HPA axis and stimulant dependence: an enigmatic relationship.

Clinical and preclinical evidence links stress to drug dependence. Stress is accompanied by the rapid modification of brain and body physiology which leads to release of neuroactive hormones, including biogenic amines and adrenal steroids, which activate the same brain circuitry, as stimulant drugs, such as cocaine and amphetamines. Some preclinical studies showed that stress and elevated plasma concentrations of glucocorticoids increase acquisition and maintenance of stimulant use in rats, whereas other studies revealed that animals with inherently hypoactive HPA axis are more vulnerable to stimulant "abuse". In humans cocaine acutely activates the HPA axis, and in chronic cocaine abusers early abstinence is accompanied by alterations of the HPA axis function, with distinct patterns of hormonal changes characteristic for different subgroups of addicts. Some of these changes correspond to psychiatric comorbidities, which may be predictive of propensity to relapse.Hemispheric laterality plays a role in the stress-induced activation of the HPA axis, with right prefrontal cortex (PFC) having mostly stimulatory effects and the left, inhibitory effects. Brain-imaging studies showed preferential alteration of structure and function of the right cerebral hemisphere in cocaine addicts. Activation of the right PFC and inhibition of the left was noted in typical depressive disorders, and right hemispheric hypoactivity was reported in attention deficit hyperactivity and antisocial personality disorders, which are highly comorbid with stimulant dependence. Distinct patterns of hemispheric predominance or hypofunction between individuals may contribute to vulnerability or resilience to stimulant dependence. The nature and significance of the link between stress and activity of HPA axis, and vulnerability to drug dependence is not clear and deserves further study.     

The significance of HPA axis disturbance in panic disorder

Agoraphobic and panic disorder patients underwent 1-mg Dexamethasone Suppression Tests (DST) before, during, and after an 8-week trial of diazepam, alprazolam, or placebo. Previously described, never-ill controls underwent similar testing. At baseline, 21 of 82 (25.6%) panic disorder and 5 of 38 (13.2%) controls were nonsuppressors. This difference grew more marked with multiple testing over a 2-month period; 18 of 44 (40.9%) panic disorder patients were nonsuppressors on at least 1 of 3 tests compared with only 5 of 35 (14.3%) controls (p = 0.006). DST results were related to severity, but not to the presence or absence, of depressive syndromes. Control for plasma dexamethasone levels left highly significant differences in postdexamethasone cortisol across diagnostic groups. Neither DST results nor plasma dexamethasone levels changed in concert with clinical change, and type of treatment had little differential effect on these measures. Nor did DST results predict subsequent course when active treatment was extended by 6 months. However, DST results during the initial 8 weeks of treatment were strongly related to relapse when medications were tapered, even though this occurred 6 months after the last DST.     

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 disturbance in obsessive-compulsive disorder

Twenty nondepressed outpatients with DSM-III obsessive-compulsive disorder entered a 10-week placebo-controlled study of clomipramine and underwent a 1-mg dexamethasone suppression test (DST) at baseline; 11 had a repeat DST at the end of treatment. Nonsuppression was rare. When compared to 82 previously described outpatients with panic disorder studied in a similar fashion, OCD patients had postdexamethasone cortisol values that were substantially lower and more stable over time. Results within the OCD group closely resembled those from a group of never-ill controls.     

HPA axis dysregulation in mice overexpressing corticotropin releasing hormone.

