Diagnosis and etiology of poststroke depression: A review

Abstract

Following an acute stroke, patients often encounter a range of impairments affecting their physical, cognitive, verbal, and social capabilities. Poststroke depression (PSD) has been identified as a significant consequence of stroke and serves as a crucial predictor of patient outcomes. The diagnosis of PSD presents a challenge, as the physical manifestations following a stroke can overlap with certain depressive symptoms, leading to a potential underdiagnosis of this condition. This review employs a narrative approach to synthesize diverse findings within this domain. PSD is categorized as an organic mood disorder, and a more accurate diagnosis may be achieved by considering the location of the stroke, the patient's specific symptoms, and the timeline of depressive symptom onset. Notably, if depressive symptoms emerge at more than one year poststroke, the likelihood of PSD diminishes. The etiology of PSD is currently understood to stem from a combination of physiological and psychosocial factors, as well as their interactions. Several mechanisms associated with PSD have been identified, including inflammation, dysregulation of the hypothalamic-pituitary-adrenal axis, oxidative stress, autophagy, apoptosis, abnormal neurotrophic responses, glutamate-mediated excitotoxicity, dysfunction within brain networks, reduced monoamine levels, locations of brain lesions, and psychosocial influences. This review also outlines potential directions for future research.

Key Words: Depression; Diagnosis; Mechanism; Ischemic stroke; Intracerebral hemorrhage; Poststroke depression; Stroke

Core Tip: Patients who have suffered stroke exhibit a higher rate of depression than do other patients with similar levels of disability. This phenomenon suggests an association between stroke and poststroke depression (PSD). Clinical challenges are encountered in diagnosing PSD, as the cognitive and physical impairments resulting from stroke can interfere with the assessment of depressive symptoms. PSD is currently believed to be the result of physiological and psychosocial factors. It is speculated that the mechanisms underlying the depressive symptoms that arise after a stroke are primarily physiological in the early stages and are later related to psychosocial factors.

INTRODUCTION

Stroke remains the second leading cause of mortality on a global scale. Despite a decline in stroke mortality and incidence rates in numerous countries in recent years, the overall numbers of stroke-related deaths and individuals living with disabilities have significantly increased, resulting in substantial global health burdens[1]. A study conducted in the United States revealed that ischemic stroke accounts for 87% of all stroke cases, whereas intracerebral hemorrhage (ICH) accounts for 10%, and subarachnoid hemorrhage (SAH) accounts for only 3% of all stroke cases[2]. A comprehensive global analysis revealed that ischemic stroke accounts for 62.4% of all incident stroke cases, followed by ICH at 27.9% and SAH at 9.7%[1]. In Taiwan, ischemic stroke is the predominant type, accounting for nearly 74% of all stroke cases, with other types occurring in the following order of frequency: ICH at 16.1%, transient ischemic attack at 6.7%, and SAH at 2.8%[3].

Following the acute phase of stroke, patients frequently experience varying degrees of impairments in physical, cognitive, communicative, and social functions. Notably, poststroke depression (PSD) has emerged as a significant sequela that serves as a critical predictor of patient outcomes. The interplay between stroke and depression is considered bidirectional; while stroke elevates the risk of developing depression, depression itself constitutes an independent risk factor for both stroke occurrence and the mortality associated with stroke[4]. PSD is typically associated with diminished functional and cognitive recovery, heightened caregiver distress, and increased mortality rates. Furthermore, depression adversely impacts patients' motivation for rehabilitation, thereby compromising rehabilitation efficacy, quality of life, and functional recovery while simultaneously increasing the burden on family caregivers. Regrettably, depressive symptoms in stroke patients are often inadequately recognized[5]. The term PSD is currently utilized in a broad context to denote the onset of depression following a stroke. The diagnosis of PSD may be established through an assessment of depressive symptoms using various scales or through an evaluation by trained professionals. The primary clinical manifestations of PSD include a depressed mood, apathy, fluctuations in weight, alterations in sleep patterns, feelings of worthlessness, anhedonia, and fatigue, with a depressed mood and apathy identified as core symptoms[6].

In clinical settings, patients who have suffered a stroke frequently exhibit difficulties in cooperating with treatment or rehabilitation efforts. This phenomenon is particularly evident when a discrepancy exists between the patients' functional capabilities and the physical sequelae resulting from the stroke, specifically, when the severity of their symptoms appears to surpass the expected impact of the stroke on their physical disabilities. In such cases, psychiatrists are often consulted to ascertain whether the observed symptoms may be attributable to depression. However, during diagnostic interviews, the subjective symptoms reported by stroke patients tend to be less reliable than those reported by the general patient population, which complicates the diagnostic process. Although many studies have been conducted on various aspects of depression after stroke, such as prevalence, screening measurements and associated factors, only a few studies have investigated the clinical manifestation of depression in stroke patients[7]. The question still remains whether the clinical manifestation of depression after stroke differs from that in other groups of patients. Furthermore, the pharmacological response of PSD is often inadequate, highlighting significant challenges and gaps in the diagnosis and treatment of PSD in clinical practice. A thorough review of the literature concerning screening, diagnosis, and etiology is essential to delineate the current understanding and identify areas that remain unexplored, thereby facilitating improved diagnostic and therapeutic strategies for clinical patients and guiding future research endeavors. This review aims to provide a comprehensive and updated overview of PSD, focusing on its screening, diagnosis, and underlying mechanisms in patients who have experienced an ischemic stroke or ICH.

METHODOLOGY

A comprehensive literature search was conducted utilizing several databases, including PubMed, MEDLINE, EMBASE, Google Scholar, and the Cochrane Database. The search employed a range of keywords, such as "stroke AND depression", "diagnosis AND poststroke depression", "mechanism AND depression", "mechanism AND poststroke depression", "ischemic stroke AND depression", "intracerebral hemorrhage AND depression", and "poststroke depression". Additionally, the references cited in the articles retrieved during the initial search were examined. Importantly, case reports and conference abstracts were excluded from this review. Given the extensive nature of the topic, the presence of existing reviews, and the heterogeneity of the studies identified, a narrative review approach was deemed most appropriate.

PREVALENCE AND INCIDENCE OF PSD

Compared with the 5%-13% prevalence of depression among adults without a history of stroke in the general population, approximately one-third of stroke survivors experience depression, with a cumulative incidence rate of 55%[8]. A systematic review and meta-analysis conducted in 2014, in which data from 61 studies involving 25488 participants were synthesized, revealed that the prevalence of depression among stroke survivors at any point within five years poststroke was 31%. Another similar investigation, encompassing 43 studies and 20293 patients, revealed a pooled prevalence of 29% for depression at any time point, and this prevalence remains consistent for up to ten years following a stroke. Furthermore, the cumulative incidence of depression within five years poststroke ranges from 39% to 52%[5]. A large-scale study revealed a 50% increased risk of developing a depressive disorder within 1.5 years after stroke compared with individuals who experienced myocardial infarction[9].

