Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone

Abstract Objectives. Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Methods. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. Results. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Conclusions. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.     

Megestrol attenuates the hormonal response to CCK-4-induced panic attacks

Progestational hormones may have anxiolytic properties. CCK-4 (cholecystokinin tetrapeptide) can be used pharmacologically to induce panic attacks both in normal controls and patients suffering from panic disorder. In this study we compared the effects of pretreatment with the progestational hormone megestrol and placebo on CCK-4-induced panic attacks and stress hormone release in healthy male controls. Using a double-blind balanced design, we pretreated 10 medically and psychiatrically healthy male controls with placebo or megestrol 160 mg at 11 p.m. and 8 a.m. (sigma=320 mg) prior to the experiment. Following 1 h of rest, 12 blood samples were drawn between 1,000 h and 1,300 h and analyzed for ACTH and cortisol levels. At 1,100 h, subjects received an intravenous injection of 50 microg CCK-4. Clinical ratings were performed at 1,045 h and 1,110 h, and included the Acute Panic Inventory (API), International Diagnostic Checklist (IDCL), as well as a visual analog scale (VAS) for anxiety and tension. CCK-4 significantly increased anxiety and tension. Pretreatment with megestrol showed no significant effect on clinical ratings. Baseline ACTH and cortisol levels, as well as ACTH and cortisol levels after administration of CCK-4, were significantly reduced after pretreatment with megestrol. In a sample of healthy male controls, pretreatment with megestrol had a profound effect on the hypothalamic-pituitary-adrenal (HPA) axis, whereas the clinical effects on panic attacks were weak. Further studies in a larger sample of subjects, including both females and patients suffering from panic disorder, seem warranted.     

Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition

Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders.     

Effect of repeat exposure on neuroendocrine and symptom responses to pentagastrin

The cholecystokinin (CCK-B) agonist pentagastrin stimulates dose-dependent release of adrenocorticotropin (ACTH) and cortisol in humans, likely via direct pharmacological action at pituitary CCK-B receptors. Pentagastrin also produces side effects, however, which may be experienced as novel or anxiety arousing and could contribute to ACTH release. Available data suggest that pentagastrin's activation of the hypothalamic-pituitary-adrenal (HPA) axis is unrelated to anxiety symptoms themselves, but novelty effects have not been examined in this model and do strongly activate this system in animals. To further explore the impact of novelty and anxiety symptoms on HPA responses, pentagastrin was administered twice to 12 subjects (six male, six female) under single-blind conditions. Repeat pentagastrin injection was associated with a slight habituation in the magnitude of symptom and HPA axis responses, but robust HPA and symptom responses were seen following both injections. No relationships were found between anxiety symptoms and HPA activity and the modest symptomatic and neuroendocrine habituation appeared to occur independently. Pentagastrin may release ACTH and cortisol through direct pharmacological action, perhaps enhanced on first exposure by psychologically mediated novelty effects. Novelty, per se, is not likely the primary mediator of the HPA response. This model may be useful for further study of cognitive-emotional modulators of HPA axis activity.     

Effects of the cortisol synthesis inhibitor metyrapone on the response to carbon dioxide challenge in panic disorder

Despite the well-known association between the hypothalamic-pituitary-adrenal (HPA) axis and normal fear, it is still unclear (a) to what extent corticotropin releasing hormone (CRH) or cortisol itself mediates fear responses, and (b) to what extent the HPA axis also affects panic disorder. The carbon-dioxide (CO2) challenge has been proposed as a model for panic. Participants received the cortisol synthesis inhibitor metyrapone 30 mg/kg of body weight once and placebo once, with 1 week between challenges, at 2300 h. The following morning, blood was taken for cortisol and ACTH levels, and then participants inhaled a single vital capacity inhalation of 35% CO2 and 65% oxygen. Before and after the inhalation, participants completed an inventory of the 13 DSM-IV symptoms of panic and the NIMH questionnaire of psychological and physical symptoms. Eight healthy controls and 14 patients with panic disorder completed the protocol. As expected, CO2 increased measures of anxiety, and metyrapone lowered cortisol and increased ACTH levels. Prechallenge anxiety was modestly lowered by metyrapone, but response to CO2 was not affected. Cortisol and ACTH levels before challenge partly predicted the response to CO2. The results support an anxiogenic role for cortisol in stress, and suggest that the pathophysiological mechanism that mediates CO2-induced panic differs from those underlying other kinds of anxiety.     

Behavioral and endocrine response to cholecystokinin tetrapeptide in patients with posttraumatic stress disorder.

