Depression in chronic kidney disease and dialysis: A psychonephrology narrative review

Abstract

Depression is one of the most prevalent yet under-recognized comorbidities in patients with chronic kidney disease (CKD), particularly among those receiving maintenance dialysis. Its presence adversely affects quality of life, treatment adherence, hospitalization rates, and survival, yet it frequently remains masked by overlapping somatic symptoms of uremia and chronic illness. Psychonephrology, an emerging interdisciplinary field, provides a framework to understand the complex bidirectional interactions between psychological health and kidney disease. This narrative review explores the epidemiology, pathophysiological mechanisms, clinical manifestations, and consequences of depression across the CKD spectrum, with a focus on patients undergoing hemodialysis and peritoneal dialysis. We discuss biological contributors including inflammation, neuroendocrine dysregulation, uremic toxin accumulation, and cerebrovascular changes, alongside psychosocial stressors such as illness chronicity, dependency, financial burden, and altered social roles. Challenges in screening and diagnosis, including the limitations of conventional depression scales in CKD populations, are highlighted. The review further examines the impact of depression on clinical outcomes, dialysis adequacy, nutritional status, and mortality. Finally, we summarize current evidence on pharmacological and non-pharmacological management strategies, emphasizing the role of integrated, multidisciplinary care models. Recognizing and addressing depression as a core component of CKD management is essential to improving holistic patient outcomes and advancing the practice of psychonephrology.

Key Words: Chronic kidney disease; Depression; Dialysis; Psychonephrology; Uremic toxins

Core Tip: Depression is one of the most common yet under-recognized comorbidities in chronic kidney disease (CKD), especially among patients receiving maintenance dialysis. Overlapping somatic symptoms of uremia often complicate its diagnosis, leading to under detection and undertreatment. Beyond its profound impact on quality of life, depression is associated with poor treatment adherence, increased hospitalization, malnutrition, reduced dialysis adequacy, and higher mortality. Emerging evidence suggests that inflammation, neuroendocrine dysregulation, uremic toxin accumulation, and psychosocial stressors collectively contribute to its pathogenesis. This review highlights the epidemiology, mechanisms, diagnostic challenges, and clinical consequences of depression across the CKD spectrum, while emphasizing the evolving role of psychonephrology in integrating psychological and renal care. Early recognition and multidisciplinary management are essential to improving holistic outcomes in CKD patients.

INTRODUCTION

Chronic kidney disease (CKD) is a serious global health problem. About 788 million people worldwide are affected, and the prevalence is between 13.4% and 14.2% globally[1]. It is the ninth leading cause of death worldwide. As the number of people with major risk factors like diabetes and hypertension grows, along with aging populations and improved survival for those with chronic diseases, more people are developing CKD.

CKD affects both physical and mental health. Though with better availability of hemodialysis, survival of CKD patients has significantly improved, it still continues to profoundly affect mental health through stress, anxiety and depression. Depression represents the most common psychiatric disorder in the CKD population[2]. As per the World Health Organization, depression is “characterized by sadness, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, feelings of tiredness, and poor concentration”. About one-quarter of all CKD patients exhibit clinically significant depression as per recent meta-analysis[3-5].

Depression and CKD both interact in a bidirectional way, such that each disorder negatively affects the other. It has been seen that adults with depression are at higher risk of developing CKD[6]. Similarly, patients with CKD are at higher risk of having depression when compared to the general population. Depression is associated with increased cardiovascular disease, inflammatory response, and malnutrition, and so affects the prognosis of CKD patients. Depression affects treatment adherence, increases the risk of progression of CKD, and increases hospitalization and mortality rates[7,8].

Pathophysiology of depression in CKD involves uremic toxins like indoxyl sulphate, which activate the aryl hydrocarbon receptor, lower serotonin levels, and cause neuroinflammation by increasing cytokines like interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), as well as activating microglia[9]. CKD-related chronic inflammation also affects the hypothalamic-pituitary-adrenal (HPA) axis, leading to higher cortisol and norepinephrine levels and promoting malnutrition, inflammation, and atherosclerosis syndrome, which worsens depressive symptoms[10].

The mental health burden in kidney disease patients is significant, leading to the development of psychonephrology. This new field combines psychological, behavioral, and biological aspects of kidney disease and should be included in routine CKD care to support a more holistic and patient-centered approach[11].

