Blood‑brain barrier dysfunction in schizophrenia: Mechanisms and implications (Review)

Introduction

Schizophrenia affects ~1% of the global population, typically emerging in late adolescence or early adulthood and significantly impairing cognitive and emotional functions (1). It is characterized by positive symptoms such as hallucinations and delusions, negative symptoms including reduced emotional expression and social withdrawal and cognitive impairments affecting attention, memory and executive functions (2). Neuroimaging studies demonstrate substantial brain alterations in patients, including reduced gray matter in the medial temporal and prefrontal regions, pronounced ventricular enlargement, extensive cortical thinning and white matter abnormalities (3,4). Emerging evidence highlights blood-brain barrier (BBB) dysfunction as a critical factor in the pathophysiology of schizophrenia, potentially triggering neuroinflammatory cascades, aberrant neurotransmission and structural remodeling that contribute to symptom onset and progression (5,6).

The BBB, a dynamic interface composed of tightly joined endothelial cells, pericytes and astrocytes (Fig. 1) regulates the molecular exchange between the bloodstream and the central nervous system (CNS). The selective permeability of the BBB depends on tight junction proteins such as claudin-5 (CLDN5) and occludin (OCLN), limited endothelial pinocytosis and efflux transporters (7,8). Beyond its barrier function, the BBB serves an active role in modulating neuroimmune signaling and maintaining neuronal homeostasis, making its integrity critical for brain health (9).

Figure 1 BBB structure. The BBB is composed of endothelial cells that form the vessel wall and are surrounded by astrocyte end-foot processes and embedded pericytes. These endothelial cells contain P-glycoproteins and mitochondria, which regulate metabolic processes and substances entering the brain. The central lumen contains blood flow. Endothelial tight junctions are formed of components such as JAM proteins, occludin and claudins. ZO proteins and the actin vinculin-based cytoskeleton provide structural support. BBB, blood-brain barrier; JAM, junctional adhesion molecules; ZO, zona occludens.

In schizophrenia, BBB disruption has emerged as a key pathological feature. Elevated cerebrospinal fluid (CSF) albumin levels and altered expression of tight junction proteins, particularly hippocampal claudin-5 deficits, indicate compromised barrier selectivity (10,11). Dysregulation of permeability regulators, including zonulin and matrix metalloproteinase 9 (MMP9), further suggests active BBB breakdown (12). Such disruptions allow the infiltration of neurotoxic substances, inflammatory cytokines and potentially pathogenic autoantibodies into the brain parenchyma. These infiltrating molecules may initiate or exacerbate pathological processes in schizophrenia, including synaptic dysfunction, glial activation and oxidative stress, all consistently observed in patients with schizophrenia (13). Notably, evidence suggests that BBB leakage may precede the clinical onset of schizophrenia, indicating its potential role as an initiating factor rather than merely a secondary consequence of disease pathology (14).

The present review synthesized current evidence linking BBB dysfunction to the pathophysiology of schizophrenia, emphasizing structural and molecular alterations in the BBB, their contribution to neuroinflammation and neurodegeneration, and the implications for therapeutic strategies targeting barrier integrity.

Schizophrenia overview

Introduction to schizophrenia

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.

Pathophysiology of schizophrenia

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.

Table I Pathophysiological factors in mechanisms of schizophrenia.

Table I

Pathophysiological factors in mechanisms of schizophrenia.

