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Impact of Childhood Adversity, as Early Life Distress, on Cytokine Alterations in Schizophrenia

Authors Miljevic C , Munjiza-Jovanovic A, Jovanovic T

Received 7 November 2022

Accepted for publication 23 February 2023

Published 11 March 2023 Volume 2023:19 Pages 579—586

DOI https://doi.org/10.2147/NDT.S396168

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Roger Pinder



Cedo Miljevic,1,2 Ana Munjiza-Jovanovic,1,3 Teodora Jovanovic4

1Department of Psychiatry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 2Clinical Trial Unit, Institute of Mental Health, Belgrade, Serbia; 3Day Hospital for Adolescents, Institute of Mental Health, Belgrade, Serbia; 4Department for Psychotic Disorders, Institute of Mental Health, Belgrade, Serbia

Correspondence: Cedo Miljevic, Department of Psychiatry, Faculty of Medicine, University of Belgrade, Milana Kasanina 3, Belgrade, 11 000, Serbia, Tel +381 11 3307500, Fax +381 33 40 629, Email [email protected]

Abstract: Even though inflammation theory has been introduced in the pathophysiology of psychosis almost a century ago, many of its aspects have remained unelucidated. Numerous studies have shown cytokine dysregulation in schizophrenia and a predominance of pro-inflammatory cytokines, but on another side, various cytokines in a pro-inflammatory group have different trends in all subtypes of schizophrenia. Alterations are also present in anti-inflammatory and regulatory cytokines, but findings are still not consistent. On the other hand, it is well known that abuse and neglect in childhood may be predictors of psychotic disorders, and childhood adversity is also associated with alterations of the immune and inflammatory response (through various mechanisms including HPA dysregulation as well). This review aims to analyze conducted studies and elucidate the link between childhood abuse, schizophrenia, and cytokine alterations. Putting together this complex psycho-immunological puzzle for the subgroup of schizophrenia-diagnosed patients with distinct immunological abnormalities and a history of childhood abuse can help us to answer the question about the future treatment of these patients.

Keywords: childhood neglect, childhood abuse, cytokines, schizophrenia

Understanding the Role of Cytokines in Brain Functioning

The role of the immune system in the pathophysiology of schizophrenia was proposed over a century ago.1 It has been shown that patients with schizophrenia have innate and adaptive immune system abnormalities. The majority of recent literature focuses on cytokine changes due to their role in immune cell signaling. Cytokines are proteins of small molecular mass that play a role as mediators in the stimulation or interaction between the cells of the immune system.

According to the role in the immune reaction, or the type of cell that creates them, cytokines are divided into several groups: interleukins (IL), chemokines, tumor necrosis factors (TNF), interferons (INF) and transformation growth factors (TGF).2 Today, more than 60 types of interleukins are known, named from IL-1 to IL-38.3 Cytokines are produced by effector CD4+ T helper (Th) lymphocytes, crucial components of the adaptive immunity, to stimulate or interact with other leukocytes, including Th cells. Of note, many cytokines are produced by innate immune cells, such as monocytes and neutrophils. Due to their role in the inflammatory reaction, cytokines are listed into two groups: pro-inflammatory and anti-inflammatory cytokines. Major pro-inflammatory cytokines are IL-1, IL-2, IL-6, INF-γ and TNF-α. Most researched anti-inflammatory cytokines include IL-4, IL-10, IL-11, IL-13, and TGF-β.4 Pro-inflammatory cytokines activate cyclo-oxygenase-2 (COX-2), increase the level of prostaglandin E2 (PGE2), activate leukocytes involved in the inflammation process, and stimulate the inflammatory response. Pro- and anti-inflammatory cytokines interact with each other to maintain homeostatic balance, but with chronic inflammation or tissue damage, the peripheral production of pro-inflammatory cytokines increases, and anti-inflammatory cytokines decrease, which can result in the development of various disorders including psychiatric ones.5

Peripheral cytokine production is largely regulated by cortisol secretion, as a result of activation of the hypothalamic–pituitary–adrenal (HPA) axis. When cortisol levels are low, the production of pro-inflammatory cytokines increases, while high cortisol concentrations inhibit the synthesis of peripheral pro-inflammatory cytokines.6 Neurotransmitters regulate peripheral cytokine synthesis via cortisol levels. For example, acetylcholine (Ach), dopamine (DA), and noradrenaline (NA) promote the secretion of corticotropin-releasing hormone (CRH) in the hypothalamus, while serotonin (5-HT) inhibits the secretion of CRH in the hypothalamus and consequently of adrenocorticotropic releasing hormone (ACTH) in the pituitary gland.7,8 In addition, the autonomic nervous system regulates the production of peripheral cytokines. Parasympathetic directly inhibits cytokine production via the vagus and acetylcholinergic transmission, while sympathetic indirectly via noradrenergic stimulation of peripheral sympathetic ganglia.9

