Psychopharmacology (2011) 213:633638 DOI 10.

1007/s00213-010-1999-0

ORIGINAL INVESTIGATION

Biological aspect of hyperthymic temperament: light, sleep, and serotonin

Nobuhiko Hoaki & Takeshi Terao & Yumei Wang & Shinjiro Goto & Kounosuke Tsuchiyama & Noboru Iwata

Received: 6 June 2010 / Accepted: 6 August 2010 / Published online: 28 August 2010 # Springer-Verlag 2010

Abstract Rationale Hyperthymic temperament is one of several premorbid temperaments putatively associated with bipolar disorder. Several reports suggest that depressive patients with hyperthymic temperament may belong to the proposed soft bipolar spectrum. Objectives To investigate biological aspects of hyperthymic temperament, the present study examined daily activity, sleep time, central serotonergic function, and other relevant variables in relation to hyperthymic temperament in healthy subjects. Methods Fifty six healthy subjects were monitored via the actigraphy system to measure daily total activity, sleep time, and illuminance. A neuroendocrine challenge test was performed to estimate central serotonergic function. Results Multiple regression analysis revealed that higher illuminance of daytime, greater fluctuation in sleep time, and lower central serotonergic function significantly and independently predicted hyperthymic temperament scores. Conclusions The present findings suggest that light, sleep, and serotonin are crucial factors in understanding hyperthymic temperament, which may be common to bipolar disorder. Keywords Actigraphy . Hyperthymic temperament . Light . Instability hypothesis . Serotonin . Sleep
N. Hoaki : T. Terao (*) : Y. Wang : S. Goto : K. Tsuchiyama Department of Neuropsychiatry, Oita University Faculty of Medicine, Idaigaoka 1-1, Hasama-machi, Yufu City, Oita 879-5593, Japan e-mail: terao@med.oita-u.ac.jp N. Iwata Department of Clinical Psychology, Hiroshima International University, Hiroshima City, Hiroshima, Japan

Introduction Over 90 years ago, Kraepelin described four basic affective dispositions: depressive, manic, cyclothymic, and irritable (Rihmer et al. 2010). Current research findings show that specific affective temperament types: depressive, cyclothymic, hyperthymic, irritable, and anxious (Akiskal and Mallya 1987; Akiskal 1995) are subsyndromal (traitrelated) manifestations and are also commonly the antecedents of minor and major mood disorders. With regard to hyperthymic temperament, Akiskal and Pinto (1999) conceptualized bipolar IV disorder as one of the soft bipolar spectrum, which is seen in individuals with longstanding and stable hyperthymic temperaments, into which a major depressive episode intrudes. Individuals with hyperthymic temperaments who are treated for depressive episodes may be at increased risk for antidepressantinduced mood cycling and may instead respond better to mood stabilizers (Stahl 2008). For example, Manning (2000) reported that some cases of energetic and productive women suffering from episodic depression responded well to mood stabilizers. With regard to the etiology of bipolar disorder, Goodwin and Jamison (1990) proposed the instability hypothesis, whereby circadian fluctuation was proposed as the core vulnerability for bipolar disorder. Based on this hypothesis, Ankers and Jones (2009) compared 31 individuals at behavioral risk of hypomania and 24 age- and gendermatched control participants by using an actigraph for 7 days to obtain sleep and circadian activity data. They found that variability in bedtime significantly discriminated between the two groups. In another actigraphic assessment of circadian activity and sleep (Jones et al. 2005), bipolar patients were found to have less stable and more variable circadian activity than controls. Furthermore, in a longer

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observing duration of 28 days, according to the ratings, Meyer and Maier (2006) found the similar result that people at risk for bipolar disorder showed a lower regularity of daily activities and their sleeping pattern. Considering the close relationship between bipolar disorder and hyperthymic temperament, it seems important to investigate sleep time and its fluctuation of hyperthymic individuals. Therefore, the first aim of the present study is to examine sleep time and its fluctuation in healthy subjects with hyperthymic temperament by using actigraphy. As to the potential biological basis of the hyperthymic temperament, Rihmer et al (2010) suggested dopaminergic dysregulation, while Savitz et al (2008) showed that the Met allele of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was associated with higher hyperthymic temperament scores. Although several researchers reported no significant association of the 5HTTLPR polymorphism with hyperthymic temperament (Gonda et al. 2006, 2009; Kang et al. 2008), to our knowledge, there have been no studies investigating hyperthymic temperament by using the serotonergic neuroendocrine challenge test which can estimate central serotonergic function. Thus, the second aim of the present study is to examine whether the central serotonergic function is associated with hyperthymic temperament.

