Prescription of psychotropic drugs in patients with chronic renal failure on hemodialysis

Abstract

Objective: Patients on hemodialysis commonly have comorbid depression and require treatment with psychotropic drugs. This study aimed to investigate the prevalence of the use of psychotropic drugs among patients on hemodialysis and to elucidate the factors associated with use of each class of psychotropic medication. Methods: This cross-sectional study enrolled 195 hemodialysis patients with a mean age of 58.5 years. Patients were assessed using the Mini International Neuropsychiatric Interview, Hospital Anxiety and Depression Scale, Chalder Fatigue Scale and Short-form Health-related Quality of Life. We analyzed the frequency of psychiatric outpatient department visits within six months prior to interview and psychotropic drugs use within one month prior to interview, including antidepressants, antipsychotics, mood stabilizers, benzodiazepines (BZDs) and hypnotics. Results: Of the 195 patients, 47 (24.1%) fulfilled the DSM-IV criteria for major depressive disorder (MDD). Only 6.4% of patients diagnosed with MDD visited the psychiatry outpatient department within six months prior to interview. Of the total patients, the proportions with use of antidepressants, antipsychotics, mood stabilizers, BZDs and hypnotics were 5.6%, 1.0%, 3.1%, 42.6% and 20.0%, respectively. Having MDD was an independent factor associated with taking antidepressants (adjusted OR = 3.98, p = 0.036) and taking hypnotics (adjusted OR = 2.75, p = 0.011). Conclusions: Depression is generally undetected or not well-managed among hemodialysis patients in the clinical setting. Only a small proportion of depressed patients received antidepressant treatment. BZDs and/or hypnotics might be exorbitantly prescribed. Clinicians should pay more attention to patients’ emotional distress and provide appropriate treatment.

• Antidepressant
• antipsychotics
• anxiolytic-hypnotics
• mood disorder
• pharmacoepidemiology
• renal disease

Introduction

Hemodialysis has a significant adverse impact on the emotional status of patients with end-stage renal disease (ESRD).1,2 In Taiwan, renal disease is one of the top 10 causes of death, and the incidence and prevalence rates of ESRD were found to be the highest in the world.3 Roughly, 95% of ESRD patients in Taiwan are on hemodialysis.4 Depression is one of the most common psychiatric comorbidities among hemodialysis patients.5,6 Previous studies have indicated that the prevalence of major depressive disorder (MDD) among ESRD patients ranges from 20% to 30%.2,7 Depression has a negative impact on the patient’s life quality and prognosis, and depression increases the rates of comorbidity and mortality.8 Therefore, it is important to recognize depression early in patients on hemodialysis and to provide appropriate treatment.

Psychotropic drugs have been demonstrated to be effective in the treatment of depression in patients on hemodialysis.9 Compelling evidence demonstrates the effect of antidepressants in hemodialysis patients with MDD and the pharmacokinetics of antidepressants in patients with renal failure.10–13 However, a recent study using the National Health Insurance Research Database in Taiwan indicated that patients with ESRD who were exposed to antidepressants had significantly higher mortality rate than those who did not. The authors suggested that the antidepressants-associated high mortality rate in ESRD patients might be a bias by indication.14 Benzodiazepines (BZDs) are also widely prescribed for hemodialysis patients with anxiety or insomnia.15 In Japan, Fukuhara et al. found that hemodialysis patients with MDD frequently use BZD instead of antidepressants.16 In the United States, Winkelmayer et al. reported that BZD or zolpidem use is associated with a 15% higher mortality rate among hemodialysis patients.17 To date, little is known about the prevalence of prescription of comprehensive psychotropic agents, including antipsychotics and mood stabilizers, in hemodialysis patients. In addition, studies of the factors associated with the prescription of psychotropic drugs in hemodialysis patients are also rare.

This study aimed to investigate the prevalence of the use of psychotropic drugs, including antidepressants, antipsychotics, mood stabilizers, BZDs and hypnotics, among patients with chronic renal failure on hemodialysis and to elucidate the factors associated with use of each class of psychotropic drugs.