Cytokines synthesized outside the central nervous system under physiological conditions cannot pass through the blood–brain and blood–cerebrospinal fluid (CSF) barriers due to their hydrophilicity. However, the permeability of the blood–brain barrier increases in pathological conditions, which allows cytokines from the blood to find their way into the extracellular fluid of the brain.10,11 Moreover, IL-1 receptors are densely distributed in glial cells near arterioles or the choroid plexus,12 suggesting a possible role in the communication of IL-1 receptors in the CNS with mediators from the peripheric circulation. In addition, cytokines synthesized in the periphery can pass into the CNS by passive diffusion across the circumventricular regions (absent blood–brain barrier regions) and neural transport by the vagus.6 Finally, the direct connection of the CNS and the immune system via lymphatic vessels was confirmed by the discovery of functional lymphatic vessels in the CNS.13

In physiological conditions, the central synthesis of cytokines is limited to T cells, astrocytes, and microglia, but in special circumstances, they can also be secreted by neurons.14 Cytokine production takes place in different regions of the neuro-network – in the hypothalamus, hippocampus, cerebellum, basal ganglia, and prefrontal regions.15 In the same regions, there is a distribution of receptors for centrally synthesized cytokines such as IL-1, IL-2, IL-6, and TNF-α. The role of central cytokine production has not yet been fully explored. Pro-inflammatory cytokines IL-1, L-6, TNF-α, and INF-γ are involved in the development of nerve tissue, neuroplasticity, synaptogenesis, and reparative mechanisms.16 In addition, pro-inflammatory cytokines promote nerve necrosis after traumatic nerve tissue injury.17

Cytokine Alterations in Patients with Schizophrenia

Central immunological changes in patients with schizophrenia are well known for the last two decades. For example, it has been shown that subclinical neuroinflammation in the CNS can lead to changes in white matter substrate, changes in connectivity, and subsequent onset of schizophrenia symptoms.18

Although knowledge in this field is rapidly increasing, cytokine changes are the most complex part of the puzzle to understand. We now have a growing number of studies that explore changes in cytokine levels in schizophrenia, but we still do not have consistent and univocal findings. Numerous meta-analyses and systematic reviews suggest cytokine dysregulation in schizophrenia and a predominance of pro-inflammatory cytokines in the serum of patients.19–25 Despite these findings regarding principally the three most studied pro-inflammatory cytokines: IL-6, IL-1β, and TNF-α, some studies did not confirm significantly higher levels of IL-6,26 IL1- β27 and TNF- α28 in patients with schizophrenia. Concentrations of IL-2 do not alter in patients with schizophrenia according to the majority of studies.23 Regarding levels of interferon γ (IFN-γ) as also one of the principality pro-inflammatory cytokines, several studies reported either no alteration29,30 or higher levels,19 but there are also rare findings on decreased levels of IFN-γ.31 Due to these data that various cytokines in a pro-inflammatory group have different trends in all subtypes of schizophrenia, we cannot state that pro-inflammatory cytokines have higher levels in patients with schizophrenia.

Similar inconsistent results are regarding anti-inflammatory cytokines: the majority of findings suggest no alteration in IL-4 levels,20,32 while few of them report decreased levels of IL-433,34 or increase ones.35 Goldsmith et al found reduced levels of IL-10 in their meta-analysis,20 in contrast to other meta-analyses reporting no alteration in levels of IL-10 in patients with schizophrenia36 and reports showing elevated levels of this cytokine.37 Similarly, concentrations of IL-13 also differ, although it has been reported elevated levels in adults with multiple episodes of schizophrenia.38,39 TGF-β is also one of the cytokines with anti-inflammatory activity but with regulatory function as well. Meta-analysis of Goldsmith found elevated levels of TGF-β in the first psychotic episode (FEP) patients.20 Also, other studies in chronic patients experiencing an acute relapse showed higher levels of TGF-β.29 No changes in concentration of this cytokine were also presented in some publications40 as well as decreased levels of TGF-β in chronic treatment-resistant patients.32

It is also very important to emphasize that alterations in cytokine levels are associated with the severity of clinical symptoms and that alterations differ between first-episode psychosis patients, acutely relapsed inpatients, and chronic patients.25

All these findings indicate that we have to search for some other, more specific, causes of this alteration that will help us to put together this complex psycho-immunological puzzle in patients with schizophrenia. In the next lines, we will focus on childhood abuse as a few authors already indicated how childhood adverse experiences may lead to a constellation of specific ecophenotype,41 subtypes of patients within the same group of disorders, eg, schizophrenia.

