Cristiano Chaves
Serdar M. Dursun
Massimo Tusconi
Jaime E. C. Hallak2,3,4- 1NeuroMood Lab, School of Medicine and Kingston Health Sciences Center (KHSC), Department of Psychiatry, Queen’s University, Kingston, ON, Canada
- 2Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
- 3National Institute for Translational Medicine (INCT-TM), CNPq, São Paulo, Brazil
- 4Department of Psychiatry (Neurochemical Research Unit) and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- 5Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
1 Introduction: a historical prelude to modern understanding
Hippocrates, often regarded as the founding figure in empirical medicine, was the first to acknowledge the impact of environmental factors on general and mental health in his work “In airs, waters, and places.” However, it took over two millennia for substantial epidemiological studies to explore the relationship between mental disorders, such as schizophrenia, and environmental factors like birth seasonality. Although Tramer’s groundbreaking 1929 study identified a pattern of winter-spring births in 3100 patients with psychosis, a consistent association with schizophrenia was established only by the end of 20th century (1).
2 Maternal immune activation (MIA) and increased relative risk of schizophrenia in offspring
Extensive epidemiological studies in the last two decades have consistently shown that exposure to prenatal MIA significantly increases the odds of developing schizophrenia later in life (2, 3). Khandaker et al.’s (2013) systematic review highlighted a two- to fivefold heightened risk (3), while a more recent metanalysis by Zhou et al. (2021), encompassing 23 observational studies, identified a more modest yet steady increase in psychosis risk among children born to mothers who experienced infections during pregnancy (OR = 1.25, 95% confidence interval (CI): 1.1-1.41; p = 0.001) (4).
It is hypothesized that inflammatory molecules, such as cytokines and chemokines (e.g., TNF-α, IL-1β, IL-6), triggered by prenatal pathogenic exposure, may penetrate the placenta, impair fetal brain development, and cause lasting disturbances in neurodevelopmental trajectories (5, 6). Support for this theory comes from various animal studies examining the effects of MIA on prenatal neurodevelopment and subsequent outcomes (6–12). Behavioral anomalies, as well as structural and functional brain changes attributable to MIA, coincide with the developmental onset of schizophrenia symptoms (13). For instance, Crum et al. (2017) reported cortical thinning in rats following MIA, as evidenced by longitudinal in vivo MRI studies (14). Furthermore, Vasistha et al. (2020) found that MIA disrupted the development of specific subtypes of cortical GABAergic interneurons (15), and Dickerson et al. (2014) noted a decline in inhibitory markers like glutamic decarboxylase in the dorsal hippocampus and abnormal synchrony between the dorsal hippocampus and the medial prefrontal cortex (16).
Notably, these findings are not confined to rodent models. Hanson et al. (2022) reviewed the impact of MIA on the development of the prefrontal cortex in nonhuman primates, illustrating the wider applicability of these results (8). Additionally, Purves-Tyson et al. (2021) detected an upsurge in immune markers within the dopaminergic midbrain in both humans with schizophrenia and murine MIA models, suggesting a potential common pathway in the disease’s complex etiology (9).
3 The vulnerability-stress-inflammation model of schizophrenia
The vulnerability-stress-inflammation model of schizophrenia has emerged from major genetic and epidemiologic studies, diverging from the traditional neural diathesis-stress disease model initially posited by Zubin and Spring in 1977 (17). This contemporary model, as discussed by Howes, McCutcheon, and Stone (2015) and Muller et al. (2015) (18, 19), integrates inflammation as a central element, emphasizing the interplay of inflammation and immune dysregulation with genetic and environmental factors (20, 21).
Inflammation and stress during critical developmental stages, such as the second trimester or early childhood, are significantly implicated in increasing the risk of schizophrenia (7). Studies consistently indicate that stress augments inflammation markers, reinforcing the connection between stress and inflammation (10, 19, 20). Moreover, childhood adversity is linked with changes in immune and inflammatory responses (22–26), which may also involve dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (27, 28). Giovanoli et al. (2013) showed that experiencing stress during puberty can expose hidden neurologic damage that results from immune activation before birth in mice (29).
Genetics also plays a crucial role in stress sensitivity, with certain variants linked to both inflammation and schizophrenia (30, 31). Steen and colleagues (2023) identified common genetic markers associated with both schizophrenia and systemic immune alterations (32). MIA can lead to methylation changes in schizophrenia-related genes, thus affecting susceptibility through genetic and environmental risk factors (33, 34).
Infections and immune dysregulation’s impact extends beyond early neurodevelopment. In a 30-year nationwide cohort of population-based register in Denmark, Benros et al. (2011) showed that autoimmune diseases combined with exposures to severe infections increased the risk of schizophrenia in a dose-response relationship: three or more infections and an autoimmune disease were associated with an incidence rate ratio of 3.40 (95% CI=2.91-3.94) (35). However, this association may be partly due to common genetic factors, particularly within the HLA region. This region, which is vital for immune system functioning, has been identified as having the most significant genetic link to schizophrenia (Benros & Mortensen, 2020) (36).
