Hypothalamic-pituitary-adrenal axis activity and sleep in posttraumatic stress disorder.

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis and sleep disturbances have been described separately in post-traumatic stress disorder (PTSD). It is not known if HPA alterations and sleep disturbances are associated in PTSD. This study examined sleep and HPA activity in 20 male medication-free subjects with PTSD and 16 matched healthy controls. Two nights of polysomnography were obtained and 24-h urinary cortisol was collected during day 2. Subjects self-administered a low-dose (0.5 mg) salivary dexamethasone test at home. Compared with controls, PTSD subjects had higher 24-h urinary microg cortisol/g creatinine (mean+/-SD 40+/-17 vs 28+/-12, p=0.03) but not significantly higher 24-h urinary cortisol (mean+/-SD 52+/-15 microg/day vs 43+/-23, p=0.19). PTSD subjects showed a trend towards less cortisol suppression after dexamethasone (73%+/-18 vs 83%+/-10, p=0.06). In the combined sample, delta sleep was significantly and negatively correlated with 24-h urinary cortisol (r=-0.36, p=0.04), and with 24-h urinary cortisol/g creatinine on a trend level (r=-0.34, p=0.06). Our results suggest that increased cortisol is negatively associated with delta sleep. This may contribute to sleep abnormalities in conditions associated with elevated cortisol, possibly including PTSD. Future studies should explore the temporal relationship between HPA activity, sleep disturbances, and psychopathology after a traumatic event.     

A placebo-controlled,cross-over trial of lamotrigine in depersonalization disorder

There is evidence to support the view that glutamate hyperactivity might be relevant to the neurobiology of depersonalization. We tested the efficacy of lamotrigine, which reduces glutamate release, as a treatment for patients with depersonalization disorder. A double-blind, placebo-controlled, cross-over design was used to evaluate 12 weeks of treatment of lamotrigine. Subjects comprised nine patients with DSM-IV depersonalization disorder. Changes on the Cambridge Depersonalization Scale and the Present State Examination depersonalization/derealization items were compared across the two cross-over periods. Lamotrigine was not significantly superior to placebo. None of the nine patients was deemed a responder to the lamotrigine arm of the cross-over. Lamotrigine does not seem to be useful as a sole medication in the treatment of depersonalization disorder.     

An open trial of naltrexone in the treatment of depersonalization disorder

Depersonalization disorder (DPD) remains one of the few disorders in modern psychiatry for which no treatments are established that are even partially effective, whether pharmacological or psychotherapeutic. Depersonalization disorder is a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition dissociative disorder characterized by a pervasive subjective sense of unreality and detachment with intact reality testing. Two recent controlled medication trials, one with lamotrigine and one with fluoxetine, failed to show efficacy. There is some evidence for dysregulation of endogenous opioid systems in depersonalization, and a few studies have suggested that opioid antagonists may have efficacy in the treatment of dissociation and depersonalization symptoms. In this prospective open treatment trial, 14 subjects were recruited and treated with naltrexone for 6 weeks to a maximum dose of 100 mg/d (first 7 subjects) or 10 weeks to a maximum dose of 250 mg/d (next 7 subjects). Mean naltrexone dose was 120 mg/d. There was an average 30% reduction of symptoms with treatment, as measured by 3 validated dissociation scales. Three patients were very much improved, and 1 patient was much improved with naltrexone treatment. These findings are potentially promising in a highly treatment-refractory disorder for which no treatment guidelines exist and warrant a randomized controlled trial.     

Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states

Rationale Environmental stimuli associated with cocaine are known to elicit drug craving and increase the likelihood of relapse. However, the psychobiological changes that occur with exposure to these stimuli and in episodes of drug craving are not well understood. This study examined the response of brain stress circuits to environmental stimuli that are known to increase cocaine craving in cocaine dependent individuals.Methods Fifty-four treatment seeking cocaine dependent individuals, who were admitted to an inpatient treatment research unit for 2–4 weeks, participated in three laboratory sessions. Subjects were exposed to a brief 5-min guided imagery procedure that involved imagining a recent personal stressful situation, a drug-related situation and a neutral-relaxing situation, one imagery per session presented in random order. Subjective ratings of craving and anxiety, cardiovascular measures, and plasma levels of adrenocorticotrophic hormone (ACTH), cortisol, prolactin, norepinephrine (NE) and epinephrine (EPI) were assessed.Results Exposure to stress and to drug cues each resulted in significant increases in cocaine craving and subjective anxiety, pulse rate, systolic blood pressure, ACTH, cortisol, prolactin and NE as compared to the response to neutral imagery. In addition, stress imagery also increased diastolic blood pressure and plasma EPI as compared to responses to the drug cue imagery and neutral-relaxing imagery.Conclusions The findings indicate a significant activation of the CRF-HPA axis and noradrenergic/sympatho-adreno-medullary (SAM) system response during stress-induced and drug cue induced cocaine craving states in cocaine dependent individuals. The role of stress system activation in cocaine craving and in cocaine use is discussed.     

