Autoimmunity and Mental Health: Exploring the Potential Links Between Schizophrenia and Two Specific Autoimmune Disorders

Substantial evidence supports the role of autoimmune factors in the etiology of psychotic disorders, especially schizophrenia (SCZ). Although complex and not fully understood, this link has been extensively studied, with numerous investigations connecting autoimmune conditions to mental illness. One of the earliest studies, by Nissen and Spencer in 1936, examined the relationship between rheumatoid arthritis (RA) and SCZ. Among 2,200 psychiatric inpatients, they found no cases of RA, prompting further research into potential associations between autoimmune diseases and psychotic disorders [1]. While this finding was inconclusive, it did not rule out immune involvement in SCZ and later studies have built on this foundation. Recent studies have deepened understanding of the link between autoimmune conditions and SCZ. A populationbased case-control study by Eaton et al. [2], using Danish national register data, explored the association between Coeliac Disease (CD) and SCZ [2]. The study proposed that immune dysfunction in CDan autoimmune response to gluten-might contribute to psychiatric disorders like SCZ. However, the findings remain inconclusive, as some studies report positive associations, while others do not identify a significant link. Studies showing no clear link between autoimmune diseases and SCZ can still offer valuable insights. For instance, the absence of a significant RA-SCZ association in Nissen and Spencer’s 1936 study may reveal important biological differences between the conditions. In science, negative findingswhere expected correlations fail-can uncover underlying mechanisms, much like Alexander Fleming’s accidental discovery of penicillin led to major advances in medicine. RA and SCZ share chronicity and immune dysfunction and are both linked to genetic predispositions. Interestingly, SCZ patients and their relatives tend to show a lower prevalence of RA and vice versa, suggesting a negative genetic correlation. Genome-wide Association Studies (GWAS) support this, showing that genetic factors increasing susceptibility to one may reduce the risk of the other [3]. Malavia et al. [3] conducted a computational analysis of genetic variants linked to SCZ and RA, showing that certain genes may increase susceptibility to autoimmune disorders while protecting against psychosis [3]. These findings highlight the complex genetic interactions between immune dysfunction and mental illness, suggesting shared pathways that influence both immunity and brain function. The negative correlation between SCZ and RA suggests that immune involvement extends beyond autoimmunity or inflammation. Immune responses to genetic or environmental triggers may influence neurodevelopment, neuroinflammation and neurodegeneration, though these mechanisms remain unclear. Further research into how the immune system affects the brain in autoimmune contexts could uncover novel treatments. It is worth noting that this paper may resonate most with proponents of the autoimmune hypothesis of SCZ.

SCZ is indeed one of the most misunderstood mental health conditions today, leading to significant stigma and discrimination that adversely affect public perception and the quality of life for those diagnosed. Understanding that SCZ has physical originssuch as immune dysregulations, imbalances in brain chemistry and structural anomalies-can help reduce social stigma. Recognizing it as a medical condition, rather than attributing it to personal failings or moral shortcomings by the public, promotes empathy and support. This shift in perspective is crucial, as stigma and discrimination can lead to social exclusion and hinder individuals from seeking necessary treatment. Immunopsychiatry is a rapidly growing field and its future promises to deepen our understanding of how the immune system affects mental health. As research advances, immunopsychiatry may lead to more personalized treatment options, tailored to an individual’s immune system profile. By targeting immune system dysfunction specifically, treatments could be more effective and have fewer side effects. As we learn more about the immune-brain connection, we may uncover novel therapeutic strategies that address both the biological and psychological aspects of mental illness. Overall, immunopsychiatry represents a hopeful step forward in integrating two traditionally separate areas-psychiatry and immunology-to provide better and more holistic treatments for those suffering from psychiatric disorders.