In a comprehensive meta-analysis of 145 studies, Romer et al. (2023) observed elevated levels of immunological markers in the cerebrospinal fluid (CSF) of individuals with psychotic disorders relative to healthy controls (37), corroborating the findings of Runge et al. (2021), who also reported significantly increased IL-8 concentrations in the CSF of patients with schizophrenia spectrum disorders (38). Additionally, a subsequent meta-analysis encompassing 86 studies by Clausen et al. (2024) further substantiated these findings by showing a widespread activation of the immune system in psychotic conditions, as evidenced by the heightened count of immune cells in both the blood and CSF of the patients assessed (39).
Halstead et al.’s (2023) meta-analysis also shows a consistent elevation in pro-inflammatory proteins, like IL-6, indicative of ongoing inflammatory protein alteration throughout the illness (40). Growing evidence indicates a genetic foundation for the association between cytokine levels and schizophrenia (41). Further extending this research, Gonzalez-Castro et al. (2024) conducted a meta-analysis involving around 5,000 patients with schizophrenia and discovered a significant correlation between genes regulating cytokines and the predisposition to the disorder (42).
The repercussions of immune dysregulation on neuronal signaling, synapse organization, and brain connectivity are also significant (19, 43, 44). Williams et al. (2022) identified a significant correlation between genetically determined IL-6 levels and gray matter volumes in the frontotemporal cortex of schizophrenia patients (45). Consequently, the review by Dwir et al. (2023) underscores redox and immune signaling as critical therapeutic targets in schizophrenia (46).
4 Expanding the two-hit model of schizophrenia: neuroprogression and alternative hypotheses
In the context of the vulnerability-stress-inflammation conceptual framework, schizophrenia is currently conceptualized as a neurodevelopmental disorder driven by a two-hit process. The first hit arises from MIA and increased inflammation during the fetal and perinatal stages. This initial hit primes the immune system, particularly impacting the microglia, the brain’s primary immune cells responsible for repairing damage and pruning neurons (5, 34, 43, 47).
Microglia, often analogized as the “gardeners of the brain,” play a crucial role in maintaining neural health. They have a lengthy lifespan of 4 years, but some cells persist for up to twenty years (10). When primed, these cells can react to stress factors by initiating exaggerated pro-inflammatory responses, adversely affecting brain development (10, 20, 48). Intriguily, post-mortem and in-vitro research has shown that microglia are more active in eliminating synapses in neural cultures of schizophrenia patients, suggesting a key role in synaptic pruning (49).
The second hit typically occurs in late adolescence and leads to a series of significant changes: dopaminergic dysregulation, increased synapse pruning, and the emergence of psychosis (21). This phase is marked by an increase in dopaminergic transmission, presumably stemming from presynaptic dysregulation and receptor number changes in schizophrenia patients (18, 50). Correspondingly, animal models using NMDAR antagonism and MIA have reported reductions in gray matter volumes (14).
While the two-hit hypothesis highlights the critical roles of both prenatal and postnatal factors in schizophrenia, it does not fully address the progressive deterioration observed in patients. One of the earliest and most prominent brain alterations in schizophrenia is the loss of cortical gray matter volume, particularly in the fronto-temporal regions. This loss tends to worsen as the illness progresses, leading to increased severity and poorer clinical outcomes (51, 52).
Furthermore, neuroimaging studies have established a connection between schizophrenia and significant brain changes, including cortical atrophy and ventricular enlargement, which persist for at least ten years following the initial onset of psychosis. Notably, the extent of cortical atrophy has a stronger correlation with the presence of negative symptoms and cognitive impairments rather than with psychotic symptoms (53, 54). However, the absence of classic neurodegenerative signs in post-mortem studies has previously led to schizophrenia being labeled “the graveyard of neuropathology” (55, 56). Actually, the cortical atrophy is attributed not to actual neuronal loss but rather to diminished synaptic connectivity on pyramidal neurons (57–63).
Several new hypotheses have been proposed to deepen our comprehension of schizophrenia. For instance, Falkai et al. (2023) suggest that diminished maturation of oligodendrocyte cells may contribute to frontotemporal dysconnectivity and subsequent cognitive deficits (64). Interestingly, Morris et al. (2022) investigates how the endocannabinoid system could be linked to the persistent elevation of nitro-oxidative stress and immune dysregulation (65). Additionally, the magnitude of immune, cardiometabolic, and endocrine alterations in schizophrenia suggests it is better understood as a systemic disorder (66).
5 Low-level inflammation and neuroprogression in schizophrenia
Recent findings indicate inflammation may contribute to brain alterations seen in schizophrenia. Elevated levels of pro-inflammatory markers, including cytokines, are present in the blood and CSF of individuals with first-episode psychosis (FEP) and chronic schizophrenia (21, 67). Such persistent, low-grade inflammation is associated with changes in both the gray and white matter (44, 52, 68, 69). Furthermore, a systematic review has found that high levels of C-reactive protein (CRP) and interleukin-6 (IL-6) are linked with worsened clinical outcomes, exacerbation of symptoms, and structural brain changes, specifically diminished hippocampal volume and cortical thickness (69).