BACKGROUND: Given the relationship between posttraumatic stress disorder (PTSD) and panic, it was of interest to examine whether panic provoking agents affect PTSD symptoms. We therefore investigated the behavioral and endocrine response of PTSD patients to the panicogen cholecystokinin tetrapeptide (CCK-4). METHODS: Eight patients with PTSD (DSM-IV) received 50 micrograms CCK-4 intravenously in a placebo-controlled, double-blind balanced design. Provocation of panic, anxiety, and flashbacks was assessed. Plasma adrenocorticotropin (ACTH) and cortisol levels after CCK-4 were measured and compared to healthy subjects matched for age, gender, and provoked symptoms. RESULTS: Despite significant effects of CCK-4 on anxiety and panic symptoms, no significant provocation of flashbacks emerged. CCK-4-induced panic symptoms showed an inverse correlation to trait dissociation. The ACTH response after CCK-4 was significantly lower in PTSD patients than in controls. Cortisol was similarly increased in both groups after CCK-4, but PTSD patients showed a more rapid decrease of stimulated cortisol concentrations. CONCLUSIONS: Panic symptoms or heightened anxiety are not necessarily conditioned stimuli for the provocation of posttraumatic flashbacks. Further studies in PTSD with different panicogens should be controlled for the potential interference of trait dissociation. Our hormone data show further evidence for a corticotropin-releasing hormone (CRH) overdrive and enhanced negative glucocorticoid feedback in PTSD patients.     

Pituitary adrenocortical unresponsiveness in lactate-induced panic

The hypothalamic-pituitary adrenal (HPA) axis responds to a variety of physical and emotional stimuli with increased output of adrenocorticotropic hormone (ACTH) and cortisol, yet there is little known about the activity of this system during episodes of severe anxiety in patients with DSM-III-defined anxiety disorders. To explore further whether alterations of the HPA axis occur during various anxiety states, we measured ACTH and cortisol during lactate infusion in patients with panic disorder and agoraphobia. In eight patients who panicked during lactate infusion, there were no elevations in either ACTH or cortisol. Further, the patterns of hormone secretion did not differ among patients who panicked, nonpanicking patients, or controls. This negative result suggests that the neurobiological mechanisms that mediate panic differ from those responsible for other fear responses.     

Cortisol response patterns in depressed women and their healthy daughters at risk: Comparison with healthy women and their daughters

A dysfunctional hypothalamic pituitary adrenal (HPA) axis is widely accepted as a significant pathophysiological aspect of Major Depressive Disorder (MDD). Despite studies suggesting that a dysfunctional HPA axis might be present before the clinical syndrome becomes apparent, the functioning of the HPA axis in high–risk populations has not been well defined. The aim of the present study was to investigate the HPA axis functioning of mothers suffering from MDD and their healthy daughters compared to age- and sex-matched healthy controls. This design allowed a comparison of HPA axis functional differences among daughter and mother groups. HPA axis function was evaluated with a modified dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, which was performed after obtaining the diurnal adrenocorticotropic hormone (ACTH) and cortisol values at 8:00, 16:00, and 23:00 h. We found that MDD mothers and their daughters had low morning cortisol and the MDD mothers additionally had low-morning ACTH compared with controls. Dexamethasone suppressed both cortisol and ACTH in all groups and subsequent HPA axis stimulation by CRH-evoked a lower cortisol response but a higher ACTH response among subjects with MDD mothers. Although high-risk daughters had comparable cortisol levels after CRH infusion, the AUC for ACTH was greater than those of controls. These patterns of results suggest that multiple level HPA dysfunctions are present in both MDD patients and their high-risk carrying daughters. However, insufficient cortisol secretion was only present in MDD mothers, while the daughters could compensate cortisol levels during CRH challenge.     

Inhibition of Naloxone-Stimulated Adrenocorticotropin Release by Alprazolam in Myotonic Dystrophy Patients

Myotonic dystrophy (DM) is an autosomal dominant disorder causing myotonia, progressive muscle weakness, and endocrine abnormalities including hypothalamic-pituitary-adrenal (HPA) axis hyperresponsiveness to CRH-mediated stimuli. This ACTH hyperresponsiveness appears directly related to the underlying genetic abnormality. Naloxone (Nal)-mediated CRH release causes ACTH release in normal humans and an ACTH hyperresponse in DM. Alprazolam (APZ) attenuates the ACTH release in response to Nal in normal individuals, probably by inhibiting CRH release. This study investigates the effects of APZ on Nal-induced HPA axis stimulation in DM. The ACTH response to Nal in DM subjects was significantly reduced by APZ. Despite this DM patients have a relative resistance to APZ inhibition of Nal-induced ACTH/cortisol release. APZ caused a smaller percentage reduction in AUC for ACTH in DM compared with controls. These findings provide further insight into the mechanism(s) of the HPA axis abnormalities in DM. In DM, there may be an increase in tonic opioid inhibition to CRH release with compensatory increases in stimulatory pathways. Alternatively, these patients may have a basal increase in pituitary vasopressin levels or an enhanced AVP/CRH synergistic mechanism at the level of the corticotroph.     

