International Journal of Psychiatry in Clinical Practice, 2010; 14: 262–267
ORIGINAL ARTICLE
Alteration of serum bilirubin level in schizophrenia
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YOUSEF SEMNANI1, FARZAD NAZEMI2, AILEEN AZARI YAM1 & MOHAMMAD JAVAD EHSANI ARDAKANI3 1Behavioral
Science Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran, and 3Deopartment of Gastroenterology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2Psychiatry
Abstract Objective. Alteration of serum bilirubin level in acute episodes of psychosis in patients with schizophrenia has been reported but the pattern of this alteration is controversial. Methods. Patients diagnosed as schizophrenia (162, group S) or bipolar disorder (155, group B) entered the study. The control group consisted of 95 patients admitted to cardiac care unit who had no personal or family history of major psychiatric disorders. Pre- and post-admission levels of bilirubin were measured and compared within and between the groups. Patients were examined to exclude all other causes of hyperbilirubinemia. Group S and B participants were also evaluated using positive and negative syndrome subscale (PANSS) both at admission and discharge. Results. The mean admission bilirubin levels of all the groups were in the normal range (significantly higher in group S than groups B and C) and were affected by the score of general psychopathology subscale rather than the scores of positive symptoms subscale. Conclusions. Although bilirubin decreased in all three groups at discharge, the rate of decrease was significantly higher in group S. The reason for this is not clear and needs further study. Key Words: Psychotic disorders, bilirubin, schizophrenia, bipolar disorder, Gilbert’s disease
Introduction The relationship between serum bilirubin level and psychiatric disorders has been addressed in several studies. These studies are mainly based upon the following observations: (1) Psychiatric patients with a history of neonatal hyperbilirubinemia. Cullberg showed a significantly higher rate of hospitalization due to psychiatric disorders in individuals with a history of neonatal hyperbilirubinemia which still remained after exclusion of the subjects with associated obstetric risk factors [1]. One animal study by Falcão et al. showed that exposure of immature neurons to unconjugated bilirubin caused neurodevelopmental abnormalities and supported the association between neonatal hyperbilirubinemia and the later development of schizophrenia [2]. (2) Patients with schizophrenia associated with Gilbert’s disease. Several studies showed bilirubin level changes in patients with schizophrenia associated
with Gilbert’s disease [3–6]. Ramos et al. reported one case of schizophrenia associated with Gilbert’s disease in which the exacerbation and remission of hyperbilirubinemia closely related with psychosis [7]. Miyaoka et al. showed a higher frequency of Gilbert’s disease in patients with schizophrenia compared to patients with affective psychosis (20 vs. 4.2%) but their study lacked a control group composed of hospitalized patients with non-psychiatric disorders. Their study showed that during hospitalization, hyperbilirubinemia decreased in 80%. The remaining 20% showed alternating decreased and increased levels of bilirubin. These, authors however, did not evaluate the rate of bilirubin alteration in individual patients of one group compared to those of other groups [8]. Brain imaging by computed tomography (CT) showed in one study that in patients with schizophrenia associated with Gilbert’s disease, the cerebral ventricles are larger than patients with schizophrenia not associated with
Correspondance: Aileen Azari Yam, Behavioral Science Research Center, Imam Hossein Hospital, Shahid Madani Avenue, Tehran, Iran. Tel./Fax: 98 21 7755 1023. E-mail: [email protected] (Received 18 February 2010; accepted 30 June 2010) ISSN 1365-1501 print/ISSN 1471-1788 online © 2010 Informa Healthcare DOI: 10.3109/13651501.2010.506007
Bilirubin and schizophrenia
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Gilbert’s disease [9]. Other studies using magnetic resonance spectroscopy revealed lower metabolism rate of anterior cingulate [10], frontotemporal cortex, limbic system, and basal ganglia [11] in patients with schizophrenia associated with Gilbert’s disease. Using fluid-attenuated inversion–recovery magnetic resonance imaging, patients with schizophrenia associated with Gilbert’s disease showed some changes of the frontotemporal cortex, limbic system and basal ganglia [12]. In proton magnetic resonance spectroscopy in the anterior cingulate gyrus, patients with schizophrenia and Gilbert’s syndrome showed significant decreases in N-acetylaspartate/creatine-phosphocreatinine (NAA/Cr), choline/creatine-phosphocreatinine (Cho/Cr) and myoinositol/creatine-phosphocreatinine (ml/Cr) ratios compared with healthy subjects and compared with patients with schizophrenia without Gilbert’s disease [13]. In Gilbert’s disease, which occurs in a significant fraction (3–5%) of the population, total bilirubin, virtually all of which is unconjugated, is typically elevated to 34–51 mmol/l (2 to 3 mg/dl); levels can increase further with fasting but seldom exceed 85 mmol/l (5 mg/dl). (3) Patients with acute episode psychosis and altered serum bilirubin levels. Muller et al. in a retrospective study found that serum billirubin level is higher in patients with schizophrenia than other psychiatric patients and attributed this finding to the alteration of membrane in red blood cells of the patients with schizophrenia [14]. Other authors hypothesize that oxidative stress may be involved in the pathophysiology of schizophrenia [15]. Yao et al. showed that bilirubin, as a particularly potent anti-oxidant, is decreased in patients with schizophrenia further supporting the hypothesis that a defect in the antioxidant defense system occurs in schizophrenia [16,17]. In one other study, different antioxidants including bilirubin were assayed in 31 patients with schizophrenia and compared with those of patients with affective disorders and also normal people. Bilirubin level was lower in patients with schizophrenia and remained constant throughout the course of the disease [18]. This finding has been reproduced in other studies [19–21]. On the other hand, there are studies that in contrast to the previously mentioned studies have reported increased serum and urine levels of bilirubin or its metabolites in different psychiatric disorders including schizophrenia [22–24].