Guo et al[10] reported that the incidence of PSD varies between 11% and 41% within two years following the event. This variability can be attributed to several factors, including differences in the diagnostic criteria for PSD, sample size variations, geographic disparities, and differing patient selection criteria. In a substantial cohort study involving 157243 first-time stroke patients from Europe[11], 25.4% of stroke patients experienced depression within two years of study entry, in contrast to 7.8% of the reference population. This study also revealed that 12.3% of patients with transient ischemic attack, 23.3% of those with hemorrhagic stroke, and 28.0% of those with ischemic stroke developed depression within two years, suggesting a greater incidence of PSD among ischemic stroke patients than among patients with other types of stroke.

However, a study conducted in Japan revealed that 42% of patients in an ICH cohort exhibited a depressed mood and PSD[12]. A study in China[13], which included 464 participants with acute ischemic stroke or ICH, reported that the incidence of PSD in the ICH group (42.3%) was significantly higher than that in the ischemic stroke group (22.9%) within one month poststroke. Moreover, ICH has been associated with an increased risk of PSD, with an odds ratio of 2.649, indicating that ICH is associated with a higher incidence of PSD in Asia.

In Taiwan, Tsai et al[14] reported a lower one-year incidence of PSD (diagnosed based on the criteria for major depressive episodes) of approximately 11% among 101 patients diagnosed with first or recurrent ischemic strokes that were confirmed through imaging and occurred within the preceding four weeks. In another study in which a self-rated scale was utilized, the prevalence rates of PSD in Taiwan ranged from 34.9% to 62.2%[15].

SCREENING AND DIAGNOSIS OF PSD

The onset of PSD can be acute, occurring within one day or a few days of a cerebrovascular accident (CVA). However, in some cases, the onset of depression occurs weeks or even months after a CVA. Approximately 30% of stroke survivors develop depressive symptoms within the first week poststroke[16]. This high rate of early-onset depressive symptoms can be understood as a reaction to a highly stressful medical event, particularly given the challenges patients face in adapting to the consequences of stroke. Studies in which the 15-item Geriatric Depression Scale (GDS-15) was used have revealed varying prevalence rates of depression after stroke: 36.5% at four weeks[17], 31.0% at three months[18], and 43.7% at six months. The prevalence then appears to decrease, with reports of 16% at 12 months, 19% at two years, and a subsequent increase to 29% at three years[18]. These findings suggest that the PSD prevalence fluctuates over time, typically peaking between three and six months poststroke and declining after one year. In an Italian study of 383 patients with PSD, 307 (80.16%) developed depression within 3 months after stroke. A total of 13.32% of PSD patients were diagnosed between the fourth and sixth months. Only 6.53% of the patients were diagnosed at 9 months[19].

The phenomenology of PSD is intricate and frequently complicated by a diverse array of poststroke morbidities, which encompass physical and cognitive impairments, functional limitations, fatigue, alterations in personality, and neurovascular changes. As delineated in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)[20], PSD is classified as a depressive disorder attributable to another medical condition (specifically, stroke). This condition may present as depressive symptoms, major depressive episodes, or mixed-mood features. Identifying a significant and enduring period characterized by a depressed mood or markedly reduced interest or pleasure in nearly all activities is essential to establish a diagnosis of depressive disorder secondary to stroke according to the DSM-5. Should a patient fulfill the criteria for a major depressive episode, the diagnosis is specified as "with a major depressive-like episode". Conversely, if the criteria for a major depressive episode are not satisfied, the diagnosis is specified as "with depressive features". For individuals exhibiting features of a mixed-mood disorder, which may include symptoms of mania or hypomania, the appropriate specifier is "with mixed-mood features". In the International Classification of Diseases, eleventh revision (ICD-11)[21], the diagnostic threshold for depressive disorder requires at least five symptoms from a list of ten (compared with nine in the DSM-5). The additional symptom in the ICD-11 is "hopelessness", which research suggests is more effective than more than half of the DSM-5 symptoms in terms of differentiating depressed individuals from nondepressed individuals[22].

In the ICD-11, PSD is defined as a mood syndrome secondary to a medical condition. PSD is characterized by prominent mood symptoms, such as depression, and is judged to be a direct pathophysiological consequence of a health condition distinct from primary mental and behavioral disorders. This judgment is based on evidence from the patient's history, physical examination, and/or laboratory findings. The symptoms and signs must be distinguished from delirium, dementia, other mental disorders (including depressive and bipolar disorders), and the effects of medications or substances (including withdrawal). Owing to their overlapping clinical features, significant challenges are encountered in distinguishing mood symptoms attributable to a medical condition from those indicative of a primary mental disorder. The diagnosis of a secondary mood syndrome necessitates the identification of a medical condition that is capable of inducing mood symptoms, as well as a definitive temporal correlation between the medical condition and the emergence of these symptoms. Essential diagnostic criteria for secondary depressive disorder include: (1) The absence of any prior depressive episodes prior to the onset of the medical condition; (2) The potential for the associated medical condition to cause or exacerbate a depressive disorder; and (3) The manifestation of depressive symptoms in close temporal proximity to the onset or exacerbation of the medical condition. Furthermore, atypical characteristics associated with primary mood disorders, such as an unusual age of onset, atypical progression, or the lack of a familial history, may heighten the suspicion of secondary mood syndrome. Mood symptoms may arise as a psychological response to the diagnosis and/or management of a severe medical condition, particularly those that are life-threatening (e.g., cancer and infections) or involve a sudden onset (e.g., heart attack, stroke, and severe injury). If no clear physiological link can be established between medical conditions and mood symptoms, a primary mental disorder, such as adjustment disorder with a depressed mood, should be considered. Table 1 lists the diagnostic criteria for PSD in the DSM-5 and ICD-11.

Table 1 Diagnostic criteria for poststroke depression in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, eleventh revision.

	DSM-5	ICD-11
Fully specified name	Depressive disorder due to another medical condition	Mood syndrome due to health condition not classified under mental and behavioral disorders
Diagnostic criteria
(1) Symptoms	One of following symptoms:	Prominent depressive, manic, or mixed mood symptoms
	(1) Prominent and persistent period of depressed mood
	(2) Markedly diminished interest pleasure in all activities
(2) Medical conditions (stroke)	Evidence from the history, physical examination, or laboratory findings	Evidence from the history, physical examination, or laboratory findings
(3) Etiological relation	(1) A temporal association between the onset, exacerbation, or remission of the general medical condition and that of the mood disturbance	(1) The medical condition is known to be capable of producing the symptoms
	(2) Features that are atypical of primary Mood Disorders (e.g., atypical age at onset or course or absence of family history)	(2) The course of the mood symptoms (e.g., onset, remission, response of the mood symptoms to treatment of the etiological medical condition) is consistent with causation by the medical condition
	(3) Evidence from the literature that suggests that there can be a direct association between the general medical condition in question
	(4) The development of mood symptoms can provide a useful context in the assessment of a particular situation
(4) Exclusion	(1) Adjustment disorder, with depressed mood, in which the stressor is a serious medical condition	(1) Delirium, dementia, another mental disorder (e.g., adjustment disorder, depressive disorder, bipolar I disorder)
	(2) Delirium	(2) Secondary catatonia syndrome
	(3) Medication-induced depressive disorder	(3) Effects of a medication or substance, including withdrawal effects
(5) Stress or impairment	Social, occupational, or other important areas of functioning	Sufficiently severe to be a specific focus of clinical attention
(6) Specifiers	(1) With depressive features: Full criteria are not met for a major depressive episode	(1) With depressive symptoms
	(2) With major depressive-like episode: Full criteria are met for a major depressive episode	(2) With manic symptoms
	(3) With mixed features: Symptoms of mania or hypomania are also present but do not predominate in the clinical picture	(3) With mixed symptoms
		(4) With unspecified symptoms

DSM-5: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders; ICD-11: The International Classification of Diseases, eleventh revision.

