Hiroaki Hanada

Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats

RATIONALE Ghrelin is a peptide of 28 amino acids found in mammals that increases the release of growth hormone, food intake, and body weight. OBJECTIVES We investigated the relationship between ghrelin and the states of anxiety and depression by giving rats either antisense DNA for ghrelin, scrambled DNA or vehicle into the lateral ventricle of rats. RESULTS In forced swimming tests, rats that received antisense DNA decreased the length of time that they were immobile in the water. Ghrelin antisense oligonucleotides produced an anxiolytic-like effects in the elevated plus maze test, black and white test, or conditioned fear tests. Treatment with antisense DNA for ghrelin significantly decreased rat body weight. No significant effect on general locomotor activity was seen. CONCLUSIONS These results suggest that administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats.

Differences in Salivary Alpha-Amylase and Cortisol Responsiveness following Exposure to Electrical Stimulation versus the Trier Social Stress Tests

Background Cortisol is an essential hormone in the regulation of the stress response along the HPA axis, and salivary cortisol has been used as a measure of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA) has also emerged as a novel biomarker for psychosocial stress responsiveness within the sympathetic adrenomedullary (SAM) system. Principal Findings We measured sAA and salivary cortisol in healthy volunteers after exposure to the Trier Social Stress Test (TSST) and electric stimulation stress. One hundred forty-nine healthy volunteers participated in this study. All subjects were exposed to both the TSST and electric stimulation stress on separate days. We measured sAA and salivary cortisol levels three times immediately before, immediately after, and 20 min after the stress challenge. The State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory test and the Profile of Mood State (POMS) tests were administered to participants before the electrical stimulation and TSST protocols. We also measured HF, LF and LF/HF Heart Rate Variability ratio immediately after electrical stimulation and TSST exposure. Following TSST exposure or electrical stimulation, sAA levels displayed a rapid increase and recovery, returning to baseline levels 20 min after the stress challenge. Salivary cortisol responses showed a delayed increase, which remained significantly elevated from baseline levels 20 min after the stress challenge. Analyses revealed no differences between men and women with regard to their sAA response to the challenges (TSST or electric stimulations), while we found significantly higher salivary cortisol responses to the TSST in females. We also found that younger subjects tended to display higher sAA activity. Salivary cortisol levels were significantly correlated with the strength of the applied electrical stimulation. Conclusions These preliminary results suggest that the HPA axis (but not the SAM system) may show differential response patterns to distinct kinds of stressors.

Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population.

Major depressive disorder (MDD) and panic disorder (PD) are common and disabling medical disorders with stress and genetic components. Dysregulation of the stress response of the hypothalamic–pituitary–adrenal axis, including the corticotrophin‐releasing hormone (CRH) signaling via primary receptors (CRHR1 and CRHR2), is considered to play a major role for onset and recurrence in MDD and PD. To confirm the association of CRHR1 and CRHR2 with MDD and PD, we investigated 12 single nucleotide polymorphisms (SNPs) (rs4076452, rs7209436, rs110402, rs242924, rs242940, and rs173365 for CRHR1 and rs4722999, rs3779250, rs2267710, rs1076292, rs2284217, and rs226771 for CRHR2) in MDD patients (n = 173), PD patients (n = 180), and healthy controls (n = 285). The SNP rs110402 and rs242924 in the CRHR1 gene and the rs3779250 in the CRHR2 gene were associated with MDD. The SNP rs242924 in the CRHR1 gene was also associated with PD. The T‐A‐T‐G‐G haplotype consisting of rs7209436 and rs173365 in CRHR1 was positively associated with MDD. The T‐A haplotype consisting of rs7209436 and rs110402 in CRHR1 was positively associated with MDD. The C‐C haplotype consisting of rs4722999 and rs37790 in CRHR1 was associated with PD. These results provide support for an association of CRHR1 and CRHR2 with MDD and PD.

