American Journal of Therapeutics 21, 275–287 (2014)

Effects of Omega-3 Fatty Acids on Depression and Quality of Life in Maintenance Hemodialysis Patients Simin Dashti-Khavidaki, PharmD, PhD,1,2 Afshin Gharekhani, PharmD,1* Mohammad-Reza Khatami, MD,2 Elham-Sadat Miri, PharmD,3 Hossein Khalili, PharmD, PhD,1 Effat Razeghi, MD,2 Seyed-Saeed Hashemi-Nazari, MD, MPH, PhD,4 and Mohammad-Ali Mansournia, MD, MPH, PhD5

Depression and health-related quality of life (HRQoL) are closely interrelated among hemodialysis (HD) patients and associated with negative impacts on patients’ clinical outcomes. Considering previous reports on clinical benefits of omega-3 fatty acids in major depression and HRQoL in other patient populations, this study examined effects of omega-3 fatty acids on depression and HRQoL in chronic HD patients. In this randomized placebo-controlled trial, 40 adult patients with a Beck Depression Inventory (BDI) score of $16 and HD vintage of at least 3 months were randomized to ingest 6 soft-gel capsules of either omega-3 fatty acids (180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid in each capsule) or corresponding placebo, daily for 4 months. At baseline and after 4 months, 2 questionnaires of BDI and the Medical Outcome Study 36-Item Short-Form Health Survey were completed by each patient. Although baseline BDI score was comparable between the 2 groups, it was significantly lower in the omega-3 group compared with the placebo group at the end of the study (P 5 0.008). Except for mental health, social functioning, and general health, other domains of HRQoL showed significant improvement in the omega-3 group compared with the placebo group at month 4 of the study (P , 0.05 for all). Regression analysis revealed that ameliorated BDI score by omega-3 treatment had considerable role in the improvement of overall HRQoL score, physical and mental component dimensions, and score of physical functioning, role-physical, and bodily pain. Supplemental use of omega-3 fatty acids in HD patients with depressive symptoms seems to be efficacious in improving depressive symptoms and HRQoL. Keywords: depression, hemodialysis, omega-3 fatty acids, health-related quality of life

1

Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran; 3Faculty of Pharmacy, International Branch, Tehran University of Medical Sciences, Tehran, Iran; 4 Department of Epidemiology, School of Public Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran; and 5Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. This study was part of a PharmD thesis, supported by Tehran University of Medical Sciences, International Branch, Tehran, Iran (grant No. 17020). The authors have no conflicts of interest to declare. *Address for correspondence: Resident of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran. E-mail: [email protected] 1075–2765 Ó 2014 Lippincott Williams & Wilkins

INTRODUCTION Comorbid depression causes substantial impacts on morbidity, mortality, self-care behavior, and healthrelated costs in patients who suffer from chronic diseases.1 The lifetime prevalence of depression in the general population is estimated to be about 16%.2 However, depression occurs as the most common psychopathology in chronic hemodialysis (HD) patients with a reported prevalence rate of 30%–60%.3 Several risk factors that have been reported to predispose endstage renal disease (ESRD) patients to develop major depression include loss of principal role in the workplace or family, diminished cognitive skills, decreased www.americantherapeutics.com

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physical function, long-term dependence on renal replacement therapy, or sexual dysfunction.4 In addition to reducing compliance with medications and dialysis therapy,4 depression is frequently associated with poor food intake, leading to aggravation of malnutrition in HD patients.5 Additionally, there is evidence indicating increased mortality among HD patients with depression.6 However, HD patients suffer from poor health-related quality of life (HRQoL), which is even worse than that in patients with other chronic diseases.7 It has been shown that the risk of hospitalization and mortality is high among HD patients with poor HRQoL.8 It is worth noting that depression and HRQoL are closely interrelated among HD patients,9,10 and depression negatively affects HRQoL in this patient population.10 Thus, it is conceivable that the interventions improving depression in HD patients may also effectively ameliorate HRQoL in this population or vice versa. Because of the high social and economic burden of concurrent depression to HD patients and the use of multiple medications by these patients, it is of clinical necessity to develop antidepressant medications with fewer adverse effects and less potential of drug interactions. It has been hypothesized that omega-3 fatty acids found in fish oil may provide such advantageous alternatives.11 Studies on animal models of mental illness are suggestive of effectiveness of omega-3 fatty acids on brain processes, including mood and anxiety.12 Furthermore, it has been shown that frequent consumption of fish is associated with less likelihood of depressive symptoms compared with its infrequent utilization.13 Moreover, some studies have indicated that administration of omega-3 supplements was more effective than placebo in the treatment of depression.14–16 Given the mentioned clinical importance of fish oilderived omega-3 fatty acids, this study was intended to examine potential effects of omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] on depressive symptoms and HRQoL in chronic HD patients.