Symptoms of depression may vary depending on the cause of the stroke. The symptomatology of depression associated with ischemic stroke and ICH may differ. A study revealed that ICH patients with depression, assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17)[23], experienced significantly more insomnia (50.1% vs 31.8%), loss of interest (36.4% vs 24.5%), psychic anxiety (61.8% vs 44.7%), and fatigue (39.0% vs 27.6%) than did ischemic stroke patients with depression. Similarly, Lisabeth et al[24] reported that compared with ischemic stroke patients, ICH patients frequently experience psychomotor retardation, psychomotor agitation, and weight reduction, all of which can contribute to increased mortality and disability. ICH patients also tend to have symptoms of decreased energy, fatigue, and sleep disorders, such as sleep-disordered breathing.

Screening for mood disorders after a stroke is widely recommended in stroke and stroke rehabilitation guidelines. Numerous screening tools are employed for detecting depression in stroke patients. These tools include the Center for Epidemiological Studies Depression Scale[25]; the Patient Health Questionnaire-9 (PHQ-9)[26]; the Patient Health Questionnaire-2[27]; the GDS, available in 30-item[28] and 15-item versions[17]; the Beck Depression Inventory[29]; the HAMD[23]; the Montgomery-Åsberg Depression Rating Scale (MADRS)[30]; the Hospital Anxiety and Depression Scale[31]; the Stroke Aphasic Depression Questionnaire[32]; the Stroke Aphasic Depression Questionnaire-Hospital version[33]; and the Poststroke Depression Scale[34], as shown in Table 2.

Table 2 Rating scales for depression associated stroke.

Tools	Type of tool	Cut off points	Total score
CESD[25]	Self-report	≥ 16: Depression	60
PHQ-9[26]	Self-report	0-4: No depression	27
		5-9: Mild depression
		10-14: Moderate depression
		15-19: Moderately-severe depression
		20-27: Severe depression
PHQ-2[27]	Self-report	≥ 3: Depression	6
GDS-30[28]	Self-report	≥ 11: Depression	30
GDS-15[17]	Self-report	0-4: Normal	15
		5-8: Mild depression
		9-11: Moderate depression
		12-15: Severe depression
HADS[31]	Self-report	0-7: Normal	21
		8-10: Mild
		11-14: Moderate
		15-21: Severe
BDI[29]	Self-report	0-13: Normal	63
		14-19: Mild depression
		20-28: Moderate depression
		29-63: Severe depression
PSDS[34]	Self-report	0-4: Normal	24
		5-9: Moderate depression
		≥ 10: Severe depression
HAMD[23]	Observational	0-9: Normal	52
		10-13: Mild depression
		14-17: Mild to moderate depression
		> 17: Moderate to severe depression
MADRS[30]	Observational	0-6: Normal	60
		7-19: Mild depression
		20-34: Moderate depression
		> 35: Severe depression
SADQ[32]	Observational	≥ 14: Depression	63
SADQ-H[33]	Observational	Not mentioned	63

CES-D: Center for Epidemiological Studies Depression Scale; PHQ-9: Patient Health Questionnaire-9; PHQ-2: Patient Health Questionnaire-2; GDS-30: Geriatric Depression Scale-30 items; GDS-15: Geriatric Depression Scale-15 items; HAMD: Hamilton Depression Rating Scale; MADRS: Montgomery-Åsberg Depression Rating Scale; HADS: Hospital Anxiety and Depression Scale; SADQ: Stroke Aphasic Depression Questionnaire; SADQ-H: Stroke Aphasic Depression Questionnaire - Hospital version; PSDS: Post Stroke Depression Scale.

While diagnostic criteria are essential, comparing symptom profiles between depressed and nondepressed stroke patients can provide valuable insights for a differential diagnosis. Studies have shown that somatic and affective symptoms account for a significant portion of the variance attributable to depression in stroke patients, suggesting that these symptoms are indicative of PSD, even when potential overlap with other poststroke conditions is considered[35,36]. This possibility is supported by findings that these symptoms are more prevalent in depressed stroke patients than in their nondepressed counterparts. However, the findings of other studies indicate that somatic symptoms may be equally prevalent in both groups[37].

Qualitative studies exploring the lived experiences of patients with depression after stroke have revealed unique themes related to stroke-related sequelae. Through these studies, profound experiences of identity loss, poststroke loneliness, self-blame, guilt, and feelings of being a burden are often identified, particularly when survivors reflect on their lives before and after the stroke[38].

Findings from a systematic review[7] indicated that anhedonia and apathy may be less common and less severe in PSD patients than in major depressive disorder (MDD) patients within the general population. In contrast, emotional dysregulation and work-related disruptions appear to be more prevalent and pronounced in individuals with PSD. Additionally, feelings of being disliked and restlessness may serve as indicators of a greater underlying depression severity among stroke patients. Moreover, patients with PSD may present with milder manifestations of typical depressive symptoms, including a depressed mood, anhedonia, disinterest, feelings of guilt, negative thought patterns, self-deprecation, suicidal ideation, and anxiety, than individuals experiencing MDD in the broader population[39]. The potential reciprocal relationship between somatic symptoms and anhedonia may create a "vicious cycle", suggesting that these two symptom dimensions could serve as useful indicators of risk and targets for intervention. Therefore, regular assessment of depression symptoms beginning during inpatient rehabilitation is crucial for identifying at-risk stroke survivors and facilitating early intervention[40].

In conclusion, differentiating PSD from MDD based solely on clinical symptoms presents significant challenges. The symptoms of PSD are often characterized by heightened emotional dysregulation and somatic manifestations, including alterations in weight, reduced appetite, and sleep disturbances, whereas the classic symptoms of depression are less frequently observed. The literature lacks consistency, complicating the differentiation between PSD and MDD based on clinical presentations. Given that PSD is categorized as an organic mood disorder, a more effective diagnostic approach may involve integrating the specific area of the stroke, synthesizing the patient's symptomatology, and considering the temporal context of depressive symptoms. The use of self-administered instruments such as the PHQ-9[26] may increase diagnostic accuracy, as the nine items on the PHQ-9 align with the nine symptoms outlined in the DSM-5, facilitating comparisons with established clinical diagnostic criteria for depression. Research conducted by Williams et al[41] has shown that the PHQ-9 has a sensitivity of 91% and a specificity of 89% when applied to stroke survivors, with a recommended cutoff score of 10. The PHQ-9 is noted for its convenience, reliability, and validity, making it a suitable tool for the early screening of both MDD and PSD patients. In instances where language barriers or aphasia are present, incorporating insights from formal caregivers and family members is advised to aid in the diagnostic process.

