Jens Gaab

Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus-pituitary-adrenal axis

Following the assumption that stressors play an important part in the etiology and maintenance of psychiatric disorders, it is necessary to evaluate parameters reflecting stress-related physiological reactions. Results from these examinations may help to deepen the insight into the etiology of psychiatric disorders and to elucidate diagnostic uncertainties. One of the best-known stress-related endocrine reactions is the hormonal release of the hypothalamic-pituitary-adrenal (HPA) axis. Dysregulations of this axis are associated with several psychiatric disorders. Profound hyperactivity of the HPA-axis has been found in melancholic depression, alcoholism, and eating disorders. In contrast, posttraumatic stress disorder, stress-related bodily disorders like idiopathic pain syndromes, and chronic fatigue syndrome seem to be associated with diminished HPA activity (lowered activity of the adrenal gland). Hypotheses referring to (a) the psychophysiological meaning and (b) the development of these alterations are discussed.

Psychological determinants of the cortisol stress response: the role of anticipatory cognitive appraisal

Psychosocial stress is a potent activator of the hypothalamus-pituitary-adrenal (HPA) axis. While the physiological mechanisms of HPA axis responses to stress as well as its short and long-term consequences have been extensively examined, less is known why someone elicits an acute neuroendocrine stress response, i.e. what are the psychological processes involved and how are they related to the acute neuroendocrine stress response. To examine this question, a questionnaire to assess anticipatory cognitive appraisal processes was developed and administered to 81 male healthy subjects in a standardized psychosocial stress situation (Trier social stress test). Cortisol stress responses were assessed with repeated measurement of salivary free cortisol. Hierarchical regression analyses show that anticipatory cognitive appraisal, in contrast to general personality factors and retrospective stress appraisal is an important determinant of the cortisol stress response, explaining up to 35% of the variance of the salivary cortisol response. The reported results emphasize the importance of psychological stress processing for the understanding of psychobiological stress responses. Since stress and its biological consequences have been shown to be associated with the onset and the maintenance of somatic illnesses and psychiatric disorders, psychological processes are prime targets for prevention and intervention.

Randomized controlled evaluation of the effects of cognitive-behavioral stress management on cortisol responses to acute stress in healthy subjects.

Psychosocial stress is a potent activator of the hypothalamus-pituitary-adrenal (HPA) axis. While neuroendocrine stress responses are essential for the maintenance of homeostasis, evidence suggests that excessive activation of the HPA axis constitutes a risk for disease and psychopathology. The purpose of the present study was to assess the effect of cognitive-behavioral stress management training on endocrine stress responses and cognitive appraisal under acute psychosocial stress among healthy young subjects. Forty-eight healthy, non-smoking male students without acute or chronic medical or psychiatric disorder on self report were randomly assigned to receive group-based cognitive-behavioral stress management training either before or after a standardized psychosocial stress test (Trier Social Stress Test, TSST). Endocrine and psychological stress responses were assessed with salivary free cortisol response and cognitive appraisal processes to the TSST. In comparison with the control group, subjects in the treatment group showed an attenuated endocrine response (F (2.55/117.41) = 3.81; P = 0.02; effect size f(2) = 0.35) to the TSST. In addition, subjects in the SIT group had lower stress appraisal and higher control expectancies (F (2/45) = 6.56; P = 0.003, effect size f(2) = 0.29) compared to controls. Short group-based cognitive-behavioral stress management training reduces the neuroendocrine stress response to an acute stressor in healthy subjects. Therefore, stress management training may prove useful in preventing detrimental effects of stress-induced neuroendocrine activation

