Kounosuke Tsuchiyama

DNA Methylation Profiles of the Brain-Derived Neurotrophic Factor (BDNF) Gene as a Potent Diagnostic Biomarker in Major Depression

Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV) at the promoters of the brain-derived neurotrophic factor (BDNF) gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray® system (SEQUENOM), and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.

Discrepancy between subjective and objective sleep in patients with depression.

Abstract The literature investigating the relationship between objective and subjective sleep in depressed patients is limited and the results are inconsistent. Furthermore, many factors that influence the aforementioned relationship have not been investigated. The present study was carried out to clarify the characteristics of self‐estimation of sleep in depressed patients. Sleep was estimated concurrently using a sleep log and polysomnography for 5 consecutive days to investigate the relationship between subjective sleep estimation and objective sleep estimation in 23 patients with major depression (Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised; DSM‐III‐R). Factors related to a discrepancy between both types of estimation were identified. The subjective total sleep time showed a significant, but moderate, positive correlation (correlation coefficient: 0.63) with the objective total sleep time. The degree of discrepancy was significantly correlated with various objective sleep variables and severity of depression. In the underestimation group in which the subjective total sleep time was shorter than the objective total sleep time, the objective total sleep time and slow‐wave sleep time were shorter, age was greater and the extroversion score (Maudsley Personality Inventory) was lower than in the overestimation group in which the subjective total sleep time was longer than the objective total sleep time. The data suggest that subjective sleep estimation in depressed patients is influenced by their objective sleep, severity of depression, age and personality.

The potential of SLC6A4 gene methylation analysis for the diagnosis and treatment of major depression.

We examined the utility of DNA methylation profiles at the CpG island of SLC6A4 (DMS) as a diagnostic biomarker for major depression (MD). In addition, the relationship between DMS and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) allele, the severity of symptoms, number of early adversities, and therapeutic responses to antidepressants were examined. Genomic DNA was extracted from peripheral blood of Japanese healthy controls and patients with MD before and after treatment. DMS was analyzed using a MassARRAY Compact System. The severity of depression was evaluated using the Hamilton Rating Scale for Depression, and early adversity was evaluated using the Early Trauma Inventory. We were unable to distinguish between and healthy controls, or between unmedicated patients and medicated patients using DMS. The 5-HTTLPR allele had no significant effect on DMS. The methylation rates for several CpGs differed significantly after treatment. Notably, the methylation rate of CpG 3 in patients with better therapeutic responses was significantly higher than that in patients with poorer responses. Although further studies examining the function of specific CpG units of SLC6A4 are required, these results suggest that the pre-treatment methylation rate of SLC6A4 is associated with therapeutic responses to antidepressants in unmedicated patients with MD.

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

RationaleHyperthymic 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.ObjectivesTo 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.MethodsFifty 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.ResultsMultiple 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.ConclusionsThe present findings suggest that light, sleep, and serotonin are crucial factors in understanding hyperthymic temperament, which may be common to bipolar disorder.

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

BACKGROUND 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. OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Predicting efficacy of electroconvulsive therapy in major depressive disorder

Abstract  The aim of this study was to investigate methods for predicting the efficacy of electroconvulsive therapy (ECT) in patients with major depressive disorder. Subjects comprised 24 inpatients with major depressive disorder diagnosed according to DSM‐IV criteria who were resistant to antidepressant therapy or who, due to adverse reactions, could not undergo pharmacotherapy at adequate doses for sufficient durations. ECT was generally performed 12 times using a sinusoidal‐wave device. Efficacy of ECT was evaluated using the 17‐item Hamilton Rating Scale for Depression (HRSD). Multiple regression analysis was performed, using the final rate of improvement with ECT as the dependent variable, and improvement rate at completion of three ECT sessions and adequacy of pharmacotherapy before ECT as independent variables. Significant positive correlations were seen between final improvement rate with ECT and improvement rate at completion of three ECT sessions (partial correlation coefficient, 0.50, P < 0.02), and significant negative correlations were seen between final improvement rate and adequacy of pharmacotherapy before ECT (partial correlation coefficient, −0.51, P < 0.02). No significant differences were identified between responders and non‐responders with respect to age, sex, duration of index episode, number of previous depressive episodes, whether depression was melancholia‐type, whether depression was accompanied by psychotic features, total HRSD score immediately before ECT, and HRSD retardation or agitation scores. These results suggest that history of pharmacotherapy prior to ECT and improvement rate at completion of three ECT sessions may offer predictors for the final rate of improvement with ECT.

Relationship between hostility and subjective sleep quality

While hostility and sleep disturbance are the potential risk factors for health problems and disease, few studies have examined the relationship between the two factors. The present study was performed to investigate the relationship between hostility and sleep problems assessed both subjectively and objectively in a nonclinical sample. Sixty-one healthy subjects were enrolled in this study. Hostility was measured according to the Cook-Medley hostility scale. Subjective sleep quality was evaluated according to the global score of the Pittsburgh Sleep Quality Index. Objective sleep was evaluated using actigraphy. A multiple regression analysis revealed that a higher level of hostility was significantly associated with the global score of the Pittsburgh Sleep Quality Index and that a higher level of depression was not associated with the global score of the Pittsburgh Sleep Quality Index. Objective sleep measures were not found to be associated with hostility. Confirming the robust relationship between poor sleep and hostility would have several important treatment implications for preventing health problems.

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

BACKGROUND 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. METHODS 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. RESULTS On the whole, depressive symptoms significantly improved, but the improvement was not associated with changes in serotonergic function. LIMITATIONS The study was open-labeled and performed with a small number of subjects and no control group. CONCLUSION Serotonergic function may not be associated with the antidepressant effects of ECT.

Effects of 8-OH-DPAT on corticosterone after acute and chronic administration of antidepressants

1. Serotonin has a facilitary role in the role of corticosterone secretion. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist, dose dependently (0.25- 1.0 mg/kg i.p.) increased rat plasma corticosterone concentration. 2. 3 days parachlorophenylalanine (PCPA) (150 mg/kg) administration did not effect the 8-OH-DPAT-induced corticosterone secretion. 3. Corticosterone responses to 8-OH-DPAT (0.5 mg/kg) were significantly attenuated by pretreatment with propranolol (5 mg/kg). Ketanserin (2 mg/kg), haloperidol (0.2 mg/kg), prazosin (0.1 mg/kg), and ICS-205930 (30 mu/kg) failed to antagonize the corticosterone response to 8-OH-DPAT. 4. 8-OH-DPAT-induced corticosterone were investigated in male rats after treatment with mianserin (2, 10 mg/kg), imipramine (5 mg/kg), desipramine (5 mg/kg), doxepine (5 mg/kg) for 1 day or 3 weeks. Chronic mianserin (10 mg/kg) and doxepine (5 mg/kg) did significantly increase 8-OH-DPAT-induced corticosterone response. Acute antidepressant, chronic imipramine, desipramine and mianserin (2 mg/kg) treatment did not change it. 5. These findings demonstrate that chronic treatment of some antidepressants potentiates 8-OH-DPAT-induced increase in plasma corticosterone, by actions at 5-HT-1A receptors located postsynaptically on 5-HT neurones.

A method for analyzing biological rhythms in healthy subjects and depressed patients

Abstract: Rectal temperature rhythms of healthy subjects and patients with depression were fitted to a waveform having cosine components of periods 8, 12, and 24 hours using the least squares method. The nadir was then used as an index of phase. The results suggest that this method gives more exact data than the conventional method of analyzing biological rhythms, which uses a least squares fit to a single, 24‐hour‐period cosine waveform.