DEPRESSION IS THE most common and serious. Association between high serum total bilirubin and post-stroke depression.

Transcription

1 Psychiatry and Clinical Neurosciences 2013; 67: doi: /pcn Regular Article Association between high serum total bilirubin and post-stroke depression Wai Kwong Tang, MD, 1 * Huajun Liang, MPhil, 1 Winnie Chiu Wing Chu, MD, 2 Vincent Mok, MD, 3 Gabor S. Ungvari, MD, PhD 4,5 and Ka Sing Wong, MD 3 Departments of 1 Psychiatry, 2 Diagnostic Radiology and Organ Imaging and 3 Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, 4 School of Psychiatry and Clinical Neurosciences, University of Western Australia and 5 University Notre Dame Australia/Marian Centre, Perth, Australia Aim: High serum bilirubin predicts depression in non-stroke subjects, but it is unknown whether it also predicts post-stroke depression (PSD). This study examined the association between the risk of PSD and bilirubin level. Methods: Six hundred and thirty-five patients with acute ischemic stroke in Hong Kong were recruited. Serum total bilirubin, alanine transaminase and alkaline phosphatase levels were measured in all patients during their hospital stay. A psychiatrist gave the Structured Clinical Interview for DSM-IV to all patients 3 months after the index stroke, with 61 patients diagnosed with PSD: 27 with major depression, 24 with minor depression and 10 with dysthymia. Results: In the full sample, the 25%, 50% and 75% percentile bilirubin levels were 7.0, 10.0 and 14.0 mmol/l, respectively. Significant differences were found between the PSD and non-psd groups in terms of bilirubin level (P = 0.006). In post-hoc comparisons, the proportion of patients with bilirubin 14.1 mmol/l was significantly higher in the PSD group (37.7% vs 19.7%, P = 0.001). In the final regression model, bilirubin level ( 14.1 mmol/l) remained a significant independent predictor of PSD, with an odds ratio of 2.4. Conclusions: High bilirubin level is associated with PSD. Further investigations are needed to clarify the underlying pathophysiological link between bilirubin level and PSD. Key words: acute ischemic stroke, bilirubin, depression, magnetic resonance imaging, stroke DEPRESSION IS THE most common and serious affective disorder following stroke, 1,2 occurring in approximately 33% of stroke patients. 3 Post-stroke depression (PSD) has been associated with both poor functional outcome 4 and higher mortality. 5 The pathogenesis of PSD remains unclear. In non-stroke subjects, depression is associated with an increase in the serum levels of some inflammatory cytokines, such as interleukins (IL) 6 and C-reactive *Correspondence: Wai Kwong Tang, MD, Department of Psychiatry, Shatin Hospital, 33 A Kung Kok Street, Ma On Shan, Shatin, NT, Hong Kong. tangwk@cuhk.edu.hk Received 29 August 2012; revised 3 December 2012; accepted 9 January protein (CRP). 7 Other molecular markers, including brain-derived neurotrophic factor (BDNF) and leptin, have been associated with the development of depression in clinical and experimental studies. 8,9 Previous studies have examined the common biomarkers of depression in stroke, including inflammatory molecular markers (IL-1b, IL-6, IL-18, intracellular adhesion molecule 1, tumor necrosis factor-a, leptin and high-sensitivity CRP), neurotrophic factors (BDNF) and vitamin B-related metabolites (homocysteine). The results were negative except for IL-18, leptin and homocysteine Bilirubin, an efficient antioxidant, is the end product of the heme cleavage pathway, which is catalyzed by heme oxygenase and biliverdin reductase

