Balance between the redox pair of nicotinamide adenine dinucleotides (oxidized NAD+ and reduced NADH), reflects the oxidative state of cells and the ability of biological systems to carry out energy production. A growing body of evidence suggests that an "immuno-oxidative" pathway including oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell-mediated immune response may contribute to disruptions in brain activity in schizophrenia (SZ). The aim of this study is to assess possible redox imbalance in SZ patients by using a novel in vivo 31 P MRS technique. The participants included 40 healthy controls, 21 chronic SZ, 13 first-episode (FE) SZ, and 18 FE bipolar disorder (BD) patients (as a psychiatric control group). All participants initially underwent structural imaging at a 3 Tesla (3 T) and 31 P MRS measurements were performed on a 4 T MR scanner. NAD+ and NADH components were determined by nonlinear least-square fitting of the model simulated spectra; these incorporated prior chemical shift and coupling constant information to in vivo resonances obtained from 31 P MRS experiments. We found a significant reduction in the NAD+/NADH ratio in chronically ill SZ patients compared to a matched healthy control group, and in FE SZ patients compared to both a matched FE BD patient group and a matched healthy control group. These findings provide evidence for redox imbalance in the brain in all phases of SZ, potentially reflecting oxidative stress.

Background Brain bioenergetic anomalies and redox dysregulation have been implicated in the pathophysiology of psychotic disorders. The present study examined brain energy-related metabolites and the balance between nicotinamide adenine dinucleotide metabolites (oxidized NAD+ and reduced NADH) using 31P-magnetic resonance spectroscopy (31P-MRS) in unaffected siblings, compared to first episode psychosis (FEP) patients and healthy controls. Methods 21 unaffected siblings, 32 FEP patients (including schizophrenia spectrum and affective psychoses), and 21 controls underwent 31P-MRS in the frontal lobe (6×6×4 cm3) on a 4T MR scanner, using custom-designed dual-tuned surface coil with outer volume suppression. Brain parenchymal pH and steady-state metabolite ratios of high energy phosphate compounds were measured. NAD+ and NADH levels were determined using a 31P-MRS fitting algorithm. 13 unaffected sibling-patient pairs were related; other patients and siblings were unrelated. ANCOVA analyses were used to examine 31P-MRS measures, with age and gender as covariates. Results The phosphocreatine/adenosine triphosphate ratio was significantly reduced in both unaffected siblings and FEP patients, compared to controls. NAD+/NADH ratio was significantly reduced in patients compared to siblings and controls, with siblings showing a reduction in NAD+/NADH compared to controls that was not statistically significant. Compared to patients and controls, siblings showed significantly reduced levels of NAD+. Siblings did not differ from patients or controls on brain pH. Discussion Our results indicate that unaffected siblings show some, but not all the same abnormalities in brain energy metabolites and redox state as FEP patients. Thus, 31P-MRS studies may identify factors related both to risk and expression of psychosis.

Our findings demonstrate abnormally elevated brain Glu and Gly levels in patients with first-episode psychosis by means of echo time-averaged proton MRS at 4T. The findings implicate dysfunction of N-methyl-D-aspartate receptor and glutamatergic neurotransmission in the pathophysiology of the acute early phase of psychotic illnesses.