Yang Y, Song HY, Zhang MJ, Wang SG, Liu WG. Evolocumab intensive lipid-lowering therapy on prognosis of post-cerebral infarction depression. World J Psychiatry 2026; 16(10): 121270 [DOI: 10.5498/wjp.121270]
Corresponding Author of This Article
Yue Yang, Department of Pharmacy, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou 061000, Hebei Province, China. 825994864@qq.com
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Psychology
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Yang Y, Song HY, Zhang MJ, Wang SG, Liu WG. Evolocumab intensive lipid-lowering therapy on prognosis of post-cerebral infarction depression. World J Psychiatry 2026; 16(10): 121270 [DOI: 10.5498/wjp.121270]
Author contributions: Yang Y conceived and designed the study, supervised the overall research process, and drafted the manuscript; Song HY and Wang SG contributed to data collection, patient record review, and participated in manuscript revision; Zhang MJ was responsible for neurological assessment of enrolled patients and provided clinical expertise on cerebral infarction management; Liu WG conducted the psychiatric evaluations, including 17-item Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale assessments, and contributed to the interpretation of depression-related outcomes. All authors reviewed and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.
AI contribution statement: The authors declare that no AI tools were used in the preparation of this manuscript, including study design, data collection, data analysis, interpretation of results, manuscript writing, or language editing. The authors assume full responsibility for the integrity, accuracy, originality, and scientific validity of the manuscript and all submitted materials.
Supported by the Key Research and Development Program of Cangzhou, No. 23244102156.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Cangzhou Central Hospital [No. 2024-1266-01(z)]. All procedures were conducted in accordance with the Declaration of Helsinki.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. No additional data are available.
Corresponding author: Yue Yang, Department of Pharmacy, Cangzhou Central Hospital, No. 16 Xinhua West Road, Cangzhou 061000, Hebei Province, China. 825994864@qq.com
Received: April 22, 2026 Revised: June 10, 2026 Accepted: July 15, 2026 Published online: October 19, 2026 Processing time: 170 Days and 23.9 Hours
Abstract
BACKGROUND
Post-cerebral infarction depression (PCID) refers to a common neuropsychiatric sequela present in 33%-45% of cerebral infarction survivors, greatly more than that of the general population; it negatively affects the process of neurologic recovery and is associated with increased mortality rates and lower quality of life. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, especially evolocumab, have demonstrated pleiotropic effects beyond regulation of lipids with effectiveness some anti-inflammatory and possible neuroprotective activity. Nevertheless, the impact of evolocumab-based intensive lipid-lowering therapy on prognosis in PCID patients has not been thoroughly investigated.
AIM
To investigate the impact of evolocumab-based intensive lipid-lowering therapy on clinical prognosis, including depression remission, functional recovery, cognitive improvement and cardiovascular recurrence in patients with PCID.
METHODS
This was a retrospective study of 144 patients with PCID enrolled from January 2022 to June 2025 at two tertiary hospitals. Patients were allocated to the intensive group (n = 72, evolocumab 140 mg biweekly plus rosuvastatin 10 mg daily) or the standard group (n = 72, rosuvastatin 10 mg daily) according to the lipid-lowering regimens prescribed by their attending physicians in routine clinical practice. The primary endpoint was depression remission rate [17-item Hamilton Depression Rating Scale (HAMD-17) < 7] at 24 weeks. Secondary endpoints were HAMD-17 and Hamilton Anxiety Rating Scale score trajectory, serum PCSK9 and lipid profile, inflammatory markers (interleukin-6, tumor necrosis factor-alpha, high-sensitivity C-reactive protein), cognitive function (Montreal Cognitive Assessment), functional independence (modified Rankin Scale, Barthel Index), recurrent cerebrovascular events and all-cause rehospitalization within 24 weeks. We used propensity score matching to balance baseline covariates.
