Serum proprotein convertase subtilisin/kexin type 9 levels correlate with depression severity in post-stroke patients

Abstract

BACKGROUND

Post-stroke depression (PSD) is a common neuropsychiatric complication affecting an estimated 30%-40% of stroke survivors and adversely affecting rehabilitation and quality of life. Emerging evidence suggests that proprotein convertase subtilisin/kexin type 9 (PCSK9) may be involved in neuroinflammation and mood regulation. Evolocumab, a PCSK9 inhibitor, may have effects beyond lipid lowering when added to statin therapy; however, its association with depressive symptoms in patients with PSD remains unclear.

AIM

To investigate the association between serum PCSK9 levels and depression severity in patients with PSD receiving evolocumab plus statin therapy and to assess the association of this combination with changes in depressive symptoms.

METHODS

This retrospective study included 128 patients with PSD: 64 received evolocumab (140 mg every 2 weeks) plus atorvastatin (20 mg daily), and 64 received atorvastatin alone (20 mg daily). The primary outcomes were serum PCSK9 concentrations and 17-item Hamilton Depression Rating Scale (HAMD-17) scores at baseline and at weeks 4, 8, and 12. Secondary outcomes included Hamilton Anxiety Scale (HAMA) scores, lipid profiles, inflammatory markers [interleukin-6 (IL-6), tumor necrosis factor-α, and high-sensitivity C-reactive protein], and cognitive function assessed using the Montreal Cognitive Assessment (MoCA). Correlation analyses examined associations between PCSK9 concentrations and clinical outcomes.

RESULTS

At week 12, serum PCSK9 levels decreased from 385.6 ± 78.4 ng/mL to 156.3 ± 42.1 ng/mL in the combination-therapy group, compared with 378.2 ± 76.9 ng/mL to 298.5 ± 68.7 ng/mL in the atorvastatin-only group (P < 0.001). HAMD-17 scores decreased from 22.8 ± 4.5 to 10.2 ± 3.1 and from 22.3 ± 4.2 to 14.6 ± 3.8, respectively (P < 0.001 for the between-group comparison at week 12). Serum PCSK9 levels were positively correlated with HAMD-17 scores at week 12 (r = 0.652, P < 0.001). Compared with the atorvastatin-only group, the combination-therapy group had lower week-12 HAMA scores (8.5 ± 2.3 vs 12.1 ± 3.2, P < 0.001) and IL-6 concentrations (3.2 ± 0.8 pg/mL vs 5.1 ± 1.2 pg/mL, P < 0.001), higher MoCA scores (25.8 ± 2.1 vs 23.4 ± 2.6, P = 0.001), and a higher depression treatment response rate (73.4% vs 48.4%, P = 0.003).

CONCLUSION

In this retrospective, evolocumab added to atorvastatin was associated with greater reductions in serum PCSK9 levels and depressive symptom scores than atorvastatin alone. The correlation between PCSK9 concentrations and depression severity suggests that PCSK9 warrants further investigation as a potential biomarker in PSD. Prospective studies are needed to establish whether PCSK9 inhibition improves depressive symptoms.

Key Words: Post-stroke depression; Evolocumab; Proprotein convertase subtilisin/kexin type 9; Statin; Depression scores; Biomarkers; Neuroinflammation

Core Tip: In this retrospective study of patients with post-stroke depression, the addition of evolocumab to atorvastatin was associated with greater reductions in serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations and depression scores than atorvastatin alone. Serum PCSK9 concentrations correlated positively with depression severity at week 12 (r = 0.652). The combination-therapy group had a higher treatment response rate (73.4% vs 48.4%, P = 0.003), lower inflammatory marker concentrations, and higher cognitive assessment scores. These findings support further evaluation of PCSK9 as a candidate biomarker and potential treatment target; causal and clinical efficacy claims require prospective confirmation.

INTRODUCTION

Ischemic stroke is a major cause of long-term disability worldwide. Although advances in acute stroke treatment and rehabilitation have improved survival, post-stroke neuropsychiatric complications remain underrecognized and undertreated[1-3]. Post-stroke depression (PSD), one of the most common complications, affects approximately 30%-40% of stroke survivors and is associated with functional impairment, reduced quality of life, and poorer long-term outcomes compared with those in survivors without depression[4-6].

