Brain and Behavior: The Diathesis-Stress Model of Schizophrenia in Autoimmune Disease Patients
Abstract
With an aim to assess the potential link between schizophrenia and autoimmune diseases of the nervous system (ADNS), this study applies the diathesis-stress model to the pathogenesis of schizophrenia in autoimmune patients. While researchers Johansson et al. (2014) found no significant correlation between schizophrenia and ADNS, Jeppesen et al. (2019) reveal that those diagnosed with ADNS have an increased risk of up to 44% of developing schizophrenia. Furthermore, limited research exists concerning the pathogenesis of schizophrenia within ADNS patients despite the potential correlations established in previous literature. In order to address this gap, a qualitative analysis of neurobiological research was conducted to apply the diathesis-stress model–developed by Paul Meehl, Manfred Bleuler, and David Rosenthal–to this correlation. The results of the collective analysis reveal that the diathesis of schizophrenia stems from the deterioration of the blood-brain barrier (BBB) over time as the autoimmune disease incapacitates defenses in the brain. The stress ranges from psychologically traumatic events to teratogens that disrupt fetal development. ADNS comprises a variety of disorders characterized by systematic decline without a recognized cure; nonetheless, delineating its association with schizophrenia may present opportunities for therapeutic advancement. Further research should be conducted on pharmacotherapy enhancing BBB integrity in order to prevent or alleviate schizophrenia symptoms in ADNS patients as it remains understudied.
Brain and Behavior: The Diathesis-Stress Model of Schizophrenia in Autoimmune Disease Patients
Though schizophrenia is recognized as an infamous psychological disorder, experts still lack a comprehensive understanding of its multifaceted etiology; thus it remains a topic of interest for current research. Delusions, hallucinations, thought disorders, and movement disorders are some of the common characteristics of schizophrenia (World Health Organization, 2022) though it’s only a fraction of what experts know about the condition. Cumulative research has attempted to uncover the enigmas of the disorder and expert debate over its pathophysiology has emerged over time. One of the more recent debates concerns the phenomenon of autoimmune patients acquiring schizophrenia with contradicting studies from researchers. The lack of knowledge regarding schizophrenia’s link to ADNS may hinder potential therapies that would aid autoimmune patients in ameliorating their psychiatric symptoms. Individuals affected by schizophrenia, especially those who experience severe psychosis, often find it strenuous to perform daily activities as the disorder debilitates their quality of life.
Multiple investigations have endeavored to unravel the pathophysiology of schizophrenia and its connections to ADNS, resulting in novel discoveries such as the role of neuroinflammation. The recent debate between experts about how the disorder emerges within ADNS patients is critical to further understanding the complexities of the psychiatric condition. Thus, this paper aims to further elucidate this potential link by applying the diathesis-stress model to this relationship, and ultimately analyzing the biopsychosocial factors that promote the onset of schizophrenia in individuals with ADNS.
The Role of Immunity in Schizophrenia
Schizophrenia is a severe psychiatric disorder that affects millions of individuals globally and has a detrimental effect on overall health. The disorder’s exact etiology is unclear; however, studies have determined multiple factors–biological, psychological, and social–that contribute to its pathogenesis. Among the biological factors, experts have focused on the role of immune dysfunctions in schizophrenia. A plethora of meta-analyses and original studies such as Howes et al. (2017) agree upon the hyperactivation and increase of microglia in the immune system of the central nervous system (CNS). Microglia are crucial in CNS immunity as they are involved in the inflammatory process and neuronal pruning, or the elimination of dead neurons and synapses (Howes et al., 2017; Ozturk, 2022). Additionally, studies have detected elevated interleukin, a proinflammatory cytokine, and C-reactive proteins which are released as a response to inflammation in schizophrenia patients (Cao et al., 2023). The studies exhibit consistent evidence of neuroinflammation with the detection of various inflammatory markers and cytokines within the brain. Furthermore, there has been evidence in multiple studies of cortical tissue loss in schizophrenia patients due to inflammation and neuronal pruning (Spielman et al., 2020). Depletion of tissue and neurons could trigger the development of psychiatric symptoms observed within schizophrenia. The cumulative research suggests that immune deregulation, specifically neuroinflammation, plays a vital role in the inception of the disorder. Nonetheless, all factors involved with the onset of schizophrenia conspire to cause the condition.
Schizophrenia’s Pathogenesis: The Diathesis-Stress Model
The diathesis-stress model which stemmed from the ideas of psychologists Paul Meehl, Manfred Bleuler, and David Rosenthal (Kendler, 2020) provides an understanding of the pathogenesis of schizophrenia and other psychiatric disorders. The model posits that an individual’s susceptibility to a psychiatric disorder, whether or not one may develop the disorder, is contingent upon their environmental stressors (Sussman, 2023). For instance, a person with a family history of clinical depression may be more vulnerable to acquiring the disorder if faced with childhood trauma. Teratogens (e.g. smoking, viral infections, etc.) that cause complications during fetal development have contributed to an increased risk of schizophrenia (Spielman et al., 2020). In addition, multiple studies have established the involvement of genetics in the condition’s etiology. Identical twins have a 50% risk of developing schizophrenia due to their genes being completely shared (Spielman et al., 2020). However, according to the diathesis-stress model, the disorder may not emerge unless a traumatic event triggers it. Other variations of the diathesis-stress model have also been established since its initial coinage.
Studies have also been conducted concerning a neural diathesis-stress model involving cortisol levels. Jones et al. (2007) state that stress acts upon a pre-existing vulnerability to cause or exacerbate the symptoms of schizophrenia by altering the synthesis of cortisol. Essentially, the neural diathesis-stress model is a neurobiological adaptation of the original model. This adaptation focuses on the involvement of the hypothalamic-pituitary-adrenal (HPA) axis which moderates cortisol release and how it impacts dopamine communication (Walker et al., 1997). Excessive dopamine has been associated with the pathogenesis of schizophrenia (Spielman et al., 2020). The neural diathesis-stress model elucidates how certain stress-related neurobiological effects cooperate with the predisposition of schizophrenia to manifest symptoms. The literature delineates that psychiatric disorders such as schizophrenia are multifactorial as many variables are responsible for its initial incarnation in an individual. Undeniably, the brain and CNS play a major role in the disorder.
The Central Nervous System (CNS) in Schizophrenia
CNS involvement in schizophrenia is substantial as the disorder affects several neuroanatomical aspects and functions. According to Luvsannyam et al. (2022), a large reduction in gray matter in the brain is one of the adverse effects of schizophrenia in patients. This coincides with a meta-analysis by Haijma et al. (2013), asserting that there is a decrease in gray matter with the disorder’s progression. Gray matter makes up most of the superficial and deep portions of the brain and is involved with movement, emotions, processing, and memory (Mercadante and Tadi, 2021). The abundance of gray matter indicates its significance as it is responsible for an abundance of the body’s typical functions. A plausible cause for gray matter loss is the hyperactivation of microglia covered earlier in this paper (Howes et al., 2017). Brain ventricular enlargement caused by schizophrenia symptoms has also been a notable observation by researchers. A ten-year longitudinal study investigating CNS neuroanatomical changes over time found ventricle dilation within chronic schizophrenia patients illustrated on Figure 1 (DeLisi et al., 2006).
The ventricles contain the choroid plexus which is the site of cerebrospinal fluid (CSF) production. Increased CSF causes ventricular enlargement and a substantial reduction in cortical tissue (American Association of Neurological Surgeons, 2019; Spielman et al., 2020). Abnormalities of the ventricles typically cause instabilities within the CNS, affecting its critical functions. In support of this, a 2019 meta-analysis found that CSF was elevated in individuals suffering from schizophrenia in comparison to their healthy counterparts (Orlovska-Waast et al., 2019). Elevated CSF in the brain may signify inflammation or infection which has been associated with schizophrenia (Mount Sinai Health System, n.d.; Orlovska-Waast, 2006). The relationship between schizophrenia and the CNS is prominent as aberrations such as increased CSF levels, ventricular enlargement, and gray matter reduction are present. Collectively, the corresponding studies and meta-analyses provide insight into the abnormal effects of schizophrenia in the CNS and are crucial to further understanding immune involvement.
Schizophrenia-ADNS Correlation
Over time, scientists have discovered an existing link between autoimmune diseases of the nervous system (ADNS) and psychiatric disorders such as schizophrenia. Some of the earliest research dates back to the 1930s, when a schizophrenia patient was detected with autoantibodies by researcher Herman Lehmann-Facius (Kayser et al., 2011, Jeppesen et al., 2019). Further research was conducted in the following decades concerning the recurring diagnosis of Celiac Disease among those suffering from schizophrenia (Jeppesen et al., 2019). These foundational studies laid the groundwork for numerous investigations that ascertained the pathopsychological elements of ADNS. Despite the discovery of this positive link, a study by Johansson et al. (2014) negates previous studies as the results exhibited a negative link between ADNS–specifically Multiple Sclerosis (MS)–and schizophrenia, but a positive association with depression and bipolar disorder instead. A register-based study from Denmark identified that the risk of schizophrenia in MS patients was increased by 44%, contradicting Johansson and their colleagues’ study (Jeppesen et al., 2019). Evidently, this topic evolved into a contentious discourse between experts over time, yielding contrasting results from both sides of the dispute. This ultimately led to the study’s primary objective: further elucidating the schizophrenia-ADNS link.
There appears to be a bidirectional relationship between ADNS and schizophrenia according to experts. A study by Benros et al. (2014) determined that the risk of ADNS diagnoses following the onset of schizophrenia heightened to 53%. In the same vein, a study from Benros et al. (2011) found that there is an elevated risk of 29% of schizophrenia in ADNS patients. There may be a potential neurological abnormality that demonstrates why both conditions are mutual risk factors for one another. Pinpointing this common denominator may prompt new treatment targeting both conditions or may even hinder the onset of either condition if diagnosed with one or the other.
Moreover, it was found that infections and inflammation contributed to the risk of ADNS in schizophrenia patients and vice versa (Benros et al., 2011; Benros et. al, 2014). Figure 2 below indicates a higher incidence rate of schizophrenia in association with infections and autoimmune diseases. The number of infections is directly proportional to the risk of acquiring schizophrenia.
A meta-analysis by Ermakov et al. (2022) delineates that anomalies in the immune system are responsible for neuroinflammation that may lead to schizophrenia and that infections also promote an intrinsic inflammatory status. For instance, the prevalence of proinflammatory cytokines was observed in patient serums and increased inflammatory markers were found in the brains of patients (Ermakov et al., 2022). The pervasiveness of infections and inflammation may be involved in the debilitation of neurological defenses and neural tissues that would allow the emergence of schizophrenia or other psychiatric disorders. Additionally, a combined diagnosis of schizophrenia with the presence of infections demonstrated an elevated risk for ADNS with an incidence rate of 2.70 as shown in Figure 3 (Benros et al., 2014).
This applies to the diagnosis of schizophrenia as well if a patient has a history of infections and a prior onset of ADNS (Benros et al., 2011). Multiple findings suggest that the presence of inflammation caused by infections in either ADNS or schizophrenia is strongly associated with the development of both conditions. The dysfunctions of body systems exhibit an apparent chain reaction that makes it easier for physical and mental conditions such as schizophrenia to develop.
Expert studies have yielded contrasting results concerning the role of genetics in the linkage between ADNS and schizophrenia. A genome-wide association study (GWAS) by Hoeffding et al. (2017) discovered two distinct loci in ADNS and was found to be linked with schizophrenia. However, the results did not conclusively demonstrate a significant “enrichment” despite the observations of “shared genetic susceptibility loci” between autoimmune disorders and schizophrenia (Hoeffding et al., 2017). On the other hand, Eaton et al.’s (2010) cohort study revealed an elevated risk of 10% in families with a history of autoimmune conditions. Another study discovered that the prevalence of ADNS such as “thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial cystitis, and Sjögren’s syndrome” were discovered prior to the onset of schizophrenia in patients and in their parents as shown in Table 1 (Eaton et al., 2006).
Although it is important to point out that these studies were methodologically different with distinct sample sizes which may explain the inconsistencies of the results. Eaton et al.’s studies were population-based and Hoeffding et al.’s study examined autoimmune conditions and their genome-wide risk variants from the NHGRI GWAS catalog. Discrepancies in various genetic studies–notably GWAS–have been observed in determining the genetic relationship between schizophrenia and autoimmunity (Birnbaum et al., 2020). Overall, it is difficult to ascertain whether or not there is a genetic link between schizophrenia and ADNS due to inconsistent results. Further research should be conducted–possibly with a different methodological approach or a larger sample size–to provide substantiation to this potential genetic relationship.