BACKGROUND: Hypersecretion of corticotropin-releasing hormone (CRH) in the brain has been implicated in stress-related human pathologies. We developed a transgenic mouse line overexpressing CRH (CRH-OE) exclusively in neural tissues to assess the effect of long-term CRH overproduction on regulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Male transgenic CRH-OE(2122) mice on a C57BL/6J background were used. Littermate wildtype mice served as control animals. Basal plasma corticotropin and corticosterone concentrations were measured, and adrenal gland weight was determined. A dexamethasone suppression test measured the effects of long-term CRH hypersecretion on negative feedback control. Additionally, we measured plasma corticosterone concentrations in reaction to stress. RESULTS: CRH-OE(2122) mice showed elevated basal plasma corticosterone concentrations, hypertrophy of the adrenal gland, and dexamethasone nonsuppression. Basal plasma ACTH concentrations of wildtype and CRH-OE(2122) mice did not differ significantly. In reaction to stress, CRH-OE(2122) mice showed a normal corticosterone response. CONCLUSIONS: The HPA axis abnormalities observed in CRH-OE(2122) mice suggest that long-term hypersecretion of CRH in the brain can be a main cause of HPA axis dysregulation. The alterations in HPA axis regulation are reminiscent of changes reported in major depressive disorder. As such, these CRH -OE(2122) mice may model the neuroendocrine changes observed in major depressive disorder.     

HPA axis hyperactivity and recovery from functional psychoses

Some patients with functional psychoses follow a chronic, deteriorating course and others recover; at present clinicians have essentially no established factors beyond diagnosis and chronicity to predict which course a psychotic patient might follow. Because data on diagnostic specificity suggested that the dexamethasone suppression test might provide another, much needed prognostic factor, the authors administered these tests to 98 consecutively admitted patients with nonmanic psychoses. High postdexamethasone cortisol levels (6 micrograms/dl or higher) at baseline predicted recovery from psychosis at 1 year, independent of episode chronicity and diagnosis. Diagnosis did not correspond well to test results but was itself an important predictor.     

Prior stressor exposure primes the HPA axis

Exposure to stressors often alters the subsequent responsiveness of many systems. The present study tested whether prior exposure to inescapable tailshock (IS) alters the corticosterone (CORT) or adrenocorticotropin hormone (ACTH) response to either an injection of bacterial endotoxin (lipopolysaccharide; LPS) or subsequent placement on a pedestal. Rats were exposed to IS or remained as home cage controls (HCC). 1, 4, 10, or 21 days later animals were injected i.p. with either 10 microg/kg LPS or equivolume sterile saline. Prior IS significantly increased plasma CORT 1 h, but not 2 or 5 h after LPS, compared to controls 1, 4, and 10 days, but not 21 days after IS. Exposure to IS 24 h earlier also significantly increased plasma ACTH 1 h after LPS. Additional animals were placed on a pedestal 24 h after IS, and plasma CORT was measured 15, 30, and 60 min later. IS significantly increased plasma CORT 15 min after pedestal exposure, but not after 30 or 60 min. These results suggest that exposure to IS sensitizes the CORT and ACTH response to subsequent HPA activation.     

The HPA axis in major depression: classical theories and new developments

Studies over the last 40 years have demonstrated that hyperactivity of the hypothalamic-pituitary-adrenal axis is one of the most consistent biological findings in major depression psychiatry, but the mechanisms underlying this abnormality are still unclear.     

Prenatal stress and the programming of the HPA axis

There are several independent prospective studies showing that a wide variety of forms of prenatal stress can have long-term effects on the behavioural and cognitive outcome for the child. Animal studies have shown that prenatal stress, as well as affecting behaviour, can also reprogram the function of the HPA axis in the offspring. However, the effects on the HPA axis are very variable depending on the nature of the stress, its timing in gestation, the genetic strain of the animal, the sex and age of the offspring and whether basal or stimulated HPA axis responses are studied. There are also several recent studies showing long-term effects of prenatal stress on basal cortisol levels, or cortisol responses to stress, in humans. The designs of these studies differ considerably, many are small, and the effects on outcome are also varied. There is little evidence, so far, that altered function of the HPA axis in the child mediates the behavioural or cognitive alterations observed to be associated with prenatal stress.     

