Comprehensive psychological and neurological rehabilitation for post-stroke depression: A retrospective comparative study with biomarker exploration

Table 1 Baseline demographic and clinical characteristics of study participants, mean ± SD/n (%)

Characteristic	CRG (n = 96)	CG (n = 82)	P value
Age (years)	61.5 ± 12.8	63.2 ± 11.5	0.352
Female	52 (54.2)	43 (52.4)	0.809
BMI (kg/m2)	24.8 ± 3.6	25.2 ± 3.4	0.452
Education (years)	10.2 ± 3.8	9.8 ± 4.0	0.490
Married	80 (83.3)	68 (82.9)	0.946
Living alone	14 (14.6)	13 (15.9)	0.814
Employed	38 (39.6)	32 (39.0)	0.939
Hypertension	60 (62.5)	50 (61.0)	0.835
Type 2 diabetes	28 (29.2)	22 (26.8)	0.714
Hyperlipidemia	30 (31.3)	25 (30.5)	0.906
Atrial fibrillation	12 (12.5)	10 (12.2)	0.951
Prior stroke/TIA	18 (18.8)	14 (17.1)	0.775
Tobacco use	28 (29.2)	22 (26.8)	0.714
Baseline HAMD-17	18.2 ± 5.0	18.6 ± 5.3	0.615
Baseline SDS	62.5 ± 8.8	63.2 ± 9.0	0.603
Baseline NIHSS	8.2 ± 3.2	8.6 ± 3.5	0.445
Baseline MBI	45.2 ± 15.5	43.8 ± 14.8	0.534
Baseline MoCA	21.5 ± 4.2	21.2 ± 4.5	0.650
Family involvement (FSQ)	31.8 ± 7.2	29.5 ± 8.0	0.068
Antidepressant use	28 (29.2)1	24 (29.3)2	0.987

¹Comprehensive rehabilitation group: Venlafaxine XR 75-150 mg/day, initiated per protocol for Hamilton Depression Rating Scale-17 ≥ 20 with insufficient response at week 4.

²Control group: Antidepressants (principally sertraline 50-100 mg/day or venlafaxine XR 75-150 mg/day) prescribed at physician discretion. Between-group difference in antidepressant use rate was not statistically significant (P = 0.987).

CRG: Comprehensive rehabilitation group; CG: Control group; BMI: Body mass index; TIA: Transient ischemic attack; HAMD-17: Hamilton Depression Rating Scale-17; SDS: Zung Self-Rating Depression Scale; NIHSS: National Institutes of Health Stroke Scale; MBI: Modified Barthel Index; MoCA: Montreal Cognitive Assessment; FSQ: Family support questionnaire.

Table 2 Stroke-related clinical features and neuroimaging parameters, mean ± SD/n (%)

Parameter	CRG (n = 96)	CG (n = 82)	P value
Admission NIHSS	8.2 ± 3.2	8.6 ± 3.5	0.445
Frontal lobe involvement	30 (31.3)	24 (29.3)	0.774
Basal ganglia-internal capsule	28 (29.2)	24 (29.3)	0.988
Limbic structures	20 (20.8)	16 (19.5)	0.832
Prefrontal-striato-thalamic circuit	26 (27.1)	22 (26.8)	0.967
Dominant hemisphere	58 (60.4)	50 (61.0)	0.941
Infarct volume (cm3)	10.2 ± 4.5	10.8 ± 4.8	0.395
Multiple infarcts	38 (39.6)	32 (39.0)	0.939
Fazekas total score	2.8 ± 1.2	3.0 ± 1.3	0.292
Periventricular WMH (Fazekas)	1.5 ± 0.6	1.6 ± 0.7	0.328
Deep WMH (Fazekas)	1.3 ± 0.6	1.4 ± 0.6	0.292
GCA frontal score	1.4 ± 0.6	1.5 ± 0.6	0.295
MTA score	1.3 ± 0.6	1.4 ± 0.7	0.348
Microbleed count	1.8 ± 1.4	1.9 ± 1.5	0.678
TOAST classification
Large artery atherosclerosis	32 (33.3)	28 (34.1)	0.895
Cardioembolism	18 (18.8)	14 (17.1)
Small vessel occlusion	34 (35.4)	30 (36.6)
Cryptogenic/other	12 (12.5)	10 (12.2)
ASITN/SIR collateral grade
0-1 (poor)	28 (29.2)	24 (29.3)	0.812
2-3 (moderate)	42 (43.8)	36 (43.9)
4 (good)	26 (27.1)	22 (26.8)

CRG: Comprehensive rehabilitation group; CG: Control group; NIHSS: National Institutes of Health Stroke Scale; WMH: White matter hyperintensity; GCA: Global cortical atrophy scale; MTA: Medial temporal atrophy; TOAST: Trial of Org 10172 in Acute Stroke Treatment; ASITN/SIR: American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology.