Depression in CKD remains a major but incompletely characterized and overlooked comorbidity. Existing literature on depression in CKD reveals several key gaps, including challenges in accurate diagnosis due to overlapping symptoms like fatigue and poor appetite, inconsistent screening practices, limited data on non-dialysis CKD and on efficacy and safety of various antidepressants. By addressing diagnostic challenges, screening approaches and multidisciplinary care gaps in patients with CKD and depression, this review provides clinically relevant insights that have been only sparsely discussed in prior mechanism-centric narrative reviews, thereby contributing to a more holistic psychonephrology practice.

There is a need to apprise health care professionals of psychological concerns related to CKD for the timely detection and to bridge diagnostic and treatment gaps effectively. This review would summarize the pathophysiology of depression in CKD, screening tools validated in the CKD population, interrelated pathways of depression and CKD, and available pharmacological and non-pharmacological treatment options.

RESEARCH METHODOLOGY

This narrative review was conducted in accordance with the Scale for the Assessment of Narrative Review Articles recommendations. A comprehensive literature search was performed using PubMed/MEDLINE, EMBASE, Cochrane Library, PsycINFO, and Google Scholar to identify relevant studies published up to March 2026. The search strategy incorporated both Medical Subject Headings and free-text keywords related to CKD and depression, including “chronic kidney disease”, “CKD”, “chronic renal insufficiency”, “depression”, “depressive symptoms”, “major depressive disorder”, “mental health”, and “psychological distress”, combined using Boolean operators (“AND”, “OR”). Eligible studies included meta-analyses, systematic reviews, randomized controlled trials (RCTs), observational studies, and narrative reviews addressing the epidemiology, pathophysiology, clinical impact, screening, diagnosis, and management of depression in CKD patients. Additional relevant studies were identified through manual screening of reference lists. Studies were excluded if they were case reports, conference abstracts without full text, duplicate publications, non-English articles, pediatric-only studies not relevant to the review objectives, or studies lacking adequate methodological quality or relevance. Study selection was performed in two stages: Screening of titles and abstracts followed by full-text assessment based on predefined eligibility criteria. Two independent reviewers screened the studies, and discrepancies were resolved through discussion and consensus. The methodological quality and relevance of included studies were critically appraised before inclusion. The authors declare no conflicts of interest related to this manuscript.

Although 80 references were cited throughout the manuscript to provide broader conceptual background and contextual discussion, only 61 studies met the predefined eligibility criteria and were included in the PRISMA-based study selection process. This approach was adopted to maintain comprehensive narrative contextualization of the topic. PRISMA-based flow diagram illustrating the study selection process, along with the characteristics of the included studies, is provided in Figure 1.

Figure 1  PRISMA flow diagram illustrating the study selection process for the narrative review on chronic kidney disease and depression.

PREVALENCE OF DEPRESSION IN CKD

CKD patients face significant physical and psychosocial challenges. Physical symptoms of disease, associated functional limitations, loss of autonomy, dietary restrictions, long-term treatments, financial strain, and uncertainty about the future, can all worsen depressive symptoms.

Depression is found in 7% of the general population[12] and is the most common psychiatric disorder found in CKD patients[2]. Approximately 25% of pre-dialysis CKD patients experience clinical depression[13]. A meta-analysis of 65 studies reported a pooled prevalence of 26.5% rising to 29.9% in hemodialysis vs 18.5% pre-dialysis[14]. Another meta-analysis by Palmer et al[3], which included 216 studies with 55982 patients, found that among those with end-stage renal disease (ESRD) on dialysis, 39.3% showed signs of depression when using screening questionnaires and 22.8% were diagnosed clinically. The prevalence of depression tends to increase as stage of CKD progresses, reported to reach up to 73% in hemodialysis patients as per one study[15,16]. The prevalence of depression was higher among patients on hemodialysis compared to those on peritoneal dialysis (30.6% vs 20.4%; P = 0.04)[14]. One study reported that at least 78.3% of patients who self-reported no depression were found to have clinical depression, suggesting that self-reporting alone is an unreliable method for assessing clinical depression[17].

RISK FACTORS FOR DEPRESSION IN CKD

Depression results from a mix of biological, clinical, and psychosocial factors. Reduced glomerular filtration rate: Reduced estimated glomerular filtration rate (< 60 mL/minute/1.73 m²) and proteinuria (> 1 g/g) lead to the accumulation of uremic toxins like indoxyl sulfate, triggering neuroinflammation via IL-6 and TNF-α cytokines. These toxins disrupt neurotransmitter pathways. The risk of depression doubles with every 10 mL/minute drop in estimated glomerular filtration rate[18]. Dietary restrictions, reduced physical ability, and the burden of treatment also contribute to depression.