INCREASING CORRELATIONS BETWEEN PERSONALITY TRAITS AND CORTISOL STRESS RESPONSES OBTAINED BY DATA AGGREGATION

Attempts to link personality traits and cortisol stress responses have often been inconclusive. The aim of this paper was to investigate this association by aggregating cortisol stress responses. Therefore, 20 healthy men were exposed to a task consisting of public speaking and mental arithmetics in front of an audience on five days. Six cortisol levels were measured in relation to the stressful task obtained at 10-min intervals on each day. Psychological assessment included the Questionnaire for Competence and Control (FKK) and the Giessen-Test (G-T). These questionnaires focus on assessing personality traits, i.e. locus of control and self-concept. Areas under the response curve (AUC) of the six cortisol samples were computed to obtain an index of the individuals cortisol stress response on each day. Since novelty is a random situational factor likely to mask individual differences in the stress response, the AUC cortisol stress responses of days two to five were consecutively aggregated, excluding the first day. Scales of the two questionnaires employed did not correlate with the AUC cortisol stress response of the first stress trial. The correlation pattern of the AUC cortisol measures of days two to five with the questionnaire scales was inconclusive. However, significant correlations emerged with an increasing number of cortisol stress responses aggregated. Correlations between the measure of social dominance and aggregated AUC cortisol stress responses rose from r = -.47 on day two of the experimental session to r = -.70 after aggregating days two to five. Similarly, measures of locus of control and cortisol stress responses became increasingly correlated with aggregation of several stress exposures. These data provide preliminary evidence for a relationship between questionnaire scales aiming at assessing personality traits and cortisol stress responses uncovered by repeated stress exposure and data aggregation. While novelty may mask the impact of personality on the cortisol stress response on the first exposure, differences in the ability to cope with the stressful situation may lead to different cortisol stress response patterns on subsequent stress exposures. With data aggregation, an association between the trait component of cortisol stress responses and questionnaire scales might be uncovered. For reliable investigation of correlations between personality variables and cortisol stress responses, repeated stress exposure and data aggregation is suggested.

Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome.

OBJECTIVE It has been suggested that a hypofunctional hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome could result in an exaggerated release of pro-inflammatory cytokines during stress. As pro-inflammatory cytokines are involved in the induction of sickness behavior and thus constitute a potential physiological correlate of stress-induced symptom exacerbation in chronic fatigue syndrome, we set out to evaluate the LPS-induced production of pro-inflammatory cytokines during psychosocial stress in CFS and healthy controls. METHOD Twenty-one CFS patients and 20 healthy controls matched for age and gender underwent a standardized psychosocial stress test (Trier social stress test, TSST). Adrenocorticotropine hormone (ACTH), salivary cortisol and plasma cortisol levels were measured before and repeatedly following exposure to the stressor. Lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-alpha were assessed at baseline as well as 10 and 60 min after the stress test. RESULTS CFS patients showed an inverse stress-induced response pattern of LPS-stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were significantly associated for TNF-alpha in controls and for both cytokines in CFS patients. Stress-induced changes in stimulated cytokine production were not associated with general fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines. However, partial correlations revealed that these results were due to the high correlations with basal LPS-induced cytokine levels. CONCLUSION CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated pro-inflammatory Il-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-alpha.

Persistent effects of cognitive-behavioral stress management on cortisol responses to acute stress in healthy subjects—A randomized controlled trial

Psychosocial stress leads to a release of cortisol. While this psychoneuroendocrine response helps to maintain physiological as well as psychological equilibrium under stress, exaggerated secretion of cortisol has been shown to have negative effects on somatic health and cognitive functioning. The study set out to examine the long-term effects of cognitive-behavioral stress management training on cortisol stress responses in healthy men and women. Eighty-three healthy subjects were randomly assigned to cognitive-behavioral stress management (CBSM) training or a control condition. Four months after the CBSM, 76 subjects underwent a standardized psychosocial stress test. Salivary cortisol responses were assessed repeatedly before and after the stress test. Subjects in the CBSM group showed significantly reduced cortisol stress responses. With regard to gender, this effect was observed in both men and women. However, the magnitude of the CBSM effect on cortisol responses was smaller in women than in men. Use of oral contraceptives in women influenced the cortisol response, but did not have an impact on the CBSM effect on cortisol. The results show that the previously reported attenuation of cortisol stress responses through CBSM persists and are observable in both men and women. Since stress-induced alterations of hypothalamus pituitary adrenal axis functioning are discussed to be involved in the onset and maintenance of both somatic and psychiatric conditions, similar interventions could be used for prevention and therapy of these detrimental stress effects.

Low-dose dexamethasone suppression test in chronic fatigue syndrome and health.

