Unconjugated bilirubin and schizophrenia: a systematic review

Dornelles, Erik Pommerening; Marques, João Gama; Ouakinin, Sílvia

doi:10.1017/s109285291800161x

Cited by 16 publications

(14 citation statements)

References 80 publications

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“…In conclusion, we support the vision of the pathological spectrum of psychoses, 1 providing the genetic factor as a possible interpretation key. In fact, it has been described that the mean bilirubin level of patients with schizophrenia could be in the reference interval, and the frequency of GS is significantly higher in patients with schizophrenia 12 .…”

Section: To the Editorsupporting

confidence: 80%

“…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.…”

Section: To the Editormentioning

confidence: 99%

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

2019

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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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Section: To the Editorsupporting

confidence: 80%

Section: To the Editormentioning

confidence: 99%

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

2019

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“…It is therefore important to analyze its hypothetical role as a biological risk factor, linked with psychotic acute phases, thus making it eligible as a possible tool for early diagnosis, subsequent followup and even a target for new treatment strategies. 23 In this study, our main objective is to assess patients suffering from acute psychosis, trying to understand if UCB mean levels may have any potential interest as a biomarker in both categorical nosological axis (SCZ vs. SAF disorder) and a severity axis (relapse vs. partial remission). Our first hypothesis is that UCB levels will be higher in patients with SCZ than in patients with SAF disorder.…”

Section: Introductionmentioning

confidence: 99%

Clinical profile in schizophrenia and schizoaffective spectrum: relation with unconjugated bilirubin in a prospective and controlled study with psychopathological and psychosocial variables

Marques

Ouakinin

2019

CNS Spectr.

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Objective. Our objective was to assess unconjugated bilirubin (UCB) as biomarker for schizophrenia (SCZ) and schizoaffective (SAF) spectrums disorder (relapse vs. partial remission). Methods. Eighty-eight psychotic patients completed first assessment during relapse at ward admission, half with SCZ and half with SAF disorder. Forty-four acute bipolar patients were used as controls. After 12-month follow-up, we collected longitudinal protocol (laboratory, psychopathological, and psychosocial data) from 60 patients, half with SCZ and half with SAF disorder. Results. During psychotic relapse (N = 88), we found a statistically significant difference (analysis of variance [ANOVA]; p = .002), confirmed after post hoc multiple comparisons (Bonferroni) between SCZ (N = 44) and both SAF (N = 44; p = .05) and bipolar controls (N = 44; p = .05); a positive correlation (Pearson’s r = .314) between UCB mean levels and Personal and Social Performance item (d) “disturbing and aggressive behaviors”; and a positive correlation (R2 = .223), with statistically significance (p = .008), between UCB mean levels and mean length of stay at the psychiatric ward in SAF patients who completed full protocol (N = 30). During partial remission (N = 60) we found: a statistically significant difference (ANOVA; p = .006), confirmed after post hoc multiple comparisons (Bonferroni) between SCZ (N = 30) and SAF (N = 30; p = .05); plus a negative correlation (Pearson’s r = −.399) between UCB mean levels and Positive and Negative Syndrome Scale item G7 “psychomotor retardation.” Comparing first and second assessments (paired samples t test) we found a statistically significant difference in UCB mean levels among SAF patients (p = .034). Conclusions. There is potential in the research of UCB as a biological marker for SCZ and SAF spectrums disorders during relapse and partial remission of both syndromes.

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“…In our study, UCB levels are clearly lower in patients with acute psychotic episodes of the schizophrenia when compared with healthy controls. Pommerening Dornelles et al ( 25 ) pointed out that studies reporting the lower UCB levels in schizophrenia ( 21 , 24 ) could indicate a chronic proinflammatory state caused by elevated reactive oxygen species and the consumption of the antioxidant potential, hence leading to neuronal damage. The study presented in this paper is the first to investigate the relation between peripheral biomarkers of inflammation derived from CBC and UCB levels.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to inflammation, oxidative stress plays a key role in the progression of schizophrenia, while bilirubin is a strong endogenous antioxidant ( 45 ). A systematic review ( 25 ) showed that UCB is in part implicated in the pathophysiological process of schizophrenia, and elevated bilirubin may be linked with lower risk of schizophrenia in the acute stage. One recent study ( 46 ) showed potential of UCB as a biological marker for schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Relation Between Unconjugated Bilirubin and Peripheral Biomarkers of Inflammation Derived From Complete Blood Counts in Patients With Acute Stage of Schizophrenia

Wei

Zheng

et al. 2022

Front. Psychiatry

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BackgroundInflammation and oxidative stress are the major leading hypothetical causes of schizophrenia. Unconjugated bilirubin (UCB) is an efficient endogenous plasma antioxidant. Inflammation is closely linked to oxidative stress. The relationship between UCB and inflammatory markers should be paid close attention in schizophrenia acute stage. In this paper, combined UCB and inflammatory markers were evaluated for their capability in predicting schizophrenia in the acute stage to find an easy and effective indicator to identify acute schizophrenia.MethodsA total of 6,937 acute schizophrenia patients and 6,404 healthy controls (HCs) were enrolled. UCB and peripheral biomarkers of inflammation derived from complete blood counts (CBC) were investigated in the subjects with acute schizophrenia, and the results were compared with HCs. Simultaneously, Spearman test was employed to assess the correlation between the variables, while logistic regression was adopted to determine the combined equation and receiver operating characteristic curve was used to evaluate the combined value of UCB and peripheral biomarkers of inflammation derived from CBC to predict schizophrenia in the acute stage.ResultsThe study indicates that white blood cells, neutrophil, monocyte, mean platelet volume (MPV), red cell distribution width (RDW), neutrophil/lymphocyte ratio (NLR), and monocyte/lymphocyte ratio (MLR) have significantly increased in schizophrenia (p < 0.05 for all), while platelet, lymphocyte, and platelet/lymphocyte ratio (PLR) in schizophrenia have significantly decreased (p < 0.05 for all). UCB exhibits negative correlation with MPV significantly (r = 0.121, p < 0.001), and no correlation with neutrophil and monocyte. The correlations between UCB and other peripheral biomarkers of inflammation derived from CBC are very weak. MPV, RDW, NLR, MLR, PLR, and UCB were taken as independent variables for a logistic regression analysis. The model was as follows:Logit (P1)=-6.141+0.827 MPV+5.613 MLR-0.005 PLR-0.346 UBC.The combination demonstrates better effectiveness in predicting schizophrenia in the acute stage (AUC 0.831, 95% CI 0.825 to 0.837).ConclusionUCB has a protective effect on acute stage of schizophrenia, which is weak and indirect by affecting the proinflammatory processes. Our findings suggest that a combination of MLR, MPV, PLR, and UBC could be used to predict acute stage of schizophrenia.

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Unconjugated bilirubin and schizophrenia: a systematic review

Cited by 16 publications

References 80 publications

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

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

Clinical profile in schizophrenia and schizoaffective spectrum: relation with unconjugated bilirubin in a prospective and controlled study with psychopathological and psychosocial variables

Relation Between Unconjugated Bilirubin and Peripheral Biomarkers of Inflammation Derived From Complete Blood Counts in Patients With Acute Stage of Schizophrenia

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