Hypothalamic-pituitary-adrenal axis early-feedback responses are preserved in melancholic depression: a study of sertraline treatment

Major depression with melancholia is associated with hypercortisolaemia. Loss of the early-phase of negative feedback - acute suppression of ACTH in response to rising cortisol levels - is the subject of conflicting reports in patients with major depression. Using a within-subjects design, six patients with DSM-IIIR melancholic depression received a 60 min infusion of hydrocortisone at 0900 with measurement of ACTH and cortisol before and after 4 weeks of antidepressant treatment. All patients responded clinically. ACTH responses (early feedback) did not differ between test conditions. Baseline cortisol fell significantly following treatment response. This provides further evidence for the preservation of the acute phase of negative feedback, even in the presence of hypercortisolism. Copyright 2000 John Wiley & Sons, Ltd.     

HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotic treatment.

The authors discuss literature evidence on the possible dysfunctioning of HPA axis and the inflammatory response system (IRS) in schizophrenia in relation to a more comprehensive bio-pathogenetic hypothesis of the disorder and to the development of specific clinical patterns or 'core' schizophrenic symptoms, like those included in the so called negative/depressive dimension. The dysfunctions of HPA axis and IRS could be linked to some neurodevelopmental damage in relevant brain areas like hippocampus and it could involve mainly the glutamatergic pathways (e.g. NMDA receptors). Moreover, these changes could have some predictive value for response to typical antipsychotics (specifically for negative symptoms and drug resistance) in schizophrenia. Finally, the differential activity of typical versus atypical antipsychotic compounds on the basic HPA axis and IRS dysregulations in schizophrenia could account, at least partly, for the better clinical stabilization achieved in patients treated with the latter drugs compared to those receiving conventional neuroleptics.     

HPA axis dysregulation following prenatal opiate exposure and postnatal withdrawal

We examined the effects of prenatal exposure to the long acting opiate l-alpha-acetylmethadol (LAAM) followed by postnatal withdrawal on hypothalamic-pituitary-adrenal (HPA) axis reactivity in neonatal and adult rats and anxiety-like behavior in adult rats. Female rats were treated with LAAM (0, 0.2, or 1.0 mg/kg/day) via oral gavage for 28 days prior to and continuing throughout pregnancy. Pups were fostered at birth to nontreated, lactating dams and underwent opiate withdrawal. On postnatal day (PND) 18, prenatal opiate-exposed male and female rat pups displayed a decreased corticosterone response 2 h after the application of an immunological stressor and 15 min following a social stressor compared to controls. In contrast, in adulthood, prenatal opiate-treated rats showed a heightened corticosterone response compared to prenatal water-treated controls at 3 h, but not 8 h, following an immunological stressor. Males prenatally treated with 1.0 mg/kg LAAM displayed elevated startle responding compared to the other prenatally treated male groups, but there was no effect of prenatal treatment in females. There were no effects of prenatal treatment in the open field test in either sex. These results suggest that prenatal opiate exposure followed by postnatal withdrawal dysregulated the HPA axis response to stressors in the neonate and adult and differentially affected adult anxiety-like behavior in males and females.     

HPA轴功能紊乱干预药物的研究进展

目的对近年来基于下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenal ,HPA）轴功能调节治疗2型糖尿病和其他代谢疾病的药物做以综述,为H PA轴功能紊乱引起的相关疾病的治疗提供理论参考。方法查阅国内外文献,分析、总结 H PA轴功能紊乱干预药物的研究现状和研究前景。结果 HPA轴功能紊乱,尤其是 HPA轴功能亢进在2型糖尿病、抑郁症等疾病的发病过程中发挥重要作用;目前有以下几类通过作用于HPA轴不同靶点调节HPA轴功能的药物,即11β-HSD1抑制剂、糖皮质激素受体拮抗剂、多巴胺受体拮抗剂和选择性5-H T再摄取抑制剂等,具体机制还有待进一步阐明。结论通过调节H PA轴活性有可能达到预防和治疗2型糖尿病及其他相关疾病的目的。     

HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotic treatment

The authors discuss literature evidence on the possible dysfunctioning of HPA axis and the inflammatory response system (IRS) in schizophrenia in relation to a more comprehensive bio-pathogenetic hypothesis of the disorder and to the development of specific clinical patterns or ‘core’ schizophrenic symptoms, like those included in the so called negative/depressive dimension. The dysfunctions of HPA axis and IRS could be linked to some neurodevelopmental damage in relevant brain areas like hippocampus and it could involve mainly the glutamatergic pathways (e.g. NMDA receptors). Moreover, these changes could have some predictive value for response to typical antipsychotics (specifically for negative symptoms and drug resistance) in schizophrenia. Finally, the differential activity of typical versus atypical antipsychotic compounds on the basic HPA axis and IRS dysregulations in schizophrenia could account, at least partly, for the better clinical stabilization achieved in patients treated with the latter drugs compared to those receiving conventional neuroleptics.     