Childhood Abuse or Neglect, Early Life Distress, and Schizophrenia Risk

Childhood abuse or neglect includes all types of physical and/or emotional ill-treatment, sexual abuse, neglect, negligence, and commercial or other exploitation, which results in actual or potential harm to the child’s health, survival, development, or dignity in the context of a relationship of responsibility, trust or power.42 Maltreatment in childhood may occur once as acute distress, or in the form of a chronic stressor, and can be present in one or multiple forms.

Childhood abuse or neglect is among the most powerful risk factors for triggering varieties of psychiatric disorders. The incidence of child abuse trauma is very high in users of psychiatric services. Some published data suggest that approximately 50% of persons using psychiatric services mention experiences of abuse in childhood.43 Some novel data suggest that around 61% of patients with the first psychotic episode reported having experienced some kind of childhood trauma.44

Early life distress can influence the development of the hypothalamic–pituitary–adrenal (HPA) axis.45 If adverse experience occurs only once, as a strong acute stressor, HPA axis function will probably be reflected through hypercortisolemia. On the other side, childhood maltreatment usually tends to last or repeat and is associated with blunted cortisol levels. Furthermore, exposure to childhood adversity was associated with alterations of an immune and inflammatory response (due to HPA dysregulation as well) and stress-related accelerated telomere erosion.46 In line with these findings, neuroimaging studies revealed changes in the brain structure of hippocampus, amygdala, corpus callosum, vermix, and in different areas of cortex47–50 and also inhibition of maturation in neuron work in abused children.51

The impact of adverse childhood experiences on the development of psychosis and schizophrenia was confirmed by several studies and meta-analyses.52–55 Meta-analyses of Matheson et al suggest increased rates of childhood adversity in schizophrenia compared to controls with medium-to-large effect.54 Also, some novel data are stating positive associations between exposures to overall or specific subtypes of childhood adversity and experiencing or persistence of psychotic experiences.56,57 Chase et al demonstrated a positive correlation between positive and negative syndrome scale (PANSS) positive symptoms and adverse childhood experiences (ACEs) total scores, including ACEs abuse, ACEs-neglect, and ACEs-dysfunction in patients with schizophrenia.58 Patients with psychotic disorders who experienced childhood abuse share some common clinical characteristics, such as a higher hospitalization rate, a more continual course of the disorder, earlier onset of symptoms, more severe episodes, greater risk of suicide and substance disorders, etc.59

Although every type of abuse or neglect comes with a higher risk for psychosis, some subtypes are more often shown as predictors in literature. For example, studie by Chase and co-writers showed that patients with schizophrenia experienced the occurrence of ACE compared to non-clinical controls, especially sexual and physical childhood abuse.58 Read and Larkin suggested a dose-dependent relationship between childhood sexual or physical abuse and psychosis later in life.52,53 Grindey and his team recently published that, in a systematic review of literature, they found a significant relationship between hallucinations and childhood sexual and physical abuse.60 It is important to highlight that individuals with multiple adverse events in childhood carry an elevated risk of experiencing positive psychotic symptoms.57

Cytokine Alteration in Patients with Schizophrenia Who Were Exposed to Childhood Abuse Trauma

Although first evidence emerged from animal models more than half a century ago, later observational human studies confirmed that childhood trauma affects later immune functioning. For example, Dance et al found that cumulative exposure to childhood maltreatment was associated with a significant elevation in inflammation levels 20 years later.61 Not too many researches tried to explain the link between childhood abuse/adverse experiences, altered cytokine profile, and schizophrenia. Summarizing this scientific field, a few novel studies gave us important results concerning this relatedness.

The association of childhood adversity/trauma, immunity, and psychosis was examined in the study of Chase et al.58 They have shown that adversity in childhood correlates with IL-6, and separately that adverse childhood experience is in positive association with positive symptoms of schizophrenia. Authors assume that childhood trauma, through alteration of IL-6, may be a risk factor for schizophrenia and that those patients may represent a distinct psychiatric phenotype. The pro-inflammatory phenotype was also demonstrated in research of Dennison et al, where patients suffering from schizophrenia with childhood trauma had higher levels of IL-6 and TNF-α than patients without trauma and healthy controls.62 They assumed that childhood trauma drives changes through epigenetics. Novel research on gene methylation changes due to different types of trauma in childhood does confirm that.63 Furthermore, in addition to epigenetics, early experience can shape the relationship between the brain and immune system,64 and environmental factors, such as childhood maltreatment, though affecting the immune system have been related to the development of schizophrenia.61

