Schizophrenia is a debilitating neuropsychiatric disorder that profoundly alters mental processes, including thought, perception and emotional regulation (15). Schizophrenia typically manifests in late adolescence or early adulthood, with rare diagnoses in childhood or later stages of life. Although the prevalence is similar across men and women, the progression and severity of symptoms exhibit notable differences; men generally experience more severe symptoms at an earlier age, while women often present with more depressive symptoms and a later onset (16,17).

Clinically, schizophrenia is categorized into three primary symptom types: Positive, negative and cognitive (1). Positive symptoms include hallucinations (commonly auditory), delusions and disorganized speech, which represent distortions or exaggerations of normal perceptions and beliefs. For instance, patients may hear non-existent voices or believe they are being persecuted without basis (18). Negative symptoms are characterized by reduced emotional expression, infrequent speech and a lack of motivation, often resulting in withdrawal and inactivity (19). Cognitive symptoms involve impairments in executive functions, such as processing complex information, maintaining focus and managing working memory, skills essential for decision-making and daily functioning (2). The Positive and Negative Syndrome Scale (PANSS) is key for assessing schizophrenia, evaluating both positive and negative symptoms (20). This scale serves a vital role in diagnosis, treatment guidance and symptom monitoring (21). Neuroimaging studies have highlighted both structural and functional brain abnormalities in schizophrenia (22). Structural imaging demonstrates decreased gray matter volume and cortical thinning, especially in regions such as the hippocampus, amygdala, thalamus and frontal cortex, areas critical for memory, emotion regulation, sensory gating and decision-making (22). Functional imaging demonstrates altered activation patterns during cognitive tasks and atypical resting-state brain activity (23). Furthermore, diffusion tensor imaging has identified white matter tract abnormalities, suggesting disrupted connectivity between brain regions (24,25).

Genetics strongly influence the development of schizophrenia, with heritability estimates ranging from 60-85% (26). The disorder is polygenic, involving complex interactions across multiple genetic loci that increase susceptibility. Genome-wide association studies (GWAS) have pinpointed several genomic regions linked to schizophrenia, highlighting the significance of synaptic organization and neurotransmission in its pathogenesis (27). Environmental factors also serve a substantial role in the onset of schizophrenia. Prenatal and perinatal exposures to infections or malnutrition, psychosocial stress, trauma, substance use during adolescence, urban living and migration all contribute to the schizophrenia development. These factors emphasize the developmental vulnerability of the brain to environmental stressors (28). Together, these findings illustrate the multifaceted nature of schizophrenia, underscoring the need for an integrated approach that considers both biological and environmental influences in its management and treatment.

The pathophysiology of schizophrenia is multifaceted, involving genetic factors, neurodevelopmental disruptions, neurotransmitter imbalances and neuroimmune alterations (Table I) (15,28-56). Each of these components contributes to the complexity of schizophrenia, emphasizing the need for comprehensive therapeutic approaches that target these diverse mechanisms.

Schizophrenia is increasingly recognized as a neurodevelopmental disorder, characterized by disruptions during critical stages of brain maturation that significantly influence its onset and progression. These disruptions are often compounded by genetic vulnerabilities and environmental factors such as prenatal exposure to toxins or infections (31). The neurodevelopmental hypothesis asserts that key developmental phases, particularly early gestation and adolescence, involve crucial processes such as cell proliferation and synaptic pruning, which are essential for normal cognitive and emotional development (32).

During adolescence, synaptic pruning serves a vital role in enhancing neuronal network efficiency by eliminating redundant synapses; however, in schizophrenia, this process may become excessive. For instance, the immune response of the brain which is mediated by microglia that clear pathogens and prune synapses, may become overactive. The activation of the complement system, particularly the complement C4-A (C4-A) gene during late adolescence, has been implicated in driving the excessive synaptic pruning observed in schizophrenia (33). C4-A is essential for synaptic pruning, marking synapses for removal by microglia, thereby establishing a direct genetic-neuropathological connection to the disorder. This excessive pruning leads to significant synaptic loss, disrupting the balance between excitatory and inhibitory signals in the brain (34,56).

