Central obesity and post-stroke depression: Implications for stroke recovery

Abstract

Post-stroke depression (PSD) is a prevalent but often underdiagnosed complication affecting stroke survivors, with significant implications for recovery and quality of life. Emerging evidence suggests that central obesity, as measured by the weight-to-waist index (WWI), may play a crucial role in PSD risk and severity. Traditional obesity metrics, such as body mass index, may not accurately capture the impact of visceral fat distribution on neuropsychiatric outcomes. This letter highlights the growing recognition of WWI as a precise indicator of metabolic and inflammatory disturbances linked to post-stroke mental health. Integrating WWI into routine stroke rehabilitation assessments could facilitate early identification of high-risk patients and improve intervention strategies. Further research is needed to establish standardized WWI cutoff values and explore potential therapeutic targets for PSD prevention.

Key Words: Central obesity; Stroke recovery; Neurovascular health; Post-stroke outcomes; Mental health; Weight-to-waist ratio

Core Tip: Post-stroke depression remains a major challenge in stroke rehabilitation and is often influenced by metabolic and inflammatory factors associated with obesity. The weight-to-waist index has emerged as a promising tool for assessing central obesity, offering better predictive value than the traditional body mass index. Recognizing the weight-to-waist index as a critical factor in post-stroke depression risk assessment could enhance early detection and intervention strategies, ultimately improving long-term outcomes for stroke survivors.

TO THE EDITOR

Stroke is a leading cause of disability and mortality worldwide, with its aftermath extending beyond physical impairments to severe psychological and cognitive consequences. Among the most pressing post-stroke complications is post-stroke depression (PSD), a condition that affects nearly one-third of stroke survivors and significantly impairs their recovery, rehabilitation outcomes, and overall quality of life[1]. While several risk factors for PSD have been studied, emerging research highlights central obesity, measured by the weight-to-waist ratio (WWR) - as a possible contributor. This letter critically reviews Li et al[2] in the context of recent findings on WWR and PSD, examining their clinical implications, and emphasizing the need for interdisciplinary strategies in stroke rehabilitation.

Obesity, particularly central obesity, has long been recognized as a major contributor to cardiovascular diseases and metabolic disorders, both of which are significant risk factors for ischemic stroke[3]. However, its potential influence on neurological recovery post-stroke is an emerging research area. Unlike the widely used body mass index (BMI), which does not distinguish between muscle and fat mass, WWR has been found to provides a more precise measure of central adiposity[4]. Lassale et al’s study[4] findings suggest that individuals with higher WWR exhibit a greater burden of neuroinflammatory markers and disrupted hypothalamic-pituitary-adrenal (HPA) axis regulation, both of which contribute to depressive symptoms post-stroke[4]. The clinical implication is that WWR could serve not only as a predictive marker for PSD risk but also as a potential target for interventions aimed at improving post-stroke rehabilitation.

Beyond its physiological impact, central obesity is known to contribute to chronic low-grade inflammation, dysregulated HPA axis function, and altered neurotransmitter activity, all of which have been implicated in the pathophysiology of depression[5]. These findings raise important questions regarding whether metabolic interventions, such as weight management and anti-inflammatory therapies, could mitigate PSD risk and enhance functional recovery in stroke survivors. If validated by further studies, this perspective could improve stroke rehabilitation by integrating metabolic health assessments into routine post-stroke care. This article critically reviews the recent findings from studies on WWR and PSD, exploring their potential clinical implications and the need for interdisciplinary approaches in stroke management.

CRITICAL APPRAISAL OF THE STUDY

The recent study by Li et al[2], published in recently, presented a compelling examination of the link between central obesity and the risk of PSD. Given the increasing prevalence of both stroke-related complications and obesity-related disorders, this research contributes to a growing body of literature seeking to uncover novel risk factors influencing neuropsychiatric outcomes after stroke. This appraisal critically examines the study’s design, methods, findings, interpretations, and broader implications while also considering its strengths and limitations.

Study design and methodology

This study employed a retrospective observational design, utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. This dataset is widely recognized for its robustness in capturing epidemiological trends in the United States, making it an appropriate resource for investigating the associations between metabolic health and psychiatric conditions. The researchers implemented a multivariable logistic regression model to assess the relationship between weight-to-waist index (WWI) and PSD, adjusting for multiple confounders such as age, sex, socioeconomic status, smoking, alcohol use, and comorbid conditions. Additionally, they incorporated propensity score matching (PSM), a statistical technique aimed at minimizing selection bias by ensuring comparable groups for analysis.