RESULTS
A total of 72 pairs were analyzed after using propensity score matching. The remission rate of depression at 24 weeks was significantly higher in the intensive group (58.3% vs 31.9%, P = 0.001). The reduction in HAMD-17 scores was significantly greater in the intensive group at 12 weeks (11.4 ± 3.3 vs 15.2 ± 4.1, P < 0.001) as well as at 24 weeks (7.8 ± 2.9 vs 12.5 ± 3.6, P < 0.001). In the intensive group, the serum PCSK9 level decreased to 148.7 ± 38.5 ng/mL compared with 285.3 ± 62.4 ng/mL in the standard group at 24 weeks (P < 0.001). The intensive group had significantly lower inflammatory markers (interleukin: 2.8 ± 0.7 pg/mL vs 4.9 ± 1.1 pg/mL, P < 0.001), higher cognitive recovery (Montreal Cognitive Assessment: 26.2 ± 1.9 vs 23.8 ± 2.5, P < 0.001), and improved functional performance outcomes (modified Rankin Scale 0-2: 72.2% vs 51.4%, P = 0.009). The intensive group had lower rates of recurrent cerebrovascular events (4.2% vs 12.5%, P = 0.065), and all-cause rehospitalization was significantly decreased (15.3% vs 30.6%, P = 0.027).
CONCLUSION
Patients with coronary artery disease already benefit from intensive lipid-lowering therapy with evolocumab, which has been shown to significantly enhance depression remission and functional independence in addition to improving their cognitive performance and reducing the burden of inflammation (high-sensitivity C-reactive protein) and rehospitalization rates. Altogether, these observations provided evidence for evolocumab to be an extensive adjunctive approach to amelioration of multidimensional prognosis in post-ischemic stroke depression.
Core Tip: This retrospective study shows that evolocumab lipid-lowering therapy greatly ameliorates the multi-dimensional prognosis in patients with post-cerebral infarction depression. The remission rates for depression nearly doubled (58.3% vs 31.9%) associated with concurrent improvements in cognition, functional independence, and rehospitalization. This parallel reduction in inflammatory markers with proprotein convertase subtilisin/kexin type 9 further supports a neuroinflammation-mediated mechanism. These results delineate evolocumab as an approach with dual therapeutic implications mitigating cardiovascular risk and neuropsychiatric sequelae in patients post-cerebral infarction.
Citation: Yang Y, Song HY, Zhang MJ, Wang SG, Liu WG. Evolocumab intensive lipid-lowering therapy on prognosis of post-cerebral infarction depression. World J Psychiatry 2026; 16(10): 121270
Cerebral infarction remains one of the most prevalent causes of mortality and long-term disability in the world with nearly 12.2 million new cases each year[1,2]. Despite major advances in acute reperfusion therapies and secondary prevention strategies, survivors frequently sustain debilitating neuropsychiatric sequela that complicate rehabilitation efforts and adversely affect long-term outcomes. Post-cerebral infarction depression (PCID) is one of common comorbidities among these complications and has been reported affecting 33%-45% of survivors during the first year[3-5]. PCID has been recognized as an independent predictor of poor functional recovery, recurrent vascular events and increased mortality.
The pathogenesis of PCID is multifactorial, involving both direct disruption of mood-regulating subnetworks in neuroanatomical circuits as well as neurotransmitter dysregulation and potential long-lasting neuroinflammation, hypothalamic-pituitary-adrenal axis hyperactivation and psychosocial stressors related to disability[6-9]. Neuroinflammation has advanced as a driver and perpetuator of depressive symptoms after cerebral infarct among these mechanisms. Various inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) are increased in the post-ischemic brain and inhibit serotonergic and glutamatergic neurotransmission, stimulate cortical kynurenine metabolic pathway activation occupying a neurotoxic role and impairing neuroplasticity[10-12]. As such, anti-neuroinflammatory therapeutic strategies may have potential for improving the outcome of PCID.
Statins are effective and widely used in cerebrovascular disease for the lower lipids and not only have very well characterized cholesterol lowering properties but also anti-inflammatory and neuroprotective properties. Observational studies and meta-analyses[13,14] have suggested an association between the use of statins and a decreased incidence and severity of depression in specific clinical populations. Statin monotherapy fulfills goals of lipid suppression in a minority of patients with cerebral infarction; the majority do not reach target lipids on statin therapy alone and the relationship between intensity of lipid lowering and neuropsychiatric outcomes is poorly defined.
The class of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors is a novel class that fundamentally changes lipid management, producing unprecedented low-density lipoprotein cholesterol (LDL-C) reductions when added to background statin therapy. Evolocumab is a fully human monoclonal antibody against PCSK9, that has consistently demonstrated cardiovascular outcomes benefit in trial and meta-analysis with large reduction of major adverse cardiovascular event and recurrent stroke[15-17]. In addition to lipid regulation, accumulating evidence indicates that PCSK9 is involved in neuroinflammation, blood-brain barrier (BBB) integrity, microglial activation and neuronal apoptosis[18-20], all of which may play roles in the pathophysiology of PCID.