Research indicates a link between autoimmune diseases and SCZ. Brain imaging studies show structural differences in SCZ patients that may increase susceptibility to autoimmunity. A 2019 review reported positive associations between psychosis and nonneurological autoimmune conditions such as psoriasis, pemphigoid, Grave’s disease and coeliac disease [4]. Epidemiological studies consistently show that infections, autoimmune diseases and atopic disorders elevate SCZ risk and that SCZ is associated with increased immune marker levels at diagnosis (Table 1). Benros et al. [5] suggested that inflammation and autoimmunity may contribute to SCZ pathogenesis, with psychotic symptoms potentially resulting from infections reaching the CNS or from systemic inflammation involving brain-reactive antibodies and cytokines [5]. Shiwaku et al. [6] found that some SCZ patients have autoantibodies against NCAM1, a molecule essential for neural communication, suggesting these antibodies may contribute to symptoms and serve as therapeutic targets [6]. Benros et al. [7] reported that autoimmune diseases increase SCZ risk by 29% [7]. Wekking et al. [8] observed that systemic lupus erythematosus frequently presents with neuropsychiatric symptoms [8]. Autoantibodies in autoimmune disorders affecting the nervous system may disrupt microtubules, leading to altered consciousness and psychotic symptoms. Dopamine over activity in SCZ might occur without excess dopamine, possibly triggered by autoantibodies. Growing evidence links immune processes to psychosis, supporting the theory that SCZ may be autoimmune in nature, given its relapsing course and immunological traits. Elevated inflammatory markers have been observed in both blood [9,10] and CSF [11,12] of psychotic patients. Studies also associate early-life inflammation with increased psychosis risk, [13,14] and higher inflammatory biomarkers with poorer treatment response in first-episode psychosis [15]. Emerging anti-inflammatory treatments have shown promising effects [16-18].

Table 1:Autoimmunity and Schizophrenia.

Interest in immunopsychiatry has grown, fueled by recent textbooks on this subject [19-21] and increasing focus on the autoimmune etiology of SCZ [22-24]. Data suggest a 45% higher SCZ risk among individuals with a family history of autoimmune disorders [25]. Eaton et al. [26] reported elevated rates of nine autoimmune diseases-including Sjögren’s syndrome, coeliac disease and thyrotoxicosis-among SCZ patients and similar patterns in the parents of affected individuals [26]. These findings highlight the need for further research into the shared pathogenesis of SCZ and autoimmune diseases. Benros et al. [5] reported that SCZ patients had a higher risk of developing autoimmune diseases, nearly doubling among those with hospital contacts, likely due to increased infection exposure [5]. Conversely, a family history of SCZ was linked to a lower autoimmune disease risk, regardless of infection history. These findings suggest shared causes-such as infections and genetics-underpin both conditions. Oken and Schulzer [27] proposed that glutamatergic system dysfunction may explain the SCZ-autoimmunity link, supporting treatment overlap [27]. This view gained support in subsequent SCZ-RA research due to overlapping symptoms. Immunopsychiatry alone may not fully explain SCZ, which could reflect a disorder of consciousness. The tsunami analogy helps illustrate this: Just as tectonic shifts-not the water itself-cause tsunamis, autoimmune disruptions might underlie SCZ symptoms by affecting consciousness [28]. Critics warn that immunopsychiatry risks becoming overly reductionist and suggest it should be integrated with consciousness studies [29].

Complex role of autoimmunity, gut inflammation and schizophrenia

A key aspect of the autoimmune hypothesis in SCZ involves the gut-immune-brain axis. Growing evidence links gastrointestinal autoimmune diseases, such as Coeliac Disease (CD), to psychiatric conditions. In CD, gluten triggers immune damage to the small intestine and this disorder has been associated with an elevated risk of schizophrenia and mood disorders. Porcelli et al. [30] reviewed the links between CD, non-coeliac gluten sensitivity and psychiatric disorders, including SCZ. While some studies found higher rates of psychiatric symptoms in untreated CD patients, the findings are inconsistent, underscoring the need for further research and the complexity of immune involvement in psychiatric conditions. Porcelli et al. [30] stressed the need to investigate how gastrointestinal disorders like CD may influence SCZ pathogenesis. Immune responses in the gut could affect the brain via systemic inflammation or gut-brain communication, including the vagus nerve. This emerging “gut-brain axis” research suggests that microbiome and immune disruptions may contribute to SCZ. Cordeiro et al. [31] argued that examining disruptions in biological pathways outside the brain is vital for understanding complex, polygenic disorders like SCZ [31]. Interactions among genetic, environmental and immune factors-especially immune dysregulation affecting organs like the gut, liver and kidneys-may contribute to psychiatric conditions. Emerging evidence suggests that SCZ may result from complex interactions among genetic predisposition, immune dysfunction, environmental factors and gut-brain communication. Investigating shared molecular and immunological pathways could clarify how immune dysregulation contributes to psychosis and highlight the roles of inflammation and autoimmunity in psychiatric disorders.

