Blunted ACTH response to dexamethasone suppression-CRH stimulation in posttraumatic stress disorder

Previous studies have suggested that patients with posttraumatic stress disorder (PTSD) have an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) system and a blunted ACTH response to corticotropin releasing hormone (CRH). The effects of two dexamethasone dosages (0.75 and 1.5 mg) on the ACTH and cortisol concentrations after CRH stimulation (100 μg) were studied in eight patients with PTSD and matched healthy control subjects. Compared to healthy subjects, patients with PTSD have a blunted ACTH response to CRH. Cortisol concentrations were only significantly influenced by dexamethasone dosage. Our results give further evidence for a central role of the pituitary in reflecting changes of the negative feedback sensitivity of the HPA system in patients with PTSD.     

Effects of parental PTSD on the cortisol response to dexamethasone administration in their adult offspring

OBJECTIVE: The authors used a low-dose dexamethasone suppression test to examine the effect of a PTSD risk factor, parental PTSD, on cortisol negative feedback inhibition in adult offspring of Holocaust survivors with PTSD (N=13) versus without PTSD (N=12) as well as a comparison group of offspring whose parents had no Holocaust exposure (N=16). METHOD: Blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of dexamethasone at 11:00 p.m., and blood samples were obtained again at 8:00 a.m. the following day. RESULTS: Enhanced cortisol suppression in response to dexamethasone was associated primarily with parental PTSD status, with minimal contribution of subjects' own trauma-related symptoms. CONCLUSIONS: Enhanced cortisol negative feedback inhibition may be associated with PTSD because it is related to the PTSD risk factor of parental PTSD.     

Alterations in cortisol negative feedback inhibition as examined using the ACTH response to cortisol administration in PTSD

OBJECTIVE: Studies using the dexamethasone suppression test (DST) have demonstrated an enhanced negative feedback inhibition at the pituitary in PTSD, but have not provided information about central feedback effects, since dexamethasone (DEX) does not penetrate the brain well. The authors therefore examined the change in ACTH and cortisol before and after cortisol administration, which acts at central feedback sites in addition to peripheral targets. METHOD: Blood was obtained from 31 male veterans (18 with PTSD) before, and 8, 40 and 95 min following injection of 17.5 mg cortisol and placebo. RESULTS: A greater decline in ACTH was observed after cortisol injection in PTSD. CONCLUSIONS: Central as well as peripheral negative feedback inhibition may be altered in PTSD.     

Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder

OBJECTIVE: To evaluate cortisol suppression following 0.5 mg of dexamethasone (DEX) in trauma survivors (N=52) with posttraumatic stress disorder (PTSD), major depressive disorder (MDD), both, or neither disorder, and in subjects never exposed to trauma (N=10), in order to examine interactions between diagnosis and trauma history on cortisol negative feedback inhibition. METHOD: Lifetime trauma exposure and psychiatric diagnoses were assessed and blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of DEX at 11:00 p.m. and blood samples for determination of cortisol and DEX were obtained at 8:00 a.m. the following day. RESULTS: PTSD was associated with enhanced cortisol suppression in response to DEX. Among trauma survivors, the presence of a traumatic event prior to the "focal" trauma had a substantial impact on cortisol suppression in subjects with MDD. Such subjects were more likely to show cortisol alterations similar to those associated with PTSD, whereas subjects with MDD with no prior trauma were more likely to show alterations in the opposite direction, i.e. relative non-suppression. CONCLUSIONS: Cortisol hypersuppression in PTSD appears not to be dependent on the presence of traumatic events prior to the focal trauma. However, prior trauma exposure may affect cortisol suppression in MDD. This finding may have implications for understanding why only some depressed patients show non-suppression on the DST.     

The response of focal ischemic cerebral edema to dexamethasone

Summary Twenty-four h after permanent occlusion of the middle cerebral artery (MCA) in the cat, the hemispheric swelling due to edema is markedly reduced under treatment with large doses of dexamethasone than is the case with the untreated group. The increase of regional water and sodium content in the MCA territory is less in the dexamethasone treated group, whereas the potassium changes in the ischemic tissue showed only small differences between the two groups. The potassium content of the non-ischemic tissue is slightly increased in the dexamethasone treated animals when comparing with the untreated group. RISA activity in the tissue is increased in the grey and the white matter of both groups. The less marked RISA^–131 activity in the cortical grey matter of the treated animals indicates blood-brain barrier damage of a smaller degree due to dexamethasone. These findings indicate a beneficial effect of dexamethasone on local ischemic edema. Regarding our results and the pharmacokinetics of this steroid the dexamethasone loading of a patient has to be in the range of about 100 mg per day for the adult, and has to be started immediately after the onset of a stroke.

