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

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.