The pathophysiology of PSD involves interactions among neuroanatomical injury, neurochemical disturbances, neuroinflammation, and psychosocial factors[7-10]. Current treatment relies primarily on antidepressants and psychotherapy, but metabolic and inflammatory pathways are being investigated as additional therapeutic targets. Statins are widely used to prevent vascular complications after stroke. In addition to their lipid-lowering effects, they have pleiotropic properties, including anti-inflammatory and potentially neuroprotective effects, that may be relevant to mood disorders[11,12].

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of cholesterol homeostasis and has also been implicated in neuroinflammation and neuronal function[13,14]. PCSK9 is expressed in brain regions involved in mood regulation, including the prefrontal cortex and limbic system. Higher PCSK9 concentrations have been associated with systemic inflammation and oxidative stress, both of which have been implicated in the pathogenesis of depression[15,16]. PCSK9 may also influence neuroplasticity and synaptic function independently of its role in lipid metabolism.

Evolocumab is a fully human monoclonal antibody targeting PCSK9. When added to statins, it substantially lowers low-density lipoprotein (LDL) cholesterol and reduces cardiovascular events[17,18]. Emerging evidence suggests that PCSK9 inhibition may also affect neuroinflammation and cerebrovascular function, although its effects on mood remain uncertain. Preclinical studies have reported reduced inflammatory cytokine production, improved endothelial function, and enhanced neuronal survival following PCSK9 inhibition[19-21].

Despite these mechanistic findings, clinical evidence regarding the effects of PCSK9 inhibitors on depressive symptoms after stroke remains limited. Few studies have directly examined the association between circulating PCSK9 concentrations and depression severity in patients with PSD. The potential association between adding evolocumab to statin therapy and depressive outcomes in this population has therefore not been established[22,23].

We conducted this retrospective study to examine the association between serum PCSK9 concentrations and depression severity in patients with PSD who received evolocumab plus atorvastatin or atorvastatin alone. We hypothesized that combination therapy would be associated with greater reductions in PCSK9 concentrations and depressive symptom scores than statin monotherapy and that changes in PCSK9 concentrations would correlate with changes in depression scores. These findings may help identify candidate biomarkers and inform the design of prospective studies of adjunctive PSD treatment.

MATERIALS AND METHODS

Study design and patient selection

This retrospective study reviewed records from January 2023 through December 2025 at Cangzhou Central Hospital. The institutional ethics committee approved the study, which was conducted in accordance with the Declaration of Helsinki. Patients with ischemic stroke and PSD were identified through medical record review. The inclusion criteria were: (1) Age 18-80 years; (2) Ischemic stroke confirmed by computed tomography or magnetic resonance imaging within 7 days of symptom onset, without permanent disability at screening; (3) Newly developed depression at week 2, defined as a 17-item Hamilton Depression Rating Scale (HAMD-17) score ≥ 15; (4) An indication for statin treatment according to clinical guidelines; (5) LDL cholesterol ≥ 2.6 mmol/L despite standard-intensity statin treatment, or LDL cholesterol ≥ 1.8 mmol/L with high cardiovascular risk[24]; and (6) Ability to complete neuropsychological assessments. The ethics committee waived the requirement for written informed consent.

The exclusion criteria were: (1) A history of a major psychiatric disorder requiring hospitalization before the stroke; (2) Severe aphasia or cognitive impairment (Mini-Mental State Examination score < 20) that precluded reliable assessment; (3) Current use of antidepressants or mood stabilizers; and (4) Contraindications to PCSK9 inhibitors or statins.

Treatment protocol

Eligible patients were classified retrospectively according to treatment received, which was determined by presentation timing and the treating physician’s clinical decision; treatment was not randomized. The combination-therapy group received evolocumab 140 mg subcutaneously every 2 weeks plus atorvastatin 20 mg orally once daily, whereas the control group received atorvastatin 20 mg orally once daily. All patients received routine stroke management, including antiplatelet therapy, blood pressure control, and rehabilitation. No psychotropic medications were initiated during the 12-week observation period. Baseline characteristics, including age, sex, stroke severity, and depression scores, were similar between groups, although residual confounding remains possible. Concomitant antiplatelet and antihypertensive treatments were documented at baseline. Aspirin use was 87.5% and 85.9%, respectively (P > 0.05), and antihypertensive medication use was reported to be similar (all P > 0.05). Atorvastatin 20 mg was selected as the common background treatment because it represents a moderate-intensity regimen recommended in Chinese guidelines for ischemic stroke management. As statin agents and doses may differ in their pleiotropic effects, future trials should account for statin type and dose.