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Zusammenfassung Vierundzwanzig Stunden nach permanentem Verschluß der Arteria cerebri media der Katze ist die ödembedingte Volumenzunahme der geschädigten Hemisphäre unter hochdosierter Dexamethasonbehandlung gegenüber nichtbehandelten Tieren deutlich geringer. Auch der Vergleich der regionalen Wasser- und Natriumzunahme ergibt für die behandelten Tiere geringere Werte. Gleichzeitig findet sich ein nur geringerer Kaliumverlust aus dem geschädigten Gewebe, während sich unter Dexamethasongabe in den ungeschädigten Hirnregionen eine erhöhte Kaliumkonzentration nachweisen läßt. Die RISA^–131-Aktivität im Hirngewebe, Indikator für eine Blut-Hirn-Schrankenschädigung, ist 24 h nach Ischämiebeginn sowohl in der grauen als auch der weißen Substanz in beiden Gruppen erhöht, wobei das Ausmaß der BHS-Schädigung im betroffenen Cortexareal der behandelten Gruppe gegenüber den Kontrollen wiederum geringer ist. Diese Befunde sprechen unter Berücksichtigung der Pharmakokinetik des Steroids für eine günstige Wirkung bei der Therapie des lokalen ischämischen Hirnödems. Voraussetzung scheint jedoch die frühzeitige, hochdosierte Steroidgabe zu sein, wobei eine Tagesdosis entsprechend über 100 mg Dexamethason beim erwachsenen Menschen erreicht werden sollte.

     

The differential ACTH responses to combined dexamethasone/CRH administration in major depressive and dysthymic disorders

In a preliminary study, we performed the combined dexamethasone/CRH test on patients with major depressive and dysthymic disorders as well as healthy controls. The ACTH response was significantly enhanced in the major depression group compared to the control group and tended to be heightened compared to the dysthymia group. The cortisol response was not significantly different among the three groups. We assume that major depression and dysthymia are neuroendocrinologically distinct disorders, although whether the difference is quantitative or qualitative remains to be examined.     

ACTH and multisteroid responses to corticotropin-releasing factor in depressive illness: relationship to multisteroid responses after ACTH stimulation and dexamethasone suppression

One hundred micrograms of ovine-corticotropin releasing factor (o-CRF) was administered intravenously to eight unmedicated patients with severe endogenous depression. Responses of immunoreactive (ir)-ACTH and the adrenal glucocorticosteroids corticosterone (B), 11-deoxycortisol (S), cortisol (F) and cortisone (E) were measured and compared with those following synthetic corticotropin stimulation and dexamethasone suppression. A comparative evaluation of the three pituitary--adrenal function tests suggests that hypersecretion of ir-ACTH and adrenal corticosteroids (B, S, F, and E) in depression reflects a central dysfunction rather than an altered responsiveness of the pituitary or adrenal glands. The data illustrate that the o-CRF paradigm is a valuable instrument to further support the hypothesis that a limbic--hypothalamic overdrive is the basic mechanism underlying exaggerated adrenocortical output in the endogenous subgroup of depressed patients.     

Brain activation in PTSD in response to trauma-related stimuli.

BACKGROUND: Repetitive recall of traumatic memories and chronic intermittent hyperarousal are characteristic of posttraumatic stress disorder (PTSD). Hyperarousal and memory dysfunction implicates "limbic" brain regions, including the amygdaloid complex, hippocampal formation, and limbic cortex, such as the orbitofrontal and anterior cingulate areas. To investigate the neurobiologic role of these brain regions in PTSD, we measured regional cerebral blood flow in PTSD with single photon emission computerized tomography (SPECT) during a symptom provocation paradigm. METHODS: Fourteen Vietnam veterans with PTSD, 11 combat control subjects, and 14 normal control subjects were studied with [99mTc]HMPAO in two sessions 48 hours apart: one session after exposure to white noise and the other following exposure to combat sounds. Skin conductance, heart rate, and subjective experience were recorded at the time of the studies. RESULTS: Activation for all three groups occurred in the anterior cingulate/middle prefrontal gyrus. Activation in the region of the left amygdala/nucleus accumbens was found in PTSD patients only. Deactivation was found in all three groups in the left retrosplenial region. CONCLUSIONS: These findings implicate regions of the "limbic" brain, which may mediate the response to aversive stimuli in healthy individuals and in patients suffering from PTSD.     

