Ayako Inoue

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.

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.

Salivary alpha-amylase and cortisol responsiveness following electrically stimulated physical stress in bipolar disorder patients

Background Bipolar disorder (BP) is often associated with a change in hypothalamus– pituitary–adrenal axis function change due to chronic stress. Salivary α-amylase (sAA) levels increase in response to psychosocial stress and thus function as a marker of sympathoadrenal medullary system activity. However, sAA has been studied less often than salivary cortisol in BP patients. Method We measured Profile of Mood States and State-Trait Anxiety Inventory scores, heart rate variability, and salivary cortisol levels during electrical stimulation stress in 25 BP patients and 22 healthy volunteers. Results Tension–anxiety, depression–dejection, anger–hostility, fatigue, and confusion scores in BP patients significantly increased compared with those of the healthy controls. In contrast, the vigor scores of BP patients significantly decreased compared with those of the healthy controls. Significant difference in the sAA levels was observed between BP patients and healthy controls. sAA of female patients was significantly higher than that of female healthy controls, and sAA in male patients tended to be higher than that of male healthy controls. No difference in salivary cortisol was observed between BP patients and the healthy controls. Only three time points were measured before and after the electrical stimulation stress. Furthermore, sAA secretion by BP patients increased before and after electrical stimulation. Conclusion These preliminary results suggest that sAA may be a useful biological marker for BP patients.

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in patients with the generalized type of social anxiety disorder.

INTRODUCTION Social anxiety disorder is believed to be a stress-induced disease. Although it can be inferred from the symptoms during attacks that there exists some abnormality of autonomic nervous system in any of the stress systems in social anxiety disorder, little evidence has been reported. This study focused on comparing the reactivity of 2 stress systems, the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis in patients with social anxiety disorder. METHODS 32 patients with the generalized type of social anxiety disorder were compared with 80 age- and gender-matched controls. We collected saliva samples from patients and controls before and after electrical stimulation to measure the concentrations of salivary alpha-amylase (sAA) and salivary cortisol. Profile of Mood State (POMS) and State-Trait Anxiety Inventory (STAI) scores and Heart Rate Variability (HRV) were also determined following stimulation. RESULTS SAA in patients displayed a significantly higher level at baseline and a significantly larger response to electrical stimulation as compared to controls, whereas no group differences were seen in any HRV. Neither within-subject nor group differences were seen in salivary cortisol levels. CONCLUSIONS These results suggest that SAD patients displayed enhanced ANS (but not HPA axis) activity vs. healthy controls.

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in obsessive-compulsive disorder patients.

Salivary α-amylase (sAA) serves as a marker of sympathoadrenal medullary system (SAM) activity. Salivary AA has not been extensively studied in obsessive-compulsive disorder (OCD) patients. In the current study, 45 OCD patients and 75 healthy volunteers were assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Profile of Mood State (POMS), and the State-Trait Anxiety Inventory (STAI). Measures of heart rate variability (HRV), sAA, and salivary cortisol were also obtained following the application of electrical stimulation stress. The Y-BOCS and POMS Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue, and Confusion scores were significantly increased in patients with OCD compared with healthy controls. In contrast, Vigor scores were significantly decreased in patients with OCD relative to scores in healthy controls. There was no difference in HRV between the patients and the controls. Salivary AA levels in female and male OCD patients were significantly elevated relative to controls both before and after electrical stimulation. In contrast, there were no differences in salivary cortisol levels between OCD patients and controls. The elevated secretion of sAA before and after stimulation may suggest an increased responsiveness to novel and uncontrollable situations in patients with OCD. An increase in sAA might be a characteristic change of OCD.

Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress.

Background Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. Methods To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). Results A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. Conclusion These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic–pituitary–adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests.

Genetic association of the transcription of neuroplasticity-related genes and variation in stress-coping style.

Stress coping has been defined as the cognitive and behavioral efforts made to conquer, endure, or decrease external and internal demands and the conflicts between them. It has two main elements: the control or modification of the person–environment relationship causing the stress (i.e., problem‐focused coping) and/or regulation of stressful feelings (i.e., emotion‐focused coping). Research suggests that the expressions of brain‐derived neurotrophic factor (BDNF) and neurotrophic tyrosine kinase receptor type 2 (NTRK2) play important roles in brain adaptation to investigate stress. To clarify the genetic basis of stress coping, we investigated the association of stress‐coping strategies and social adaptation with single‐nucleotide polymorphisms (SNPs) involved in neural plasticity, anxiety, and depression.

FKBP5 is associated with amygdala volume in the human brain and mood state: A voxel-based morphometry (VBM) study

Abstract The present study was to investigate the effects of 6 FK506 binding protein 51 (FKBP5) single nucleotide polymorphisms (SNPs) on brain structure using voxel-based morphometry (VBM) and the psychological tests to psychological stress. We genotyped 112 healthy controls with respect to 6 SNPs (rs) of FKBP5. We examined the Beck Depression Inventory and the State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory and the Profile of Mood States (POMS) to evaluate mood. The right amygdala was larger in subjects with the minor allele (C) of rs3800373 and rs992105 and the minor allele (T) of rs1360780. The right middle orbitofrontal region in those with the minor allele (C) of rs3800373 and the right inferior orbitofrontal region in those with the minor allele (T) of rs9470080 was larger. Both the amygdala volumes were associated significantly with FKBP5 SNPs. We found significant relationships between factors in POMS and the right and left amygdala and left insula. Our results suggest that FKBP5 SNPs are associated with the alternations of volumes in right amygdala and the right middle and inferior orbitofrontal region. Genetic variants of FKBP5 may be associated with depressive and anxiety state via differential effects on amygdala and orbitofrontal region.

