CLINICAL FEATURES Circadian Phenotype in Patients with the Co-Morbid Alcohol Use and Bipolar Disorders

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1 Alcohol & Alcoholism Vol. 43, No. 5, pp , 2008 Advance Access publication 20 July 2008 doi: /alcalc/agn057 CLINICAL FEATURES Circadian Phenotype in Patients with the Co-Morbid Alcohol Use and Bipolar Disorders Taina Hätönen 1,2,3, Sebastian Forsblom 1,, Tuula Kieseppä 1,3, Jouko Lönnqvist 1,3 and Timo Partonen 1, 1 Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland, 2 Finnish Student Health Service, Helsinki, Finland and 3 Department of Psychiatry, University of Helsinki, Helsinki, Finland Corresponding author: Department of Mental Health and Alcohol Research, National Public Health Institute, Mannerheimintie 166, FI Helsinki, Finland Tel: ; Fax: ; timo.partonen@ktl.fi (Received 24 November 2006; first review notified 26 February 2007; in revised form 17 March 2008; accepted 19 June 2008; advance access publication 20 July 2008) Abstract Aims: Alcohol misuse is associated with bipolar. Abnormalities in the circadian clockwork play a role in the pathogenesis of bipolar. Alcohol intake is likely to affect the circadian phenotype. We aimed at analysing the behavioural trait of the preference to morning or evening hours for the daily activities in bipolar patients with or without the co-morbid alcohol use. Methods: Our nationwide sample of families included patients with bipolar born during having at least one hospitalization due to bipolar during and their first-degree relatives. All the 148 participants were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders and assessed using the Morningness Eveningness Questionnaire whose factor matrix applying for the maximum likelihood principle was calculated for the first time. Results: Patients with the co-morbid alcohol use were more of the morning type as compared with patients with bipolar only. Conclusions: Co-morbid patients preferred more the morning hours for their daily activities, indicative of alcohol consumption having an effect on the circadian clock. INTRODUCTION Abnormalities in circadian rhythms may constitute a key component in the pathogenesis of bipolar in particular, or affective s in general (Bunney and Bunney, 2000; Mansour et al., 2005a). Individuals place themselves on a continuum from morningness to eveningness (early birds to night owls) as a function of time of the day they routinely feel the best and refer to the preferred time of day for their daily activities (Kerkhof, 1985; Taillard et al., 1999; 2004). Evening types are predisposed to anxiety (Broman and Hetta, 1998), depression (Drennan et al., 1991; Broman and Hetta, 1998; Chelminski et al., 1999; Taillard et al., 2001; Murray et al., 2003) and initial insomnia (Broman and Hetta, 1998), whereas morning types spend time awake longer and have a lowered quality of sleep (Carrier et al., 1997; Taillard et al., 1999). Data are conflicting though (Gale and Martyn, 1998). The behavioural trait of morningness to eveningness seems to reflect the phase position of the circadian rhythms and correlate with the circadian period (Kerkhof and Van Dongen, 1996; Duffy et al., 2001). There is a difference in the phase positions of core temperature rhythm and sleep between the morning and evening types (Estroff et al., 1985; Kerkhof and Van Dongen, 1996; Duffy et al., 1999). This explains why manic episodes of bipolar may be triggered by disruption in the sleep wake cycle (Wehr et al., 1987), whereas sleep deprivation tends to alleviate depression in patients with bipolar (Colombo et al., 2000). Lithium is commonly used to treat bipolar. In experiments with cultured cells, GSK3-beta phosphorylates and stabilizes the orphan nuclear receptor NR1D1, a negative component of the circadian pacemaker. Treatment of cells with lithium inhibits glycogen synthase kinase 3-beta, leading to degradation of NR1D1 and activation of the Arntl gene, a These authors contributed equally to this work. positive component of the circadian pacemaker (Yin et al., 2006). Lithium acts directly on the circadian pacemaker cells and lengthens the period of circadian rhythms (Reghunandanan et al., 1989; Khalsa et al., 1993; Abe et al., 2000; Padiath et al., 2004). Since data on the circadian phenotype of patients with bipolar are still scarce, we aimed at analysing the preference to the morning or evening hours in individuals with or without the co-morbid alcohol use to provide information about their circadian-type preference. METHODS Subjects The search for participants began with the nationwide Hospital Discharge Register of Finland, which was used to identify all patients who were hospitalized due to bipolar (probands) in inclusive (ICD-8 codes or before the year 1987, or DSM-III-R codes 296.4, or during ). Data on relatives were gathered from the nationwide Population Register and linked back to the records of the hospital discharge register in order to track the first-degree relatives of those born in inclusive and to construct pedigrees. All available medical records of the whole family (siblings and parents) were collected. On the basis of these records and blinded to each other, specialists in psychiatry assessed the primary diagnosis plus co-morbid conditions according to the DSM-IV criteria. Diagnoses were discussed for consensus, and no disagreement remained after this procedure. Probands were contacted through their physician in charge, and if the proband gave permission other family members were contacted. All those who gave their informed consent were interviewed using the SCID-I (Structured Clinical Interview for DSM-IV Axis I Disorders). Finally, the study sample included 148 individuals, of whom 47 (11 with and 36 without the co-morbid alcohol use ) had bipolar C The Author Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved

2 Circadian Phenotype in Bipolar Disorder 565, 26 had alcohol use, 30 had mental exclusive of bipolar or alcohol use s and 56 had no diagnosis. Self-report The Morningness Eveningness Questionnaire (MEQ) includes 19 items estimating the preference for the timing of different activities and behaviours (Horne and Östberg, 1976). The sum of these 19 items yields the Morningness Eveningness Score (MES), ranging from 16 to 86. Considering the daily activities (behavioural traits), the highest scores indicate a definite preference to the morning hours (morningness) and the lowest a definite preference to the evening hours (eveningness). Ethics The Ministry of Social Affairs and Health and the Ethics Committee of the National Public Health Institute approved the study. After complete description of the study to all subjects, they signed the written informed consent for participation. Statistics Concerning the MEQ, the sum score may override components of the morning- and evening-based traits being distinct from one another. In order to analyse, whether any component of significance was to contribute to the MES, a factor matrix according the maximum likelihood principle and employing the algorithm by Jöreskog (1977) was produced for analysis of the MEQ. In order to observe, whether there were any association between the circadian preference and affection status, partial correlation coefficients were calculated and controlled for age (in years), sex (male or female), education (in years), psychotropic medication (yes or no), smoking (yes or no) and body mass index in each analysis. In order to judge, whether the affection status was an independent predictor of the circadian preference, the MES or the score on a factor of the MEQ was the dependent variable in the linear regression models. Age (in years), sex (male or female), education (in years), psychotropic medication (yes or no), smoking (yes or no), body mass index and affection status (bipolar with or without co-morbid alcohol use ) were the covariates in each model. Post hoc comparisons were calculated in order to find out between-group differences (bipolar with or without co-morbid alcohol use designated as Groups 1 and 2, respectively). Statistical analyses were performed using the SSPS 13.0 and Survo MM software. RESULTS Factor analysis The factor analysis yielded four factors (see Table 1). The reliability for the unweighted sum of all items, considering the factor images and scores, was good (Cronbach s alpha = 0.82). The factor F1 contains six items (general preferences), F2 eight items (morning activities), F3 four items (evening activities) and F4 one item (times for physical work). In subsequent linear regression models, separate for each factor, the R 2 values explaining the variance of the MES were 0.713, 0.557, and for the first to the fourth factor, respectively. Table 1. Factors and loadings on each item of the Morningness Eveningness Questionnaire Factors MEQ item Factor 1 Factor 2 Factor 3 Factor 4 Sum R 2 Item Item Item Item Item Item Item Item Item Item Item Item Item Item Item Item Item Item Item Sum R MEQ = Morningness Eveningness Questionnaire. Table 2. Correlation of affection status with the circadian phenotype a Bipolar Diagnosis Alcohol use Co-morbid r P r P r P MES Factor Factor Factor Factor a Controlled for age, sex, education, psychotropic medication, smoking and body mass index. MES = Morningness Eveningness Score. In the linear regression model for those six items that loaded most on the factors (items 15, 9, 7, 4, 12 and 17), the corresponding R 2 value was In the linear regression model for those six items that correlated most to the MES (items 9, 17, 19, 15, 7 and 4), the corresponding R 2 value was The linear regression model that explained best the most of the variance in the MES included 12 of the 19 items, with the R 2 value of 0.933, excluding 7 items (items 1, 3, 6, 10, 14, 16 and 18). Correlation coefficients Since four factors emerged from the factor analysis, correlation coefficients were calculated for the MES and each factor, and for the affection status of interest (bipolar or alcohol use, or both as co-morbid). Whereas bipolar or alcohol use did not correlate significantly with the circadian phenotype, the co-morbid was associated with the factor F2 (r = 0.52, P = 0.04; see Table 2).

