Central Serotonergic Function Research Articles

Fluoxetine-induced Hypotension: A Case Report

Fluoxetine is a Selective Serotonin Reuptake Inhibitor (SSRI) that exerts its anti-depressive effect by blocking the presynaptic reuptake of the neurotransmitter serotonin, 5-hydroxytryptamine (5-HT). Although fluoxetine is usually considered safe for most patients, in the present case report, we describe a young patient with Mixed Anxiety and Depression Disorder (MADD) treated with fluoxetine 10 mg/day, who developed hypotension when the dosage was titrated up to 20 mg/day. After discontinuing the use of fluoxetine, the symptoms of hypotension improved. A temporal association and dose-dependent relationship between the hypotension and the use of fluoxetine was observed. To the best of our knowledge, this is the first case report that precisely associates regular doses of fluoxetine with the presence of hypotension. Because boosting central serotonergic function lowers blood pressure, it is suggested that a significant effect of fluoxetine on the vasomotor center may be responsible for the reduction of blood pressure. Thus, physicians should be aware of the possible risk of hypotension induced by fluoxetine and recommend patients discontinue the drug immediately if complications have occurred.

Neurobiological Functioning and the Personality-Trait Hierarchy: Central Serotonergic Responsivity and the Stability Metatrait

Trait domains of the five-factor model are not orthogonal, and two metatraits have often been estimated from their covariation. Here, we focus on the stability metatrait, which reflects shared variance in conscientiousness, agreeableness, and (inversely) neuroticism. It has been hypothesized that stability manifests, in part, because of individual differences in central serotonergic functioning. We explored this possibility in a community sample (N = 441) using a multiverse analysis of (a) multi-informant five-factor-model traits and (b) stability as a predictor of individual differences in central serotonergic functioning. Differences in serotonergic functioning were assessed by indexing change in serum prolactin concentration following intravenous infusion of citalopram, a selective serotonin reuptake inhibitor. Results were mixed, showing that trait neuroticism, agreeableness, and conscientiousness, as well as the stability metatrait, were significantly associated with prolactin response but that these findings were contingent on a number of modeling decisions. Specifically, these effects were nonlinear, emerging most strongly for participants with the highest levels (or lowest, for neuroticism) of the component traits.

The effects of 5-hydroxytryptophan on attention and central serotonin neurochemistry in the rhesus macaque

Psychiatric disorders, particularly depression and anxiety, are often associated with impaired serotonergic function. However, serotonergic interventions yield inconsistent effects on behavioral impairments. To better understand serotonin’s role in these pathologies, we investigated the role of serotonin in a behavior frequently impaired in depression and anxiety, attention. In this study, we used a quantitative, repeated, within-subject, design to test how L-5-hydroxytryptophan (5-HTP), the immediate serotonin precursor, modulates central serotoninergic function and attention in macaques. We observed that intramuscular 5-HTP administration increased cisternal cerebrospinal fluid (CSF) 5-HTP and serotonin. In addition, individuals’ baseline looking duration, during saline sessions, predicted the direction and magnitude in which 5-HTP modulated attention. We found that 5-HTP decreased looking duration in animals with high baseline attention, but increased looking duration in low baseline attention animals. Furthermore, individual differences in 5-HTP’s effects were also reflected in how engaged individuals were in the task and how they allocated attention to salient facial features—the eyes and mouth—of stimulus animals. However, 5-HTP constricted pupil size in all animals, suggesting that the bi-directional effects of 5-HTP cannot be explained by serotonin-mediated changes in autonomic arousal. Critically, high and low baseline attention animals exhibited different baseline CSF concentrations of 5-HTP and serotonin, an index of extracellular functionally active serotonin. Thus, our results suggest that baseline central serotonergic functioning may underlie and predict variation in serotonin’s effects on cognitive operation. Our findings may help inform serotonin’s role in psychopathology and help clinicians predict how serotonergic interventions will influence pathologies.