Moreover, schizophrenia patients exhibiting inflammation have shown increased macrophage activity and altered gene expression patterns in the brain endothelial cells within the frontal cortex (70). In a post-mortem study, Zhang et al. (2016) also observed an association between elevated levels of cytokines and reduced cortical gray matter volumes (71).
In addition to these structural brain changes, recent cohort studies have provided promising evidence for a link between inflammation and the negative symptoms associated with schizophrenia (72, 73). Interestingly, Kerkova et al. (2023) observed that a history of childhood trauma significantly moderates the relationship between inflammation and cognitive functioning in FEP (74). Furthermore, the increased size of the choroid plexus volume in antipsychotic-naïve FEP lends additional support to the significant influence of neuroinflammation on cerebral impairment (75).
6 Potential biomarkers for schizophrenia diagnosis and treatment
Schizophrenia diagnosis relies principally on clinical observation; however, assessing symptoms alone is subjective and lacks specificity for accurate diagnosis. In contrast, biomarkers offer a promising complement that can further delineate the boundaries of the diverse biological processes collectively termed schizophrenia (52). Biomarker discovery could bring a revolution with early detection, precise diagnosis, and more effective, targeted treatments (52, 76).
For instance, increased IL-6 levels in blood and CSF fluid are associated with more severe symptoms and poorer treatment response in schizophrenia patients (77, 78). Further, recent advances have identified several promising neuroinflammation biomarkers, particularly cytokines like interleukin-1β and interleukin-6 (19, 77, 79).
A significant breakthrough is the direct identification of markers indicative of microglial activation, such as the expression of 18-kDa translocator protein (TPSO), enabling the in vivo examination of microglia activation and neuroinflammation via TPSO PET imaging in the brain (20, 43). Despite the caveat that TSPO is found in various types of brain cells, not just in microglia (20), a metanalysis by Marques et al. (2019) found a significant increase in TSPO binding potential in patients with schizophrenia compared to controls (80).
Additionally, inverse correlations between CRP levels and cognitive function in acute psychosis have been documented (81–85). Further, Fathian et al. (2019) noted that reductions in CRP serum levels during acute psychosis are predictive of cognitive improvement over a six-month period (86).
Moreover, while a meta-analysis by Pilinger et al. (2019) on peripheral immune parameters in psychosis showed elevated cytokines, it did not support an immune subgroup hypothesis after adjusting for confounders (87). Contrarily, Enrico et al. (2023) identified a subgroup of FEP patients with high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A, and CXCR3), suggesting heterogeneity within the condition (88).
7 Research studies in the present topic
The current Frontiers in Psychiatry Research Topic, titled “Further Findings in the Role of Inflammation in the Etiology and Treatment of Schizophrenia,” includes four original research studies that use inflammatory biomarkers as informative tools for schizophrenia diagnosis and treatment.
7.1 Predicting schizophrenia treatment outcomes with immune and metabolic parameters
Low-grade inflammation, present in both FEP and chronic schizophrenia, can be detected in routine laboratory tests. Skalniak et al.’s study indicates that lower CRP and C4 complement levels predict greater symptom improvement after 12 weeks of antipsychotic treatment (89). In accordance, Dr Yolken’s team, with over two decades of research on infections and immune dysregulation in schizophrenia, recently published a pilot study discussing the potential value of CRP and C4 complement as informative biomarkers in schizophrenia (90).
7.2 Exploring cellular senescence-related genes in schizophrenia diagnosis and treatment
Mounting evidence suggests an accelerated aging process, known as senescence, in individuals with schizophrenia and severe mental illnesses (91). Shortened telomeres in white blood cells serve as a key indicator of cell senescence. Feng et al.‘s study employs genetic tools to explore novel treatments for schizophrenia, highlighting the immunoglobulin gene myosin light chain kinase (MYLK) as a potential drug target for mental health therapeutic intervention (92).
7.3 The impact of exercise on inflammatory markers in individuals with schizophrenia
Given the implication of chronic low-grade inflammation in schizophrenia, Bigseth et al.‘s study investigates the effects of high-intensity exercise on inflammatory markers in schizophrenia patients (93). Despite the 12-week exercise program having no reducing effect on inflammatory markers, this outcome aligns with a recently published study on the same sample. The earlier study demonstrated no improvement in schizophrenia symptoms; however, a notable positive correlation was observed with the amelioration of depressive symptoms (94).
7.4 Clozapine’s role in inflammation among outpatients with schizophrenia
A recent investigation by the FondaMental Expert Centers for Schizophrenia in France (FACE-SZ) revealed a potential immune signature associated with the IL-23/IL-17 pathway in treatment-resistant schizophrenia (95). Additionally, Cordova et al.‘s study explores the immune profile of clozapine by comparing users and non-users. The study observes a correlation between clozapine use and an increased systemic immune inflammation index (SII) (96). However, a comprehensive understanding requires longitudinal studies with larger sample sizes to thoroughly assess the intricate relationships between inflammatory markers, disease progression, and the response to clozapine.
