Depression in maintenance hemodialysis patients: What do we need to know?

Abstract

Chronic kidney disease (CKD) is now recognized as a major public health problem in the world. The global prevalence of CKD is estimated at 13.4% (11.7–15.1%), with an estimated 490.2 to 7.083 million patients with End stage renal disease requiring renal replacement therapy. Hemodialysis is the main treatment for End stage renal disease patients because of its high safety and efficiency. The survival time of these patients was significantly prolonged, but many psychological problems followed. Depression is a type of mood disorder caused by a variety of causes, often manifested as disproportionate depression and loss of interest, sometimes accompanied by anxiety, agitation, even hallucinations, delusions and other psychotic symptoms. Depression has become the most common mental disorder in maintenance hemodialysis (MHD) patients according to the meta-analysis. In recent years, depression has seriously affected the quality of life and prognosis of MHD patients from dietary, sleep, treatment adherence, energy and other dimensions. This article reviews the epidemiology, etiology, diagnosis and treatment of depression in MHD patients.

1. Epidemiology of depression in MHD patients

According to the World Health Organization, some 280 million people worldwide suffer from depression, of which 92% are adults and 21% are over 60 years of age [1]. More than 700,000 people in China commit suicide each year due to depression, which has become the second most cause of disabilities in China and is expected to be the world's number one cause of disability by 2030. An observational study of 55,982 patients with Chronic kidney disease (CKD) by Palmer et al. [2] showed that about a quarter of patients with CKD suffered from depression and maintenance hemodialysis (MHD) patients had a higher risk. Domestic and foreign studies showed that the overall prevalence of depression in MHD patients is 20%–47% [[3], [4], [5], [6], [7], [8], [9], [10]]. The prevalence of depression in MHD patients in China was 29.1%, lower than the 38.2% reported in the Greek study, 44.1% in India, 46% in the United States, 62% in Iran and 75% in Pakistan [6,[11], [12], [13], [14], [15]]. Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) assessed 72 relatively healthy MHD patients, 43% of mild and over mild, and with 33% severe depressive patients [16]. A study in Singapore reported that about 35% of MHD patients had persistent depressive symptoms, but about 12.7%–18.5% of MHD patients had new depressive symptoms or depressive symptoms reduced over time [10]. Depression increases the likelihood of cardiovascular disease, malnutrition, inflammatory response, and affects the prognosis of hemodialysis patients. A meta-analysis reported that the presence of depressive symptoms increased the mortality risk in MHD patients by 51% and was an important factor in mortality [17].

2. Causes of depression in MHD patients

The incidence of depression in MHD patients is more than four times that of the general population, and the reasons for this difference are multifaceted and related to physiology, behavior and social mechanism (Fig. 1).

Fig. 1.

Patients with maintenance hemodialysis suffer from depression due to physiological, behavioral and gender factors. Brain-derived neurotrophic factor (BDNF) and transforming growth factor (TGF)-β1 serve as predictive markers for people with major depression.

2.1. Physiological factors

2.1.1. Cerebrovascular disease

In addition to traditional cardiovascular risk factors such as hypertension and diabetes mellitus, MHD patients also have a variety of risk factors associated with nephropathy, such as the disorders of calcium phosphate metabolism, hypercoagulability, inflammation and oxidative stress [[18], [19], [20], [21], [22], [23]]. These risk factors also threaten the cerebrovascular. Focal injury of cerebral vessels disrupts the frontal subcortical limbic pathway and affects the mood of patients by regulating neural connections in the regulating center [24]. Studies have found that MHD patients experienced very low cerebral blood flow perfusion, hypoxia and changes in cerebral blood flow perfusion imaging such as generalized brain atrophy during the dialysis. There is also a correlation between brain abnormalities and treatment time. It is speculated that the iatrogenic adverse brain reaction is related to hemodialysis [25]. Low perfusion rates and abnormal inflammatory responses lead to the development of depression and contribute to the chronicity of depression [26]. The “vascular depression” hypothesis partially explains the process of depressive syndrome induced by cerebrovascular disease in MHD patients [27].