3 566 Hätönen et al. Table 3. Background, circadian preference and levels of functioning in bipolar with (Group 1) or without (Group 2) the co-morbid alcohol use Group1(n = 11) Group 2 (n = 36) Mean 95% CI SD Mean 95% CI SD Age Education BMI MES Factor Factor Factor Factor GAF GAF CI = confidence interval; SD = standard deviation; BMI = body mass index; MES = Morningness Eveningness Score; GAF1 = global assessment of functioning, current; GAF2 = global assessment of functioning, highest past year. Table 4. Regression analysis of the circadian phenotype a Beta b t P Age Sex Education Psychotropic medication Smoking Body mass index Co-morbid a Adjusted R 2 = 0.09 for the model of Factor 2 as the dependent variable. b Standardized coefficients. Regression models Regression analysis of 47 bipolar patients as described in detail in Table 3 was carried out. Since four factors emerged from the factor analysis, five regression models (one for the MES and one for each factor) were formulated. Whereas the co-morbid alcohol use was not a significant explanatory factor for the MES or the factors F1, F3 or F4 (data not shown), it did have an independent effect on the factor F2 (t = 2.26, P = 0.04; see Table 4). Group comparisons First, our primary focus was on bipolar with (Group 1) or without (Group 2) the co-morbid alcohol use. There were no significant differences between the two groups, except that the proportions of men and smokers were greater in Group 1 than in Group 2 (Fisher s exact test: P = 0.02 and P = 0.003, respectively). Second, we analysed whether there was any difference between bipolar patients (with or without alcohol use ) and the remaining. Bipolar patients did not differ significantly from the remaining patients in the families, except that the proportion of those having psychotropic medication was greater in bipolar patients (Fisher s exact test: P = 0.03). Bipolar patients did not differ significantly from individuals having no diagnosis, except that bipolar patients scored lower on the factor F1 and higher on the factor F4 (z = 2.33, P = 0.02 and z = 2.98, P = 0.003, respectively), indicative of more preference to the evening (six items) and morning (one item) hours, respectively, and that the proportion of smokers was greater in bipolar patients (Fisher s exact test: P = 0.001). DISCUSSION For our work we carried out a retrospective lifetime diagnostic assessment together with a self-report of behavioural trait. Both correlation computations and regression models indicated that patients having the co-morbid bipolar and alcohol use s displayed the circadian preference in direction to the morning hours. Post hoc comparisons indicated further that scores on two factors were on average antithetical (positive versus negative) in Group 1 and Group 2, respectively, suggesting traits towards the preference to the morning hours among those with comorbid alcohol use. In addition, comparing bipolar patients with the subjects of no diagnosis yielded a difference in two factors, suggesting more the preference of evening hours (six items) instead of morning hours (one item) in bipolar patients. Our findings agree with a study in which the circadian-type preference for evening activities has been shown in bipolar type 1 (Mansour et al., 2005b). On the other hand, they are in contrast to the results from our previous study in which seasonal variations were associated with bipolar whereas the circadian-type preference was not (Hakkarainen et al., 2003). However, the samples of participants were different between the present and earlier studies (bipolar families and bipolar twins, respectively), which probably explain this conflict. Our key finding herein is that the co-morbid alcohol use makes a difference in the circadian preference. For explanation, there are at least two possibilities. First, the circadian preferences have been different before the onset of illness, the co-morbid patients having more preference