hyperthymic temperament using the TEMPS-A score as a continuous variable. In addition, all subjects were screened for present and past psychiatric disorder using Mini International Neuropsychiatric Interview (MINI; Sheehan et al. 1998), 17-item Hamilton Rating Scale for Depression (HRSD-17; Hamilton 1967), and Young Mania Rating Scale (YMRS; Young et al. 1978). Actigraphy Actigraphy is a form of ambulatory monitoring via a wristwatch-sized movement sensor. Activity data is captured via an accelerometer located within the device and stored digitally over hours, days, or months. Data is then downloaded and analyzed to produce estimates of various circadian and sleep parameters (Ankers and Jones 2009). Morgenthaler et al (2007) cited eight studies comparing actigraphic with polysomnographic estimates of total sleep time and reported an average correlation of 0.71. Therefore, actigraphy may provide a relatively accurate estimate of sleep patterns. In the present study, subjects were instructed to place the actiwatch (Actiwatch-L Minimitter, Respironics, Bend, OR) on the nondominant wrist for 7 consecutive days and nights. They were instructed to continue their normal activities and sleep wake rhythms at home as usual, but were requested to remove it only during hard exercise, handwashing, and bathing. During the actigraphic study period, participants kept a sleep and activity diary to corroborate the data of the actigraphy. To test our hypothesis that sleep time and its fluctuation would be associated with hyperthymic temperament, sleep time, standard deviation (SD) of sleep time, and total activity were analyzed. Additionally, the actiwatch has another function of measuring illuminance, and illuminance of daytime was also analyzed. Illuminance was measured as subjects exposure to brightness including not only sunshine but also artificial light, and illuminance of daytime means total exposure to brightness during waking time. Neuroendocrine testing In order to estimate central serotonergic function, various serotonergic probes have been utilized (Cowen 1993). Stemming from the work of Reist et al. (1996), we established a paroxetine challenge test (Kojima et al. 2003; Iwakawa et al. 2004; Soya et al. 2006; Inoue et al. 2007). Therefore, also in the present study, paroxetine was used as a probe. The paroxetine challenge test was performed in our laboratory, and subjects attended the laboratory at around 7:40 a.m., having fasted from midnight, and an intravenous cannula was inserted. Subjects were put in a sitting position and not allowed to sleep. Baseline blood samples were taken just before subjects received 20 mg of paroxetine orally at 8:00 a.m. Further

Materials and methods Subjects Initially, 59 healthy volunteers, including medical staff, students, and other workers, were recruited from our university hospital. Demographic data, such as age, gender, work (worker or student), and exercise (times per week), were identified by auto-questionnaires. Subsequently, one subject was excluded as she was taking contraceptive pills, which might have affected hormone levels. Another two subjects were also excluded because they could not comply with our instruction for actigraphy. Consequently, 56 were included in this study. Written informed consent was obtained from all the subjects, and the study was approved by the university ethical committee. Temperament and psychiatric assessments The subjects completed the Japanese standardized version of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego auto-questionnaire version (TEMPS-A), which is a 110-item truefalse questionnaire measuring the temperament dimensions: depressive, cyclothymic, hyperthymic, irritable, and anxious (Matsumoto et al. 2005). In this study, we specifically measured the tendency toward

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blood sampling was carried out at 1-h intervals for the next 6 h. After taking blood samples, the plasma was immediately separated from heparinized venous blood samples by centrifugation and stored at 40C. Plasma adrenocorticotropic hormone (ACTH) was measured by a third party. In addition, the area under the curve of ACTH (ACTH AUC) was calculated using the trapezoidal method with subtraction of baseline ACTH secretion extrapolated at the start of neuroendocrine testing. This ACTH AUC is considered to estimate the central serotonergic function (Reist et al. 1996; Kojima et al 2003). Due to the circadian rhythm where ACTH decreases from morning to afternoon, the value of ACTH AUC is expected to be usually below 0. Statistical analysis Pearsons correlation coefficient was used to test the correlation of hyperthymic temperament scores with measures of actigraphic study and ACTH AUC. Then stepwise regression analysis was used to identify possible demographic variables and independent predictors of hyperthymic temperament scores.

Actigraphic and neuroendocrine data Unexpectedly, as depicted in Fig. 1, illuminance of daytime was significantly and positively associated with hyperthymic temperament scores. As shown in Table 1, there was no association between hyperthymic temperament scores and the other variables such as sleep time, SD of sleep time, or total activity. Also, ACTH AUC was not associated with hyperthymic temperament scores. Multiple regression analysis As shown in Table 2, according to the stepwise regression analysis, three variables were determined as independent predictors on hyperthymic temperament scores: illuminance of daytime, ACTH AUC, and SD of sleep time. These variables explained 33.0% of hyperthymic temperament scores. Surprisingly, ACTH AUC, which reflected central serotonergic function, and SD of sleep time, which reflected the fluctuation of sleep time day by day, were entered into the final regression model, although there had been no significant association with hyperthymic temperament scores (Table 1). Conversely, exercise was not included in the final model, although it had been significantly associated with hyperthymic temperament scores (Table 1).

Results According to MINI, no subject had evidence of psychiatric disorder. As shown in Table 1, the subjects were young and male-dominant. Only exercise was significantly and positively associated with hyperthymic scores. Both HRSD-17 scores and YMRS scores were within normal limits and had no significant association with hyperthymic scores.
Table 1 Demographic data and correlation with hyperthymic temperament scores

Discussion In our study, multiple regression analysis revealed greater illuminance of daytime, higher SD of sleep time, and less ACTH AUC were significant independent predictors of

Characteristic

Total (N=56) N (%) MeanSD Significance

Gender Male Female Job Worker Student Age (year) Exercise (times/week) HRSD-17 YMRS Sleep time (min/day) SD of sleep time Total activity (/day) Illuminance of daytime (lux) ACTH AUC (hx g/ml)

39 (70) 17 (30) 24 (43) 32 (57) 26.95.9 1.32.0 1.21.4 0.40.9 399.059.1 99.057.1 263,105.750,372.0 184.2149.4 99.9117.7

0.208

0.245 0.243 0.022 0.312 0.493 0.964 0.518 0.625 0.0002 0.428

HRSD-17 17-item Hamilton Rating Scale For Depression, YMRS Young Mania Rating Scale, SD standard deviation, ACTH AUC the area under the curve of adrenocorticotropic hormone

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Fig. 1 The illuminance of daytime was significantly and positively correlated to hyperthymic temperament scores (r=0.47, p=0.0003)

hyperthymic temperament scores. Together, these three variables explained one-third of the variance of hyperthymic temperament. With regard to how variables fail to correlate with hyperthymic temperament but then come significantly into the regression analysis, simple correlation revealed that illuminance of daytime significantly correlated with hyperthymic temperament scores (r = .47), whereas both ACTH AUC (r=.11) and SD of sleep time (r = .09) did not reach at a significant level. On the one hand, illuminance of daytime tended to correlate positively with ACTH AUC (r = .26) and negatively with SD of sleep time (r=.17). Thus, when the (positively) correlated components of illuminance of daytime were controlled at the first step of the stepwise regression, the remaining components of ACTH AUC (r = .11) might become stronger (=.31) and those of SD of sleep time (r =.09) would be the same ( = .25). Therefore, observed contributions of these two variables should be regarded as being significant only if the effects of illuminance of daytime were taken into account (or were partialled out/controlled). In the next part, we discuss illuminance of daytime, SD of sleep time, and ACTH AUC. First, illuminance of daytime was not expected to be associated with hyperthymic temperament, and to our knowledge, this significant and positive association is a new finding. Since there was no significant association between total activity and hyperthymic temperament scores as shown Table 1, it seems unlikely that hyperactivity in some hyperthymic subjects exposes them to more light. On the other hand, illuminance of daytime was significantly and negatively associated with even low HRSD-17 scores (r=0.28, p<0.05). So regardless of euthymic mood, it appears that the greater illuminance of daytime at least partially influenced hyperthymic temperament via elevating mood. This is in line with reports that light therapy improves seasonal affective disorder (Lee and Chan 1999; Golden et al. 2005; Rastad et al. 2008) and nonseasonal depression (Golden et al. 2005; Even et al. 2008).