2.1.2. Inflammation

The levels of inflammatory markers in depressed patients are higher than those in the general population. Several studies have confirmed that levels of pro inflammatory cytokine (interleukin-1, interleukin-6) and tumor necrosis factor- α (TNF-α) in patients with major depression are significantly higher [[28], [29], [30]]. Numerous studies have shown that peripheral immune activation causes changes in mood and behavior by stimulating the hypothalamic-pituitary-adrenal (HPA) axis to induce serotonin dysfunction and hypercortisolemia, and increases the prevalence and mortality of depression [[31], [32], [33]]. Chronic inflammatory state is very common in MHD patients and is the main cause of depression and death in MHD patients [34]. Clinically, depressive symptoms and elevated levels of inflammatory cytokines often coexist in MHD patients [30]. The unclear relationship between inflammation and depression in MHD patients needs further study.

2.1.3. Malnutrition

At present, there is evidence that malnutrition and inflammation are closely related and jointly promote vascular calcification, so some people speculate that depression may be related to malnutrition, inflammation and Atherosclerosis Syndrome [35,36]. MHD patients need to strictly control their diet, and depression is often accompanied by poor food intake. The lack of energy and protein leads to malaise, decreased appetite and loss of interest in MHD patients, accelerating the occurrence and development of depression. A large number of studies have found that depression is related to low body fat, Hypoproteinemia and anemia [[37], [38], [39], [40]]. CKD also often accompanied by a decline in albumin, malnutrition further led to poor quality of life in MHD patients, promoting the production and development of anxiety and depression.

2.1.4. Alteration of autonomic activity

One of the basic pathophysiological mechanisms of depression is autonomic dysfunction. Along with the development of the sympathetic nerves in depression, the control of autonomic nerves gradually became unbalanced [41]. Functional and morphological evidence showed that the uptake of norepinephrine on neurons and granular membranes of adrenergic terminal fibers in End stage renal disease (ESRD) patients was inhibited, and the lack of norepinephrine caused dysfunction of autonomic nerves [42,43]. MHD patients often experience palpitations, chest tightness, dizziness, sweating and severe hypotension during hemodialysis because of impaired autonomic function. A study found that the prevalence of autonomic neurological dysfunction in ESRD patients was 62%, and the parasympathetic nervous system (50%) was more vulnerable than the sympathetic nervous system (28%) [44]. G. Vita et al. [45] ruled out the effects of variables such as sex, course, etiology and natural aging on autonomic function and found that older MHD patients had more severe autonomic damage than middle-aged patients. It is worth mentioning that heart rate variability (HRV) is mediated by parasympathetic and sympathetic nerves. The higher HRV amplitude represents a higher ability of parasympathetic to suppress autonomic excitement and a lower cardiovascular risk and fewer anxiety symptoms. So HRV analysis is increasingly used to assess anxiety, depression and other diseases caused by autonomic dysfunction [[46], [47], [48]].

2.2. Behavioral factors

Chronic complications and financial burdens from long-term hemodialysis lead to a decline in the quality of life of MHD patients. The health-related quality of life (HRQoL) problem has become an important part of public health surveillance [49]. It reflects the effect of the individual's health condition on their somatic, emotional, behavioral and social functions, and is often used to evaluate the quality of life and predict mortality and morbidity in different disease groups [50]. Studies have demonstrated a correlation between lower quality of life and higher prevalence of depression in MHD patients compared to the general population [51]. Complications caused by uremia, such as restless leg syndrome, are one of the causes of fatigue and poor quality of life in MHD patients [52]. Compared with healthy people and patients who choose treatment methods of peritoneal dialysis and kidney transplant, MHD patients have more problems in their lives due to frequent visits to hospitals, and the evaluation of positive quality of life is significantly lower [[53], [54], [55]]. In addition, MHD patients' dependence on dialysis threatens their social role, threatening their self-awareness, and thus the quality of life during their illness [53,[56], [57], [58]].