MATERIALS AND METHODS Subject selection This study was designed as a randomized placebocontrolled trial in the HD centers of 2 teaching hospitals (Sina Hospital and Imam–Khomeini Hospital Complex) affiliated to Tehran University of Medical Sciences, Tehran, Iran. Adult patients receiving regular HD treatment for at least 3 months were included in this trial. All participating patients received the same American Journal of Therapeutics (2014) 21(4)

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HD prescription as a 4-hour, thrice-weekly treatment using polysulfone capillary dialyzers and bicarbonatebuffered dialyzate with dialyzate flow rate of 500 mL/ min and blood flow rate of 250–300 mL/min. Exclusion criteria were as follows: Beck Depression Inventory (BDI) score of ,16, inability to fill in the questionnaires, unwillingness to participate, malignancy, pregnancy, the presence of other psychiatric disorders, hypothyroidism, concurrent participation in other trials, a history of surgical or medical illness in recent 3 months, poor adherence to medication or HD treatment, malabsorption syndrome, coagulopathies or increased risk of bleeding, chronic anticoagulation therapy (warfarin), consumption of fish oil or supplements containing omega-3 fatty acids in recent 3 months, hypersensitivity to fish or fish-derived products, concurrent use of antipsychotic or antidepressant. The protocol of this study was approved by the local Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran. The trial was registered in the Iranian Registry of Clinical Trials (registry number: IRCT201202203043N5). All patients were informed about the trial and gave a written informed consent before the study initiation. Study design Five blocks of size 8 were used for permuted block randomization of study subjects to 2 groups. Each block contained an equal number of omega-3 and control group selections, with the order of the blocks permuted. Random numbers to allocate blocks and randomize group selection were generated using Microsoft Office Excel software. All participants, care providers, and data monitors were blinded to the identity of treatments throughout the study. Patients were randomly placed into either the omega-3 or the placebo group. Patients in the omega-3 group consumed 2 soft-gel capsules of omega-3 fatty acids (Omega-3; Zahravi Pharm. Co., Tabriz, Iran), each containing 180 mg EPA and 120 mg DHA, 3 times daily with meal for 4 months, whereas participants in the placebo group ingested 2 corresponding identical capsules of paraffin oil. The patients were advised not to alter their dietary habits, drug regimens, and physical activity during the 4-month study period. To encourage adherence to supplement regimens and monitor possible adverse effects, each patient was visited by a nephrologist monthly. Any patient complaints or changes in medications were recorded during the study period. Before and after 4 months of intervention period, all participants were given 2 questionnaires of BDI and the Medical Outcome Study 36-Item ShortForm Health Survey (SF-36) and were asked to complete them while undergoing HD treatment. Both questionnaires were formatted into a user-friendly style without www.americantherapeutics.com

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altering the concept of the original questions or their answers. Any question asked by patients with respect to the clarity, relevance, or other aspects of the questionnaires were answered carefully. Hemodialysis adequacy Dialysis adequacy based on the Kt/V urea was calculated for each patient at baseline by existing Kt/V calculator software using information extracted from patients’ medical files, including pre- and postdialysis blood urea nitrogen concentrations, dialysis session length, post-dialysis weight, and ultrafiltration volume. Assessment of depression The presence and/or degree of depressive symptoms was assessed using the BDI questionnaire, which has been validated and frequently used in ESRD patients.17,18 It has been shown that the BDI has a high sensitivity and specificity in detection of depression in dialysis patients.19 The BDI is a 21-item selfadministered questionnaire that measures characteristic symptoms of depression. Score for each item range from 0 to 3, with a higher score indicating a greater problem. The total score ranges from 0 to 63.10 Ghasemzadeh et al20 have studied the validation and reliability of the BDI in Iranian population. A BDI score of $ 16 was established as a cut-off point for detecting depression in Iranian population. Thus, we used this value to consider individuals as having depressive symptoms. Assessment of HRQoL Patients’ HRQoL were assessed using the selfadministered questionnaire SF-36.21 This questionnaire has been frequently used and validated in ESRD patients.22 The questionnaire comprises 36 items evaluating 8 domains of HRQoL: namely, physical functioning (10 items), role-physical (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), social functioning (2 items), role-emotional (3 items), and mental health (5 items). Each scale was scored with a range from 0 to 100. The first 5 scales constitute physical component summary (PCS), and the last 5 scales constitute mental component summary. The scales vitality and general health are included in both dimensions. Thus, each dimension has 3 specific and 2 overlapping scales.23,24 Total SF-36 score and the scores of 2 dimensions are calculated according to mathematical averaging of the scale components.23 Higher score indicates a better state of HRQoL. The SF-36 questionnaire was given to patients to complete during routine HD treatment. It was read for subjects who were unable to read. www.americantherapeutics.com