Table 3 Primary and secondary efficacy outcomes at 6 and 12 weeks, mean ± SD/n (%)

Outcome measure	CRG (n = 96)	CG (n = 82)	P value	Effect size (Cohen’s d)
Primary outcomes
HAMD-17 at 6 weeks	10.5 ± 3.8	15.8 ± 4.2	< 0.001	1.34
HAMD-17 at 12 weeks	7.2 ± 3.4	13.8 ± 4.6	< 0.001	1.67
ΔHAMD-17 (baseline to 12 weeks)	-11.0 ± 4.2	-4.8 ± 3.5	< 0.001	1.62
Remission rate (HAMD-17 < 7)	65 (67.7)	24 (29.3)	< 0.001
SDS score at 12 weeks	42.5 ± 7.8	55.2 ± 9.5	< 0.001	1.51
Secondary outcomes
FMA at 12 weeks	78.5 ± 14.2	58.3 ± 16.8	< 0.001	1.31
MBI at 12 weeks	76.8 ± 13.5	58.6 ± 15.2	< 0.001	1.27
NIHSS at 12 weeks	2.4 ± 1.8	5.4 ± 2.2	< 0.001	1.50
MoCA at 12 weeks	24.8 ± 3.5	21.5 ± 4.2	< 0.001	0.85
SS-QOL at 12 weeks	168.5 ± 28.5	142.3 ± 30.2	< 0.001	0.89
FSS at 12 weeks	28.5 ± 8.2	38.2 ± 9.5	< 0.001	1.09

CRG: Comprehensive rehabilitation group; CG: Control group; HAMD-17: Hamilton Depression Rating Scale-17; SDS: Zung Self-Rating Depression Scale; FMA: Fugl-Meyer Assessment; MBI: Modified Barthel Index; NIHSS: National Institutes of Health Stroke Scale; MoCA: Montreal Cognitive Assessment; SS-QOL: Stroke-Specific Quality of Life; FSS: Fatigue Severity Scale.

Table 4 Serum biomarker profiles at baseline and 12-week follow-up, mean ± SD/n (%)

Biomarker	CRG baseline	CRG 12 weeks	CG baseline	CG 12 weeks	Inter-group P (12 weeks)
Neuropeptides and neurotrophins
NPY (pg/mL)	76.2 ± 15.8	98.6 ± 18.4a	74.8 ± 16.5	80.5 ± 17.2	< 0.001
BDNF (ng/mL)	13.8 ± 4.6	22.5 ± 5.2a	13.5 ± 4.4	15.2 ± 4.8	< 0.001
NGF (pg/mL)	42.5 ± 10.2	58.8 ± 12.6a	41.8 ± 10.8	46.2 ± 11.5	< 0.001
VEGF (pg/mL)	185.2 ± 42.5	248.6 ± 55.8a	182.8 ± 40.8	198.5 ± 45.2	< 0.001
Inflammatory cytokines
IL-1β (pg/mL)	10.5 ± 2.6	5.8 ± 2.2a	10.8 ± 2.8	8.5 ± 2.5a	< 0.001
IL-6 (pg/mL)	9.8 ± 2.5	5.2 ± 1.8a	10.2 ± 2.8	8.2 ± 2.4a	< 0.001
IL-10 (pg/mL)	8.2 ± 2.8	12.8 ± 3.5a	8.5 ± 3.0	9.5 ± 3.2	< 0.001
TNF-α (pg/mL)	16.8 ± 3.8	11.2 ± 3.0a	17.2 ± 4.0	14.8 ± 3.5a	< 0.001
Neuroendocrine markers
Morning cortisol (nmol/L)	385.2 ± 88.5	338.5 ± 82.5a	382.8 ± 90.2	378.2 ± 90.5	< 0.001
ACTH (pg/mL)	40.2 ± 8.8	33.8 ± 7.5a	41.5 ± 9.2	39.5 ± 8.8	< 0.001
Oxidative stress and neuronal injury
SOD (U/mL)	82.5 ± 18.5	108.2 ± 22.8a	80.8 ± 17.8	88.5 ± 20.2	< 0.001
MDA (nmol/mL)	8.5 ± 2.2	5.2 ± 1.8a	8.8 ± 2.5	7.2 ± 2.2a	< 0.001
NSE (μg/L)	16.8 ± 4.5	10.2 ± 3.2a	17.2 ± 4.8	13.8 ± 3.8a	< 0.001
S100B (μg/L)	0.58 ± 0.18	0.32 ± 0.12a	0.60 ± 0.20	0.48 ± 0.16a	< 0.001

^aP < 0.05 vs respective baseline (paired t-test or Wilcoxon signed-rank).