Furthermore, if depressive symptoms manifest more than one year after stroke, the likelihood of PSD diminishes, whereas the probability of an adaptive reaction or MDD increases. In addition to clinical assessments for PSD, the incorporation of biomarkers or neuroimaging techniques may enhance diagnostic validity, as evidenced by research on MDD. Notably, a multiassay serum-based test that includes peripheral biomarkers has been reported to achieve a specificity of 81.3% and a sensitivity of 91.7%[42]. Additionally, abnormalities in gray matter volume across various brain regions are positively correlated with MDD. Functional magnetic resonance imaging studies have revealed that hypoconnectivity within the frontoparietal network, the default mode network (DMN), and midline cortical regions is associated with MDD. Moreover, resting-state functional magnetic resonance imaging is emerging as a valuable neuroimaging modality for investigating functional connectivity within the brain[43]. However, further research is warranted to validate the efficacy of biomarker and imaging-assisted diagnostic approaches.

ETIOLOGY OF PSD

PSD is posited to be affected by mechanisms that are unique to brain injury rather than being exclusively attributable to the psychological responses associated with physical disability. This assertion is supported by the observation that stroke survivors exhibit higher rates of depression than patients experiencing comparable levels of disability resulting from other physical health conditions[44]. The development of PSD is suggested to be multifactorial and involves both biological and psychosocial factors.

The pathophysiological mechanisms underlying PSD remain inadequately understood. PSD is characterized as a heterogeneous condition, and no singular pathophysiological mechanism can comprehensively account for its occurrence[45]. Both biological and psychosocial factors are likely to play roles in the manifestation of PSD. Some potential interactions between these factors that may contribute to the onset and persistence of depressive symptoms have been proposed: (1) The direct influence of medical comorbidities and neurobiological changes; (2) The presence of stroke-specific negative attributes; (3) The effect of cognitive dysfunction on information processing that favors depression-reinforcing evaluations, and (4) The impacts of physical impairments on engagement in activities and social participation[46].

Several primary pathophysiological mechanisms associated with PSD have been identified, including the inflammation hypothesis, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, abnormal neurotrophic responses to stroke, glutamate-mediated excitotoxicity, reduced levels of monoamines, and the location of brain lesions. The effects of these processes appear to be most significant in the frontal lobes, hippocampus, limbic regions, and projections from the basal ganglia[45]. Both ischemia and ICH may activate various signaling pathways, including inflammatory, oxidative, autophagic, and apoptotic pathways, which serve as a link between stroke and the development of depression.

Inflammation hypothesis and dysfunction of the HPA axis

The HPA axis serves as the principal neuroendocrine system responsible for the stress response, playing a critical role in the regulation of mood, immune function, and metabolic processes[47]. Following stroke, a pronounced acute inflammatory response that is characterized by elevated levels of proinflammatory cytokines, including interleukin (IL)-6, C-reactive protein, IL-1β, interferon-gamma, and tumor necrosis factor-alpha (TNF-α), occurs[45,48]. This inflammatory response triggers the release of glucocorticoids. Numerous studies have substantiated the involvement of proinflammatory cytokines in the onset of PSD, with elevated glucocorticoid levels being associated with PSD because of HPA axis dysregulation[49,50]. These mechanisms contribute to a reduction in the transcription of genes encoding neurotrophic factors, thereby impairing neurogenesis and neuroplasticity within the frontal cortex and hippocampus[45]. Furthermore, increased levels of inflammatory cytokines diminish the synthesis and availability of serotonin by increasing the activity of the enzyme indoleamine 2,3-dioxygenase[49].

Molecular aspects of brain injury related to stroke: Both ischemia and hemorrhage in the brain may activate several essential signaling pathways, including inflammation, oxidative stress (OS), autophagy, and apoptosis. These pathways are suspected to play roles in the association between stroke and depression.

Inflammation: Ischemic stroke and ICH are pathological conditions characterized by a reduced blood supply to the brain. Neuroinflammation, which results from hypoxia or hypoxic-ischemic insults, represents a crucial cellular pathway involved in cellular injury and significantly affects the degree of neural tissue damage as well as the potential for functional recovery[51]. Following an ischemic event, inflammatory mediators are released from damaged and necrotic cells, initiating localized inflammation and worsening the ischemic condition. The inflammation that follows ischemia is characterized predominantly by the activation of microglia and macrophages, along with the secretion of chemokines, cytokines, and reactive oxygen species (ROS). The release of these inflammatory mediators after ischemic injury promotes the transcription of various genes, including those encoding TNF, nuclear factor kappa B (NF-kB), and Toll-like receptors (TLRs), which are integral in modulating inflammatory reactions[52]. TLRs are a class of pattern recognition receptors that play a vital role in recognizing pathogen-associated molecular patterns. These receptors can recognize proteins, lipids, and nucleic acids from various pathogens and are expressed by neurons, astrocytes, and antigen-presenting cells in the brain. Furthermore, many types of cytokines, such as interferons and ILs found in ischemic brain areas, can activate TLRs. TLRs may also facilitate several adaptive proteins that activate NF-kB, contributing to the expression of proinflammatory genes, cytokines, and adhesion molecules[53]. A greater increase in TLR expression at the time of admission is correlated with poorer clinical outcomes and a greater increase in the residual cavity volume[54]. The activation of NF-kB signaling mediated by TLRs has also been reported in animal models of ICH[55]. An accumulating body of evidence indicates that TLRs are associated with blood-brain barrier disruption, brain edema, neuronal death and inflammatory reactions following brain injury, as well as unfavorable outcomes in patients with ischemic stroke[56]. Additionally, subsequent hematoma elaboration and disappointing outcomes are associated with inflammatory markers at the early stage of ICH[57]. In an animal model of depression associated with chronic stress, increases in TLR4 mRNA and protein expression, along with elevated levels of inflammatory mediators in the prefrontal cortex, were observed[58]. In contrast, the inhibition of TLR2 and TLR4 has been shown to obstruct the stress-induced increase in proinflammatory responses in the hippocampus following a 24-hour in vivo immune challenge[59]. TLRs are proposed to play a significant role in mediating the inflammatory responses induced by stress, which are associated with behaviors resembling depression[60]. Notably, the TLR mRNA was differentially expressed in individuals with MDD compared with healthy controls, with TLR4 identified as an independent factor correlated with the severity of depression[61]. Furthermore, a reduction in TLR mRNA levels was observed in depressed patients after four weeks of treatment with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, suggesting a potential TLR-mediated anti-inflammatory effect of these antidepressants[62]. An analysis of tissue homogenates for RNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) revealed elevated levels of TLR3 and TLR4 mRNA expression and increased TLR3 and TLR4 protein levels in patients who died by suicide compared with those in control participants[63]. Collectively, both preclinical and clinical studies have identified a potential association between inflammatory responses and depression in the context of PSD.