Possible role of a dysregulation of the endogenous opioid system in antisocial personality disorder

Around half the inmates in prison institutions have antisocial personality disorder (ASPD). A recent theory has proposed that a dysfunction of the endogenous opioid system (EOS) underlies the neurobiology of borderline personality disorder (BPD). In the present theoretical paper, based on a comprehensive database and hand search of the relevant literature, this hypothesis is extended to ASPD, which may be the predominant expression of EOS dysfunction in men, while the same pathology underlies BPD in women. According to evidence from human and animal studies, the problematic behaviours of persons with antisocial, callous, or psychopathic traits may be seen as desperate, unconscious attempts to stimulate their deficient EOS, which plays a key role in brain reward circuits. If the needs of this system are not being met, the affected persons experience dysphoric mood, discomfort, or irritability, and strive to increase binding of endogenous opioids to receptors by using the rewarding effects of aggression by exertion of physical or manipulative power on others, by abusing alcohol or substances that have the reward system as target, by creating an “endorphin rush” by self‐harm, by increasing the frequency of their sexual contacts, or by impulsive actions and sensation seeking. Symptoms associated with ASPD can be treated with opioid antagonists like naltrexone, naloxone, or nalmefene. Copyright © 2015 John Wiley & Sons, Ltd.     

Effect of naloxone therapy on depersonalization: a pilot study.

To test the hypothesis of the role for the opioid system in the pathogenesis of depersonalization, the effect of naloxone (an opioid receptor blocker) on the symptoms and corticosteroids secretion was studied in patients with depersonalization syndrome. Fourteen depersonalization patients were treated with naloxone: 11 patients received single doses (1.6 or 4 mg i.v.) and three others received multiple infusions, with the maximal dosage being 10 mg, and the effect of naloxone on symptom severity was determined. In eight patients, the cortisol, cortisone and corticosterone content in the blood plasma was determined prior to and after the 4 mg naloxone infusion. A reversed-phase microcolumn high-performance liquid chromatography with ultraviolet detection was applied for assessment of glucocorticoids. In three of 14 patients, depersonalization symptoms disappeared entirely and seven patients showed a marked improvement. The therapeutic effect of naloxone provides evidence for the role of the endogenous opioid system in the pathogenesis of depersonalization.     

Persistent depressive state after chronic stress in rats is accompanied by HPA axis dysregulation and reduced prefrontal dopaminergic neurotransmission

Exposure to stress is thought to play an important role in the etiology of depression. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis characterized by glucocorticoid negative feedback resistance is frequently observed in human depressives. Additionally, dysfunctions of the dopaminergic and serotonergic systems in the prefrontal cortex (PFC) are thought to be involved in the development of a depressive state. In rats, chronic stress induces a behaviorally depressive state, concomitant with dysregulation of the HPA axis and reductions in dopaminergic and serotonergic transmissions in the PFC. Considering that dysregulation of the HPA axis is associated with relapse and persistency of depression, it is possible that the chronic stress-induced depressive state persists during long-term rest after its exposure. In the present study, we examined this possibility in rats and found that the behaviorally depressive state in the rotarod test, negative feedback resistance in the dexamethasone suppression test, and a decrease in the extracellular concentration of dopamine but not serotonin in the PFC persisted for 3 months following a 4-week stress session. These results suggest that dysregulation of the HPA system and reduced dopaminergic transmission in the PFC underlies persistent behavioral depression following chronic stress.     

Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses

The aim of the study was to evaluate the association between post-traumatic disorder (PTSD) and hypothalamic-pituitary-adrenal (HPA) axis responses to the triggering trauma. A companion paper evaluates the adrenergic response and interactions between the two. We measured plasma and saliva cortisol, hourly urinary excretion of cortisol, plasma levels of adrenocorticotropin (ACTH), and the leukocyte glucocorticoid receptor (GR) density of 155 non-injured survivors of traumatic events (91 males and 64 females; 125 road traffic accidents, 19 terrorist attacks, 11 others). Measurements were taken during survivors' admissions to an emergency room (ER) of a general hospital, and in the mornings, 10 d, 1 month, and 5 months later. Symptoms of peri-traumatic dissociation, PTSD, and depression were assessed on each follow-up session. The clinician-administered PTSD scale (CAPS) conferred a diagnosis of PTSD at 5 months. Survivors with (n=31) and without (n=124) PTSD at 5 months had similar levels of hormones at all times. Plasma cortisol levels decreased with time in both groups. Female subjects had lower ACTH levels than males. PTSD in females was associated with higher levels of ACTH. In unselected cohorts of trauma survivors, PTSD is not preceded by a detectable abnormality of peripheral HPA axis hormones.