One of the methodological strengths of this study lies in its use of restricted cubic spline analysis, which allowed the researchers to explore potential non-linear associations between WWI and PSD risk. This is particularly relevant given the increasing recognition that many biological relationships are non-linear rather than strictly linear. However, while these statistical techniques enhance the validity of the study, the retrospective design inherently limits causal inferences. The reliance on self-reported stroke status and depressive symptoms [via the Patient Health Questionnaire-9 (PHQ-9)] introduces potential recall and reporting biases, which could influence the accuracy of the PSD classification.

Findings and interpretations

Li et al[2] reported a significant association between higher WWI values and increased PSD risk, even after adjusting for confounding variables. Individuals in the highest tertile of WWI exhibited more than twice the likelihood of developing PSD compared to those in the lowest tertile. Even after PSM, the association remained significant, albeit with reduced effect size. These findings suggest that central obesity, as captured by WWI, may contribute to post-stroke mental health outcomes beyond traditional obesity metrics, such as BMI.

The discussed study further highlights a non-linear relationship, wherein the risk of PSD plateaus at higher WWI values. This observation is important as it suggests the existence of a threshold beyond which the association does not strengthen further. The potential mechanisms underlying this association have been extensively discussed, particularly the role of systemic inflammation, dysregulated metabolic pathways, and neuroendocrine imbalances in linking central obesity to depression. Elevated visceral adiposity is known to be associated with increased levels of pro-inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor α (TNF-α)], insulin resistance, and altered HPA axis activity, all of which are implicated in the pathophysiology of PSD[5].

While the findings of Li et al[2] align with those of previous research on obesity and depression, the authors appropriately acknowledge the absence of longitudinal data to establish a definitive causal relationship. It remains unclear whether higher WWI directly contributes to PSD, or if individuals with depression post-stroke are more likely to develop obesity due to lifestyle changes and reduced mobility. This bidirectional complexity necessitates further prospective research.

Discussion of the findings

The discussion section by Li et al[2] effectively contextualizes the findings within the broader landscape of stroke rehabilitation and mental health. The authors emphasize that traditional obesity markers such as BMI may not adequately capture the risk profile for PSD, advocating for the incorporation of WWI as a more precise screening tool in clinical practice. This perspective is particularly relevant given that BMI does not differentiate between muscle and fat mass, whereas WWI specifically targets abdominal adiposity, which is more metabolically active and pro-inflammatory.

A particularly noteworthy aspect of the discussion is the observed need to integrate metabolic health assessments into post-stroke rehabilitation programs. Given the findings of this study, it is reasonable to suggest that stroke survivors with high WWI values should undergo routine screening for depression, allowing for early intervention strategies. However, while the discussion highlights the significance of these findings, there is limited exploration of the potential confounders that might drive the observed association. For instance, pre-stroke obesity and mental health status were not accounted for, leaving room for the possibility that individuals with higher WWI already have a predisposition for depressive symptoms. Additionally, factors such as gut microbiome alterations, which have been increasingly recognized as contributors to both obesity and depression[6], were not considered.

STRENGTHS OF THE STUDY

This NHANES dataset enhances the generalizability of the findings to the broader United States population, reducing concerns about selection bias that affects smaller, single-center studies. The use of rigorous statistical methodologies, including multivariable logistic regression analysis and PSM, further strengthened the validity of the study’s conclusions by mitigating the influence of potential confounding factors. PSM, in particular, is a powerful tool in observational research as it mimics the effects of randomization by creating comparable groups, thereby improving the reliability of the reported associations.

Another notable strength is the introduction of WWI as an alternative obesity metric in stroke research. While BMI has traditionally been the most commonly used measure of obesity, its limitations in distinguishing muscle mass from fat mass and failure to account for regional fat distribution are well documented. In contrast, WWI specifically captures central adiposity, which is more metabolically active and has been linked to systemic inflammation, insulin resistance, and neuroendocrine dysregulation, all of which may contribute to PSD risk[3]. The emphasis of the discussed study on WWI as a superior obesity marker aligns with the growing recognition that central obesity may be more clinically relevant than overall body weight when assessing metabolic and psychiatric disorders.