Clinical profile and changes in values of mean platelet volume among panic disorder patients

Context: The serotonin system is involved in the pathophysiology of anxiety disorders, but it is not practical to measure the serotonin levels inside the brain. Peripheral serotonin activity may reflect the central serotonergic function. An affordable and easy measure of peripheral serotonergic function is the mean platelet volume (MPV). Hence, MPV could possibly be used as a measure of central serotonergic function and hence could be a predictor of treatment outcome and response in panic disorder. Aims: This study aims to study the changes in MPV in patients with panic disorder with or without agoraphobia compared to healthy controls, thereby elucidating the relationship between panic disorder and MPV. Subjects and Methods: Patients (n = 65) who fulfilled the selection criteria and healthy controls (n = 65) were taken up for the study. Sociodemographic details and clinical variables were recorded in a special pro forma prepared for the study. Mini International Neuropsychiatry Interview-Plus was used for screening psychiatric morbidity. The diagnosis of panic disorder was made using the International Classification of Diseases-10 diagnostic criteria. Panic disorder severity scale and panic and agoraphobia scale were administered to all patients. MPV was assessed, and variations in MPV were studied between the groups. Statistical Analysis Used: Two-tailed independent sample t-test was used to compare the cases and controls. Results: It was observed that MPV values were higher for patients with panic disorder than healthy controls. Conclusion: MPV values were higher in panic disorder patients when compared to the healthy controls, so they could serve as predictors/indicators of treatment outcome and response in panic disorder.

Auricular vagus nerve stimulation enhances central serotonergic function and inhibits diabetic neuropathy development in Zucker fatty rats

Painful neuropathy is a frequent comorbidity in diabetes. Zucker diabetic fatty (fa/fa) rats develop type 2 diabetes spontaneously with aging and show nociceptive hypersensitivity at the age of 13 weeks. In preclinical and clinical studies, the treatment of diabetic neuropathy is challenging, but complementary medicine such as transcutaneous auricular vagus nerve stimulation (taVNS) appears beneficial to the relief of neuropathic pain. However, the mechanism behind the effectiveness of taVNS remains unclear. In this study, we show that daily 30-min taVNS (2/15 Hz, 2 mA) for consecutive 27 days effectively inhibited the development of nociceptive hypersensitivity in Zucker diabetic fatty rats as detected by thermal hyperalgesia and mechanical allodynia in hindpaw. We also demonstrated that this beneficial effect in nociceptive behavior is related to an elevated serotonin (5-HT) plasma concentration and an upregulated expression of 5-HT receptor type 1A (5-HT1AR) in hypothalamus. We conclude that daily 30-min taVNS sessions lessen diabetic neuropathy development by enhancing serotonergic function in genetically diabetes prone individuals. Perspective This article presents taVNS as a new approach to inhibit the development of diabetic neuropathy in genetically prone individuals. This approach could potentially help clinicians who seek to avoid the complication of neuropathic pain in diabetic patient or to relieve the pain if there was one.

Platelet monoamine oxidase activity and interpersonal violence in male suicide attempters

Low platelet monoamine oxidase B (MAO-B) activity, proxy of low central serotonergic functions, has been shown to correlate with criminal behavior in adolescents that come from an unfavorable psychosocial environment but not in adolescents from good conditions, indicating a link between environment, MAO-B activity and aggressive behavior. The purpose of this study was to examine the association between MAO-B activity and lifetime interpersonal violence in suicide attempters. The study included a total of 28 suicide attempters (18 men and 10 women). Assessments of childhood exposure to and expressed interpersonal violence during childhood and as an adult were carried out with the Karolinska Interpersonal Violence Scale (KIVS). Platelet MAO-B activity was measured with 2-phenylethylamine (b-PEA) as substrate. Broken down by gender, the correlations between platelet MAO-B activity and both exposure scores to interpersonal violence as a child and expressed lifetime interpersonal violence were significant in male suicide attempters (r = −0.61, p = 0.035; r = −0.84, p = 0.0005), but not in women. Our finding of significant associations between interpersonal violence and low MAO-B activity need to be replicated in other cohorts of suicide attempters.

Brain responses to sound intensity changes dissociate depressed participants and healthy controls

Depression is associated with bias in emotional information processing, but less is known about the processing of neutral sensory stimuli. Of particular interest is processing of sound intensity which is suggested to indicate central serotonergic function. We tested weather event-related brain potentials (ERPs) to occasional changes in sound intensity can dissociate first-episode depressed, recurrent depressed and healthy control participants. The first-episode depressed showed larger N1 amplitude to deviant sounds compared to recurrent depression group and control participants. In addition, both depression groups, but not the control group, showed larger N1 amplitude to deviant than standard sounds. Whether these manifestations of sensory over-excitability in depression are directly related to the serotonergic neurotransmission requires further research. The method based on ERPs to sound intensity change is fast and low-cost way to objectively measure brain activation and holds promise as a future diagnostic tool.