In a similar study associations between schizophrenia and IL-6, TNF-α, and CRP were explored compared to healthy controls (HC), with an assessment of the Childhood Trauma Questionnaire.65 They showed higher levels of IL-6, TNF-α, and CRP in patients with schizophrenia compared to the HC group, as well as a positive association between CRP and sexual abuse in patients with schizophrenia. Among the first researchers that explored this link, Aas et al demonstrated that childhood trauma altered immune activation via elevated highly sensitive CRPa in a large sample of patients with schizophrenia.66 They emphasize that as patients had more types of abuse in childhood experience – CRP was higher. In the publication of Li et al, plasma concentrations of IL-6 and TNF-α were significantly elevated in patients with early-onset schizophrenia compared with healthy subjects, and plasma IL-6 and TNF-α concentrations were closely related to childhood maltreatment.67 These results partly explain the previous thesis that pro-inflammatory cytokine gene complexes may be linked to an increased likelihood of developing schizophrenia.68 Different types of trauma trigger different immunological mechanisms and lead to pertinent alterations in sensitive periods of preadolescent brain maturation,69 making the susceptible field to the development of different psychopathologies. It is also important to emphasize that IL-6 and TNF-α can trigger hypothalamic-pituitary-adrenocortical activity,70 suggesting that chronic inflammation contributes to the aberrant stress response found in patients with schizophrenia.71

Two other studies explored this link but comprised multiple cytokine profiles.72,73 Foiselle et al investigated levels of 18 different cytokines among the 310 adult patients who meet DSM-IV criteria for schizophrenia or schizoaffective disorders, with 47% of those having suffered from moderate-to-severe childhood abuse. Results showed elevated levels of IL-6, IL-7, IL-12/23 p40, and IL-16 moreover lower levels of TNF-α were associated with metabolic syndrome. Unfortunately, they did not investigate the correlation with childhood abuse.72 Corsi-Zuelli and colleagues examined cytokine levels (IL-1β, IL-6, TNF-α, IFN-γ, IL-4, IL-10, and TGF-β) in 114 patients with FEP, 57 unaffected biological siblings of FEP patients, and 251 community-based controls, with assessment for childhood abuse. They have found that FEP patients had a higher pro- and anti-inflammatory cytokine profile (IL-1β, IL-6, TNF-α, IL-10, and TGF-β), which was not observed in unaffected siblings. Physical childhood abuse was associated with increased levels of TGF-β in FEP patients, but they did not find similar findings for other cytokines.73 Higher TGF-β, with both regulatory and anti-inflammatory function, is a potentially very important part of the puzzle that can explain a much older thesis on how chronic stress may be associated with more permanent inflammatory changes.74 Having in mind the IL-6 and TGF-β interplay, it is possible to hypothesize that higher TGF-β levels could be a consequence of long-term increased IL-6 concentrations.75

Our knowledge is significantly updated with a novel multidisciplinary study (GAP study) carried out in South London, which recruited 410 first episode of psychosis patients and 370 controls that have demonstrated how biological pathways involved in the stress response (both HPA axis and immune system) provide important mechanisms linking risk factors (such as childhood adversity) to the development of psychotic symptoms.55 TNF- α levels were particularly high in FEP patients with a history of childhood trauma.76 Also in FEP patients, Hepgul et al showed higher serum levels of C-reactive protein in patients with experience of childhood sexual abuse than both healthy controls and patients without childhood sexual abuse.77 Previously, researchers of GAP study showed that increased levels of IL-6, as well as low levels of the neurotrophic factor BDNF and high levels of cortisol during the day, independently affected hippocampal volume in FEP patients.78,79 Higher IL-6 levels were associated with smaller left hippocampal volume,79 directly implicating influence on brain architectonic changes.

Several limitations of these studies should be considered. These studies are rare and include relatively small sample sizes. Mostly, patients received respectable doses of medication. Due to this, it is impossible to exclude the effects of illness duration and pharmacodynamic effects of medication on results. Previous meta-analyses suggest different parameters of inflammation have different sensitivity to medication.80 Simply, the inclusion of drug naïve patients would have been an advantage in this regard. At the same time, it is noteworthy, the possible use of anti-inflammatory drugs was not recorded. Moreover, we should bear in mind that these studies measure trauma exposure retrospectively in samples of adults which lay questions on recollection bias (especially since the age of onset or duration of trauma was not assessed). Finally, occasionally several important factors have not been recorded such as body mass index, nicotine consumption, and comorbid medical diseases that may have contributed to the observed findings.

