Studies on Depression and Fatigue in People With End Stage Kidney Disease Receiving Haemodialysis

Depression is common in haemodialysis (HD) patients and is often unrecognised and undertreated, though associated with excess morbidity and mortality. Diagnosis is challenging due to symptom overlap with kidney failure, with fatigue being the most common overlapping symptom. Research on the effectiveness of antidepressant medication in this setting is sparse. A recent systematic review advocated well-designed Randomised Controlled Trials (RCTs) in this setting. The studies reported in this thesis had a number of aims. The main aim was to undertake a multicentre feasibility randomised, double blind, placebo-controlled trial of sertraline in patients on HD with Major Depressive Disorder (MDD). To identify suitable patients for this, a screening phase was required, which also allowed determination of the prevalence of depression in this setting and of the relative effectiveness of screening tools Patient Health Questionnaire-2 (PHQ-2), Patient Health Questionnaire-9 (PHQ-9), and Beck Depression Inventory-II (BDI-II). It also allowed examination of the relationships of fatigue in this setting (assessed mainly by the Multidimensional Fatigue Inventory (MFI), including those with a diagnosis, and management of depression. The finding, during screening, that a large proportion of the HD cohort was already on antidepressant treatment, presented the opportunity to study ‘real-life’ practice patterns in the management of antidepressant treatment in this setting. Recruitment into the RCT was difficult. 1,355 patients in five HD centres were considered for screening, but 243 of these were excluded, mainly because of their inability to read and understand English. Of the remaining 1,110 patients, 709 consented to screening. 231 of these screened positive for high depression symptoms but 130 were not considered for the trial phase, mainly because of concurrent treatment for depression (68 patients), and other contraindicated conditions and medication. In addition, 38 patients declined to take part in the psychiatric interview necessary for diagnosis of MDD. Of the 63 who underwent the diagnostic interview, 37 (58.7%) were diagnosed with MDD and 30 consented to enter the RCT and were randomised into sertraline or placebo groups. This was half of the anticipated recruitment into the RCT. Twenty-one patients (70%) completed the six-month study, eight of 15 in the sertraline group and 13 of 15 in the placebo group (p<0.05). Drop out was mainly due to adverse or serious adverse events. Depression scores (BDI-II and Montgomery-Åsberg Depression Rating Scale (MADRS)) improved significantly in both the sertraline and placebo groups over six months but there were no significant differences between the treatment groups. There was a slight suggestion of more rapid improvement over the first two months on sertraline, but this was not significant. Fatigue scores were high in all sub-domains – with only a weak relationship with age and comorbidity. Mental fatigue was the strongest independent predictor of high depressive symptoms (BDI-II ≥16, PHQ-9 ≥8), while physical fatigue had the strongest relationship with dialysis recovery time, and survival. Distinguishing between these components of fatigue may have a role in refining the diagnosis and management of MDD. Forty-one of the 76 patients on antidepressant medication at screening were followed up for a mean of 14±5 months. Ten different antidepressant agents were being taken – the most common being Citalopram (39%). Most had been prescribed by GPs. Two-thirds of patients either deteriorated or failed to improve in terms of BDI-II scores during follow-up, many of whom had had no adjustment of medication during this time. Diagnostic evaluation at follow-up showed 37% to be suffering from current or recurrent major depressive episodes (MDE), 48% to have evidence of past MDE, and 15% to have no evidence of ever having been depressed. These empirical studies confirm that depression is very common in HD patients. Its diagnosis is complicated due to symptom overlap with the uraemic syndrome. Fatigue seems to be a key area of overlap with symptoms of depression with a complex relationship. There was no obvious benefit from antidepressants in this feasibility RCT and there was a high drop-out rate due to adverse events, particularly in the sertraline group. These findings raise concerns about the benefits and risks of antidepressants in patients on HD. Current practice patterns may be subjecting patients to substantial risk for little or no benefit. Identifying whether antidepressant medication is effective in this context is a major clinical need, hence the requirement for a definitive study. There is no doubt that to undertake a definitive study would pose considerable recruitment challenges. The findings presented here emphasise the importance of finding ways to overcome these challenges that might include efforts to incorporate patients already taking antidepressants

Self-reported depression symptoms in haemodialysis patients: Bi-factor structures of two common measures and their association with clinical factors