Additionally, this research provides a more refined understanding of the association between obesity and depression post-stroke. Specifically, Li et al[2] examined the non-linear relationship between WWI and PSD using restricted cubic spline analysis. This method revealed a “threshold effect”, meaning that at a certain point, further increases in WWI no longer increased the risk of PSD. This insight is particularly valuable for clinicians, as it suggests that beyond a certain level, increasing abdominal adiposity may no longer exacerbate the risk of PSD. Such findings may inform personalized intervention, wherein patients with moderate WWI elevations may benefit more from lifestyle modifications compared to those at the highest end of the spectrum, where the relationship plateaus.

Furthermore, the study highlights systemic inflammation, HPA axis dysregulation, and metabolic disturbances as potential mechanisms through which central obesity could influence post-stroke mental health outcomes. Given that elevated pro-inflammatory cytokines (e.g., IL-6 and TNF-α) have been implicated in both obesity and depression, these findings support the emerging hypothesis that metabolic and inflammatory processes may play a critical role in PSD pathogenesis. By integrating perspectives from both neurology and psychiatry, the study by Li et al[2] promotes a multidisciplinary approach to stroke rehabilitation, advocating for metabolic health assessments alongside conventional psychiatric screenings.

LIMITATIONS OF THE STUDY

Despite its significant contributions, the study by Li et al[2] was constrained by several methodological and interpretational limitations that must be acknowledged. The cross-sectional design remains the most critical limitation, as it precludes the ability to establish a causal relationship between WWI and PSD. While these findings demonstrate a clear association, it is impossible to determine whether high WWI contributes to PSD development or whether PSD leads to changes in weight and fat distribution post-stroke. A longitudinal study design with repeated measurements over time would have been more suitable for assessing the temporal relationships and causal pathways.

Another major limitation is the reliance on self-reported data for both stroke history and depressive symptoms. NHANES collects self-reported stroke status data, which introduces the possibility of misclassification bias, as some individuals may fail to recall or accurately report past stroke events. Similarly, PSD was assessed using PHQ-9, a widely used screening tool, rather than a formal psychiatric diagnosis. While the PHQ-9 is a validated instrument for detecting depressive symptoms, it does not replace clinical evaluation by a mental health professional. Consequently, some PSD cases may have been overestimated or underestimated, leading to potential classification errors in the outcome measures discussed in the study.

Li et al’s study[2] also lacked crucial pre-stroke health data regarding baseline mental health status and pre-existing obesity-related conditions. Without accounting for whether participants had depression before their stroke or longstanding obesity, it remains uncertain whether the observed association is truly a post-stroke phenomenon or a continuation of pre-existing health patterns. Additionally, lifestyle factors such as diet, physical activity levels, medication use (including antidepressants), and social support networks have not been fully explored, although these variables could significantly influence both obesity metrics and mental health outcomes. Future research should incorporate detailed lifestyle and behavioral data to provide a more comprehensive understanding of the factors influencing PSD risk.

Another limitation is the lack of ethnic and genetic subgroup analyses. Given that both obesity patterns and depression risk vary across racial and ethnic groups, it would have been valuable to investigate whether the WWI-PSD relationship holds across diverse populations. Certain ethnic groups, such as Asian populations, tend to develop metabolic complications at lower BMI thresholds, while others, such as African American populations, may have different fat distribution patterns. Failing to stratify the analysis by ethnicity, sex, or genetic predisposition limits the applicability of the study to specific demographic subgroups.

Finally, while the study proposed WWI as a potential screening tool for PSD risk, it did not establish a clinically actionable threshold for intervention. The identification of a plateau effect in the WWI-PSD relationship is intriguing, however, without clear cut-off values for when WWI becomes clinically concerning, its utility in real-world practice remains uncertain. Future studies should aim to establish WWI reference ranges specific to stroke populations to inform targeted screening protocols in neurology and rehabilitation clinics.

COMPARISON WITH EXISTING LITERATURE

The association between central obesity and PSD has received increasing research attention, however, the underlying mechanisms and implications for stroke recovery remain a topic of ongoing investigation. This study explored the relationship between waist-to-waist ratio, a key indicator of central obesity, and PSD, providing novel insights into how adiposity may influence post-stroke mental health outcomes[2]. To contextualize these findings, it is essential to compare them with existing literature.