Comorbidities: Conditions like diabetes, hypertension, cardiovascular disease, and anemia cause oxidative stress and low oxygen levels, which affect serotonin transport and brain-derived neurotrophic factor (BDNF)[19]. Biological mechanisms: Chronic inflammation, oxidative stress, and buildup of uremic toxins can interfere with neurotransmitter pathways and brain function[20]. Hormonal imbalance: Lower testosterone in men and disrupted circadian rhythms from uremia that lead to sleep problems are closely linked to depression[19]. Socioeconomic factors: The high cost of dialysis, medications, and hospital visits, combined with the loss of ability to work, creates a heavy financial burden for CKD patients. Unemployed individuals and those from lower socioeconomic groups, and those with lower education level are more likely to experience depression[19,21]. Demographic factors: Being older (particularly over 65 years) and being female are associated with a higher risk of depression[20]. Psychosocial factors: Chronic illness is often stigmatized, and patients may withdraw from social activities. They may feel like a burden to their families, leading to low self-esteem. Poor social support and living alone are also linked to depression. Low self esteem and pain interference also is associated with depression[22,23]. Treatment-related factors: Being on dialysis for more than a year and experiencing frequent hypotension during hemodialysis are independent risk factors[24].

APPROACH TO DIAGNOSIS

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), a diagnosis of depression requires at least five of nine specific symptoms to be present for at least two weeks, with at least one symptom being a depressed mood or loss of interest/pleasure (anhedonia)[25]. Figure 2 highlights the DSM-5 diagnostic criteria for major depressive disorder.

Figure 2 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria for major depressive disorder. DSM: Diagnostic and Statistical Manual of Mental Disorders.

Core DSM-5 diagnostic criteria (major depressive episode)

Depressed mood: Feeling sad, empty, or hopeless (or irritable in children/adolescents) most of the day, nearly every day. Anhedonia: Markedly diminished interest or pleasure in activities. Appetite/weight changes: Significant weight loss/gain or change in appetite. Sleep disturbances: Insomnia or hypersomnia. Psychomotor changes: Agitation or retardation (observable by others). Fatigue: Loss of energy. Worthlessness/guilt: Excessive or inappropriate guilt. Cognitive issues: Diminished ability to think, concentrate, or make decisions. Suicidality: Recurrent thoughts of death or suicidal ideation.

Differentiating depressive symptoms from uremic manifestations in patients with CKD is challenging because several somatic symptoms, including fatigue, sleep disturbance, anorexia, and cognitive impairment, overlap significantly. Therefore, greater emphasis should be placed on core affective symptoms that are more specific to depression, particularly persistent depressed mood and anhedonia. Symptoms that vary with dialysis adequacy or metabolic status are more likely to reflect uremia, whereas sustained negative affect, hopelessness, social withdrawal, and loss of pleasure favour a depressive disorder.

CKD-DEPRESSION AXIS: A BIDIRECTIONAL INTERACTION

CKD and depression exhibit a well-established bidirectional relationship, where each condition increases the risk and worsens outcomes of the other. This interplay contributes to higher morbidity, faster disease progression, and elevated mortality in affected patients[26-28].

The CARDIA study (Coronary Artery Risk Development in Young Adults) study looked at people in their early adulthood (ages 18 to 30) and found that those with depressive symptoms were more likely to develop CKD later in life[29]. Over more than 20 years of follow-up, these individuals had about a 20% to 30% higher risk of reduced kidney function compared to those without depression. On the other hand, people with CKD were also more likely to develop depression, with a 36% increased risk over the same time period. This bidirectional connection indicates a vicious cycle, where the presence of one condition complicates the management and prognosis of the other. Similar findings came from the China Health and Retirement Longitudinal Study, where depression was linked to a 38% increased risk of CKD, and CKD was associated with a 48% higher risk of depression[26].

DEPRESSION AND ITS CONTRIBUTION TO CKD ONSET AND PROGRESSION

The China Health and Retirement Longitudinal Study included people over the age of 45 and found that those with depressive symptoms at the start of the study had a 38% to 45% higher risk of developing CKD over a follow-up period of 9 years compared to those without depressive symptoms. The risk of CKD also increased with the severity of the depression, as the study found a direct link between the total score on the Centre for Epidemiologic Studies Depression Scale and the risk of developing CKD.

Depression does more than just affect the mind; it also plays a key role in the progression and outcomes of CKD. Multiple studies have shown that CKD patients who have depressive symptoms are at higher risk of disease progression compared to those without depression. Patients with stage 5 CKD had the highest risk of developing depression[27,28].