Advancing understanding of SCZ requires a multidisciplinary approach involving immunology, genetics, neuroscience and psychiatry. Emerging tools-such as population data, genetic sequencing and imaging-may clarify links between autoimmune diseases and SCZ. Clinical trials on immune-modulating therapies could also yield new treatment strategies targeting immune dysfunction. Although still evolving, evidence increasingly supports the role of immune dysfunction in psychotic disorders [32,33]. The negative genetic correlation between RA and SCZ, links with coeliac disease and gut–brain interactions suggest autoimmune involvement in SCZ development [34]. Ongoing research into genetic, immunological and environmental factors is essential for more targeted treatments [35]. Autoimmune and autoinflammatory diseases both involve immune dysregulation and systemic inflammation [36]. However, they differ in the immune components and mechanisms involved [37]. Distinguishing between them is essential for developing targeted therapies, especially where inflammation contributes to neuropsychiatric symptoms [38].

Deregulated adaptive immunity

In autoimmune diseases, the adaptive immune system becomes misdirected and attacks healthy cells and tissues, mistaking them as foreign. Normally, T-cells and B-cells target specific pathogens, but in autoimmune conditions, this distinction fails, resulting in the production of autoantibodies and activation of autoreactive T-cells. These responses lead to inflammation and tissue damage across various organs. Common autoimmune diseases include Rheumatoid Arthritis (RA), type 1 diabetes, Systemic Lupus Erythematosus (SLE) and Multiple Sclerosis (MS). Each targets specific systems, for example, RA affects the joints, type 1 diabetes targets pancreatic beta cells and MS attacks the myelin sheath, impairing nerve signal transmission. Chronic inflammation, a hallmark of autoimmune diseases, causes lasting organ damage and symptoms like fatigue, pain, fever, weight loss and joint degeneration. Increasingly, research highlights the neuropsychiatric effects of autoimmune diseases. SLE has been linked to cognitive impairments, mood disorders and psychosis, while MS can lead to depression, anxiety and cognitive dysfunction. These symptoms likely arise from chronic inflammation in the brain and autoimmunity targeting neural tissues.

Jeppesen and Benros [25] observed that individuals with autoimmune diseases such as SLAE and MS are more likely to develop neuropsychiatric symptoms [25]. This suggests that inflammation may affect the central nervous system, impairing cognition, mood and behavior. These manifestations may stem from both direct immune effects-via autoantibodies or immunemediated damage-and indirect effects of systemic inflammation.

Deregulated innate immunity

By contrast, autoinflammatory diseases result from abnormalities in the innate immune system, the body’s first defense against infections and injuries. This system includes macrophages, neutrophils, dendritic cells and signaling molecules like cytokines and interleukins [39]. In these conditions, immune responses are overactive or dysregulated, even in the absence of infection, triggering excessive release of pro-inflammatory cytokines such as IL-1, TNF-α and IL-6, leading to widespread inflammation and tissue damage. Autoinflammatory diseases are marked by uncontrolled inflammation, often affecting multiple organs. Symptoms typically include fever, skin rashes and joint swelling [40]. Notable examples include Familial Mediterranean Fever (FMF), periodic fever syndromes, gout and Cryopyrin-Associated Periodic Syndromes (CAPS) [41]. These conditions are characterized by recurrent flares, often triggered by environmental stressors, infections, or unknown stimuli [42]. Unlike autoimmune diseases, autoinflammatory conditions do not involve autoantibodies or T-cell responses. Instead, they are driven by innate immune dysregulation [43]. CAPS, for example, results from mutations in the NLRP3 gene, which cause an overactive inflammasome and excessive IL-1β release, leading to recurrent, severe inflammation [44]. Though autoinflammatory diseases mainly affect the joints, skin and organs, recent studies show they can also involve neuropsychiatric symptoms. In FMF, brain inflammation has been linked to cognitive and mood disturbances [45]. While mechanisms remain unclear, excess cytokines may cross the blood-brain barrier and disrupt neural signaling, potentially causing depression, anxiety, or cognitive dysfunction [38].

Overlap between autoimmune and autoinflammatory diseases

Many diseases involve overlapping autoimmune and autoinflammatory features. For example, RA and lupus involve both adaptive and innate immune dysfunction [46]. This suggests that these two arms of the immune system interact rather than function independently. In RA, T-cells and macrophages act in concert to sustain inflammation and joint damage [47]. SLE also involves the innate immune system, including activation of macrophages, dendritic cells and the complement system [48]. These components contribute to inflammation and damage in the kidneys, skin and nervous system, leading to neuropsychiatric symptoms like lupus psychosis and cognitive dysfunction [49]. This overlap underscores how inflammation-regardless of its immune origin-can significantly affect the brain. As our understanding of immune interactions grows, it may become clear that many conditions previously seen as strictly autoimmune or autoinflammatory involve both systems [50].

