Pyridoxamine: A novel treatment for schizophrenia with enhanced carbonyl stress.

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.

Clinical features of schizophrenia with enhanced carbonyl stress.

Accumulating evidence suggests that advanced glycation end products, generated as a consequence of facilitated carbonyl stress, are implicated in the development of a variety of diseases. These diseases include neurodegenerative illnesses, such as Alzheimer disease. Pyridoxamine is one of the 3 forms of vitamin B6, and it acts by combating carbonyl stress and inhibiting the formation of AGEs. Depletion of pyridoxamine due to enhanced carbonyl stress eventually leads to a decrease in the other forms of vitamin B6, namely pyridoxal and pyridoxine. We previously reported that higher levels of plasma pentosidine, a well-known biomarker for advanced glycation end products, and decreased serum pyridoxal levels were found in a subpopulation of schizophrenic patients. However, there is as yet no clinical characterization of this subset of schizophrenia. In this study, we found that these patients shared many clinical features with treatment-resistant schizophrenia. These include a higher proportion of inpatients, low educational status, longer durations of hospitalization, and higher doses of antipsychotic medication, compared with patients without carbonyl stress. Interestingly, psychopathological symptoms showed a tendency towards negative association with serum vitamin B6 levels. Our results support the idea that treatment regimes reducing carbonyl stress, such as supplementation of pyridoxamine, could provide novel therapeutic benefits for this subgroup of patients.