Assessment schedule and outcome measures

Outcomes were assessed at baseline (2 weeks after stroke) and at weeks 4, 8, and 12. The primary outcomes were: (1) Serum PCSK9 concentration measured by enzyme-linked immunosorbent assay (ELISA), using commercial kits with reported intra-assay and inter-assay coefficients of variation < 10%; and (2) Depression severity measured using the HAMD-17 (total score, 0-52; 7-16, mild depression; 17-23, moderate depression; and ≥ 24, severe depression).

Secondary outcomes included: (1) Anxiety severity assessed using the 14-item Hamilton Anxiety Scale (HAMA; score range, 0-56); (2) The depression treatment response rate, defined as the proportion of patients with a ≥ 50% reduction in HAMD-17 score from baseline; (3) Lipid parameters, including total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides; (4) Inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP); and (5) Cognitive function assessed using the Montreal Cognitive Assessment (MoCA; score range, 0-30).

Laboratory procedures

Fasting blood samples were collected between 07:00 and 09:00. Serum was separated by centrifugation at 3000 rpm for 15 minutes and stored at -80 °C until analysis. PCSK9 concentrations were measured using a human PCSK9 ELISA kit (R&D Systems, Minneapolis, MN, United States) according to the manufacturer's instructions. The reported analytical range was 31.2-2000 ng/mL, and the reported limit of detection was 9.4 ng/mL. Lipid profiles were measured using standard enzymatic methods on an automated analyzer. IL-6 and TNF-α concentrations were measured using high-sensitivity ELISA kits (R&D Systems), and hs-CRP was measured by immunoturbidimetry.

Safety monitoring

Safety was evaluated throughout the 12-week observation period. Adverse events were assessed for severity and possible relationships to the medications. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) were measured at each visit. Newly occurring neurological signs and worsening of preexisting neurological deficits were also documented and evaluated.

Statistical analysis

Statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, United States) and GraphPad Prism version 9.0. A sample-size calculation assuming a between-group difference of 4 points in the reduction in HAMD-17 score, a standard deviation of 5 points, a two-sided α of 0.05, and 80% power indicated that 50 patients per group were required. The study included 64 patients per group to allow for an approximately 20% attrition. Normally distributed continuous variables are presented as mean ± SD, and nonnormally distributed variables as median (interquartile range). Categorical variables are presented as n (%). Between-group comparisons used the independent-samples t-test or Mann-Whitney U test for continuous variables and the χ² test or Fisher’s exact test for categorical variables, as appropriate. Repeated-measures analysis of variance or mixed-effects models were used to evaluate longitudinal changes. Associations between PCSK9 concentrations and clinical outcomes were assessed using Pearson or Spearman correlation coefficients, as appropriate. Multiple linear regression was used to examine predictors of improvement in depression scores. Two-sided P values < 0.05 were considered statistically significant.

RESULTS

Patient characteristics

The study included 128 patients with PSD: 64 received evolocumab plus atorvastatin and 64 received atorvastatin alone. Complete 12-week outcome data were available for 61 patients in the combination-therapy group and 62 in the control group; three and two patients, respectively, were lost to follow-up. Baseline characteristics are summarized in Table 1. Mean age was 65.3 ± 10.8 years in the combination-therapy group and 66.1 ± 11.2 years in the control group (P = 0.685). The groups were reported to be similar in educational attainment, marital status, smoking and alcohol histories, and comorbidities, including hypertension, diabetes, and hyperlipidemia.

Table 1 Baseline characteristics of the study participants.