CONSEQUENCES OF DEPRESSION IN CKD

Depression is not only a psychological consequence of CKD, but it is a critical determinant of adverse outcomes across the disease spectrum. Depression is linked to higher mortality rates in CKD[24]. After considering traditional risk factors, research has shown that people with depression and CKD are more likely to die from any cause, including heart-related issues[30].

Many studies have found that depression is associated with worse health outcomes, like more hospitalizations and longer stays in the hospital[31]. These reflect the economic burden on the patient’s family and the healthcare system. An interesting study showed that persistent depressive symptoms are associated with worse clinical outcomes. This justifies early screening and treatment of depression to reverse or prevent poor clinical consequences.

The Stockholm CREAtinine Measurements project followed 157398 adults with CKD stages 3 to 5 who weren’t on dialysis and found that 8.1% of them developed depression within 5.1 years. Depression was also linked to a 38% increased risk of CKD progressing[32]. Another study showed that depression is associated with new onset CKD, ESRD and hospitalizations due to acute kidney injury[33]. Depression has been linked to a lower quality of life for people with CKD.

MECHANISMS BY WHICH DEPRESSION LEADS TO ADVERSE OUTCOMES IN CKD

Behavioral factors: Depression can lead to poor adherence to dialysis treatments and non-compliance with medications and dietary rules. This can result in frequent fluid overload, requiring hospitalization. People with depression are also more likely to smoke, be physically inactive, and make unhealthy dietary choices, all of which can harm their health[34-36].

Neurological and hormonal factors: Both depression and CKD can cause the HPA axis to become overactive, leading to higher levels of cortisol and norepinephrine. This leads to inflammation, malnutrition and atherosclerosis. Depression triggers chronic inflammation and hastens glomerular filtration rate fall[37-39].

PATHOPHYSIOLOGY OF DEPRESSION IN CKD

Pathophysiology of depression involves multiple factors, including the complex interactions between chronic inflammation seen in CKD, changes in the gut-brain microbiota (dysbiosis), and the presence of uremic toxins.

Chronic inflammation

CKD is a chronic inflammatory state. Inflammation leads to cytokine generation, neural pathway disruption, and HPA axis dysregulation (Table 1). Cytokine generation-chronic inflammation: CKD is an ongoing inflammatory condition. Inflammation leads to the production of pro-inflammatory cytokines like IL-6, TNF-α, and C-reactive protein[13,16]. These can cross the blood-brain barrier, triggering microglia and astrocytes in brain regions that control mood, such as the hippocampus and prefrontal cortex[9,38,40].

Table 1 Role of inflammatory mediators in depression pathogenesis in chronic kidney disease.

Inflammatory mediator	Depression mechanism	Key impact	Variation across different CKD stages
IL-6	Microglial activation, BBB permeability	HPA dysregulation, hippocampal loss	Increases progressively; significantly higher in stages 3-5
TNF-α	Serotonin ↓, NO ↑	Anhedonia, neuroinflammation	Mild progressive increase from stage 1 to stage 3, not always significant
CRP	Vascular damage, endothelial dysfunction	Cerebral hypoperfusion	Elevated in advanced stages (stage 4 and 5)

CKD: Chronic kidney disease; IL-6: Interleukin-6; BBB: Blood-brain barrier; HPA: Hypothalamic-pituitary-adrenal; TNF-α: Tumor necrosis factor-α; NO: Nitric oxide; CRP: C-reactive protein.

Neural pathway disruption - inflammation will reduce monoamine synthesis and increase reuptake, lower serotonin, norepinephrine and dopamine availability[41]. This depleted brain serotonin will promote excitotoxicity and damage neurons. HPA axis dysregulation-cytokines sensitize the hypothalamus, causing HPA axis hyperactivity with excess cortisol. Chronic hypercortisolemia leads to hippocampal atrophy, impaired neurogenesis (BDNF decreasing), and glucocorticoid resistance, mirroring core depression features like anhedonia and cognitive deficits[42].

Dysbiosis

Dysbiosis is a reduction in beneficial bacteria and increased intestinal permeability. Disruption of gut microbiota in CKD contributes to depression by increasing uremic toxins (indoxyl sulfate, p-cresyl sulfate), impairing short-chain fatty acid production, promoting systemic inflammation, and altering the gut-brain axis; these changes activate microglia, dysregulate neurotransmitters, and worsen mood symptoms. So, gut health and mental health are interrelated, with dysbiosis exacerbating inflammation and depression[43].

Uremic toxins

Uremic toxins originate primarily from gut metabolism of dietary proteins, amino acids, and endogenous waste. In health, kidneys efficiently clear these via glomerular filtration and tubular secretion. As glomerular filtration rate declines, there is an accumulation of uremic toxins in the body. With CKD progression, more and more solutes accumulate in our body, increasing the prevalence of depression with advancing stages of CKD[9].

Most uremic toxins are derived from tryptophan, an essential amino acid obtained from the diet (recommended intake approximately 4-5 mg/kg/day), which is metabolized through three principal pathways. The kynurenine pathway accounts for approximately 90% of metabolism and occurs primarily in the liver, immune cells, and kidneys, generating metabolites such as kynurenine, kynurenic acid, and xanthurenic acid, ultimately contributing to nicotinamide adenine dinucleotide synthesis[44]. The serotonin pathway (approximately 1%-2%) converts tryptophan to serotonin and subsequently melatonin, with clinical relevance to mood regulation. The indole pathway (approximately 4%-6%), mediated by gut microbiota, produces indole, which is further metabolized in the liver to compounds such as indoxyl sulfate, a key uremic toxin. Among the most extensively studied uremic toxins are kynurenines, indoxyl sulfate, and p-cresyl sulfate (Table 2).

Table 2 Enlist key uremic toxins and their effect on depression.

Uremic toxins	Origin	Mechanism	Impact on brain
Indoxyl sulfate	Gut microbiota and liver	Activates aryl hydrocarbon receptor, increases BBB permeability	Reduce serotonin synthesis (approximately 40%), ↑ neuroinflammation (IL-6, TNF-α, NO)[46-48]
Kynurenines	Tryptophan kynurenine pathway	Modulate glutamatergic signaling, regulate inflammation	Imbalance in KA/QA ratio linked to severe depression[44]
p-cresyl sulfate	Phenylalanine metabolism	Poorly understood	May contribute to mood dysregulation[49]
4-ethylphenyl sulfate	Gut-derived phenol	Behavioral effects in mice	Possible link to anxiety and cognition[50]
Indole-3-propionic acid	Gut microbiota	Neuroprotective in some contexts	May improve social function (Janus-faced effect)[51]

BBB: Blood-brain barrier; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; NO: Nitric oxide; KA/QA: Kynurenic acid/quinolinic acid.

Kynurenine metabolites alter glutaminergic signaling and so are involved in mood disorders. They play a role in regulating inflammation, which is thought to be a key factor in severe depression. Low kynurenic acid concentration in urine and a decreased kynurenic acid/quinolinic acid ratio has been associated with severe depression. Indoxyl sulfate is formed when tryptophan is broken down by gut bacteria into indole, which is then converted into indoxyl sulfate in the liver. Normally, this substance is removed from the body through organic anion transporters (OAT1 and OAT3) in the kidneys. In CKD, due to changes in gut bacteria (dysbiosis), more indoxyl sulfate is produced, and its removal is reduced. This toxin can activate microglia and astrocytes in the brain and increase inflammatory substances like IL-6 and TNF-α[45]. It also activates the aryl hydrocarbon receptor[46], contributing to brain inflammation and increasing the permeability of the blood-brain barrier. Indoxyl sulfate can cause the production of reactive oxygen species through pathways like nicotinamide adenine dinucleotide phosphate, reduced form oxidase. It may also indirectly affect serotonin production[47,48].

Para-cresyl sulfate, a breakdown product of phenylalanine, also contributes to depression[49]. 4-Ethylphenyl sulfate, part of the p-cresyl sulfate family, has been linked to anxiety in animal studies[50]. Indole-3-propionic acid may offer some protection, although more research is needed to confirm this in people with CKD[51].

SCREENING FOR DEPRESSION IN CKD

Considering the significant prevalence of depression in the CKD population and the fact that depression has implications for the clinical outcomes of these patients, it is prudent to screen CKD individuals for depression for early detection and timely intervention.

CHALLENGES OF SCREENING IN CKD PATIENTS

CKD patients often experience physical symptoms that are similar to the symptoms of depression. Somatic symptoms like tiredness, poor sleep, loss of energy, and reduced appetite, which are associated with depression, are frequently seen in CKD patients[52,53]. However, these symptoms may be caused by inadequate dialysis, poor nutrition, dementia, or other co-existing conditions rather than major depressive disorder, leading to uncertainty about the accuracy of existing screening tools. CKD patients may display atypical depressive symptoms such as apathy or lack of motivation instead of the classic signs of depression observed in the general population. Depression might be underreported in CKD patients because depressive symptoms are often blamed on the physical challenges of living with CKD. Although the diagnostic criteria are clear, the lack of biomarkers makes it hard to diagnose depression. There’s also a lack of validated screening tools, especially in those with non-dialytic CKD. A higher cutoff score is needed for these scales in ESRD patients, as somatic symptoms tend to appear in later stages of CKD[54].