Gender determines cortisol and alpha-amylase responses to acute physical and psychosocial stress in patients with borderline personality disorder

Borderline personality disorder (BPD) is characterized by affective instability, unstable relationships, and identity disturbance. We measured salivary alpha-amylase (sAA) and salivary cortisol levels in all participants during exposure to the Trier Social Stress Test (TSST) and an electric stimulation stress. Seventy-two BPD patients were compared with 377 age- and gender- matched controls. The State and Trait versions of the Spielberger Anxiety Inventory test (STAI-S and STAI-T, respectively), the Profile of Mood State (POMS) tests, and the Beck Depression Inventory (BDI), the Depression and Anxiety Cognition Scale (DACS) were administered to participants before electrical stimulation. Following TSST exposure, salivary cortisol levels significantly decreased in female patients and significantly increased in male patients compared with controls. POMS tension-anxiety, depression-dejection, anger-hostility, fatigue, and confusion scores were significantly increased in BPD patients compared with controls. In contrast, vigor scores were significantly decreased in BPD patients relative to controls. Furthermore, STAI-T and STAI-S anxiety scores and BDI scores were significantly increased in BPD patient compared with controls. DACS scores were significantly increased in BPD patient compared with controls. Different stressors (e.g., psychological or physical) induced different responses in the HPA and SAM systems in female or male BPD patients.

Genetic association of the oxytocin receptor genes with panic, major depressive disorder, and social anxiety disorder

Oxytocin (OXT) is secreted into the brain through the pituitary gland. It stimulates neurons expressing oxytocin receptors (OXTR) and controls multiple physiologic and reproductive functions. OXT plays a role in the modification of stress response and stress-related behaviors (Arletti and Bertolini, 1987). OXT also plays an important role in anxiety and social interaction. Serum OXT level is related to parent–child bonding behavior, romantic feelings, and trust (Feldman et al., 2007). The individuals with the A allele (AG/AA) showed lower empathy and higher stress reactivity compared with the individuals who were homozygous for the G allele (GG) in humans (Rodrigues et al., 2009). The girls who both were heterozygous for the OXTR rs2254298 polymorphism and had high early adversity reported the highest levels of symptoms of depression, physical anxiety, and social anxiety (Thompson et al., 2011). The objective of this study was to investigate the relationship between polymorphisms of OXTR rs2254298 and rs53576 and panic disorder, social anxiety disorder, and major depressive disorder risk through a case–control study of 1257 Japanese participants. The patient and the control group comprised 643 controls and 210 panic disorder, 117 social anxiety disorder, 287 major depressive disorder patients diagnosed according to the criteria of Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) (the MiniInternational Neuropsychiatric Interview). This study was approved by the Ethics Committee for Genome Research of the Oita University Faculty of Medicine. All participants provided written informed consent. The proportion of AA, AG, and GG of rs2254298 in panic disorder, social anxiety disorder, and major depressive disorder healthy individuals was 8.7, 30.1, 61.2%; 14.5, 38.5, 47.0%; 15.4, 39.0, 45.6%; and 11.3, 39.8, 48.9%, respectively. The proportion of AA, AG, and GG of rs53576 was 41.3, 44.6, 14.1%; 43.6, 42.7, 13.7%; 42.0, 51.4, 6.6%; and 43.5, 48.0, 8.5%, respectively. The frequencies of the genotypes did not fit the Hardy– Weinberg equilibrium. The presence of the AA+AG genotype of rs2254298 in panic disorder had a protective effect compared with the GG genotype [odds ratio (OR)=1.6 (1.2–2.3), P=0.002]. The presence of the AA+AG genotype of rs53576 in panic disorder had a protective effect compared with the GG genotype [OR=1.8 (1.1–2.8), P=0.02]. The presence of the AA+AG genotype of rs53576 was associated with increased major depressive disorder risk compared with the GG genotype [OR=0.3 (0.2–0.4), P<0.0001]. However, there was no association between rs2254298 and major depressive disorder [OR=0.9 (0.7–1.2), P=0.36]. There was no association between OXTR rs2254298 and rs53576, and social anxiety disorder [OR=0.9 (0.6–1.4), P=0.71; OR=0.8 (0.4–1.3), P=0.34]. Some reports showed that there was a positive association between the GG genotype of OXTR rs53576 and major depressive disorder (Costa et al., 2009). However, there are no reports on the association between OXTR genotype and social anxiety disorder. Some reports showed that there was a significant relationship between OXTR and panic disorder (Johnson et al., 2010). Our data suggest that G carriers of the OXTR thus might have been more vulnerable to panic and major depressive disorder.