Post-stroke depression in patients with chronic stroke

Abstract

Stroke is the second leading cause of death worldwide and a major cause of disability among adults. With the advancement of medical technology, the survival period of stroke patients has been significantly prolonged, but the neuropsychiatric sequelae in the chronic stage have become increasingly prominent. Post-stroke depression is one of the very important manifestations. This article conducts a further discussion on this issue.

Key Words: Stroke; Post-stroke depression; Neutrophil-to-lymphocyte ratio; Platelet-to-lymphocyte ratio; Letter

Core Tip: Stroke is one of the major diseases affecting global health at present. With the improvement of treatment levels, the mortality and disability rates have improved compared with before. However, various diseases after stroke still affect patients' long-term lives, such as post-stroke depression (PSD). This article is in response to the paper by Han et al. We will further discuss PSD in the hope of enhancing everyone's understanding.

TO THE EDITOR

We read with great interest the article by Han et al[1] entitled “Influencing factors and construction of a nomogram for post-stroke depression in patients with chronic stroke”, recently published in the World Journal of Psychiatry. The authors are to be commended for identifying several independent risk factors, namely, lower educational level, elevated neutrophil-to-lymphocyte ratio, and elevated platelet-to-lymphocyte ratio, that are associated with post-stroke depression (PSD) in patients with chronic stroke. Moreover, their study provides a clinically valuable nomogram for individualized risk prediction.

Stroke remains the second leading cause of death globally and the foremost cause of long-term disability among adults[2]. With advances in medical technology, the survival period of stroke patients has been markedly extended; however, neuropsychiatric sequelae during the chronic phase (> 3 months) have become increasingly prominent. The incidence of PSD during this stage has been reported to reach 30%-40%, substantially compromising rehabilitation adherence, functional recovery, and quality of life, while increasing readmission rates and mortality, and placing a considerable burden on families and healthcare systems[3,4]. Despite its clinical relevance, systematic investigations focusing specifically on chronic-stage PSD remain scarce. Its risk profile differs from that in the acute phase, and reliable predictive tools tailored to this population are still lacking. Thus, the work of Han et al[1] represents a timely and meaningful contribution to the field.

Building upon recent preclinical and clinical advances, we believe that the evolving therapeutic strategies and their underlying pathophysiological mechanisms warrant further discussion. Nanomedicine offers a novel avenue for enhancing central nervous system drug delivery by overcoming the limitations of poor solubility and restricted blood-brain barrier permeability characteristic of conventional pharmacotherapies.

Lv et al[5] have developed a macrophage-derived exosome-functionalized PLGA nanocarrier (CMC-EXPL) co-loaded with celastrol, a triterpene with potent anti-inflammatory activity, and minocycline, a tetracycline antibiotic with neuroprotective properties, for PSD management. In vitro studies have demonstrated that CMC-EXPL is efficiently internalized by BV-2 microglial cells, attenuating LPS-induced M1 polarization (reduced expression of CD80 and iNOS) while promoting M2 polarization (increased expression of CD206 and Arg-1)[5,6]. Nutritional interventions also play a pivotal role in addressing malnutrition and its secondary complications in PSD. Zielińska-Nowak et al[7] have reviewed the therapeutic potential of amino acid and vitamin D supplementation, as well as neuroprotective diets, in post-stroke rehabilitation, emphasizing their influence on neuroplasticity and immune modulation.

From the perspective of traditional Chinese medicine, preclinical evidence indicates that Chaihu-Shugan-San (CSS) exerts antidepressant-like effects through regulation of the JAK/STAT3-GSK3 β-PTEN/Akt signaling cascade. Mechanistically, CSS inhibits STAT3 phosphorylation, upregulates GSK3β, and activates PTEN/Akt signaling, thereby shifting microglial polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 state[5,8]. ELISA and western blotting analyses further confirm that CSS downregulates pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) while upregulating IL-10. Transmission electron microscopy reveals restoration of hippocampal synaptic ultrastructure[1,3]. Similarly, Echinacoside (ECH) (7.5-30 mg/kg) has been shown by Yang et al[9] to ameliorate depressive-like behaviors in PSD rats, reflected by increased sucrose preference and decreased immobility in the forced swim test. ECH also reduces cerebral infarct volume and neuronal apoptosis, as evidenced by TTC staining and TUNEL assay[9,10]. Mechanistic studies have revealed that ECH promotes Nrf2 acetylation through interaction with the CREB-binding protein, thereby enhancing BDNF promoter binding and transcriptional activation[9,11]. This process activates the TrkB/Akt pathway, increases phosphorylation of GSK3β and CREB, and upregulates anti-apoptotic proteins such as Bcl-2[9]. Molecular docking and microscale thermophoresis confirm that ECH directly binds to Nrf2 with high affinity (Kd = 0.166 μM), underscoring Nrf2 as a critical target[9]. With respect to surgical interventions, Feng et al[12] have conducted a multicenter randomized controlled trial evaluating right C7 neurotomy at the intervertebral foramen combined with intensive speech and language therapy for chronic post-stroke aphasia, a frequent comorbidity of PSD. The primary outcome, change in Boston Naming Test score, shows a significantly greater improvement in the neurotomy group (11.16 points vs 2.72 points at 1 month; P < 0.001), with sustained benefits at 6 months (8.26-point difference; P < 0.001)[12]. Functional magnetic resonance imaging demonstrates enhanced neuroplasticity within the right hemisphere, with increased activation in the right supramarginal and inferior frontal gyri during picture-naming tasks[12,13]. Finally, Koob et al[8] have conducted a longitudinal investigation into incentive motivation as a preventive factor for chronic PSD. Their findings suggest that early, reward-based rehabilitative interventions may mitigate long-term depressive symptoms by reinforcing motivational circuitry in the post-stroke brain.

Taken together, these converging lines of evidence, from molecular and nutritional to neurorehabilitative and surgical domains, underscore the importance of multidisciplinary strategies in addressing PSD in chronic stroke. The study by Han et al[1] thus provides a crucial foundation upon which future translational and interventional research can build.