Key genes such as neuregulin-1 and disrupted-in-schizophrenia-1 (DISC1) also serve pivotal roles in brain development and are functionally interconnected (35,36). For example, DISC1 influences neurogenesis in the dentate gyrus and is involved in synaptic transmission and astrocyte development (57). Furthermore, environmental factors such as prenatal infections, malnutrition and early-life stress exacerbate genetic predispositions, increasing the complexity and susceptibility of schizophrenia (39). This pathological synaptic loss significantly affects gray matter volume in critical brain regions, such as the prefrontal cortex, which is essential for higher cognitive functions (38,44).

The initial model of schizophrenia attributed positive symptoms, such as hallucinations and delusions, to hyperdopaminergic activity in the mesolimbic pathway, while negative symptoms, such as social withdrawal and apathy, were linked to dopaminergic hypoactivity in the mesocortical pathway (58). Consistently, elevated dopamine synthesis and release capacity have been observed in the striatum of individuals with schizophrenia (59). Recent research, however, presents a more nuanced perspective, emphasizing that the timing, specific sites of dopamine release and receptor sensitivities are critical factors in understanding the variability of symptoms among patients (60-62). This approach moves beyond dopamine dysregulation, offering further insights into the neurochemical dynamics underlying the disorder (46).

There is increasing recognition of the complex interactions between dopamine and other neurotransmitter systems, particularly glutamate, in schizophrenia (46,56). Glutamate, the primary excitatory neurotransmitter, has been implicated in both cognitive deficits and negative symptoms, underscoring its pivotal role in the pathology of schizophrenia (45,47). Variations in glutamate levels across brain regions highlight the potential role of region-specific glutamatergic dysfunction in the development and symptom heterogeneity of schizophrenia (47). Dopaminergic activity in the midbrain is heavily influenced by glutamatergic inputs from the frontal cortex. This interaction forms a complex neural circuit, where cortical pyramidal glutamatergic neurons activate GABAergic interneurons, which, in turn, inhibit further glutamate release from cortical neurons projecting to midbrain dopamine neurons. This regulatory mechanism helps control the excitatory inputs received by dopamine-producing neurons (50,63). γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the CNS, is critical for maintaining neural circuit balance. In schizophrenia, disrupted N-methyl-D-aspartate receptor (NMDAR) activity on GABA interneurons impairs inhibitory control, contributing to the cognitive deficits associated with the disorder (59). Imbalances in this system can lead to either increased or decreased dopaminergic output, significantly affecting the pathophysiology of schizophrenia (64). These disturbances highlight the need to elucidate the complex interplay between neurotransmitter systems, as this may reveal novel therapeutic targets, such as glutamatergic modulators or GABAergic enhancers, offering more effective interventions for schizophrenia.

The etiology of schizophrenia is increasingly viewed in terms of neuroimmune interactions, highlighting the complex interplay between genetic predispositions, environmental triggers and immune system dysregulation (65,66). This perspective shifts the traditional understanding of neuroinflammation from a consequence to a potential contributing factor in schizophrenia development (67).

The major histocompatibility complex on chromosome 6, essential for immune regulation, is associated with schizophrenia (68,69). Dysregulation of genes within this locus, related to innate immunity, may induce a pro-inflammatory state in the CNS, exacerbating synaptic and neurotransmitter disturbances (27,49). Increased levels of inflammatory markers in both blood and CSF have been consistently observed in patients with schizophrenia (70-72). Specifically, IL-6 levels are significantly higher in the CSF of patients with schizophrenia compared with that of healthy controls (73). IL-6 levels remain elevated in both acute and chronic phases of psychosis, reinforcing the complex relationship between neuroinflammatory processes and schizophrenia pathology (71,74). This inflammation, marked by increased levels of cytokines such as IL-6, influences neurotransmitter systems, including dopaminergic and glutamatergic pathways, which may exacerbate schizophrenia symptoms (51,75). Furthermore, increased IL-6 levels correlate with cognitive decline and greater severity of both positive and negative symptoms. Elevated C-reactive protein, a systemic inflammation marker, has also been associated with worsened cognitive function during acute psychosis (76). The entry of pro-inflammatory cytokines and neurotoxic compounds into the CNS triggers an inflammatory cascade linked to reactive oxygen species (ROS) production. While ROS are normally byproducts of cellular metabolism, excessive production leads to substantial cellular damage. This inflammatory response, in conjunction with elevated ROS, activates microglia and astrocytes, critical immune cells in the brain, further promoting cytokine release and ROS production. The resulting cycle of increased oxidative stress damages cellular components, including membranes, proteins and DNA, contributing to neuronal injury and dysfunction (77,78).