Plasma ACTH and cortisol concentrations before and after dexamethasone

Alteration in the hypothalamic-pituitary-adrenal (HPA) axis occurs in up to 50% of depressed patients and is demonstrated by the failure to suppress cortisol concentrations after dexamethasone administration. Evidence suggesting that these cortisol abnormalities reflect hypothalamic-pituitary dysfunction has been inconsistent. We administered the dexamethasone suppression test to 28 psychiatric inpatients, including 17 cortisol suppressors and 11 nonsuppressors. Adrenocorticotropic hormone (ACTH) concentrations at 8 a.m. pre- and postdexamethasone were significantly greater in cortisol nonsuppressors than in suppressors. Our data support the hypothesis that pituitary ACTH secretion is altered in depressed patients who have HPA axis abnormalities demonstrated by plasma cortisol measurements.     

Neurohormonal responses to cholecystokinin tetrapeptide: a comparison of younger and older healthy subjects

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 microg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.     

The HPA axis response to insulin hypoglycemia in depression

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, demonstrated by failure to suppress cortisol secretion after dexamethasone, is found in approximately 50% of patients with major depression (MD). In this study, we examined the response of adrenocorticotrophic hormone (ACTH) and cortisol to insulin-induced hypoglycemia in 20 healthy controls and 18 inpatients with MD [12 dexamethasone suppressors (S) and 5 dexamethasone nonsuppressors (NS)]. After the administration of 0.15 U/kg of regular insulin, both controls and patients with MD showed an increase in plasma ACTH and cortisol levels. Controls had a significantly higher ACTH peak (p less than 0.01) and ACTH increment (p less than 0.01) than MD patients. There were no statistically significant differences between patients who were S and NS. Although baseline plasma cortisol levels were significantly higher in MD patients, there were no significant differences in the peak cortisol or increment in plasma cortisol after hypoglycemia between patients with MD and controls or between patients who were S and those who were NS. These findings suggest that a defect exists in the regulation of the HPA axis at the pituitary level in MD and that this defect is not necessarily reflected in the dexamethasone suppression status of the patient.     

HPA axis activity in patients with panic disorder: review and synthesis of four studies

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in panic disorder. HPA studies in patients with panic disorder, however, have produced inconsistent results. Seeking to understand the inconsistencies, we reexamined endocrine data from four studies of patients with panic disorder, in light of animal data highlighting the salience of novelty, control, and social support to HPA axis activity. Patients with panic disorder were studied (1) at rest over a full circadian cycle, (2) before and after activation by a panicogenic respiratory stimulant (doxapram) that does not directly stimulate the HPA axis, and (3) before and after a cholecystokinin B (CCK-B) agonist that is panicogenic and does directly stimulate the HPA axis. Patients with panic disorder had elevated overnight cortisol levels, which correlated with sleep disruption. ACTH and cortisol levels were higher in a challenge paradigm (doxapram) than in a resting state study, and paradigm-related ACTH secretion was exaggerated in patients with panic disorder. Panic itself could be elicited without HPA axis activation. Patients with panic disorder showed an exaggerated ACTH response to pentagastrin stimulation, but this response was normalized by prior exposure to the experimental context or psychological preparation to reduce novelty and enhance sense of control. Novelty is one of a number of contextual cues known from animal work to activate the HPA axis. The HPA axis abnormalities seen in patients with panic disorder in the four experiments reviewed here might all be due to exaggerated HPA axis reactivity to novelty cues. Most of the published panic/HPA literature is consistent with the hypothesis that HPA axis dysregulation in panic is due to hypersensitivity to contextual cues. This hypothesis requires experimental testing.     

Do neonatal bilateral ibotenic acid lesions of the hippocampal formation or of the amygdala impair HPA axis responsiveness and regulation in infant rhesus macaques (Macaca mulatta)?