Treatment Implications

The ultimate question is whether observed immunological abnormalities in patients with schizophrenia have therapeutic potential. First, treatment with anti-inflammatory drugs as an adjunct to standard antipsychotic therapy in patients with schizophrenia is nothing new. Several drugs have been tried (ie, celecoxib, minocycline), but studies are usually small, and we need large, double-blind, multicenter trials. Moreover, even Bleuler wrote about “a group of schizophrenia”, not about schizophrenia, clearly meaning that there is not only one, etiologically homogenous disease but rather a group of etiologically different diseases with a probable common final pathway resulting in clinically diagnosed schizophrenia. Having this in mind, it is obvious that we have to divide patients into more precious groups based on their immune phenotype with a history of childhood abuse or neglect. Finally, these considerations about the role of immunoactive drugs in the treatment of schizophrenia can be viewed as a part of the fundamental question of the future of the treatment of schizophrenia, ie, do we need a magic bullet or a magic shotgun?81 Clearly, establishing the therapeutic efficacy of immunoreactive drugs in schizophrenia would be a highly specific “bullet” for which treatment would be justified and indicated only in a subgroup of patients with distinct immunological abnormalities and a history of childhood abuse.

Conclusion

Despite such a long time since inflammation theory has been introduced in the pathophysiology of psychosis,1 many of its aspects have remained unelucidated. For several years now, childhood trauma/adverse experience has been explored as a third important variable to additionally substantiate the hypothesis of a link between immune alterations and schizophrenia. Despite the big GAP multidisciplinary study,55 we have found only 7 new original researchers regarding this connection.58,62,65–67,72,73 All studies are published in the last 10 years and the majority of them in the last 4 years. Still, so far pro-inflammatory cytokines have been much more studied in this link, while regulatory and anti-inflammatory were investigated much less.73 On the other side, we still have a crucial question to answer: does trauma leads to immune changes and the occurrence of psychopathology that coincide, or trauma triggers immune alteration that later drives the occurrence of psychopathology? The third option is that people with trauma experience are more susceptible to developing psychopathology (both dynamically and biologically) and that immune instability is just coinciding and contributing as a cofactor in the development of psychotic disorders. Present knowledge indicates that it is more likely that trauma induces immune alterations that become permanent and that immune alterations drive the pathogenesis of psychotic disorders. Nevertheless, we have enough strong evidence to promote the hypothesis that childhood maltreatment is associated with permanent immune alterations and the development of schizophrenia. We now have parts of this complex psycho-immunological puzzle for the subgroup of schizophrenia-diagnosed patients with distinct immunological abnormalities and a history of childhood abuse that can help us to answer the question about the future treatment of these patients and promote a strong need for further research in this area.

Acknowledgments

No funding was received for the preparation of this paper.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Dameshek W. The white blood cells in dementia praecox and dementia paralytica. Arch Neurol Psychiatry. 1930;24:855.

2. Jeon SW, Kim YK. Neuroinflammation and cytokine abnormality in major depression: cause or consequence in that illness? World J Psychiatry. 2016;6(3):283–293. doi:10.5498/wjp.v6.i3.283

3. Akdis M, Aab A, Altunbulakli C, et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2016;138(4):984–1010. doi:10.1016/j.jaci.2016.06.033

4. Kronfol Z, Remick DG. Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry. 2000;157(5):683–694. doi:10.1176/appi.ajp.157.5.683

5. Felger JC, Miller AH. Neurotherapeutic implications of brain-immune interactions. Neuropsychopharmacology. 2014;39(1):242–243. doi:10.1038/npp.2013.213

6. Watkins LR, Nguyen KT, Lee JE, Maier SF. Dynamic regulation of proinflammatory cytokines. Adv Exp Med Biol. 1999;461:153–178. doi:10.1007/978-0-585-37970-8_10

7. Calogero AE, Gallucci WT, Chrousos GP, Gold PW. Catecholamine effects upon rat hypothalamic corticotropin-releasing hormone secretion in vitro. J Clin Invest. 1988;82(3):839–846. doi:10.1172/JCI113687

8. Calogero AE, Bernardini R, Margioris AN, et al. Effects of serotonergic agonists and antagonists on corticotropin-releasing hormone secretion by explanted rat hypothalami. Peptides. 1989;10(1):189–200. doi:10.1016/0196-9781(89)90096-x

9. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853–859. doi:10.1038/nature01321

10. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46–56. doi:10.1038/nrn2297

11. Gadek-Michalska A, Tadeusz J, Rachwalska P, Bugajski J. Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems. Pharmacol Rep. 2013;65(6):1655–1662. doi:10.1016/s1734-1140(13)71527-5

12. Wong M-L, Bongiorno PB, Gold PW, Licinio J. Localization of Interleukin-1βP converting enzyme mRNA in rat brain vasculature: evidence that the genes encoding the interleukin-1 system are constitutively expressed in brain blood vessels. Neuroimmunomodulation. 1995;2(3):141–148. doi:10.1159/000096884

13. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–341. doi:10.1038/nature14432

14. Freidin M, Bennett MV, Kessler JA. Cultured sympathetic neurons synthesize and release the cytokine interleukin 1 beta. Proc Natl Acad Sci USA. 1992;89(21):10440–10443. doi:10.1073/pnas.89.21.10440