Experimental data have shown that a deficiency of PCSK9 or its pharmacological inhibition also reduces neuroinflammatory responses, infarct volumes, and improved behavioral evaluations in preclinical models of stroke[21,22]. Additionally, PCSK9 is expressed in brain regions essential for mood regulation (e.g., the prefrontal cortex and hippocampus), hinting at a potential direct involvement of this pathway in depressive pathophysiology[23,24]. However, direct clinical evidence regarding the potential benefit of PCSK9 inhibitor-based intensive lipid-lowering therapy to alter prognosis in PCID patients is still lacking.
The current study aims to fill this critical knowledge gap using a retrospective cohort analysis to compare multidimensional prognostic outcomes among cerebral infarction patients with depression treated with evolocumab-based intensive lipid-lowering therapy against standard statin monotherapy. We hypothesized that there would be superior depression remission following intensive therapy, as well as improved functional and cognitive recovery, decreased neuroinflammatory burden, and fewer adverse clinical events over a 24-week follow-up period.
MATERIALS AND METHODS
Study design and setting
Retrospective study at Cangzhou Central Hospital and all procedures were performed in accordance with the Declaration of Helsinki. Due to the retrospective nature of the study and adequate de-identification of patient records, a waiver for individual informed consent was obtained.
Patient selection
Eligible patients were identified through their electronic medical records. Inclusion criteria were: (1) Age 40-80 years; (2) Acute cerebral infarction diagnosed by computed tomography or magnetic resonance imaging within 72 hours of onset; (3) New depressive symptoms at the second follow-up examination 2-4 weeks post-infarction, as defined by 17-item Hamilton Depression Rating Scale (HAMD-17) ≥ 8; (4) Stable neurological deficit determined over two days prior to depression assessment using change in National Institutes of Health Stroke Scale score ≤ 2; (5) Baseline LDL-C ≥ 1.8 mmol/L; and total cholesterol > 4.1 mmol/L, and cerebral depression independent from indexes drive mechanism in time course post-stroke; and (6) Complete medical records with a follow-up period of at least 6 months.
Exclusion criteria were: (1) Pre-existing major depressive disorder or bipolar disorder; (2) Antidepressants, anxiolytics or antipsychotic use at stroke onset; (3) Severe aphasia (Boston Diagnostic Aphasia Examination ≤ 2) or impaired consciousness (Glasgow Coma Scale < 13); (4) Hemorrhagic transformation requiring intervention; and (5) Severe hepatic (Child-Pugh B/C) or renal impairment (estimated glomerular filtration rate < 30 mL/minute/1.73 m2), and/or active malignancy, immunosuppressive therapy, hypersensitivity to PCSK9 inhibitors/statins and participation in concurrent trials.
Treatment groups and protocol
Patients were classified into 2 groups based on the lipid-lowering regimens prescribed by attending physicians. The intensive group was given evolocumab 140 mg subcutaneously every 2 weeks, plus rosuvastatin 10 mg per os quaque die. The study group received rosuvastatin 10 mg orally once daily as monotherapy. The addition of evolocumab was based on physician choice according to cardiovascular risk stratification; LDL-C levels; and patient willingness, which is representative for routine clinical practice. All patients received standardized post-infarction management that included antiplatelet therapy with either aspirin 100 mg/day and/or clopidogrel 75 mg/day, antihypertensive medication when rely upon, glucose control regarding diabetic patients as well as tailored rehabilitation plans. Because depressive symptoms were followed up under a watchful waiting approach according to the institutional protocol for PCID, no patients received antidepressant medications during the study period. This approach was applied based on clinician judgment, accounting for the time-limited nature of early post-infarction depressive reactions and the bleeding risks associated with selective serotonin reuptake inhibitors in patients on concurrent antiplatelet therapy. All patients were monitored closely at scheduled intervals, with reassessment for pharmacological intervention if symptoms failed to improve by week 8. It should be noted that mean baseline HAMD-17 scores (approximately 20) correspond to moderate-to-severe depression; findings from this study therefore apply specifically to pharmacologically naive PCID and should not be extrapolated to settings where early antidepressant initiation is standard practice.
