Unconjugated bilirubin and schizophrenia: a systematic review

Schizophrenia is a complex syndrome of unknown etiology and difficult to manage. Unconjugated bilirubin has been researched as a potential biological marker of this syndrome. The objective of this review article was to gather the studies published to date on the relationship between this molecule and schizophrenia. Broad inclusion criteria have been used (PRISMA) to include as many relevant studies as possible. Fourteen studies were selected: 3 analyzed the effects of unconjugated hyperbilirubinemia in animal models; 6 demonstrated an increased incidence of schizophrenia in patients with increased unconjugated bilirubin; 2 reported an increased incidence of the disease in patients with decreased unconjugated bilirubin; and 3 linked an increased incidence of schizophrenia with an increased excretion of the oxidative product of bilirubin, the so-called biopyrrins. Because of apparently contradictory reported results, the hypothesis that the relationship between schizophrenia and unconjugated bilirubin was not linear and that there was an inflammatory dysfunction explaining this was considered. The 2 most accepted models for the pathophysiology of schizophrenia are described, and the possible role of the molecule in each is clarified. The bilirubin buffer system and its role in antioxidant defense was explored. The average levels of unconjugated bilirubin in patients with schizophrenia, schizoaffective disorder, and bipolar disorder were also compared, having been hypothesized that these diseases could be different points of a same pathological spectrum. Finally, it was concluded that unconjugated bilirubin is a promising molecule that could be used as a possible biological marker for schizophrenia, and the necessity of subsequent efforts for its research was considered.