15. Maier SF, Watkins LR. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev. 1998;105(1):83–107. doi:10.1037/0033-295x.105.1.83

16. Khairova RA, Machado-Vieira R, Du J, Manji HK. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol. 2009;12(4):561–578. doi:10.1017/S1461145709009924

17. Ziebell JM, Morganti-Kossmann MC. Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics. 2010;7(1):22–30. doi:10.1016/j.nurt.2009.10.016

18. Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015;161(1):102–112. doi:10.1016/j.schres.2014.04.041

19. 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):663–671. doi:10.1016/j.biopsych.2011.04.013

20. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21(12):1696–1709. doi:10.1038/mp.2016.3

21. Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis: a systematic review and metaanalysis. Schizophr Res. 2014;155(1–3):101–108. doi:10.1016/j.schres.2014.03.005

22. Zhou X, Tian B, Han HB. Serum interleukin-6 in schizophrenia: a system review and meta-analysis. Cytokine. 2021;141:155441. doi:10.1016/j.cyto.2021.155441

23. Momtazmanesh S, Zare-Shahabadi A, Rezaei N. Cytokine alterations in schizophrenia: an updated review. Front Psychiatry. 2019;10:892. doi:10.3389/fpsyt.2019.00892

24. Rodrigues-Amorim D, Rivera-Baltanas T, Spuch C, et al. Cytokines dysregulation in schizophrenia: a systematic review of psychoneuroimmune relationship. Schizophr Res. 2018;197:19–33. doi:10.1016/j.schres.2017.11.023

25. 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

26. Hope S, Melle I, Aukrust P, et al. Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor. Bipolar Disord. 2009;11(7):726–734. doi:10.1111/j.1399-5618.2009.00757.x

27. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801–808. doi:10.1016/j.biopsych.2007.09.024

28. Turhan L, Batmaz S, Kocbiyik S, Soygur AH. The role of tumour necrosis factor alpha and soluble tumour necrosis factor alpha receptors in the symptomatology of schizophrenia. Nord J Psychiatry. 2016;70(5):342–350. doi:10.3109/08039488.2015.1122079

29. Borovcanin M, Jovanovic I, Radosavljevic G, et al. Antipsychotics can modulate the cytokine profile in schizophrenia: attenuation of the type-2 inflammatory response. Schizophr Res. 2013;147(1):103–109. doi:10.1016/j.schres.2013.03.027

30. De Witte L, Tomasik J, Schwarz E, et al. Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophr Res. 2014;154(1–3):23–29. doi:10.1016/j.schres.2014.02.005

31. Reale M, Patruno A, De Lutiis MA, et al. Dysregulation of chemo-cytokine production in schizophrenic patients versus healthy controls. BMC Neurosci. 2011;12:13. doi:10.1186/1471-2202-12

32. Ş K, Gönenir EL, Zayman PE, Ö O, Karabulut BA, Kartalcı G. IL-4, TGF-b, NF-kB and MPO levels in Patients with Treatment Resistant Schizophrenia. Turk Psikiyatri Derg. 2016;27(3):170–175. doi:10.5080/u13642

33. Noto C, Maes M, Ota VK, et al. High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World J Biol Psychiatry. 2015;16(6):422–429. doi:10.3109/15622975.2015.1062552

34. Balõtšev R, Koido K, Vasar V, et al. Inflammatory, cardio-metabolic and diabetic profiling of chronic schizophrenia. Eur Psychiatry. 2017;39:1–10. doi:10.1016/j.eurpsy.2016.05.010

35. Eftekharian MM, Omrani MD, Arsang-Jang S, Taheri M, Ghafouri-Fard S. Serum cytokine profile in schizophrenic patients. Hum Antibodies. 2019;27(1):23–29. doi:10.3233/HAB-180344

36. Boerrigter D, Weickert TW, Lenroot R, et al. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation. 2017;14(1):188. doi:10.1186/s12974-017-0962-y

37. Fu G, Zhang W, Dai J, et al. Increased peripheral interleukin 10 relate to white matter integrity in schizophrenia. Front Neurosci. 2019;13:52. doi:10.3389/fnins.2019.00052

38. Frydecka D, Krzystek-Korpacka M, Lubeiro A, et al. Profiling inflammatory signatures of schizophrenia: a cross-sectional and meta-analysis study. Brain Behav Immun. 2018;71:28–36. doi:10.1016/j.bbi.2018.05.002

39. Maxeiner H-G, Schneider EM, Kurfiss S-T, Brettschneider J, Tumani H, Bechter K. Cerebrospinal fluid and serum cytokine profiling to detect immune control of infectious and inflammatory neurological and psychiatric diseases. Cytokine. 2014;69(1):62–67. doi:10.1016/j.cyto.2014.05.008

40. Hong W, Zhao M, Li H, et al. Higher plasma S100B concentrations in schizophrenia patients, and dependently associated with inflammatory markers. Sci Rep. 2016;6:27584. doi:10.1038/srep27584

41. Teicher HM, Samson AJ. Childhood maltreatment and psychopathology: a case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. Am J Psychiatry. 2013;170(10):1114–1133. doi:10.1176/appi.ajp.2013.12070957

42. World Health Organisation. Report on consultation on child abuse prevention. World Health Organization, Document WHO/HSC/PVI/99.1; 1999.