Methods

Participants and procedures

In this cross-sectional study, we enrolled 200 patients aged ≥18 years who had undergone hemodialysis at Chang Gung Memorial Hospital, Keelung, between 2007 and 2009. Case recruitment, study procedures and measurement tools have been described elsewhere in detail.18,19 We performed chart reviews to collect patients’ information regarding psychotropic drugs used within one month prior to interview. Whether the patients visited a psychiatric outpatient department within six months prior to interview was also recorded. Written informed consent was obtained from each patient prior to participation. This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital.

Definition of psychotropic drugs

Psychotropic drugs were classified into antidepressants (amitriptyline, clomipramine, doxepin, imipramine, maprotiline, moclobemide, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, bupropion, mirtazapine, venlafaxine and trazodone), antipsychotics (chlorpromazine, flupentixol, haloperidol, loxapine, sulpiride, thioridazine, trifluoperazine, amisulpride, clozapine, olanzapine, quetiapine, risperidone and zotepine), mood stabilizers (lithium, valproic acid and carbamazepine), BZDs (alprazolam, bromazepam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, cloxazolam, diazepam, fludiazepam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, oxazolam and prazepam) and hypnotics (estazolam, flunitrazepam, flurazepam, zolpidem and zopiclone).

Psychiatric evaluation

All hemodialysis patients underwent psychiatric diagnostic interviews using the Mini International Neuropsychiatric Interview (MINI) and assessment using the Hospital Anxiety and Depression Scale (HADS), the Chalder Fatigue Scale (CFS) and the Short-form Health-related Quality of Life (SF-36).

The MINI is a short structured diagnostic interview for psychiatric disorders.20 The inter-rater reliability of the Chinese version of the MINI, which was translated by the Taiwan Society of Psychiatry, has been established in a previous study.21 The HADS is a 14-item self-administered questionnaire for assessing the severity of depression.22 Each of the items has a four-point Likert scale score ranging from 0 to 3. Seven items assess anxiety (HADS-A) and seven assess depression (HADS-D). The HADS is a valid screening instrument for detecting depression in ESRD patients.23 The Chinese version of the HADS has been proved to have good reliability and validity.24 The CFS is a self-reported questionnaire consisting of 11 items scored on a four-point Likert scale covering the physical and mental aspects of fatigue.25 The Chinese version of the CFS is valid and reliable among Chinese adults.26 The SF-36 is a widely used tool for surveying the health-related quality of life of patients.27 A standard scoring algorithm aggregates the scores into a physical component summary (PCS) and a mental component summary (MCS).

Statistical analysis

All data processing and statistical analyses were performed using the Statistical Package for the Social Sciences, version 16.0 (SPSS Inc., Chicago, IL). All tests were two-tailed, and the level of significance was p < 0.05.

Five patients who did not complete the MINI were excluded from the analyses. Continuous variables are described using summary statistics such as means ± standard deviations. Categorical variables are described using frequencies and percentages. Continuous variables were analyzed using the independent t-test, and the χ² test or Fisher’s exact test was used for categorical variables. Multivariate logistic regression was used to examine the factors associated with use of each class of psychotropic medication.

Results

One-hundred ninety-five patients on hemodialysis (92 men and 103 women), with a mean age of 58.5 ± 13.9 years, were included in the study. Of the 195 subjects, 47 (24.1%) fulfilled the DSM-IV criteria for MDD. Table 1 summarizes the demographic characteristics, psychological characteristics and prescription of psychotropic drugs in the patients undergoing hemodialysis. There were no significant differences in the gender ratio, age, education level, duration of hemodialysis and number of comorbid diseases between patients with and without MDD. Compared with patients without MDD, patients with MDD had significantly higher scores for the HADS-D (p < 0.001), HADS-A (p < 0.001) and CFS (p < 0.001). Meanwhile, patients with MDD had significantly lower scores of the MCS (p < 0.001), but not the PCS of the SF-36.