8 Conclusion: the future of inflammation-based schizophrenia research
While these studies contribute valuable insights, ongoing research, collaboration, and advanced technologies are crucial for unraveling the complex role of immune dysregulation in schizophrenia pathophysiology. The identification of potential biomarkers related to inflammation opens new paths for precise diagnosis and tailored treatments, offering promise for individuals grappling with this challenging mental health disorder.
Author contributions
CC: Conceptualization, Writing – original draft, Writing – review & editing. SD: Conceptualization, Writing – review & editing. MT: Conceptualization, Writing – review & editing. JH: Conceptualization, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: A review of the literature. Schizophr Res (1997) 28(1):1–38. doi: 10.1016/S0920-9964(97)00092-3
2. Davies C, Segre G, Estrade A, Radua J, De Micheli A, Provenzani U, et al. Prenatal and perinatal risk and protective factors for psychosis: A systematic review and meta-analysis. Lancet Psychiatry (2020) 7(5):399–410. doi: 10.1016/S2215-0366(20)30057-2
3. Khandaker GM, Zimbron J, Lewis G, Jones PB. Prenatal maternal infection, neurodevelopment and adult schizophrenia: A systematic review of population-based studies. Psychol Med (2013) 43(2):239–57. doi: 10.1017/S0033291712000736
4. Zhou YY, Zhang WW, Chen F, Hu SS, Jiang HY. Maternal infection exposure and the risk of psychosis in the offspring: A systematic review and meta-analysis. J Psychiatr Res (2021) 135:28–36. doi: 10.1016/j.jpsychires.2020.12.065
5. Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev (2014) 38:72–93. doi: 10.1016/j.neubiorev.2013.11.006
6. Massrali A, Adhya D, Srivastava DP, Baron-Cohen S, Kotter MR. Virus-Induced Maternal immune activation as an environmental factor in the etiology of autism and schizophrenia. Front Neurosci (2022) 16:834058. doi: 10.3389/fnins.2022.834058
7. Mawson ER, Morris BJ. A consideration of the increased risk of schizophrenia due to prenatal maternal stress, and the possible role of microglia. Prog Neuropsychopharmacol Biol Psychiatry (2023) 125:110773. doi: 10.1016/j.pnpbp.2023.110773
8. Hanson KL, Grant SE, Funk LH, Schumann CM, Bauman MD. Impact of Maternal Immune activation on nonhuman primate prefrontal cortex development: Insights for schizophrenia. Biol Psychiatry (2022) 92(6):460–9. doi: 10.1016/j.biopsych.2022.04.004
9. Purves-Tyson TD, Weber-Stadlbauer U, Richetto J, Rothmond DA, Labouesse MA, Polesel M, et al. Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation. Mol Psychiatry (2021) 26(3):849–63. doi: 10.1038/s41380-019-0434-0
10. Han VX, Patel S, Jones HF, Dale RC. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat Rev Neurol (2021) 17(9):564–79. doi: 10.1038/s41582-021-00530-8
11. Choudhury Z, Lennox B. Maternal immune activation and schizophrenia-evidence for an immune priming disorder. Front Psychiatry (2021) 12:585742. doi: 10.3389/fpsyt.2021.585742
12. Haddad FL, Patel SV, Schmid S. Maternal Immune Activation by Poly I:C as a preclinical Model for Neurodevelopmental Disorders: A focus on Autism and Schizophrenia. Neurosci Biobehav Rev (2020) 113:546–67. doi: 10.1016/j.neubiorev.2020.04.012
13. Meyer U, Feldon J, Schedlowski M, Yee BK. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci Biobehav Rev (2005) 29(6):913–47. doi: 10.1016/j.neubiorev.2004.10.012
14. Crum WR, Sawiak SJ, Chege W, Cooper JD, Williams SCR, Vernon AC. Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study. Brain Behav Immun (2017) 63:50–9. doi: 10.1016/j.bbi.2016.12.008
15. Vasistha NA, Pardo-Navarro M, Gasthaus J, Weijers D, Muller MK, Garcia-Gonzalez D, et al. Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner. Mol Psychiatry (2020) 25(10):2313–29. doi: 10.1038/s41380-019-0539-5
16. Dickerson DD, Overeem KA, Wolff AR, Williams JM, Abraham WC, Bilkey DK. Association of aberrant neural synchrony and altered GAD67 expression following exposure to maternal immune activation, a risk factor for schizophrenia. Transl Psychiatry (2014) 4(7):e418. doi: 10.1038/tp.2014.64
17. Zubin J, Spring B. Vulnerability–a new view of schizophrenia. J Abnorm Psychol (1977) 86(2):103–26. doi: 10.1037/0021-843X.86.2.103
18. Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: An update for the 21st century. J Psychopharmacol (2015) 29(2):97–115. doi: 10.1177/0269881114563634
19. Muller N, Weidinger E, Leitner B, Schwarz MJ. The role of inflammation in schizophrenia. Front Neurosci (2015) 9:372. doi: 10.3389/fnins.2015.00372
20. Howes OD, McCutcheon R. Inflammation and the neural diathesis-stress hypothesis of schizophrenia: A reconceptualization. Transl Psychiatry (2017) 7(2):e1024. doi: 10.1038/tp.2016.278
21. Muller N. Inflammation in Schizophrenia: Pathogenetic aspects and therapeutic considerations. Schizophr Bull (2018) 44(5):973–82. doi: 10.1093/schbul/sby024
22. Miljevic C, Munjiza-Jovanovic A, Jovanovic T. Impact of childhood adversity, as early life distress, on cytokine alterations in schizophrenia. Neuropsychiatr Dis Treat (2023) 19:579–86. doi: 10.2147/NDT.S396168
23. Thomas M, Rakesh D, Whittle S, Sheridan M, Upthegrove R, Cropley V. The neural, stress hormone and inflammatory correlates of childhood deprivation and threat in psychosis: A systematic review. Psychoneuroendocrinology. (2023) 157:106371. doi: 10.1016/j.psyneuen.2023.106371
24. Foiselle M, Lajnef M, Hamdani N, Boukouaci W, Wu CL, Naamoune S, et al. Immune cell subsets in patients with bipolar disorder or schizophrenia with history of childhood maltreatment. Brain Behav Immun (2023) 112:42–50. doi: 10.1016/j.bbi.2023.05.015
25. Kappelmann N, Perry BI, Khandaker GM. Prenatal and childhood immuno-metabolic risk factors for adult depression and psychosis. Harv Rev Psychiatry (2022) 30(1):8–23. doi: 10.1097/HRP.0000000000000322
26. Quide Y, Bortolasci CC, Spolding B, Kidnapillai S, Watkeys OJ, Cohen-Woods S, et al. Systemic inflammation and grey matter volume in schizophrenia and bipolar disorder: Moderation by childhood trauma severity. Prog Neuropsychopharmacol Biol Psychiatry (2021) 105:110013. doi: 10.1016/j.pnpbp.2020.110013
27. Farcas A, Christi P, Iftene F. Cortisol and cytokines in schizophrenia: A scoping review. Compr Psychoneuroendocrinol. (2023) 15:100192. doi: 10.1016/j.cpnec.2023.100192
28. Mikulska J, Juszczyk G, Gawronska-Grzywacz M, Herbet M. HPA axis in the pathomechanism of depression and schizophrenia: New therapeutic strategies based on its participation. Brain Sci (2021) 11(10):1298. doi: 10.3390/brainsci11101298
29. Giovanoli S, Engler H, Engler A, Richetto J, Voget M, Willi R, et al. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science. (2013) 339(6123):1095–9. doi: 10.1126/science.1228261
30. van der Meer D, Cheng W, Rokicki J, Fernandez-Cabello S, Shadrin A, Smeland OB, et al. Clustering schizophrenia genes by their temporal expression patterns aids functional interpretation. Schizophr Bull (2023). doi: 10.1101/2022.08.25.22279215
31. Bishop JR, Zhang L, Lizano P. Inflammation subtypes and translating inflammation-related genetic findings in schizophrenia and related psychoses: A perspective on pathways for treatment stratification and novel therapies. Harv Rev Psychiatry (2022) 30(1):59–70. doi: 10.1097/HRP.0000000000000321
32. Steen NE, Rahman Z, Szabo A, Hindley GFL, Parker N, Cheng W, et al. Shared genetic loci between schizophrenia and white blood cell counts suggest genetically determined systemic immune abnormalities. Schizophr Bull (2023) 49(5):1345–54. doi: 10.1093/schbul/sbad082
33. Hogenaar JTT, van Bokhoven H. Schizophrenia: Complement cleaning or killing. Genes (Basel). (2021) 12(2):259–. doi: 10.3390/genes12020259
34. Johnson T, Saatci D, Handunnetthi L. Maternal immune activation induces methylation changes in schizophrenia genes. PloS One (2022) 17(11):e0278155. doi: 10.1371/journal.pone.0278155
35. Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry (2011) 168(12):1303–10. doi: 10.1176/appi.ajp.2011.11030516
36. Benros ME, Mortensen PB. Role of infection, autoimmunity, atopic disorders, and the immune system in schizophrenia: Evidence from epidemiological and genetic studies. Curr Top Behav Neurosci (2020) 44:141–59. doi: 10.1007/7854_2019_93