Characteristic	Treatment group (n = 64)	Control group (n = 64)	P value
Age (years)	65.3 ± 10.8	66.1 ± 11.2	0.685
Sex (female, %)	52.5	48.4	0.638
Education (college or higher, %)	34.4	32.3	0.799
NIHSS score at admission	7.2 ± 2.1	7.1 ± 2.0	0.774
History of hypertension (%)	68.8	65.6	0.683
History of diabetes (%)	28.1	26.6	0.837
Smoking history (%)	32.8	29.7	0.688
Baseline HAMD-17 score	22.8 ± 4.5	22.3 ± 4.2	0.516
Baseline HAMA score	18.6 ± 4.2	18.1 ± 3.9	0.478
Baseline MoCA score	22.5 ± 3.2	22.3 ± 3.1	0.715

HAMD-17: 17-item Hamilton Depression Rating Scale; NIHSS: National Institutes of Health Stroke Scale; HAMA: Hamilton Anxiety Scale; MoCA: Montreal Cognitive Assessment.

Changes in serum PCSK9 levels

Baseline serum PCSK9 concentrations were similar in the combination-therapy and control groups (385.6 ± 78.4 ng/mL vs 378.2 ± 76.9 ng/mL, P = 0.587). By week 4, PCSK9 concentrations had decreased to 245.7 ± 58.3 ng/mL in the combination-therapy group (P < 0.001 vs baseline), compared with 365.8 ± 72.1 ng/mL in the control group (change from baseline, not statistically significant). The corresponding values were 192.5 ± 48.6 ng/mL and 321.4 ± 69.5 ng/mL at week 8, and 156.3 ± 42.1 ng/mL and 298.5 ± 68.7 ng/mL at week 12 (Table 2). Repeated-measures analysis of variance identified a significant group-by-time interaction for PCSK9 concentration (F = 156.8, P < 0.001), indicating that the trajectories differed between groups.

Table 2 Changes in serum proprotein convertase subtilisin/kexin type 9 concentrations over 12 weeks.

Time point	Treatment group (ng/mL)	Control group (ng/mL)	P value
Baseline	385.6 ± 78.4	378.2 ± 76.9	0.587
4 weeks	245.7 ± 58.3	365.8 ± 72.1	< 0.001
8 weeks	192.5 ± 48.6	321.4 ± 69.5	< 0.001
12 weeks	156.3 ± 42.1	298.5 ± 68.7	< 0.001

Depression and anxiety score changes

Baseline HAMD-17 scores were similar in the combination-therapy and control groups (22.8 ± 4.5 vs 22.3 ± 4.2, P = 0.516). Scores decreased in both groups over 12 weeks, with lower scores in the combination-therapy group at week 12 (10.2 ± 3.1 vs 14.6 ± 3.8, P < 0.001; Table 3). The treatment response rate, defined as a ≥ 50% reduction in HAMD-17 score, was 73.4% (45/61) in the combination-therapy group and 48.4% (30/62) in the control group (P = 0.003). Week-12 HAMA scores were also lower in the combination-therapy group (8.5 ± 2.3 vs 12.1 ± 3.2, P < 0.001).

Table 3 Changes in depression and anxiety scores over 12 weeks.

Outcome measure	Treatment group	Control group	P value
HAMD-17 score at baseline	22.8 ± 4.5	22.3 ± 4.2	0.516
HAMD-17 score at 4 weeks	18.3 ± 3.8	19.6 ± 3.9	0.076
HAMD-17 score at 8 weeks	13.7 ± 3.5	16.8 ± 3.7	< 0.001
HAMD-17 score at 12 weeks	10.2 ± 3.1	14.6 ± 3.8	< 0.001
HAMA score at 12 weeks	8.5 ± 2.3	12.1 ± 3.2	< 0.001
Treatment response rate (%)	73.4 (45/61)	48.4 (30/62)	0.003
Remission rate (HAMD-17 < 7, %)	52.5 (32/61)	29.0 (18/62)	0.007

HAMD-17: 17-item Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Scale.

Associations between PCSK9 levels and depression scores

Pearson correlation analysis showed positive associations between serum PCSK9 concentrations and HAMD-17 scores at all assessment points. The correlation coefficient increased from r = 0.428 at baseline to r = 0.652 at week 12 (both P < 0.001; Figure 1). At week 12, the correlation coefficients were r = 0.721 (P < 0.001) in the combination-therapy group and r = 0.556 (P < 0.001) in the control group. This post hoc subgroup analysis was not adjusted for multiple comparisons and should be interpreted cautiously. Multiple linear regression included age, sex, baseline National Institutes of Health Stroke Scale score, baseline HAMD-17 score, baseline LDL cholesterol, and change in PCSK9 concentration as covariates. All variance inflation factors were < 2.0, indicating no substantial multicollinearity. The model explained 48% of the variance (R² = 0.48; adjusted R² = 0.45). After covariate adjustment, the change in PCSK9 concentration remained associated with improvement in HAMD-17 score (β = 0.524, P < 0.001). Figure 2 depicts the parallel time courses of PCSK9 concentrations and depression scores in both groups. Between-group differences in both measures were reported at weeks 4, 8, and 12; however, the week-4 HAMD-17 comparison in Table 3 was not statistically significant (P = 0.076).