In response to stressful events, the HPA axis is activated triggering the successive release of CRF, ACTH, and glucocorticoids. The glucocorticoids in turn provide a negative feedback signal to terminate the stress response. The amygdala and the hippocampus are involved in the regulation of the HPA axis. In rodents, their respective roles have been identified; the amygdala exerts a stimulatory effect, whereas the hippocampus provides negative feedback control. In primates, however, their regulatory roles are still not well defined. The present study compared HPA axis responsiveness and regulation in 3- to 5-month-old rhesus macaques that received neonatal (15 +/- 3 days old) bilateral ibotenic acid lesions of the hippocampus or amygdala, or sham lesions. Group differences in plasma cortisol response to separation from the mother and relocation in a novel environment were assessed as well as response to dexamethasone suppression and ACTH challenge. Results revealed that the initial cortisol levels after separation/relocation did not differ between groups. Subjects with hippocampus lesions did not show a suppression of cortisol in response to dexamethasone, suggesting a loss of negative feedback control of HPA regulation. Subjects with amygdala and sham lesions did not differ in response to dexamethasone. Indeed, bilateral neonatal lesions of the amygdala have little impact on HPA axis responsiveness and regulation in contrast to lesions in adult monkeys. Finally, females displayed higher cortisol levels than males, independently of their lesion, indicating that the development of sex differences in the regulation of the HPA axis does not involve the amygdala or hippocampus.     

Effects of propranolol on symptom and endocrine responses to pentagastrin

Intravenous injections of CCK-B agonists, such as pentagastrin, produce symptoms of panic and potent activation of the human hypothalamic-pituitary-adrenal (HPA) axis. It is unclear whether these psychological and endocrine effects are mediated by similar or independent processes. Independence is supported by prior evidence that beta-adrenergic receptor blockade attenuates cardiovascular and symptom but not vasopressin responses to CCK-4. To further explore associations between somatic, emotional and endocrine responses to CCK-B agents, and potential beta-adrenergic mediating mechanisms, symptom and endocrine responses to pentagastrin were examined after propranolol pre-treatment. Cardiovascular, symptom, and endocrine (ACTH, cortisol, epinephrine) responses to pentagastrin were measured in 16 healthy adult subjects randomly assigned to receive propranolol or placebo pre-treatment. Propranolol significantly blocked the normal cardiac acceleration produced by pentagastrin, but did not reduce panic symptom or anxiety effects. It delayed and perhaps enhanced the cortisol response. No relationship between HPA and symptom responses following pentagastrin could be detected, though pre-pentagastrin cortisol was inversely related to post-injection panic symptom intensity. Endocrine, cardiovascular and symptom responses to pentagastrin appear to be separately mediated, as they did not change in concert in response to propranolol pre-treatment, nor were they correlated with one another. The results are consistent with the presence of inhibitory beta-adrenergic mediation of the HPA axis in humans. They support the hypothesis that the HPA response to pentagastrin is not secondary to the psychological stress of its side effects.     

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.

BACKGROUND: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS: We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS: Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS: Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.     

Anna-Monika Award Lecture,DGPPN Kongress, 2013: The role of the hypothalamic–pituitary–adrenal (HPA) axis in the pathogenesis of psychotic major depression

Objectives. This Anna Monika Award Lecture updates the role of the hypothalamic–pituitary–adrenal (HPA) axis in the pathogenesis and treatment of psychotic major depression (PMD). Methods. Published reports from our group and others on the clinical phenomenology (including cognition), HPA axis activity, and genetics of PMD are reviewed as are published trials of the GR antagonist, mifepristone. Results. Current prevalence of PMD is 0.4%. PMD patients demonstrate significant elevations in HPA activity (e.g., particularly high rates of dexamethasone non-suppression, high post-dexamethasone cortisol, etc.) as well as significant impairment in cognition (attention, executive function/response inhibition and verbal and visual memory). High cortisol levels correlate with a number of cognitive deficits (e.g., verbal memory). Allelic variants of the glucocorticoid receptor (GR) gene contribute significantly to both cortisol levels and to measures of psychosis; corticotropin-releasing hormone receptor 1 variants contribute to measures of depression and psychosis. GR antagonists have produced rapid improvement in psychotic symptoms, although failed trials indicate a therapeutic blood level that may require a dose of 1,200 mg/day that is much higher than the commonly tested 600 mg/day. Conclusions. HPA axis over-activity appears to play a major role in the pathogenesis of PMD and is a target of drug development.     