43. Read J. Child abuse and the severity of disturbance among adult psychiatric inpatients. Child Abuse Negl. 1998;22(5):359–368. doi:10.1016/s0145-2134(98)00009-x

44. Vila-Badia R, Del Cacho N, Butjosa A; for Group PROFEP. Prevalence and types of childhood trauma in first episode psychosis patients. Relation with clinical onset variables. J Psychiatr Res. 2022;146:102–108. doi:10.1016/j.jpsychires.2021.12.033

45. Kalinichev M, Easterling KW, Plotsky PM, Holtzman SG. Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long-Evans rats. Pharmacol Biochem Behav. 2002;73(1):131–140. doi:10.1016/s0091-3057(02)00781-5

46. Oh DL, Jerman P, Silvério Marques S, et al. Systematic review of pediatric health outcomes associated with childhood adversity. BMC Pediatr. 2018;18(1):83. doi:10.1186/s12887-018-1037-7

47. Anderson CM, Teicher MH, Polcari A, Renshaw PF. Abnormal T2 relaxation time in the cerebellar vermis of adults sexually abused in childhood: potential role of the vermis in stress-enhanced risk for drug abuse. Psychoneuroendocrinology. 2002;27(1–2):231–244. doi:10.1016/s0306-4530(01)00047-6

48. Teicher MH, Dumont NL, Ito Y, Vaituzis C, Giedd JN, Andersen SL. Childhood neglect is associated with reduced corpus callosum area. Biol Psychiatry. 2004;56(2):80–85. doi:10.1016/j.biopsych.2004.03.016

49. Weniger G, Lange C, Sachsse U, Irle E. Amygdala and hippocampal volumes and cognition in adult survivors of childhood abuse with dissociative disorders. Acta Psychiatr Scand. 2008;118(4):281–290. doi:10.1111/j.1600-0447.2008.01246.x

50. Teicher MH, Samson JA. Annual research review: enduring neurobiological effects of childhood abuse and neglect. J Child Psychol Psychiatry. 2016;57(3):241–266. doi:10.1111/jcpp.12507

51. Glaser D. Child abuse and neglect and the brain – a review. J Child Psychol Psychiatry. 2001;41(1):97–116. doi:10.1111/1469-7610.00551

52. Read J, Van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatrica Scand. 2005;112(5):330–350. doi:10.1111/j.1600-0447.2005.00634.x

53. Larkin W, Read J. Childhood trauma and psychosis: evidence, pathways and implications. J Postgrad Med. 2008;54(4):287–293. doi:10.4103/0022-3859.41437

54. Matheson SL, Shepherd AM, Pinchbeck RM, Laurens KR, Carr VJ. Childhood adversity in schizophrenia: a systematic meta-analysis. Psychol Med. 2013;43(2):225–238. doi:10.1017/S0033291712000785

55. Murray RM, Mondelli V, Stilo SA, et al. The influence of risk factors on the onset and outcome of psychosis: what we learned from the GAP study. Schizophr Res. 2020;225:63–68. doi:10.1016/j.schres.2020.01.011

56. Trotta A, Murray RM, Fisher HL. The impact of childhood adversity on the persistence of psychotic symptoms: a systematic review and meta-analysis. Psychol Med. 2015;45(12):2481–2498. doi:10.1017/S0033291715000574

57. Liu J, Shahwan S, Abdin E, et al. Adverse childhood experiences and positive psychotic symptoms: a nationally representative study in Singapore. Child Abuse Negl. 2022;131:105778. doi:10.1016/j.chiabu.2022.105778

58. Chase KA, Melbourne JK, Rosen C, et al. Traumagenics: at the intersect of childhood trauma, immunity and psychosis. Psychiatry Res. 2019;273:369–377. doi:10.1016/j.psychres.2018.12.097

59. Kaufman J, Torbey S. Child maltreatment and psychosis. Neurobiol Dis. 2019;131:104378. doi:10.1016/j.nbd.2019.01.015

60. Grindey A, Bradshaw T. Do different adverse childhood experiences lead to specific symptoms of psychosis in adulthood? A systematic review of the current literature. Int J Ment Health Nurs. 2022;31(4):868–887. doi:10.1111/inm

61. Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007;104(4):1319–1324. doi:10.1073/pnas.0610362104

62. Dennison U, McKernan D, Cryan J, Dinan T. Schizophrenia patients with a history of childhood trauma have a pro-inflammatory phenotype. Psychol Med. 2012;42(9):1865–1871. doi:10.1017/S0033291712000074

63. Løkhammer S, Stavrum AK, Polushina T, et al. An epigenetic association analysis of childhood trauma in psychosis reveals possible overlap with methylation changes associated with PTSD. Transl Psychiatry. 2022;12(1):177. doi:10.1038/s41398-022-01936-8

64. Danese A, Lewis J. Psychoneuroimmunology of early-life stress: the hidden wounds of childhood trauma? Neuropsychopharmacology. 2017;42(1):99–114. doi:10.1038/npp.2016.198

65. Quidé Y, Bortolasci CC, Spolding B, et al. Association between childhood trauma exposure and pro-inflammatory cytokines in schizophrenia and bipolar-I disorder. Psychol Med. 2019;49(16):2736–2744. doi:10.1017/S0033291718003690

66. Aas M, Dieset I, Hope S, et al. Childhood maltreatment severity is associated with elevated C-reactive protein and body mass index in adults with schizophrenia and bipolar diagnoses. Brain Behav Immun. 2017;65:342–349. doi:10.1016/j.bbi.2017.06.005

67. Li Y, Jinxiang T, Shu Y, et al. Childhood trauma and the plasma levels of IL-6, TNF-α are risk factors for major depressive disorder and schizophrenia in adolescents: a cross-sectional and case-control study. J Affect Disord. 2022;305:227–232. doi:10.1016/j.jad.2022.02.020

68. Ellman LM, Deicken RF, Vinogradov S, et al. Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8. Schizophr Res. 2010;121(1–3):46–54. doi:10.1016/j.schres.2010.05.014

69. Munjiza A, Kostic M, Pesic D, Gajic M, Markovic I, Tosevski DL. Higher concentration of interleukin 6 - A possible link between major depressive disorder and childhood abuse. Psychiatry Res. 2018;264:26–30. doi:10.1016/j.psychres.2018.03.072

70. Dunn AJ. Cytokine activation of the HPA axis. Ann N Y Acad Sci. 2000;917:608–617. doi:10.1111/j.1749-6632.2000.tb05426.x

71. Girshkin L, Matheson SL, Shepherd AM, Green MJ. Morning cortisol levels in schizophrenia and bipolar disorder: a meta-analysis. Psychoneuroendocrinology. 2014;49:187–206. doi:10.1016/j.psyneuen.2014.07.013

72. Foiselle M, Barbosa S, Godin O; for FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) Groups. Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort. Brain Behav Immun Health. 2022;22:100436. doi:10.1016/j.bbih.2022.100436

73. Corsi-Zuelli F, Loureiro CM, Shuhama R, et al. Cytokine profile in first-episode psychosis, unaffected siblings and community-based controls: the effects of familial liability and childhood maltreatment. Psychol Med. 2020;50(7):1139–1147. doi:10.1017/S0033291719001016

74. Rohleder N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med. 2014;76(3):181–189. doi:10.1097/PSY.0000000000000049

75. Jovanovic AM, Mitkovic-Voncina M, Kostic M, et al. Childhood maltreatment correlates with higher concentration of transforming growth factor beta (TGF-β) in adult patients with major depressive disorder. Psychiatry Res. 2021;301:113987. doi:10.1016/j.psychres.2021.113987

76. Di Nicola M, Cattaneo A, Hepgul N, et al. Serum and gene expression profile of cytokines in first-episode psychosis. Brain Behav Immun. 2013;31:90–95. doi:10.1016/j.bbi.2012.06.010

77. Hepgul N, Pariante CM, Dipasquale S, et al. Childhood maltreatment is associated with increased body mass index and increased C-reactive protein levels in first episode psychosis patients. Psychol Med. 2012;42(9):1893–1901. doi:10.1017/S0033291711002947

78. Mondelli V, Pariante CM, Navari S, et al. Higher cortisol levels are associated with smaller left hippocampal volume in first-episode psychosis. Schizophr Res. 2010;119(1–3):75–78. doi:10.1016/j.schres.2009.12.021

79. Mondelli V, Cattaneo A, Murri MB, et al. Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: a pathway to smaller hippocampal volume. J Clin Psychiatry. 2011;72(12):1677–1684. doi:10.4088/JCP.10m06745

80. Fernandes BS, Steiner J, Bernstein HG, et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Mol Psychiatry. 2016;21:554–564. doi:10.1038/mp.2015.87

81. Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004;3(4):353–359. doi:10.1038/nrd1346

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