Mechanism	Related factors	Results	(Refs.)
Neurodevelopment	NRG1 gene variations	Altered neuronal development and synaptic plasticity; disturbed cognitive function.	(29)
	C4-A gene activation	Pruned and lost synapses	(30,31)
	Microglial overactivity	Disturbed synaptic maintenance and stability	(32)
	Mutation or dysfunction of DISC1 gene	Compromised neurogenesis; destabilized neuronal networks.	(33,34)
	Malnutrition	Compromised neurogenesis; disrupted fetal brain development.	(35,36)
	Early-life stress	Compromised neurogenesis; destabilized neuronal networks.	(37-39)
Neurotransmitter dysregulation	COMT gene variations	Disturbed neurotransmitter regulation	(40)
	Variations in MAO-B gene	Disturbed astrocytic enzyme levels; affected neurotransmitter dynamics.	(41,42)
	Increased dopamine receptor sensitivity	Elevated dopamine activity; destabilized neuronal networks.	(38,43,44)
	Increased dopamine synthesis and release	Elevated dopamine activity.	(43,45)
	NMDAR dysfunction	Dysregulated glutamate; imbalanced neurotransmitters.	(45-47)
	Norepinephrine dysregulation	Disrupted synaptic transmission; distorted stress response mechanisms.	(48)
Neuroimmune interactions	MHC genes	Dysregulated immunity; exacerbated neuroinflammation.	(49,50)
	Elevated cytokines (TNF-α, IL-4, IL-6, IgM, PON1)	Exacerbated neuroinflammation; disturbed neurotransmitter function.	(51,52)
	Prenatal infections (influenza, Toxoplasma gondii)	Activated maternal immune responses.	(53,54)
	p75 neurotrophin receptor	Compromised neuroprotection; neurotoxicity.	(55)

[i] NRG1, neuregulin 1; C4-A, complement C4-A; MAO-B, monoamine oxidase B; NMDAR, N-methyl-D-aspartate receptor; PON1, paraoxonase 1; COMT, catechol-O-methyltransferase.; MHC, major histocompatibility complex; DISC1, disrupted-in-schizophrenia-1.

Neurodevelopmental factors

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).

Neurotransmitter dysregulation

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.

Neuroimmune interactions

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.

Treatment of 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).

BBB

Structure and function

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).

Evidence of BBB dysfunction in schizophrenia

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.

Table II BBB-associated molecules in schizophrenia.

Table II

BBB-associated molecules in schizophrenia.

Marker	Normal function	Change observed in schizophrenia	Implication	(Refs.)
Q-Alb	Maintains blood environment	Elevated in CSF	Increased BBB permeability	(103)
Total protein	-	Elevated in CSF	Increased BBB permeability	(18,71)
S100B	Supports astrocyte function and CNS homeostasis	Elevated in blood	Increased CNS leakage due to compromised BBB	(104)
MMP9	Regulates extracellular matrix integrity and tight junction stability in the BBB	Elevated in blood	Compromised BBB	(105,106)
Claudin-5	Key component in maintaining tight junctions that seal the BBB	Decreased in postmortem hippocampus	Damaged BBB	(13,107)
Zonulin	Regulates tight junctions and intestinal barrier function, extrapolated to BBB	Elevated in blood	Damaged BBB	(108-110)
Soluble P-selectin	Serves a role in vascular health and regulating inflammation	Elevated in blood	May facilitate worsening of neuroinflammation, cognitive deficits and psychotic symptoms	(111)

[i] BBB, blood-brain barrier; CSF, cerebrospinal fluid; CNS, central nervous system; Q-Alb, CSF/serum albumin quotient, an indicator of blood-brain barrier integrity.

Biochemical indicators

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 insights

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).

Evidence of genetic and developmental correlation

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.

Mechanisms linking BBB dysfunction to schizophrenia

The breakdown of the BBB in schizophrenia contributes to disease progression through multiple mechanisms (Fig. 2), facilitating the entry of inflammatory mediators and immune cells into the CNS. This disruption exacerbates neuroinflammation, further affecting key neurotransmitter systems and CBF, which are critical for the development of cognitive and psychotic symptoms (10,14).

Figure 2 Mechanisms linking BBB breakdown to schizophrenia. The disruption of the BBB in schizophrenia serves a key role in disease progression through several mechanisms: i) Impairment of cerebral blood flow, which limits nutrient and oxygen delivery to brain tissue; ii) facilitation of neuroinflammation, where BBB breakdown allows peripheral immune cells and inflammatory cytokines to enter the central nervous system; and iii) alteration of neurotransmitter systems, including NMDAR autoantibody and dysregulation in neurotransmitter synthesis. BBB, blood-brain barrier; NMDAR, N-methyl-D-aspartate receptor.