2 260 W. K. Tang et al. Psychiatry and Clinical Neurosciences 2013; 67: Bilirubin level may be related to the risk and outcome of stroke. Serum bilirubin is reported to be negatively correlated with carotid atherosclerosis, 14 whereas a high bilirubin level has been associated with stroke severity 15 and poor prognosis for ischemic stroke. 16 The role of serum bilirubin level in depression in non-stroke subjects has been explored, with low nocturnal bilirubin level found to be associated with winter seasonal depression. 17 Increased concentration of bilirubin oxidative metabolites (biopyrrins) was found in the urine of patients with psychiatric disorders, and biopyrrin level was found to be correlated with Hamilton Depression Rating Scale score. 18 To date, however, no study has examined the relationship between serum bilirubin level and PSD. The lack of data in this field provided the impetus for the study reported herein. METHODS Subjects Patients with first-ever or recurrent acute ischemic stroke admitted to the Acute Stroke Unit of the Prince of Wales Hospital between June 2004 and November 2008 were screened for study entry. The Prince of Wales Hospital is a university-affiliated general hospital serving a population of in Hong Kong. The study s inclusion criteria were: (i) Chinese ethnicity; (ii) Cantonese as the primary language; (iii) age 18 years; (iv) well-documented (clinical presentation and computed tomography of the brain) first or recurrent acute stroke occurring within the 7 days before admission; (v) magnetic resonance imaging (MRI); (vi) Mini-Mental State Examination (MMSE) score 20; 19 and (vii) the ability and willingness to give informed consent. The exclusion criteria included: (i) transient ischemic attack; (ii) history of any central nervous system disease such as dementia, tumor, trauma or hydrocephalus; (iii) history of depression or other psychiatric disorders before the index stroke; (iv) severe aphasia (best language score on the National Institute of Health Stroke Scale [NIHSS] on admission 2), severe visual or auditory impairment; (v) history of liver disease or physically unfit for interview; and (vi) recurrent stroke before 3-month interview. The study protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. All participants signed a consent form. Collection of demographic, clinical and radiological data A trained research nurse, who was blind to the psychiatrist s diagnoses, collected the demographic data (age and sex) and assessed stroke severity using the NIHSS 20 within 2 days of admission. A research assistant evaluated all subjects with the MMSE, Lubben Social Network Scale (LSNS), 21 Modified Life Event Scale (MLES) 22 and Barthel index (BI) 23 3 months after the onset of the index stroke. Cronbach s a for the NIHSS, MMSE and BI were 0.92, 0.86 and 0.93, respectively. 19,24,25 The LSNS is a composite social network scale that was designed for use in the elderly. It measures the level of social support that patients receive and their social interactions with relatives and friends. The LSNS has been translated into Chinese and validated in the Hong Kong elderly, with a Cronbach s a of The MLES records the presence of 18 adverse and distressing life events in the past 6 months. The score indicates the total number of adverse events encountered by subjects. Data on statin treatment and living environment were also recorded. MRI with diffusion-weighted imaging (DWI) and conventional sequences, including a gradient echo (blood product-sensitive) sequence, was performed on each participant with a 1.5-T system (Sonata, Siemens Medical, Erlangen, Germany) within 7 days of admission. The locations and volumes of acute brain infarcts were recorded. Their total area on DWI was measured using manual outlines with restricted water diffusion identified on DWI with b values of The total volume was calculated by multiplying the total area by the sum of the slice thickness and the gap. Assessment of PSD Three months after the onset of the index stroke, two psychiatrists who were blind to the subjects laboratory results gave them the Chinese version of the Structured Clinical Interview for DSM-IV (SCID- DSM-IV). 27,28 Inter-rater reliability was examined in 25 patients and the kappa was The timing of the assessment was chosen to avoid the period of transient emotional adjustment to the disability caused by the stroke. 29 Laboratory test Blood samples were obtained within 24 h of the subjects index admission. Serum total bilirubin was