Nuclear receptors represent a category of transcription factors that are essential for the modulation of target gene expression, thereby impacting a range of physiological processes, such as growth, development, metabolism, reproduction, and homeostasis. The peroxisome proliferator-activated receptors (PPARs) include three different types of nuclear receptors (PPARα, PPARγ, and PPARβ/δ), each encoded by an individual gene[64]. Recent studies have highlighted the beneficial effects of PPARα activation on vascular integrity and function, leading to the clinical use of PPARα agonists for the management of cardiovascular diseases. In recent years, PPARα has garnered attention as a potential therapeutic target for ischemic stroke. Emerging preclinical evidence indicates that the activation of PPARα may modulate several pathophysiological features associated with stroke, such as OS, dysfunction of the blood-brain barrier, and neuroinflammation, thereby facilitating functional recovery. Furthermore, low blood levels of anti-inflammatory neurosteroids and impaired PPAR-α function have been linked to mood disorders and inflammatory processes. Modulators of PPAR-α activity have been shown to reduce systemic inflammation and alleviate depressive-like behaviors and fear responses. PPAR-α exerts significant anti-inflammatory effects by inhibiting the TLR4-mediated NF-kB signaling pathway in immune cells, neurons, and glial cells[65]. PPAR-γ is also involved in inflammatory processes[66]. In experimental models of ICH, treatment with PPAR-γ activators has been shown to accelerate the regression of hematomas in the brain and reduce neurological damage in adult animals following ICH. PPAR-γ agonists can increase PPAR-γ levels in the short term, are associated with increased CD36 expression, and expedite hematoma resolution. Additionally, these treatments have been linked to improvements in neurological function, as well as reductions in long-term ventricular dilation and white matter loss following ICH[67]. Given the roles of PPARs in neuroimmunity and inflammatory processes, PPARs may also play roles in stroke and PSD.

OS: The excessive generation of ROS and the depletion of antioxidant defenses initiate proinflammatory signaling pathways, which compromise essential macromolecules and promote cellular apoptosis. The inability of cells to sustain oxidative-reduction (redox) homeostasis, coupled with the production of proinflammatory mediators, ultimately result in cell necrosis. The heightened susceptibility of the brain to OS can be attributed to its elevated oxygen consumption, high lipid content, and relatively weak antioxidant defenses. OS is a significant factor contributing to neurodegeneration and has been associated with the pathogenesis of MDD. Both OS and proinflammatory signaling have been recognized as essential elements in the etiology of MDD[68]. Reperfusion therapy is considered the standard treatment for patients experiencing ischemic stroke; however, this therapy may also induce ischemia-reperfusion injury. OS and inflammation are critical pathological processes linked to cerebral ischemia/reperfusion injury[69]. ICH can lead to a rapid and sustained increase in intracranial ROS levels, resulting in prolonged OS within the cranial cavity and subsequent neuronal death, which may contribute to secondary neurological deficits[70]. OS refers to a physiological condition characterized by the overproduction of ROS and reactive nitrogen species (RNS) in response to harmful agents. This state can lead to mitochondrial dysfunction and disturbances in the internal cellular environment, which are often the result of various cellular molecules and signaling pathways that contribute to an imbalance in redox reactions. Such imbalances are marked by an increase in ROS and RNS production alongside a reduction in antioxidant defenses. The excessive generation of ROS and RNS can lead to molecular oxidation, alterations in cell membrane integrity, and enzyme inactivation, culminating in cellular damage and functional impairment[71].

Nuclear factor erythroid 2-related factor (Nrf2) is a critical element of the antioxidant system. Nrf2 functions as a transcription factor that can identify antioxidant response elements to modulate the expression of several genes. The activation of the Nrf2 pathway increases the levels of antioxidants, thereby safeguarding cells from the accumulation of free radicals. The neuroprotective role of Nrf2 is underscored by findings that Nrf2 knockout mice exhibit greater brain damage that is associated with elevated ROS levels and increased apoptosis than their wild-type counterparts[72]. In patients with ischemic stroke, Nrf2 can induce the expression of antioxidant genes and protect against damage caused by OS[73]. Furthermore, in a study of fluoxetine, activation of the Nrf2 signaling pathway was shown to be associated with the blockade of serotonin transporters rather than the upregulation of brain-derived neurotrophic factor (BDNF) expression[74].

ROS and RNS are involved not only in oxidative damage but also in apoptosis signaling pathways. The phosphatidylinositol 3-kinase (PI3K/Akt), p38 mitogen-activated protein kinase, and NF-kB pathways are three principal activators of OS-mediated signaling[75]. Akt, a protein kinase and target of PI3K, serves as a signaling molecule for numerous downstream target genes and plays a crucial role in the cell cycle. The evidence suggests that PI3K and Akt can activate immune cells by modulating key inflammatory cytokines, indicating that alterations in the PI3K/Akt pathway may yield specific therapeutic benefits for depression[76]. Research has shown that fluoxetine, atorvastatin, valproic acid, and insulin-like growth factor 1 can mitigate depression-like behaviors through the PI3K/Akt signaling pathway[77,78]. The p38 MAPK signaling pathway serves as a crucial regulator of the biosynthesis of proinflammatory cytokines at both the transcriptional and translational levels. This pathway has the capacity to affect neuroendocrine functions, monoamine neurotransmission, and various pathophysiological mechanisms associated with behavior. Furthermore, stress may trigger a series of molecular and cellular events leading to the activation of p38α MAPK, which subsequently alters the hyposerotonergic state that is implicated in drug-seeking behaviors and depression-like symptoms[79].

Autophagy: Autophagy is a highly conserved intracellular catabolic degradation pathway that is activated in response to conditions of starvation and stress. This process facilitates the delivery of cytoplasmic components to lysosomes for degradation, thereby enabling cells to maintain homeostasis through the recycling of metabolic byproducts. Autophagy is essential for cellular survival; however, excessive autophagy can adversely affect cellular functions, leading to cellular injury or death. In the context of ischemic stroke, autophagy may contribute to neuronal damage following ischemic events[80]. Furthermore, autophagy can promote apoptosis, ultimately resulting in neuronal cell death.

A study of the prefrontal cortex of rodent models indicated that maternal separation, chronic stress, and prenatal stress significantly increase the expression of markers associated with autophagy. Additionally, increased levels of autophagy-related factors have been observed in the postmortem brain tissues of individuals with depression[81]. Mammalian target of rapamycin (mTOR), a protein kinase of the phosphoinositide kinase-related kinase family, plays a crucial role in regulating protein development, synthesis, proliferation, and survival[82]. The activation of mTOR has been shown to mitigate ischemia/reperfusion-induced autophagy, thereby reducing brain damage[83]. Postmortem studies have indicated significant impairments in mTOR signaling within the prefrontal cortex of patients with depression[84]. In patients with recent onset bipolar disorder, a reduction in the expression levels of mRNAs associated with the mTOR pathway has been noted, suggesting the involvement of autophagy-related pathways in emotional disorders[82]. The antidepressant effects on animal models have been partially attributed to the upregulation of mTOR expression in the prefrontal cortex and hippocampus, which plays a role in mediating antioxidant effects[85].

The NF-kB pathway can be activated by autophagy-related proteins and can also directly regulate autophagy. The evidence suggests that autophagy is activated following ICH, possibly resulting in cerebral damage in animal models. NF-kB signaling may play a critical contributory role in neuronal damage by accelerating inflammation[86].

Apoptosis: The pathophysiological alterations associated with ischemic stroke include disturbances in energy metabolism within brain tissue, OS-induced injury, excitotoxicity due to elevated levels of excitatory amino acids, and inflammatory responses. In the ischemic core, the supply of glucose and oxygen is nearly entirely halted, leading to irreversible cellular damage and subsequent cell death through necrosis and apoptosis[87]. Both necrosis and apoptosis have also been documented in individuals following ICH. Experimental studies have revealed the occurrence of apoptotic processes in brain tissues from both animals and individuals with ICH[88,89].

Mitochondria serve as the main cellular energy source and are involved in crucial processes in OS and apoptosis. Abnormal brain energy metabolism-related apoptosis in specific cerebral regions is associated with depression. Disruptions in metabolism, neurotransmission, and neuroplasticity may be involved in the development of depression. Impaired expression of mitochondria-related genes, damaged mitochondrial membrane proteins and lipids, breakdown of the electron transport chain, and increased levels of OS and apoptosis have been reported in preclinical models of depression[90]. Antidepressant medications, including paroxetine[91], agomelatine[92], and duloxetine[93], may play significant roles in the pathophysiology of depression by reducing apoptotic cell death and promoting neurogenesis in the hippocampus.

Abnormal neurotrophic response

Neurotrophins represent a diverse group of soluble molecules that play critical roles in various functions of the nervous system, including cellular growth, differentiation, and plasticity. Among these neurotrophins, BDNF is one of the most extensively researched. In the central nervous system, mature BDNF is instrumental in facilitating synaptic plasticity, promoting dendritic branching, regulating both inhibitory and excitatory neurotransmitter systems, and supporting neuronal growth[94]. Following stroke, neurotrophic activity, including the growth, maturation, and survival of neurons, serves as an acute compensatory and adaptive response to ischemic injury and the loss of neurological tissue[45]. Furthermore, low levels of BDNF are associated with lower National Institute of Health Stroke Scale scores, larger infarct volumes, and unfavorable long-term functional recovery[95]. The neurotrophic hypothesis and neuroplasticity also represent some of the theoretical frameworks for depression. However, individuals experiencing PSD exhibit significantly reduced serum levels of BDNF. A meta-analysis encompassing 33 studies with a total of 1893 participants revealed that patients with PSD had lower serum BDNF levels than did stroke patients who did not exhibit depressive symptoms[96,97]. The reduction in BDNF levels was posited to contribute to the onset of depression.

Glutamate-mediated excitotoxicity

Excitotoxicity is defined by the extracellular accumulation of elevated levels of glutamate or other excitatory amino acids, which results in the excessive activation of glutamate receptors. This overactivation can lead to neuronal death through mechanisms involving calcium influx[98]. Excitotoxicity is prevalent in various chronic central nervous system disorders and is recognized as a primary mechanism underlying neuronal dysfunction and cell death following acute ischemic stroke[99]. During a stroke event, glutamate levels in the extracerebral fluid in the brain and cerebrospinal fluid can increase 300 to 400 times[100]. Consequently, this excess glutamate is disseminated, inflicting neuronal damage in regions beyond the infarcted brain area. The excessive activation of glutamate receptors by excess glutamate results in cellular swelling, apoptosis, and neuronal death, ultimately leading to adverse neurological consequences[97,101]. This phenomenon of overexcitation may particularly impair neurological function in the frontal cortex[45]. Furthermore, glutamate-mediated excitotoxicity has emerged as a significant theoretical framework for elucidating the roles of neurotransmitters in depression. Elevated plasma glutamate levels are correlated with the severity of depression. Postmortem analyses of human frontal cortical tissue have revealed increased glutamate levels in individuals with a history of depression compared with control individuals[102]. Magnetic resonance spectroscopy has revealed a significant relationship between glutamate and PSD via regional variations in glutamate levels[103].

Cerebral small vessel disease

Cerebral small vessel disease (CSVD) is a chronic and progressive condition affecting the arterioles, capillaries, and small veins that supply the white matter and deep structures of the gray matter in the brain. This disorder is characterized by a heterogeneous clinical presentation, as well as distinct alterations observable through neuroimaging and neuropathological assessments. CSVD is associated with various adverse outcomes in elderly individuals, including gait disturbances, cognitive deficits, dementia, depression, and stroke. The etiology of CSVD is multifactorial, with common contributing factors, including arteriosclerosis, cerebral amyloid angiopathy (CAA), genetic small vessel angiopathy, inflammatory and immune-mediated small vessel diseases, and venous collagenosis[104]. Research has revealed that the presence and increased number of silent cerebral ischemic lesions are correlated with a heightened risk of stroke[105]. Most incident strokes are classified as ischemic (81%-89%), whereas hemorrhagic strokes account for 11%-19% of stroke cases[104].

A higher CSVD burden score, which comprises white matter hyperintensities, subcortical lacunar infarcts, and enlarged perivascular spaces, has been reported to be associated with PSD[106]. CSVD is also regarded as the underlying cause of spontaneous ICH. Most ICH cases can be attributed to hypertensive arteriopathy (also referred to as arteriolosclerosis or deep perforator arteriopathy) and CAA. The assessment of CSVD typically involves neuroimaging techniques that evaluate disease etiology and severity by analyzing the characteristics of hematomas (lobar versus nonlobar), white matter hyperintensities, lacunes, cerebral microbleeds, cortical superficial siderosis, and enlarged perivascular spaces. Stroke survivors with CAA-related lobar ICH are at increased risk of depression, are less likely to experience an alleviation of depressive symptoms, and demonstrate diminished responsiveness to antidepressant therapies[107].

Brain network dysfunction

Animal model research has provided insights into the dysfunction of brain networks associated with depression, which may also contribute to the development of PSD. The amygdala, an important structure for the processing of sensory information via thalamic projections, plays a vital role in affective regulation in response to sensory stimuli, facilitated by its connections to the dorsal anterior cingulate cortex and insula. Notably, in patients with MDD, the evidence indicates the hyperconnectivity and enlargement of the amygdala[108]. Furthermore, the nucleus accumbens and its associated neural networks have been implicated in the pathophysiology of depression, as observed in various animal studies. The nucleus accumbens receives dopaminergic input from the ventral tegmental area through the medial forebrain bundle, which is a component of the mesolimbic dopamine (DA) pathway. The suppression of mesolimbic DA release disrupts defensive responses during depressive states, such as learned helplessness, and reduces reward responsiveness, a phenomenon referred to as anhedonia, in individuals suffering from depression[109].

Furthermore, large-scale cortical networks are associated with depressive symptoms in individuals with MDD, potentially due to diminished top-down regulation of emotional processing. Observations have revealed reduced responsiveness and smaller volumes in the DLPFC among individuals with MDD. Notably, at either 10 days[110] or 3 months[111] after stroke, attenuated functional connectivity within the DLPFC has been observed.

Investigations[112,113] have not yielded consistent findings regarding the relationship between the lesion size or location and PSD. One plausible explanation for this inconsistency is that an infarction may trigger a cascade of events, leading to structural and functional alterations in the brain that extend beyond the injury visible on standard MRI scans, thereby affecting behaviors critical for the individual. Advances in microstructural and functional MRI techniques provide methods to characterize these alterations.