Propensity score matching
To reduce the selection bias explained by the retrospective design, a propensity score matching was conducted using a multivariable logistic regression model. Covariates were defined as follows: Age (years); sex; years of school; comorbidities before the infarction (hypertension, diabetes mellitus, history of atrial fibrillation, and stroke); infarction status (National Institutes of Health Stroke Scale score[9]), infarction site in accordance with Trial of Org 10172 in Acute Stroke Treatment classification[10] and infarct volume[11]; baseline level of HAMD-1712; the level of LDL-C at enrollment, and the Montreal Cognitive Assessment (MoCA) score 8. Matching without replacement was conducted using one-to-one nearest neighbors with a caliper width of 0.2 standard deviations of the logit of the propensity score. The balance of covariates after matching was evaluated using standardized mean differences, with an acceptable threshold of < 0.1.
Outcome measures and assessment schedule
All assessments were made at baseline (2-4 weeks post-infarction, before evolocumab initiation in the intensive group), 8 weeks, 12 weeks and 24 weeks. The main outcome was the rate of remission at 24 weeks as defined by Hamilton Depression Rating Scale, 17 items (HAMD-17) score < 7. Secondary endpoints were: (1) Longitudinal trajectories of HAMD-17 and Hamilton Anxiety Rating Scale (HAMA) scores; (2) Treatment response rate (≥ 50% reduction in HAMD-17 from baseline) at 12 and 24 weeks; (3) Serum PCSK9 levels by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN, United States); (4) Lipid profiles: LDL-C, total cholesterol, HDL-C, triglycerides; (5) Inflammatory biomarkers: IL-6, TNF-α, high-sensitivity C-reactive protein (hs-CRP); (6) Cognitive function assessed by MoCA; (7) Functional independence appraised with modified Rankin Scale (mRS) and Barthel Index; (8) Recurrent cerebrovascular events ischemic stroke transient ischemic attack within 24 weeks; and (9) All-cause rehospitalization within 24 weeks.
Laboratory procedures
Each assessment time point had venous blood samples drawn from 7:00-9:00 clock AM after an overnight fast. Serum was separated by centrifugation (3000 rpm for 15 minutes) and stored at -80 °C until the batch analysis. PCSK9 levels were measured by using a commercially available enzyme-linked immunosorbent assay kit (Quantikine, R&D Systems, Minneapolis, MN, United States) with a detection range of 31.2-2000 ng/mL and intra-assay and inter-assay coefficients of variation of < 8% or < 10%, respectively. Lipid panels were determined by routine enzymatic colorimetric methods on an automated biochemistry analyzer (Cobas 8000, Roche Diagnostics, Germany). High-sensitivity enzyme-linked immunosorbent assay kits (R&D Systems, Minneapolis, MN, United States) were used to measure IL-6 and TNF-α, and hs-CRP was assessed by latex-enhanced immunonephelometry.
Safety monitoring
Safety evaluations were performed at every follow-up visit. In addition, hepatic function (alanine aminotransferase, aspartate aminotransferase), creatine kinase, and fasting glucose was monitored. Adverse events were recorded and graded according to the Common Terminology Criteria for Adverse Events version 5.0. We systematically documented injection site reactions, musculoskeletal symptoms, and any new neurological deficits.
Statistical analysis
Analyses utilized R 4.3.1. Assuming a 25% difference in remission rates (55% vs 30%; α = 0.05, power = 0.80), a minimum of 58 patients per group was needed; 84 and 72 patients were enrolled in the intensive and standard groups, respectively, and 72 matched pairs (144 patients) were retained after propensity score matching for the primary analysis. Continuous variables are presented as mean ± SD or median (interquartile range); categorical variables as frequency and percentage. Comparisons of groups used t-tests, Mann-Whitney U, χ2 or Fisher exact tests. Linear mixed-effects models (random intercepts and slopes) were used to assess longitudinal changes. Time-to-event outcomes were compared using random-effects Kaplan-Meier curves with log-rank tests and Cox regression to identify predictors of rehospitalization. Subgroup analyses were pre-specified by sex, age (≥ 65 vs < 65 years), and baseline depression severity. Primary and key secondary endpoints were adjusted for multiplicity (Benjamini-Hochberg method); exploratory analyses are descriptive. All tests were two-sided (P < 0.05).