Ghrelin gene polymorphism is associated with depression, but not panic disorder.

Ghrelin, which was identified for the first time by Kojima et al. in rat stomach, is a novel peptide of 28 amino acids, which acts as endogenous ligand for the growth hormone secretagogue receptor (Kojima et al., 1999; Kojima and Kangawa, 2005). Thus, one function of ghrelin is to increase pituitary release of growth hormone (Arvat et al., 2000). Regional distribution of ghrelin receptors suggests that the peptide could be related to emotional processes. Some researchers reported that both central (e.g. intraventricular) and peripheral (e.g. intraperitoneal) administration of ghrelin is a potent inducer of anxiogenic behavior in mice (Asakawa et al., 2001; Carlini et al., 2002). Similar research indicates that ghrelin induces anxiogenesis in rats. Recently, we reported that administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats (Kanehisa et al., 2006).

Anticipatory anxiety-induced changes in human lateral prefrontal cortex activity.

It has been suggested that frontal brain asymmetry is associated with differences in basic emotional dimensions, particularly in activation of systems underlying avoidance-withdrawal behavior. We examined regional cerebral oxygenated hemoglobin (O2Hb) levels in human medial prefrontal cortex (MPFC) using near-infrared reflection spectroscopy (NIRS) prior to and during anticipatory anxiety to determine if NIRS could detect any anxiety-related changes. Transient anxiety was induced in 56 normal volunteers by anticipation and a painful shock to the right-hands median nerve. Pre- and post-anxiety affective statuses were measured using the State-Trait Anxiety Inventory (STAI) and Temperature Character Inventory (TCI). NIRS recorded from the left and right frontal brain regions. Right MPFC O2Hb was significantly increased relative to left MPFC O2Hb during anticipation of the shock. Right-sided O2Hb increases were significantly correlated with the TCI Harm Avoidance subscale. These results support the hypothesis that O2Hb levels in the right frontal region correlate with anxiety or heightened negative affect.

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in panic disorder patients

Psychosocial stress-induced activation of salivary α-amylase (sAA) functions is as a marker of sympathoadrenal medullary system (SAM) activity. However, in contrast to salivary cortisol, sAA has been less extensively studied in panic disorder patients. The present study measured sAA and salivary cortisol levels in patients with panic disorder following electrical stimulation stress. The authors determined Profile of Mood State (POMS) scores and State-Trait anxiety Inventory (STAI) scores, heart rate variability (HRV), and levels of sAA and salivary cortisol in 34 patients with panic disorder and 41 healthy volunteers following the application of electrical stimulation stress. 34 alprazolam-treated patients with panic disorder were divided into non-responder and responder group. Vigor scores in patients with panic disorder were significantly decreased compared with healthy controls. Another score in POMS in patients with panic disorder were significantly increased compared with healthy controls. Trait and state anxiety of STAI in panic disorder patients were higher than healthy controls. There was no difference in either HRV or threshold of electrical stimulation applied between panic disorder patients and healthy controls. SAA levels in the responder group were significantly elevated compared with the non-responder group and controls both before and after electrical stimulation. In addition, there were no differences in salivary cortisol levels between responder and non-responder groups of patients with panic disorder and control. The sample may not be representative of the general population. These preliminary results suggest that sAA might be useful predictive biological markers of treatment responsiveness in patients with panic disorder.

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in major depressive disorder patients.