The DMN constitutes a large-scale neural network predominantly involving the dorsal medial prefrontal cortex, posterior cingulate cortex, precuneus, angular gyrus, bilateral lateral temporal lobes, and hippocampus. Empirical studies have demonstrated that the DMN plays crucial roles in monitoring both internal and external stimuli, introspection, emotional processing, memory retrieval, and cognitive maintenance[114]. Notably, abnormalities within the DMN during the resting state have been identified as significant neuropathological mechanisms contributing to the etiology of depression[115]. The inability of the DMN to deactivate during cognitive or emotional tasks has been posited as a network-based mechanism that may exacerbate depressive symptoms. Furthermore, heightened activity within the DMN is associated with negative rumination in individuals experiencing depressive episodes[116]. In patients with PSD, reductions in gray matter volume in the right posterior cingulate cortex, along with microstructural alterations in the bilateral posterior cingulate cortex, right medial prefrontal cortex, and medial forebrain bundle - which serve as a principal projection pathway linking the nucleus accumbens and the medial prefrontal cortex-are correlated with the severity of depressive symptoms. The manifestation of depression following a stroke is characterized by a decrease in mutual inhibition between functional circuits, including the nucleus accumbens and the DMN, in addition to volumetric and microstructural alterations within these networks. Consequently, the aberrant network dynamics observed in people with PSD are likely affected by extensive changes in both gray and white matter, occurring distally from the location of the cerebral injury[117]. Moreover, dysfunction in the functional connectivity of the DMN, particularly in relation to emotional regulation, is suggested to be associated with the severity of PSD[118].

Decreased levels of monoamines

Monoamines include 5-hydroxytryptamine (5-HT, or serotonin), DA, and norepinephrine (NE), and the principal monoaminergic nuclei are located in the brainstem[119]. In depression associated with stroke, researchers have hypothesized that ischemic and hemorrhagic damage to these nuclei or to their projections may result in diminished monoamine levels, interrupt the ascending biogenic amine-containing axons from the brainstem to the cerebral cortex and lead to a decreased availability of monoamines (5-HT, DA, and NE) in the frontal cortex, the reward system, and the basal ganglia. These regions are directly or indirectly linked to symptoms of a depressed mood and fatigue[50]. Consistent with findings related to MDD, numerous studies have shown that individuals with depression exhibit lower monoamine levels than those without depression. Additionally, reduced cerebrospinal fluid levels of 5-HT or NE metabolites are significantly correlated with the severity of PSD[120].

Lesion location and PSD

Findings from studies examining the influence of lesion lateralization on PSD are inconsistent. Various meta-analyses have revealed no considerable effect of lesion lateralization[121,122], while some studies have shown left hemispheric lateralization[123], and others have revealed right hemispheric lateralization[124]. The severity of global depression is associated primarily with right hemispheric lesions located in the DLPFC and inferior frontal gyrus[125]. Additionally, a correlation has been established between an increased severity of depression and lesions in the right insular cortex, putamen, and inferior frontal gyrus, as well as structural disconnections in the white matter of the right temporal lobe[126]. Infarcts in the right amygdala and pallidum, along with disconnections in the right limbic and frontal cortico-basal ganglia-thalamic circuits, are proposed to be associated with PSD[127].

Research has indicated that the lateralization of lesions in PSD may be associated with distinct symptoms. Employing the MADRS, investigators have classified depressive symptoms into five domains: Emotional, cognitive deficit, anxiety, motivational, and somatic symptoms. Notably, anxiety symptoms are correlated primarily with lesions localized to the left hemisphere, whereas emotional, somatic, motivational, and cognitive symptoms are associated predominantly with lesions in the right hemisphere[125].

Specifically, lesions impacting the dorsal thalamus, anterior insula, and somatosensory cortex are significantly correlated with emotional symptoms, such as feelings of sadness. Lesions of the DLPFC are linked to impairments in concentration, as well as cognitive symptoms such as guilt and self-reproach. Additionally, anxiety symptoms correlate with lesions in the central operculum, insula, and inferior frontal gyrus. The motivational deficit symptoms correlate with lesions in the DLPFC, orbitofrontal cortex, pre- and postcentral gyri, and basal ganglia, including the putamen and pallidum. Furthermore, somatic symptoms, such as appetite loss and sleep disturbances, are related to lesions in the insula, parietal operculum, and amygdala[125].

The pathophysiological mechanisms underlying PSD can be delineated as follows: (1) Inflammatory processes disrupt intracellular signaling pathways, leading to a decrease in BDNF levels, which are crucial for the regulation of glutamate neurotransmission; (2) Inflammation exacerbates OS, resulting in cellular apoptosis; (3) The occurrence of a stroke enhances autophagic activity, which contributes to neuronal damage and subsequently promotes apoptosis; (4) Stroke increases glutamate levels within the brain, which can induce excitotoxicity in neurons, a phenomenon closely associated with neuronal apoptosis; (5) CSVD, which is linked to stroke, may also precipitate white matter pathology and vascular depression; (6) When a stroke affects regions responsible for emotional regulation, it can directly contribute to the onset of depression and disrupt the functioning of neural networks and projections, thereby exacerbating depressive symptoms; and (7) Ischemic and hemorrhagic damage resulting from a stroke in primary nuclei and neural pathways that govern monoamine activity may hinder the transmission of monoamine axons from the brainstem to the cerebral cortex, consequently diminishing the availability of monoamines in pertinent brain regions. Furthermore, inflammatory responses may also impede serotonin synthesis. The mechanisms by which depression is associated with stroke are summarized in Figure 1.

Figure 1 Conceptual framework of the pathophysiology of poststroke depression.

Psychosocial factors

Research findings indicate that the relationship between biological factors and depression is more pronounced within the initial six months following a stroke, whereas psychological factors become increasingly significant in the later stages of PSD. For example, social isolation emerges as a critical risk factor at one year poststroke, although it is not as relevant immediately after the event[128]. Following a cerebrovascular incident, many patients experience varying degrees of physical dysfunction, which can lead to a diminished capacity for work and daily living. The interplay of familial, societal, and physiological influences contributes to both physiological and psychological imbalances in stroke survivors. Psychosocial elements, including diminished living skills, adverse life events, familial burdens, and the level of social support, may all play a role in the development of PSD. This condition appears to stem not solely from biological factors but rather from a multifaceted origin, aligning with the biopsychosocial model of mental health[114].

An examination of the preexisting personality traits of individuals with PSD revealed that characteristics such as pessimism, neuroticism, introversion, emotional instability, negative coping mechanisms, and high dependency are associated with an increased likelihood of developing PSD[129].

Social support encompasses two dimensions: Objective support, which refers to tangible or practical assistance, and subjective support, which pertains to emotional backing. Adequate social support can improve a patient's psychological resilience, thereby indirectly facilitating recovery and improving the quality of life of stroke survivors. Conversely, individuals lacking social support are at a heightened risk of developing PSD. The evidence suggests that stroke patients residing in community-oriented environments experience lower rates of PSD than those without community engagement do, indicating that appropriate rehabilitative activities may mitigate the risk of PSD[130]. The social support experienced by stroke patients can be understood through their relationships with family, friends, and social networks. Assessing both the positive factors that contribute to familial harmony and the negative impacts that arise from disruptions in family dynamics following a stroke is essential[131]. Key elements that foster harmonious family life include the abilities to contribute to and maintain roles, negotiate support and independence, and express and receive affection. Conversely, the loss of roles, alterations in daily routines, diminished family activities, the management of intense emotions, and communication challenges are factors that can disrupt familial relationships poststroke[132]. With respect to the influence of stroke on friendships and social engagement, the loss of friends, reduced participation in social activities, and feelings of loneliness can hinder the maintenance of social connections[133]. Stroke-related sequelae, such as disability, fatigue, environmental changes and obstacles, loss of activities, financial problems, communication deficits, and labeling, contribute to decreased social participation[134,135]. However, adequate familial support and prestroke friendships can strengthen social engagement and lead to a positive outlook among stroke patients. Additionally, the subjective experiences and value of friendships and social activities, such as interactions with new acquaintances and peer support from stroke support groups, are significant factors in social support. Emotional support, companionship, and assistance that promote independence are also critical components influencing social support[136,137].