RESULTS
Baseline characteristics
In total, 289 patients were screened; 156 entered (intensive group n = 84, standard group n = 72), and 144 were retained after propensity score matching (72 per group). The intensive group had higher baseline LDL-C (3.28 ± 0.74 mmol/L vs 2.96 ± 0.68 mmol/L, P = 0.006) and higher prior stroke history (19.2% vs 10.3%) before matching. After matching, all standardized mean differences were < 0.1, indicating adequate covariate balance (Table 1). The mean age was 63.8 ± 9.6 years in the intensive group and 64.5 ± 10.1 years in the standard group (P = 0.658). HAMD-17 score at baseline was similar between groups (20.6 ± 4.8 vs 20.1 ± 4.5, P = 0.510), meaning that depression severity at study entry were matched across both the treatment and placebo groups.
Table 1 Baseline characteristics after propensity score matching, n (%)/mean ± SD.
The intensive group had a significantly higher rate of the primary endpoint at 24 weeks [depression remission (HAMD-17 < 7): 58.3%, 42/72 vs standard: 31.9%, 23/72; P = 0.001] and secondary endpoints as compared to the standard group. The absolute risk difference was 26.4% (95% confidence interval: 11.2%-41.6%), and the number needed to treat was 3.8, meaning that one additional patient achieved remission for every four treated with evolocumab-based intensive therapy over standard statin monotherapy.
Depression and anxiety trajectories
Both groups improved on the HAMD-17 over time; however, the intensive group declined much more steeply and sustained over time compared with a placebo. Responses of HAMD-17 scores: At 8 weeks, between-group differences in the mean values (normal brothers vs offspring) were already evident (15.2 ± 3.6 vs 17.4 ± 3.9; P = 0.001), with progressive widening at 12 weeks (11.4 ± 3.3 vs 15.2 ± 4.1; P < 0.001) and, finally, to a mean difference of 7.8 ± 2.9 vs 12.5 ± 3.6 at 24 weeks (P < 0.001; Table 2, Figure 1). Using a linear mixed-effects modeling approach, we found a statistically significant group-by-time interaction (β = -0.38, 95% confidence interval: -0.49 to -0.27, P < 0.001), suggesting both accelerated and greater overall improvement in the intensive group when comparing change from baseline across treatment groups at each timepoint. At 24 weeks, treatment response rates (≥ 50% HAMD-17 reduction) were 79.2% in the intensive group compared with 50.0% in the standard group (P < 0.001). Increased anxiety symptoms also improved to a greater extent in the intensive group with HAMA scores 24 weeks to 7.2 ± 2.1 vs standard: 11.8 ± 3.0, P < 0.001; Table 3).
Figure 1 Longitudinal changes in depression severity and proprotein convertase subtilisin/kexin type 9 levels.
Trajectories of 17-item Hamilton Depression Rating Scale (HAMD-17) scores (left Y-axis, solid lines) and serum proprotein convertase subtilisin/kexin type 9 levels (right Y-axis, dashed lines) over 24 weeks. Red and blue lines represent the intensive and standard groups for HAMD-17, respectively. Purple and teal lines represent proprotein convertase subtilisin/kexin type 9 levels. Gray dotted line indicates remission threshold (HAMD-17 < 7), orange dotted line indicates mild depression threshold (HAMD-17 = 14). cP < 0.001 for between-group differences at indicated time points. Data are presented as mean values. HAMD-17: 17-item Hamilton Depression Rating Scale; PCSK9: Proprotein convertase subtilisin/kexin type 9.
Table 2 Longitudinal depression severity and treatment response, n (%)/mean ± SD.
In each group, baseline serum PCSK9 levels were similar (intensive: 392.4 ± 81.6 ng/mL; standard: 386.8 ± 78.3 ng/mL, P = 0.667). At 24 weeks, participants in the intensive group experienced significantly greater suppression of PCSK9 (148.7 ± 38.5 ng/mL vs 285.3 ± 62.4 ng/mL), with percent reductions from baseline of 62.1% vs 26.2%, respectively (P < 0.001; Figure 1). Results of LDL-C at 24 weeks were significantly lower in the intensive group (1.2 ± 0.3 mmol/L vs 2.0 ± 0.5 mmol/L, P < 0.001), with 81.9% of patients in the intensive group achieving an LDL-C < 1.4 mmol/L compared with only 27.8% (P < 0 ·001; Table 4).