DEPRESSION SCREENING TOOLS IN CKD

Kondo et al[55] conducted a systematic review to identify depression screening tools suitable for patients with kidney failure. They found that the Beck Depression Inventory II was the most appropriate screening tool. However, it has some drawbacks, including the cost and the time required to complete the 21-item questionnaire[2,56,57]. Shorter versions like the Patient Health Questionnaire-9 and the Geriatric Depression Scale for older adults were also found to be effective[55]. The Patient Health Questionnaire-9 is a 9-item self-report questionnaire that is free and takes about 3 minutes to complete.

Other available tools include the self-reported Quick Inventory of Depressive Symptomatology, which has been validated in patients with stages 2 to 5 CKD[58] and used in clinical trials of depression treatments in patients with kidney failure[59,60] (Table 3)[55-58,61-64].

Table 3 Enumerates various screening tools which have been validated in people with chronic kidney disease.

Screening tool	Number of questions	Time	Kidney population studied	Desired score/cut-off	Strengths and limitations
Beck Depression Inventory-II[55-57]	21	15-20 minutes	CKD (all stages), especially HD and PD	≥ 11-14 (CKD stage 1-5), ≥ 16 (dialysis)	Widely used in dialysis; limitation: Somatic symptom overlap → overestimation, time consuming
Patient Health Questionnaire-9[57]	9	Approximately 5 minutes	CKD stages 3-5, HD, PD	≥ 10 non-dialysis CKD; > 12-15 (HD)	Quick, freely available; limitation: Somatic confounding
Patient Health Questionnaire-2	2	< 2 minutes	CKD and dialysis screening	≥ 3 non-dialysis CKD and HD and PD	Ultra-rapid, sensitive; limitation: Low specificity → needs follow-up
Hospital anxiety Depression scale[61,62]	7	5-10 minutes	HD, PD	≥ 7 non-dialysis CKD, HD, PD	Avoids somatic symptoms → better in CKD; limitation: Not diagnostic
Centre for Epidemiologic studies Depression scale[56]	20	5-10 minutes	HD	≥ 18	Good for population screening; limitation: Low specificity in chronic illness
Hamilton Depression rating scale[63]	21	15-20 minutes	CKD and dialysis patient	≥ 10 non-dialysis CKD, HD, PD	Freely available; limitation: Time-consuming, emphasize few symptoms over other
Geriatric Depression Scale Short Form[64]	15	10-15 minutes	Elderly on hemodialysis	≥ 5 non-dialysis CKD, HD, PD	Simple for elderly; limitation: Not valid in younger patients
Quick Inventory of Depressive Symptomatology[58]	16	5-7 minutes	Non dialysis CKD	≥ 10	DSM-based, brief; limitation: Limited CKD validation

CKD: Chronic kidney disease; HD: Hemodialysis; PD: Peritoneal dialysis; DSM: Diagnostic and Statistical Manual of Mental Disorders.

SCREENING ALGORITHM IN CKD

Validated screening tools should be used to identify CKD patients who are at risk of depression every 6 months. Those who have a negative screen, should be rescreened annually[60]. Patients who have positive screening results indicate elevated risk. However, structured clinical interviews based on DSM-5 criteria remains the gold standard for diagnosing major depressive disorder. In those who meet the cut off of screening tools, the presence of sadness or anhedonia should be confirmed with a confirmatory interview and also that the symptoms must be present for at least 2 weeks to qualify as major depressive disorder. It is important to rule out secondary causes of depression at the outset like thyroid dysfunction, anemia, cognitive impairment, substance abuse or drug side effects. Also, its important to rule out active suicidal ideation as this would require immediate attention by health care professional. If DSM- 5 criteria are met and secondary causes of depression are ruled out, then the patient should be diagnosed with depression and undergo treatment (Figure 3).

Figure 3 Proposed screening algorithm for depression in chronic kidney disease patient. CKD: Chronic kidney disease; DSM: Diagnostic and Statistical Manual of Mental Disorders.

MANAGEMENT

Depression in CKD is not just comorbidity but a modifiable risk factor that has a major effect on survival, disease progression, and the overall outcomes for patients. Because of this, it’s very important to treat depression in people with CKD. However, kidney disease makes managing depression more complex, so treatment should be tailored to the individual, and extra care should be taken to offer comprehensive care.

Kidney disease affects antidepressants in multiple ways, making the treatment more challenging (Table 4). Chronic inflammation, higher levels of IL-6 and TNF, and increased kynurenines have been found to lower serotonin levels and reduce the effectiveness of selective serotonin reuptake inhibitors (SSRIs)[65]. Additionally, it has been observed to change the structure of white matter through abnormal activity in glial cells[66]. In rodent models of CKD, increased blood-brain barrier permeability has been linked to aryl hydrocarbon receptor activation by indoxyl sulphate[46]. The pharmacokinetics of antidepressants is also altered in kidney disease. Reduced removal of the drug and its breakdown products in renal disease can extend the duration of the drug in the body, leading to more side effects, which can cause patients to stop taking the medication[67]. Changes in the volume of distribution and protein binding can affect drug levels and make the drug’s effect unpredictable. CKD patients usually take many medications, which raises concerns about drug interactions[68].

Table 4 Chronic kidney disease related factors contributing to resistance to antidepressants.

CKD related factors	Mechanism
Chronic inflammation, cytokines, uremic toxins[65]	↓ Serotonin/dopamine signaling IL-6/TNF-α blunt SSRI response
Vascular disease/endothelial dysfunction[66]	White matter hyperintensities
Blood-brain barrier impairment[46]	Uremic toxins disrupt BBB permeability, ↓CNS drug delivery
Pharmacokinetic alterations[67]	↓ Renal clearance (50%-70%), altered protein binding, drug accumulation
High pill burden/poor adherence[68]	Drug - drug interactions

CKD: Chronic kidney disease; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; SSRI: Selective serotonin reuptake inhibitors; BBB: Blood-brain barrier; CNS: Central nervous system.

PHARMACOTHERAPY

SSRIs are the most commonly used antidepressants in patients with CKD[69]. Among these, sertraline has been the most thoroughly studied in trials involving CKD patients. However, only a few RCTs have specifically examined antidepressants in this population (Table 5).

Table 5 Comparison of relevant studies on antidepressants in chronic kidney disease.

Studies	ASCEND	CAST	CRIC
Study population	CKD on MHD	Non dialysis CKD	Non dialysis CKD
Study design	RCT	RCT	Prospective observational cohort
Depression severity	MDD	MDD	Moderate depression
Scale used	QIDS-C	QIDS	BDI
Study groups	CBT vs sertraline	Sertraline vs placebo	Sertraline vs placebo
Follow up	12 weeks	12 weeks	BDI repeated over years
Results	Sertraline leads to modest improvement in symptoms	Sertraline not superior than placebo	Antidepressants did not reduce the risk associated with depression

CKD: Chronic kidney disease; MHD: Maintenance hemodialysis; RCT: Randomized controlled trial; MDD: Major depressive disorder; QIDS-C: Quick Inventory of Depressive Symptomatology Clinician Rated; QIDS: Quick Inventory of Depressive Symptomatology; BDI: Beck depression inventory; CBT: Cognitive behavioral therapy.

The ASCEND trial, [A trial of sertraline vs cognitive behavioral therapy (CBT) for ESRD patients with depression] was a significant multicenter, open-label RCT that compared sertraline with CBT in hemodialysis patients who had clinically significant depression. The study found that sertraline led to modest improvement in depressive symptoms, as measured by the Quick Inventory of Depressive Symptomatology Clinician Rated scale, after 12 weeks. However, there was no control group for comparison. Additionally, non-serious adverse events were more common in the sertraline group[59]. However, another RCT found no benefit of sertraline vs placebo in patients with major depressive disorder undergoing hemodialysis[70].

In the CRIC (chronic renal insufficiency cohort) study, which analyzed 4839 non-dialysis CKD patients, the use of antidepressants was found not to reduce the risks associated with depression and was actually linked to worse clinical outcomes. Among those with elevated depressive symptoms (Beck Depression Inventory ≥ 11), antidepressants did not lower the risks of cardiovascular events, hospitalization, or mortality[71].

The CAST (CKD antidepressant sertraline trial) study was the largest placebo-controlled SSRI trial in CKD patients. It included individuals with CKD stages 3-5 and compared sertraline with a placebo in those with moderate depression. The study found that sertraline did not lead to better improvement in depressive symptoms compared to a placebo[72].

There is limited strong data on the safety and effectiveness of various antidepressants in the CKD population. Sertraline reduces depressive symptoms in dialysis-dependent ESRD[70], but benefit in non-dialysis-dependent CKD is not clear[72]. Sertraline, fluoxetine, and paroxetine are SSRIs that have a lower risk of causing QT prolongation and, therefore, a lesser risk of sudden cardiac death compared to other SSRIs like citalopram and escitalopram[73]. Systematic review evidence indicates that sertraline may have advantages over some other antidepressants, including higher efficacy than fluoxetine and better acceptability and tolerability than amitriptyline, imipramine, paroxetine, and mirtazapine[74]. Mirtazapine is a tetracyclic antidepressant known as a noradrenergic and specific serotonergic antidepressant. Mirtazapine has lower risk of gastrointestinal bleeding but is associated with higher mortality[75]. Antidepressants should be started at a low dose and the dose should be increased gradually while being careful to monitor for any adverse effects. Sertraline is recommended to start at 25-50 mg daily for patients on hemodialysis. Dose should be escalated gradually with frequent monitoring of side effects.

NONPHARMACOLOGICAL TREATMENT

Non-pharmacological treatments can be effective alternatives or helpful additions to antidepressants for managing depression in CKD patients, primarily due to concerns about the safety and effectiveness of antidepressants. Depressive symptoms impair motivation and concentration, creating a cycle in which low mood reduces adherence. Socioeconomic constraints and limited access to multidisciplinary psychological care add to noncompliance to treatment. CKD patients face time and logistic constraints due to their dialysis sessions, also post treatment fatigue and travel time to treatment centers reduce available time and energy for additional interventions. Hence, tele-psychotherapy, home based exercise programs and intradialytic exercise are likely to be more practical than standard clinic-based programs.

Tele-psychotherapy allows counselling on mental health issues to patients through telephonic conversations, video calls, messaging, email etc. It therefore provides an accessible, convenient and effective way of providing mental health support irrespective of location and physical constraints and hence improve compliance of patients to treatment[76]. CBT is a structured and time-limited form of psychotherapy that focuses on the relationship between thoughts, feelings, and actions to reduce depression symptoms. In the ASCEND trial, although sertraline led to more improvement in depressive symptoms than CBT, CBT still resulted in improved depression symptoms from baseline with fewer side effects[70].

Another study showed that CBT can improve both depression and pain scales over a 12-week period in hemodialysis patients. However, the benefits were not long-lasting, suggesting the need for a longer duration of CBT for sustained results[77]. Exercise has also been found to significantly decrease depressive symptoms in patients with kidney disease, according to a recent meta-analysis[78]. Intradialytic exercise can help in utilizing the treatment time and can improve patient engagement, thereby serving as an important nonpharmacological means of treating depression.

Behavioral activation therapy is a structured, evidence-based psychotherapy that breaks depression’s vicious cycle by systematically increasing engagement in meaningful, rewarding activities, even when motivation is low. The CONCORD evaluated the efficacy of bupropion and behavioral activation therapy in CKD patients[79].

Depression management in elderly CKD patients (> 65 years) diverges markedly from non-elderly adults (18-64 years), driven by age-related pharmacokinetic changes, frailty, and coexisting comorbidities. SSRI are preferred in elderly patients also, but there should be dose adjustment with frequent monitoring of serum sodium levels. Also, nonpharmacologic interventions include cognitive behavior therapy and exercise yield better results vs pharmacotherapy alone[80].

LIMITATIONS AND FUTURE DIRECTIONS

The proposed screening approach represents a clinically practical framework derived from existing literature rather than a validated diagnostic algorithm. As a narrative review, the manuscript is limited by heterogeneity among included studies and the absence of quantitative evidence synthesis. There is a need for large multicenter prospective studies, validation of CKD-specific diagnostic and predictive models, mechanistic studies exploring causal pathways, and long-term interventional trials evaluating clinical and cost-effectiveness outcomes in CKD-associated depression. Future research in psych-nephrology should prioritize the identification and clinical validation of biomarkers such as IL-6, C-reactive protein, BDNF, microbiota-related uremic metabolites, metabolomic profiles, neuroimaging markers, and integrated multi-omics approaches to improve early detection and individualized management of depression in CKD. Well-designed RCTs are needed with standardized psychiatric evaluation, consistent depression classification, CKD stage-tailored interventions, dialysis-specific subgroup analyses, and extended follow-up to accurately determine treatment efficacy, safety, and long-term patient outcomes.

CONCLUSION

Depression is highly prevalent among patients with CKD, yet it remains frequently under-recognized. There appears to be a two-way connection between depression and CKD, where each condition can make the other worse. Depression can lead to worse health outcomes, higher risk of death, more heart problems, and more hospital stays. This review emphasizes the need for regular mental health checks using proven tools for CKD patients. Including support for mental health, early help from psychiatrists, and focused treatments might help reduce the impact of depression and improve overall health. More research is needed to explore how integrated, multidisciplinary models of care (combining nephrologists, psychiatrists, and psychologists) can better manage depression in people with CKD.