The aforementioned etiological factors of PSD suggest that dysfunction within brain networks and specific lesion locations may be more critical in the assessment and diagnosis of PSD, as these elements represent distinctive disease characteristics compared with those of MDD. Clinical depressive symptoms and the location of stroke in the brain are easier to assess and clearly correlated. In the context of pharmacological development and therapeutic interventions, the roles of inflammation, glutamate, and BDNF may be particularly significant. However, importantly, the mechanisms associated with inflammation, glutamate, and BDNF exhibit considerable overlap in the etiologies of both PSD and MDD. Since these physiological factors have been utilized to elucidate the causal pathways for either condition, relying solely on these mechanisms to delineate the etiology of PSD may not effectively differentiate it from MDD, as shown in Table 3. Furthermore, within the neuroendocrine framework, the etiology of MDD incorporates the gamma-aminobutyric acid (GABA) theory, which is less frequently referenced in relation to PSD. In contrast to glutamate, GABA serves as the primary inhibitory neurotransmitter, and its role in maintaining the balance of excitatory neurotransmission is vital for optimal brain function. Numerous studies have indicated that individuals with depression exhibit neurotransmission or functional impairments related to GABA, with findings showing that GABA levels in the brains of depressed patients are lower than those in healthy controls. Postmortem analyses have revealed diminished levels of the GABA-synthesizing enzyme glutamic acid decarboxylase in the prefrontal cortex of individuals diagnosed with depression[138]. Another relevant mechanism is the microbiome-gut-brain axis, which posits that the gut microbiota may interact with the brain through various pathways, including the HPA axis, as well as the neuroendocrine, autonomic, and neuroimmune systems[139]. Additionally, genes associated with circadian rhythms, particularly their critical interactions (such as those between the HPA axis and mitochondrial metabolism), have also been linked to the etiology of MDD[140].

Table 3 Comparison of etiology for poststroke depression.

	Inflammation	Abnormal neurotrophic response, glutamate excitotoxicity	Brain network dysfunction, lesion location	Cerebral small vessel disease	Decreased levels of monoamines	Psychosocial factors
Mechanism	Extracellular, intracellular	Extracellular, intracellular	Extracellular	Extracellular	Extracellular	Environmental, interpersonal
Main study subjects	Animals	Animals	Human	Human	Human	Human
Study samples	Smaller	Smaller	Larger	Larger	Larger	Larger
Study design	Experimental, comparative	Experimental, comparative	Comparative, systematic review	Comparative, cohort study	Comparative, cross sectional	Cohort study, systematic review
Linked to depressive symptoms in study	Not yet	Not yet	Yes	Not yet	Yes	Yes
Role in major depression	Significant	Significant	Less significant	Significant	Significant	Significant
Role in poststroke depression	Significant, within 6 months after stroke	Significant, within 6 months after stroke	Significant, within 6 months after stroke	Significant, within 6 months after stroke	Significant, within 6 months after stroke	Significant, impact is greater after 6 months

Regarding psychosocial factors, physiological mechanisms appear to be more influential in the development of PSD within the first six months following an acute stroke, whereas psychosocial factors become more significant than physiological factors after this period. Notably, psychosocial factors may also serve as risk factors for the onset of PSD.

CONCLUSION

Approximately one-third of individuals who have suffered a stroke develop PSD throughout their recovery, a prevalence that exceeds that of depression in the general population. The occurrence of PSD is notably increased during the initial phase following a stroke, particularly within the first year. Research conducted in Western countries indicates that patients with ischemic stroke have a higher incidence of PSD than do their counterparts with hemorrhagic stroke. Conversely, studies in Eastern countries, including Japan and China, have revealed that the incidence of PSD is higher among patients with hemorrhagic stroke than among those with ischemic stroke. Further research on this phenomenon is needed. In diagnosing PSD, studies often use scales to assist in determining the diagnosis. The use of objective tools, such as diagnostic interviews by researchers or semistructural measurements, can increase the diagnostic accuracy of self-report scales. However, since stroke patients may exhibit physical symptoms, such as a decline in physical strength and cognitive impairment, these symptoms can be confused with those of depression. Therefore, exploring the differences in symptoms between PSD and depression in the general population is an important topic for which further research is needed. The diagnosis of PSD presents significant challenges. Distinguishing PSD from MDD based solely on symptomatic criteria is insufficient. Refining and augmenting the measurement tools by assigning greater weight to the individual symptoms of PSD that exhibit greater discriminatory power may be essential to enhance the differential diagnosis through clinical symptomatology. Furthermore, the exploration and implementation of biomarkers and imaging techniques to aid in the differentiation between PSD and MDD represent promising avenues for future research. The etiology of PSD is currently believed to result from physiological and psychosocial factors or the interplay between them. Several pathophysiological mechanisms associated with PSD have been identified, including inflammation, dysfunction of the HPA axis, OS, autophagy, apoptosis, abnormal neurotrophic responses, glutamate-mediated excitotoxicity, brain network dysfunction, reduced levels of monoamines, and the location of brain lesions. With respect to the psychosocial etiologies of PSD, poststroke cognitive deficits, physical dysfunction, diminished living skills, adverse life events, familial burdens, a past psychiatric history, premorbid personality traits, and the level of social support are the primary associated factors. Several avenues remain for further investigation concerning the pathogenic mechanisms underlying PSD. Notably, the roles of genes, GABA, and the microbiome-gut-brain axis, which are frequently referenced in the etiology of MDD, warrant exploration in the context of PSD. While alterations in DMN function have been implicated in the etiology and mechanisms of both PSD and MDD, whether specific changes in DMN functionality occur in the brain following a stroke that is uniquely associated with PSD remains to be determined. Identifying such distinct findings could enhance the differential diagnostic processes. Further research must be conducted to ascertain whether varying etiological factors yield different clinical presentations, to facilitate more precise assessment and treatment strategies, as well as to establish connections between etiology and clinical manifestations. Additionally, investigations into the neuroinflammatory responses associated with different stroke locations and brain networks are necessary, along with an examination of the relationship between physiological responses in these regions and the clinical symptoms of depression. Finally, the interplay between the area affected by stroke or CSVD, alterations in monoamine neurotransmitter levels, and the resulting clinical symptoms and manifestations should be explored, as this knowledge could inform pharmacological interventions.

ACKNOWLEDGEMENTS

The authors thank the geriatric psychiatry team of our hospital for their advice and assistance in reviewing the literature.