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Compliance For the ascertainment of patient compliance, we interviewed each patients 3 times weekly and provided them with weekly dose of capsules with instructions to give the unconsumed capsules back from the prior week. Compliance rate was determined for each patient according to the number of returned unconsumed capsules from the previous week. Patients were considered compliant if they consumed at least 90% of the issued omega-3 or placebo soft-gel capsules. Statistical methodology Continuous variables with normal distribution were expressed as means 6 SDs, and non-normally distributed variables were expressed as medians and interquartile range. Categorical variables were presented as numbers. Between-group comparison of continuous variables was performed using unpaired t test or 2-sample Wilcoxon rank-sum (Mann–Whitney) test, whereas within-group comparison was carried out by paired t test or Wilcoxon matched-pairs signed rank test. The x2 or Fisher exact test was used to compare categorical variables between groups. Moreover, we estimated the effect of omega-3 supplement on BDI score and components of HRQoL in separate models using the linear regression model with demographic, social, and clinical data of patients as explanatory variables. To account for non-normality and heterogeneity of variances of the residual distributions, we used nonparametric bootstrap method with 2000 replications to obtain empirical standard errors and bias-corrected and accelerated (BCa) confidence intervals. To estimate the effect of omega-3 supplement on HRQoL score independent of its effect on BDI score, we entered the pre- and post-treatment BDI score in the above models and examined the coefficients of intervention in these models. If the coefficients remained significant, it was concluded that the omega-3 treatment changed the HRQoL independently from BDI score. All statistical analyses were performed using the SPSS version 16.0 (SPSS, Inc., Chicago, IL) and Stata software (Stata Statistical Software: Release 12; StataCorp. 2011, College Station, TX). The P value ,0.05 was considered to be statistically significant.

RESULTS Figure 1 displays patients’ screening and randomization procedure in the study. Among 40 patients who accepted to participate in the study, there were 6 dropouts (4 in the placebo and 2 in the omega-3 group) during the study period. Thus, the study was ended with 34 patients (16 placebo and 18 omega-3), in whom American Journal of Therapeutics (2014) 21(4)

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FIGURE 1. Study’s flowchart indicating patients’ screening and randomization procedure.

the final analysis was performed on the data. Baseline demographic, social, and clinical data as well as BDI score and HRQoL of the patients who completed the study have been summarized in Table 1. As shown, there was no significant difference between the 2 groups at baseline with respect to the mentioned characteristics. American Journal of Therapeutics (2014) 21(4)

As presented in Table 2, administration of omega-3 fatty acids for 4 months caused a significant reduction in the BDI score compared with the baseline value (P 5 0.001), whereas no significant change appeared in the placebo group during this time period. Furthermore, BDI score in the omega-3 group was significantly lower www.americantherapeutics.com

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Table 1. Patients’ demographic, social, clinical, BDI, and HRQoL data in the placebo and omega-3 group at the beginning of the study. Characteristics Sex (male/female) Age* (yrs) Marital status Single Married Education* (yrs) Occupation Occupied Nonoccupied Smokers Months on dialysis* Dialysis dose (Kt/V)* Leading cause to ESRD Diabetes Hypertension Diabetes and hypertension Others Kidney transplantation history BDI score† HRQoL† Overall score Physical functioning Role-physical Role-emotional Vitality Mental health Social functioning Bodily pain General health PCS Mental component summary

Placebo group (n 5 16)

Omega-3 group (n 5 18)

P

8/8 56.5 6 14.5

9/9 56.1 6 13.9

1 0.928 0.476

2 14 6.5 6 5.7

1 17 7.6 6 4.6

4 12 1 72.0 6 56.6 1.27 6 0.15

3 15 3 70.7 6 45.1 1.39 6 0.22

2 7 3 4 0 20 (16.5–23.5)

4 7 2 5 2 25 (17–34)

0.487 0.096

56.9 (38.1–66.2) 55.0 (48.8–81.3) 50.0 (25.0–75.0) 33.3 (33.3–75.0) 37.5 (26.2–63.3) 61.7 (41.9–75.2) 62.5 (46.9–87.5) 55 (22.5–100.0) 37.5 (23.8–50.0) 49.7 (40.6–63.7) 51.7 (36.1–63.8)