Objective Subtle dysregulations of the hypothalamus-pituitary-adrenal axis in chronic fatigue syndrome have been described. The aim of this study was to examine the negative feedback regulations of the hypothalamus-pituitary-adrenal axis in chronic fatigue syndrome. Methods In 21 patients with chronic fatigue syndrome and 21 healthy control subjects, awakening and circadian salivary free cortisol profiles were assessed over 2 consecutive days and compared with awakening and circadian salivary free cortisol profiles after administration of 0.5 mg of dexamethasone at 11:00 PM the previous day. Results Patients with chronic fatigue syndrome had normal salivary free cortisol profiles but showed enhanced and prolonged suppression of salivary free cortisol after the administration of 0.5 mg of dexamethasone in comparison to the control subjects. Conclusions Enhanced negative feedback of the hypothalamus-pituitary-adrenal axis could be a plausible explanation for the previously described alterations in hypothalamus-pituitary-adrenal axis functioning in chronic fatigue syndrome. Because similar changes have been described in stress-related disorders, a putative role of stress in the pathogenesis of the enhanced feedback is possible.

Reduced reactivity and enhanced negative feedback sensitivity of the hypothalamus–pituitary–adrenal axis in chronic whiplash-associated disorder

Abstract Dysregulations of the hypothalamus–pituitary–adrenal (HPA) axis have been discussed as a physiological substrate of chronic pain and fatigue. The aim of the study was to investigate possible dysregulations of the HPA axis in chronic whiplash‐associated disorder (WAD). In 20 patients with chronic WAD and 20 healthy controls, awakening cortisol responses as well as a short circadian free cortisol profile were assessed before and after administration of 0.5 mg dexamethasone. In comparison to the controls, chronic WAD patients had attenuated cortisol responses to awakening, normal cortisol levels during the day, and showed enhanced and prolonged suppression of cortisol after the administration of 0.5 mg dexamethasone. Dysregulations of the HPA axis in terms of reduced reactivity and enhanced negative feedback suppression exist in chronic WAD. The observed endocrine abnormalities could serve as a systemic mechanism of symptoms experienced by chronic WAD patients.

Neuroendocrine mechanisms of stress and social interaction: implications for mental disorders

Purpose of review The purpose of the present review is to consider further evidence for the role of neuroendocrine mechanisms in mental disorders by focusing on recent trends and advances in the field of psychoneuroendocrinology. Recent findings Recent studies confirm the importance of the hypothalamic–pituitary–adrenal axis for the development and course of mental disorders. Notably, the neuropeptide oxytocin has been shown to reduce the responsiveness of the hypothalamic–pituitary–adrenal axis to social stress and to improve social approach behavior. A better understanding of the neuroendocrine mechanisms of action underlying normal behavior has recently been translated to studies investigating novel therapeutic approaches using hormone administration. Summary Neuroendocrine systems relevant to behavior clearly demonstrate their impact for the field of psychiatry. Further neuroendocrine research provides insight into the origins of mental disorders both from an etiological perspective and an interventional perspective.

Increased psychological and attenuated cortisol and alpha-amylase responses to acute psychosocial stress in female patients with borderline personality disorder

OBJECTIVE Borderline personality disorder (BPD) is characterized by increased self-reported stress and emotional responding. Knowledge about the psychological and physiological mechanisms that underlie these experiences in BPD patients is scarce. The objective was to assess both psychological and endocrinological responses to a standardized psychosocial stressor in female BPD patients and healthy controls. METHODS A total of 15 female BPD patients and 17 healthy control subjects were included in a case-control study. All subjects were free of any medication, had a regular menstrual cycle, and were investigated during the luteal phase of their menstrual cycle. Co-occurring current major depression, current substance abuse/dependence, and lifetime schizophrenia or bipolar I disorder were excluded. Psychological measures of stress, salivary cortisol, salivary alpha-amylase, plasma ACTH, plasma norepinephrine and epinephrine concentrations were measured before, during, and after exposure to a standardized psychosocial stress protocol. RESULTS BPD patients displayed maladaptive cognitive appraisal processes regarding the upcoming stressor as well as significantly higher subjective stress, coupled with a substantial cortisol and alpha-amylase hyporeactivity to the stressor in comparison to the controls. No significant differences for ACTH and catecholaminergic responses were observed, while the ACTH:cortisol ratio was higher in BPD patients than in controls. CONCLUSIONS Attenuated cortisol responsiveness in BPD patients might in part be explained by decreased adrenal responsiveness to endogenous ACTH and altered central noradrenergic activation as reflected by alpha-amylase.