Pyridoxamine: A novel treatment for schizophrenia with enhanced carbonyl stress

Abstract

Aim: The aim of this clinical trial was to obtain proof of concept for high-dose pyridoxamine as a novel treatment for schizophrenia with enhanced carbonyl stress. Methods:Ten Japanese schizophrenia patients with high plasma pentosidine, which is a representative biomarker of enhanced carbonyl stress, were recruited in a 24-week, open trial in which high-dose pyridoxamine (ranging from 1200 to 2400 mg/day) was administered using a conventional antipsychotic regimen. Main outcomes were the total change in Positive and Negative Syndrome Scale score and the Brief Psychiatric Rating Scale score from baseline to end of treatment at week 24 (or at withdrawal).Results: Decreased plasma pentosidine levels were observed in eight patients. Two patients showed marked improvement in their psychological symptoms. A patient who harbors a frameshift mutation in the Glyoxalase 1 gene also showed considerable reduction in psychosis accompanied with a moderate decrease in plasma pentosidine levels. A reduction of greater than 20% in the assessment scale of drug-induced Parkinsonism occurred in four patients. Although there was no severe suicide-related ideation or behavior, Wernicke's encephalopathy-like adverse drug reactions occurred in two patients and were completely suppressed by thiamine supplementation. Conclusion:High-dose pyridoxamine add-on treatment was, in part, effective for a subpopulation of schizophrenia patients with enhanced carbonyl stress. Further randomized, placebo-controlled trials with careful monitoring will be required to validate the efficacy of high-dose pyridoxamine for these patients.

Cutting‐edge morphological studies of post‐mortem brains of patients with schizophrenia and potential applications of X‐ray nanotomography (nano‐CT)

“…79 These studies have evolved into a clinical trial that is now underway. 58 Here, it is truly interesting that the schizophrenia case with the highest neurite curvature carried a mutation related to carbonyl stress. 44,57 By assuming that this observation reflects the involvement of the carbonylcompound metabolism in the structural maintenance of neurons, we can suggest that the carbonyl stress has some relation with the neuronal structural change in the high curvature case.…”

“…As one of these factors, a nearly uniform population of schizophrenia cases was determined by using a chemical pathology marker called ‘carbonyl stress.’ A methodology to obtain reproducible observations regarding this subgroup has also been proposed . These studies have evolved into a clinical trial that is now underway . Here, it is truly interesting that the schizophrenia case with the highest neurite curvature carried a mutation related to carbonyl stress .…”

“…It has been reported that a number of genes involved in neurite formation have relations with schizophrenia . The carbonyl stress caused by the GLO1 gene mutation has been identified as a marker for defining a subgroup of schizophrenia . The other problem of methodological reproducibility can be overcome by analyzing brain tissue in 3‐D .…”

“…50,[53][54][55] The carbonyl stress caused by the GLO1 gene mutation has been identified as a marker for defining a subgroup of schizophrenia. [56][57][58] The other problem of methodological reproducibility can be overcome by analyzing brain tissue in 3-D. 44 The 3-D hallmarks of schizophrenia neurons should be investigated by visualizing the brain tissue without sectioning, as structural distortions are introduced in the conventional histology. Such 3-D visualizations can only be performed by using light that passes through the brain tissue.…”

Right treatment for the right schizophrenic patients based on carbonyl stress pathophysiology

“…Thus, Itokawa et al have conducted an open label study to obtain proof of concept for high‐dose pyridoxamine as a novel treatment for schizophrenia with enhanced carbonyl stress . Consequently, high‐dose pyridoxamine as an add‐on treatment improves clinical symptoms in this subset of schizophrenia patients.…”