Major depressive disorder (MDD) is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis by chronic stress. In comparison, psychosocial stress-induced activation of salivary α-amylase (sAA) functions as a marker of sympathoadrenal medullary system (SAM) activity. However, in contrast to salivary cortisol, sAA has been less extensively studied in MDD patients. The present study measured sAA and salivary cortisol levels in patients with MDD. The authors determined Profile of Mood State (POMS) and State-Trait anxiety Inventory (STAI) scores, Heart Rate Variability (HRV), and sAA and salivary cortisol levels in 88 patients with MDD and 41 healthy volunteers following the application of electrical stimulation stress. Patients with major depressive disorder were 8 points or more on Hamilton Depression Scale (HAM-D) scores. Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue, and Confusion scores in patients with major depressive disorder were significantly increased compared to healthy controls. In contrast, Vigor scores in patients with MDD were significantly decreased compared with healthy controls. There was no difference in heart rate variability measures between MDD patients and healthy controls. The threshold of electrical stimulation applied in MDD patients was lower than that in healthy controls. SAA levels in female MDD patients were significantly elevated relative to controls both before and after electrical stimulation. Finally, there were no differences in salivary cortisol levels between major depressive patients and controls. In the present study only three time points were explored. Furthermore, the increased secretion of sAA before and after stimulation could allude to an increased responsiveness of novel and uncontrollable situations in patients with MDD. These preliminary results suggest that sAA might be a useful biological marker of MDD.

Serum Ghrelin Levels and the Effects of Antidepressants in Major Depressive Disorder and Panic Disorder

Background: Two opposing models for the action of ghrelin in the behavioral responses to stress were recently proposed. Some studies suggest that an increase in ghrelin contributes to the mechanisms responsible for the development of stress-induced depression and anxiety, while others suggest that it helps minimize what otherwise would be more severe manifestations of depression and anxiety following stress. Methods: We measured serum ghrelin levels, Profile of Mood States (POMS) scores and State-Trait Anxiety Inventory scores in nonresponders (treatment-resistant patients; 30) and responders (38) with major depressive disorder (MDD), nonresponders (29) and responders (51) with panic disorder and 97 healthy controls. Results: The ghrelin concentration in nonresponders with MDD was higher than that of responders with MDD and normal controls. The ghrelin concentration in nonresponders with panic disorder was higher than that of normal controls. POMS vigor scores in patients with MDD and panic disorder were significantly decreased compared with those in healthy controls. Other POMS scores in patients with MDD and panic disorder were significantly increased compared with those of healthy controls. Trait and state anxiety of the State-Trait Anxiety Inventory in MDD and panic disorder patients were higher than those in healthy controls. Conclusions: These results indicate that decreased serum ghrelin levels might be associated with antidepressant treatment to confer the maximum therapeutic effect in patients with MDD and panic disorder.

Elevated salivary α-amylase and cortisol levels in unremitted and remitted depressed patients.

Abstract Objective. Major depressive disorder (MDD) is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis via chronic stress. Psychosocial stress-induced activation of salivary α-amylase (sAA) represents sympathoadrenal medullary system (SAM) activity, and sAA has become an emerging biomarker for sympathetic nervous system activity. In contrast to salivary cortisol, sAA has been less extensively studied in depressed patients. The present study sought to address this problem by measuring sAA and salivary cortisol levels in patients with major depressive disorder. Methods. The authors recorded Spielberger State-Trait Anxiety Inventory (STAI) scores along with, levels of sAA and salivary cortisol in 28 patients with unremitted major depressive disorder, 43 remitted patients and 103 healthy volunteers. Results. STAI (State or Trait) measurements in unremitted patients with MDD were significantly increased compared with healthy controls and remitted patients. SAA and cortisol levels in unremitted patients were also significantly elevated compared to controls and remitted patients. Finally, sAA levels were significantly correlated with HRSD in unremitted patients with MDD. Conclusion. These preliminary results suggest that sAA may be a state-dependent marker of major depressive disorder in addition to salivary cortisol.

A young woman with visual hallucinations, delusions of persecution and a history of performing arson with possible three‐generation Fahr disease

Objective:  Fahr disease (FD) is a rare neurological and psychiatric disorder. The disease is classified by intracranial calcification of the basal ganglia with the globus pallidus region being particularly affected. We examined a young woman with visual hallucinations, delusions of persecution and a history of performing arson with possible third‐generation FD.