Neuropsychiatric symptoms in autoimmune and autoinflammatory diseases

Autoimmune and autoinflammatory diseases are increasingly recognized for their potential to cause neuropsychiatric symptoms. Both types of diseases involve systemic inflammation that can affect various organs, including the Central Nervous System (CNS) [51]. In autoimmune diseases like MS and SLE, inflammation in the brain can lead to mood disorders, cognitive dysfunction and psychosis [52,53]. In autoinflammatory diseases like FMF, neuropsychiatric symptoms are less commonly discussed but are nonetheless significant, with individuals reporting symptoms like depression, irritability, anxiety and cognitive difficulties during inflammatory flare-ups [54]. Systemic inflammation may influence the brain through cytokines-key molecules in both immune arms. Cytokines affect neurotransmitter metabolism and neural circuits linked to mood and cognition [55]. When elevated, they can increase blood-brain barrier permeability, allowing inflammatory molecules into the brain [56] where they disrupt emotional regulation, learning and memory, possibly leading to cognitive and mood disorders [57]. Thus, systemic inflammation, whether autoimmune or autoinflammatory, can have profound neurological effects. Neuropsychiatric symptoms in MS, SLE and FMF may result from such inflammation and managing immune dysfunction may help alleviate them [50]. While autoimmune and autoinflammatory categories are useful, the distinction is not always clear in practice, as many conditions exhibit features of both [58]. Chronic inflammation, whether from adaptive or innate responses-is a key contributor to neuropsychiatric symptoms [59]. Understanding how inflammation affects brain function is essential to improve physical and mental health outcomes in diseases like SLE, MS and FMF [53]. Ongoing research into immune-brain interactions may reveal better ways to manage both physical and neuropsychiatric symptoms. This could lead to more comprehensive therapies targeting inflammatory processes and easing the burden on affected individuals.

Rheumatoid arthritis

RA and SCZ are chronic conditions that share several similarities and differences. Both follow a relapsing-remitting course and show familial aggregation, with heritability estimates of 0.65 for RA and 0.81 for SCZ. Each involves multiple genetic risk factors influenced by environmental triggers. However, RA typically begins between ages 25-55, while SCZ onset occurs between 16-30 years. The male/female ratio is 1:3 for RA and 1.4:1 for SCZ [60]. A persistent epidemiological puzzle is the reduced prevalence of RA among SCZ patients and their relatives. SCZ incidence is strikingly low among RA patients [61,62] Initially attributed to antipsychotic effects when observed in 1936, later studies ruled out medication as a cause. Torrey and Yolken [62] proposed that this inverse relationship might indicate a shared infectious or immune pathology, where developing one condition reduces the likelihood of developing the other [62]. Further research in this area may help clarify SCZ etiology. Pearce [63] suggested that the SCZ-RA connection may support an autoimmune basis for SCZ, as both conditions involve genes from the Major Histocompatibility Complex (MHC), albeit different ones [63]. Environmental triggers, such as infections, could initiate either condition, depending on which MHC gene variants an individual inherits. Since the MHC gene complex lies on chromosome 6-a focus of SCZ genetic research-this region remains of particular interest. According to Pearce [63], exposure to a virus may activate an immune cascade that predisposes individuals either to RA, through pro-inflammatory responses, or to SCZ, through antiviral immune activation [63].

Eusden et al. [64], however, challenged the genetic overlap hypothesis, suggesting any shared biological mechanisms are more likely environmental than genetic [64]. They proposed that SCZ’s apparent protective effect against RA could stem from the antiinflammatory actions of antipsychotic medications or confounding factors in study design (Table 2). They called for further investigation into the etiologies of SCZ and RA to resolve this contradiction. Globally, SCZ affects over 22 million people, while nearly 4 million have RA [65]. RA involves chronic joint inflammation, bone erosion and widespread pain and may lead to complications such as osteoporosis, vasculitis, cardiovascular disease and lung fibrosis. In contrast, SCZ is not linked to these physical conditions. SCZ is associated with dopamine imbalance in the brain and patients are typically treated with dopamine antagonists. These receptors may help explain the SCZ-RA link [66,67]. Capellino [68] demonstrated dopamine’s effects on immune responses, bone remodeling and joint inflammation in humans and animal models of arthritis, proposing that the dopaminergic system is implicated in RA and that dopaminergic drugs could potentially treat arthritis [68].

