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Letter to the Editor

Unconjugated Bilirubin in Schizophrenia/Schizoaffective Disorder Spectrum: An Overlooked and Underestimated Biomarker Candidate

João Gama Marques, MD

Published: April 23, 2020

Unconjugated Bilirubin in Schizophrenia/Schizoaffective Disorder Spectrum: An Overlooked and Underestimated Biomarker Candidate

To the Editor: With great enthusiasm, I read an article1 published in the Primary Care Companion for CNS Disorders regarding a prospective study of unconjugated bilirubin levels of patients diagnosed with schizophrenia or bipolar affective disorder. This article1 was published just 2 days after publication of an article2 by my colleagues and I that described a 5-year retrospective, observational, controlled study that included not only patients with schizophrenia and bipolar disorder, but also patients with schizoaffective disorder. Thus, I was delighted to learn that researchers from other world regions are interested in studying unconjugated bilirubin as a psychosis biomarker and that they are doing it prospectively. My group has been suggesting this kind of longitudinal methodology for studies with unconjugated bilirubin as a biomarker candidate in the schizophrenia/schizoaffective disorder spectrum,3 and results of a prospective study were recently published.4

My interest in this fascinating topic began a few years ago following the presentation of a single psychotic patient to the emergency department.5 My colleagues and I then began pooling clinical data and managed to publish a preliminary small report.6 More recently, after hypothesizing that these disorders could be different points of a same pathological spectrum, a systematic review7 was conducted that compared the mean levels of unconjugated bilirubin in patients with schizophrenia, schizoaffective disorder, and bipolar disorder. It was concluded that unconjugated bilirubin is a promising molecule that could be used as a possible biological marker for schizophrenia, and more research is needed.7 Indeed, there is an impending necessity for further research in this area, and I applaud any subsequent efforts.


1. Pradeep JR, Acharya MS, Radhakrishnan R, et al. Elevated unconjugated bilirubin in schizophrenia compared to bipolar affective disorder. Prim Care Companion CNS Disord. 2019;21(4):19m02448. PubMed CrossRef

2. Gama Marques J, Pedro I, Ouakinin S. Unconjugated bilirubin and acute psychosis: a five years retrospective observational and controlled study in patients with schizophrenia, schizoaffective and bipolar disorders. Int J Psychiatry Clin Pract. 2019;23(4):281-285. PubMed CrossRef

3. Gama Marques J, Arantes-Gonçalves F. A perspective on a possible relation between the psychopathology of the schizophrenia/schizoaffective spectrum and unconjugated bilirubin: a longitudinal protocol study. Front Psychiatry. 2018;9:146. PubMed CrossRef

4. Gama Marques J, Ouakinin S. Clinical profile in schizophrenia and schizoaffective spectrum: relation with unconjugated bilirubin in a prospective and controlled study with psychopathological and psychosocial variables. CNS Spectr. 2019;1-8. PubMed CrossRef

5. Gama Marques J. Mitsuda psychosis and holodysphrenia revisited: an atypical psychosis in a patient with parieto-occipital paroxysmal electroencephalographic activity and high unconjugated bilirubin. Psychiatry Clin Neurosci. 2017;71(2):148-149. PubMed CrossRef

6. Gama-Marques J, Tinoco I, Pedro I, et al. Unconjugated bilirubin and acute schizophrenia: a probable correlation? Actas Esp Psiquiatr. 2017;45(2):79-88. PubMed

7. Pommerening Dornelles E, Gama Marques J, Ouakinin S. Unconjugated bilirubin and schizophrenia: a systematic review. CNS Spectr. 2019;24(6):577-588. PubMed CrossRef

João Gama Marques, MDa,b

aHospital Júlio de Matos, Centro Hospitalar Psiquiátrico de Lisboa, Lisbon, Portugal

bClínica Universitária de Psiquiatria e Psicologia Médica, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

Published online: April 23, 2020.

Potential conflicts of interest: None.

Funding/support: None.

Prim Care Companion CNS Disord 2020;22(2):19l02525

To cite: Gama Marques J. Unconjugated bilirubin in schizophrenia/schizoaffective disorder spectrum: an overlooked and underestimated biomarker candidate. Prim Care Companion CNS Disord. 2020;22(2):19l02525.

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© Copyright 2020 Physicians Postgraduate Press, Inc.

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