3 Psychiatry and Clinical Neurosciences 2013; 67: High serum total bilirubin and PSD 261 determined with the diazotization method using DP Modular Analytics (Roche Diagnostics, Indianapolis, IN, USA). Alanine transaminase and alkaline phosphatase were recorded in IU/L and bilirubin was recorded in mg/dl and divided into four quartiles ( 8.0 mmol/l, mmol/l, mmol/l and 14.1 mmol/l), as the raw bilirubin data were skewed. The number of patients in each quartile was recorded; because of ties, the number of patients in each quartile was not even. Statistical methods The distribution of the data was examined using the Kolgomorov Smirnov test. The demographic and clinical variables (age, sex, previous stroke, and NIHSS, MMSE, LSNS and MLES scores) and bilirubin level quartiles of patients with (PSD group) and without PSD (non-psd group) were compared using the c 2 test, t-test and Mann Whitney U test, as appropriate. Risk factors with P < 0.10 were then analyzed via multivariate logistic regression. In this analysis, the odds ratio of quartiles of bilirubin levels 15 and other independent risk factors was interpreted as the risk of subsequent PSD when all other risk factors were held constant. All statistical tests were performed using SPSS for Windows (Release 14.0; SPSS, Chicago, IL, USA). The level of significance was set at RESULTS A total of 3976 consecutively admitted patients with ischemic stroke were screened, and 635 met the entry criteria (Fig. 1). Patients excluded from the study had a higher mean ( SD) age ( years vs years; t = 4.314, d.f. = 1418, P < 0.001), were more likely to be female (47.6% vs 37.5%; P < 0.001) and had a higher NIHSS mean score ( vs ; t = 8.314, d.f. = 1419, P <0.001). Of the 635 patients who formed the study sample, 61 (32 men, 29 women) were diagnosed with PSD: 27 with major depression, 24 with minor depression and 10 with dysthymia. None of them received antidepressant treatment. Patient demographic and stroke-related data stratified by PSD status are listed in Table 1. The PSD and non-psd groups did not differ in terms of age or previous stroke, but the PSD group had a lower level of social support, poorer cognitive function, more adverse life events, more Assessed at 3-month post-stroke follow up (n = 790, 19.9%) Final sample (n = 635, 16.0%) With MRI (n = 1470, 37.0%) Acute stroke admissions (n = 3976) With history of depression, or other psychiatric disorders (n = 89, 2.2%) Not assessed at 3- month post-stroke follow up (n = 680, 17.1%) Without MRI (n = 2506, 63.0%) MMSE < 20 (n = 54, 1.4%) Liver diseases (n = 12, 0.3%) Figure 1. Study recruitment profile. Not assessed at 3-month post-stroke follow up (n = 680, 17.1%): loss to follow up (n = 203, 5.1%), refused participation (n = 142, 3.6%), physical frailty (n = 78, 2.0%), history of central nervous system diseases (n = 61, 1.5%), aphasia (n = 41, 1.0%), history of dementia (n = 40, 1.0%), recurrent stroke (n = 36, 0.9%), severe auditory or visual impairment (n = 27, 0.7%), deceased (n = 24, 0.6%), non-chinese ethnicity or non-cantonese speaking (n = 22, 0.6%), transient ischemic attack (n = 6, 0.2%).. MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging. severe stroke and lower level of functioning. The PSD group also had more female subjects. A significant difference in bilirubin level was found between the two groups (P = 0.006). In post-hoc comparisons, the proportion of patients in the highest quartile ( 14.1 mmol/l) was significantly higher in the PSD group (37.7% vs 19.7%, c 2 = , d.f. = 1, P = 0.001; Table 1). The following variables were entered into the regression model: bilirubin level, female sex, and LSNS, MLES, MMSE, NIHSS and BI scores. Bilirubin level ( 14.1 mmol/l) remained a significant independent predictor of PSD, with an odds ratio of 2.4 (Table 2). DISCUSSION To the best of our knowledge, this is the first paper to report an association between bilirubin level and PSD. The results suggest that the bilirubin level is an important biological marker for the risk of depression in patients with ischemic stroke. Bilirubin, a powerful antioxidant, increases after hemorrhagic stroke. 30 Higher bilirubin level was associated with more severe stroke on univariate analysis,

