Haruo Nagayama

Assessment of the Dexamethasone/CRH Test as a State-Dependent Marker for Hypothalamic-Pituitary-Adrenal (HPA) Axis Abnormalities in Major Depressive Episode: A Multicenter Study

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary–adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.

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.

MULTI-CENTER STUDY OF SEASONAL AFFECTIVE DISORDERS IN JAPAN : A PRELIMINARY REPORT

A multi-center study on seasonal affective disorder (SAD) was conducted from the autumn of 1988 to the spring of 1989 with the cooperation of 16 facilities in Japan. Forty-six SAD patients were identified among 1104 respondents to our advertisements in mass media, or patients seen at the outpatient clinics. Essentially similar findings to other previous reports were obtained in terms of onset age of the first episode, duration of episode, high proportion of depression in first-degree relatives and atypical vegetative symptoms. However, a nearly equal sex ratio, together with a high proportion of unipolar depression, is characteristic of the present study. Increased appetite and carbohydrate craving were predominant only in female patients, whereas hypersomnia was prominent in both sexes. Effective response to light therapy was found in 17 SAD patients. However, a controlled study on a large number of patients is required to allow final conclusions on the efficacy of light therapy in Japanese SAD patients.

Frontal Brain Hypoactivity as a Biological Substrate of Anxiety in Patients with Panic Disorders

Frontal brain asymmetry is associated with differences in the basic dimensions of emotion. It seems to reflect the activation of specialized systems for avoidance-withdrawal behavior. Since patients with panic disorder are characterized by having both negative emotions and avoidance-withdrawal behavior, we expected them to show greater asymmetry in the frontal hemisphere change activation. Near-infrared reflection spectroscopy was recorded from the left and right frontal regions of 23 patients with panic disorder without depression and from 31 healthy control participants in the following conditions: confrontation at rest with neutral (mushroom), anxiety-relevant (spider and snake) or anxiety-irrelevant but emotionally relevant stimuli (erotic picture). Emotional states and traits were assessed by the State-Trait Anxiety Inventory. The left frontal oxyhemoglobin in patients was significantly lower than in control subjects when confronted with anxiety-relevant or anxiety-irrelevant but emotionally relevant stimuli. There was no frontal brain asymmetry when patients or control subjects observed any stimuli. These data suggest that patients with panic disorder are characterized by having a greater decrease in the activation of a left frontal avoidance-withdrawal system in situations with a negative valence. The findings are interpreted as biological evidence for a disturbed cortical processing in patients with panic disorder.

Effect of corticotropin releasing factor receptor 1 antagonist on extracellular norepinephrine, dopamine and serotonin in hippocampus and prefrontal cortex of rats in vivo

Corticotropin releasing factor (CRF) is a major mediator of adaptive responsiveness to stress. We measured changes in extracellular concentrations of catecholamine and indoleamines in freely moving rats in response to administration of CRF1 antagonist CP-154,526 by using in vivo microdialysis. Dialysis probes were placed stereotaxically in either the hippocampus or the prefrontal cortex. We examined the response in the hippocampus or the prefrontal cortex to 32.0 mg/kg i.p. administration of CP-154,526. CP-154,526 reduced the extracellular concentration of norepinephrine (NE) from 30 min to 180 min and 5-hydroxytryptamine (5-HT) from 30 min to 60 min after injection in the hippocampus. CP-154,526 did not remarkably change dopamine (DA). There were no significant differences between CP-154,526 and vehicle in NE, 5-HT and DA in the prefrontal cortex. The present results indicate that CRF1 receptor antagonist produced a decrease in dialysate concentration of NE and 5-HT, but not DA, in the hippocampus. These results suggest that the CRH-1 receptor antagonist suppresses the release of NE and 5-HT in the hippocampus.

Lack of association between a polymorphism in the promoter region of the dopamine D2 receptor and personality traits.

Disturbances of the dopaminergic neurotransmitter system have been associated with a personality trait that involves novelty seeking. A functional polymorphism in the promoter region of the dopamine D2 receptor gene (DRD2) has been reported to be associated with schizophrenia. We examined the association between this polymorphism in the DRD2 promoter region and personality traits, as assessed with the Tridimensional Personality Questionnaire. No significant association emerged between the polymorphism in the DRD2 promoter region and personality traits. Entering sex and age as covariates in an analysis of covariance did not change the results. These data fail to confirm an association between a polymorphism in the promoter region of the DRD2 and personality traits.

Effects of antidepressants on intracellular Ca2+ mobilization in CHO cells transfected with the human 5-HT2C receptors

Serotonin 5-HT2C receptor-mediated intracellular Ca2+ mobilization was investigated in 5-HT2C receptors expressed in Chinese hamster ovary (CHO) cells; and fura-2/AM was used to investigate the regulation of 5-HT2C receptor function. CHO cells, transfected with a cDNA clone for the 5-HT2C receptor, expressed 287 fmol/mg of the receptor protein as determined by mianserin-sensitive [3H]-mesulergine binding (kd = 0.49 nM). The addition of 5-HT mobilized intracellular Ca2+ in a dose-dependent fashion, ranging from basal level of 99 +/- 1.8 nM up to 246 +/- 21.2 nM, with an EC50 value for 5-HT of .015 microM. Exposure to 5-HT, a 5-HT receptor agonist, mCPP [1-(3-chlorophenyl)piperazine dihydrochloride], a 5-HT2C agonist, and DOI [1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane], a 5-HT2C and 5-HT2 agonist, resulted in increased intracellular Ca2+ levels. Mianserin, mesulergine, ritanserin, and ketanserin each blocked 5-HT-mediated intracellular Ca2+ mobilization more effectively than spiperone. Mianserin and amoxapine inhibited 5-HT-mediated intracellular Ca2+ mobilization completely; amitriptyline, nortriptyline, and imipramine reduced it about 50%. These results suggest that antagonism in CHO cells transfected with human 5-HT2C receptors is a component of the serotonergic properties of a number of established antidepressants.

Prediction of efficacy of antidepressant by 1-week test therapy in depression

Forty patients suffering from depression were treated with fixed doses of clomipramine for 4 weeks. The most effective predictor of efficacy during the 4 weeks was the percentage improvement in the Hamilton rating scale for depression during the first week. Baseline severity did not show any predictive ability. The Beck depression rating scale had only low predictive ability, and the dexamethasone suppression test did not predict the outcome at all. These results suggest the benefit of 1-week test therapy for predicting the efficacy of antidepressants.

Increased anxiety behavior in OLETF rats without cholecystokinin-A receptor.

Cholecystokinin (CCK) may have a role in the mediation of human panic disorder and anxiogenic (anxiolytic)-like activity in an animal model of anxiety. Otsuka Long Evans Tokushima Fatty (OLETF) rats lacked CCK A receptors (CCKAR) because of a genetic abnormality. In order to elucidate the involvement of CCKAR in the regulation of anxiety, we investigated the exploratory behavior on elevated plus-maze test, the black and white box test, and open field test with OLETF rats in comparison with normal [Long-Evans Tokushima Otsuka (LETO)] rats. And OLETF rats increased the number of stretched attend postures and decreased open arm entry and the % time of open arm in an elevated plus-maze test. Time spent in the white box decreased significantly in OLETF rats than LETO rats. The total line crossing decreased significantly in OLETF rats compared to LETO rats. The missing CCKAR had a significant anxiogenic-like effect. These data support the involvement of the CCKAR in the neurobiological mechanism of anxiety.

Association between the CCK‐A receptor gene and panic disorder

Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in the brain. CCK appears to play an important role in the neurobiology of anxiety and panic disorders (PD) in both humans and animals. Recently, we reported that lack of CCKAR had a significant anxiogenic‐like effect in rats. In this study, to investigate the role of CCKAR in PD, we compared the CCKAR gene in PD patients and normal controls. Subjects who fulfilled the DSM‐IV criteria for PD were 17 males and 26 females. The sequence containing the Pst I polymorphic site in the boundary between intron 1 and exon 2 of the CCKAR gene was studied. Pst I digestion of the PCR products gave two individual alleles: A1 and A2. The A1 allele was the undigested fragment and the A2 allele was the digested one with two variant bands at 264 and 180 bp. Genotypic frequencies were 20.9% (A1‐A1), 55.8% (A1‐A2), and 41.7% (A2‐A2) in patients, and 20.5% (A1‐A1), 46.2% (A1‐A2), and 33.3% (A2‐A2) in controls. Allelic frequencies were 48.8% (A1) and 51.2% (A2) in patients, and 43.6% (A1) and 56.4% (A2) in controls. The chi‐square test did not show a significant difference in either genotypic or allelic frequencies between patients and control subjects. The Pst polymorphism of CCKAR may not be associated with PD.