Figure 1 Correlation between serum proprotein convertase subtilisin/kexin type 9 concentrations and 17-item Hamilton Depression Rating Scale scores at 12 weeks. The scatterplot depicts the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations and 17-item Hamilton Depression Rating Scale (HAMD-17) scores at week 12 (reported r = 0.652, P < 0.001). Blue circles indicate the combination-therapy group (evolocumab plus atorvastatin), and orange triangles indicate the control group (atorvastatin alone). The fitted regression line illustrates the positive association between PCSK9 concentration and depression severity. Within-group correlations were r = 0.721 (P < 0.001) in the combination-therapy group and r = 0.556 (P < 0.001) in the control group; these exploratory subgroup analyses were not adjusted for multiple comparisons. PCSK9: Proprotein convertase subtilisin/kexin type 9; HAMD-17: 17-item Hamilton Depression Rating Scale.

Figure 2 Time course of serum proprotein convertase subtilisin/kexin type 9 concentrations and depression scores. The dual-axis line graph shows serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations (left axis, ng/mL) and 17-item Hamilton Depression Rating Scale (HAMD-17) scores (right axis) during the 12-week observation period. Solid lines indicate the combination-therapy group (evolocumab plus atorvastatin); dashed lines indicate the control group (atorvastatin alone). PCSK9 concentrations were lower in the combination-therapy group at weeks 4, 8, and 12. HAMD-17 scores differed significantly between groups at weeks 8 and 12, but not at week 4 (P = 0.076; Table 3). Parallel changes in PCSK9 concentrations and depression scores are descriptive and do not establish a causal mechanism. Error bars represent the standard error of the mean. PCSK9: Proprotein convertase subtilisin/kexin type 9; HAMD-17: 17-item Hamilton Depression Rating Scale.

Inflammatory markers and lipid profiles

At week 12, inflammatory marker concentrations were lower in the combination-therapy group than in the control group (Table 4): IL-6, 3.2 ± 0.8 pg/mL vs 5.1 ± 1.2 pg/mL (P < 0.001); TNF-α, 8.4 ± 1.6 pg/mL vs 12.3 ± 2.1 pg/mL (P < 0.001); and hs-CRP, 2.8 ± 0.9 mg/L vs 4.3 ± 1.3 mg/L (P < 0.001). Lipid parameters also differed between groups at week 12. LDL cholesterol was 1.4 ± 0.4 mmol/L vs 2.1 ± 0.6 mmol/L (P < 0.001), and total cholesterol was 3.6 ± 0.7 mmol/L vs 4.3 ± 0.8 mmol/L (P < 0.001), respectively.

Table 4 Inflammatory markers and lipid profiles at 12 weeks.

Indicator	Treatment group (12 weeks)	Control group (12 weeks)	P value
IL-6 (pg/mL)	3.2 ± 0.8	5.1 ± 1.2	< 0.001
TNF-α (pg/mL)	8.4 ± 1.6	12.3 ± 2.1	< 0.001
hs-CRP (mg/L)	2.8 ± 0.9	4.3 ± 1.3	< 0.001
LDL-cholesterol (mmol/L)	1.4 ± 0.4	2.1 ± 0.6	< 0.001
Total cholesterol (mmol/L)	3.6 ± 0.7	4.3 ± 0.8	< 0.001
HDL-cholesterol (mmol/L)	1.2 ± 0.3	1.2 ± 0.3	0.856
Triglycerides (mmol/L)	1.5 ± 0.6	1.6 ± 0.7	0.412

IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; hs-CRP: High-sensitivity C-reactive protein; LDL: Low-density lipoprotein; HDL: High-density lipoprotein.