Table 2:Schizophrenia and Rheumatoid Arthritis: Factors Influencing the Inverse Relationship.

Coeliac disease

The coexistence of SCZ and autoimmune diseases is gaining increasing recognition, supporting the growth of immunopsychiatry. SLE, a classic autoimmune disease, has been associated with psychosis in about 25% of cases [63]. Similarly, in a population-based case-control study, Eaton et al. [2] used Danish national registry data and found a higher prevalence of Coeliac Disease (CD) in individuals with SCZ than in controls. They also noted that the genetic marker for CD was located near the disbanding locus, a region implicated in SCZ, suggesting a possible genetic link (Table 3). CD is an autoimmune disorder that impairs the ability to digest gluten, often presented with diarrhoea, weight loss and malnutrition. Eaton et al. [2] linked CD and SCZ by examining records of 7,997 first-time psychiatric admissions in Denmark (1981-1998). These were compared with national patient registry data to investigate associations with CD, Crohn’s disease, dermatitis herpetiformis and ulcerative colitis. Although both SCZ and CD are rare in Denmark-1.5 and 0.5 per 1,000 respectively-the difference in CD prevalence remained significant after adjustment. No associations were found between SCZ and Crohn’s disease or ulcerative colitis. The authors called for studies involving more diverse populations to validate their findings. If the SCZ-CD link is confirmed, a gluten-free diet could benefit SCZ patients with CD or those at risk [2]. In several cases, adopting a gluten-free diet led to remission of SCZ symptoms [69-72]. Interestingly, individuals with CD are twice as likely to develop RA compared to non-coeliacs [73]. A bidirectional Mendelian randomization study revealed a causal link from RA to CD, but not the reverse.

Table 3:Potential Connections between schizophrenia and coeliac disease.

The immune system exists to defend the body, but when it becomes the attacker, it is absolute chaos. In recent years, researchers have uncovered a striking relationship between autoimmune disorders and psychiatric illnesses, particularly SCZ. Traditionally seen as a neurodevelopmental disorder, SCZ is increasingly being studied through the lens of immunology. A growing body of evidence suggests that certain autoimmune diseases, including SLE and CD, may contribute to-or even mimic-the psychiatric symptoms commonly associated with SCZ [7]. SCZ is marked by hallucinations, delusions, disorganized thinking and emotional blunting. While dopamine dysregulation has long dominated explanatory models, emerging data reveal elevated inflammatory cytokines (e.g., IL-6, TNF-alpha), increased levels of C-reactive protein and evidence of microglial activation in people with SCZ [74]. Genome-wide association studies have further identified shared genetic risk loci between SCZ and several immune-related genes [75], suggesting a potential immune contribution to the disease’s aetiology. SLE offers one of the clearest illustrations of how autoimmunity can affect the brain. SLE is a multisystem autoimmune disorder known for its neuropsychiatric manifestations-including depression, anxiety, cognitive dysfunction and psychosis. Studies show that up to 75% of SLE patients experience some form of neuropsychiatric involvement [76]. In certain cases, the presence of anti-neuronal or anti-NMDA receptor antibodies can lead to psychotic symptoms that are virtually indistinguishable from SCZ [77]. This overlap poses a serious diagnostic challenge. A young woman presenting with hallucinations and cognitive disorganization might receive a SCZ diagnosis when, in fact, she may be experiencing neuropsychiatric lupus-a condition that could respond better to immunosuppressive therapy than to antipsychotic drugs.

CD is another autoimmune condition with surprising psychiatric implications. While most commonly associated with gastrointestinal symptoms, CD is now understood to affect multiple systems, including the central nervous system. Some individuals with CD report experiencing anxiety, depression, brain fog and in rare cases, psychosis [78]. Intriguingly, people with SCZ are significantly more likely to exhibit elevated anti-gliadin antibodiesmarkers of gluten sensitivity-even if they do not meet diagnostic criteria for celiac disease [79]. A randomized trial by Jackson et al. [80] demonstrated that a gluten-free diet significantly reduced SCZ symptoms in antibody-positive individuals, underscoring a potential immune-mediated gut-brain connection [80]. These findings suggest that inflammation and autoimmunity may not merely accompany psychiatric symptoms-they may drive them. This has profound implications. First, screening for autoimmune markers such as antinuclear antibodies (ANA), anti-NMDA receptor antibodies, or anti-gliadin antibodies in new-onset psychosis could help distinguish between primary SCZ and autoimmune-related syndromes. Second, targeted treatments such as immunosuppressants or gluten-free diets may offer symptom relief in subsets of patients who are unresponsive to conventional antipsychotics.

