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Association between unconjugated bilirubin and schizophreniaContents lists available at ScienceDirect j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p syc h r e s Association between unconjugated bilirubin and schizophrenia Rajiv Radhakrishnan a,⁎, Milanduth Kanigere b, Jayakumar Menon b, Sam Calvin b,Annuncia Janish b, Krishnamachari Srinivasan b a Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USAb Department of Psychiatry, St. Johns Medical College, Bangalore 560034, India The evidence regarding the association between schizophrenia and the fractions of bilirubin is mixed. In a retrospective case-control design we examined the association between total bilirubin, conjugated bilirubin, unconjugated bilirubin and schizophrenia. The relevance of our ﬁndings and that of the association of unconjugated bilirubin to schizophrenia is discussed.
2011 Elsevier Ireland Ltd. All rights reserved.
Keywords:SchizophreniaBiomarkerUnconjugated bilirubin The aim of the study was to examine the association between total bilirubin, conjugated bilirubin, unconjugated bilirubin and schizo- Schizophrenia, compared to other psychiatric conditions, has been phrenia compared to patients with bipolar disorder.
associated with hyperbilirubinemia in a number of studies (Mülleret al., 1991; Miyaoka et al., 2005). Among patients with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome), those withincreased plasma bilirubin levels are more likely to have schizophre- The study was a retrospective, case–control study conducted at a general medical nia (Miyaoka et al., 2000). Furthermore, the level of bilirubin was hospital's psychiatric inpatient unit. The charts of inpatients from September 2006 to found to correlate with symptom severity and to decrease with July 2009 were screened in a consecutive fashion until a target number of 100 caseswere reached.
resolution of psychosis. Bilirubin and its metabolites may hence be Patients with ICD-10 diagnosis of SCZ or BD (control group) were included. All useful as biomarkers in schizophrenia (Yasukawa et al., 2007).
subjects were inpatients and were assessed by a treating team consisting of two Total bilirubin (TB) in serum consists of two fractions, conjugated psychiatrists. The subtypes of schizophrenia were grouped as paranoid schizophrenia bilirubin (CB), formed by glucuronide conjugation catalyzed by the (P-SCZ) and non-paranoid schizophrenia (NP-SCZ) for the purpose of this study.
enzyme UGT (uridyl glucuronide transferase); and unconjugated Patients with co-morbid psychiatric disorders (including substance use disorders) andmedical diagnosis were excluded.
bilirubin (UCB), which is bound to albumin (McDonagh, 2010). While Blood chemistries were analyzed by Dimension® RxL-Max® Integrated Chemistry some investigators found an association between increased UCB and System (Siemens Healthcare Diagnostics). Serum levels of aspartate aminotransferase schizophrenia (Miyaoka et al., 2005), others did not ﬁnd an (AST), alanine aminotransferase (ALT), TB, CB and UCB were obtained. The type and association between schizophrenia-spectrum disorders and CB dosage of antipsychotic medication at the time of admission were noted.
Data were analyzed using SPSS 15.0. Independent sample t-Tests and Kruskal– Wallis one-way analysis of variance (ANOVA) were used to compare the means in two There is a growing recognition that bipolar disorder (BD) and groups (SCZ and BD) and the three subgroups (P-SCZ vs. NP-SCZ vs. BD), respectively.
schizophrenia (SCZ) lie on a psychosis spectrum. The commonalities The effect of age was examined in a one-way analysis of covariance (ANCOVA).
between BD and SCZ include shared genetic risk factors, common Multiple linear regression analysis was done to examine the effects of gender, environmental risk factors, and shared biomarkers (Carpenter et al., medication status and antipsychotics.
2009). The comparison of levels of bilirubin and its fractions in BD andSCZ is hence relevant.
The charts of 100 patients each with SCZ and BD were screened.
Those with substance use, elevated AST (cut off = 37 IU/L) and ALT ⁎ Corresponding author at: Department of Psychiatry, 950 Campbell Avenue, (cut off = 65 IU/L), or incomplete data were excluded. The ﬁnal Building 1, 9th Floor, VA Healthcare System, West Haven, CT 06516, USA. Tel.: +1 analysis was conducted on 140 subjects (BD = 69, SCZ = 71(P- E-mail address: firstname.lastname@example.org (R. Radhakrishnan).
