RXR-PPAR-γ axis dysregulation and executive dysfunction in first-episode schizophrenia and bipolar I disorder: An exploratory study

Dysregulation of the retinoid X receptor (RXR)-peroxisome proliferator-activated receptor-γ (PPAR-γ) axis has been implicated in severe mental disorders, including schizophrenia and bipolar I disorder. Whether this dysregulation is present in first-episode schizophrenia and bipolar I disorder and whether it relates to concurrent cognitive dysfunction remains unknown.

We enrolled 37 individuals with first-episode bipolar I disorder (FEBD-I), 36 with first-episode schizophrenia (FES), and 38 neurotypical controls. Levels of RXR-α, PPAR-γ, and PPAR-γ coactivator-1α (PGC-1α) were assessed in all participants, who also completed the Wisconsin Card Sorting Test (WCST).

Generalized linear models indicated significantly lower levels of PGC-1α and RXR-α in both the FES and FEBD-I groups compared with neurotypical controls (Wald χ² = 9.568, p = 0.008; Wald χ² = 9.229, p = 0.010). Higher PGC-1α levels were associated with a lower % nonperseverative errors on the WCST (B = -8.659; Wald χ² = 5.471; p = 0.019), independent of diagnosis. However, this association was no longer statistically significant after Bonferroni correction. Neither PGC-1α nor RXR-α levels were associated with clinical symptom severity.

Both the FES and FEBD-I groups showed lower circulating PGC-1α and RXR-α levels than controls. Given the exploratory nature of the study, these findings should be considered preliminary and require confirmation in larger independent samples.