Copyright © 2018 Elsevier Inc. All rights reserved.Objective: To validate the factor structure of two common self-report depression tools in a large sample of haemodialysis (HD) patients and to examine their demographic and clinical correlates, including urine output, history of depression and transplantation. Methods: Factor structures of the Beck Depression Inventory (BDI-II) and Patient Health Questionnaire (PHQ-9) were evaluated using confirmatory factor analysis (CFA). Data was utilised from the screening phase (n = 709) of a placebo-controlled feasibility randomised control trial (RCT) of sertraline in HD patients with mild to moderate Major Depressive Disorder. Alternative factor models including bi-factor models for the BDI-II and PHQ-9 were evaluated. Coefficient omega and omega-hierarchical were calculated. Results: For both measures, bi-factor measurement models had the overall best fit to the data, with dominant general depression factors. Omega-hierarchical for the general BDI-II and PHQ-9 factors was 0.94 and 0.88 respectively. Both general factors had high reliability (coefficient omega = 0.97 and 0.94 respectively) and explained over 85% of the explained common variance within their respective models. BDI-II and PHQ-9 general depression factors were negatively associated with age and urine output and positively with a history of depression, antidepressant use within the last 3 months and a history of failed transplantation. In adjusted regression models, age, urine output and a history of depression remained significant. Conclusions: These data suggest that both the BDI-II and PHQ-9 are sufficiently unidimensional to warrant the use of a total score. Younger age, lower urine output and a history of depression appear consistent correlates of depression severity among HD patients.Peer reviewedFinal Accepted Versio

Sertraline Versus Placebo in Patients with Major Depressive Disorder Undergoing Hemodialysis : A Randomized, Controlled Feasibility Trial

This document is the Accepted Manuscript version of the following article: Karin Friedli, et al, ‘Sertraline Versus Placebo in Patients with Major Depressive Disorder Undergoing Hemodialysis: A Randomized, Controlled Feasibility Trial’, Clinical Journal of the American Society of Nephrology, Vol. 12 (2): 280-286, February 2017. The final, published version is available online at DOI: https://doi.org/10.2215/​CJN.02120216.BACKGROUND AND OBJECTIVES: Depression is common in patients on hemodialysis, but data on the benefits and risks of antidepressants in this setting are limited. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of sertraline over 6 months in patients on hemodialysis with depression to determine study feasibility, safety, and effectiveness. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on hemodialysis at five United Kingdom renal centers completed the Beck Depression Inventory II. Those scoring ≥16 and not already on treatment for depression were invited to undergo diagnostic interview to confirm major depressive disorder. Eligible patients with major depressive disorder were randomized to receive the study medication-either sertraline or placebo. Outcomes included recruitment and dropout rates, change in the Montgomery-Asberg Depression Rating Scale and Beck Depression Inventory II, and qualitative information to guide design of a large-scale trial. RESULTS: In total, 709 patients were screened and enrolled between April of 2013 and October of 2014; 231 (32.6%) had Beck Depression Inventory II scores ≥16, and 68 (29%) of these were already receiving treatment for depression. Sixty-three underwent diagnostic interview, 37 were diagnosed with major depressive disorder, and 30 were randomized; 21 completed the trial: eight of 15 on sertraline and 13 of 15 on placebo (P=0.05). Dropouts due to adverse and serious adverse events were greater in the sertraline group. All occurred in the first 3 months. Over 6 months, depression scores improved in both groups. Beck Depression Inventory II score fell from 29.1±8.4 to 17.3±12.4 (P<0.001), and Montgomery-Asberg Depression Rating Scale score fell from 24.5±4.1 to 10.3±5.8 (P<0.001). There were no differences between sertraline and placebo groups. CONCLUSIONS: Although small, this is the largest randomized trial to date of antidepressant medication in patients on hemodialysis. Our results highlight recruitment issues. No benefit was observed, but trial size and the substantial dropout render consideration of benefit inconclusive. A definitive trial could use shorter follow-up and include depressed patients already taking antidepressants.Peer reviewedFinal Accepted Versio

A study of sertraline in dialysis (ASSertID) : a protocol for a pilot randomised controlled trial of drug treatment for depression in patients undergoing haemodialysis

