الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
U
nconjugated 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).
The interest of this literature lies in the possibility of finding an objective, measurable, and potentially influenceable parameter which could help complement the still somewhat subjective approach to the diagnosis, management, and even prevention of schizophrenia. If this possibility turned out to be true, it would imbue medical professionals with a powerful weapon against schizophrenia (Dornelles et al., 2019).
Our hypothesis is that unconjugated bilirubin is a state biological marker increasing in patients with schizophrenia in acute relapses as compared to healthy individuals.
This study is a Cross-sectional observational study carried out in Okasha Institute of Psychiatry, Ain Shams University, between June 2020 and December 2020 aiming to assess unconjugated (indirect) bilirubin in patients with schizophrenia in acute episode and analyze its correlation with the psychopathological, psychosocial and neuropsychological dimensions.
Scientific and ethical approval was obtained from ethical committees of institute of psychiatry and faculty of medicine, Ain Shams University. Subjects who were ready to participate agreed to the informed consent provided for the study.
Data was collected from 40 cases in relapse, 40 cases in remission, and 40 healthy individuals. Each subject answered close ended direct questions about socio-demographic data (name, age, gender, education, employment status, and smoking). Weight and height were measured to calculate body mass index (BMI). Clinical variables of patients with schizophrenia were noted (duration of the psychotic disorder, duration of untreated psychosis, family psychiatric history, and antipsychotic medications status).
Structured Clinical Interview for DSM-IVTM Axis I Disorders (SCID-I) was applied to ensure the diagnosis of the patients with schizophrenia. Positive and Negative Syndrome Scale (PANSS) scale, Global Assessment of Functioning (GAF), and Trail Making Test (TMT) were applied to patients with schizophrenia to assess severity of symptoms, social functioning, and cognitive functioning respectively. All subjects underwent a blood draw to measure serum bilirubin level.
The collected data was revised, coded, tabulated and introduced to a PC using Statistical package for Social Science (SPSS 20). Data was presented and suitable analysis was done according to the type of data obtained for each parameter. Results were displayed to answer questions raised in the hypothesis of this study.
The main findings in our study are:
Mean bilirubin serum levels were within normal laboratory reference range except for two patients in the relapse group who had a total bilirubin value = 1mg/dL which is the upper limit in the laboratory reference range; and one patient in the remission group who had a total bilirubin value > 1mg/dL and this patient was directed to seek internal medicine consultation.
The relapse, remission, and healthy groups showed no significant statistical difference for conjugated (direct) bilirubin (p>0.05).
Via Post Hoc analysis by LSD, total and unconjugated (indirect) bilirubin in the relapse and remission groups were statistically significantly higher than the healthy group (p<0.001). However, there was no statistically significant difference between the relapse and remission groups as regarding total and unconjugated (indirect) bilirubin (p>0.05).
In the relapse group, the results revealed statistically significant positive correlation for total, and indirect bilirubin serum levels with total PANSS score and its general psychopathology symptoms subscale (P<0.05). Yet, positive symptoms subscale score and negative symptoms subscale score didn’t show any statistically significant correlation with bilirubin serum levels.
In the remission group, the results revealed no statistically significant correlation for total, direct, nor indirect bilirubin serum levels with total PANSS score or any of its subscales.
In both relapse and remission groups, no statistically significant correlation was found for serum levels of either total, direct or indirect bilirubin; with GAF score, TMT-A, or TMT-B time score.
Further investigations via longitudinal studies and on larger samples are recommended to settle specific causal paths between the two variables.
Clinicians should be aware of alteration of unconjugated bilirubin serum levels in the course of schizophrenia, so as not to subject these patients to unnecessary clinical or laboratory investigations or improper withholding of antipsychotics, while being a pathophysiological change in the course of the disorder.