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Also, it has recently been shown that thioredoxin, one of the oxidative stress markers, was increased significantly in first-episode schizophrenic patients compared to chronic schizophrenic patients on antipsychotic medication [26]. In a review Rigato et al. showed that the incidence and severity of schizophrenia are increased by elevated bilirubin levels which might counteract the oxidative stress associated with this disorder [27]. Bach et al. have found no association between schizophrenia and hyperbilirubinemia; however, according to their study, some schizophrenic subtypes had significantly higher bilirubin levels compared to others [28]. (4) Correlation of bilirubin level with fluctuations of the psychiatric symptom severity. According to the study of Miyaoka et al., patients with hyperbilirubinemia show significantly higher scores on the positive and general psychopathology subscales of PANSS (positive and negative syndrome subscales) than patients without hyperbilirubinemia [8]. Another study showed that the severity of Gilbert’s disease, general psychopathology (assessed by PANSS) and antipsychotic side effects (assessed by Prins Henrry Hospital Akathesia Scale, PHAS) in schizophrenia is greater than other psychiatric disorders [29]. Regarding the overt controversy in literature about the pattern of bilirubin level change in patients with schizophrenia, small sample size of most studies [8,18], failure to use precise diagnostic tools for psychiatric disorders, and lack of suitable control groups [8], this study was done to answer the questions like whether the pattern of bilirubin change is different in patients with schizophrenia compared to patients with other psychiatric and non-psychiatric disorders.
Material and methods This observational cross-sectional comparative study (30) was conducted at the psychiatry ward of Imam Hossein Hospital, Tehran, Iran (affiliated with Shahid Beheshti University of Medical Sciences) from 2003 to 2007. Patients with acute psychotic symptoms admitted sequentially to the ward, entered the study after they provisionally met DSM-IV criteria for schizophrenia or bipolar disorder I. The exclusion criteria included age under 20, overt cognitive impairment, history of smoking [31,32], substance abuse during the preceding 6 months, recent (2 months) use of psychiatric medications [33] or phenobarbital [34], and a history of other psychiatric comorbidities or neurological insult. This information was ascertained by
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interview. Patient information including age and gender was compiled. Control subjects were recruited from cardiac patients on their first day of admission to coronary care unit (CCU) [25]. Additional exclusion criteria for control subjects included personal or family history of psychosis. These patients were supposed to be under severe stress due to the acute nature of their disease and hospitalization, so were considered as suitable control group in order to estimate the contribution of psychological stress in the elevation of serum bilirubin level in schizophrenic patients. An informed consent form was signed by all the participants. The study was approved by the ethics committee of the Shahid Beheshti University of Medical Sciences. The psychiatric patients were evaluated using Persian translation of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV SCID) [35,36] and entered one of the groups (schizophrenia or bipolar) after the establishment of diagnosis. Blood samples were collected from all the participants both at admission and discharge. Serum levels of total and direct bilirubin were determined using standard dichloroanylin method in which bilirubin looses nitrogen and converts to red azobilirubin detected by spectrophotometry (Parsazmoon bilirubin DCA diagnostic kit, Parsazmoon Co., Tehran, Iran) [37]. To determine total bilirubin level, the bound bilirubin is first detached from albumin by detergents. The analytic method of the process was under monitoring by two high and low levels of control material. The upper limit of normal for total and direct bilirubin levels were 20.4 mmol/l (1.2 mg/l) and 4.25 mmol/l (0.25 mg/dl), respectively. It should be noted that in this study none of the specimens was visibly lipemic or hemolytic. The admission and discharge levels of serum bilirubin were compared within and between the groups. In order to rule out other causes of hyperbilirubinemia, serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase were measured by Hitachi 704 Chemistry Analyzer (Borhringer Mannheim Diagnostic, Mannheim, Germany). The reticulocyte count and prothrombin time of the samples were also assessed. Abnormality in the result of any of these tests led to the exclusion of the patient from the study. Patients with increased total bilirubin level (20.4 mmol/l [ 1.2 mg/dl]) yet normal direct bilirubin at admission were diagnosed as Gilbert’s disease, if the total bilirubin level was back to normal level (20.4 mmol/l [1.2 mg/dl]) at discharge. The severity of positive symptoms and general psychopathology were also measured both at admission and discharge using positive and negative syndrome
subscale (PANSS) in all group S and B participants [38]. PANSS, previously used in a similar study [8], is a suitable tool for the assessment of positive symptoms (delusions, hallucinatory behavior, grandiosity, suspiciousness/persecution, and hostility), negative symptoms (e.g., retarded affection), and general psychopathology (e.g., aggression, uncooperativeness) in psychotic patients. This tool allocates seven items for positive symptoms, seven for negative symptoms, and 16 for general psychopathology. The severity is graded from 1 to 7. In this study the negative symptoms were not assessed because of lack of these symptoms in group B patients. Evaluation by PANSS was done independently by the second author of this article. We used analysis of variances (ANOVA) to compare the mean bilirubin level at admission between the three groups.To compare the rate of bilirubin decrease after treatment in each group we used paired t-test and ANOVA. We used paired t-test to examine whether the bilirubin decrease after treatment in each group was significant. To test the significance of the observed difference among mean PANSS scores of the groups S and B, we used independent samples t-test. Analysis of covariances (ANCOVA) was used to determine the effect of positive and general scores of PANSS on admission bilirubin level. Results Eighteen schizophrenic (10%), 10 bipolar I (6%) and 23 CCU patients (19%) were excluded because of premature discharge from hospital before the final tests could be done. Finally, 162 patients with schizophrenia (group S), 155 patients with bipolar disorder I (group B) and 95 patients with cardiac disease (group C) entered the study. Table I shows some data of the participants. No significant differences in age and sex were found among the 3 groups (Table I). The initial mean total bilirubin level of group S patients was in the normal range but significantly higher than bipolar patients (post hoc Bonferroni, P0.0001). The initial mean bilirubin level was higher in group B than group C (post hoc Bonferroni, P0.02). All schizophrenic patients received antipsychotic medications including halopridol (100 patients), risperidone (53 patients), and clozapine (9 patients). Fifty-seven (38%) of bipolar patients also went under antipsychotic therapy (haloperidol, 42 patients), perphenazine (1 patient), and risperidone (14 patients). The mean bilirubin level was decreased in all three groups at discharge (P0.15) so that the mean bilirubin level at discharge was not significantly different between the three groups (Table I), but the mean rate of decrease during the course of treatment was higher in group S than group B (post hoc Bonferroni, P0.0001)
Bilirubin and schizophrenia Table I. Demographic data in schizophrenic (S), bipolar I (B), and control (C) groups.