Loudness dependence of auditory evoked potentials (LDAEP) in clinical monitoring of suicidal patients with major depression in comparison with non-suicidal depressed patients and healthy volunteers: A follow-up-study

Differences in central serotonergic function due to affective disorders and due to extraordinary situations like suicidality may be visualized using the loudness dependence of auditory evoked potentials (LDAEP). Twenty patients (mean age 43.25±10.85, age range 20–61, 11 male) suffering from a major depressive episode who had either acutely attempted suicide or who had suicidal plans and behavior, which are reflected by item 3 of Hamilton Depression Rating Scale ≥3 (suicidality), were included in the study. Furthermore, we intended to compare their LDAEP to those of non-suicidal depressed patients as well as to healthy volunteers, each matched according to age and gender. LDAEP measurement and psychometric tests took place about 2, 5, 9, 16 and 30 days after acute suicidal action or suicide attempts. In contrast to previous results, significant differences in LDAEP could not have been shown in between the suicidal group, or by comparing results of suicidal patients to non-suicidal depressed patients or to healthy volunteers. However, when the LDAEP of non-suicidal depressed patients were compared to healthy volunteers, there was a trend for a higher LDAEP in the healthy volunteers. Further studies are necessary to detect and describe further influences on serotonergic function and confounding factors like medication, smoking, age, gender, comorbidities and methods of suicidal attempts.

Influence of Levothyroxine in Augmentation Therapy for Bipolar Depression on Central Serotonergic Function

Adjunctive treatment with supraphysiological doses of levothyroxine (L-T4) in bipolar depression shows promise, but the neurobiological mechanisms underlying clinical improvement are unknown. It has been postulated from animal studies that exogenous thyroid hormones may exert their modulatory effects in patients with affective disorders via an increase in serotonergic neurotransmission. Therefore, we investigated the loudness dependence of auditory evoked potentials (LDAEP) as a measure of central serotonergic activity and response to L-T4. This 6-week, double-blind, randomized, placebo-controlled study assessed the efficacy of L-T4 adjunctive to continuing treatment with mood stabilizer and/or antidepressant medication in 20 patients with bipolar depression. LDAEP was assessed before and after treatment with L-T4. Scores of the Hamilton Depression Rating Scale and Montgomery Asberg Depression Rating Scale decreased significantly during the study. There was no difference in pre- and post-treatment LDAEP between the groups, and no correlation between LDAEP and psychometric measures in the course of the study. The hypothesis of a relationship between response of augmentation therapy with levothyroxine in bipolar depression and serotonergic activity could not be confirmed.

Differential impact of serotonin transporter activity on temperament and behavior in persons with a family history of alcoholism in the Oklahoma Family Health Patterns Project.

Central serotonergic (5-HT) function is implicated in pathways to alcohol dependence, including dysphoria manifested by symptoms of anxiety and depression. However, little is known about genetic variation in central 5-HT function and its potential impact on temperament and behavior in persons with a family history of alcoholism (FH+). We tested 314 healthy young adults (23.5 years of age, 57% female; 193 FH- and 121 FH+) enrolled in the Oklahoma Family Health Patterns project, a study of alcoholism risk in relation to temperament and behavioral dyscontrol. Dysphoria was assessed using the Eysenck neuroticism and Beck depression scales, and Cloninger's Tridimensional Personality Questionnaire. Risk taking was assessed with the Iowa Gambling Task (IGT) and Balloon Analogue Response Task (BART). All subjects were genotyped for a functional polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4). FH+ subjects with the gain-of-function 5-HTTLPR genotype scored higher in neuroticism, harm avoidance, and symptoms of depression (p-values ≤ 0.03). No effect of 5-HTTLPR genotype was seen in FH-. FH+ carriers of the gain-of-function 5-HTTLPR genotype played to minimize their frequency of losses in the IGT, whereas FH- carriers played a balanced strategy (p < 0.003). No 5-HTTLPR effects were seen in the BART. Results were unaffected by sex, education, drug use, and antisocial characteristics. The functional 5-HTTLPR polymorphism predicted significant variation in negative moods and poorer affect regulation in FH+ persons, with possible consequences for behavior, as seen in a simulated gambling task. This pattern may contribute to a drinking pattern that is compensatory for such affective tendencies.

Effects of serotonin-2A receptor binding and gender on personality traits and suicidal behavior in borderline personality disorder

Impulsivity and aggressiveness are personality traits associated with a vulnerability to suicidal behavior. Behavioral expression of these traits differs by gender and has been related to central serotonergic function. We assessed the relationships between serotonin-2A receptor function, gender, and personality traits in borderline personality disorder (BPD), a disorder characterized by impulsive-aggression and recurrent suicidal behavior. Participants, who included 33 BPD patients and 27 healthy controls (HC), were assessed for Axis I and II disorders with the Structured Clinical Interview for DSM-IV and the International Personality Disorders Examination, and with the Diagnostic Interview for Borderline Patients-Revised for BPD. Depressed mood, impulsivity, aggression, and temperament were assessed with standardized measures. Positron emission tomography with [18F]altanserin as ligand and arterial blood sampling was used to determine the binding potentials (BPND) of serotonin-2A receptors in 11 regions of interest. Data were analyzed using Logan graphical analysis, controlling for age and non-specific binding. Among BPD subjects, aggression, Cluster B co-morbidity, antisocial PD, and childhood abuse were each related to altanserin binding. BPND values predicted impulsivity and aggression in BPD females (but not BPD males), and in HC males (but not HC females.) Altanserin binding was greater in BPD females than males in every contrast, but it did not discriminate suicide attempters from non-attempters. Region-specific differences in serotonin-2A receptor binding related to diagnosis and gender predicted clinical expression of aggression and impulsivity. Vulnerability to suicidal behavior in BPD may be related to serotonin-2A binding through expression of personality risk factors.

Study on association between lipid profile values and psychiatric disorders.

Cholesterol is especially abundant in nervous system, where it plays important role in different aspects of cellular structure (e.g. fluidity of cell membranes) and function (e.g. membrane). Several studies showed that there may be a link between depression and low cholesterol because of altered central serotonergic functions. On the other hand, some studies also showed either no such association or yielded inconsistent results. However, many studies have related low cholesterol with different psychiatric disorders. Hence, we intend to see the possible link between the two. To study the association between lipid profile and psychiatric disorders. Patients attending Amala Institute of medical science, Psychiatry clinic in the month of January 2013 and whose lipid profile data before the start of treatment is available. Descriptive study. The patients were classified into Neurotic and Psychotic spectrum after being diagnosed with the psychiatric diseases based on International Classification of Diseases, 10(th) edition (ICD10) by a Psychiatrist. There lipid profile (Total cholesterol; LDL=Low Density Lipoprotein; HDL=High Density Lipoprotein; TAG=Triacylglycerol) were estimated before the initiation of anti-psychotic treatment. The lipid profile values though showed some statistically significant association between the psychotic and neurotic spectrum, there was no statistical significance between the low lipid profile and different psychiatric diseases. We have found that there is no significant association between low lipid profile and any psychiatric diseases.

Effects of Acute Tryptophan Depletion on Brain Serotonin Function and Concentrations of Dopamine and Norepinephrine in C57BL/6J and BALB/cJ Mice

Video presentation of the entire lecture can be accessed here Background : Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT) synthesis. Administration of large neutral amino acids (LNAA) limits the transport of endogenous tryptophan (TRP) across the bloodbrain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on the specificity and efficacy of the ATD paradigm for inhibition of central nervous 5-HT has arisen. ATD Moja-De is a revised mixture of AAs which is less nauseating than conventional protocols, possibly because of an administration in accordance with the body weight of the subjects. It has been used in the preliminary clinical studies, but its effects on central 5-HT mechanisms and other neurotransmitter systems have not been validated in an animal model. Design : We tested ATD Moja-De (TRP-) in two strains of mice, C57BL/6 and BALB/cJ, which are reported to have impaired 5-HT synthesis relative to other strains of mice. Results : ATD Moja-De lowered brain TRP, significantly decreased central nervous 5-HT synthesis as indexed by 5-HTP levels after decarboxlyase inhibition, and lowered 5-HT and 5 HIAA in both strains of mice, however, more so in C57 BL/6 than in BALB/cJ. Dopamine and its metabolites as well as norepinephrine were not affected. A tryptophan-balanced control mixture did not increase 5-HT or 5-HIAA. Conclusion : The present findings suggest that ATD Moja-De effectively suppresses central serotonergic function, and that the effects of ATD Moja-De are specific to serotonin function. (Published: 9 September 2013) Citation: Translational Developmental Psychiatry 2013, 1 : 18747 - http://dx.doi.org/10.3402/tdp.v1i0.18747