Table 1. The demographic data, psychiatric characteristics and patterns of psychotropic drugs use among hemodialysis patients with and without major depressive disorder (MDD).

	Total (N = 195)	With MDD (N = 47)	Without MDD (N = 148)	Statistics
Sex (female/male)	103 (52.8)/92 (47.2)	27 (57.4)/20 (42.6)	76 (51.4)/72 (48.6)	χ^2 = 0.53
Age (years)	58.5 ± 13.9	57.2 ± 13.9	58.9 ± 13.9	t = 0.76
Education (years)	7.1 ± 4.6	6.9 ± 5.1	7.2 ± 4.4	t = 0.39
Duration of hemodialysis (months)	68.0 ± 66.2	57.8 ± 57.7	71.3 ± 68.5	t = 1.22
Number of comorbid diseases	2.0 ± 1.6	2.1 ± 1.9	2.0 ± 1.5	χ^2 = 0.59
Any visit to a psychiatric OPD within six months	5 (2.6)	3 (6.4)	2 (1.4)	χ^2 = 3.62
Anxiety score in HADS	4.6 ± 4.0	7.4 ± 4.7	3.7 ± 3.3	t = 5.11***
Depression score in HADS	6.3 ± 5.6	11.6 ± 5.8	4.7 ± 4.3	t = 7.54***
Fatigue score in CFS	19.7 ± 5.9	24.5 ± 6.0	18.1 ± 5.0	t = 7.29***
Physical component summary in SF-36	52.4 ± 26.9	47.4 ± 28.1	54.0 ± 26.4	t = 1.46
Mental component summery in SF-36	66.6 ± 29.4	39.0 ± 27.2	75.5 ± 24.2	t = 8.72***
Psychotropic drugs use^a
Antidepressants	11 (5.6)	6 (12.8)	5 (3.4)	χ^2 = 5.99*
Antipsychotics	2 (1.0)	2 (4.3)	0 (0)	χ^2 = 6.42*
Mood stabilizers	6 (3.1)	1 (2.1)	5 (3.4)	χ^2 = 0.18
Benzodiazepines	83 (42.6)	22 (46.8)	61 (41.2)	χ^2 = 0.52
Hypnotics	39 (20.0)	16 (34.0)	23 (15.5)	χ^2 = 7.83**
Any psychotropic medication	101 (51.8)	28 (59.6)	73 (49.3)	χ^2 = 1.66

Notes: Values are expressed as n (%) or mean ± SD.

*p < 0.05, **p < 0.01, ***p < 0.001.

OPD: outpatient department; HADS: Hospital Anxiety and Depression Scale; CFS: the Chalder Fatigue Scale; SF-36: The Short-form Health-related Quality of Life. ^aPsychotropic medication use was defined as usage within one month prior to interview.

Of the total patients, only five [(2.6%); three (6.4%) in the MDD group and two (1.4%) in the non-MDD group, p = 0.091] visited the psychiatric outpatient department within six months prior to interview. Within one month prior to interview, the numbers of patients who received treatment with antidepressants, antipsychotics, mood stabilizers, BZDs and hypnotics were 11 (5.6%), 2 (1.0%), 6 (3.1%), 83 (42.6%) and 39 (20.0%), respectively. Among patients with MDD, the proportion of patients who received treatment with antidepressants, antipsychotics, mood stabilizers, BZDs and hypnotics were 12.8%, 4.3%, 2.1%, 46.8% and 34.0%, respectively. Compared with patients without MDD, patients with MDD had significantly higher rates for the use of antidepressants (p = 0.014), antipsychotics (p = 0.011) and hypnotics (p = 0.005).

Table 2 presents the results of logistic regression analysis of the independent effects of demographic variables on the use of each class of psychotropic medication. The results showed that patients who took antidepressants were independently associated with having MDD (adjusted OR = 3.98, p = 0.036). No factors significantly associated with BZD use were found. Patients who took hypnotics were also associated with having MDD (adjusted OR = 2.75, p = 0.011). Except MDD, no other factors were independently associated with the prescription of psychotropic drugs in our study population.

