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.

Table 2 Pharmacological mechanisms of selected traditional Chinese medicine formulations in post-stroke depression

Prescription/preparation	Active ingredients	Mechanism of action	Level of evidence (oxford)1	GRADE quality of evidence2	Ref.
Shuyu capsules relieve liver	Adhyperforin, etc.	Reversing the disruptions of the p-ERK, p-CREB and BDNF	5	Not applicable (pre-clinical)	[103]
Chaihu Shugan powder	Seven Chinese herbs including bupleurum	Chaihu-Shugan-San inhibits neuroinflammation in the treatment of post-stroke depression through the JAK/STAT3-GSK3β/PTEN/Akt pathway	5	Not Applicable (pre-clinical)	[50,105]
Danzhi Xiaoyao San	Eight Chinese herbs including Paeoniae Radix Alba	Reducing neuroinflammation through PKCγ/p38/NF-κB signaling pathway	5	Not applicable (pre-clinical)	[106,107]
Jiao-tai-wan (JTW)	Jatrorrhizine	JTW could exert antidepressant effects by modulating neuroinflammation via inhibition of the STING pathway	5	Not applicable (pre-clinical)	[108]
Flavones	Apigenin, etc.	Flavones exert protective effects against depression in mice, primarily by stimulating neurotrophic factors and modulating inflammatory pathways	5	Not applicable (pre-clinical)	[109]
Dendrobium officinale	Dendrobine (DEN) and erianin (ERI)	DEN and ERI alleviated LPS-induced microglial activation and neuroinflammation by binding to PDE4B and preventing TLR4/NF-κB signaling pathway	5	Not applicable (pre-clinical)	[110]
Corydalisyanhusuopolysaccharides (CYP)	CYP	Corydalis yanhusuo polysaccharides regulates HPA-axis mediated microglia activation and inhibits astrocyte A1 transformation to improve depression-like behavior	5	Not applicable (pre-clinical)	[111]

¹Oxford Centre for Evidence-Based Medicine 2011 levels of evidence: Level 5 refers to mechanism-based reasoning or expert opinion, which encompasses findings from experimental/mechanistic studies that form the basis for future clinical research.

²GRADE assessment: The evidence summarized in this table is derived from preclinical studies elucidating potential mechanisms of action. As such, it is classified as mechanistic exploration and a formal GRADE rating (high, moderate, low, very low) is not applicable (N/A). This evidence is crucial for understanding biological plausibility but requires validation in human clinical trials before any conclusions regarding clinical efficacy can be drawn.

HPA: Hypothalamic-pituitary-adrenal; LPS: Lipopolysaccharide.

Table 3 Evidence from recent randomized controlled trials for post-stroke depression interventions