55.4 (50.3–61.7) 62.5 (35.0–87.5) 50.0 (6.3–68.8) 45.0 (23.3–90.0) 40.0 (30.0–53.8) 63.3 (52.5–78.5) 87.5 (65.6–100.0) 52.5 (25.0–85.0) 40.0 (25.0–63.8) 44.5 (36.2–64.2) 54.7 (49.8–63.7)

0.53 0.81 0.85 0.57 0.90 0.31 0.05 0.53 0.72 0.65 0.29

0.609 0.681

0.604 0.917 0.057 0.833

*Data are expressed as mean 6 SD. †Data are expressed as median (interquartile range).

than that in the placebo group at the end of the study (P 5 0.008). In addition, HRQoL showed a significant improvement in the omega-3 group during the study, as reflected in the overall score (P 5 0.002), PCS (P 5 0.004), mental component summary (P 5 0.002), and domains of physical functioning (P 5 0.009), rolephysical (P 5 0.006), role-emotional (P 5 0.02), and mental health (P 5 0.04). Conversely, HRQoL decreased or did not alter in the placebo group through the study period. Also, comparison of 2 groups after 4 months of intervention showed that with the exception of mental www.americantherapeutics.com

health, social functioning, and general health, HRQoL in the omega-3 group significantly increased compared with the placebo group (P , 0.05 for all). To estimate the effects of omega-3 fatty acids supplement on BDI score and domains of HRQoL in a multiple linear regression model, all the demographic, social, and clinical characteristics of the patients entered into the model. Marital status, smoking, dialysis adequacy, leading cause to ESRD, and transplant history showed no significant correlation (P . 0.2) and were excluded from the final model. As seen in American Journal of Therapeutics (2014) 21(4)

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Table 2. BDI score and HRQoL in the omega-3 and placebo groups at baseline and after 4 months of intervention. Omega-3 group (n 5 18) Baseline BDI score Overall score Physical functioning Role-physical Role-emotional Vitality Mental health Social functioning Bodily pain General health PCS Mental component summary

25 56.9 55.0 50.0 33.3 37.5 61.7 62.5 55 37.5 49.7 51.7

Placebo group (n 5 16)

After 4 mo

P*

(17–34) 12 (8.5–19) (38.1–66.2) 68.0 (64.4–75.9) (48.8–81.3) 85.0 (70.8–100.0) (25.0–75.0) 82.0 (57.0–100.0) (33.3–75.0) 100.0 (65.3–100.0) (26.2–63.3) 57.0 (49.5–77.0) (41.9–75.2) 72.8 (65.8–82.2) (46.9–87.5) 82.0 (57.0–100.0) (22.5–100.0) 75.8 (49.5–97.0) (23.8–50.0) 39.5 (22.0–62.0) (40.6–63.7) 66.1 (56.9–70.6) (36.1–63.8) 64.2 (55.8–76.2)

0.001 0.002 0.009 0.006 0.02 0.14 0.04 0.05 0.31 0.25 0.004 0.002

Baseline 20 55.4 62.5 50.0 45.0 40.0 63.3 87.5 52.5 40.0 44.5 54.7

(16.5–23.5) (50.3–61.7) (35.0–87.5) (6.3–68.8) (23.3–90.0) (30.0–53.8) (52.5–78.5) (65.6–100.0) (25.0–85.0) (25.0–63.8) (36.2–64.2) (49.8–63.7)

After 4 mo 21 45.9 60.0 20.0 61.7 32.5 64.2 76.3 51.3 40.0 34.3 53.7

(15–27.2) (36.3–71.6) (31.3–87.5) (0.0–70.0) (28.3–95.0) (20.0–50.0) (52.4–80.8) (57.5–95.0) (21.9–72.5) (16.3–53.8) (24.9–66.7) (40.3–72.3)

P*

P†

0.842 0.24 0.59 0.47 0.06 0.06 0.88 0.21 0.28 0.38 0.11 0.78

0.008 0.01 0.008 0.003 0.02 0.001 0.20 0.89 0.03 0.53 0.002 0.03

Data are expressed as median (interquartile range). Statistically significant differences are in bold faces (P , 0.05). *Pertaining to within-group comparison. †Pertaining to between-group comparison.

Table 3, omega-3 treatment showed a significant negative correlation with the BDI scores in HD patients. In addition, supplemental use of omega-3 fatty acids was a significant positive predictor of increased overall HRQoL score and both physical and mental components of HRQoL, as well as domains of physical functioning, role-physical, vitality, and bodily pain. Age of patients showed significant positive association with BDI scores; however, it was significant a negative predictor of physical functioning score, mental health, and physical component dimension. Both female gender and occupation were significant negative predictors of general health. Educational level of patients demonstrated significant positive association with BDI score, whereas it showed a significant negative association with general health score and physical component of SF-36. There were no marked correlation between HD treatment length and any of the outcome variables measured in this study. To clarify the potential role of improved depressive symptoms in the amelioration of HRQoL in the omega-3 group, baseline and post-treatment BDI scores were included in each one of the regression models specific for individual domain of HRQoL. As displayed in Table 4, improved BDI score by omega-3 treatment had considerable role in the improvement of overall HRQoL score, physical and mental component dimensions, and score of physical functioning, role-physical, and bodily pain because omega-3 treatment was not a significant predictor of the mentioned scales any more in the presence of BDI scores in the regression model. American Journal of Therapeutics (2014) 21(4)

All patients were considered compliant in this study because they had consumed more than 90% of the issued omega-3 or placebo soft-gel capsules. Additionally, both omega-3 and placebo soft-gel capsules were well-tolerated through the study period, with no serious side effects causing patient withdrawal. Mild transient gastrointestinal complaints including loose stool, nausea, and burping were noted in 8 patients ingesting omega-3 soft-gel capsules, that resolved by taking the supplement with meals in 5 patients and transient dose reduction with subsequent increase in the remaining 3 patients.

DISCUSSION Screening tools for depression, including BDI, are typical self-rating scales that require individual patient to rate symptom frequency and severity. Although none of them is diagnostic, several tools have been validated against diagnostic criteria. Validation is performed by evaluation of the sensitivity and specificity of a certain symptom cut-off score against a diagnosis of clinical depression.1 A BDI score of more than 16 has been demonstrated to possess 91% sensitivity and 86% specificity for diagnosis of clinical depression in dialysis patients as assessed by the structured clinical interview for depression.17 It has been suggested that abnormal polyunsaturated fatty acid compositions may be involved in the etiology of depression.25 DHA has been reported to be involved www.americantherapeutics.com

Independent variables Dependent variable

Omega-3

Age

Sex

Occupation

Education

HD length

0.10 20.36 to 0.37 0.566

27.90 212.17 to 22.94 0.001

0.25 0.08 to 0.53 0.029

4.29 20.53 to 9.32 0.085

5.61 24.30 to 14.42 0.234

0.63 0.13 to 1.14 0.019

20.01 20.06 to 0.04 0.813

0.45 0.07 to 0.90 0.03

22.02 11.02 to 32.65 0.000

20.51 20.88 to 0.09 0.059

1.14 212.86 to 14.68 0.871

22.98 222.32 to 16.70 0.761

21.06 22.29 to 0.25 0.099

20.06 20.19 to 0.06 0.303

0.47 0.12 to 0.78 0.006

23.59 9.62 to 40.15 0.003

21.32 22.21 to 20.43 0.002

0.53 218.94 to 16.07 0.952

221.02 251.41 to 4.73 0.152

20.91 23 to 0.96 0.362

20.12 20.32 to 0.04 0.218

0.28 20.12 to 0.69 0.185

35.95 12.69 to 57.24 0.002

20.60 22.56 to 0.34 0.363

213.89 243.86 to 12.35 0.333

214.46 254.62 to 38.21 0.540

21.58 25.44 to 1.53 0.364

20.06 20.29 to 0.21 0.638

20.05 20.52 to 0.39 0.818

13.68 211.11 to 37.12 0.267

20.02 21.49 to 1.04 0.969

15.18 217.45 to 47.95 0.367

9.67 232.08 to 49.57 0.647

0.29 23.51 to 2.73 0.851

20.17 20.47 to 0.10 0.238

0.19 20.14 to 0.57 0.327

24.65 9.47 to 39.58 0.001

20.56 21.20 to 0.51 0.223

25.23 225.69 to 12.43 0.586

28.78 236.46 to 22.01 0.551

20.97 22.50 to 1.18 0.321

20.01 20.16 to 0.14 0.883

0.11 20.17 to 0.44 0.486

9.50 20.46 to 19.08 0.061

20.53 21.23 to 20.07 0.047

24.63 216.20 to 7.21 0.440

210.23 226.11 to 5.96 0.207

21.12 22.80 to 0.16 0.129

20.08 20.17 to 0.03 0.154

0.33

13.49

20.15

6.31

13.26

21.55

0.03 281

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BDI score b 95% CI P Overall Score b 95% CI P Physical functioning b 95% CI P Role-physical b 95% CI P Role-emotional b 95% CI P Vitality b 95% CI P Mental health b 95% CI P Social functioning b

Baseline

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Table 3. Regression analysis reflecting the effect of omega-3 supplement on BDI score and HRQoL after adjustment for their baseline values and patients’ demographic, social, and clinical data.

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Table 3. (Continued) Regression analysis reflecting the effect of omega-3 supplement on BDI score and HRQoL after adjustment for their baseline values and patients’ demographic, social, and clinical data. Independent variables Dependent variable

Baseline

Omega-3

Age

Sex

Occupation

Education

HD length

95% CI P Bodily pain b 95% CI P General health b 95% CI P PCS b 95% CI P Mental component summary b 95% CI P

20.02 to 0.65 0.051

26.21 to 28.54 0.138

20.94 to 0.61 0.710

214.18 to 23.35 0.501

219.57 to 39.25 0.356

23.36 to 0.27 0.105

20.15 to 0.21 0.747

0.27 20.19 to 0.68 0.222

23.58 4.63 to 41.31 0.011

20.59 21.54 to 0.57 0.282

7.39 218.79 to 27.12 0.517

8.13 224.48 to 38.82 0.610

21.57 24.57 to 1.40 0.333

20.09 20.30 to 0.14 0.408

0.20 20.24 to 0.60 0.350

7.33 24.68 to 20.58 0.253

20.54 21.24 to 0.25 0.134

223.46 240.08 to 27.14 0.005

222.47 246.74 to 22.65 0.037

22.22 23.90 to 20.45 0.010

20.12 20.24 to 0.01 0.068

0.55 0.16 to 0.98 0.007

23 11.44 to 33.14 0.000

20.77 21.27 to 20.23 0.005

25.39 219.40 to 6.99 0.420

29.12 224.46 to 12.10 0.333

21.65 23.52 to 20.11 0.054

20.08 20.20 to 0.05 0.186

0.26 20.18 to 0.63 0.210

13.78 3.53 to 24.59 0.010

20.33 20.81 to 0.23 0.218

20.52 214.71 to 13.16 0.941

21.96 223.30 to 18.67 0.851

20.99 22.25 to 0.06 0.080

20.06 20.18 to 0.06 0.322

All dependent variables represent post-treatment values of outcome measures. P value ,0.05 or 95% CI (with bootstrap method) not including null value was considered as statistically significant (bold faces). CI, confidence interval.

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Effects of Omega-3 on Depression and Quality of Life Table 4. Regression coefficient of omega-3 supplement before and after adjusting components of HRQoL for preand post-treatment BDI scores.

Dependent variable Overall score b 95% CI P Physical functioning b 95% CI P Role-physical b 95% CI P Role-emotional b 95% CI P Vitality b 95% CI P Mental health b 95% CI P Social functioning b 95% CI P Bodily pain b 95% CI P General health b 95% CI P PCS b 95% CI P

Unadjusted for BDI score* Regression coefficient

Adjusted for BDI score† Regression coefficient

22.02 11.02 to 32.65 0.000

11.73 22.85 to 24.26 0.101

23.59 9.62 to 40.15 0.003

9.21 212.62 to 39.15 0.469

35.95 12.69 to 57.24 0.002

14.63 217.61 to 47.82 0.378

13.68 211.11 to 37.12 0.267

24.15 235.73 to 29.84 0.813

24.65 9.47 to 39.58 0.001

16.22 0.65 to 31.59 0.034

9.50 20.46 to 19.08 0.061

7.20 24.37 to 22.61 0.266

13.49 26.21 to 28.54 0.138

4.27 215.72 to 26.43 0.687

23.58 4.63 to 41.31 0.011

19.01 219.90 to 48.43 0.247

7.33 24.68 to 20.58 0.253

9.60 27.41 to 24.64 0.228

23 11.44 to 33.14 0.000

13.95 22.91 to 30.09 0.099

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283 Table 4. (Continued) Regression coefficient of omega-3 supplement before and after adjusting components of HRQoL for pre- and post-treatment BDI scores.