Cognitive function and functional outcomes

MoCA scores increased from 22.5 ± 3.2 at baseline to 25.8 ± 2.1 at week 12 in the combination-therapy group, compared with an increase from 22.3 ± 3.1 to 23.4 ± 2.6 in the control group (P = 0.001 for the week-12 comparison; Table 5). Functional independence, defined as a modified Rankin Scale (mRS) score of 0-2 at week 12, was observed in 63.9% and 46.8% of patients, respectively (P = 0.047). Mean week-12 Barthel Index scores were 82.3 ± 14.6 and 75.4 ± 16.8, respectively (P = 0.015).

Table 5 Cognitive and functional outcomes.

Outcome measure	Treatment group	Control group	P value
MoCA score at baseline	22.5 ± 3.2	22.3 ± 3.1	0.715
MoCA score at 12 weeks	25.8 ± 2.1	23.4 ± 2.6	0.001
mRS 0-2 at 12 weeks (%)	63.9	46.8	0.047
Mean mRS at 12 weeks	2.1 ± 1.0	2.6 ± 1.1	0.011
Barthel Index at baseline	65.4 ± 18.2	64.8 ± 17.9	0.854
Barthel Index at 12 weeks	82.3 ± 14.6	75.4 ± 16.8	0.015

MoCA: Montreal Cognitive Assessment; mRS: Modified Rankin Scale.

Safety and adverse events

Both regimens were generally well tolerated during the observation period, and no serious adverse events attributed to the study medications were reported. Six patients (9.8%) in the combination-therapy group experienced mild injection-site reactions, all of which resolved spontaneously within 48 hours. Muscle-related symptoms without CK elevation occurred in three patients (4.9%) in the combination-therapy group and two (3.2%) in the control group (P = 0.672). No rhabdomyolysis or clinically significant elevations in ALT or AST (> 3 times the upper limit of normal) were reported. As shown in Table 6, PCSK9 concentrations were positively correlated with depression severity, with the correlation coefficients increasing from r = 0.428 at baseline to r = 0.652 at week 12 (all P < 0.001). At week 12, PCSK9 concentrations were also positively correlated with HAMA scores (r = 0.587), IL-6 (r = 0.543), and TNF-α (r = 0.498), and inversely correlated with MoCA scores (r = -0.456; P < 0.001). These associations suggest that circulating PCSK9 merits further investigation as a marker of depressive symptoms, inflammation, and cognitive function in PSD.

Table 6 Correlations between serum proprotein convertase subtilisin/kexin type 9 concentrations and clinical outcomes.

Correlation analysis	Pearson r	P value
PCSK9 vs HAMD-17 at baseline	0.428	< 0.001
PCSK9 vs HAMD-17 at 4 weeks	0.512	< 0.001
PCSK9 vs HAMD-17 at 8 weeks	0.589	< 0.001
PCSK9 vs HAMD-17 at 12 weeks	0.652	< 0.001
PCSK9 vs HAMA at 12 weeks	0.587	< 0.001
PCSK9 vs IL-6 at 12 weeks	0.543	< 0.001
PCSK9 vs TNF-α at 12 weeks	0.498	< 0.001
PCSK9 vs MoCA at 12 weeks	-0.456	< 0.001

PCSK9: Proprotein convertase subtilisin/kexin type 9; HAMD-17: 17-item Hamilton Depression Rating Scale; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; MoCA: Montreal Cognitive Assessment; HAMA: Hamilton Anxiety Scale.

DISCUSSION

This retrospective study identified a positive association between serum PCSK9 concentrations and depression severity in patients with PSD. Compared with atorvastatin alone, evolocumab plus atorvastatin was associated with lower PCSK9 concentrations and depression scores at 12 weeks. The principal findings were: (1) A positive correlation between PCSK9 concentrations and HAMD-17 scores (r = 0.652 at week 12); (2) Lower week-12 HAMD-17 scores with combination therapy (10.2 ± 3.1 vs 14.6 ± 3.8, P < 0.001); (3) Treatment response rates of 73.4% and 48.4%, respectively; and (4) Lower inflammatory marker concentrations and higher cognitive assessment scores in the combination-therapy group. The 25-percentage-point difference in response rates is clinically noteworthy, but the observational design precludes attributing this difference to evolocumab alone.