Dysregulating CBF

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).

Neuroinflammation promotion

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).

Alteration of neurotransmitter systems

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).

Limitations and future directions

Limitations and novel techniques of current studies

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.

Biomarkers and advanced imaging techniques

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.

BBB-targeted therapies in schizophrenia

Future directions regarding BBB-targeted therapies

The development of drugs targeting BBB tight junctions represents an emerging and promising avenue for schizophrenia treatment. Preclinical studies have shown that restoration of the endothelial glycocalyx can reduce oxidative stress by up to 40% and enhance the expression of tight junction proteins (160). Combination strategies, such as pairing BBB stabilizers (e.g., mucin-domain glycoproteins) with conventional antipsychotics, may not only improve therapeutic efficacy but also allow dose reduction and minimize systemic side effects (161).

Molecular modulators that reinforce tight junction architecture, including CLDNs and OCLNs, are central to BBB stabilization. Experimental evidence indicates that specific peptides can promote the assembly of these proteins and restore barrier integrity (162). Epalrestat, an aldose reductase inhibitor with an established safety profile, has been shown to improve BBB function and enhance neurobehavioral outcomes in animal models (163). Gene therapy approaches, such as adeno-associated virus-mediated overexpression of mucin biosynthesis enzymes (e.g., C1galt1), have successfully reversed BBB dysfunction and cognitive deficits in preclinical models (164). In addition, small molecules targeting frizzled receptors have demonstrated the ability to upregulate CLDN5 and OCLN, further supporting their potential in preserving tight junction integrity (165).

Innovative dual-action strategies are also gaining attention. For instance, co-administration of the LRP1-targeting peptide KS-487 with the VIPR2 antagonist KS-133 has been shown to enhance BBB penetration, reduce neuroinflammation and improve cognitive performance in murine models, reflected by a ~30% increase in novel object recognition (166). Such approaches, which simultaneously target psychiatric symptoms and BBB dysfunction, exemplify a new generation of therapeutics that extend beyond neurotransmitter modulation. Ultimately, integrating BBB stabilization strategies with standard pharmacological treatments may lead to more effective, biologically grounded interventions for schizophrenia and related neuropsychiatric disorders (85,160,161).

Impact of improving drug efficacy and side effects

BBB variability serves a critical role in influencing the therapeutic efficacy and side effects of antipsychotic drugs. P-gp, a key efflux transporter at the BBB, directly regulates the CNS concentration of these medications (167). P-gp actively exports numerous antipsychotics from the brain, creating variability in patient responses and increasing the risk of side effects due to suboptimal drug levels in the brain (167). Genetic polymorphisms or drug interactions can alter P-gp activity (168). Among the most studied variants, the ABCB1 C3435T single nucleotide polymorphism has been associated with reduced P-gp expression and activity. Individuals carrying the T allele often exhibit higher plasma and CNS concentrations of P-gp substrates, including antipsychotics such as olanzapine and risperidone (169). This increased CNS exposure has been linked to both enhanced therapeutic effects and a higher incidence of adverse reactions, such as sedation and extrapyramidal symptoms. Furthermore, pharmacokinetic interactions involving P-gp inhibitors, such as verapamil and ketoconazole, can also lead to elevated brain-to-plasma concentration ratios of co-administered P-gp substrates in both preclinical and clinical settings, raising concerns about potential neurotoxicity and altered efficacy (170). Chronic exposure to antipsychotics in patients with compromised BBB function may also lead to cumulative side effects or long-term neurovascular changes (171,172). Ongoing research suggests that prolonged medication use can deteriorate neurovascular integrity, potentially worsening BBB dysfunction and exacerbating psychiatric symptoms (133). Addressing the increased activity of P-gp at the BBB, a significant contributor to pharmacoresistance, is a key focus of current research, which serves to advance treatment models and improve outcomes for patients with schizophrenia (173). Various strategies have been developed to enhance drug delivery to the CNS, such as intranasal administration, incorporation of nanomaterials, RNA interference and extracellular vesicles (174-177). Advanced delivery platforms, including ligand-conjugated nanoparticles targeting receptors such as LRP1, offer the potential for more efficient BBB crossing and improved therapeutic outcomes (178). Combining anti-inflammatory agents, such as minocycline, with nanoparticle-based delivery systems presents a promising approach to stabilizing BBB function and alleviating schizophrenia symptoms (166). However, most of these methods assume a functional BBB in patients, often overlooking the dynamic nature of the BBB and the potential dysfunction in psychiatric populations.

