Post-stroke depression update 2025: Mechanisms, prediction, and management

Table 1 Emerging biomarkers and risk factors for prediction and stratification of post-stroke depression

Category	Risk factor	Explanation	Data source	Reported performance (AUC)	Level of evidence (oxford)1	GRADE quality of evidence2	Ref.
Inflammatory and immunological biomarkers	Higher monocyte-to-HDL cholesterol ratio (MHR)	A pro-inflammatory/pro-atherosclerotic marker reflecting monocyte activation and HDL dysfunction; elevated MHR links systemic inflammation to PSD	Single-center	0.660 (internal validation)	3b	Very low	[35]
	Early Th1-Th2 cytokine imbalance	An early shift in Th1/Th2 ratio (e.g., increased pro-inflammatory Th1 or decreased anti-inflammatory Th2) disrupts neuroinflammation and neurotransmitter regulation-core pathophysiological mechanisms of PSD	Single-center	0.741 (internal validation)	3b	Very low	[36]
	Higher plasma putrescine and spermidine levels	These polyamines modulate oxidative stress and neuroinflammation; elevated levels indicate imbalanced cellular metabolism, contributing to mood dysregulation post-stroke	CATIS trial	Correlation reported (needs external validation)	4	Low	[37]
	Higher serum Dickkopf-1 (Dkk-1) levels	Dkk-1 inhibits the Wnt/β-catenin pathway (critical for neurogenesis/synaptic plasticity); increased Dkk-1 reduces neural repair, raising PSD risk	CATIS trial	Correlation reported (needs external validation)	4	Low	[38]
	Elevated serum growth differentiation factor 15	A stress-responsive cytokine linked to oxidative stress and mitochondrial dysfunction; higher levels predict PSD by exacerbating neuronal damage	CATIS Trial	Correlation reported (needs external validation)	4	Low	[39]
Nutritional and metabolic biomarkers	Homocysteine level	Elevated homocysteine is neurotoxic, damages blood vessels, and disrupts methylation; high levels correlate with PSD via neuronal injury and vascular dysfunction	Single-center	0.881 (internal validation)	3b	Low	[10]
	Insulin resistance	Alters glucose metabolism and promotes systemic inflammation, disrupting brain insulin signaling and contributing to post-stroke mood disorders	Single-center	0.760 (internal validation)	3b	Very low	[30]
	Higher oxidative balance score (OBS)	OBS reflects oxidative-antioxidant balance; higher scores may indicate unresolved oxidative damage to neurons, facilitating PSD	NHANES (cross-sectional)	Association reported (needs external validation)	4	Low	[34]
	Vitamin B intake	Deficiency in B vitamins (B6, B9, B12) impairs neurotransmitter synthesis (serotonin/dopamine) and methylation, increasing PSD susceptibility	NHANES (cross-sectional)	Association reported (needs external validation)	4	Low	[40]
	Lower serum BDNF levels at baseline	BDNF supports neuroplasticity; low baseline levels impair emotional regulation circuits, raising PSD risk	CATIS trial	Correlation reported (needs external validation)	4	Low	[41]
	Helicobacter pylori infection	Chronic infection triggers systemic inflammation (IL-6, TNF-α) and gut-brain axis dysregulation-both implicated in PSD pathogenesis	Single-center	Association reported (needs external validation)	4	Very low	[42]
	MMSE, NIHSS and CSVD burden score	Cerebral small vessel disease (lacunes, white matter disease) causes cumulative brain damage, cognitive decline, and mood dysregulation-associating with PSD	Single-center	0.926 (internal validation)	3b	Low	[43]
	Cardiometabolic index (CMI)	A composite of waist circumference, BMI, blood pressure, and lipids; higher CMI indicates greater cardiometabolic risk, correlating with PSD via inflammation	Single-center	Association reported (needs external validation)	4	Very low	[32]
	Non-HDL-C/HDL-C ratio (NHHR)	Atherogenic lipid profile marker; elevated NHHR associates with vascular damage and systemic inflammation, increasing PSD risk	NHANES (cross-sectional)	Association reported (needs external validation)	4	Low	[44]
	Atherogenic index of plasma (AIP)	Measures plasma atherogenicity [log (TG/HDL-C)]; higher AIP indicates increased cardiovascular risk and links to PSD via shared metabolic/inflammatory pathways	NHANES (cross-sectional)	Association reported (Needs external validation)	4	Low	[45]
	Cardiac history	Pre-stroke cardiac conditions (e.g., MI, heart failure) cause hemodynamic instability, reduced cerebral perfusion, and inflammation-predisposing to PSD	CHARLS Cohort	Association reported (needs external validation)	4	Low	[46]
Sleep and functional impairments	Sleep disorders and short sleep duration	Sleep disruption alters circadian rhythms, reduces serotonin synthesis, and increases amygdala reactivity-strong predictors of PSD	NHANES (cross-sectional)	Association reported (needs external validation)	4	Low	[33]
	Poststroke dysphagia	Difficulty swallowing leads to poor nutrition, dehydration, and social isolation-modifiable factors exacerbating post-stroke mood symptoms	Single-center	Association reported (needs external validation)	4	Low	[47]

¹Level of evidence is based on the oxford centre for evidence-based medicine levels, where 3b indicates systematic review of case-control studies or individual case-control study with non-consecutive patients, and 4 indicates case-series or cross-sectional studies. This provides a quick reference for the robustness of the evidence.

²The GRADE quality of evidence assessment further refines this by evaluating limitations, imprecision, and indirectness. The predominantly 'very low' grading underscores that most current evidence is preliminary and requires confirmation from more robust studies.

Validation status: “Internal validation” indicates model performance was assessed on the same dataset it was trained on. “Needs external validation” indicates that the factor has been identified as a significant predictor, but its predictive power within a formal model has not been tested on an independent cohort, or the study design was cross-sectional/observational without formal predictive modeling. This table highlights a key challenge in the field: While many factors show promising predictive value, the evidence for most is derived from single-center studies or requires further validation in multi-center cohorts, as emphasized by the TRIPOD/PROBAST guidelines. AUC: Area under the curve; CATIS: China Antihypertensive Trial in Acute Ischemic Stroke; CHARLS: China Health and Retirement Longitudinal Study; NHANES: National Health and Nutrition Examination Survey; BMI: Body mass index; PSD: Post-stroke depression; HDL: High-density lipoprotein; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; MMSE: Mini-Mental State Examination; NIHSS: National Institutes of Health Stroke Scale; CSVD: Cerebral small vessel disease; TG: Triglyceride; HDL-C: High-density lipoprotein cholesterol; MI: Myocardial infarction.