37. Romer TB, Jeppesen R, Christensen RHB, Benros ME. Biomarkers in the cerebrospinal fluid of patients with psychotic disorders compared to healthy controls: A systematic review and meta-analysis. Mol Psychiatry (2023) 28(6):2277–90. doi: 10.1038/s41380-023-02059-2
38. Runge K, Fiebich BL, Kuzior H, Saliba SW, Yousif NM, Meixensberger S, et al. An observational study investigating cytokine levels in the cerebrospinal fluid of patients with schizophrenia spectrum disorders. Schizophr Res (2021) 231:205–13. doi: 10.1016/j.schres.2021.03.022
39. Clausen M, Christensen RHB, da Re M, Benros ME. Immune cell alterations in psychotic disorders: A comprehensive systematic review and meta-analysis. Biol Psychiatry (2024). doi: 10.1016/j.biopsych.2023.11.029
40. Halstead S, Siskind D, Amft M, Wagner E, Yakimov V, Shih-Jung Liu Z, et al. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: A systematic review and network meta-analysis. Lancet Psychiatry (2023) 10(4):260–71. doi: 10.1016/S2215-0366(23)00025-1
41. Dawidowski B, Gorniak A, Podwalski P, Lebiecka Z, Misiak B, Samochowiec J. The role of cytokines in the pathogenesis of schizophrenia. J Clin Med (2021) 10(17):3849. doi: 10.3390/jcm10173849
42. Beatriz Gonzalez-Castro T, Alfonso Tovilla-Zarate C, Esther Juarez-Rojop I, Hernandez-Diaz Y, Lilia Lopez-Narvaez M, Felicita Ortiz-Ojeda R. The association of cytokines genes (IL-6 and IL-10) with the susceptibility to schizophrenia: A systematic review and meta-analysis. Brain Res (2024) 1822:148667. doi: 10.1016/j.brainres.2023.148667
43. Chaves C, Zuardi AW, Hallak JE. The role of inflammation in schizophrenia: an overview. Trends Psychiatry Psychother. (2015) 37(2):104–5. doi: 10.1590/2237-6089-2015-0007
44. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune system abnormalities in schizophrenia: An Integrative view and translational perspectives. Front Psychiatry (2022) 13:880568. doi: 10.3389/fpsyt.2022.880568
45. Williams JA, Burgess S, Suckling J, Lalousis PA, Batool F, Griffiths SL, et al. Inflammation and brain structure in schizophrenia and other neuropsychiatric Disorders: A mendelian randomization study. JAMA Psychiatry (2022) 79(5):498–507. doi: 10.1001/jamapsychiatry.2022.0407
46. Dwir D, Khadimallah I, Xin L, Rahman M, Du F, Ongur D, et al. Redox and immune signaling in schizophrenia: New therapeutic potential. Int J Neuropsychopharmacol (2023) 26(5):309–21. doi: 10.1093/ijnp/pyad012
47. Ferrucci L, Cantando I, Cordella F, Di Angelantonio S, Ragozzino D, Bezzi P. Microglia at the tripartite synapse during postnatal development: Implications for autism spectrum disorders and schizophrenia. Cells. (2023) 12(24):2827. doi: 10.3390/cells12242827
48. Rodrigues-Neves AC, Ambrosio AF, Gomes CA. Microglia sequelae: brain signature of innate immunity in schizophrenia. Transl Psychiatry (2022) 12(1):493. doi: 10.1038/s41398-022-02197-1
49. Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci (2019) 22(3):374–85. doi: 10.1038/s41593-018-0334-7
50. Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry (2003) 160(1):13–23. doi: 10.1176/appi.ajp.160.1.13
51. Dempster K, Norman R, Theberge J, Densmore M, Schaefer B, Williamson P. Cognitive performance is associated with gray matter decline in first-episode psychosis. Psychiatry Res Neuroimaging. (2017) 264:46–51. doi: 10.1016/j.pscychresns.2017.04.007
52. Kraguljac NV, McDonald WM, Widge AS, Rodriguez CI, Tohen M, Nemeroff CB. Neuroimaging biomarkers in schizophrenia. Am J Psychiatry (2021) 178(6):509–21. doi: 10.1176/appi.ajp.2020.20030340
53. Coyle JT, Balu DT, Puhl MD, Konopaske GT. History of the concept of disconnectivity in schizophrenia. Harv Rev Psychiatry (2016) 24(2):80–6. doi: 10.1097/HRP.0000000000000102
54. de Bartolomeis A, Barone A, Vellucci L, Mazza B, Austin MC, Iasevoli F, et al. Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic changes: Translational relevance for schizophrenia and antipsychotic treatment: A Systematic review. Mol Neurobiol (2022) 59(10):6460–501. doi: 10.1007/s12035-022-02976-3
55. Corsellis JAN. Psychoses of obscure pathology. In: Greenfield's Neuropathology. Year Book Medical Publishers, Chicago (1976). p. 903–15.
56. Plum F. Prospects for research on schizophrenia. 3. Neurophysiology. Neuropathological findings. Neurosci Res Program bulletin. (1972) 10(4):384–8.