to the morning activities and probably a shorter circadian period. Second, the circadian preferences have been similar but changed in the course of illness because of alcohol use or other reasons that are not characterized yet. Our cross-sectional design does not allow causative deductions. However, we suggest that a prolonged alcohol misuse, leading to a lifetime diagnosis of alcohol abuse or alcohol dependence, may result in the situation in which the circadian preference has changed from the evening to morning type in individuals with bipolar. This hypothesis needs testing in subsequent studies. A limitation is that we assessed the circadian preference with a self-report and did not measure actual indicators of the circadian rhythms. However, we present herein for the first time a factor matrix of the MEQ and point out a significant association of the co-morbid alcohol use with the score on the eight items of morning activities. The self-report instrument used in our study, i.e. the Horne and Östberg MEQ, has been evaluated as a fair predictor of the endogenous circadian period and phase (Sack et al., 2007). In addition, laboratory studies applying for constant routine protocols have demonstrated that the phases of circadian melatonin and temperature rhythms are related to the self-reported circadian preference (Duffy et al., 1999; Griefahn, 2002). It is possible or even plausible that alcohol misuse induced the change in the circadian preference from evening to morning hours in our study, thereby indicating a link of abnormalities in

4 Circadian Phenotype in Bipolar Disorder 567 the circadian clockwork induced by alcohol misuse to shorter circadian periods or advanced circadian phase positions. Our results herein show that patients with bipolar having co-morbid alcohol use are prone to have a circadian phenotype of the morning type as compared with those having bipolar only. Earlier studies have pointed out that alcohol misuse is associated with bipolar. Patients with alcohol dependence have a greater prevalence of bipolar s than the general population, and patients with bipolar have increased rates of alcohol use s (Freed, 1969; Mendlewicz et al., 1972; Morrison, 1974; Dunner et al., 1979; Estroff et al., 1985; Regier et al., 1990). This high prevalence of co-morbid substance use s in bipolar suggests that this kind of co-morbid condition may be an intrinsic component of bipolar s (Schulze et al., 2006). Moreover, alcohol consumption has an effect on the human physiology that is dependent on the circadian time (see the review by Danel and Touitou (2004)). For example, craving for the first drink of the day occurs most often in the mid-morning (Danel et al., 2003). Repeated alcohol intake influences the circadian rhythm of core body temperature and results in hypothermic and hyperthermic effects during the day and night, respectively (Danel et al., 2001). In rats, chronic ethanol intake reduces the responsiveness of the circadian system to acute stimulation with light exposure (Rosenwasser et al., 2005), which agrees with the findings of the vulnerability of the circadian pacemaker to chronic alcohol administration (Chen et al., 2004). Alcohol use enhances the serum testosterone levels (Danel et al., 2006) and disrupts the secretion of melatonin (Danel and Touitou, 2004). But, there are contradictory findings as well that challenge the desynchronization of the circadian rhythms as a plausible mechanism of action for alcohol consumption on the circadian clockwork (Danel and Touitou, 2006). Links between the circadian system, alcohol consumption and bipolar are highlighted on the basis of genetic studies. Administration of ethanol to rats for a period of 2 weeks disrupts the expression of the rper2 gene in the arcuate and suprachiasmatic nuclei, suggesting the effect on the circadian pacemaker (Chen et al., 2004). In addition, mper2 (Brdm1) mutant mice whose circadian period is shortened display lowered