Interestingly, taking these findings together, hyperthymic temperament may lead to heliotropism, which is associated with higher illuminance of daytime and thereby can help to maintain a cheerful disposition in healthy subjects. Secondly, SD of sleep time was significantly and positively associated with hyperthymic temperament. This association was expected by our hypothesis, while its simple correlation with hyperthymic temperament scores did not reach a significance (Table 1). After controlling for the variance of illuminance of daytime and ACTH AUC, this variable was entered into the regression model at final step in the analysis. Therefore, this association may be modest but in line with the recent report that variability in bedtime significantly discriminated individuals at risk of hypomania and healthy volunteers (Ankers and Jones 2009). Ehlers et al. (1988) proposed the social zeitgeber theory to explain how life events may trigger unipolar depressive symptoms. This theory proposes that life events can disrupt social zeitgeber, which causes disruptions in the regularity of our daily activities or our circadian rhythms. As a result, such disruptions may cause depressive symptoms in vulnerable individuals. Recent findings suggest that the theory may also apply to hypomanic and manic episodes and also to bipolar disorder (Meyer and Maier 2006; Grandin et al. 2006; Sylvia et al. 2009). Taking into consideration the notion that hyperthymic temperament may be a precursor of bipolar disorder, the present findings suggest a continuity between hyperthymic temperament and bipolar disorder and further suggest that the instability hypothesis can be applied not only to bipolar disorder but also to hyperthymic temperament. Since a social rhythm therapy has been developed on the basis of this theory for treating patients with bipolar disorder (Frank et al. 1997, 2000), it may be speculated that correcting this instability by social rhythm therapy could help to normalize hyperthymic temperament and prevent the development of bipolar disorder. Finally, hyperthymic temperament scores were significantly and negatively associated with ACTH AUC which estimates central serotonergic function. Previous reviews of serotonergic challenge studies indicate that serotonergic activity is reduced in both manic and depressed bipolar
Table 2 The multiple regression analysis of hyperthymic temperament scores Variables selected Illuminance of daytime ACTH AUC SD of sleep time R2 0.59 0.31 0.25 0.33 Significance <.0001 .013 .042 <.0001

ACTH AUC the area under the curve of adrenocorticotropic hormone, SD standard deviation

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637 Science and the Research Grant (21-B-2) for Nervous and Mental Disorders from the Ministry of Health.

patients (Mahamood and Silverstone 2001; Sobczak et al. 2002). As hyperthymic temperament is the proximal phenotype in premorbid course of bipolar disorder, our findings suggest hyperthymic temperament may have a similar basis of serotonergic dysfunction as that of bipolar disorder. While Rihmer et al. (2010) suggested the possibility of a link between hyperthymic temperament and dopaminergic regulation, the serotonergic system has strong anatomical and functional interactions with the dopaminergic system (Seo et al. 2008). Given that the serotonergic system may at least partially inhibit dopaminergic activity in some areas of the brain, lower serotonergic function of hyperthymic temperament may be attributed to disinhibition of dopaminergic activity. With regard to the limitations of the present study, firstly, hyperthymic temperament was identified by only using TEMPS-A, which might have been affected by incorrect memory and/or deviate self-assessment. Secondly, the subjects were deviated to students and workers at university hospital. Therefore, it may be difficult to generalize the present findings to all the individuals with hyperthymic temperament. Nonetheless, the present findings can reveal the biological aspects of hyperthymic temperament of healthy subjects and the revealed aspects are free from the effects of psychiatric disorders or psychotropics. Finally, another limitation is a lack of placebo in a neuroendocrine challenge test. However, we had previously administered placebo, 20 mg of paroxetine, and 40 mg of paroxetine (Kojima et al. 2003). By using the data of Kojima et al. (2003), we calculated the association between the difference of ACTH AUC (between 20 mg of paroxetine and placebo) and ACTH AUC of 20 mg of paroxetine, retrospectively. Consequently, there was a significant association ( = 0.65, p=0.015). Although this finding was derived from the data of Kojima et al. (2003) but not from the present data, this suggests that ACTH AUC induced by 20 mg of paroxetine administration may be associated with the difference between 20 mg of paroxetine and placebo, which is free from placebo effects and diurnal rhythm of ACTH and reflects at least partially central serotonergic function. Taking this into consideration, it seems likely that despite the lack of placebo the present method may be useful to estimate at least partially central serotonergic function. In conclusion, the present findings suggest that light, sleep, and serotonin are crucial factors in understanding hyperthymic temperament and that healthy subjects with hyperthymic temperament may have similar biological factors to bipolar patients.
Acknowledgments We would like to express our great appreciation to Dr. Tsuyoshi Akiyama for his kind permission of the use of TEMPSa Japanese version. This work was supported by Grant-in-Aid for Scientific Research (C) (21591523) from Japanese Society for the Promotion of

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