HPA axis disturbance and treatment outcome in panic disorder

Some patients with panic disorder exhibit an abnormal response to dexamethasone. As this phenomenon may reflect disturbances in the central noradrenergic system and as alprazolam may work through this system to produce improvement, we predicted a particularly robust response among nonsuppressors. Fifty-two patients with panic disorder or with agoraphobia with panic attacks were given alprazolam as the sole treatment during either of 2, 8-week, double-blind, placebo-controlled trials. Though baseline clinical severity predicted globally rated outcome, baseline Dexamethasone Suppression Test results did not.     

Prenatal stress and the programming of the HPA axis

There are several independent prospective studies showing that a wide variety of forms of prenatal stress can have long-term effects on the behavioural and cognitive outcome for the child. Animal studies have shown that prenatal stress, as well as affecting behaviour, can also reprogram the function of the HPA axis in the offspring. However, the effects on the HPA axis are very variable depending on the nature of the stress, its timing in gestation, the genetic strain of the animal, the sex and age of the offspring and whether basal or stimulated HPA axis responses are studied. There are also several recent studies showing long-term effects of prenatal stress on basal cortisol levels, or cortisol responses to stress, in humans. The designs of these studies differ considerably, many are small, and the effects on outcome are also varied. There is little evidence, so far, that altered function of the HPA axis in the child mediates the behavioural or cognitive alterations observed to be associated with prenatal stress.     

Childhood stressful events,HPA axis and anxiety disorders

Anxiety disorders are among the most common of all mental disorders and their pathogenesis is a major topic in psychiatry, both for prevention and treatment. Early stressful life events and alterations of hypothalamic pituitary adrenal (HPA) axis function seem to have a significant role in the onset of anxiety. Existing data appear to support the mediating effect of the HPA axis between childhood traumata and posttraumatic stress disorder. Findings on the HPA axis activity at baseline and after stimuli in panic disordered patients are inconclusive, even if stressful life events may have a triggering function in the development of this disorder. Data on the relationship between stress, HPA axis functioning and obsessive-compulsive disorder (OCD) are scarce and discordant, but an increased activity of the HPA axis is reported in OCD patients. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. While several hypothesis have attempted to explain these findings over time, currently the most widely accepted theory is that early stressful life events may provoke alterations of the stress response and thus of the HPA axis, that can endure during adulthood, predisposing individuals to develop psychopathology. All theories are reviewed and the authors conclude that childhood life events and HPA abnormalities may be specifically and transnosographically related to all anxiety disorders, as well as, more broadly, to all psychiatric disorders.     

The role of BDNF and HPA axis in the neurobiology of burnout syndrome

Chronic stress is known to affect the HPA axis. The few clinical studies which have been conducted on HPA-axis function in burnout have produced inconsistent results. The etiological relationship between sBDNF and burnout has not yet been studied. The aim of the current study was to investigate the role of BDNF and HPA axis in the neurobiology of burnout. In the current study 37 clinically diagnosed burnout participants were compared with 35 healthy controls in terms of BDNF, HPA axis, burnout symptoms, depression, anxiety and psychosomatic complaints. Basal serum cortisol, sBDNF and cortisol level after 1 mg DST was sampled. We found no significant differences in terms of HPA-axis function (for basal serum cortisol, p=0.592; for cortisol level after 1 mg DST, p=0.921), but we did find lowered sBDNF levels in burnout group (88.66+/-18.15 pg/ml) as compared to healthy controls (102.18+/-20.92 pg/ml) and the difference was statistically significant (p=0.005). Logistic Regression Analysis revealed that emotional exhaustion (p=0.05), depersonalization (p=0.005) and depression (p=0.025) were significantly associated with burnout. sBDNF levels correlated negatively with emotional exhaustion (r=-,268, p=0.026), depersonalization (r=-,333, p=0.005) and correlated positively with competence (r=0.293, p=0.015) sub-scales of burnout inventory. However, there were no significant relationships between cortisol levels and sBDNF levels (r=0.80, p=0.51), depression, anxiety, psychosomatic complaints and burnout inventory. Our results suggest that low BDNF might contribute to the neurobiology of burnout syndrome and it seems to be associated with burnout symptoms including altered mood and cognitive functions.     