Table 2. Multivariable logistic regression analysis of factors associated with psychotropic medication use in hemodialysis patients (N = 195).

Predictors	Any antidepressant	Any benzodiazepine	Any hypnotic
	aOR (95% CI)	aOR (95% CI)	aOR (95% CI)
Sex (female vs. male)	1.16 (0.27–5.00)	1.17 (0.60–2.34)	1.04 (0.44–2.45)
Age	0.99 (0.93–1.05)	0.99 (0.97–1.02)	0.98 (0.95–1.01)
Years of education	0.96 (0.81–1.14)	0.93 (0.86–1.01)	0.93 (0.84–1.03)
Duration of hemodialysis	1.00 (0.99–1.01)	1.00 (1.00–1.01)	1.00 (1.00–1.01)
Number of comorbid diseases	1.38 (0.95–2.01)	1.03 (0.85–1.26)	1.08 (0.85–1.36)
MDD (with vs. without)	3.98 (1.10–14.48)*	1.35 (0.68–2.70)	2.75 (1.27–5.95)*

Notes: aOR: adjusted odds ratio; 95% CI: 95% confidence interval; MDD: major depressive disorder; *p < 0.05.

Discussion

The results of this study showed that although 24.1% of patients on hemodialysis had MDD, only a small proportion of hemodialysis patients visited psychiatric outpatient departments (2.6%). Even among patients diagnosed with MDD, patients who visited psychiatric outpatient departments were still scarce (6.4%). Although depression is common in chronic renal disease, our data showed that depression among dialysis patients is commonly undetected or not well-managed. Similar to our findings, Johnson and Dwyer also reported a high prevalence of untreated depression in hemodialysis patients.28 Nearly 70% of patients were unaware of symptoms of depression/anxiety or did not perceive the need for help. Symptoms of uremia and depression could overlap and be difficult to distinguish, such as fatigue, sleep disturbance and changes in appetite and weight, nausea or pain.1,29,30 For primary care physicians, it is difficult to judge arbitrarily whether symptoms are due to the direct physiological effects of renal failure or to depression. In addition, patients with MDD might be reluctant to seek help because they are worried about social stigma.31 These issues might be barriers to the identification and treatment of depression in hemodialysis patients.

We found that only 5.6% of the total hemodialysis patients were prescribed antidepressants. Although MDD is an independent factor of antidepressants prescription (Table 2), the proportion of those receiving antidepressant treatment among patients with MDD validated by a structured interview was still low (12.8%). In Japan, the proportion under antidepressant treatment was found to be 1.2% of overall hemodialysis patients and 16.1% of patients with physician-diagnosed depression.16 In the United States, Watnick et al. reported that only 16% of hemodialysis patients identified as having depression using a self-administered questionnaire were being treated with antidepressants.32 Hedayati et al. used a DSM-IV-validated interview to screen patients with chronic hemodialysis, and they found that less than 50% of the depressed patients were being treated with antidepressants.33 Together with our findings, the relatively low rate of antidepressant use in East Asian countries may be attributed to either patients’ resistance or physicians’ decisions. Physicians may hesitate to prescribe antidepressants in patients with ESRD because of the side effects, noncompliance and dosage adjustment.10 A physician’s lack of information about medication and depression might also contribute to inadequate treatment.11 Furthermore, patients with MDD, especially in Asian countries, might be resistant to antidepressant treatment because they are worried about the social stigma. Previous studies have demonstrated that antidepressants were effective on improving the symptoms of depression and quality of life in hemodialysis patients.34,35 Therefore, clinicians should be more alert to patients’ emotional distress and provide appropriate antidepressant treatment for hemodialysis patients with depression.