While biological markers derived from genomics, proteomics and metabolomics have been associated with these conditions [81,82], none have yet achieved the necessary sensitivity and specificity for standalone diagnostic use. This underscores a critical gap in the precision medicine approach to mental health. Recent advances in systems biology and molecular medicine, however, are beginning to address this limitation. Biomarkers already utilized in managing chronic diseases-such as diabetes, cardiovascular disorders and autoimmune conditions-are now being repurposed for neuropsychiatric applications [83,84]. Emerging research highlights the role of chronic inflammation, oxidative stress, mitochondrial dysfunction and Endoplasmic Reticulum (ER) stress in psychiatric disorders [85,86]. These pathways serve as key intersections between immune dysregulation, neurodegeneration and psychiatric symptomatology. A particularly promising area of investigation involves ER stress and its downstream effects, particularly mitophagy, a selective autophagy process that eliminates damaged mitochondria. Dysregulated ER stress-induced mitophagy has been linked to neuronal apoptosis and implicated in the pathophysiology of multiple psychiatric and neurodegenerative disorders [87,88]. Therapeutic targeting of these stressresponse mechanisms may offer novel strategies to mitigate disease progression. Additionally, mounting evidence indicates that metabolic disturbances-including insulin resistance, lipid dysregulation and micronutrient deficiencies-frequently co-occur with neuropsychiatric conditions [89,90]. Nutritional assessments have revealed significant associations between metabolic health and psychiatric symptoms, reinforcing the importance of dietary interventions in mental health management. Genomic medicine is also making strides in early risk identification. Polygenic risk scoring and the detection of Single Nucleotide Polymorphisms (SNPs) associated with psychiatric vulnerability now enable more targeted preventive strategies [91,92]. These approaches are particularly relevant for autoimmune-related psychiatric risks, given the shared inflammatory pathways between these conditions [5]. Functional foods, enriched with bioactive compounds that modulate nuclear receptors (e.g., PPARs, LXRs) represent another frontier in neuropsychiatric care. These foods may influence gene expression related to inflammation, neuroplasticity and mitochondrial function [93,94]. By maintaining ER homeostasis and reducing neuroinflammation, functional foods could help prevent excessive mitophagy and associated neurodegeneration.

Metabolic abnormalities have been linked to neuropsychiatric disorders and careful nutritional assessment of patients has been emphasized in many published studies. Early diagnosis combined with personalized nutritional interventions has shown potential to stabilize symptoms in conditions such as depression, schizophrenia and bipolar disorder [95]. Nutritional modulation of inflammation, mitochondrial function and neurotransmitter synthesis may serve as a foundation for long-term management strategies. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase that regulates key biological processes such as aging, metabolism, inflammation and stress responses. Initially investigated for its role in longevity and metabolic control [96], SIRT1 has garnered attention for its significant involvement in both immune regulation and brain function. Its ability to influence inflammatory pathways and protect neurons positions it as a promising therapeutic target for autoimmune and neuropsychiatric disorders.

SIRT1 and autoimmune disease

Autoimmune diseases, including Systemic Lupus Erythematosus (SLE), rheumatoid arthritis and multiple sclerosis, are characterized by aberrant immune activation and chronic inflammation. SIRT1 helps maintain immune homeostasis by deacetylating transcription factors like NF-κB, thereby reducing the production of pro-inflammatory cytokines. It also supports the function of regulatory T cells (Tregs) while inhibiting the differentiation of pro-inflammatory Th17 cells [97]. Additionally, SIRT1 enhances autophagy and mitochondrial function, which helps mitigate cellular stress and damage. These properties make SIRT1 activation a potential therapeutic strategy in autoimmune diseases, with compounds such as resveratrol and synthetic SIRT1 activators being actively studied [97].

SIRT1 in neuropsychiatric disorders

Within the Central Nervous System (CNS), SIRT1 has neuroprotective effects, influencing neuronal survival, synaptic plasticity and mitochondrial health. It regulates the expression of Brain-Derived Neurotrophic Factor (BDNF), which is essential for cognitive function and emotional stability. Furthermore, SIRT1 helps mitigate oxidative stress and supports mitochondrial biogenesis [96]. These functions are particularly relevant in neuropsychiatric conditions such as schizophrenia (SCZ), major depressive disorder and bipolar disorder, where patients often show evidence of mitochondrial dysfunction, oxidative damage and neuroinflammation. Decreased SIRT1 activity may exacerbate these pathological processes [98].