创伤后应激障碍患者下丘脑-垂体-肾上腺轴系统研究进展

创伤后应激障碍（Post-traumatic stress disorder,PTSD）是一种严重的应激相关障碍,是机体经历严重创伤事件后延迟出现的精神障碍,其临床表现以重复创伤性体验为特征,伴有情绪的易激惹和回避行为等,国外有调查显示其终身患病率约为7.8%[1].下丘脑-垂体-肾上腺（Hypothalamic pituitary adrenal,HPA）轴在调节人体功能中发挥着重要的作用,也通过负反馈抑制调节神经,内分泌,免疫系统功能.研究显示PTSD患者存在HPA轴功能异常,本文主要就PTSD患者HPA轴研究进展进行综述.     

HPA axis function in depression and dementia: A review

This article reviews recent advances in the understanding of hypothalamic-pituitary-adrenal (HPA) dysfunction in depression and dementia. Although the dexamethasone suppression test (DST) has proved disappointing as a diagnostic test, more recent tests of HPA axis function have not yet been adequately investigated in this regard. There is mounting evidence from both animal and human studies that a complex interrelationship exists between mood, age, cognitive function, brain structure and HPA axis dysfunction. To explore this relationship further, studies combining clinical, neuroimaging and neuroendocrine investigation are required.     

The impact of treatment on HPA axis activity in unipolar major depression

Dysregulation of hypothalamic-pituitary-adrenal axis activity in major depressive disorder has been found to normalize with successful treatment, though inconsistencies exist. To determine the magnitude of change in cortisol levels from pre to post-treatment in individuals with unipolar depression quantitative methods of meta-analysis were applied. Thirty-four studies met inclusion criteria and consisted of a total of 1049 depressed patients across study samples. The overall mean effect size of pre-post-treatment cortisol measures indicated that approximately 56% of depressed participants had similar cortisol levels before and after treatment regardless of symptom improvement. The mean effect size of pre-post cortisol measures for those who responded to treatment was larger than the mean effect size of non-responders; however, this difference did not reach statistical significance. As well, no significant differences in mean effect size of pre-post cortisol measures based on type of treatment (e.g. antidepressant vs. ECT) were found. Subtype of depressive illness and length of treatment may contribute to the magnitude of change in cortisol measure before and after treatment. Inconsistent findings within the reviewed literature may confound the overall results. The type of treatment and response to treatment do not appear to impact the magnitude of change in cortisol level pre to post-treatment. Our findings suggest that the utility of cortisol as an outcome measure may be limited to specific subsets of the depressed population, and that given the variability in HPA results between studies, it is premature to state that cortisol is not a good outcome measure.     

The relationship between basal and acute HPA axis activity and aggressive behavior in adults

The hypothalamic–pituitary–adrenal (HPA) axis seems to play a major role in the development, elicitation, and enhancement of aggressive behavior in animals. Increasing evidence suggests that this is also true for humans. However, most human research on the role of the HPA axis in aggression has been focusing on highly aggressive children and adolescent clinical samples. Here, we report on a study of the role of basal and acute HPA axis activity in a sample of 20 healthy male and female adults. We used the Taylor Aggression Paradigm to induce and measure aggression. We assessed the cortisol awakening response as a trait measure of basal HPA axis activity. Salivary free cortisol measures for the cortisol awakening response were obtained on three consecutive weekdays immediately following awakening and 30, 45, and 60 min after. Half of the subjects were provoked with the Taylor Aggression Paradigm to behave aggressively; the other half was not provoked. Acute HPA axis activity was measured four times, once before and three times after the induction of aggression. Basal cortisol levels were significantly and negatively related to aggressive behavior in the provoked group and explained 67% of the behavioral variance. Cortisol levels following the induction of aggression were significantly higher in the provoked group when baseline levels were taken into account. The data implicate that the HPA axis is not only relevant to the expression of aggressive behavior in clinical groups, but also to a large extent in healthy ones.