Several pathways could potentially explain these associations. PCSK9 is expressed in brain regions including the prefrontal cortex, hippocampus, and cerebellum[25,26], suggesting functions beyond cholesterol regulation in the central nervous system. In preclinical studies, PCSK9 deficiency or inhibition has been associated with reduced microglial activation and cytokine production and improved neuronal survival[27,28]. These findings are consistent with, but do not establish a mechanism for, the lower IL-6 and TNF-α concentrations observed in the combination-therapy group[29]. The neuroinflammatory hypothesis of depression proposes that proinflammatory cytokines activate the kynurenine pathway[30], potentially reducing serotonin availability and dysregulating the hypothalamic-pituitary-adrenal axis[31]. Whether PCSK9 inhibition modifies these pathways in patients with PSD remains to be determined.

PCSK9 has also been implicated in pathways involving N-methyl-D-aspartate receptor trafficking[32,33] and brain-derived neurotrophic factor signaling[34], which are relevant to synaptic plasticity and neurotransmission. The higher MoCA scores observed in the combination-therapy group may be compatible with improved cognitive outcomes but do not demonstrate neuroprotection. In addition, pathways involving LDL receptor-related protein 1 and blood-brain barrier integrity have been proposed as possible links between PCSK9 activity and central nervous system inflammation[35]. These mechanistic hypotheses require direct investigation in patients with PSD.

The correlation between PCSK9 concentrations and depression scores increased from baseline (r = 0.428) to week 12 (r = 0.652), suggesting that circulating PCSK9 may warrant evaluation as a candidate marker of depression severity[36]. Measurement in peripheral blood is feasible and potentially useful alongside clinical assessment. However, a concurrent correlation does not establish that PCSK9 predicts treatment response, and the present study excluded patients with severe aphasia or cognitive impairment. Prospective studies should determine whether baseline concentrations or early changes in PCSK9 predict subsequent clinical outcomes.

The combination-therapy group had a 73.4% treatment response rate at week 12. Published reports describe response rates of approximately 40%-60% with selective serotonin reuptake inhibitor treatment for PSD[37], although differences in study populations and designs preclude direct comparisons. Between-group differences in HAMD-17 scores were significant by week 8 but not at week 4 (Table 3); this study cannot establish whether evolocumab has a faster onset than conventional antidepressants. No serious medication-related adverse events were reported during the 12-week follow-up, and injection-site reactions were mild.

These observations raise the possibility that adding evolocumab to statin therapy could be relevant to both vascular risk management and depressive symptoms in selected patients with PSD. Nevertheless, randomized prospective studies with an active antidepressant comparator, longer follow-up, and cost-effectiveness assessments are needed before conclusions about its role in PSD treatment can be drawn.

Previous trials have demonstrated cardiovascular benefits of evolocumab in populations with atherosclerotic cardiovascular disease[38,39], but cardiovascular outcomes were not assessed in the present cohort. Depression has been associated with adverse outcomes after stroke[40]; whether simultaneous management of vascular risk and depressive symptoms improves long-term outcomes remains unknown. The observed between-group differences in mRS and Barthel Index scores suggest an association with functional status, but longer follow-up is needed to assess their clinical implications.

Limitations

This study has several limitations. Its retrospective, nonrandomized, single-center design introduces a risk of selection bias and residual confounding and limits generalizability. The 12-week follow-up was insufficient to assess long-term outcomes. Cerebrospinal fluid PCSK9 concentrations were not measured, and neither a placebo group nor an active antidepressant comparator was included. The LDL cholesterol eligibility thresholds may limit applicability to patients with lower baseline lipid concentrations. Post hoc subgroup correlations were not adjusted for multiple comparisons. As all patients received atorvastatin 20 mg as background therapy, findings cannot be generalized to other statins or doses. Prospective randomized controlled trials are required to confirm these associations and establish whether evolocumab has a causal effect on depressive symptoms.

CONCLUSION

In this retrospective of patients with PSD, the addition of evolocumab to atorvastatin was associated with lower serum PCSK9 concentrations, lower depression and anxiety scores, higher cognitive assessment scores, and lower inflammatory marker concentrations than atorvastatin alone at 12 weeks. Serum PCSK9 concentrations were positively correlated with depression severity, suggesting a potential role as a candidate biomarker. These findings are hypothesis-generating and require validation in prospective randomized studies before clinical efficacy in PSD can be established.