Obesity and PSD: Expanding the evidence base

Several studies have established a strong association between obesity and depression in the general population, as well as in individuals with chronic conditions, including stroke survivors. Lassale et al[4] conducted a systematic review and meta-analysis, confirming a bidirectional relationship between obesity and depression, largely mediated by inflammatory mechanisms. Similarly, Milaneschi et al[5] emphasized the roles of systemic inflammation, HPA axis dysregulation, and metabolic disturbances as shared biological pathways. These insights provide a strong theoretical framework that supports the findings of Li et al[2], who demonstrated that a higher WWI, a proxy for central obesity, is independently associated with increased PSD risk. Li et al’s study[2] expands on this body of evidence by applying WWI to a stroke population, thus extending the clinical relevance of these established mechanisms to the domain of post-stroke mental health outcomes.

In addition to inflammation, other studies have considered the neurovascular and metabolic factors that contribute to PSD in obese individuals. Zhang et al[7] highlighted the role of vascular dysfunction in post-stroke cognitive decline, emphasizing that obesity-related neurovascular damage may prolong stroke recovery and worsen mental health outcomes[7]. The findings of the present study support this perspective, as they highlight an association between central adiposity and poorer post-stroke psychological well-being.

The impact of adiposity on stroke recovery outcomes

Existing research also suggests that obesity may affect stroke recovery through mechanisms beyond depression. Carrasco-Poyatos et al[8] conducted a randomized trial on exercise-based rehabilitation in obese stroke patients and, demonstrated that structured physical activity not only improves functional recovery but also reduces depressive symptoms[8]. This finding supports the argument that managing obesity through lifestyle interventions may mitigate the risk of PSD and enhance overall stroke recovery.

Milaneschi et al[5] explored the complex relationship between obesity and mental health, highlighting shared biological mechanisms, such as dysregulated inflammation, altered HPA axis activity, and neuroendocrine dysfunction. Their findings suggest that while obesity is linked to an increased risk of depression, including PSD, this relationship is largely mediated by metabolic disturbances and inflammatory responses rather than obesity itself being a direct causal factor. These insights align with the notion that PSD risk is multifactorial and, influenced by pre-existing psychiatric conditions, medication use, and metabolic dysregulation, rather than central obesity alone[5].

Neuroinflammation and the gut-brain axis: Emerging perspectives

Recent research has explored the role of the gut-brain axis in linking obesity and depression. Asadi et al[6] highlighted how alterations in the gut microbiota composition, often observed in obese individuals, can influence neuroinflammatory processes and neurotransmitter pathways, thereby increasing susceptibility to mood disorders such as depression. The study emphasizes that gut dysbiosis, characterized by an imbalance in microbial diversity, contributes to systemic inflammation, metabolic dysfunction, and disruptions of the HPA axis, which have been implicated in both obesity and PSD. Given these findings, obesity-driven microbial imbalances may play a crucial role in the neurobiological mechanisms underlying PSD, suggesting that biomarkers, such as gut microbiota composition or metabolic endotoxemia could provide deeper insights into mental health risks post-stroke.

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Sandu et al[9] emphasized the role of neuroinflammation in central nervous system disorders, highlighting that inflammation-driven pathologies are often exacerbated by comorbid conditions, including obesity. Their findings suggest that pro-inflammatory cytokines such as IL-6 and TNF-α contribute to both neuronal damage and psychiatric disorders, including depression. This aligns with the emphasis of the discussed study on neuroinflammation as a key factor in PSD and further supports the need for anti-inflammatory therapeutic interventions in obese stroke survivors to mitigate cognitive and emotional decline.

Contrasting findings and areas for further research

Despite strong evidence linking obesity and PSD, some studies have reported mixed or contradictory results. Thomas et al[10] investigated the effectiveness of behavioral activation (BA) therapy in managing PSD through a BEADS feasibility randomized controlled trial. Their findings suggest that structured psychological interventions, such as BA, can significantly improve mood and overall mental well-being in stroke survivors. Unlike traditional cognitive-behavioral therapy (CBT), BA focuses on increasing engagement in meaningful activities, which may help mitigate depressive symptoms regardless of obesity status[10]. These findings highlight the potential of targeted psychological interventions to modify the relationship between obesity and PSD, an aspect not extensively explored in the current study.