expression levels of the glutamate transporter Eaat1 gene and increases in ethanol intake (Spanagel et al., 2005a). Interestingly, treatment with acamprosate reduces the extracellular levels of glutamate and normalizes the increased ethanol intake in these mice. Recently, the D site of albumin promoter (albumin D-box)- binding protein has been identified as a candidate gene for bipolar and alcohol dependence (Niculescu et al., 2000), and the stress reactive genetic animal model of bipolar and co-morbid alcoholism has been reported (Le-Niculescu et al., 2008). Another recent study reveals that there are maniclike behaviours in Clock mutant mice and that some of these behaviours can be reversed with lithium treatment (Roybal et al., 2007). In addition to these animal studies, variants in the Per2 gene have been associated with alcohol consumption in humans (see the review by Spanagel et al. (2005b)). Altogether, further studies of both phenotype and genotype are important to elucidate clinically relevant and tailored treatment interventions. In conclusion, patients having the co-morbid alcohol use and bipolar s have more often the circadian phenotype of the morning type as compared with those with bipolar only. Acknowledgements This study was supported in part by grants and (to T.P.) from the Academy of Finland. REFERENCES Abe M, Herzog ED, Block GD. (2000) Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport 11: Broman JE, Hetta J. (1998) Sleep and wake in morning and evening types: an epidemiological survey. J Sleep Res 7:31s. Bunney WE, Bunney BG. (2000) Molecular clock genes in man and lower animals: possible implications for circadian abnormalities in depression. Neuropsychopharmacology 22: CarrierJ,Monk TH,BuysseDJ et al. (1997) Sleep and morningness eveningness in the middle years of life (20 59 years). J Sleep Res 6: Chelminski I, Ferraro FR, Petros TV et al. (1999) An analysis of the eveningness morningness dimension in depressive college students. J Affect Disord 52: Chen CP, Kuhn P, Advis JP et al. (2004) Chronic ethanol consumption impairs the circadian rhythm of pro-opiomelanocortin and period genes mrna expression in the hypothalamus of the male rat. J Neurochem 88: Colombo C, Lucca A, Benedetti F et al. (2000) Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression: replication of main effects and interaction. Psychiatry Res 95: Danel T, Jeanson R, Touitou Y. (2003) Temporal pattern in consumption of the first drink of the day in alcohol-dependent persons. Chronobiol Int 20: Danel T, Libersa C, Touitou Y. (2001) The effect of alcohol consumption on the circadian control of human core body temperature is time dependent. Am J Physiol Regul Integr Comp Physiol 281:R52 5. Danel T, Touitou Y. (2004) Chronobiology of alcohol: from chronokinetics to alcohol-related alterations of the circadian system. Chronobiol Int 21: Danel T, Touitou Y. (2006) Alcohol consumption does not affect melatonin circadian synchronization in healthy men. Alcohol Alcohol 41: Danel T, Vantyghem M-C, Touitou Y. (2006) Responses of the steroid circadian system to alcohol in humans: importance of the time and duration of intake. Chronobiol Int 23: Drennan MD, Klauber MR, Kripke DF et al. (1991) The effects of depression and age on the Horne Ostberg morningness eveningness score. J Affect Disord 23:93 8. Duffy JF, Dijk DJ, Hall EF et al. (1999) Relationship of endogenous circadian melatonin and temperature rhythms to self reported preference for morning or evening activity in young and older people. J Investig Med 47: Duffy JF, Rimmer DW, Czeisler CA. (2001) Association of intrinsic circadian period with morningness eveningness, usual wake time, and circadian phase. Behav Neurosci 115: Dunner DL, Hensel BM, Fieve RR. (1979) Bipolar illness: factors in drinking behavior. Am J Psychiatry 136: Estroff TW, Dackis CA, Gold MS et al. (1985) Drug abuse and bipolar s. Int J Psychiatry Med 15: Freed EX. (1969) Alcohol abuse by manic patients. Psychol Rep 25:280. Gale C, Martyn C. (1998) Larks and owls and health, wealth, and wisdom. Br Med J 317: Griefahn B. (2002) The validity of the temporal parameters of the daily rhythm of melatonin levels as an indicator of morningness. Chronobiol Int 19: Hakkarainen R, Johansson C, Kieseppä T et al. (2003) Seasonal changes, sleep length and circadian preference among twins with bipolar. BMC Psychiatry 3:1 7. Horne JA, Östberg O. (1976) A self-assessment questionnaire to determine morningness eveningness in human circadian rhythms. Int J Chronobiol 4:

5 568 Hätönen et al. Jöreskog KG. (1977) Factor analysis by least-squares and maximum likelihood methods. In Enslein K, Ralston A, Wilf HS (eds). Statistical Methods for Digital Computers, Vol. III. NewYork: Wiley, Kerkhof GA. (1985) Inter-individual differences in the human circadian system: a review. Biol Psychol 20: Kerkhof GA, Van Dongen HP. (1996) Morning-type and evening type individuals differ in the phase position of their endogenous circadian oscillator. Neurosci Lett 218: Khalsa SB, Michel S, Block GD. (1993) The effects of lithium on a neuronal in vitro circadian pacemaker. Chronobiol Int 10: Le-Niculescu H, McFarland MJ, Ogden CA et al. (2008) Phenomic, convergent functional genomic, and biomarker studies in a stressreactive genetic animal model of bipolar and co-morbid alcoholism. Am J Med Genet (Part B) 147: Mansour HA, Monk TH, Nimgaonkar VL. (2005a) Circadian genes and bipolar. Ann Med 37: Mansour HA, Wood J, Chowdari KV et al. (2005b) Circadian phase variation in bipolar I. Chronobiol Int 22: Mendlewicz J, Fieve RR, Rainer JD et al. (1972) Manic-depressive illness: a comparative study of patients with and without a family history. Br J Psychiatry 120: Morrison JR. (1974) Bipolar affective and alcoholism. Am J Psychiatry 131: Murray G, Allen NB, Trinder J. (2003) Seasonality and circadian phase delay: prospective evidence that winter lowering of mood is associated with a shift towards eveningness. J Affect Disord 76: Niculescu AB, Segal DS, Kuczenski R et al. (2000) Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach. Physiol Genomics 4: Padiath QS, Paranjpe D, Jain S et al. (2004) Glycogen synthase kinase 3beta as a likely target for the action of lithium on circadian clocks. Chronobiol Int 21: Reghunandanan V, Badgaiyan RD, Marya RK et al. (1989) Lithium chloride SCN injection alters the circadian rhythm of food intake. Chronobiol Int 6: Regier DA, Farmer ME, Rae DS et al. (1990) Comorbidity of mental s with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA 264: Rosenwasser AM, Logan RW, Fecteau ME. (2005) Chronic ethanol intake alters circadian period responses to brief light pulses in rats. Chronobiol Int 22: Roybal K, Theobold D, Graham A et al. (2007) Mania-like behavior induced by disruption of clock. Proc Natl Acad Sci USA 104: Sack RL, Aucley D, Auger RR et al. (2007) Circadian rhythm sleep s: part I, basic principles, shift work and jet lag s. Sleep 30: Schulze TG, Hedeker D, Zandi P et al. (2006) What is familial about familial bipolar? Arch Gen Psychiatry 63: Spanagel R, Pendyala G, Abarca C et al. (2005a) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11: Spanagel R, Rosenwasser AM, Schumann G et al. (2005b) Alcohol consumption and the body s biological clock. Alcohol Clin Exp Res 29: Taillard J, Philip P, Bioulac B. (1999) Morningness/eveningness and the need for sleep. J Sleep Res 8: Taillard J, Philip P, Chastang JF et al. (2001) Is self-reported morbidity related to the circadian clock? J Biol Rhythms 16: Taillard J, Philip P, Chastang JF et al. (2004) Validation of Horne and Ostberg morningness eveningness questionnaire in a middleaged population of French workers. J Biol Rhythms 19: Wehr TA, Sack DA, Rosenthal NE. (1987) Sleep reduction as a final common pathway in the genesis of mania. Am J Psychiatry 144: YinL,WangJ,KleinPSet al. (2006) Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science 311: