UGT1A1 mutations and psychoses: towards understanding the relationship with unconjugated bilirubin

Abstract

We read with great interest the recent systematic review in your journal, which gathers the studies on the relationship between unconjugated bilirubin (UCB) and schizophrenia. 1 The authors, based on the articles they cited, support the existence of a correlation between UCB and schizophrenia, but point out that the relationship between the two is not clear. Indeed, it is uncertain whether there is a direct or inverse relation between serum UCB levels and the incidence of schizophrenia, because a discrepancy exists in the literature: some studies claim an increased incidence of schizophrenia with higher levels of UCB, others with lower levels. Moreover, some studies reveal a reduction in plasma UCB levels after treatment; others report even a correlation with symptomatic scales. The authors conclude that, given the complex nature of schizophrenia, the association might be multifactorial and nonlinear, with UCB and the pathophysiology of schizophrenia being mutually influenced by each other. This hypothesis is based on the complex role of UCB in antioxidant and inflammatory responses. In fact, UCB has been associated with in vitro and in vivo neurotoxicity, and the threshold above which UCB starts to miss its favorable antioxidant effects seems to be fairly small. Ultimately, the core of the problem could be an impairment in the inflammatory mechanisms in the brain. If plasma UCB levels were too high, it would directly cause neuroinflammation, reactive oxygen species (ROS) production, and cell apoptosis; if it were too low, nevertheless, it could weaken the antioxidative defenses and also result in increased inflammation and ROS levels. Thus, the authors conclude that schizophrenia is the cause and effect of fluctuations in UCB levels and vice versa, creating a vicious circle that would sustain the symptoms of schizophrenia. Moreover, extending the role of UCB in different stages of the progression of schizophrenia, schizoaffective disorders, and bipolar disorder, one hypothesis is that these could be different points of the same pathological spectrum. A thine criticism to this review is the small space dedicated to the possible genetic implications. Interestingly, homozygotic recessive-jaundiced animal models (Gunn rats), presenting schizophrenia-like behavior, have a congenital deficiency of the bilirubin liver conjugating enzyme, UGT1A1. Gunn rat is also a molecular and metabolic model of Crigler-Najjar syndrome type 1 (CN1), consistently exhibiting acute central nervous system dysfunction and kernicterus.We have the opportunity to deepen the discussion and support this vision of the pathological spectrum of psychoses providing the genetic aspect as a possible explanation, thanks to two patients of ours. We present B (39 years old) and her mother, R (69 years old), affected by mental illness at different degrees. B, a unique daughter, was diagnosed with CN2 when she was a child, because of the jaundice and total serum bilirubin level of 17.0 mg/dL. Although initially very effective, phenobarbital and photothera...

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