CRG: Comprehensive rehabilitation group; CG: Control group; NPY: Neuropeptide Y; BDNF: Brain-derived neurotrophic factor; IL: Interleukin; NGF: Nerve growth factor; VEGF: Vascular endothelial growth factor; TNF: Tumor necrosis factor; ACTH: Adrenocorticotropic hormone; SOD: Superoxide dismutase; MDA: Malondialdehyde; NSE: Neuron-specific enolase.

Table 5 Multivariable logistic regression analysis of independent predictors of treatment response

Variable	β	SE	Wald χ2	OR (95%CI)	P value
Early psychological intervention initiation (≤ 2 weeks)	1.416	0.302	21.98	4.12 (2.28-7.44)	< 0.001
Baseline serum NPY ≥ 82.5 pg/mL	1.217	0.281	18.75	3.38 (1.95-5.86)	< 0.001
Mild-to-moderate depression (HAMD-17 < 17)	1.079	0.286	14.24	2.94 (1.68-5.14)	< 0.001
High family involvement (FSQ ≥ 28)	0.975	0.264	13.64	2.65 (1.58-4.44)	< 0.001
Intact cognition (MMSE ≥ 24)	0.884	0.261	11.45	2.42 (1.45-4.04)	0.001
Non-dominant hemisphere lesion	0.732	0.273	7.19	2.08 (1.22-3.55)	0.008
Baseline IL-1β < 8.2 pg/mL	0.621	0.269	5.33	1.86 (1.10-3.15)	0.021
Non-significant variables (P ≥ 0.10)
Homocysteine < 15 μmol/L	0.468	0.278	2.83	1.60 (0.93-2.75)	0.093
Baseline NSE < 15 μg/L	0.435	0.265	2.69	1.55 (0.92-2.60)	0.101
Infarct volume < 10 cm3	0.388	0.258	2.26	1.47 (0.89-2.44)	0.133
No diabetes mellitus	0.342	0.260	1.73	1.41 (0.85-2.34)	0.189
Good collateral circulation	0.318	0.272	1.37	1.37 (0.81-2.33)	0.242

Hosmer-Lemeshow goodness-of-fit: χ² = 6.45, P = 0.597. OR: Odds ratio; CI: Confidence interval; NPY: Neuropeptide Y; HAMD-17: Hamilton Depression Rating Scale-17; FSQ: Family support questionnaire; MMSE: Mini-Mental State Examination; IL: Interleukin; NSE: Neuron-specific enolase.

Table 6 Depression severity subgroup analysis: Rehabilitation outcomes and biomarker trajectories

Characteristic	Mild (n = 62) HAMD 8-16	Moderate (n = 72) HAMD 17-23	Severe (n = 44) HAMD ≥ 24	P trend
Baseline HAMD-17	11.5 ± 2.2	19.8 ± 1.8	26.5 ± 3.0	< 0.001
Admission NIHSS	5.8 ± 2.0	8.8 ± 2.8	11.5 ± 3.2	< 0.001
Dominant hemisphere, %	50.0	62.5	72.7	0.018
Frontal lobe involvement, %	22.6	33.3	47.7	0.012
CRG remission rate (%)	82.4	62.5	38.5	< 0.001
CG remission rate (%)	40.5	21.7	10.5	< 0.001
12-week MBI	80.5 ± 11.8	72.5 ± 13.0	62.8 ± 14.5	< 0.001
Post-intervention biomarker changes (CRG only)
ΔNPY (pg/mL)	26.8 ± 8.5	21.2 ± 7.8	14.5 ± 6.5	< 0.001
ΔBDNF (ng/mL)	12.5 ± 3.8	8.8 ± 3.2	5.5 ± 2.8	< 0.001
ΔIL-1β (pg/mL)	-5.8 ± 2.0	-4.2 ± 1.8	-2.5 ± 1.5	< 0.001
ΔTNF-α (pg/mL)	-7.2 ± 2.5	-5.5 ± 2.2	-3.2 ± 1.8	< 0.001
Baseline NPY (pg/mL)	82.5 ± 14.5	72.8 ± 15.2	62.5 ± 13.8	< 0.001
Fazekas total score	2.2 ± 1.0	3.0 ± 1.2	4.0 ± 1.3	< 0.001
Family involvement (FSQ)	35.8 ± 6.8	30.5 ± 7.5	26.8 ± 7.0	< 0.001

P trend calculated by Jonckheere-Terpstra test for ordered alternatives. Δ denotes post-intervention minus baseline change in comprehensive rehabilitation group. HAMD: Hamilton Depression Rating Scale; NIHSS: National Institutes of Health Stroke Scale; CRG: Comprehensive rehabilitation group; CG: Control group; MBI: Modified Barthel Index; NPY: Neuropeptide Y; BDNF: Brain-derived neurotrophic factor; IL: Interleukin; TNF: Tumor necrosis factor; FSQ: Family support questionnaire.