Additionally, maternal immune activation during pregnancy due to infections such as influenza or Toxoplasma gondii can disrupt immune regulation in the developing fetus. The associated increase in cytokines such as IL-6 may impair normal brain development, elevating the risk of schizophrenia in offspring (79). This emerging understanding underscores the significant role immune system interactions serve in shaping the neuropsychiatric outcomes of individuals predisposed to schizophrenia.

Antipsychotics remain the primary treatment for schizophrenia, targeting dopamine receptors to alleviate core symptoms such as delusions and hallucinations. These medications are broadly classified into two categories: Typical (first-generation) and atypical (second-generation) antipsychotics. Typical antipsychotics, such as haloperidol and chlorpromazine, exert their effects mainly through dopamine D2 receptor antagonism and are often associated with significant adverse effects, including extrapyramidal symptoms (EPS), tardive dyskinesia and neuroleptic malignant syndrome (80,81). By contrast, atypical antipsychotics, including risperidone, olanzapine, quetiapine and aripiprazole, target both dopamine D2 and serotonin 5-HT2A receptors. While these agents carry a reduced risk of motor side effects, they are more frequently linked to metabolic complications, such as weight gain, insulin resistance and increased cardiovascular risk (82,83). Current treatment guidelines, such as those from the American Psychiatric Association and the National Institute for Health and Care Excellence, recommend second-generation antipsychotics as first-line therapy, with drug selection tailored to individual symptom profiles, side effect tolerance and comorbid conditions. Despite their efficacy, ~33% of patients with schizophrenia exhibit resistance to standard antipsychotic treatments (84,85).

Targeting the BBB has demonstrated new therapeutic avenues for treating schizophrenia. Although no FDA-approved drugs currently regulate tight junction proteins, existing anti-inflammatory therapies have demonstrated promise in improving schizophrenia symptoms. Cyclooxygenase inhibitors, minocycline, neurosteroids, N-acetylcysteine (NAC), statins and estrogens have all shown consistent benefits (86). Minocycline inhibits microglial activation and TNF-α production, indirectly stabilizing BBB integrity (87). NAC boosts glutathione levels and inhibits IL-6 and IL-1β, reducing oxidative stress (88). A 6-month course of NAC at 2 g/day has been shown to reduce overall symptom severity significantly (PANSS effect size=0.45) (89).

Among novel therapies, lumateperone (Caplyta^®) has shown potential as a treatment option. Lumateperone modulates dopaminergic, serotonergic and glutamatergic neurotransmission, while its anti-inflammatory properties reduce cytokines such as IL-1β, IL-6 and TNF-α. By restoring BBB integrity, lumateperone improves barrier function and mitigates inflammation triggered by immune challenges or stress (90). Clinical trials, including ITI-007-301 and ITI-007-005, have shown significant efficacy in managing schizophrenia and bipolar depression symptoms (91). The favorable side effect profile of lumateperone, lower rates of EPS and minimal metabolic impact, makes it an attractive treatment option. Lumateperone also reduced relapse risk by 63% over 26 weeks (hazard ratio=0.37), with relapse rates of 16.4% compared with 38.6% for placebo. The drug demonstrated a favorable safety profile, with low akathisia rates (2.1 vs. 6.9% placebo), minimal sedation [24%; number needed to harm (NNH)=8] and few treatment discontinuations. Serious adverse events, such as seizures (0.2%) and orthostatic hypotension (0.3%), were rare (92). However, variability in clinical trial outcomes underscores the need for further studies to further understand the long-term benefits and limitations, particularly in diverse patient subgroups (93,94).

The BBB serves a critical role in maintaining CNS homeostasis by regulating the exchange of substances between the blood and the brain. Comprised of endothelial cells lining the capillaries of the brain, the BBB is specifically structured to protect the brain from potential harm while facilitating the efficient transport of essential nutrients into the environment of the brain (95).