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Group B
Group C
34.7 8.7
33.2 9.4
32.4 0.7
100 (61.7) 62 (38.3)
100 (64.5) 55 (35.5)
68 (71.6) 27 (28.4)
0.63 0.3 0.36 0.1
0.49 0.2 0.35 0.1
0.41 0.1 0.37 0.1
0.26 0.3 162
0.14 0.1 155
.7
Mean Bilirubin Level (mg/dL)
Agea (meanSD) Genderb Male (%) Female (%) Bilirubin (mg/dl) Admissionc Discharged Difference between admission and dischargee Total
Group S
.6
.5
.4
0.04 0.1 9
Bilirubin level is significantly decreased at discharge compared to admission in schizophrenics (t11.2, df161, P0.0001), bipolar I patients (t12.8, df154, P0.0001) and CCU patients (t3.5, df94, P0.001). aF2.38, P0.1. bχ22.58, dF2, P0.28. cF34.2, P0.0001. dF1.96, P0.15. eF36.9, P0.0001.
and in group B than group C (post hoc Bonferroni, P0.0001). Figure 1 summarizes these results. Twenty-three of the schizophrenic patients (5.6%), and five of the bipolar patients (1.2%) had Gilbert’s disease. None of the group C patients were diagnosed as Gilbert’s disease. The frequency of Gilbert’s disease was significantly higher in group S than both group C (Fisher’s exact test, P0.0001) and group B (χ211.8, df 1, P0.001). The frequency of Gilbert’s disease was not significaently higher in group B than both group C (Fisher’s exact test, P0.16). The mean scores of the positive symptoms and general psychopathology subscales were not significantly different between groups S and B (t0.89, df 315, P0.37). After treatment, positive symptoms and general psychopathology scores decreased in severity in both groups S and B. We found that bilirubin decrease during treatment in both group S and group B patients was primarily correlated by the improvement of general
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admission discharge
.3 group S
group B
group C
Figure 1. Comparison of serum bilirubin levels at admission and discharge in patients with schizophrenia (group S, n162), bipolar I disorder (group B, n155), and cardiac disease (group C, n95). The mean levels of bilirubin at admission and the mean rate of bilirubin decrease are highest in group S. Mean bilirubin level is significantly decreased at discharge compared to admission in schizophrenics (t11.2, df161, P0.0001), bipolar I patients (t12.8, df154, P0.0001) and CCU patients (t3.5, df94, P0.001).
psychophysiology scores of PANSS (type III sum of squares1.12, F23.8, P0.0001) rather than positive symptom scores (type III sum of squares0.01, F 0.27, P0.6). According to Table II, Gilbert’s disease was associated with higher general psychopathology subscale scores in both groups S and B while the mean score of positive symptoms was not significantly different among Gilbert and non-Gilbert associated patients of both S and B groups.
Discussion Done with a larger sample size compared to others [8,18], this study showed that though the mean bilirubin level of patients with schizophrenia was in the reference interval, it was significantly higher than that of bipolar and non-psychiatric patients. With the
Table II. Comparison of the mean scores of positive symptoms and general psychopathology subscale in schizophrenic and bipolar patients with and without Gilbert’s disease. Schizophrenia
Mean positive symptoms score Mean general psychopathology score aP0.002. bP0.0001. cP0.12. dP0.6.
Bipolar
with Gilbert’s disease
without Gilbert’s disease
t df160
with Gilbert’s disease
without Gilbert’s disease
22.70 26.48
20.91 22.11
1.24a 3.21c
19.6 31.6
20.65 22.91
t df153 5.7b 0.52d
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remission of acute symptoms of psychosis upon applying therapy, bilirubin level decreased and no significant difference in the mean bilirubin level existed between the three groups at discharge. Measuring bilirubin levels serially in an individual, as we did in this study, is informative because bilirubin is one of the analytes that their values from a given individual fluctuate in a narrow range of reference interval so serial changes may be more useful than comparing each of the measurements with the reference interval [39]. Our findings are in contrast with those of Reddy et al. [18] who showed bilirubin level was lower in patients with schizophrenia than normal individuals and its level remained constant during treatment. Their small sample size might explain this contradiction. Also, they compared the bilirubin level of patients with schizophrenia only with normal people and did not address the bilirubin changes in other psychiatric patients. Yamaguchi et al. have shown that the concentration of bilirubin oxidative metabolite is elevated in urine from subjects exposed to psychological stress [25]. Although we did not use any special tool to asses the severity of stress in the subjects of our study groups, it could be inferred from the mean general psychopathology subscale score which is frequently considered as a function of the stress severity [40,41]. We found that the mean general psychopathology subscale score was not significantly different among groups S and B. Therefore stress can not by itself explain the higher bilirubin level in group S and further studies are required to determine other causes such as possible common genes involved in pathogenesis of both schizophrenia and hyperbilirubinemia. We found that the frequency of Gilbert’s disease was higher in patients with schizophrenia. Some authors argue that Gilbert’s disease is being overdiagnosed, since it is frequently diagnosed in young adults in whom normal bilirubin ranges are higher – reaching their highest levels in adolescence and young adulthood [42,43]. This concern was not addressed in the study of Miyaoka et al. [8] in which the mean age of the patients with schizophrenia was significantly different from that of affective patients. In our study no significant difference existed between the mean ages of the groups. We also showed that serum bilirubin alteration during the course of disease was affected by the severity of the psychiatric disorder just as Miyaoka et al. had shown [8]. Although our findings showed that the rise and decrease of bilirubin level paralleled the exacerbation and remission of psychotic symptoms, establishing a causal relationship needs further studies.
Finally, we suggest that clinicians should be aware of bilirubin level alteration in the course of psychotic disorders especially schizophrenia in order not to subject these patients to unnecessary clinical or laboratory investigations or improper withholding of psychiatric medication while this biochemical change reverses back to normal as the disease is controlled and symptoms are suppressed.
Key points • There have been many reports of association between schizophrenia and alteration of serum bilirubin level • We showed that the mean serum bilirubin level is higher in psychotic attacks of schizophrenia compared to bipolar and non-psychiatric diseases and this alteration parallels with exacerbation and remission of the symptoms • Our study suggests that the pathophysiological pathways leading to schizophrenia may have some common routes with bilirubin metabolism but a causal relationship is not established and needs further research
Acknowledgements We wish to acknowledge Dr Foroozan Karimi for her valuable help in manuscript preparation. Statement of interest The authors have no conflict of interests to disclose. References [1] Cullberg DC. Neonatal hyperbilirubinaemia-a vulnerablity factor for mental disorder? Acta Psychiatr Scand 1999;100: 469–71. [2] Falcão A, Silva R, Pancadas S, Fernandes A, Brito M, Brites D. Apoptosis and impairment of neurite network by short exposure of immature rat cortical neurons to unconjugated bilirubin increase with cell differentiation and are additionally enhanced by an inflammatory stimulus. J Neurosci Res 2007;85(6):1229–39. [3] Freund N. A psychiatric patient with elevated liver values. Psychiatrischer patient mit leberwerterhohung. Praxis 2006;95 (14):549–50. [4] Mahdi AS, Elameer MS. Co-occurrence of Gilbert’s syndrome and psychosis. Psychiatr Bull 1998;22(9):566–8. [5] Miyaoka T, Seno H, Maeda T, Itoga M, Horiguchi J. Schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert’s syndrome): 3 Case reports. J Clin Psychiatry 2000;61(4):299–300. [6] Powell AJ, Hansen LK. Gilbert’s syndrome in a patient with predominantly negative symptoms of schizophrenia. Int J Psychiatry Clin Pract 2007;11(3):239–41. [7] Ramos RM, Curto SV, Ramos JMM. Gilbert’s syndrome and schizophrenia. Actas Esp Psiquiatr 2006;34(3):206–8.
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[25] Yamaguchi T, Shioji I, Sugimoto A, Yamaoka M. Psychological stress increases bilirubin metabolites in human urine. Biochem Biophys Res Commun 2002;293:517–20. [26] Zhang X, Chen D, Xiu M, Wang F, Qi L, Sun H, et al. The novel oxidative stress marker thioredoxin is increased in first-episode schizophrenic patients. Schizophr Res 2009; 113(2–3):151–7. [27] Rigato I, Ostrow J, Tiribelli C. Bilirubin and the risk of common non-hepatic diseases. Trends Mol Med 2005;11(6): 277–83. [28] Bach D, Kindler J, Strik W. Elevated bilirubin in acute and transient psychotic disorder. Pharmacopsychiatry 2010;43(1):12. [29] Miyaoka T, Yasukawa R, Mizuno S, Sukegawa T, Inagaki T, Horiguchi J. Clinical features of schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert’s Syndrome). Int J Psychiatry Clin Pract 2003;7(3):199–203. [30] Trochim MK. Research Methods the concise Knowledge base. 1st ed. Mason, OH: Thomson Corporation; 2005. p. 134–49. [31] Schwertner HA. Association of smoking and low serum bilirubin antioxidant concentrations. Atherosclerosis 1998;136(2): 383–7. [32] Van Hoydonck PG, Temme EH, Schouten EG. Serum bilirubin concentration in a Belgian population: the association with smoking status and type of cigarettes. Int J Epidemiol 2001;30(6):1465–72. [33] Atasoy N, Erdogan A, Yalug I, Ozturk U, Konuk N, Atik L, et al. A review of liver function tests during treatment with atypical antipsychotic drugs: a chart review study. Prog Neuropsychopharmacol Biol Psychiatry 2007;31(6):1255–60. [34] Hansen TW, Tommarello S. Effect of phenobarbital on bilirubin metabolism in rat brain. Biol Neonate 1998;73(2): 106–11. [35] Sharifi V, Assadi S, Mohammadi M, Amini H, Kaviani H, Semnani Y, et al. A persian translation of the structured clinical interview for diagnostic and statistical manual of mental disorders: psychometric properties. Comp Psychiatry 2009;50(1):86–91. [36] Sharifi V, Assadi SM, Mohammadi MR, Amini H, Kaviani H, Semnani Y, et al. Reliability and feasibility of the Persian version of the structured diagnostic interview for DSM-IV (SCID). Adv Cogn Sci 2004;6:10–22. [37] Miller NJ, Rice-Evans C, Davies MJ. A new method for measuring antioxidant activity. Biochem Soc Trans 1993;21 (2):95S. [38] Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13(2):261–76. [39] Lacher D, Hughes J, Carroll M. Estimate of biological variation of laboratory analytes based on the Third National Health and Nutrition Examination Survey. Am Assoc Clin Chem 2005:450–2. [40] Hamner MB, Faldowski RA, Ulmer HG, Frueh BC, Huber MG, Arana GW. Adjunctive risperidone treatment in post-traumatic stress disorder: a preliminary controlled trial of effects on comorbid psychotic symptoms. Int Clin Psychopharmacol 2003;18(1):1. [41] Hamner MB, Frueh BC, Ulmer HG, Huber MG, Twomey TJ, Tyson C, et al. Psychotic features in chronic posttraumatic stress disorder and schizophrenia: comparative severity. J Nerv Ment Dis 2000;188(4):217. [42] Bulpitt CJ, Shipley MJ, Broughton PM, Fletcher AE, Markowe HL, Marmot MG, et al. Age differences in biochemical and hematological measures during middle age. Aging (Milano) 1994;6(5):359–67. [43] Rosenthal P, Pincus M, Fink D. Sex-and age-related differences in bilirubin concentrations in serum. Clin Chem 1984;30(8):1380–2.
ORIGINAL ARTICLE
Alteration of serum bilirubin level in schizophrenia
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YOUSEF SEMNANI1, FARZAD NAZEMI2, AILEEN AZARI YAM1 & MOHAMMAD JAVAD EHSANI ARDAKANI3 1Behavioral
Science Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran, and 3Deopartment of Gastroenterology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2Psychiatry
Abstract Objective. Alteration of serum bilirubin level in acute episodes of psychosis in patients with schizophrenia has been reported but the pattern of this alteration is controversial. Methods. Patients diagnosed as schizophrenia (162, group S) or bipolar disorder (155, group B) entered the study. The control group consisted of 95 patients admitted to cardiac care unit who had no personal or family history of major psychiatric disorders. Pre- and post-admission levels of bilirubin were measured and compared within and between the groups. Patients were examined to exclude all other causes of hyperbilirubinemia. Group S and B participants were also evaluated using positive and negative syndrome subscale (PANSS) both at admission and discharge. Results. The mean admission bilirubin levels of all the groups were in the normal range (significantly higher in group S than groups B and C) and were affected by the score of general psychopathology subscale rather than the scores of positive symptoms subscale. Conclusions. Although bilirubin decreased in all three groups at discharge, the rate of decrease was significantly higher in group S. The reason for this is not clear and needs further study. Key Words: Psychotic disorders, bilirubin, schizophrenia, bipolar disorder, Gilbert’s disease
Introduction The relationship between serum bilirubin level and psychiatric disorders has been addressed in several studies. These studies are mainly based upon the following observations: (1) Psychiatric patients with a history of neonatal hyperbilirubinemia. Cullberg showed a significantly higher rate of hospitalization due to psychiatric disorders in individuals with a history of neonatal hyperbilirubinemia which still remained after exclusion of the subjects with associated obstetric risk factors [1]. One animal study by Falcão et al. showed that exposure of immature neurons to unconjugated bilirubin caused neurodevelopmental abnormalities and supported the association between neonatal hyperbilirubinemia and the later development of schizophrenia [2]. (2) Patients with schizophrenia associated with Gilbert’s disease. Several studies showed bilirubin level changes in patients with schizophrenia associated
with Gilbert’s disease [3–6]. Ramos et al. reported one case of schizophrenia associated with Gilbert’s disease in which the exacerbation and remission of hyperbilirubinemia closely related with psychosis [7]. Miyaoka et al. showed a higher frequency of Gilbert’s disease in patients with schizophrenia compared to patients with affective psychosis (20 vs. 4.2%) but their study lacked a control group composed of hospitalized patients with non-psychiatric disorders. Their study showed that during hospitalization, hyperbilirubinemia decreased in 80%. The remaining 20% showed alternating decreased and increased levels of bilirubin. These, authors however, did not evaluate the rate of bilirubin alteration in individual patients of one group compared to those of other groups [8]. Brain imaging by computed tomography (CT) showed in one study that in patients with schizophrenia associated with Gilbert’s disease, the cerebral ventricles are larger than patients with schizophrenia not associated with
Correspondance: Aileen Azari Yam, Behavioral Science Research Center, Imam Hossein Hospital, Shahid Madani Avenue, Tehran, Iran. Tel./Fax: 98 21 7755 1023. E-mail: [email protected] (Received 18 February 2010; accepted 30 June 2010) ISSN 1365-1501 print/ISSN 1471-1788 online © 2010 Informa Healthcare DOI: 10.3109/13651501.2010.506007
Bilirubin and schizophrenia
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Gilbert’s disease [9]. Other studies using magnetic resonance spectroscopy revealed lower metabolism rate of anterior cingulate [10], frontotemporal cortex, limbic system, and basal ganglia [11] in patients with schizophrenia associated with Gilbert’s disease. Using fluid-attenuated inversion–recovery magnetic resonance imaging, patients with schizophrenia associated with Gilbert’s disease showed some changes of the frontotemporal cortex, limbic system and basal ganglia [12]. In proton magnetic resonance spectroscopy in the anterior cingulate gyrus, patients with schizophrenia and Gilbert’s syndrome showed significant decreases in N-acetylaspartate/creatine-phosphocreatinine (NAA/Cr), choline/creatine-phosphocreatinine (Cho/Cr) and myoinositol/creatine-phosphocreatinine (ml/Cr) ratios compared with healthy subjects and compared with patients with schizophrenia without Gilbert’s disease [13]. In Gilbert’s disease, which occurs in a significant fraction (3–5%) of the population, total bilirubin, virtually all of which is unconjugated, is typically elevated to 34–51 mmol/l (2 to 3 mg/dl); levels can increase further with fasting but seldom exceed 85 mmol/l (5 mg/dl). (3) Patients with acute episode psychosis and altered serum bilirubin levels. Muller et al. in a retrospective study found that serum billirubin level is higher in patients with schizophrenia than other psychiatric patients and attributed this finding to the alteration of membrane in red blood cells of the patients with schizophrenia [14]. Other authors hypothesize that oxidative stress may be involved in the pathophysiology of schizophrenia [15]. Yao et al. showed that bilirubin, as a particularly potent anti-oxidant, is decreased in patients with schizophrenia further supporting the hypothesis that a defect in the antioxidant defense system occurs in schizophrenia [16,17]. In one other study, different antioxidants including bilirubin were assayed in 31 patients with schizophrenia and compared with those of patients with affective disorders and also normal people. Bilirubin level was lower in patients with schizophrenia and remained constant throughout the course of the disease [18]. This finding has been reproduced in other studies [19–21]. On the other hand, there are studies that in contrast to the previously mentioned studies have reported increased serum and urine levels of bilirubin or its metabolites in different psychiatric disorders including schizophrenia [22–24].
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Also, it has recently been shown that thioredoxin, one of the oxidative stress markers, was increased significantly in first-episode schizophrenic patients compared to chronic schizophrenic patients on antipsychotic medication [26]. In a review Rigato et al. showed that the incidence and severity of schizophrenia are increased by elevated bilirubin levels which might counteract the oxidative stress associated with this disorder [27]. Bach et al. have found no association between schizophrenia and hyperbilirubinemia; however, according to their study, some schizophrenic subtypes had significantly higher bilirubin levels compared to others [28]. (4) Correlation of bilirubin level with fluctuations of the psychiatric symptom severity. According to the study of Miyaoka et al., patients with hyperbilirubinemia show significantly higher scores on the positive and general psychopathology subscales of PANSS (positive and negative syndrome subscales) than patients without hyperbilirubinemia [8]. Another study showed that the severity of Gilbert’s disease, general psychopathology (assessed by PANSS) and antipsychotic side effects (assessed by Prins Henrry Hospital Akathesia Scale, PHAS) in schizophrenia is greater than other psychiatric disorders [29]. Regarding the overt controversy in literature about the pattern of bilirubin level change in patients with schizophrenia, small sample size of most studies [8,18], failure to use precise diagnostic tools for psychiatric disorders, and lack of suitable control groups [8], this study was done to answer the questions like whether the pattern of bilirubin change is different in patients with schizophrenia compared to patients with other psychiatric and non-psychiatric disorders.
Material and methods This observational cross-sectional comparative study (30) was conducted at the psychiatry ward of Imam Hossein Hospital, Tehran, Iran (affiliated with Shahid Beheshti University of Medical Sciences) from 2003 to 2007. Patients with acute psychotic symptoms admitted sequentially to the ward, entered the study after they provisionally met DSM-IV criteria for schizophrenia or bipolar disorder I. The exclusion criteria included age under 20, overt cognitive impairment, history of smoking [31,32], substance abuse during the preceding 6 months, recent (2 months) use of psychiatric medications [33] or phenobarbital [34], and a history of other psychiatric comorbidities or neurological insult. This information was ascertained by
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interview. Patient information including age and gender was compiled. Control subjects were recruited from cardiac patients on their first day of admission to coronary care unit (CCU) [25]. Additional exclusion criteria for control subjects included personal or family history of psychosis. These patients were supposed to be under severe stress due to the acute nature of their disease and hospitalization, so were considered as suitable control group in order to estimate the contribution of psychological stress in the elevation of serum bilirubin level in schizophrenic patients. An informed consent form was signed by all the participants. The study was approved by the ethics committee of the Shahid Beheshti University of Medical Sciences. The psychiatric patients were evaluated using Persian translation of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV SCID) [35,36] and entered one of the groups (schizophrenia or bipolar) after the establishment of diagnosis. Blood samples were collected from all the participants both at admission and discharge. Serum levels of total and direct bilirubin were determined using standard dichloroanylin method in which bilirubin looses nitrogen and converts to red azobilirubin detected by spectrophotometry (Parsazmoon bilirubin DCA diagnostic kit, Parsazmoon Co., Tehran, Iran) [37]. To determine total bilirubin level, the bound bilirubin is first detached from albumin by detergents. The analytic method of the process was under monitoring by two high and low levels of control material. The upper limit of normal for total and direct bilirubin levels were 20.4 mmol/l (1.2 mg/l) and 4.25 mmol/l (0.25 mg/dl), respectively. It should be noted that in this study none of the specimens was visibly lipemic or hemolytic. The admission and discharge levels of serum bilirubin were compared within and between the groups. In order to rule out other causes of hyperbilirubinemia, serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase were measured by Hitachi 704 Chemistry Analyzer (Borhringer Mannheim Diagnostic, Mannheim, Germany). The reticulocyte count and prothrombin time of the samples were also assessed. Abnormality in the result of any of these tests led to the exclusion of the patient from the study. Patients with increased total bilirubin level (20.4 mmol/l [ 1.2 mg/dl]) yet normal direct bilirubin at admission were diagnosed as Gilbert’s disease, if the total bilirubin level was back to normal level (20.4 mmol/l [1.2 mg/dl]) at discharge. The severity of positive symptoms and general psychopathology were also measured both at admission and discharge using positive and negative syndrome
subscale (PANSS) in all group S and B participants [38]. PANSS, previously used in a similar study [8], is a suitable tool for the assessment of positive symptoms (delusions, hallucinatory behavior, grandiosity, suspiciousness/persecution, and hostility), negative symptoms (e.g., retarded affection), and general psychopathology (e.g., aggression, uncooperativeness) in psychotic patients. This tool allocates seven items for positive symptoms, seven for negative symptoms, and 16 for general psychopathology. The severity is graded from 1 to 7. In this study the negative symptoms were not assessed because of lack of these symptoms in group B patients. Evaluation by PANSS was done independently by the second author of this article. We used analysis of variances (ANOVA) to compare the mean bilirubin level at admission between the three groups.To compare the rate of bilirubin decrease after treatment in each group we used paired t-test and ANOVA. We used paired t-test to examine whether the bilirubin decrease after treatment in each group was significant. To test the significance of the observed difference among mean PANSS scores of the groups S and B, we used independent samples t-test. Analysis of covariances (ANCOVA) was used to determine the effect of positive and general scores of PANSS on admission bilirubin level. Results Eighteen schizophrenic (10%), 10 bipolar I (6%) and 23 CCU patients (19%) were excluded because of premature discharge from hospital before the final tests could be done. Finally, 162 patients with schizophrenia (group S), 155 patients with bipolar disorder I (group B) and 95 patients with cardiac disease (group C) entered the study. Table I shows some data of the participants. No significant differences in age and sex were found among the 3 groups (Table I). The initial mean total bilirubin level of group S patients was in the normal range but significantly higher than bipolar patients (post hoc Bonferroni, P0.0001). The initial mean bilirubin level was higher in group B than group C (post hoc Bonferroni, P0.02). All schizophrenic patients received antipsychotic medications including halopridol (100 patients), risperidone (53 patients), and clozapine (9 patients). Fifty-seven (38%) of bipolar patients also went under antipsychotic therapy (haloperidol, 42 patients), perphenazine (1 patient), and risperidone (14 patients). The mean bilirubin level was decreased in all three groups at discharge (P0.15) so that the mean bilirubin level at discharge was not significantly different between the three groups (Table I), but the mean rate of decrease during the course of treatment was higher in group S than group B (post hoc Bonferroni, P0.0001)
Bilirubin and schizophrenia Table I. Demographic data in schizophrenic (S), bipolar I (B), and control (C) groups.
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Group B
Group C
34.7 8.7
33.2 9.4
32.4 0.7
100 (61.7) 62 (38.3)
100 (64.5) 55 (35.5)
68 (71.6) 27 (28.4)
0.63 0.3 0.36 0.1
0.49 0.2 0.35 0.1
0.41 0.1 0.37 0.1
0.26 0.3 162
0.14 0.1 155
.7
Mean Bilirubin Level (mg/dL)
Agea (meanSD) Genderb Male (%) Female (%) Bilirubin (mg/dl) Admissionc Discharged Difference between admission and dischargee Total
Group S
.6
.5
.4
0.04 0.1 9
Bilirubin level is significantly decreased at discharge compared to admission in schizophrenics (t11.2, df161, P0.0001), bipolar I patients (t12.8, df154, P0.0001) and CCU patients (t3.5, df94, P0.001). aF2.38, P0.1. bχ22.58, dF2, P0.28. cF34.2, P0.0001. dF1.96, P0.15. eF36.9, P0.0001.
and in group B than group C (post hoc Bonferroni, P0.0001). Figure 1 summarizes these results. Twenty-three of the schizophrenic patients (5.6%), and five of the bipolar patients (1.2%) had Gilbert’s disease. None of the group C patients were diagnosed as Gilbert’s disease. The frequency of Gilbert’s disease was significantly higher in group S than both group C (Fisher’s exact test, P0.0001) and group B (χ211.8, df 1, P0.001). The frequency of Gilbert’s disease was not significaently higher in group B than both group C (Fisher’s exact test, P0.16). The mean scores of the positive symptoms and general psychopathology subscales were not significantly different between groups S and B (t0.89, df 315, P0.37). After treatment, positive symptoms and general psychopathology scores decreased in severity in both groups S and B. We found that bilirubin decrease during treatment in both group S and group B patients was primarily correlated by the improvement of general
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admission discharge
.3 group S
group B
group C
Figure 1. Comparison of serum bilirubin levels at admission and discharge in patients with schizophrenia (group S, n162), bipolar I disorder (group B, n155), and cardiac disease (group C, n95). The mean levels of bilirubin at admission and the mean rate of bilirubin decrease are highest in group S. Mean bilirubin level is significantly decreased at discharge compared to admission in schizophrenics (t11.2, df161, P0.0001), bipolar I patients (t12.8, df154, P0.0001) and CCU patients (t3.5, df94, P0.001).
psychophysiology scores of PANSS (type III sum of squares1.12, F23.8, P0.0001) rather than positive symptom scores (type III sum of squares0.01, F 0.27, P0.6). According to Table II, Gilbert’s disease was associated with higher general psychopathology subscale scores in both groups S and B while the mean score of positive symptoms was not significantly different among Gilbert and non-Gilbert associated patients of both S and B groups.
Discussion Done with a larger sample size compared to others [8,18], this study showed that though the mean bilirubin level of patients with schizophrenia was in the reference interval, it was significantly higher than that of bipolar and non-psychiatric patients. With the
Table II. Comparison of the mean scores of positive symptoms and general psychopathology subscale in schizophrenic and bipolar patients with and without Gilbert’s disease. Schizophrenia
Mean positive symptoms score Mean general psychopathology score aP0.002. bP0.0001. cP0.12. dP0.6.
Bipolar
with Gilbert’s disease
without Gilbert’s disease
t df160
with Gilbert’s disease
without Gilbert’s disease
22.70 26.48
20.91 22.11
1.24a 3.21c
19.6 31.6
20.65 22.91
t df153 5.7b 0.52d
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remission of acute symptoms of psychosis upon applying therapy, bilirubin level decreased and no significant difference in the mean bilirubin level existed between the three groups at discharge. Measuring bilirubin levels serially in an individual, as we did in this study, is informative because bilirubin is one of the analytes that their values from a given individual fluctuate in a narrow range of reference interval so serial changes may be more useful than comparing each of the measurements with the reference interval [39]. Our findings are in contrast with those of Reddy et al. [18] who showed bilirubin level was lower in patients with schizophrenia than normal individuals and its level remained constant during treatment. Their small sample size might explain this contradiction. Also, they compared the bilirubin level of patients with schizophrenia only with normal people and did not address the bilirubin changes in other psychiatric patients. Yamaguchi et al. have shown that the concentration of bilirubin oxidative metabolite is elevated in urine from subjects exposed to psychological stress [25]. Although we did not use any special tool to asses the severity of stress in the subjects of our study groups, it could be inferred from the mean general psychopathology subscale score which is frequently considered as a function of the stress severity [40,41]. We found that the mean general psychopathology subscale score was not significantly different among groups S and B. Therefore stress can not by itself explain the higher bilirubin level in group S and further studies are required to determine other causes such as possible common genes involved in pathogenesis of both schizophrenia and hyperbilirubinemia. We found that the frequency of Gilbert’s disease was higher in patients with schizophrenia. Some authors argue that Gilbert’s disease is being overdiagnosed, since it is frequently diagnosed in young adults in whom normal bilirubin ranges are higher – reaching their highest levels in adolescence and young adulthood [42,43]. This concern was not addressed in the study of Miyaoka et al. [8] in which the mean age of the patients with schizophrenia was significantly different from that of affective patients. In our study no significant difference existed between the mean ages of the groups. We also showed that serum bilirubin alteration during the course of disease was affected by the severity of the psychiatric disorder just as Miyaoka et al. had shown [8]. Although our findings showed that the rise and decrease of bilirubin level paralleled the exacerbation and remission of psychotic symptoms, establishing a causal relationship needs further studies.
Finally, we suggest that clinicians should be aware of bilirubin level alteration in the course of psychotic disorders especially schizophrenia in order not to subject these patients to unnecessary clinical or laboratory investigations or improper withholding of psychiatric medication while this biochemical change reverses back to normal as the disease is controlled and symptoms are suppressed.
Key points • There have been many reports of association between schizophrenia and alteration of serum bilirubin level • We showed that the mean serum bilirubin level is higher in psychotic attacks of schizophrenia compared to bipolar and non-psychiatric diseases and this alteration parallels with exacerbation and remission of the symptoms • Our study suggests that the pathophysiological pathways leading to schizophrenia may have some common routes with bilirubin metabolism but a causal relationship is not established and needs further research
Acknowledgements We wish to acknowledge Dr Foroozan Karimi for her valuable help in manuscript preparation. Statement of interest The authors have no conflict of interests to disclose. References [1] Cullberg DC. Neonatal hyperbilirubinaemia-a vulnerablity factor for mental disorder? Acta Psychiatr Scand 1999;100: 469–71. [2] Falcão A, Silva R, Pancadas S, Fernandes A, Brito M, Brites D. Apoptosis and impairment of neurite network by short exposure of immature rat cortical neurons to unconjugated bilirubin increase with cell differentiation and are additionally enhanced by an inflammatory stimulus. J Neurosci Res 2007;85(6):1229–39. [3] Freund N. A psychiatric patient with elevated liver values. Psychiatrischer patient mit leberwerterhohung. Praxis 2006;95 (14):549–50. [4] Mahdi AS, Elameer MS. Co-occurrence of Gilbert’s syndrome and psychosis. Psychiatr Bull 1998;22(9):566–8. [5] Miyaoka T, Seno H, Maeda T, Itoga M, Horiguchi J. Schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert’s syndrome): 3 Case reports. J Clin Psychiatry 2000;61(4):299–300. [6] Powell AJ, Hansen LK. Gilbert’s syndrome in a patient with predominantly negative symptoms of schizophrenia. Int J Psychiatry Clin Pract 2007;11(3):239–41. [7] Ramos RM, Curto SV, Ramos JMM. Gilbert’s syndrome and schizophrenia. Actas Esp Psiquiatr 2006;34(3):206–8.
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