urgent care visits for mental health, home vs clinic-based dialysis); other. Abbreviations: CES-D = Center for Epidemiologic Studies Depression Scale; BDI = Beck Depression Inventory; BP = blood pressure; ED = emergency department; ESRD = End- stage Renal Disease; HADS = Hospital Anxiety and Depression Scale; HAM-D = Hamilton Depression Rating Scale; NRCT = Non-randomized controlled trial; PHQ-9 = Patient Health Questionnaire-9; RCT = Randomized controlled trial; VHA = Veterans Health Administration

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Table S2. Strength of Evidence Domains and Grading

Strength of Evidence Domains Study Limitations Directness Consistency Precision Reporting Bias (Internal Validity) • Direct: the evidence links • Degree to which • Degree of certainty • Publication bias: • Degree to which intervention to a health outcome included studies surrounding an effect nonreporting of the full the include • Indirect: only intermediate find either the estimate with respect study studies for a outcomes are available same direction or to a given outcome • Selective outcome given outcome (e.g., lab tests) when similar magnitude based on the reporting bias: have a high outcomes of interest are of effect sufficiency of sample nonreporting or likelihood of health outcomes (e.g., • Direction of effect: size and number of incomplete reporting of adequate mortality effect sizes have events planned outcomes or protection against • Indirect: data come from proxy the same sign (are • In a meta-analysis, reporting of unplanned bias assessed respondents on the same side of consider whether the outcomes through: • Indirect: data do not come from no effect or a MID) CI crossed a • Selective analysis o Study Design head-to-head comparisons but • Magnitude of threshold for a MID reporting bias: reporting o Study Conduct from two or more bodies of effect: The range of • Consider the of one or more favorable evidence effect sizes is narrowness of analyses for a given similar (may individual study CI outcome while not Indirectness implies that more consider overlap in ranges or reporting other, less than one body of evidence is confidence significance of p- favorable analyses required to link evidence to the intervals) values in evidence most important health outcomes. base Strength of Evidence Grades Low Insufficient Moderate High We have limited confidence that the We have no evidence, we are We are moderately confident We are very confident that the estimate of effect lies close to the true unable to estimate an effect, or that the estimate of effect lies estimate of effect lies close to effect for this outcome. we have no confidence in the close to the true effect for this the true effect for this

estimate of effect for this outcome. outcome. The body of evidence has major or outcome. numerous deficiencies (or both). We The body of evidence has The body of evidence has few believe that additional evidence is No evidence is available, or the some deficiencies. We believe or no deficiencies. We believe needed before concluding either that body of evidence has that the findings are likely to that the findings are stable, the findings are stable or that the unacceptable deficiencies, be stable, but some doubt that is, another study would estimate of effect is close to the true precluding reaching a conclusion. remains. not change the conclusions. effect. Abbreviations: CI = confidence interval; MID = minimum important difference; SOE = strength of evidence Note: This table provides a summary of the elements described in Berkman and colleagues, 20156

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References

1. Department of Veterans Affairs, Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. 2016;Verson 3.0. 2. CMS Center for Clinical Standards & Quality. Summary of Representative Clinical Depression Screening Tools. November 30, 2015. 3. Furukawa TA, Reijnders M, Kishimoto S, et al. Translating the BDI and BDI-II into the HAMD and vice versa with equipercentile linking. Epidemiol Psychiatr Sci. 2019:1-13. 4. Stafford L, Berk M, Jackson HJ. Validity of the Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9 to screen for depression in patients with coronary artery disease. Gen Hosp Psychiatry. 2007;29(5):417-424. 5. Applied Health Sciences (Mental Health). Assessing the validity of the PHQ-9, HADS, BDI-II and QIDS-SR in measuring severity of depression in a UK sample of primary care patients with a diagnosis of depression. University of Aberdeen. 2011. 6. Berkman ND, Lohr KN, Ansari MT, et al. Grading the strength of a body of evidence when assessing health care interventions: an EPC update. J Clin Epidemiol. 2015;68(11):1312-1324.

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