The BBB is reinforced by endothelial cells connected by tight junctions formed by transmembrane proteins, including OCLN and CLDNs, particularly CLDN5 (96). These proteins are essential for maintaining the selective permeability of the barrier, permitting the passage of essential nutrients while blocking harmful substances. Scaffolding proteins such as zonula occludens-1 (ZO-1) and junctional adhesion molecules (JAMs) provide structural support and facilitate cellular signaling critical for regulating barrier function and integrity. Surrounding the endothelial cells, the basal lamina offers additional reinforcement, incorporating proteins such as collagen type IV, laminin and fibronectin (95). Collagen type IV forms a scaffold supporting endothelial cells and pericytes, laminin enhances cell adhesion and influences differentiation and migration, while fibronectin facilitates cell adhesion and modulates growth and migration (97). These interactions are pivotal for the organization and stability of the BBB (98). Embedded in this extracellular matrix, pericytes regulate blood flow and contribute to BBB integrity, serving a pivotal role in processes such as angiogenesis and barrier repair. Astrocytic end-feet closely envelop the endothelium, augmenting tight junction functionality and supporting the overall operations of the barrier. This intricate structure ensures that the BBB effectively controls the entry and exit of substances, maintaining the protected environment of the brain (98).

The tight junctions of the BBB limit the diffusion of hydrophilic molecules, allowing only selective substances to penetrate. This selective permeability is essential for preventing harmful substances from entering the brain while enabling the passage of necessary nutrients. Nutrient transport across the BBB is mediated by specialized transporter proteins, such as GLUT1 for glucose and LAT1 for amino acids, which are essential for supplying neuronal cells with the substrates required for energy production and neurotransmitter synthesis (99). In addition to nutrient transport, the BBB employs efflux transporters such as P-glycoprotein (P-gp) to actively expel potentially harmful substances, such as neurotoxins and excess neurotransmitters, that may have crossed into the brain. This protective mechanism helps maintain chemical stability and safeguards the brain against toxic threats, ensuring optimal function (100,101). Transport across the BBB occurs via several mechanisms: Passive diffusion for small lipophilic molecules, carrier-mediated transport for essential nutrients, receptor-mediated transcytosis for larger molecules and efflux pumps for removing potentially harmful substances (7). Furthermore, the BBB serves a critical role in maintaining ion balance, preventing electrolyte disturbances that could disrupt neuronal function. It also dynamically adjusts its permeability in response to both physiological and pathological stimuli, such as inflammation, to meet the needs of the CNS (3).

Clinical studies and case reports (76,102) provide compelling evidence of BBB abnormalities in individuals diagnosed with schizophrenia, suggesting that BBB dysfunction may serve a significant role in the pathophysiology of schizophrenia (Table II) (13,18,71,103-111). A meta-analysis demonstrated that ~16% of patients with first-episode psychosis exhibit increased BBB permeability (18), indicating that BBB dysfunction may manifest early in the illness and potentially serve as a biomarker. However, it is essential to consider potential confounding factors such as medication use, concurrent medical conditions and lifestyle factors, all of which may impact BBB integrity (112-114). Furthermore, the heterogeneity among patients with schizophrenia, including variations in symptomatology, disease progression and treatment response, presents challenges in generalizing these findings across the broader patient population (115). Future studies should address these confounders and explore subgroup analyses to refine the current understanding of BBB dysfunction in specific cohorts.

BBB dysfunction in schizophrenia is evident in both the CSF and systemic biomarkers. For example, studies have shown that ~29.4% of patients with schizophrenia display elevated CSF/serum albumin quotient (Q-Alb) levels, indicating impaired barrier selectivity that allows blood-derived proteins to infiltrate the CNS (103,116). In addition to increased Q-Alb, elevated total protein levels in CSF further underscore the extent of BBB disruption, reflecting a loss of selective permeability. This indicates that the BBB is no longer effectively restricting the passage of large plasma-derived proteins, allowing non-specific leakage into the central nervous system (18,71).

