Unconjugated Bilirubin in Patients with Schizophrenia in Acute episode

Abstract

Unconjugated bilirubin is the water insoluble fraction of total bilirubin in serum that crosses the blood brain barrier. Having antioxidant effects, it increases in response to the in situ neurotoxic psychotic episode (Dore et al.; 1999, Rund; 2014). On the other hand, it has both direct and indirect toxic effects on central nervous system and brain tissue connectivity, even in healthy human subjects without bilirubin metabolism dysfunction, making neurons more susceptible to further inflammatory damage which is believed to underlie the clinical and cognitive symptoms of schizophrenia (Glimore et al., 2004; Brites, 2012; Gama Marques et al., 2019). Hence, it may be consequence or cause of a psychotic state. Evidence supporting a correlation between unconjugated bilirubin and schizophrenia is considerable and most previous studies have managed to report a statistically relevant link between the two variables (Dornelles et al., 2019). In animal studies, chronic microglial activation in Gunn rats by toxic levels of unconjugated bilirubin (due to genetic deficiency in glucuronyl transferase) has been found to contribute to behavioural and neuropsychological changes in these rats that might be attenuated by antipsychotics, as in human patients with schizophrenia (Liaury et al., 2012; Tsuchie et al., 2013). This rat has already been used as schizophrenia animal model (Rice & Shapiro, 2008). In human studies, infants with neonatal unconjugated hyperbilirubinemia (due to decreased erythrocytes survival and deficient hepatic clearance) have presented with later diagnoses of mental disorders and shown a higher risk for schizophrenia when compared to a control group (Jones, 1994; Dalman & Cullberg, 1999). Gilbert's syndrome (idiopathic chronic mild unconjugated hyperbilirubinemia due to genetic deficiency in UDP-glucuronosyltransferase-1 enzyme) is found in up to 10% of general population but reaches the double of that prevalence among patients with schizophrenia (Bosma et al., 1995). Patients with schizophrenia especially during acute episode showed significantly higher frequency of elevated unconjugated bilirubin mean levels when compared with patients in remission phase, other psychiatric patients and general populations (Muller et al., 1991; Bach et al. 2010). They also showed a positive correlation between these higher levels and positive and negative syndrome scale (PANSS) score in addition to a poor outcome (Powell & Hansen, 2007; Gama Marques and Arantes-Gonçalves, 2018).