Adolescent male rats are less sensitive than adults to the anxiogenic and serotonin-releasing effects of fenfluramine

Risk taking behavior increases during adolescence, which is also a critical period for the onset of drug abuse. The central serotonergic system matures during the adolescent period, and its immaturity during early adolescence may contribute to adolescent risk taking, as deficits in central serotonergic function have been associated with impulsivity, aggression, and risk taking. We investigated serotonergic modulation of behavior and presynaptic serotonergic function in adult (67–74 days old) and adolescent (28–34 days old) male rats. Fenfluramine (2 mg/kg, i.p.) produced greater anxiogenic effects in adult rats in both the light/dark and elevated plus maze tests for anxiety-like behavior, and stimulated greater increases in extracellular serotonin in the adult medial prefrontal cortex (mPFC) (1, 2.5, and 10 mg/kg, i.p.). Local infusion of 100 mM potassium chloride into the mPFC also stimulated greater serotonin efflux in adult rats. Adult rats had higher tissue serotonin content than adolescents in the prefrontal cortex, amygdala, and hippocampus, but the rate of serotonin synthesis was similar between age groups. Serotonin transporter (SERT) immunoreactivity and SERT radioligand binding were comparable between age groups in all three brain regions. These data suggest that lower tissue serotonin stores in adolescents limit fenfluramine-stimulated serotonin release and so contribute to the lesser anxiogenic effects of fenfluramine.

Effects of Acute Tryptophan Depletion on Brain Serotonin Function and Concentrations of Dopamine and Norepinephrine in C57BL/6J and BALB/cJ Mice

Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT). Administration of large neutral amino acids (LNAA) limits the transport of endogenous tryptophan (TRP) across the blood brain barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on the specificity and efficacy of the ATD paradigm for inhibition of central nervous 5-HT has arisen. Moreover, side effects such as vomiting and nausea after intake of amino acids (AA) still limit its use. ATD Moja-De is a revised mixture of AAs which is less nauseating than conventional protocols. It has been used in preliminary clinical studies but its effects on central 5-HT mechanisms and other neurotransmitter systems have not been validated in an animal model. We tested ATD Moja-De (TRP−) in two strains of mice: C57BL/6J, and BALB/cJ, which are reported to have impaired 5-HT synthesis and a more anxious phenotype relative to other strains of mice. ATD Moja-De lowered brain TRP, significantly decreased 5-HT synthesis as indexed by 5-HTP levels after decarboxlyase inhibition, and lowered 5-HT and 5-HIAA in both strains of mice, however more so in C57BL/6J than in BALB/cJ. Dopamine and its metabolites as well as norepinephrine were not affected. A balanced (TRP+) control mixture did not raise 5-HT or 5-HIAA. The present findings suggest that ATD Moja-De effectively and specifically suppresses central serotonergic function. These results also demonstrate a strain- specific effect of ATD Moja-De on anxiety-like behavior.

Loudness dependence of auditory evoked potentials (LDAEP) in clinical monitoring of suicidal patients with major depression: a pilot study

Loudness dependence of auditory evoked potentials (LDAEP) is a validated in vivo marker of central serotonergic function. We aimed at measuring serotonergic activity in a follow-up study of suicidal patients. It should be investigated whether suicide attempts or suicidal states cause changes in the LDAEP. Thirteen patients (mean age, 40.9±11.3years; age range, 20-61, 6 male) with a major depressive episode who had attempted suicide or had suicidal plans (Hamilton Depression Rating Scale item 3 [suicidality] ≥3) were included in the study. LDAEP and psychometric measurements took place about 2, 5, 9 and 16days after attempted suicide or suicidal action. On day 9, LDAEP was significantly higher compared to day 2 and day 16; there was a similar tendency compared to day 5. Instability of central serotonergic function is suggested resulting in reduced serotonergic activity about 1week after suicide attempt. Further studies are necessary that include larger samples in order to distinguish between different psychiatric diseases and to consider confounding factors like gender, smoking, medication, impulsivity or lethality of suicidal action.

Is serotonergic function associated with the antidepressant effects of modified-electroconvulsive therapy?