Table 4 Biomarkers and neuroprotective indicators at 24 weeks, mean ± SD.
Baseline inflammatory markers were comparable between groups. The reductions in all inflammatory biomarkers were significantly greater in the intensive group compared with standard at 24 weeks (Table 4). IL-6 concentrations fell to 2.8 ± 0.7 pg/mL in the intensive group and 4.9 ± 1.1 pg/mL in the standard group (P < 0.001). The circulating levels of TNF-α were 7.6 ± 1.4 pg/mL vs 11.8 ± 2.3 pg/mL (P < 0.001). hs-CRP levels were 2.2 ± 0.7 mg/L compared to 3.9 ± 1.2 mg/L (P < 0.001). Pearson correlation showed a positive association between changes of PCSK9 from baseline to 24 weeks and alterations in IL-6 (r = 0.523, P < 0.001), TNF-α (r = 0.487, P < 0.001) and HAMD-17 score (r = 0.618, P < 0.001).
Cognitive and functional outcomes
There was no difference in the baseline MoCA score between groups (intensive: 21.8 ± 3.4; standard: 21.5 ± 3.2, P = 0.581). The intensive group showed a much larger degree of cognition improvement at 24 weeks than the standard group (MoCA: 26.2 ± 1.9 vs 23.8 ± 2.5; P < 0.001; Table 5), an absolute mean difference of 2.4 points functional independence (mRS 0-2) at 24 weeks was achieved by 72.2% of the intensive group and by 51.4% of the standard group (P = 0.009). Mean Barthel Index scores were also higher in the intensive group (86.5 ± 12.3 vs 76.8 ± 15.7, P < 0.001). Subgroup analyses identified the benefits of intensive therapy in patients ≥ 65 years (mRS 0-2: 68.4% vs 42.1%, P = 0.014) and those with severe baseline depression (HAMD-17 ≥ 24; mRS 0-2: 65.0% vs 35.0%, P = 0.023).
Table 5 Cognitive function and functional outcomes at 24 weeks, n (%)/mean ± SD.
The intensive group showed in Table 6 a good clinical event profile vs the standard one. For recurrent cerebrovascular events, rates were numerically lower in the intensive group (4.2% vs 12.5%), although this difference was not statistically significant. On the contrary, all-cause rehospitalization (15.3% vs 30.6%, P = 0.027), cardiovascular rehospitalization (6.9% vs 18.1%, P = 0.038), and depression-related hospitalization (4.2% vs 15.3%, P = 0.021) were reduced significantly. The depression relapse rates were lower (11.1% vs 29.2%, P = 0.007) and mean time to relapse was longer (18.3 ± 2.7 weeks vs 14.6 ± 3.1 weeks, P = 0.003) in intensive group compared with control group as well. In terms of safety, overall rates of adverse events were similar across groups and injection site reactions occurred significantly more often in the intensive group (9.7% vs 0%; P = 0.006). Serious adverse events and all-cause mortality did not differ significantly.
Table 6 Clinical events and safety outcomes during 24-week follow-up, n (%).
Associations between biomarker changes and clinical outcomes
All biomarker changes from baseline to week 24 were significantly intercorrelated (all P < 0.001, shown in Table 7). PCSK9 changes were correlated most strongly with depression severity (ΔPCSK9 vs ΔHAMD-17: r = 0.618) followed by anxiety (ΔHAMA: r = 0.542), inflammatory markers (ΔIL-6, ΔTNF-α, Δ hs-CRP: r = 0.456-0.523), and cognitive function (ΔMoCA: r = -0.412) with higher reductions in PCSK9 corresponding to greater improvements. Inflammatory markers were similarly positively correlated with ΔHAMD-17 (r = 0.445-0.578), while Δbrain-derived neurotrophic factor (BDNF) was inversely correlated with ΔHAMD-17 (r = -0.528) and positively correlated with the ΔMoCA (r = 0.492), indicating that increases in BDNF counters mood/cognitive impairments suggestive as also supporting mood recovery. Finally, changes in depression severity (ΔHAMD-17) were negatively associated with amelioration of cognitive function (ΔMoCA: r = -0.465) and functional independence (ΔBarthel Index: r = -0.521). Overall, we speculate that effects of PCSK9 suppression on depression lead to changes in neuroinflammation and BDNF levels that work together to promote overall functional status improvement.
Table 7 Correlations between changes in biomarkers and clinical outcomes.
This study provides novel clinical evidence regarding the multidimensional prognosis of PCID by evaluating the association of intensive lipid-lowering therapy with evolocumab with outcomes in these patients. Principal findings were as follows: (1) Depression remission at 24-week was almost doubled in the intensive vs standard group (58.3% vs 31.9%, number needed to treat = 3.8); (2) Intensive therapy was associated with accelerated trajectories of improvement for both depression and anxiety symptoms; (3) Parallel reductions in both PCSK9 levels and inflammatory biomarkers were consistent with a neuroinflammation-mediated mechanism; and (4) Cognitive function and functional independence were significantly better in the intensive group; and, importantly, all-cause rehospitalization was reduced by half. As this was a retrospective observational study, these findings reflect associations rather than causal relationships, and prospective randomized controlled trials are needed to confirm these observations. The observed improvement in depression remission in our study may reflect the convergence of multiple mechanistic pathways, though causality cannot be established from the present data. The neuroinflammatory hypothesis of depression has become one of the most convincing theoretical models within contemporary psychiatry[25,26]. An enduring elevation of pro-inflammatory cytokines, most consistently IL-6 and TNF-α, in PCID patient plasma has been observed more than three decades ago, with these also mechanistically linked to depression via the loss of monoaminergic neurotransmission[25], activation of the indoleamine 2,3-dioxygenase-kynurenine pathway[26], interference with BDNF signaling[27] and dysregulation of hypothalamic-pituitary-adrenal axis activity[27,28]. One of aims of this study was to investigate the relationship between changes in serum concentrations of PCSK9 and adjustment with IL-6 (r = 0.523, P < 0.001), HAMD-17 scores (r = 0.618, P < 0.001). In the present study we found that depressed patients benefitted from a modulation of inflammation-related mechanisms which associated strongly with clinical outcomes and evolving signs across time by comparing blood samples from preintervention period vs postintervention[9,10]. Activating macrophages and microglia with PCSK9 has been shown in previous studies to activate nuclear transcription factor-kappa B signaling and modulate pro-inflammatory cytokine secretion[29]. Likewise, the reduction in inflammatory markers in the intensive group correlated with greater depression improvement[8], consistent with a neuroinflammatory mechanism, although causal inference is non-determinable from observational data. The anti-inflammatory response may contribute significantly to the setting of cerebral infarction; inflammation that occurs after an initial ischemic insult can persist for weeks to months[30,31]. Moreover, PCSK9 inhibition might also modulate mood through effects on cerebrovascular function and BBB permeability. PCSK9 is expressed in brain endothelial cells and pericytes, which physiologically modulates BBB permeability through regulation of the lipoprotein receptor-related protein 1[32]. A dysfunction of the BBB induced by a cerebral infarction are suggested to permit invasion of peripheral immune cells and inflammatory mediators into brain parenchyma in these areas which promote neuronal damage in mood-controlling circuits like those including prefrontal cortex, anterior cingulate cortex, and hippocampus. The decrease in PCSK9 levels in the intensive group may represent attenuation of this secondary inflammatory insult to neural tissue and restoration of disrupted neural networks, although direct correlations with neuroimaging or cerebrospinal fluid data would be needed. This idea is consistent with the enhanced cognitive evaluations shown at 24 weeks in our intensive group, and preclinical evidence describing greater hippocampal neurogenesis and synaptic plasticity after PCSK9 inhibition. The primary endpoint is an important finding with implications for the use of healthcare resources, and this discovery can be grounded in functional recovery and rehospitalization following intensive lipid-lowering therapy. Evolocumab group cerebral events previously unreported for Occulton 2005 being more frequent but all-cause studied rehospitalizations (15.3% vs 30.6%) and functional independence (mRS 0-2: 72.2%, including mRS = 0: 48.1% vs mRS = 51.4% in Evolocumab intensive experimental, including mRS = 0: 28%) with evolocumab intensive group at the end of study as well likely represent benefits observed in doing so over time during their outpatient follow-up period may extend beyond traditional lab end points to clinicians essential outcomes such as rehospitalization and functional independence/quality of life efficacy measures not yet reported thereafter, respectively It follows that depression is now verified to be an impartial factor of unfavorable functional prognosis, recurrent vascular incidents