Intervention approach	Ref.	Study design	Year	Sample size	Evidence summary and critical appraisal	Key limitations/uncertainties	Evidence maturity	Level of evidence (oxford)1	GRADE quality of evidence2
Acupuncture	Kalaoğlu et al[8]	RCT	2024	54 patients	The study was negative on its primary outcomes. While secondary outcomes showed signal of potential benefit, the results are inconclusive	Very small sample size; high risk of performance bias; primary outcome was not met	Pilot	1	Very low
SSRIs (escitalopram vs sertraline)	Yan and Hu[81]	RCT	2024	60 patients	Suggests comparable efficacy between escitalopram and sertraline for anxiety and functional outcomes in PSD. However, the difference in HAMD scores was not consistent across timepoints	Small sample size; short follow-up period; some outcome measures showed no significant difference	Early phase	1	Low
SSRIs (escitalopram and sertraline)	Naseralallah et al[83]	RCT	2024	401 patients	Focuses on safety, finding both drugs are associated with a comparable and increased risk of mild hyponatremia	Study was not primarily designed to assess efficacy for depression; highlights an important adverse effect	Early phase (for safety profile)	1	Moderate (for safety outcome)
Electroacupuncture vs escitalopram	Ma et al[119]	RCT	2024	150 participants	Suggests electroacupuncture may be non-inferior or superior to escitalopram at 10 weeks for mild-to-moderate PSD, with modulatory effects on inflammation	Unblinded design (high risk of performance bias); specific mechanisms remain exploratory; requires larger-scale replication	Early phase	1	Low
Pharmacotherapy (Edaravone Dexborneol)	Xu et al[120]	RCT	2024	93 patients	Suggests potential for preventing early PSD and modulating inflammatory cytokines	Single, relatively small RCT; mechanism is exploratory; requires confirmation in larger trials focused on depression treatment	Pilot	1	Low
SSRI (fluoxetine)	Tay et al[121]	RCT	2023	1500 participants	A large RCT found fluoxetine reduced depressive scores but increased apathy scores, demonstrating a differential effect on depressive vs apathetic symptoms	Complex effects (beneficial for depression but potentially detrimental for apathy); risk-benefit profile needs careful consideration	Established but with trade-offs	1	Moderate
SSRI (sertraline)	Stuckart et al[122]	RCT	2021	114 patients	Suggests a potential benefit for preventing incident depression and functional recovery, but the groups were not balanced at baseline	Non-randomized comparison (major limitation); baseline severity differed between groups, confounding results	Pilot	1	Very low
SSRIs vs nootropics	Arcadi et al[123]	RCT	2021	44 patients	SSRIs showed a large effect size for depression/anxiety compared to nootropics in a very small sample	Very small sample size; preliminary nature of findings	Pilot	1	Very low
Agomelatine vs SSRIs	Yao et al[86]	RCT	2021	165 patients	Agomelatine, sertraline, and escitalopram were all more effective than control, with no significant differences between them	Lacks a placebo control; unable to establish absolute efficacy vs no treatment	Early phase	1	Moderate
Bright light therapy + escitalopram	Xiao et al[124]	RCT	2020	106 patients	Combination therapy improved sleep and depression scores more than escitalopram monotherapy	Single study; unblinded design for light therapy; focuses on PSD with insomnia subtype	Pilot	1	Low
Vitamin D (risk factor)	Tan et al[125]	Meta-analysis	2025	3537 patients (7 studies)	Observational data links low vitamin D levels in acute stroke phase to higher risk of developing PSD	Evidence is associative, not interventional; does not prove causation or treatment efficacy	Early phase (for association)	1	Low (for association)
Agomelatine vs SSRIs/SNRIs	Chen et al[126]	Meta-analysis	2024	857 patients (9 studies)	Agomelatine was comparable to SSRIs/SNRIs for depression reduction but showed better functional improvement (Barthel Index) and safety profile	Limited to short-term (6-12 weeks) studies; majority of included RCTs may be of moderate quality	Early phase	1	Moderate
SSRI (Fluoxetine)	Wu et al[127]	Meta-analysis	2023	6584 patients (14 RCTs)	Meta-analysis indicates fluoxetine reduces depression/anxiety risk but did not improve functional outcomes (e.g., mRS, BI) compared to placebo	Lack of benefit on key functional scales; mixed evidence profile	Mixed quality	1	Moderate
SSRIs (Prevention)	Zhou et al[128]	Meta-analysis	2021	5370 patients (10 RCTs)	Early SSRI use reduces the risk of PSD occurrence, but did not improve functional independence	No functional benefit despite preventing depression; significant heterogeneity in some analyses	Mixed quality	1	Moderate
SSRIs (prevention)	Richter et al[129]	Meta-analysis	2021	6560 patients (6 RCTs)	Confirms early SSRIs reduce PSD incidence, but at the cost of increased risk of bone fractures and nausea	Clear trade-off between benefit and harms (fractures, nausea)	Established but with trade-offs	1	High
SSRI (paroxetine)	Li et al[130]	Meta-analysis	2020	212 patients (4 studies)	Finds no significant advantage of paroxetine over control treatments, indicating limited evidence for its use	Very limited number of small studies; fails to establish efficacy	Mixed quality (leaning towards ineffective)	1	Low
Animal studies	Dong et al[131]	Animal experiment	2025	Rats model	Suggests a potential mechanism for vortioxetine in improving post-stroke recovery in rats	Pre-clinical evidence; direct applicability to human PSD patients is unknown	Pilot (pre-clinical)	5	N/A (preclinical)
Animal studies	Zhang et al[132]	Animal experiment	2025	Rats model	Proposes a novel mechanism for cilostazol in preventing PSD in mouse models	Pre-clinical evidence; requires validation in human trials	Pilot (pre-clinical)	5	N/A (preclinical)
Animal studies	Wei et al[133]	Animal experiment	2022	Rats model	Explores the mechanism of fluoxetine on neuronal differentiation in rat models	Pre-clinical evidence; mechanistic study	Pilot (pre-clinical)	5	N/A (preclinical)
Animal studies	Shyu et al[134]	Animal experiment	2021	Rats model	Investigates antidepressants for post-stroke pain and comorbid depression in rats	Pre-clinical evidence; focuses on a specific pain comorbidity	Pilot (pre-clinical)	5	N/A (preclinical)

¹Evidence maturity: Labels such as ‘pilot’ or 'early phase' describe the developmental stage of the evidence, indicating the need for further validation or larger studies. Level of evidence (Oxford Centre for Evidence-Based Medicine): This hierarchy is based primarily on study design, where level 1 represents the highest quality (e.g., randomized controlled trials, meta-analyses).

²GRADE quality of evidence: This dynamic assessment starts with the study design and then adjusts the quality rating (high, moderate, low, very low) based on limitations, imprecision, inconsistency, and other factors, providing a more nuanced estimate of confidence in the evidence.

PSD: Post-stroke depression; SSRI: Selective serotonin reuptake inhibitor; N/A: Not applicable; RCT: Randomized controlled trial; HAMD: Hamilton Depression Rating Scale.