57. Konopaske GT, Lange N, Coyle JT, Benes FM. Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry (2014) 71(12):1323–31. doi: 10.1001/jamapsychiatry.2014.1582
58. Ren W, Lui S, Deng W, Li F, Li M, Huang X, et al. Anatomical and functional brain abnormalities in drug-naive first-episode schizophrenia. Am J Psychiatry (2013) 170(11):1308–16. doi: 10.1176/appi.ajp.2013.12091148
59. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry (2011) 68(2):128–37. doi: 10.1001/archgenpsychiatry.2010.199
60. Sweet RA, Henteleff RA, Zhang W, Sampson AR, Lewis DA. Reduced dendritic spine density in auditory cortex of subjects with schizophrenia. Neuropsychopharmacology. (2009) 34(2):374–89. doi: 10.1038/npp.2008.67
61. Buckley PF, Friedman L, Jesberger JA, Schulz SC, Jaskiw G. Head size and schizophrenia. Schizophr Res (2002) 55(1-2):99–104. doi: 10.1016/S0920-9964(01)00160-8
62. Pierri JN, Volk CLE, Auh S, Sampson A, Lewis DA. Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. Arch Gen Psychiatry (2001) 58(5):466–73. doi: 10.1001/archpsyc.58.5.466
63. Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, et al. Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: Preliminary findings. Arch Gen Psychiatry (2000) 57(4):349–56. doi: 10.1001/archpsyc.57.4.349
64. Falkai P, Rossner MJ, Raabe FJ, Wagner E, Keeser D, Maurus I, et al. Disturbed oligodendroglial maturation causes cognitive dysfunction in schizophrenia: A new hypothesis. Schizophr Bull (2023) 49(6):1614–24. doi: 10.1093/schbul/sbad065
65. Morris G, Sominsky L, Walder KR, Berk M, Marx W, Carvalho AF, et al. Inflammation and nitro-oxidative stress as drivers of endocannabinoid system aberrations in mood disorders and schizophrenia. Mol Neurobiol (2022) 59(6):3485–503. doi: 10.1007/s12035-022-02800-y
66. Pillinger T, D'Ambrosio E, McCutcheon R, Howes OD. Is psychosis a multisystem disorder? A meta-review of central nervous system, immune, cardiometabolic, and endocrine alterations in first-episode psychosis and perspective on potential models. Mol Psychiatry (2019) 24(6):776–94. doi: 10.1038/s41380-018-0058-9
67. Song X, Fan X, Li X, Zhang W, Gao J, Zhao J, et al. Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naive, first-episode schizophrenia. Psychopharmacol (Berl). (2014) 231(2):319–25. doi: 10.1007/s00213-013-3382-4
68. Gou M, Chen W, Li Y, Chen S, Feng W, Pan S, et al. Immune-inflammatory response and compensatory immune-regulatory reflex systems and white matter integrity in schizophrenia. Schizophr Bull (2024) 50(1):199–209. doi: 10.1093/schbul/sbad114
69. Kose M, Pariante CM, Dazzan P, Mondelli V. The role of peripheral inflammation in clinical outcome and brain imaging abnormalities in psychosis: A systematic review. Front Psychiatry (2021) 12:612471. doi: 10.3389/fpsyt.2021.612471
70. Cai HQ, Catts VS, Webster MJ, Galletly C, Liu D, O'Donnell M, et al. Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation. Mol Psychiatry (2020) 25(4):761–75. doi: 10.1038/s41380-018-0235-x
71. Zhang Y, Catts VS, Sheedy D, McCrossin T, Kril JJ, Shannon Weickert C. Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation. Transl Psychiatry (2016) 6(12):e982. doi: 10.1038/tp.2016.238
72. Dunleavy C, Elsworthy RJ, Upthegrove R, Wood SJ, Aldred S. Inflammation in first-episode psychosis: The contribution of inflammatory biomarkers to the emergence of negative symptoms, a systematic review and meta-analysis. Acta Psychiatr Scand (2022) 146(1):6–20. doi: 10.1111/acps.13416
73. Goldsmith DR, Rapaport MH. Inflammation and negative symptoms of schizophrenia: Implications for reward processing and motivational deficits. Front Psychiatry (2020) 11:46. doi: 10.3389/fpsyt.2020.00046
74. Kerkova B, Knizkova K, Vecerova M, Sustova P, Furstova P, Hruby A, et al. Inflammation and cognitive performance in first-episode schizophrenia spectrum disorders: The moderating effects of childhood trauma. Schizophr Res (2023) 261:185–93. doi: 10.1016/j.schres.2023.09.034
75. Zeng J, Zhang T, Tang B, Li S, Yao L, Bishop JR, et al. Choroid plexus volume enlargement in first-episode antipsychotic-naive schizophrenia. Schizophr (Heidelb). (2024) 10(1):1. doi: 10.1038/s41537-023-00424-2
76. Noto C, Maes M, Ota VK, Teixeira AL, Bressan RA, Gadelha A, et al. High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World J Biol Psychiatry (2015) 16(6):422–9. doi: 10.3109/15622975.2015.1062552
77. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry (2011) 70(7):663–71. doi: 10.1016/j.biopsych.2011.04.013
78. Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia–significance for activation of the kynurenine pathway. J Psychiatry Neurosci (2015) 40(2):126–33. doi: 10.1503/jpn.140126