Serum biomarkers also support the evidence of BBB compromise. S100 calcium binding protein B (S100B), an astrocyte-derived protein, leaks into the bloodstream when the BBB is disrupted, correlating with neuroinflammatory activity (104). Similarly, elevated MMP9 levels in schizophrenia contribute to the degradation of tight junction proteins and extracellular matrix components, perpetuating BBB leakage and neurovascular remodeling (105,106). Increased zonulin levels, a regulator of paracellular permeability, in the serum of patients with schizophrenia further indicate compromised BBB integrity (108).

Neuroimaging studies, particularly dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), have notably advanced the current understanding of BBB dysfunction in schizophrenia (14,23,102). These studies demonstrate substantial BBB leakage in patients at their first episode of psychosis, suggesting that such disruptions may be foundational to disease onset rather than secondary manifestations and could potentially serve as early biomarkers (117). DCE-MRI findings demonstrate that increased BBB permeability, quantified by the volume transfer constant (Ktrans), correlates with increased symptom severity and longer disease duration (118).

Advancements in positron emission tomography (PET) imaging have also enhanced the current understanding by enabling non-invasive assessments of BBB permeability using specialized radiotracers. Advancements in positron emission tomography (PET) imaging have also enhanced the current understanding by enabling non-invasive assessments of BBB permeability using specialized radiotracers. In schizophrenia, PET studies utilizing tracers such as [¹¹C]-verapamil and [¹¹C]-L-dopa have demonstrated region-specific reductions in P-glycoprotein function and altered dopamine synthesis capacity, particularly in the striatum and prefrontal cortex (10,119). Additionally, functional MRI (fMRI) can assess cerebral blood flow (CBF) and neuronal activity, offering insights into how BBB dysfunction affects the clinical symptoms of schizophrenia (12,120).

Genetic and developmental factors serve a pivotal role in the pathogenesis of BBB dysfunction in schizophrenia (12). The genetic basis of BBB disruption is exemplified by 22q11.2 deletion syndrome (22qDS), a disorder caused by a deletion of a small DNA segment on chromosome 22, which not only elevates schizophrenia risk but also impairs key genes essential for BBB integrity (120). Notably, CLDN5, encoding claudin-5, a protein critical for maintaining BBB tight junctions, is significantly affected in this context and implicated in the pathophysiology of schizophrenia (107). Induced pluripotent stem cell models derived from patients with 22qDS exhibit a 'leaky' BBB phenotype, marked by disorganized claudin-5 and enhanced permeability (120,121).

Additionally, GWAS have identified loci linked to both schizophrenia susceptibility and vascular health, highlighting genes such as slit guidance ligand (SLIT)1, SLIT3 and roundabout guidance receptor 1, which regulate endothelial signaling and angiogenesis (13,122). The Frizzled Class Receptor 1 (FZD1) gene, integral to the Wnt signaling pathway that governs endothelial function and BBB integrity, shows a notable independent genetic association with schizophrenia, as identified in GWAS and supported by transcriptomic analyses of patient-derived brain tissue (123). In particular, reduced FZD1 expression has been observed in the prefrontal cortex of individuals with schizophrenia, suggesting impaired Wnt signaling may contribute to BBB dysfunction and heightened neuroinflammatory susceptibility (124).

These findings underscore the direct impact of genetic predispositions on BBB integrity in schizophrenia, increasing susceptibility to environmental factors and potentially accelerating disease progression.

CBF quantifies the volume of blood flow through brain tissue over time, increasing in response to neuronal activity to ensure adequate oxygen and glucose supply for metabolic demands (125). However, in schizophrenia, reduced CBF impairs this process, exacerbating neuronal damage and cognitive deficits, including auditory verbal hallucinations (AVHs) (126). A failure in neurovascular coupling has been identified, correlating with specific symptoms such as AVHs (127), as well as a broader reduction in CBF associated with cognitive decline and dementia progression (128).

The BBB is integral in regulating CBF and maintaining brain health by stabilizing the microenvironment and facilitating the clearance of metabolic waste (40,129). BBB dysfunction disrupts CBF regulation, leading to the accumulation of neurotoxic substances and the amplification of neuroinflammatory processes that impair synaptic function (130). This relationship underscores the critical role of BBB integrity in mitigating the progression and symptom severity of schizophrenia (131).

In schizophrenia, BBB disruption permits the entry of peripheral immune components into the CNS, exacerbating deficits in synaptic pruning and neurotransmitter imbalances central to the pathology of schizophrenia (10).