4 262 W. K. Tang et al. Psychiatry and Clinical Neurosciences 2013; 67: Table 1. Subject characteristics vs PSD status Variables Yes (n = 61) mean SD or n (%) PSD No (n = 574) mean SD or n (%) Statistics Age (years) t = Female sex 29 (47.5) 209 (36.4) c 2 = Institutionalized 3 (4.9) 18 (3.1) 0.44 Hypertension 40 (65.6) 405 (70.8) c 2 = Diabetes mellitus 21 (34.4) 186 (32.5) c 2 = Hyperlipidemia 35 (57.4) 359 (62.7) c 2 = Ischemic heart disease 4 (6.6) 41 (7.2) 0.86 Previous stroke 13 (21.3) 114 (19.9) c 2 = On statins 6 (9.8) 68 (11.8) c 2 = MMSE score t = NIHSS total score t = BI score t = LSNS score t = <0.001 MLES score t = Volume of acute infarcts (ml) z = Location of acute infarcts Frontal lobe 6 (9.8) 42 (7.3) 0.44 Parietal lobe 1 (1.3) 41 (7.1) 0.17 Temporal lobe 1 (1.3) 23 (4.0) 0.72 Occipital lobe 3 (4.9) 10 (1.7) 0.12 Subcortical white matter 14 (23.0) 166 (28.9) c 2 = Basal ganglia 8 (13.1) 55 (9.6) c 2 = Infratentorial 11 (18.0) 106 (18.5) c 2 = ALT (IU/L) t = ALP (IU/L) t = Bilirubin c 2 = Quartile 1 12 (19.7) 152 (26.5) c 2 = Quartile 2 18 (29.5) 166 (28.9) c 2 = Quartile 3 8 (13.1) 143 (24.9) c 2 = Quartile 4 23 (37.7) 113 (19.7) c 2 = t-test.; c 2 test; Fisher s exact test; Mann Whitney U-test. Post-hoc comparison; level of significance adjusted to (c 2, d.f.). ALP, alkaline phosphatase; ALT, alanine transaminase; BI, Barthel index; LSNS, Lubben Social Network Scale; MLES, Modified Life Events Scale; MMSE, Mini-Mental State Examination; NIHSS, National Institute of Health Stroke Scale; PSD, post-stroke depression. P possibly reflecting the intensity of initial oxidative stress, even though the level of bilirubin may not be an independent prognostic factor. 15 Severe stroke is also a known risk factor for PSD. 31 Hence, stroke severity could be a partial explanation for the link between bilirubin level and PSD. In this study, however, the association between bilirubin level and PSD was independent of stroke severity. Accordingly, there should be other explanations for the association. High levels of psychological stress have been reported in stroke survivors. 32 Acute psychological stress increases bilirubin metabolites in human urine, 33 the level of which is correlated with the level of perceived stress. Bilirubin metabolites can be useful markers of stress. 33 Although the level of bilirubin was not reported in the aforementioned study, it is possible that an acute stroke, which is a lifethreatening condition, acts as a major psychological stressor, which in turn increases the level of bilirubin

5 Psychiatry and Clinical Neurosciences 2013; 67: High serum total bilirubin and PSD 263 Table 2. Multivariate logistic model of the clinical determinants of PSD Variable Odds ratio (95%CI) P Bilirubin (quartile 4) ( ) MLES score ( ) <0.001 LSNS score ( ) <0.002 Female sex 0.06 NIHSS score 0.12 MMSE score 0.29 BI score 0.58 R square 0.15 Logistic regression. BI, Barthel index; CI, confidence interval; LSNS, Lubben Social Network Scale; MLES, Modified Life Events Scale; MMSE, Mini-Mental State Examination; NIHSS, National Institute of Health Stroke Scale; PSD, post-stroke depression. excluded. It should also be emphasized that the observed association should not be treated as a measure of depression to inform clinical practice. A further limitation was that MRI was not performed on the same day after the onset of the stroke. The literature suggests that serum bilirubin decreases during the acute phase of ischemic stroke, 16 which may have affected the present results. Finally, all subjects were of Chinese ethnicity. These selection biases limit the generalizability of the findings. Conclusion High bilirubin level is associated with the risk of PSD. Further investigations are needed to clarify the underlying pathophysiological link between bilirubin level and PSD. production. A higher level of bilirubin, like a higher level of cortisol, 34 may indicate a higher level of perceived stress, which increases the risk of depression. 