2.3. Gender factor

An observational cross-sectional study of 414 MHD patients from 24 dialysis centers in Greece by G. Gerogianni et al. [59], found higher rates of anxiety and depression in female patients than in men. Interpersonal stress, hormonal factors, social status, social roles and cultural constraints are among the risk factors for the high prevalence of depression in women. As daughters, wives and mothers in the extended family, women play a more responsible and patient social role, while most of them also face workplace pressures. Because of frequent hemodialysis, they are often unable to fulfil their previous family or social responsibilities and therefore bear more psychological burdens. A study in Taiwan found that women with hemodialysis were more stressed by physical symptoms and vascular problems than men [60]. In addition, women are more likely to immerse themselves in negative emotions and produce depressive symptoms, while men prefer to actively digest depressive emotions [61]. It is important to mention that sleep is essential to everyone's physical and mental health, and many studies have demonstrated that insomnia is a risk factor for emerging and recurrent major depression [[62], [63], [64]]. An Iranian study of 310 MHD patients found that 73.5% of MHD patients had poor sleep quality, while the probability of poor sleep quality in women was 85% higher than in men [65].

3. Diagnosis of depression in MHD patients

Depression can be diagnosed using diagnostic criteria such as Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) or the International Classification of Diseases (ICD-11). According to DSM-V, major depression is defined as loss of pleasure or interest within 2 weeks, accompanied by 5 or more psychological, physical and behavioral symptoms. Depression, loss of interest, sleep disturbance, worthless feelings of guilt, fatigue, reduced thinking and attention, weight loss and loss of appetite, excitement or delay in exercise, suicide are symptoms associated with depression.

3.1. Screening modality

In clinical studies, patients' self-assessment questionnaires were often used to screen for depressive symptoms, including the 9-item Patient Health Questionnaire (PHQ-9), kidney disease quality of life form, Center for Epidemiological Survey, Depression Scale (CES-D), Self-Rating Depression Scale (SDS), Beck Depression Inventory (BDI), Hamilton depression scale (HAMD-24), etc. Self-contained assessment scales can be prioritized for screening and clinical research, reducing the burden on patients and not affected by subjective factors among researchers. But there are large differences between different diagnostic tools. When the self-assessment questionnaire is applied to people with chronic diseases, it is easy to be confused because fatigue, sleep disorders and loss of appetite are not only physical symptoms of ESRD, but also physical indicators of depression. Patients with significant uremic symptoms tend to have a higher score for depression assessment as well. Therefore, researchers are often unable to distinguish the associated somatic symptoms caused by depression, the original disease or both, leading to a higher diagnosis of depression. Structured clinical interviews with patients by experienced psychiatrists (SCID) are the gold standard for the definite diagnosis of major depression in MHD patients. In order to reduce the effect of somatic factors on depression assessment, BDI is the most accurate and effective method for MHD patients [[66], [67], [68]].

3.2. Predictive factors

3.2.1. Brain-derived neurotrophic factor (BDNF)

BDNF is an important member of the family of neurotrophic factors that can cross the blood-brain barrier and promote the survival, differentiation and maintenance of neurons in the peripheral and central nervous systems [69]. It is associated with a variety of neuropsychiatric disorders such as eating disorders, mood disorders, schizophrenia and epilepsy [70]. There is increasing evidence of the important role of BDNF in glutamatergic neurotransmission, suggesting that levels of BDNF in plasma or serum can be a predictive marker for patients with major depression [71]. However, some studies have found that BDNF is not entirely associated with depression. Because of biological incompatibility, direct contact between the blood of MHD patients and synthetic material circulating in vitro can result in increased oxidative stress response. Serum BDNF concentrations are affected by reducing the synthesis of BDNF in the brain and other tissues and increasing the utilization of BDNF in damaged cells [72].

3.2.2. TGF-β1

TGF-β1 plays a role in immunosuppressive, anti-inflammatory and antiapoptotic effect. It has a neuroprotective effect on neurodegenerative changes induced by amyloid β (Aβ) and plays a key role in memory formation and synaptic plasticity [73]. TGF-β1 decreased expression in patients with major depression and significantly increased drug resistance in patients with major depression [74]. The genetic level of TGF-β1 may affect the severity of depressive symptoms and the number of depressive episodes [75]. Based on research by Zhao M et al. [76] TGF-β1 it is speculated that it can be used for clinical diagnosis and treatment in MHD patients.

4. Treatment of depression in MHD patients

4.1. Non-pharmacological treatment

4.1.1. Cognitive behavior therapy (CBT)

CBT is a relatively short-term, focused psychotherapy for a wide range of psychological problems, including depression. It aims to change patients' bad thoughts, behaviors and negative emotions through classroom teaching, group discussion and scenario simulation [77]. In a number of controlled studies, the symptoms of anxiety and depression in the CBT intervention group decreased significantly compared with the control group, and the quality of life score improved significantly. CBT can reduce anxiety and mind warping, improve self-efficacy, improve HRQoL, and serve as a long-term treatment for improving depression, anxiety, and quality of life compared to routine treatment. As a result, CBT has been shown to be effective in the treatment of depression in MHD patients [[78], [79], [80]]. With the rising prevalence of ESRD and the multifaceted burden of hemodialysis, more patients should be ensured prompt and appropriate CBT treatment (Fig. 2).

Fig. 2.

At present, maintenance hemodialysis patients with depression are treated in the form of cognitive behavior therapy, traditional exercise, music therapy, phototherapy, healthy diet, antidepressants and Ketamine.

4.1.2. Traditional exercise

Exercise has been studied extensively to improve the prognosis of cardiovascular disease and depression, and is positively correlated with the effect of hemodialysis, physical function and HRQoL [81,82]. Endorphins and serotonin released through exercise reduce blood cortisol levels, reduce stress and anxiety, and increase pleasure [83]. Tests in Korea and Poland have found that exercise can reduce physical pain and the occurrence of hypotension events in hemodialysis in MHD patients, reducing their levels of anxiety and depression [84,85]. A Taiwanese study found that exercise during 12 weeks of hemodialysis could safely and effectively improve HRQoL and the symptoms of depression in MHD patients without changing their dialysis prescriptions [86]. According to Kouidi et al. [87], depression in patients with CKD is associated with cardiac autonomic dysfunction, and aerobic training may improve cardiac autonomic activity to reduce the incidence of depression.

4.1.3. Music therapy

Music therapy is a simple, accessible, noninvasive and non-side-effect method. Music can provide relaxation, remoteness from sadness, guilt, and loneliness, so all activities involving music can be therapeutic. Studies across the globe have found significant improvements in patients' depressive symptoms and quality of life in the post-stage of music therapy [[88], [89], [90], [91], [92]]. Burrai et al. [93], speculate that music can prevent pain signals from reaching the brain by activating type II sensory fibers and triggering inhibitory interneurons.

4.1.4. Light therapy

Light irradiation of the pineal gland with different length and intensity can inhibit melatonin [94]. It is an accepted way to treat Seasonal Affective Disorder. And now many researchers have suggested that light therapy has a mild and moderate therapeutic effect in reducing depressive symptoms and can be used as a clinical treatment for Non-Seasonal Affective Disorder [95]. Tao. L et al. [96], through meta-analysis, found that light therapy less than 60 min/day in the morning had the better therapeutic effect.