Elevated levels of soluble P-selectin (sP-selectin) and soluble intercellular adhesion molecule in patients indicate a pro-inflammatory state that promotes immune cell migration across the compromised BBB (111). This infiltration activates glial cells, including microglia and astrocytes, which release pro-inflammatory cytokines such as IL-6 and TNF-α (132), exacerbating cognitive and psychotic symptoms by disrupting neurotransmitter systems, particularly glutamatergic and dopaminergic pathways (73,132). Additionally, inflammation can further disrupt GABAergic signaling, disrupting the delicate balance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission, essential for cognitive function (10,133). Inflammation related to BBB dysfunction may also affect serotonin transporter activity and receptor function, influencing these symptoms (10). Furthermore, the neuroinflammatory process may damage the BBB further, creating a harmful feedback loop that exacerbates the symptoms and progression of schizophrenia (134,135). The increased vulnerability of the brain to immune mediators following BBB compromise highlights the need for longitudinal studies on BBB function in individuals at high risk for psychosis to further understand and address these complex interactions (133,136).

BBB disruption in schizophrenia leads to neurochemical imbalances, significantly impacting neurotransmitter systems essential for CNS homeostasis, and contributing to a wide range of symptoms including hallucinations, delusions, social withdrawal, apathy and cognitive deficits. Hammer et al (137) suggested that although NMDAR autoantibody prevalence is similar between patients with schizophrenia and controls, these autoantibodies correlate with more severe neurological and affective symptoms in patients exhibiting markers of BBB disruption, such as a history of head trauma or the presence of the apolipoprotein E4 allele. Animal models further support these findings by demonstrating that the pathogenic effects of neuronal autoantibodies manifest only when BBB integrity is compromised (10). In one study, mice passively infused with human-derived anti-NMDAR IgG displayed no behavioral abnormalities under normal BBB conditions; however, when BBB permeability was transiently increased, via systemic lipopolysaccharide injection or mannitol-induced osmotic opening, mice developed anxiety-like behaviors, memory impairments and reduced exploratory activity (138). Molecular analyses revealed decreased synaptic NMDAR density and altered glutamatergic signaling in the hippocampus. These findings highlight that circulating autoantibodies require BBB disruption to access neuronal targets and exert neurotoxic effects, underscoring the pivotal role of BBB integrity in modulating autoimmune contributions to schizophrenia-like phenotypes.

The BBB also regulates the transport of essential nutrients and precursors required for neurotransmitter synthesis. For instance, dopamine synthesis depends on the availability of tyrosine, an amino acid that must cross the BBB. When BBB permeability is compromised, the transport of key precursors such as tyrosine is hindered, resulting in reduced dopamine synthesis and potentially affecting other neurotransmitters (9,46,139,140). Increased BBB permeability allows neurotoxic substances and bioactive molecules, such as glutamate, norepinephrine, epinephrine and glycine, to infiltrate the brain, disrupting neurotransmitter balance. This dysregulation further impairs neuronal communication, intensifying cognitive dysfunction, emotional instability and psychotic symptoms in schizophrenia (141).

Research on BBB permeability in schizophrenia has become a pivotal area of investigation, providing insight on the neurobiological mechanisms underlying of the disorder. Given the heterogeneity of schizophrenia, with distinct subtypes potentially exhibiting different pathophysiological mechanisms, variability in BBB dysfunction may arise and should be considered a potential source of bias (142).

Demographic factors such as age, sex and comorbidities such as depression may also influence BBB permeability. Furthermore, the impact of medications, particularly antipsychotics, on BBB integrity represents a significant confounding factor. For instance, clozapine may stabilize BBB function in certain patients, complicating causal interpretations (143). Environmental factors, including stress and trauma, commonly experienced by individuals with psychosis, can further impact BBB function (144).