0165-1781/$ – see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.psychres.2011.03.003 R. Radhakrishnan et al. / Psychiatry Research 189 (2011) 480–482 UCB, but not CB, compared to BD, and this association persisted after controlling for age and medication. Levels were signiﬁcantly higher in males. The rate of hyperbilirubinemia was signiﬁcantly higher in SCZcompared to BD. There was no difference in levels of TB, UCB or CB in Hyperbilirubinemia among patients with schizophrenia has been variously explained as being due to red cell membrane abnormalities (Glen et al., 1994), effect of medication (Dincsoy and Saelinger, 1982) Bach et al. (2010) showed that CB was not increased in the schizophrenia-spectrum disorders, but in a sub-group analysis, CB was signiﬁcantly elevated in the Acute Transient Psychotic Disorder (ATPD) group. Furthermore, the elevated bilirubin level could not beexplained by alterations in the UGT gene. Our study supports theirﬁnding with regard to CB not being signiﬁcant in the P-SCZ group.
The SCZ and BD groups were comparable on variables of age, Additionally, we did not include ATPD in the study. It is also possible gender and AST/ALT levels (Table 1). The mean ages of the groups were that different subtypes of schizophrenia have different proﬁles with 36.02 ± 12.04 years and 38.9 ± 15.5 years, respectively (p = 0.22). The gender distribution (p = 0.98) and AST (p = 0.29)/ALT levels The role of UGT and UCB is of direct relevance to brain processes.
(p = 0.26) between the groups were not statistically signiﬁcant.
UGT is involved in the metabolism of dopamine. Dopamine glucuronide There was no statistically signiﬁcant difference between P-SCZ, in the cerebrospinal ﬂuid is present at concentrations similar to that of NP-SCZ and BD groups for age (p = 0.45), gender (p = 0.38) or levels dopamine (Uutela et al., 2009). Since relatively small changes in levels of dopamine can have signiﬁcant pharmacological effects, UGT may play a The SCZ group had signiﬁcantly higher levels of TB and UCB signiﬁcant role in regulating levels of dopamine (Uutela et al., 2009).
(in mg/dl) compared with the BD group (mean TB = 0.62 ± 0.44 vs.
UCB is neurotoxic and results in glial cell injury leading to glutamate 0.47 ±0.26, t(138) = 2.37, p = 0.02; mean UCB = 0.46 ± 0.44 vs.
dysregulation and an increase in inﬂammatory cytokines. Furthermore, 0.32 ± 0.24, t(138)=2.26, p=0.03). There was no signiﬁcant difference exposure of immature neurons to UCB results in increased apoptosis and between the groups on levels of CB (mean CB=0.16±0.07 vs. 0.15± decreased neurite extension (Falcão et al., 2007). Similar abnormalities 0.07, t(138)=0.642, p=0.52). Twelve patients in the SCZ group had a TB are seen in schizophrenia. UCB may hence be more relevant to the value ≥1 mg/dl (hyperbilirubinemia) compared with three patients in BD pathophysiology of schizophrenia than TB or CB as exempliﬁed by the UGT – deﬁcient, schizophrenia animal model (Hayashida et al., 2009).
The ANCOVA for the effects of age on TB and UCB [Between- A number of studies show lower levels of TB among patients with subjects factor: Group (SCZ, BD); Covariate: Age] revealed no main schizophrenia compared to healthy controls (Yao et al., 1998, 2000; Pae effect for age on TB [F(1,137) = 3.54, p = 0.062] and UCB [F(1,137) = et al., 2004; Vítek et al., 2010). This is in concordance with the hypothesis of an antioxidant deﬁcit in schizophrenia. Vítek et al. (2010) In a regression model, gender had a signiﬁcant effect on TB studied the relative contributions of serum bilirubin and UGT1A1 (β = 0.13, t(137) = 2.1, p b0.05, R2 = 0.06, F(2,137) = 5.1, p b 0.05) promoter gene variations to the association with schizophrenia. They and UC(β = 0.19, t(137) = 2.24, p b 0.05, R2 = 0.07, F(2,137)= 5.2, found that the TA7 allele and G allele at the C-3279 position were p b 0.05). In a separate multiple regression analyses of the effects of associated with an increase in serum bilirubin levels. However, in their medication on TB and UCB, patients were categorized based on study the serum bilirubin concentration at all UGT1A1 promoter ge- medication status (on or off medication) and dose of antipsychotics notypes was lower in patients with schizophrenia. Our ﬁndings may (CPZ equivalents). The effects of medication status and CPZ equiva- appear to be contradictory to these studies. However, ﬁrstly, although lents were not signiﬁcant on TB (β = 0.05, t(137) = 0.619, p N 0.05, the authors concluded that factors other than genotype contributed to R2 = 0.042, F(2,137) = 2.9, p = 0.05; β = 0.004, t(137) =0.042, the association of TB with schizophrenia, another likely interpretation is p N 0.05, R2 = 0.039, F(2,137)= 2.79, p N 0.05, respectively) and UCB that different subtypes of schizophrenia may differ in the relative levels (β = 0.06, t(137) = 0.680, p N 0.05, R2 = 0.039, F(2,137)= 2.78, contributions of genotype to psychosis. Secondly, since UCB is neu- p N 0.05; β = 0.01, t(137) = 0.116, p N0.05, R2 = 0.036, F(2,137)= 2.55, rotoxic, unlike TB which has antioxidant properties, the increase in UCB would result in a relative antioxidant deﬁcit. It hence remains consistent On comparing the P-SCZ and NP-SCZ groups, the mean serum TB and with the antioxidant deﬁcit hypothesis. These may explain the apparent UCB (in mg/dl) were signiﬁcantly higher in the P-SCZ (mean TB=0.60± contradiction in the literature with regard to the association of bilirubin 0.43, t(69) = 2.08, p = 0.03; mean UCB = 0.44 ± 0.43, t(69) = 1.95, p =0.05) and NP-SCZ groups (mean TB= 0.80 ±0.49, t(69)= 2.76, The retrospective design and small numbers in the schizophrenia p=0.03; mean UCB=0.65±0.43, t(69)=2.99, p=0.004) compared subgroups are limitations of the study.
with the BD, (mean TB=0.47±0.07, mean UCB=0.32±0.23) group butthere was no signiﬁcant difference between the P-SCZ and NP-SCZ groups(mean TB =0.60±0.43 vs 0.8±0.48, t(69) = 1.07, p = 0.29; mean UCB = 0.44 ± 0.43 vs 0.65 ± 0.43, t(69) =1.11, p = 0.26).
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NP-SCZ, and BD) tended towards signiﬁcance for TB (p=0.06, d.f.=2) Carpenter, W.T., Bustillo, J.R., Thaker, G.K., van Os, J., Krueger, R.F., Green, M.J., 2009. The and UCB (p = 0.06, d.f. = 2) but not for CB (p = 0.8, d.f. = 2).
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Falcão, A.S., Silva, R.F., Pancadas, S., Fernandes, A., Brito, M.A., Brites, D., 2007. Apoptosis and Our ﬁndings are consistent with other studies on the association of impairment of neurite network by short exposure of immature rat cortical neurons tounconjugated bilirubin increase with cell differentiation and are additionally bilirubin with schizophrenia (Miyaoka et al., 2000; Yasukawa et al., enhanced by an inﬂammatory stimulus. Journal of Neuroscience Research 85, 2007). We found that SCZ had signiﬁcantly higher levels of TB and R. Radhakrishnan et al. / Psychiatry Research 189 (2011) 480–482 Glen, A.I., Glen, E.M., Horrobin, D.F., Vaddadi, K.S., Spellman, M., Morse-Fisher, N., Ellis, K., Pae, C.U., Paik, I.H., Lee, C., Lee, S.J., Kim, J.J., Lee, C.U., 2004. Decreased plasma Skinner, F.S., 1994. A red cell membrane abnormality in a subgroup of schizophrenic antioxidants in schizophrenia. Neuropsychobiology 50, 54–56.
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