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

Clinical implications

The findings from Li et al’s study[2] study highlights the importance of a multidimensional approach to managing PSD, particularly in obese individuals. Given the evidence linking obesity to heightened neuroinflammation, gut microbiota dysbiosis, and altered metabolic pathways[6], clinicians must move beyond traditional PSD management strategies and incorporate a holistic, patient-centered model. This model should integrate targeted anti-inflammatory therapies, as pro-inflammatory cytokines such as IL-6 and TNF-α have been implicated in PSD pathophysiology[5]. Pharmacological interventions that modulate systemic inflammation and neuroinflammation, including statins, omega-3 fatty acids, and biologics, may offer therapeutic benefits and should be further investigated in clinical trials.

Another promising avenue is the modulation of the gut microbiota, given its emerging role in the gut-brain axis. Probiotics, prebiotics, and dietary modifications may serve as adjunctive treatments in mitigating depressive symptoms post-stroke, and clinicians should consider assessing gut microbiota profiles as part of PSD management[6]. In addition to biological interventions, psychosocial therapies must be adapted to obese individuals with PSD. While CBT and mindfulness-based interventions have been effective in addressing PSD, obesity-related psychological burdens such as body image distress and emotional eating require tailored mental health approaches that address both PSD and weight-related concerns.

Personalized rehabilitation strategies are also essential, as traditional stroke rehabilitation often fails to accommodate obesity as a key determinant of recovery outcomes. Exercise-based interventions should be customized to obese stroke survivors, incorporating low-impact activities that promote neuroplasticity while addressing metabolic health. Sleep disturbances are another critical yet frequently overlooked factor in PSD. Since poor sleep quality has been linked to both obesity and depression, targeted interventions such as CBT for insomnia (CBT-I), melatonin regulation, and sleep hygiene education should be incorporated into routine post-stroke care, particularly for obese individuals with a high risk of obstructive sleep apnea[11].

Future directions

Future research should aim to bridge the existing knowledge gaps and refine intervention strategies for PSD in obese stroke survivors. Longitudinal studies are needed to clarify the causal relationship between obesity and PSD, as the current evidence is largely derived from cross-sectional analyses. Investigating whether weight reduction strategies influence the onset and progression of PSD could provide valuable insights into the modifiable risk factors. Moreover, advances in precision medicine should be leveraged to identify biomarkers of neuroinflammation, metabolic dysfunction, and gut dysbiosis in PSD patients. The integration of biomarker-driven interventions could facilitate early detection and enable targeted therapeutic approaches in high-risk obese stroke survivors.

Randomized controlled trials are necessary to evaluate the efficacy of multimodal treatment approaches combining anti-inflammatory agents, microbiota modulation, structured psychosocial therapy, and tailored rehabilitation programs. Despite growing evidence supporting the role of the gut-brain axis in PSD, further mechanistic research is required to determine whether specific microbial signatures predict PSD severity, and whether gut-targeted interventions such as fecal microbiota transplantation, dietary polyphenols, or synbiotics could serve as viable treatment options[6].

Artificial intelligence holds significant potential in PSD prediction and management. Machine learning algorithms can be used to identify high-risk stroke patients by integrating neuroimaging, inflammatory markers, and metabolic data. Artificial intelligence-driven personalized treatment plans may enhance clinical decision making and improve patient outcomes by optimizing interventions based on individual risk profiles[12]. Additionally, research on sleep disorders in PSD should be expanded, particularly with respect to obesity. Examining whether improving sleep quality through interventions such as CBT-I, circadian rhythm modulation, or continuous positive airway pressure therapy for sleep apnea can indirectly reduce PSD severity and modulate inflammatory pathways linked to depression could open new therapeutic possibilities[11].

The intersection of obesity, inflammation, gut microbiota, and PSD presents a complex but promising area for clinical innovation. A multifactorial approach that integrates precision medicine, behavioral therapy, and metabolic interventions has the potential to revolutionize PSD management in obese individuals[6]. Future research must continue to refine targeted, personalized treatment strategies to optimize recovery and long-term well-being in stroke survivors.

CONCLUSION

Li et al[2] explored the complex interplay between obesity and PSD, emphasizing the role of neuroinflammation, metabolic dysfunction, and gut-brain interactions in mediating depressive symptoms. Although obesity exacerbates these pathogenic mechanisms, it remains uncertain whether it is a direct cause or facilitator of PSD. Clinical management should shift toward a holistic approach integrating anti-inflammatory therapies, metabolic regulation, and tailored psychological interventions. Future research should refine mechanistic insights through biomarker-driven studies and longitudinal analyses to clarify the relationship between obesity and PSD. A tailored, patient-centered approach is necessary to enhance recovery and mental health in obese stroke survivors.