Cognitive modulation of the endocrine stress response to a pharmacological challenge in normal and panic disorder subjects

CONTEXT: The hypothalamic-pituitary-adrenal (HPA) axis may mediate the deleterious effects of stress on health. It is sensitive to cognitive and emotional aspects of organism-environment interactions, such as familiarity, control, and social support. Scientific study of how such factors moderate human HPA axis activity has been limited. Their relevance to HPA axis disturbances in psychiatric patients is largely unexplored. OBJECTIVE: To determine whether cognitive manipulation can alter HPA axis activity in laboratory studies and whether patients with panic disorder are differentially sensitive to the manipulated factors. DESIGN: Pharmacological activation paradigm (cholecystokinin-B agonist pentagastrin) by which we examined symptom and endocrine effects on subjects randomly assigned to a standard introduction or a cognitive intervention. SETTING: Clinical research center. PARTICIPANTS: Recruited from university clinic and newspaper advertisements. Fourteen patients with panic disorder and 14 controls, individually matched for age and sex.Intervention Half of each group received a 9-minute cognitive intervention designed to reduce novelty, increase cognitive coping, and provide a sense of control. MAIN OUTCOME MEASURES: Corticotropin (ACTH) and cortisol levels. RESULTS: The cognitive intervention significantly reduced cortisol (P = .02) and ACTH (P = .01) levels, despite pentagastrin's robust stimulation of both hormones (P<.001). The intervention effect was evident in patients and controls, who did not differ in basal HPA axis activity or response to pentagastrin. They did differ in panic symptom responses, which were unaffected by the intervention, and in ACTH effects of the intervention. Patients' exaggerated anxiety responses to pentagastrin were normalized by the intervention. CONCLUSIONS: Cognitive/emotional manipulation can substantially modulate HPA axis responses to pharmacological activation in humans, and HPA disturbances in panic disorder may be secondary to manipulable cognitive/emotional sensitivities. Further study of such factors as novelty, control, and coping may help clarify the origins of HPA axis disturbance in psychiatric disorders and the mediators linking psychosocial stress to disease.     

Hypothalamic-pituitary-adrenal axis function and exposure to stress factors and cannabis use in recent-onset psychosis

Abstract

Objectives: Previous studies suggest that childhood trauma, stressful life events, and cannabis use are associated with psychosis. We aimed to explore whether these environmental factors have an effect on hypothalamic–pituitary–adrenal (HPA) axis indices in recent-onset psychosis.

Methods: We studied 56 recent-onset psychosis outpatients and 47 healthy controls. Childhood trauma was assessed with the Childhood Trauma Questionnaire. Stressful life events were assessed with the Holmes-Rahe Social Readjustment Scale. Cannabis use was assessed by semistructured interviews. Several HPA axis measures were analysed in saliva: cortisol awakening response (CAR), diurnal cortisol slope, and dexamethasone suppression test ratio (DSTR) after 0.25?mg of dexamethasone. Multiple linear regression analyses were conducted to explore the contribution of environmental factors to each HPA axis measure while adjusting for covariates (diagnosis, age, gender, smoking, body mass index and treatments).

Results: There were no significant differences in HPA axis measures between diagnostic groups. Cannabis use was associated with a more flattened diurnal cortisol slope (standardized β?=?0.21, p?=?0.038), independent of recent-onset psychosis diagnosis. No associations were found between environmental factors and other HPA axis measures (CAR, DSTR).

Conclusions: Our study provides evidence for the effect of cannabis exposure in cortisol secretion patterns in both healthy controls and recent-onset psychosis patients.     

The low-dose dexamethasone suppression test in fibromyalgia

OBJECTIVE: Fibromyalgia syndrome (FMS) has been associated with decreased cortisol secretion. Patients with posttraumatic stress disorder (PTSD) exhibit similar hypocortisolism in the context of increased negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. Because trauma and PTSD have been associated with fibromyalgia, we evaluated whether patients with fibromyalgia demonstrate increased HPA feedback sensitivity. METHOD: Baseline blood samples were obtained at 0800 h, and 0.5 mg of dexamethasone was administered to 15 female patients with FMS and 20 normal controls at 2300 h. Adrenocorticotropin (ACTH), cortisol, and dexamethasone levels were measured at 0800 h after dexamethasone intake. RESULTS: There were no group differences in mean ACTH or cortisol levels or in ACTH/cortisol ratio at baseline. After dexamethasone intake, patients with FMS exhibited more pronounced suppression of cortisol but not of ACTH, as well as increased ACTH/cortisol ratios compared with controls. Percent cortisol suppression was associated with pain and fatigue, while ACTH/cortisol ratio and dexamethasone availability were associated with stress and anxiety measures. CONCLUSION: Our results suggest increased sensitivity to glucocorticoid feedback, manifested at the adrenal level, in FMS.