Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis.
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.
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 3 andar, CEP 04039-032, Sao Paulo, SP, Brazil. csnoto@gmail.com.|First Episode Psychosis Program, Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), Sao Paulo, Brazil. csnoto@gmail.com.
Cristiano
0000-0002-2706-9118
C
Noto
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 3 andar, CEP 04039-032, Sao Paulo, SP, Brazil.|Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Vanessa Kiyomi
VK
Ota
Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Marcos Leite
ML
Santoro
First Episode Psychosis Program, Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), Sao Paulo, Brazil.|Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Eduardo Sauerbronn
ES
Gouvea
Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Patricia Natalia
PN
Silva
Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Leticia Maria
LM
Spindola
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 3 andar, CEP 04039-032, Sao Paulo, SP, Brazil.|First Episode Psychosis Program, Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), Sao Paulo, Brazil.
Quirino
Q
Cordeiro
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 3 andar, CEP 04039-032, Sao Paulo, SP, Brazil.
Rodrigo Affonseca
RA
Bressan
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 3 andar, CEP 04039-032, Sao Paulo, SP, Brazil.
Ary
A
Gadelha
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo, 669, 3 andar, CEP 04039-032, Sao Paulo, SP, Brazil.
Elisa
E
Brietzke
Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Sintia Iole
SI
Belangero
Health Sciences Graduate Program, Health Sciences Center, State University of Londrina (UEL), Londrina, Brazil.|Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand.
Michael
M
Maes
D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood*; D003710:Demography; D003863:Depression / Q000097:blood / Q000188:drug therapy*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016015:Logistic Models; D011618:Psychotic Disorders / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D014150:Antipsychotic Agents; D015415:Biomarkers; D016207:Cytokines; D012333:RNA, Messenger
Antipsychotic naïve; Depression; First-episode psychosis; Gene expression; Immune; Inflammation; Neuroprogression; Schizophrenia