Patients undergoing hemodialysis may experience temporary psychosis, especially delirium.36,37 Delirium is a syndrome that presents as transient disorientation and confusion and frequently appears among the elderly with a long duration of hemodialysis.38 In these patients, antipsychotics are often used temporarily until the delirium subsides. Mood stabilizers are used to treat chronic pain and seizure in patients with ESRD.39 The situation aforementioned might be less commonly observed than depression among dialysis patients, and therefore only a small proportion of patients were prescribed antipsychotics (1%) and mood stabilizers (3.1%) in this study.

We found that BZDs (42.6%) and hypnotics (20%) were the two most frequently prescribed categories of psychotropic drugs in this study. Anxiety and insomnia are commonly seen in HD patients.40 BZDs have been successfully used to relieve symptoms of anxiety, and hypnotics are also widely prescribed for HD patients with insomnia.15 In the United States, Winkelmayer et al. reported that 14% of incident dialysis patients took a BZD or zolpidem, and hypnotics prescription is more frequent among patients with other medical illnesses.17 In Japan, the proportion of those administered BZDs was found to be 19.2% in overall hemodialysis patients and 32.3% in patients with physician-diagnosed depression.16 Compared with data reported in international studies, BZDs and/or hypnotics are exorbitantly used in hemodialysis patients in Taiwan. It has been suggested that BZDs or zolpidem use may be associated with greater mortality among hemodialysis patients.17 Clinicians need to cautiously consider the necessity of long-term use of BZDs in dialysis patients. It is noteworthy that MDD was independently associated with hypnotics use in our study. This may indicate that sleep disturbance, a common sign of depression, was easily detected in hemodialysis patients. However, primary care physicians do not differentiate carefully whether insomnia is related to patients’ emotional problems or just to a physiological change in ESRD. In addition, physicians might be anxious to deal with patients’ physical discomfort.1,12,17 Therefore, before prescribing BZDs or hypnotics, clinicians should pay more attention to the possibility that patients are actually suffering from depression when they have insomnia.

There are several limitations of this study. First, much clinical information was not recorded in this study. For example, the indications of medication prescriptions and the individual drugs in each category of psychotropic agents were not recorded. In addition, information regarding primary care physicians was not analyzed. It could not be distinguished whether the prescription of psychotropic drugs was derived from physicians’ own intentions or from a suggestion by a psychiatrist via consultation. Second, diagnosing depression is sometimes difficult in hemodialysis patients because MDD and renal failure have many similar somatic symptoms. The diagnoses of other mental disorders, except MDD, were not validated using a structural interview. Moreover, we performed a chart review to collect patients’ information regarding psychotropic drugs used within one month prior to interview. Therefore, the duration of patients suffering from MDD might not exactly correspond to the duration of drugs use. Third, this was a cross-sectional study, and the causal inference regarding psychotropic drugs use and patients’ mental health was unclear. Finally, the sample size was small, and subjects in this study were recruited from a single site. Hence, the sample in this study does not represent all hemodialysis patients in Taiwan, and the external validity may be limited.

Despite these limitations, this study provides initial data regarding the prevalence and associated factors of psychotropic drugs use among hemodialysis patients in Taiwan. In conclusion, the findings suggest that MDD, a common psychiatric comorbidity in patients on hemodialysis, is generally undetected or not well-managed in the clinical setting. Only a small proportion of depressed patients received antidepressant treatment. BZDs and/or hypnotics might be prescribed exorbitantly among hemodialysis patients. Clinicians should be more alert to patients’ emotional distress, and depressed patients could be identified early and offered appropriate treatment with psychotropic agents.

Declaration of interest

All authors declare that there are no conflicts of interest. This study was supported by the National Science Council, Taiwan (NSC 96-2314-B-182A-090-MY2).

Authors’ contributions

C-Y.Y. and C-K.C. are the joint first authors. C-Y.Y. wrote the first draft of this manuscript. C-K.C. was responsible for protocol development and gathered the data. H-J.H., I-W.W., C-Y.S., C-C.C. and C-C.L. recruited the participants. L-J.W. carried out the literature search and edited the submitted manuscript.

Acknowledgements

The authors wish to express their deepest gratitude to all the patients who participated in this study.