From a methodological perspective, imaging techniques used to assess BBB permeability, such as DCE-MRI and ASL, could undergo further rigorous evaluation in improve reliability and standardization across participants. The generalizability of current findings is constrained by relatively small sample sizes (schizophrenia, n=29; controls, n=18) (14). Larger and more diverse cohorts are essential to determine the applicability of these findings to a broader schizophrenia population. Furthermore, inconsistencies across studies may arise from heterogeneity in imaging parameters, contrast agent administration protocols, region-of-interest definitions and permeability quantification models. For instance, while some DCE-MRI studies have reported increased BBB leakage in regions such as the hippocampus and temporal cortex, others have not detected significant changes, likely due to variations in acquisition timing, contrast dosage or differences in permeability metrics (e.g., Ktrans vs. Vp) (14). ASL, although non-invasive and contrast-free, measures cerebral perfusion rather than direct barrier permeability, making it difficult to disentangle BBB disruption from secondary vascular changes (129). Addressing these gaps will deepen the current understanding of BBB permeability changes in schizophrenia and guide future research directions.

Recent technological advancements have provided new avenues for molecular, physiological, neurophysiological and genomic insights. Dynamic in vitro BBB models, microfluidic BBB and BBB-on-a-chip platforms offer sophisticated systems for studying BBB permeability (145-147). Additionally, new cell culture scaffolds containing essential anchoring or adhesion molecules allow more precise control over cell differentiation, interactions and responses (148).

Patient-derived brain organoids have emerged as invaluable models for investigating BBB dysfunction in schizophrenia. Organoids derived from patients with schizophrenia exhibit a 30-50% increase in paracellular permeability and display elongated microvascular networks, associated with the dysregulated expression of tight junction proteins CLDN5 and OCLN. Differential gene expression analysis of endothelial cells isolated from schizophrenia patient-derived brain organoids reveals significant enrichment of genes related to angiogenesis, vascular regulation and inflammatory responses when compared with controls (149,150).

Using primary cultures derived from human cells could mitigate species-specific differences; however, their availability is limited due to ethical considerations. The olfactory system, closely associated with significant olfactory deficits in patients with schizophrenia, has become a key model in schizophrenia research (151,152). The olfactory epithelium (OE) offers a 'unique' window into the brain, providing an opportunity to assess various hypotheses related to the neurodevelopmental models of schizophrenia (153). Recent single-cell RNA sequencing of cultured nasal turbinate cells derived from patients with schizophrenia has shown that these cells closely resemble neural progenitors and mesenchymal cells found in the olfactory neuroepithelium and the developing brain (154). The OE presents a minimally invasive source of neurons and precursor cells, sharing developmental origins with CNS cells, facilitating the study of gene-genomic interactions and neurophysiological processes relevant to both schizophrenia and BBB pathology (155).

These innovations enable researchers to further simulate the complex interactions underlying BBB dysfunction and explore potential therapeutic interventions for conditions such as schizophrenia.

Current research on BBB dysfunction in schizophrenia highlights the critical role of biomarkers and imaging techniques in understanding and diagnosing the disorder. However, the reliable assessment of BBB integrity remains challenging due to the indirect nature of numerous existing biomarkers and imaging methods. For instance, plasma S100β levels have been shown to correlate with negative symptoms and cognitive deficits in schizophrenia (156). Meta-analyses further indicate a positive association between S100β levels, positive symptoms and disease progression, suggesting that BBB permeability may increase as the disease advances (157). However, it remains unclear whether elevated S100β directly reflects increased BBB permeability or merely signifies enhanced glial cell production/secretion or degeneration.

The integration of blood-based biomarkers with advanced neuroimaging techniques has potential for more comprehensive and patient-specific diagnostic approach. For example, while DCE-MRI Ktrans values provide valuable insights into BBB dysfunction, they lack the molecular specificity needed to fully elucidate the mechanisms underlying BBB impairment (14). To overcome this limitation, combining DCE-MRI with PET imaging could enable molecular-level visualization. PET could employ radiolabeled probes targeting specific BBB markers such as CLDN5 or OCLN, which are vital for tight junction formation and permeability regulation. However, these PET tracers are still in early developmental stages, and conclusive evidence supporting their clinical application for BBB visualization, particularly in schizophrenia, remains lacking (158,159).

By integrating these biomarkers with advanced imaging techniques, diagnostic accuracy can be significantly improved, enabling longitudinal tracking of BBB dysfunction. This combined approach would facilitate more targeted, personalized diagnostics, enhancing the monitoring of disease progression and therapeutic responses in individual patients with schizophrenia.