Summary: Reduced levels of an amino acid called betaine is associated with schizophrenia pathology. Supplementing betaine levels improved cognitive and behavioral deficits in mouse models of schizophrenia. The amino acid also reduced oxidative stress at the molecular level.
Many psychiatric drugs act on the receptors or transporters of certain neurotransmitters in the brain. However, there is a great need for alternatives, and research is looking at other targets along the brain’s metabolic pathways. Lack of glycine betaine contributes to brain pathology in schizophrenia, and new research from the RIKEN Center for Brain Science (CBS) shows that betaine supplementation can counteract psychiatric symptoms in mice.
Betaine comes from a normal diet but is also synthesized in the body where it contributes to metabolism in various ways, including as an anti-inflammatory agent. Levels of betaine (glycine betaine or trimethylglycine) in the blood plasma of patients with schizophrenia has previously been found to be low, which suggested it is a possible therapeutic target.
In the new study, mice missing the Chdh gene, which is involved in making betaine, showed depressive behaviors and greatly reduced betaine levels in both the brain and blood. Betaine levels in the brain recovered when the it was given to the mice as a supplement in drinking water, demonstrating that betaine can pass through the blood-brain barrier.
Psychedelic drugs like PCP and methamphetamine can also produce schizophrenia-like behaviors in both humans and mice. The researchers tested whether betaine supplementation could help alleviate symptoms induced by PCP and methamphetamine in mice. They found that betaine not only improved cognitive deficits and behavioral abnormalities, it also reversed oxidative stress at the molecular level. Oxidative stress is thought to be one mechanism through which these drugs cause psychiatric symptoms in humans.
Finally, investigation of postmortem human brain samples did indeed show reduced betaine levels in patients with schizophrenia, which was unrelated to the amount of antipsychotic drugs taken before death. They also found a subset of brains with “betaine-deficit oxidative stress”, a pathology that occurred in cases with severe psychotic symptoms. The researchers were able to replicate this pathology in induced pluripotent stem cells that simulate the oxidative stress condition, and counteract it with the betaine treatment.
“We suggest that one of betaine’s functions is to promote antioxidant activity in the metabolic cycles in which it participates,” says senior author Takeo Yoshikawa of RIKEN CBS. “However, supplementation of betaine is not a silver bullet for schizophrenia or other psychiatric conditions.” The researchers also identified a genetic variant that could predict betaine’s treatment efficacy, a potential example of precision medicine in psychiatry. Betaine is already used as a drug for the autosomal recessive metabolic disorder homocystinuria, so it could be considered as therapy for psychiatric conditions with minimal concern for adverse effects.
About this neuroscience research article
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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 Presidential Fund (100214–201801063606-340120) (TY).