© 2015 Friedli et al. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedBACKGROUND: The prevalence of depression in people receiving haemodialysis is high with estimates varying between 20 and 40 %. There is little research on the effectiveness of antidepressants in dialysis patients with the few clinical trials suffering significant methodological issues. We plan to carry out a study to evaluate the feasibility of conducting a randomised controlled trial in patients on haemodialysis who have diagnosed Major Depressive Disorder.METHODS/DESIGN: The study has two phases, a screening phase and the randomised controlled trial. Patients will be screened initially with the Beck Depression Inventory to estimate the number of patients who score 16 or above. These patients will be invited to an interview with a psychiatrist who will invite those with a diagnosis of Major Depressive Disorder to take part in the trial. Consenting patients will be randomised to either Sertraline or placebo. Patients will be followed-up for 6 months. Demographic and clinical data will be collected at screening interview, baseline interview and 2 weeks, and every month (up to 6 months) after baseline. The primary outcome is to evaluate the feasibility of conducting a randomised, double blind, placebo pilot trial in haemodialysis patients with depression. Secondary outcomes include estimation of the variability in the outcome measures for the treatment and placebo arms, which will allow for a future adequately powered definitive trial. Analysis will primarily be descriptive, including the number of patients eligible for the trial, drug exposure of Sertraline in haemodialysis patients and the patient experience of participating in this trial.DISCUSSION: There is an urgent need for this research in the dialysis population because of the dearth of good quality and adequately powered studies. Research with renal patients is particularly difficult as they often have complex medical needs. This research will therefore not only assess the outcome of anti-depressants in haemodialysis patients with depression but also the process of running a randomised controlled trial in this population. Hence, the outputs of this feasibility study will be used to inform the design and methodology of a definitive study, adequately powered to determine the efficacy of anti-depressants in patient on haemodialysis with depression.TRIAL REGISTRATION: ISRCTN registry ISRCTN06146268 and EudraCT reference: 2012-000547-27.Peer reviewedFinal Published versio

Depression Symptoms in Haemodialysis Patients Predict All-Cause Mortality but Not Kidney Transplantation: A Cause-Specific Outcome Analysis

Background:Depression is common in haemodialysis (HD) patients and associated with poor outcomes. Purpose:To evaluate whether depression symptoms predict survival and transplantation in a large sample of haemodialysis patients using cause-specific survival models. Methods:Survival data was collected between April 2013 and November 2015, as part of the screening phase of a multicentre randomised placebo-controlled trial of sertraline in HD patients. Depression was measured using the Beck Depression Inventory-II (BDI-II) and the Patient Health Questionnaire-9 (PHQ-9). Demographic and clinical data were collected via a self-report questionnaire and medical records. Competing risk survival analysis involved cause-specific and subdistribution hazard survival models. All models were adjusted for appropriate covariates including co-morbidity and C-reactive protein (CRP) in a subanalysis. Results:Of 707 cases available for analysis, there were 148 deaths. The mean survival time was 787.5 days. Cumulative survival at 12 months was 88.5%. During the study follow-up period, there were 92 transplants. The cumulative transplant event rate at 12 months was 7.8%. In separate adjusted models, depression symptoms predicted mortality (BDI-II HR = 1.03 95% CI 1.01, 1.04; PHQ-9 HR = 1.04 95% CI 1.01, 1.06). With respect to screening cut-off scores, a PHQ-9 ≥ 10 was associated with mortality (HR = 1.51 95% CI 1.01, 2.19) but not a BDI-II ≥ 16. Depression symptoms were not associated with time to transplantation in either cause-specific or subdistribution model. Conclusions:Consistent with past findings in HD patients, depression symptoms predicted survival but were not associated with kidney transplantation. Suitable treatments for depression need further evaluation, and their impact upon quality of life and clinical outcomes determined. Trial Registration Number:(ISRCTN06146268)

C reactive protein and depressive symptoms in haemodialysis patients:a questionable association

