Association between unconjugated bilirubin and schizophrenia
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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.
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.
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).
Bach, D.R., Kindler, J., Strik, W.K., 2010. Elevated bilirubin in acute and transient
On Kruskal–Wallis ANOVA, comparisons of the three groups (P-SCZ,
psychotic disorder. Pharmacopsychiatry 43, 12–16.
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).
psychoses: cluster 3 of the proposed meta-structure for DSM-V and ICD-11.
Psychological Medicine 39, 2025–2042.
Dincsoy, H.P., Saelinger, D.A., 1982. Haloperidol-induced chronic cholestatic liver
disease. Gastroenterology 83, 694–700.
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.
patients: evidence for two diseases. Schizophrenia Research 12, 53–61.
Uutela, P., Karhu, L., Piepponen, P., Käenmäki, M., Ketola, R.A., Kostiainen, R., 2009.
Hayashida, M., Miyaoka, T., Tsuchie, K., Yasuda, H., Wake, R., Nishida, A., Inagaki, T.,
Discovery of dopamine glucuronide in rat and mouse brain microdialysis samples
Toga, T., Nagami, H., Oda, T., Horiguchi, J., 2009. Hyperbilirubinemia-related
using liquid chromatography tandem mass spectrometry. Analytical Chemistry 81,
behavioral and neuropathological changes in rats: a possible schizophrenia animal
model. Progress in Neuropsychopharmacology & Biological Psychiatry 33, 581–588.
Vítek, L., Novotná, M., Lenícek, M., Novotný, L., Eberová, J., Petrásek, J., Jirsa, M., 2010.
McDonagh, A.F., 2010. Controversies in bilirubin biochemistry and their clinical
Serum bilirubin levels and UGT1A1 promoter variations in patients with
relevance. Seminars in Fetal & Neonatal Medicine 15, 141–147.
schizophrenia. Psychiatry Research 178, 449–450.
Miyaoka, T., Seno, H., Itoga, M., Horiguchi, J., 2000. Schizophrenia-associated idiopathic
Yao, J.K., Reddy, R., McElhinny, L.G., van Kammen, D.P., 1998. Reduced status of plasma
unconjugated hyperbilirubinemia (Gilbert's syndrome). Journal of Clinical Psychi-
total antioxidant capacity in schizophrenia. Schizophrenia Research 32, 1–8.
Yao, J.K., Reddy, R., van Kammen, D.P., 2000. Abnormal age-related changes of plasma
Miyaoka, T., Yasukawa, R., Yasuda, H., Shimizu, M., Mizuno, S., Sukegawa, T., Inagaki, T.,
antioxidant proteins in schizophrenia. Psychiatry Research 97, 137–151.
Horiguchi, J., 2005. Urinary excretion of biopyrrins, oxidative metabolites of
Yasukawa, R., Miyaoka, T., Yasuda, H., Hayashida, M., Inagaki, T., Horiguch, J., 2007.
bilirubin, increases in patients with psychiatric disorders. European Neuropsycho-
Increased urinary excretion of biopyrrins, oxidative metabolites of bilirubin, in
patients with schizophrenia. Psychiatry Research 153, 203–207.
Müller, N., Schiller, P., Ackenheil, M., 1991. Coincidence of schizophrenia and
hyperbilirubinemia. Pharmacopsychiatry 24, 225–228.
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