4.1.5. Healthy diet

Nutrients are necessary for the production of neurotransmitters such as Serotonin, dopamine and Norepinephrine, which are involved in the regulation of the emotion, appetite and cognition [97]. Therefore, strengthening the intake of nutrients in MHD patients can reduce the generation of depression and anxiety. Research has found that increased intake of seafood, olive oil, vegetables, fruits, and nuts can reduce the risk of depression [98]. It is recommended that stable MHD patients have a protein intake of 1.0–1.2 g * kg (ideal body weight) to maintain stable nutritional status. In clinic, doctors and nurses need to strengthen the education of healthy dietary patterns for patients to avoid the occurrence of malnutrition [99].

4.2. Medical treatment

Anti-depressant medication (ADM) can be classified into Monoamine oxidase inhibitor (MAOIs), Tricyclic antidepressants (TCAs), Tetracyclic antidepressants, Selective serotonin reuptake inhibitor (SSRIs), Serotonin and norepinephrine reuptake inhibitor (SNRIs) and other by chemical structure and mechanism of action. MAOIs and TCAs are clinically long-used drug types, while drugs that block serotonin and norepinephrine reuptake are recent years of research and development. At present, SSRIs are still the first line choices, including citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, while TCAs are used less because of their risk of arrhythmia and long QT syndrome [100]. The newly developed SNRIs are more extensive, safe and effective antidepressant [101,102]. A meta-analysis compared the efficacy of 21 antidepressants or placebo treatments in 1979–2016, with fluoxetine, fluvoxamine, reboxetine and trazodone considered less effective [103]. Because of ESRD patients' conditions, there are many constraints and risks in medication, sertraline can reduce the levels of inflammation significantly by reducing proinflammatory cytokines, increasing anti-inflammatory cytokines and improve depressive symptoms in MHD patients, so sertraline seems to be a relatively safe and effective drug [104,105]. However, a contradictory result was obtained in five dialysis centers in the United Kingdom. In randomized controlled studies of MHD patients with moderate and major depression, sertraline group withdrew from adverse events and serious adverse events due to certain side reactions. Although the depression scores of sertraline and placebo were improved, there was no significant difference, which showed that sertraline had limited antidepressant effect in patients with moderate and severe depression [106]. Most antidepressants play a therapeutic role after treatment for 2–4 weeks, and can easily cause gastrointestinal and cardiovascular reactions. As a result, the patient's compliance is low, which is a difficult point in drug treatment for depression. Recently, there is increasing evidence that ketamine, as N-methyl-d-aspartate receptor (NMDAR) antagonist acts directly on the receptor and increases the synthesis and release of BDNF, causing synapse occurrence, AMPA receptor dependence on excitatory synaptic transmission enhancement, play a long-term and stable antidepressant role [107]. And (R) -Ketamine has greater potency and longer-lasting antidepressant effects than (S) -Ketamine and has less harmful side effects [108]. R M Berman et al. [109], in a clinical trial, found that ketamine achieved a powerful antidepressant effect 4 h after intravenous injection (40-min infusion) at a subanesthetic dose of 0.5 mg/kg. Studies have also found that ketamine can rapidly reduce suicidal thoughts in people with depression within a day and can be effective for up to a week [110]. (R) - Ketamine acts directly on the brain through nasal intake using olfactory neural pathways, which will be a new trend in the treatment of depression.

5. Conclusion

Nowadays, with the popularization of dialysis technology, the survival of more and more ESRD patients is extended. People with MHD have high rates of depression and low rates of diagnosis. The risk factors are numerous, and the pathogenesis is unclear. The high incidence of depression seriously impairs the social and life function of patients, lowers the quality of life and prognosis of patients, and leads to high mortality. With the increasing emphasis on the spiritual dimension, timely and effective screening and treatment of depression is essential. In the future, we hope that more scholars will focus on depression in MHD patients, further clarify how risk factors are involved in the occurrence and development of depression, and continue to explore effective integrated management strategies. We should develop a more suitable combination treatment scheme for different patients, based on the patients' individual needs, feedback and current economic support.

Author contribution statement

All authors listed have significantly contributed to the development and the writing of this article.

Data availability statement

No data was used for the research described in the article.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.