Blood-Brain Barrier (BBB) Hyperpermeability
The biological abnormality that renders ADNS patients more vulnerable to schizophrenia is the increased permeability of the Blood-Brain Barrier (BBB). The BBB is essential in limiting interplay between specific and nonspecific immunity which is crucial for the brain’s defense mechanisms (Najjar et al., 2017). Preventing malignancies such as bacteria from entering and damaging the CNS is a critical function of this barrier. Although immune dysfunctions in ADNS patients may suffer from a highly permeable BBB. A longitudinal study by Benros et al. (2011) states that those with ADNS have been detected with BBB hyperpermeability due to neuroinflammation, stressors, and infections which promotes the incursion of brain-reactive antibodies and proinflammatory cytokines in the brain. Brain-reactive antibodies have been correlated with the manifestation of autoimmune symptoms as they destroy cerebral tissue in “pathologic conditions” (Diamond et al., 2017; Brimberg et al., 2013). Essentially, hyperpermeability of the BBB allows invaders to harm the brain causing neuroinflammation that could increase the risk of schizophrenia. This coincides with a study by Najjar et al. (2017) noting that inflammation in the CNS causes deprivation of astrocytes which weaken the BBB, resulting in hyperpermeability. Furthermore, abnormalities in CSF/serum albumin ratios that have been observed in schizophrenia patients indicate a deterioration of the BBB (Orlovska et al., 2019). The evidence illustrates how disruption of immunoprotective mechanisms in the brain leaves an individual more vulnerable to severe psychiatric symptoms, particularly if they are suffering from autoimmunity.
Methodology
The collective information from the critical literature review was obtained from Google Scholar (1993 to 2023) and the OpenStax Psychology 2e textbook (2020). Chapter 15, “Psychological Disorders” from the textbook was utilized for the overview of the diathesis-stress model, and keyword searches from Google Scholar included “autoimmune disease and schizophrenia,” “diathesis-stress model of schizophrenia,” “schizophrenia and immunity,” and “blood-brain barrier and autoimmune disease.” The studies that focused on immune dysfunctions in schizophrenia such as Immune system abnormalities in schizophrenia: An integrative view and translational perspectives by Ermakov et al. (2022) were critical as they are the framework for this paper.
Results
The diathesis-stress model of schizophrenia in autoimmune disease patients consists of several immune dysfunctions conspiring with environmental stressors according to the collective research in the previous literature. Ultimately, impairments in immune defenses of the CNS such as neuroinflammation causing hyperpermeability of the BBB become the predisposition (i.e., diathesis) of schizophrenia. The stress is wholly contingent upon the individual’s environment. Any event that can disrupt one’s psychological homeostasis–such as emotional stress–or fetal complications from teratogens would fit the criteria for stress. Overall, the application of the diathesis-stress model may elucidate the pathogenesis of schizophrenia in individuals suffering from ADNS.
Discussion and Implications
Results from the cumulative study suggest that the interplay between environmental stressors and the biological predisposition is responsible for the risk of ADNS patients acquiring schizophrenia. The most notable discovery in this research is the diathesis, which is the deterioration of CNS barriers due to the autoimmune condition. It is important to recognize that genetics is not the only source of vulnerabilities to psychological disorders although it is a common predisposition. A diathesis may also result from biological elements, particularly if they have been present in an individual and have remained constant for an extended period (Sussman, 2023). Furthermore, the duration of autoimmune diseases in an individual may elevate their risk of developing schizophrenia as the condition debilitates the BBB chronically. When the amalgamated interaction between the biological diathesis and stress transcends a certain baseline, the autoimmune disease patient may develop schizophrenia (Lazarus, 1993). A potential intervention to the onset of schizophrenia would be therapy targeted toward repairing the BBB. However, medications to restore BBB integrity are currently non-existent (Professional, 2024). Researchers from Stanford University investigated different molecules targeting blood vessels in the brain that bind to Frizzled, a family of proteins that serve as receptors for the WNT signaling pathway which is significant in BBB homeostasis (Moskal, 2023). The development of new medications that can be utilized to treat BBB can not only potentially hinder the onset of schizophrenia symptoms in ADNS, but also treat other brain conditions such as Alzheimer’s and Epilepsy (Cleveland Clinic, n.d.). Essentially, this prospective new generation of treatments may aid in alleviating a myriad of medical disorders involving the CNS as the BBB is critical in immunoprotection. Pharmacotherapies focused on enhancing the BBB are still in their initial stages with the recent Stanford study, thus it can be expanded upon in future research.
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