Investigation of betaine as a novel psychotherapeutic for schizophrenia

Abstract

Background Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. We aimed to test the role of betaine in schizophrenia pathophysiology, and to evaluate its potential as a novel psychotherapeutic. Methods Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. Findings The Chdh -deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations in the brain. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine (PCP) treatments. Betaine also showed a prophylactic effect on behavioral abnormality induced by PCP. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with “betaine deficit-oxidative stress pathology”. We revealed the decrease of betaine levels in glyoxylase 1 ( GLO1 )-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis -expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. Interpretation The present study revealed the role of betaine in psychiatric pathophysiology and underscores the potential benefit of betaine in a subset of schizophrenia. Fund This study was supported by the Strategic Research Program for Brain Sciences from AMED (Japan Agency for Medical Research and Development) under Grant Numbers JP18dm0107083 and JP19dm0107083 (TY), JP18dm0107129 (MM), JP18dm0107086 (YK), JP18dm0107107 (HY), JP18dm0107104 (AK) and JP19dm0107119 (KH), by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05433 (AH.-T), JP18H05428 (AH.-T and TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). In addition, this study was supported by the Collaborative Research Project of Brain Research Institute, Niigata University under Grant Numbers 2018–2809 (YK) and RIKEN Epigenetics ...

Translational research identifies a metabolism pathway involved in first-episode of schizophrenia: Towards precision medicine

“…At the time of these first psychotic symptoms, neurobiological processes underlying schizophrenia have already been ongoing for many years. The identification of key pathophysiological pathways to the clinical picture of FESZ is needed if we aim to intervene before the window of opportunity is closed and deviations in the brain have become hard-wired [2].In an article in EBioMedicine, Ohnishi and colleagues demonstrate for the first time that betaine metabolism pathway is involved in psychiatric pathophysiology and the betaine potential as a novel psychotherapeutic [3]. This article is a translational approach based on exciting results obtained by Koike et al [4].…”

“…This article is a translational approach based on exciting results obtained by Koike et al [4]. They used capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) to demonstrate altered levels of betaine from peripheral blood samples of patients with a FESZ.Ohnishi and colleagues use a variety of state-of-the-art translational approaches to analyze betaine metabolic pathways on both mouse and human experimental models [3]. They focused on Choline Dehydrogenase (CHDH) enzyme that is involved in betaine biosynthesis.…”

“…Regulation of these genes was mediated by the nuclear receptor genes Rxr and Ppar, whose promoters were hypermethylated. Manganeseenhanced MRI that allows detecting activated neurons through calcium channels identified higher signals in the medial prefrontal cortex (mPFC) and the nucleus accumbens shell.In EBioMedicine, Ohnishi et al [3] analyzed transcriptomics of Chdh knockout mice. They first found a deregulation of eIF2 signaling that is known to be central to synaptic plasticity, learning and memory.…”

“…In an article in EBioMedicine, Ohnishi and colleagues demonstrate for the first time that betaine metabolism pathway is involved in psychiatric pathophysiology and the betaine potential as a novel psychotherapeutic [3]. This article is a translational approach based on exciting results obtained by Koike et al [4].…”

“…Ohnishi and colleagues use a variety of state-of-the-art translational approaches to analyze betaine metabolic pathways on both mouse and human experimental models [3]. They focused on Choline Dehydrogenase (CHDH) enzyme that is involved in betaine biosynthesis.…”