Dependent variable

Unadjusted for BDI score* Regression coefficient

Adjusted for BDI score† Regression coefficient

Mental component summary b 95% CI P

13.78 3.53 to 24.59 0.010

6.36 24.93 to 17.62 0.285

The P value ,0.05 or 95% CI (with bootstrap method) not including null value was considered as statistically significant (bold faces). *Adjusted for baseline value, demographic, social, and clinical data. †Adjusted for baseline value, demographic, social, and clinical data plus pre- and post-BDI score. CI, confidence interval.

in neuronal membrane stability and in serotonin and dopamine neurotransmission and is potentially linked to the causes of mood disturbance and cognitive expressions of depression.26 Alternatively, EPA plays a pivotal role in maintaining the balance between the immune and neuronal functions by competitive inhibition of the membrane omega-6 polyunsaturated fatty acids and reducing prostaglandin E2 synthesis.27 At the same way, previous observational studies have shown association between clinical depression and relatively low levels of omega-3 fatty acids in erythrocyte membrane, plasma, and brain tissue.28,29 Despite diverse clinical benefits to HD patients, omega-3 fatty acids are neither routinely recommended nor used in this population. This negligence may in part be related to a general lack of familiarity with the clinical and biochemical benefits of omega-3 fatty acids.30 In this study, supplemental use of omega-3 fatty acids for 4 months significantly improved depressive symptoms of chronic HD subjects. However, although positive effects of omega-3 fatty acids in clinical depression have been supported by recent studies,31–33 our study was the first to indicate antidepressant properties of omega-3 fatty acids in maintenance HD patients. Although the patients’ characteristics including marital status, smoking, dialysis adequacy, leading cause to ESRD, and kidney transplantation history might have affect patients’ depressive symptoms and HRQoL, there was no significant correlation between the BDI score and HRQoL domains with any of them in multiple linear regression models. However, American Journal of Therapeutics (2014) 21(4)

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exclusion of the mentioned characteristics improved predictive power of the regression models (improved adjusted R-squared), and thus, we chose to excluded them from the final regression models. In particular, because of the more likelihood that failed kidney transplantation history might have more adverse impacts on depressive symptoms and HRQoL of HD patients, we did perform reanalysis on patients’ data after exclusion of 2 patients with a transplant history from the omega-3 group. However, no change appeared in data regarding depressive symptoms and HRQoL scales of the patients in the omega-3 group neither at baseline nor at the end of the study after the exclusion of 2 patients’ data (data not shown). Moreover, regression analysis revealed that both age and educational level of patients were significantly associated with the increased BDI score. Advanced age has been mentioned as predisposing factor to development of depression.34 This relationship may be explained by increased prevalence of stressful comorbid conditions, poorer quality of life, or more dependence on family members to perform daily living activities in aged HD patients. In addition, patients with higher educational level may be more reactive to being dependent on dialysis machine for their survival than those with lower educational level, and thus more prone to have depressive mood. There exist several tools to assess HRQoL; some of them with generic application and some with diseasespecific use. The generic HRQoL tools are used in general population and patients with different disease types. SF-36 is one of the frequently used generic types.21 Examples of HRQoL questionnaires specific for ESRD patients include Kidney Disease Quality of Life Short Form (KDQOL-SF),35 Quality of Life IndexDialysis (QLI-D),36 and Renal Quality of Life Profile (RQLP).37 A good correlation between RQLP, as a HD-specific HRQoL survey, and SF-36 has been reported previously.38 Moreover, validation of the Persian version of the SF-36 has been performed in Iranian patients, and Iranian psychologists/psychiatrists widely use this questionnaire in their practice. Furthermore, the SF-36 questionnaire has been used by other researchers in HD patients as well.23 Hence, we used the SF-36 instrument to assess HRQoL in our patients. HD patients are known to have poor quality of life.23 In 2001, Mittal et al39 showed that chronic HD is associated with more impaired quality of life than many other chronic diseases, including rheumatoid arthritis, chronic obstructive pulmonary diseases, angina pectoris, and heart failure. In the Dialysis Outcomes and Practice Patterns Study (DOPSS), as a large study on dialysis patients’ HRQoL, quality of life was regarded as a strong predictor of mortality and American Journal of Therapeutics (2014) 21(4)