Recent research has begun to explore the specific role of SIRT1 in schizophrenia. Genetic studies suggest that polymorphisms in the SIRT1 gene may increase susceptibility to SCZ [98]. In preclinical animal models, activating SIRT1 has been shown to reverse schizophrenia-like behavioural and cognitive impairments. SIRT1 influences pathways that regulate dopamine signalling, oxidative balance and cortical development-all of which are disrupted in SCZ. These findings suggest that pharmacological or nutritional upregulation of SIRT1 could be a novel intervention strategy, potentially complementing or enhancing existing antipsychotic treatments [98].

SIRT1’s ability to modulate both immune and neuronal pathways presents an exciting therapeutic opportunity. Strategies to enhance SIRT1 activity could serve as disease-modifying interventions for conditions that lie at the intersection of chronic inflammation and neurodegeneration. Future research should focus on validating SIRT1 as a biomarker in clinical populations, developing more potent and bioavailable SIRT1 activators and investigating the use of functional foods (such as those containing resveratrol, quercetin, or curcumin) as adjunct therapies. Longitudinal studies in high-risk populations may also help determine whether SIRT1 activation can prevent disease onset or progression in schizophrenia and autoimmune conditions. SIRT1 represents a promising molecular target that bridges immune dysfunction and neuropsychiatric pathology. Its therapeutic activation may provide neuroprotection, restore immune balance and alleviate symptoms in disorders such as schizophrenia and autoimmune diseases. Continued exploration of SIRT1 could lead to innovative treatments that address the underlying causes of these complex conditions rather than merely managing symptoms.

There is substantial work to be done to clarify the mechanisms involved in autoimmunity in general and SCZ in particular. A key point in the evolution of psychiatric understanding is the shift from attributing these conditions to the mind or external forces, to focusing on the physical brain and neurotransmitters. However, this may only reveal part of the picture. The role of autoimmunity in SCZ and other psychiatric disorders is complex and increasingly studied. Autoimmune reactions occur when the body’s immune system mistakenly attacks its own cells and growing evidence suggests this may contribute to psychiatric illness. Still, the exact mechanisms remain unclear and further research is needed. This could potentially open new avenues for treatment and prevention. Psychiatric disorders are complex and multifactorial, shaped by genetics, environment and lifestyle. A recent University of Chicago study found that interactions between genetics and environment may explain much of the variability in disorders like PTSD and anxiety. The four main conditions discussed here-SCZ, RA, CD and leprosy-offer valuable insights. While the psychiatric features of SCZ are well studied, literature on its autoimmune aspects remains limited. The autoimmune etiology of SCZ has aptly been likened to tsunami formation triggered by tectonic shifts. It is important to remember that psychiatric disorders result from a combination of factors. Neurotransmitters and the brain are central to understanding them, but not the whole picture. The search for deeper etiological factors continues and is inherently multidimensionalspanning mind, brain and biology. SCZ, RA, CD and leprosy serve as models in this paper to explore immunoregulatory functions. Although the psychiatric side of SCZ is well documented, studies on its autoimmune aspects are scarce. The autoimmune dimensions of RA and CD are well described, but their emerging connections to SCZ are only recently gaining attention. As stated earlier, the tectonic shift analogy highlights how underlying immune factors may trigger visible psychiatric symptoms.

The interplay between the immune system and psychiatric disorders like SCZ is a growing area of study. Recent research has identified immune-linked genes and immune cell infiltration patterns in SCZ. These findings suggest overlaps between SCZ, RA and CD. Just as tectonic shifts under the sea can trigger a tsunami, subtle immune changes may trigger psychiatric disorders. However, understanding these mechanisms requires extensive research and sophisticated tools. Exploring autoimmune contributions to SCZ and links with RA and CD is a promising direction in medical research. It holds the potential for novel therapies and better patient outcomes. Despite plausible hypotheses, the mechanisms behind the inverse SCZ-RA relationship and the direct SCZ-CD link remain unclear and merit further investigation. The development of therapeutic antibodies has marked a significant advance in treating autoimmune and inflammatory conditions. Second-generation antibodies, developed through cutting-edge engineering, offer improved clinical efficacy and safety. Their potential use in SCZ is particularly exciting. The concept of using “anti-autoantibodies” to manage autoimmune processes could open new treatment possibilities. Enzyme treatments converting autoantibodies into anti-inflammatory antibodies-shown effective in animal modelsfurther underscore this potential. Mental health professionals must begin exploring therapies beyond neurotransmitter-based drugs. Mental health treatment is inherently complex and requires diverse strategies. New approaches may lead to more effective, personalized care. This is a fascinating area of research with important implications for mental health’s future.

