Polygenic score for schizophrenia worsens the effect of bipolar disorder course on neuronal metabolism and white matter microstructure

Aim: Bipolar disorder (BD) and schizophrenia (SCZ) share many clinical and neurobiological features, and a continuum between the two has been postulated. Bipolar patients leaning toward the SCZ pole of the continuum may have a higher risk of neuroprogression. Here we investigated the relationships between illness course, white matter integrity, levels of N-acetylaspartate (NAA), and polygenic score (PRS) of SCZ. Methods: A sample of 103 depressed bipolar inpatients underwent magnetic resonance imaging (MRI) acquisition to perform diffusion tensor imaging (DTI) analysis and magnetic resonance spectroscopy to assess NAA. Genotyping and PRS calculation were also performed in a subsample of 75 patients. Associations between illness course, NAA, and white matter microstructure were explored; indirect effects were investigated through mediation models; further, a possible moderating effect of SCZ-PRS was tested. Results: Negative associations emerged between number of affective episodes and NAA. Manic episodes were also negatively associated with white matter integrity, and NAA significantly mediated the effect of manic episodes on DTI metrics. SCZ-PRS moderated the relation between illness duration and NAA. Moderated mediation analyses showed that only at high SCZ-PRS, illness duration negatively affected NAA, which in turn was linked to reduced fractional anisotropy. Conclusion: Our results support the concept of neuroprogression in BD, suggesting a deleterious effect of acute episodes, particularly manic ones, on neurochemical and white matter alterations. Further, patients with a higher SCZ-PRS seem to show detrimental effects related to illness duration, possibly suggesting a longitudinal course closer to SCZ.