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hospitalization.40 Therefore, new therapeutic strategies are urgently needed to improve HRQoL in maintenance HD patients. Although strategies such as frequent HD (5–6 times weekly as short daily or nocturnal dialysis) rather than conventional thriceweekly HD have been promising for improving quality of life and prolonging patient’s survival,41 but they have not been adequate to obviate the need for other therapeutic approaches. Interestingly, results of our study showed that except for domains of mental health, social functioning, and general health, all other components of HRQoL significantly improved in chronic HD patients after daily administration of 1800 mg omega-3 fatty acids for 4 months. We found no studies on this population in available literature to compare our results. However, positive effects of omega-3 fatty acids on quality of life have been reported in other patient populations. Kianifar et al42 showed that daily administration of 900 mg omega-3 fatty acids for 3 months in 11 pediatric patients (aged 2–12) with cystic fibrosis produced significant increase in the total score of the Pediatric Quality Of Life Inventory TM 4.0 Short Form (PedsQLTM4.0 SF15). Physical and social domains of this survey also improved significantly during the study, whereas domains of emotional and school functioning did not. van der Meij et al43 randomly administered 2 cans per day of either a protein- and energy-dense oral nutritional supplement (containing a total of 2.02 g EPA and 0.92 g DHA) or isocaloric control oral nutritional supplement for 5 weeks in 40 patients with stage III nonsmall cell lung cancer undergoing multimodality treatment. Patients who received nutritional omega-3 supplement experienced a clinically significant improvement in their quality of life. Furthermore, Jelinek et al44 found that patients with multiple sclerosis who were consuming fish more frequently or taking omega-3 fatty acids supplements had significantly better HRQoL in all tested components. In addition, there was a clear dose response relationship between fish consumption and improved components of quality of life. Although mechanism(s) responsible for positive effects of omega-3 fatty acids in these studies was not clearly identified, immunomodulatory effects of omega-3 fatty acids and reducing tissue wasting effects of pro-inflammatory cytokines have been suggested to be of particular importance.43 As indicated in Table 3, linear regression analysis revealed that age of patients was a significant independent predictor of reduced mental health score and physical dimension of HRQoL. This finding may be explained by increased rate of anxiety, depression, and comorbidities as well as impaired physical www.americantherapeutics.com

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activities of daily living in older patients in general, and older patients receiving HD treatment in particular.45 Additionally, female gender showed a significant negative association with the general health domain of HRQoL. It could be because of more susceptibility of females to have worse perception of their health status. In line with this claim, worse HRQoL in women receiving HD therapy has been reported in previous studies especially in domains of physical functioning, bodily pain, and vitality.35,38 In our study, employment was a significant independent predictor of reduced general health. Conversely, Dashti-Khavidaki et al46 found that employed patients had significantly higher score in vitality domain of HRQoL. DOPPS study found reverse association between unemployment and HRQoL, especially in domains of role-emotional and role-physical.35 In this study, educational level of HD patients showed significant negative association with general health and PCS. This relation may partly be because of possible reverse association of high educational level with HD adherence and life-long dependence on dialysis therapy, which would adversely affect HRQoL and particularly impair physical component dimension. In search to identify potential role of ameliorated depression in the improvement of HRQoL in the omega-3 group, we found that positive effects of omega-3 treatment on HRQoL were largely dependent on their ameliorative effects on depressive symptoms. No similar study was found in literature to compare our result. Nevertheless, previous studies on different patient populations have reported concomitant improvement of depression and quality of life after therapeutic intervention. Rondanelli et al45 demonstrated that daily ingestion of 2.5 g omega-3 fatty acids for 8 weeks by elderly women with major depression caused a significant reduction in depressive symptoms and a marked amelioration in both physical and mental dimensions of HRQoL, as reflected in the SF-36 survey. Additionally, Atalay et al10 observed a significant improvement in both depressive symptoms and all domains of HRQoL when they treated peritoneal dialysis patients with sertraline for 12 weeks. Although they observed a significant positive correlation between HRQoL and depression at baseline, they did not assess interrelation between these 2 outcome measures during the study. To the best of our knowledge, our findings have never been achieved in HD patients before and appear of great clinical value in HD population by considering the frequent under-diagnosis and under-treatment of depression and poor HRQoL in this population. However, our study had some limitations including small www.americantherapeutics.com

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sample size and short follow-up period, monitoring of patient compliance with “pill counting” practice instead of in vivo testing of omega-3 fatty acids, lack of serial assessment of depressive symptoms and HRQoL to identify a potential trend over time and reduce variance of estimates of treatment effects, distortion of subject blindness in the placebo arm due to “Fishy” smells of omega-3 soft-gel capsules, and lack of careful assessment of patients’ dietary intake. In conclusion, supplemental use of omega-3 fatty acids in HD patients with depressive symptoms was beneficial in the improvement of both depressive symptoms and HRQoL. The results of our study seem of relevant clinical interest by considering the high incidence of depression and poor HRQoL in HD patients and their subsequent adverse effects on patients’ outcomes.

ACKNOWLEDGMENTS The authors thank Zahravi Pharmaceutical Co., Tabriz, Iran, for providing placebo free of charge and Dr Amir Hekmat for his kind coordinating between researchers’ team and the pharmaceutical company. The authors also appreciate valuable helps of hemodialysis nursery teams of Imam–Khomeini Hospital complex and Sina Hospital, especially Mrs. Abdpoor.

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