Impact of antipsychotic medication on IL‐6/<scp>STAT3</scp> signaling axis in peripheral blood mononuclear cells of drug‐naive schizophrenia patients

Subbanna, Manjula; Shivakumar, Venkataram; Venugopal, Deepthi; Narayanaswamy, Janardhanan C.; Berk, Michael; Varambally, Shivarama; Venkatasubramanian, Ganesan; Debnath, Monojit

doi:10.1111/pcn.12938

Cited by 27 publications

(16 citation statements)

References 47 publications

(48 reference statements)

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“…Heterogeneity among studies was marked (I 2 = 74%). After exclusion of the two main heterogeneity contributing studies (Azizi et al [ 38 ]; Subbanna et al [ 35 ]) the results provided the same conclusion. At baseline measurements, levels of IL-1β were significantly higher ( p = 0.02) than HC, but after treatment, this elevation became statistically insignificant ( p = 0.13).…”

Section: Resultssupporting

confidence: 52%

A Meta-Analysis of the Influence of Antipsychotics on Cytokines Levels in First Episode Psychosis

Marcinowicz

Więdłocha

Zborowska

et al. 2021

JCM

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Background: Cytokines have a major impact on the neurotransmitter networks that are involved in schizophrenia pathophysiology. First Episode Psychosis (FEP) patients exhibit abnormalities in cytokines levels prior to the start of treatment. Previous studies showed that antipsychotic treatment modulates cytokines levels. The aim of this meta-analysis is to further investigate this relationship. Methods: Several online databases were searched. For meta-analysis of selected studies, we analysed variables containing the number of cases, mean and standard deviation of IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ levels before, and after, antipsychotic treatment. Results: 12 studies were included in the meta-analysis. Our main results demonstrate that, in FEP patients, antipsychotic treatment is related to decreased concentrations of pro-inflammatory IL-1β, IL-6, IFN-γ, TNF-α and anti-inflammatory IL-4, IL-10 cytokines. On the other hand, levels of pro-inflammatory IL-2 and IL-17 remain unaffected. Conclusions: When compared with other meta-analyses of studies involving FEP individuals, results we obtained are consistent regarding decrease in IL-1β, IL-6. Comparing outcomes of our study with meta-analyses of schizophrenic subjects, in general, our results are consistent in IL-1β, IL-6, TNF-α, IFN-γ, IL-2. Our meta-analysis is the only one which indicates a decrease in anti-inflammatory IL-10 in FEP patients after antipsychotic treatment.

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Section: Resultssupporting

confidence: 52%

A Meta-Analysis of the Influence of Antipsychotics on Cytokines Levels in First Episode Psychosis

Marcinowicz

Więdłocha

Zborowska

et al. 2021

JCM

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“…Interestingly, antipsychotic treatment for 3 months was found to significantly reduce plasma levels of Th17-pathway related cytokines like IL-6 and IL-17A (71). Contradictorily, a four-week treatment with antipsychotic agents did not affect circulating levels of IL-23 or IL-17 (72,73). The differences noted above are most likely due to the comparison of various research groups, such as MNP vs. SNP/controls or schizophrenia vs. controls.…”

Section: Discussionmentioning

confidence: 86%

“…Interestingly, antipsychotic treatment for 3 months was found to significantly reduce plasma levels of Th17pathway related cytokines like IL-6 and IL-17A (71). Contradictorily, a four-week treatment with antipsychotic agents did not affect circulating levels of IL-23 or IL-17 (72,73)…”

Section: Increased Cytokine Levels In Mnpmentioning

confidence: 97%

The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

Al‐Hakeim

Alhusseini

Al-Dujaili

et al. 2022

Preprint

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Schizophrenia and especially defcit schizophrenia (DSCZ)) are characterized by highly significantly increased activities of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There are no data whether the interleukin(IL)-6/IL-23/Thelper-17 (IL6/IL23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia. This study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL6/IL23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and phenome of schizophrenia. Increased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-α. The IL6/IL23/Th17-axis score, as assessed by a LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL6/IL23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL6/IL23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively). In conclusion, the pathogenic IL6/IL23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia and especially that of DSCZ due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.

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“…This is reminiscent of our finding of increased in vivo spontaneous firing in the DR of serotonergic STAT3 KO and supports a role for STAT3-regulated transcriptional networks in neurotransmission. Further support for the involvement of STAT3 in psychopathology is derived from studies implicating it in the action of multiple pharmacological and non-pharmacological psychiatric treatment approaches in experimental model systems [27,29,31,32,[68][69][70][71][72][73]. Importantly, several important STAT3 upstream regulators may converge on activation of STAT3, including among others cytokine receptors, receptor tyrosine kinases and non-receptor tyrosine kinases as well as G-Protein coupled receptors and small regulatory RNAs (reviewed in [24]), all of which are critically involved in neural function underlying "normal" behavioural processes and their deviation in psychopathology (reviewed in [74]).…”

Section: Discussionmentioning

confidence: 99%

STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology

et al. 2020

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The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology.

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Impact of antipsychotic medication on IL‐6/STAT3 signaling axis in peripheral blood mononuclear cells of drug‐naive schizophrenia patients

Cited by 27 publications

References 47 publications

A Meta-Analysis of the Influence of Antipsychotics on Cytokines Levels in First Episode Psychosis

A Meta-Analysis of the Influence of Antipsychotics on Cytokines Levels in First Episode Psychosis

The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology

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