35 Future studies should measure the level of perceived stress in acute stroke to test this hypothesis. In this study, the volume and location of acute infarcts were not associated with PSD. Despite numerous attempts to establish a relationship between localization of stroke and PSD, this issue remains contentious, 36 possibly due to differences in study design, measurement of depression and neuroimaging methods. 37 Doubts have been raised about the classical single-stroke-based neuroanatomical model of PSD, suggesting that the vascular burden due to the chronic accumulation of small macro- and microvascular lesions may be the crucial determinant of PSD. 38 The main limitation of this study was the fairly low recruitment rate and frequency of PSD, which resulted in a relatively small number of affected patients and, in turn, reduced the statistical power of the study. The low PSD frequency may be because subjects with a history of depression were excluded and the severity of stroke in the sample was mild. Another limitation was that PSD assessment was made only once, at the 3-month follow up, whereas the NIHSS was used only at the acute stage. Patients who had more severe stroke died before the 3-month follow up or became depressed later were not included. Those who were unable to give informed consent due to dementia or aphasia were also ACKNOWLEDGMENT There is no conflict of interest. REFERENCES 1. Gordon WA, Hibbard MR. Poststroke depression: An examination of the literature. Arch. Phys. Med. Rehabil. 1997; 78: White CL, McClure LA, Wallace PM et al. The correlates and course of depression in patients with lacunar stroke: Results from the Secondary Prevention of Small Subcortical Strokes (SPS3) study. Cerebrovasc. Dis. 2011; 32: Hackett ML, Yapa C, Parag V, Anderson CS. Frequency of depression after stroke: A systematic review of observational studies. Stroke 2005; 36: Pohjasvaara T, Vataja R, Leppävuori A, Kaste M, Erkinjuntti T. Depression is an independent predictor of poor long-term functional outcome post-stroke. Eur. J. Neurol. 2001; 8: Linden T, Blomstrand C, Skoog I. Depressive disorders after 20 months in elderly stroke patients: A case-control study. Stroke 2007; 38: Tiemeier H, Hofman A, van Tuijl HR, Kiliaan AJ, Meijer J, Breteler MM. Inflammatory proteins and depression in the elderly. Epidemiology 2003; 14: Panagiotakos DB, Pitsavos C, Chrysohoou C et al. ATTICA study. Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study. Eur. Heart J. 2004; 25: Sairanen M, Lucas G, Ernfors P, Castrén M, Castrén E. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal

6 264 W. K. Tang et al. Psychiatry and Clinical Neurosciences 2013; 67: turnover, proliferation, and survival in the adult dentate gyrus. J. Neurosci. 2005; 25: Lu XY, Kim CS, Frazer A, Zhang W. Leptin: A potential novel antidepressant. Proc. Natl Acad. Sci. USA 2006; 103: Jiménez I, Sobrino T, Rodríguez-Yáñez M et al. High serum levels of leptin are associated with post-stroke depression. Psychol. Med. 2009; 39: Yang L, Zhang Z, Sun D, Xu Z, Zhang X, Li L. The serum interleukin-18 is a potential marker for development of post-stroke depression. Neurol. Res. 2010; 32: Pascoe MC, Crewther SG, Carey LM, Noonan K, Crewther DP, Linden T. Homocysteine as a potential biochemical marker for depression in elderly stroke survivors. Food Nutr. Res 2012; 11: Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235: Yang XF, Chen YZ, Su JL, Wang FY, Wang LX. Relationship between serum bilirubin and carotid atherosclerosis in hypertensive patients. Intern. Med. 2009; 48: Pineda S, Bang OY, Saver JL et al. Association of serum bilirubin with ischemic stroke outcomes. J. Stroke Cerebrovasc. Dis. 2008; 17: Kurzepa J, Bielewicz J, Stelmasiak Z, Bartosik-Psujek H. Serum bilirubin and uric acid levels as the bad prognostic factors in the ischemic stroke. Int. J. Neurosci. 