Patients with impaired P-gp functionality may experience higher drug concentrations in the brain, potentially exacerbating side effects such as EPS due to enhanced dopamine receptor blockade (179,180). By contrast, robust P-gp activity could lower brain drug levels, potentially reducing efficacy and decreasing side effect risks. This dynamic is supported by research using Mdr1a/b knockout mice, which lack functional P-gp and show increased brain concentrations of drugs such as risperidone (167), highlighting critical role of P-gp in modulating CNS drug access. Emerging strategies aim to optimize BBB penetration without provoking unwanted side effects. For instance, the novel TAAR1 agonist compound 50B demonstrates favorable BBB permeability and does not induce EPS, suggesting that strategic drug design can enhance efficacy while minimizing adverse effects (181). Furthermore, individual variability in BBB integrity underscores the importance of personalized treatment approaches. While some patients maintain intact BBB function, others exhibit significant permeability changes, necessitating tailored therapeutic strategies that account for individual differences in BBB dysfunction.

Conclusion

The present review synthesized key findings on the role of BBB dysfunction in schizophrenia, emphasizing its association with the neuropathological features of schizophrenia. Notable insights include increased BBB permeability, reduced expression of tight junction proteins, and elevated inflammatory markers. These alterations not only exacerbate neuroinflammation but also disrupt neurotransmitter systems, thereby influencing symptom severity and treatment response (100). Thus, maintaining BBB integrity is critical for the comprehensive management of schizophrenia, underscoring its importance in both disease strategy and patient care.

Future research focused on the BBB could revolutionize diagnostic and therapeutic approaches in schizophrenia by facilitating early detection and improving treatment outcomes (4). Non-invasive imaging techniques, such as DCE-MRI, and biomarker discovery could enable earlier identification of BBB dysfunction, leading to timely interventions (23,182). Furthermore, integrating DCE-MRI with PET tracers may enhance diagnostic accuracy, facilitating the detection of early BBB changes. Additionally, the development of BBB-targeted therapies, including pharmacological agents that promote BBB repair and nanoparticle-based drug delivery systems, holds the potential to significantly improve treatment efficacy by enhancing drug penetration into the brain (75,183). However, challenges remain, particularly regarding the safe delivery of therapeutics across the BBB and minimizing potential toxicity to non-target brain regions. Personalized medicine approaches, incorporating genetic profiling related to BBB integrity, could enable the development of tailored treatment plans that address both symptom management and the underlying neurobiological mechanisms of schizophrenia (184). Monitoring biomarkers of BBB integrity, such as changes in the levels of tight junction proteins and inflammatory markers, could offer valuable insights into the effectiveness of treatment and inform the refinement of disease management strategies (185). Tailored treatment strategies, informed by genetic factors affecting BBB function, may further enhance antipsychotic efficacy by targeting both the symptoms and the underlying neurobiological mechanisms of the disorder (133,186). Thus, future research into diagnostic tools such as DCE-MRI and BBB-targeting therapies have potential to improve the management and treatment of schizophrenia.

Availability of data and materials

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Authors' contributions

SL contributed to the writing and editing of this review. CL collected the data. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

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Funding

No funding was received.

References