Lessons learned from the first wave of antibody therapies have laid the groundwork for newer, more effective treatments. Advanced technologies are now enhancing therapeutic antibody development. “Anti-autoantibodies” and enzyme treatments that convert damaging antibodies into beneficial ones show promise for future application. Mental health professionals remain overly reliant on neurotransmitter-focused drugs-a mindset that needs to shift. Exploring alternative treatment strategies is essential. Immunopsychiatry aims to understand how immune dysfunction contributes to psychiatric disorders such as SCZ. Investigating environmental and genetic factors in both autoimmune diseases and SCZ is a key focus. Historically, mental health professionals have overlooked physical ailments, leading to fragmented care. Advances in immunology could change that, supporting the development of more integrated, effective treatment strategies for SCZ and related conditions. This emerging intersection between psychiatry and immunology represents an exciting frontier for research and clinical care. SIRT1 represents a promising molecular target that bridges immune dysfunction and neuropsychiatric pathology. Its therapeutic activation may provide neuroprotection, restore immune balance and alleviate symptoms in disorders such as schizophrenia and autoimmune diseases. Continued exploration of SIRT1 could lead to innovative treatments that address the underlying causes of these complex conditions rather than merely managing symptoms. A comprehensive strategy-combining biomarker-driven diagnostics, genomic risk assessment, metabolic and nutritional interventions and targeted functional food applications-holds transformative potential for neuropsychiatric care. This multi-system perspective acknowledges the complex interplay of biological pathways underlying mental illness and paves the way for more precise, individualized and preventive treatments.

This systematic review has certain limitations that must be clearly acknowledged when interpreting the findings. These limitations are essential for a balanced interpretation of the results and for guiding future research in this area. Limited Focus and Sample Size: The review is based on a select number of major studies and involves a small sample size of patients, which may reduce the statistical power of the findings. Geographical Bias: Immunopsychiatry is not widely recognized across many regions and most studies originate from developed countries where psychiatry is more established. This may introduce a geographical skew. Cultural and Social Aspects: Cultural and social factors, especially in developing countries, are often neglected due to the stigma surrounding SCZ and Hansen’s disease. Nature of the Review: As the review draws primarily on observational studies, strong clinical recommendations cannot be made based on its findings. Despite these limitations, the novel insights offered on the intersection of immunology and psychiatry-termed “immunopsychiatry”- are meaningful and hold significant implications for future SCZ research and clinical practice. Advances in immunology are likely to contribute positively to the development of this emerging field. The interplay between environmental and genetic factors in the risk of both autoimmune diseases and SCZ is a particularly important area of study. The long-standing tendency among mental health professionals to overlook physical health issues remains a major concern that must be addressed.

A more holistic approach that integrates both mental and physical health has the potential to improve patient care and outcomes. Broadening the scope of data collection in future studies could improve research accuracy and yield more comprehensive findings. This, in turn, could lead to breakthroughs in our understanding of SCZ and other psychotic disorders, including bipolar disorders. The field of cognitive science could also benefit from increased attention to immunopsychiatry. This interdisciplinary framework may offer new insights into the pathogenesis of various mental disorders and foster the development of novel treatment approaches. Ongoing research into SCZ and related medical conditions is a source of hope for many. As we continue to uncover the immune system’s role in these disorders, we move closer to a future marked by deeper understanding, heightened awareness, better treatments and even preventive strategies. This body of research opens promising new pathways for exploring the connection between physical and mental health. It reinforces the importance of adopting holistic approaches in both research and clinical care. The potential for prevention marks a shift from reactive to proactive healthcareaimed at forestalling the onset of conditions like SCZ rather than simply managing them after diagnosis. Moreover, these insights point to the need for a more integrated medical model. Psychiatry has traditionally operated independently of immunology and gastroenterology, but the emerging research suggests that true mental wellness may require a whole-body approach. Collaborative care between disciplines could help identify treatable causes of psychiatric symptoms and prevent misdiagnoses that delay appropriate care. While not all SCZ cases are linked to autoimmunity, the immune system’s role in shaping brain function and behavior can no longer be ignored.

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