and rise of medical service usage following cerebral infarction[33,34]. Intensive treatment may improve depressive symptoms, which may lead to enhanced patient engagement in rehabilitation, increased adherence to medications and improved health-related behaviors of lifestyle; thus creating a positive feedback through treatment effects across many outcome domains. Our results highlighted treatment group (for readmission at 6 months), along with baseline HAMD-17 score and IL-6 level as independent predictors of rehospitalization in our Cox regression analysis, demonstrating the interrelatedness between inflammation, depression and clinical outcomes in this population[35]. Subgroup analyses yielded additional clinically relevant insights. Notably, elderly patients aged ≥ 65 years and those with severe baseline depression (HAMD-17 ≥ 24) derived particularly prominent functional benefits from intensive therapy, suggesting a benefit of treatment personalization. Given that older cerebral infarction patients are generally more susceptible to neuroinflammation, have greater degrees of BBB disruption, and possess a lower capacity for neuroplasticity, this may further render them particularly amenable to the anti-inflammatory and neuroprotective effects of PCSK9 inhibition[36]. Moreover, patients with more severe depression generally show higher levels of inflammatory biomarkers and greater neurotransmitter dysregulations, thus availability of larger therapeutic window for modulation over the inflammation-depression axis. These findings indicate that evolocumab-based intensive therapy may hold particular value in higher-risk subgroups, for whom existing treatment options often are insufficient.
Our findings confirm and expand emerging data associating PCSK9 to neuropsychiatric outcomes. Most previous studies have primarily focused on examining the cardiovascular effects of PCSK9 inhibitors and their neurocognitive safety profile, and our study is one of the first to systematically assess their potential psychiatric benefits in a well-described clinical cohort[37,38]. The overall safe profile noted in our studies, consistent with large randomized trials, strongly supports the feasibility of using evolocumab as part of comprehensive post-infarction clinical pathways. At 24 weeks, the intensive group response rate of 79.2% is in line with reported rates for selective serotonin reuptake inhibitors used for post-stroke depression (ranging from about 45%-65%). Moreover, the evolocumab-based paradigm provides the exclusive benefit of simultaneously treating cardiovascular risk reduction and neuropsychiatric improvement without drug interactions, sexual dysfunction, and bleeding events that are traditionally associated with pharmacological treatment of depression in the post-infarction cohort.
Limitations
Several limitations should be acknowledged. First, the retrospective design creates an intrinsic selection bias; while propensity score matching adjusted for measured confounders, unmeasured variables such as socioeconomic status, social support networks, and caregiver involvement could have affected outcomes. Second, the lack of a placebo injection arm prevents evaluation of potential placebo effects associated with the subcutaneous injection schedule. Third, cerebrospinal fluid PCSK9 levels and advanced neuroimaging are lacking, so we were unable to evaluate central nervous system effects directly. Fourth, the 24 weeks of follow-up, although longer than many similar trials, is not long enough to make judgements about the durability of benefits and delayed adverse effects; a 52-week extended follow-up is currently underway at both participating centers. Fifth, and importantly, the exclusion of patients on antidepressant medications is a major constraint on generalizability: Since mean baseline HAMD-17 scores (approximately 20) reflect moderate-to-severe depression, findings apply specifically to pharmacologically naive PCID and cannot be extrapolated to clinical settings where early antidepressant initiation is standard practice. Sixth, although the dual-center design enhances generalizability relative to single-center studies, it still requires validation in larger multicenter cohorts across varied populations.
CONCLUSION
Our study shows that evolocumab-based intensive lipid lowering therapy can significantly improve the multidimensional prognosis of PCID with remarkable higher remission rates, faster improvement in mood and anxiety symptoms as well cognitive and functional recovery, less all-cause rehospitalization. The concomitant reduction of both PCSK9 levels and inflammatory biomarkers supports the hypothesis that a neuroinflammation-mediated mechanism underlies these clinical benefits. Such findings offer a solid basis to pilot prospective randomized controlled trials in confirmation of PCSK9 inhibitor-based intensive lipid-lowering therapy as an adjuvant treatment strategy for cognitive and functional improvements in cerebral infarction survivors with comorbid depression.
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