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Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis

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Abstract

In schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α) were analyzed in 174 antipsychotic naïve first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine × treatment × gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype.

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    Authors and Affiliations

    1. Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 3 andar, CEP 04039-032, Sao Paulo, SP, Brazil

      Cristiano Noto, Vanessa Kiyomi Ota, Quirino Cordeiro, Rodrigo Affonseca Bressan, Ary Gadelha & Elisa Brietzke

    2. First Episode Psychosis Program, Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), Sao Paulo, Brazil

      Cristiano Noto, Eduardo Sauerbronn Gouvea & Quirino Cordeiro

    3. Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil

      Vanessa Kiyomi Ota, Marcos Leite Santoro, Eduardo Sauerbronn Gouvea, Patricia Natalia Silva, Leticia Maria Spindola & Sintia Iole Belangero

    4. Health Sciences Graduate Program, Health Sciences Center, State University of Londrina (UEL), Londrina, Brazil

      Michael Maes

    5. Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand

      Michael Maes

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    Correspondence to Cristiano Noto.

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    All participants provided written informed consent prior to enrollment in this study. The study was approved by the Research Ethics Committee of UNIFESP (Sao Paulo, Brazil) and carried out in accordance with the Declaration of Helsinki.

    Conflict of Interest

    Dr. Noto has received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Dr. Gadelha was on the speakers’ bureau and/or has acted as a consultant for Janssen-Cilag in the last 12 months and has also received research support from Brazilian government institutions (CNPq). Dr. Bressan has received research funding from FAPESP, CNPq, CAPES, Fundação Safra, Fundação ABADS, Janssen, Eli Lilly, Lundbeck, Novartis and Roche, has served as a speaker for Astra Zeneca, Bristol, Janssen, Lundbeck and Revista Brasileira de Psiquiatria, and is a shareholder of Radiopharmacus Ltda and Biomolecular Technology Ltda. Dr. Maes is supported by CNPq (Conselho Nacional de Desenvolvimento Cientifico e Technologia) PVE fellowship at the Health Sciences Graduate Program, Londrina State University (UEL). The other authors have no conflicts of interest to disclose.

    Role of Funding Source

    Funding for this study was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2010/08968-6, 2010/19176-3, 2011/50740-5 and 2013/10498-6), Brazil.x

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    Cristiano Noto and Vanessa Kiyomi Ota contributed equally to this work.

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    Noto, C., Ota, V.K., Santoro, M.L. et al. Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis. Mol Neurobiol 53, 5701–5709 (2016). https://doi.org/10.1007/s12035-015-9489-3

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