The effect of modified-electroconvulsive therapy (m-ECT) on central serotonergic function has not been sufficiently investigated. The aim of the present study is to investigate this effect via the neuroendocrine challenge test. Sixteen inpatients (9 men and 7 women) with major depressive disorder who were receiving m-ECT at our university hospital were recruited. A neuroendocrine challenge test to estimate central serotonergic function was performed both before and after m-ECT treatment. On the whole, depressive symptoms significantly improved, but the improvement was not associated with changes in serotonergic function. The study was open-labeled and performed with a small number of subjects and no control group. Serotonergic function may not be associated with the antidepressant effects of ECT.

Examination of the effect of acute levodopa administration on the loudness dependence of auditory evoked potentials (LDAEP) in humans

The loudness dependence of the auditory evoked potential (LDAEP) is considered a noninvasive in vivo marker of central serotonergic functioning in humans. Nevertheless, results of genetic association studies point towards a modulation of this biomarker by dopaminergic neurotransmission. We examined the effect of dopaminergic modulation on the LDAEP using L-3,4-dihydroxyphenylalanine (levodopa)/benserazide (Madopar®) as a challenge agent in healthy volunteers. A double-blind placebo-controlled challenge design was chosen. Forty-two healthy participants (21 females and 21 males) underwent two LDAEP measurements, following a baseline LDAEP measurement either placebo or levodopa (levodopa 200 mg/benserazide 50 mg) were given orally. Changes in the amplitude and dipole source activity of the N1/P2 intensities (60, 70, 80, 90, and 100 dB) were analyzed. The participants of neither the levodopa nor the placebo group showed any significant LDAEP alterations compared to the baseline measurement. The test-retest reliability (Cronbachs Alpha) between baseline and intervention was 0.966 in the verum group and 0.759 in the placebo group, respectively. The administration of levodopa showed no effect on the LDAEP. These findings are in line with other trials using dopamine receptor agonists.

Association between wind-up ratio and central serotonergic function in healthy subjects and depressed patients

Temporal summation of C-fiber evoked responses generates an increase in action potential discharge in second-order neurons and in perceived pain intensity (wind-up). This may be related to the central serotonergic system which modulates and partly inhibits sensory input. Aim of the study was to investigate the relationship between wind-up and serotonergic activity using loudness dependence of auditory evoked potentials (LDAEP). 18 healthy subjects were compared to 18 patients with major depression, a disease with a putative serotonin deficit. They were examined with quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain (DFNS), including the wind-up ratio (WUR), LDAEP, and psychometric measurements. We found a slight positive correlation between WUR and LDAEP both in healthy controls and depressed patients combined (r=0.340, p=0.043), indicating that WUR may be modulated by serotonergic activity. It can be concluded that inhibitory control to noxious stimuli is partly associated with the central serotonergic function as indicated by LDAEP.

Type A behavior pattern and hyperthymic temperament: Possible association with bipolar IV disorder

Type A behavior pattern (TABP) has traditionally been reported to be associated with coronary heart disease and, more recently, several researchers have examined its association with depression and bipolar disorder. According to Akiskal and Pinto (1999), there are 2 subtypes of bipolar spectrum which are not associated with manic or hypomanic state. These are bipolar II1/2 (depression in those who have cyclothymic temperament) and bipolar IV (depression in those who have hyperthymic temperament). Our hypothesis is that individuals with hyperthymic temperament may have a tendency towards TABP. The purposes of the present study are to investigate the association between TABP and hyperthymic temperament and to determine other biological factors associated with TABP. Fifty healthy subjects were assessed for TABP and hyperthymic temperament by self-rating scales, daily activity, sleep time and illuminance by actigraphy, and central serotonergic function via the neuroendocrine challenge test. Serum brain-derived neurotrophic factor (BDNF) levels were also measured. Stepwise regression analysis indicated that hyperthymic temperament score was positively associated with TABP scores and both sleep time and snooze time were negatively associated with TABP scores. BDNF levels were not associated with TABP scores. These findings suggest that individuals with hyperthymic temperament may have a tendency towards TABP, and TABP persons may have short sleep time and short snooze time. Although further studies are required to investigate the association between TABP and affective disorders, the present findings clearly indicate the association between TABP and hyperthymic temperament, which may be associated with bipolar IV disorder. Taking TABP as a risk factor of cardiovascular events into consideration, this association between TABP and bipolar IV disorder may account for the well-known cardiovascular mortality in bipolar disorder.