2009; 119: Oren DA, Desan PH, Boutros N, Anand A, Charney DS. Effects of light on low nocturnal bilirubin in winter depression: A preliminary report. Biol. Psychiatry 2002; 51: Miyaoka T, Yasukawa R, Yasuda H et al. Urinary excretion of biopyrrins, oxidative metabolites of bilirubin, increases in patients with psychiatric disorders. Eur. Neuropsychopharmacol. 2005; 15: Chiu HFK, Lee HC, Chung WS, Kwong PK. Reliability and validity of the Cantonese version of the mini-mental state examination: A preliminary study. Hong Kong J. Psychiatry 1994; 4: Brott T, Adams HP Jr, Olinger CP et al. Measurements of acute cerebral infarction: A clinical examination scale. Stroke 1989; 20: Lubben J. Assessing social network among elderly populations. Fam. Community Health 1998; 11: Paykel ES, Prusoff BA, Uhlenhuth EH. Scaling of life events. Arch. Gen. Psychiatry 1971; 25: Mahoney FI, Barthel DW. Functional evaluation: The Barthel Index. Md State Med. J. 1965; 14: Sun TK, Chiu SC, Yeh SH, Chang KC. Assessing reliability and validity of the Chinese version of the stroke scale: Scale development. Int. J. Nurs. Stud. 2006; 43: Leung SO, Chan CC, Shah S. Development of a Chinese version of the Modified Barthel Index: Validity and reliability. Clin. Rehabil. 2007; 21: Chi I, Boey KW. A Mental Health and Social Support Study of the Old-Old in Hong Kong Department of Social Work and Social Administration. Resource Paper Series, University of Hong Kong, Hong Kong, American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association, Washington, DC, Kam IWK. Development of the bilingual (Chinese/ English) SCID-I (Structured Clinical Interview for DSM-IV Axis I disorder): A study of its reliability and validity in an in-patient population. Dissertation for Part III Examination of Fellowship. Hong Kong College of Psychiatrists, Hong Kong, Tang WK, Chan SS, Chiu HF et al. Poststroke depression in Chinese patients: Frequency, psychosocial, clinical, and radiological determinants. J. Geriatr. Psychiatry Neurol. 2005; 18: Dohi K, Mochizuki Y, Satoh K et al. Transient elevation of serum bilirubin (a heme oxygenase-1 metabolite) level in hemorrhagic stroke: Bilirubin is a marker of oxidant stress. Acta Neurochir. Suppl. 2003; 86: Robinson RG, Spalletta G. Poststroke depression: A review. Can. J. Psychiatry 2010; 55: Ostwald SK, Bernal MP, Cron SG, Godwin KM. Stress experienced by stroke survivors and spousal caregivers during the first year after discharge from inpatient rehabilitation. Top. Stroke Rehabil. 2009; 16: Yamaguchi T, Shioji I, Sugimoto A, Yamaoka M. Psychological stress increases bilirubin metabolites in human urine. Biochem. Biophys. Res. Commun. 2002; 293: Schlotz W, Hammerfald K, Ehlert U, Gaab J. Individual differences in the cortisol response to stress in young healthy men: Testing the roles of perceived stress reactivity and threat appraisal using multiphase latent growth curve modeling. Biol. Psychol. 2011; 87: Kuiper NA, Olinger LJ, Lyons LM. Global perceived stress level as a moderator of the relationship between negative life events and depression. J. Hum. Stress 1986; 12: Carson AJ, MacHale S, Allen K et al. Depression after stroke and lesion location: A systematic review. Lancet 2000; 8: Bhogal SK, Teasell R, Foley N, Speechley M. Lesion location and poststroke depression: Systematic review of the methodological limitations in the literature. Stroke 2004; 35: Santos M, Kövari E, Gold G et al. The neuroanatomical model of post-stroke depression: Towards a change of focus? J. Neurol. Sci. 2009; 283: