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

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.

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.

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.

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.

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.