79. Miller BJ, Goldsmith DR. Evaluating the hypothesis that schizophrenia is an inflammatory disorder. Focus (Am Psychiatr Publ). (2020) 18(4):391–401. doi: 10.1176/appi.focus.20200015
80. Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, Dazzan P, et al. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med (2019) 49(13):2186–96. doi: 10.1017/S0033291718003057
81. Inoshita M, Numata S, Tajima A, Kinoshita M, Umehara H, Nakataki M, et al. A significant causal association between C-reactive protein levels and schizophrenia. Sci Rep (2016) 6. doi: 10.1038/srep26105
82. Fernandes BS, Steiner J, Bernstein HG, Dodd S, Pasco JA, Dean OM, et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: Meta-analysis and implications. Mol Psychiatry (2016) 21(4):554–64. doi: 10.1038/mp.2015.87
83. Miller BJ, Culpepper N, Rapaport MH. C-reactive protein levels in schizophrenia: A review and meta-analysis. Clin Schizophr Related Psychoses. (2014) 7(4):223–30. doi: 10.3371/CSRP.MICU.020813
84. Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yolken R. Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus type 1 on cognitive impairment in individuals with schizophrenia. Schizophr Res (2012) 134(1):83–8. doi: 10.1016/j.schres.2011.10.003
85. Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res (2007) 93(1-3):261–5. doi: 10.1016/j.schres.2007.03.022
86. Fathian F, Loberg EM, Gjestad R, Steen VM, Kroken RA, Jorgensen HA, et al. Associations between C-reactive protein levels and cognition during the first 6 months after acute psychosis. Acta Neuropsychiatr (2019) 31(1):36–45. doi: 10.1017/neu.2018.25
87. Pillinger T, Osimo EF, Brugger S, Mondelli V, McCutcheon RA, Howes OD. A Meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis. Schizophr Bull (2019) 45(5):1120–33. doi: 10.1093/schbul/sby160
88. Enrico P, Delvecchio G, Turtulici N, Aronica R, Pigoni A, Squarcina L, et al. A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup. Mol Psychiatry (2023) 28(3):1190–200. doi: 10.1038/s41380-022-01911-1
89. Skalniak A, Krzysciak W, Smierciak N, Szwajca M, Donicz P, Kozicz T, et al. Immunological routine laboratory parameters at admission influence the improvement of positive symptoms in schizophrenia patients after pharmacological treatment. Front Psychiatry (2023) 14:1082135. doi: 10.3389/fpsyt.2023.1082135
90. Severance EG, Prandovszky E, Yang S, Leister F, Lea A, Wu CL, et al. Prospects and pitfalls of plasma complement C4 in schizophrenia: Building a better biomarker. Dev Neurosci (2023) 45(6):349–60. doi: 10.1159/000534185
91. Campeau A, Mills RH, Stevens T, Rossitto LA, Meehan M, Dorrestein P, et al. Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia. Mol Psychiatry (2022) 27(2):1217–25. doi: 10.1038/s41380-021-01339-z
92. Feng Y, Shen J, He J, Lu M. Schizophrenia and cell senescence candidate genes screening, machine learning, diagnostic models, and drug prediction. Front Psychiatry (2023) 14:1105987. doi: 10.3389/fpsyt.2023.1105987
93. Bigseth TT, Engh JA, Andersen E, Bang-Kittilsen G, Egeland J, Falk RS, et al. Alterations in inflammatory markers after a 12-week exercise program in individuals with schizophrenia-a randomized controlled trial. Front Psychiatry (2023) 14:1175171. doi: 10.3389/fpsyt.2023.1175171
94. Bang-Kittilsen G, Engh JA, Holst R, Holmen TL, Bigseth TT, Andersen E, et al. High-intensity interval training may reduce depressive symptoms in individuals with schizophrenia, putatively through improved VO(2)max: A randomized controlled trial. Front Psychiatry (2022) 13:921689. doi: 10.3389/fpsyt.2022.921689
95. Leboyer M, Godin O, Terro E, Boukouaci W, Lu CL, Andre M, et al. Immune signatures of treatment-resistant schizophrenia: A fondaMental academic centers of expertise for schizophrenia (FACE-SZ) study. Schizophr Bull Open (2021) 2(1):sgab012. doi: 10.1093/schizbullopen/sgab012
Keywords: inflammation, schizophrenia, biomarkers, psychiatric genetics, neurobiology, neuroinflammation, psychotic disorders
Citation: Chaves C, Dursun SM, Tusconi M and Hallak JEC (2024) Neuroinflammation and schizophrenia – is there a link? Front. Psychiatry 15:1356975. doi: 10.3389/fpsyt.2024.1356975
Received: 16 December 2023; Accepted: 30 January 2024;
Published: 08 February 2024.
Edited by:
Eugenia Kravariti, King’s College London, United KingdomReviewed by:
Milica Milovan Borovcanin, University of Kragujevac, SerbiaCopyright © 2024 Chaves, Dursun, Tusconi and Hallak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Cristiano Chaves, cristianochaves@alumni.usp.br