Introduction: Patients with advanced chronic kidney disease (CKD) on haemodialysis (HD) may have increased C reactive protein (CRP) values and depressive symptoms. There is debate about the strength and nature of previously reported associations. We investigated these issues in a cohort of patients on HD. Methods: We screened for depressive symptoms using two valadiated depression screening tools: the Beck Depression Inventory‐II (BDI‐II), Patient Health Questionnaire (PHQ‐9). Demographic and clinical correlates of depression symptoms were eveluated in adjusted linear and logistic regression models, which included extra renal comorbidity and high CRP (>5 mg/L). Findings: Three hundred and ninety‐six HD patients were studied; 63.1% male, mean age 63.1 ± 16.4 years, median CRP 6 (5–15) mg/L. Depression scores were similar in those with normal and high CRP (BDI‐II (9(5–17) vs. 11(6–20)) or PHQ (4(2–9) vs. 6(2–10)). In adjusted multivariable regression BDI‐II scores were associated with previous history of depression (β 10.8, P < 0.001), serum albumin (β 0.41, P < 0.001), anuria (β 2.4, P < 0.037), diabetes (β 2.7, P = 0.033), and age (β −0.10, P = 0.009). High CRP was not independently associated with BDI‐II (β 2.20, P = 0.057), though was with PHQ‐9 (β 1.20, P = 0.046). In logistic regression those with high CRP were 1.9 times more likely to score ≥16 on BDI‐II screening (P = 0.016), but did not relate significantly to a PHQ‐score ≥10. Discussion: A relationship was observed between CRP and depression symptoms, though the effect was small, of unlikely clinical significance, and inconsistent between depression measures. Previous reports of this association may reflect overlap between symptoms of depression and advanced CKD

Antidepressant Usage in Haemodialysis Patients: Evidence of Sub-optimal Practice Patterns

Background: Depression is common in patients on haemodialysis and associated with adverse outcomes. Antidepressant use is widespread though evidence of efficacy is limited. Objectives: To study antidepressant management practices in patients on haemodialysis with reference to NICE guidelines on management of depression in adults with chronic physical health problems. Design: Prospective, multicentre, longitudinal cohort study with 6–15 month follow‐up. Participants: Patients on haemodialysis established on antidepressant medication. Measurements: Baseline assessment of mood was undertaken using Beck Depression Inventory (BDI‐II). Demographic, clinical and medication data were also collected. Changes in clinical and life circumstances and medication during follow‐up were recorded. At follow‐up, BDI‐II was reassessed and diagnostic psychiatric assessment undertaken. Results: Forty‐one patients were studied. General practitioners were the main prescribers (68%). Ten agents were in use, the commonest being Citalopram (39%). Doses were often suboptimal. At baseline, 30 patients had high BDI‐II scores (≥16) and 22 remained high at follow‐up. Eleven had BDI‐II < 16 at baseline. In five, this increased on follow‐up to ≥16. Sixteen patients (39%) had no medication review during follow‐up, 14 (34%) had a dose review, and 11 (27%) a medication change. On psychiatric assessment at follow‐up, eight patients had current major depressive disorder (MDD), seven recurrent and 20 evidence of past MDD. Six displayed no evidence of ever having MDD. Conclusions: Antidepressant management in patients on haemodialysis reflected poor drug selection, overprescription, under‐dosing and inadequate follow‐up suggesting sub‐optimal adherence to NICE guidelines. Most patients had high depression scores at follow‐up. Antidepressant use in haemodialysis requires reappraisal

Measuring fatigue using the Multidimensional Fatigue Inventory (MFI-20): a questionable factor structure in haemodialysis patients

BACKGROUND/AIMS: Fatigue is recognised as a common and burdensome symptom among dialysis patients. A growing body of research is devoted to understanding fatigue in advanced kidney disease, yet its measurement is challenging within this context. Our aim was to evaluate the factor structure underlying the multidimensional fatigue inventory (MFI-20) and to examine its associations with clinical factors and mood. METHODS: Data was evaluated for confirmatory factor analysis (CFA) from the screening phase of a multicentre randomised placebo-controlled trial of sertraline in haemodialysis (HD) patients. Four hundred seventy patients completed the MFI-20, which purports to measure 5 components of fatigue (general fatigue, mental fatigue, physical fatigue, reduced motivation and reduced activity). CFA models were evaluated in MPlus 7.3 using the robust maximum likelihood (MLR) estimation. RESULTS: The evaluation of the original 5 factors revealed low internal reliability for the general factor and reduced activity, and high intercorrelations between all sum scores. CFA revealed poor model fit for the original 5-factor MFI-20 model (confirmatory fit index = 0.738; Tucker-Lewis index = 0.689; root mean squared error of approximation = 0.101). Alternative models, including 1, 3 and bi-factor models all demonstrated poor fit to the data. No reliable factor model was confirmed prohibiting the examination of factors associated with fatigue. CONCLUSIONS: We were not able to confirm the factor structure of the MFI-20 in a large sample of HD patients. Certain items may lack suitable face validity in this context