Measurement of ACTH and prolactin in the dexamethasone suppression test

Plasma concentrations of ACTH and prolactin were measured in psychiatric inpatients at 8 a.m. and 4 p.m. before and after the standard 1 mg overnight Dexamethasone Suppression Test (DST). Plasma concentrations of cortisol were measured at 8 a.m. and 4 p.m., and 11 p.m. before and after 1 mg dexamethasone. Dexamethasone suppressed plasma concentrations of ACTH, prolactin and cortisol in the subject group as a whole. "Cut Points" obtained using Fisher's Exact Test identified plasma ACTH values at 8 a.m. baseline, 4 p.m. baseline and 8 a.m. post-dexamethasone and plasma prolactin values at all four times that significantly differentiated patients with bipolar depressive disorder and major depressive disorder from other psychiatric patients. There were no cut points found at any of the six times for plasma levels of cortisol that significantly differentiated between these two diagnostic groups. Of interest in this subject population, basal (pre-dexamethasone) plasma concentrations were of more diagnostic information than post-dexamethasone values. These pilot findings suggest that monitoring plasma prolactin and ACTH concentrations before and after dexamethasone might increase the sensitivity and specificity of this laboratory test for depression.     

The response to ACTH is determined early in the treatment of infantile spasms

Although adrenocorticotropic hormone is the most commonly used treatment for infantile spasms in the United States, the optimal regimen for this indication is not known. The purpose of this study was to elucidate the optimal adrenocorticotropic hormone treatment duration. We conducted a retrospective chart review of response to adrenocorticotropic hormone among all patients with infantile spasms managed at our institution from January 2009 to September 2013. Treatment response was defined as clinical remission for greater than or equal to 28 days starting at any point within the adrenocorticotropic hormone course and remission of hypsarrhythmia (or definite EEG improvement if hypsarrhythmia was absent at baseline). For responders, the diagnostic and post‐treatment EEG tracings were reviewed. Electroclinical remission was achieved in 21 of 39 patients (54%) receiving adrenocorticotropic hormone, including 11/25 (44%) receiving a long course (typically 12 weeks) and 10/14 (71%) receiving a short course (typically four weeks). The mean time to clinical remission was 5.8 days (median: 5 days; range: 1–20 days). Only one patient responded beyond two weeks of treatment. This study provides Class IV evidence that among patients with infantile spasms, the response to adrenocorticotropic hormone is most often determined early in the treatment course. Given the importance of rapid remission, clinicians should consider adding or changing treatment if infantile spasms do not resolve within two weeks of adrenocorticotropic hormone initiation. Further study is needed to determine the optimal adrenocorticotropic hormone regimen for infantile spasms.     

Cortisol response to dexamethasone in women with premenstrual syndrome

There were no significant differences in post-dexamethasone cortisol between the follicular and luteal phase of the menstrual cycle in both women with premenstrual syndrome (PMS) and control subjects tested on these two occasions. Within each menstrual cycle phase, there were also no differences in post-dexamethasone cortisol between the two groups. In a second group of control subjects tested on a single occasion, post-dexamethasone cortisol values were higher when subjects were tested in the middle 2 weeks of the menstrual cycle compared with the first and last weeks of the cycle. This phenomenon, possibly due to estrogen effects, suggests that post-dexamethasone cortisol should be assessed weekly in women with PMS to determine whether they also manifest this normally observed menstrual cycle phase-related pattern, or whether it is absent, reflecting a reproductive endocrine abnormality in this patient group.     

Cortisol response to dexamethasone and noradrenergic function in depression

Positive correlations between measures of hypothalamic-pituitary-adrenal (HPA)-axis activity and noradrenergic turnover have been reported in depression. To investigate this relationship the authors measured peak postdexamethasone cortisol levels (8 a.m., 4 p.m. and 11 p.m.) and the 24-hour urinary 3-methoxy-4-hydroxy-phenylglycol (MHPG) flow in 84 depressed patients. The results show that there is no positive association between those measures of HPA-axis and noradrenergic activity. On the contrary, patients with severe non-suppression (greater than or equal to 10 micrograms/dl or 277 nmol/l) tended to have a lower MHPG-excretion.     

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.     

Plasma ACTH levels in primary depression: relationship to the 24-hour dexamethasone suppression test

The failure of adequate cortisol suppression after 1 mg dexamethasone in 50% of patients with endogenous depression has been attributed to abnormal hypothalamic-pituitary-adrenal axis regulation, resulting in high levels of adrenocorticotropic hormone (ACTH). Because studies of plasma ACTH have been conflicting, we studied plasma ACTH levels during the 24-hour dexamethasone suppression test in a homogeneous group of 29 hospitalized patients with primary endogenous depression and 19 normal volunteers. No differences were found in ACTH levels among normal volunteers, depressed cortisol suppressors, and depressed cortisol nonsuppressors at either 4 p.m. or 11 p.m.     

The genetic background to PTSD

Although extensive research has already been done on the genetic bases of psychiatric disorders, little is known about polygenetic influences in posttraumatic stress disorder (PTSD). This article reviews molecular genetic studies relating to PTSD that were found in a literature search in Medline, Embase and Web of Science. Association studies have investigated 8 major genotypes in connection with PTSD. They have tested hypotheses involving key candidate genes in the serotonin (5-HTT), dopamine (DRD2, DAT), glucocorticoid (GR), GABA (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY). The studies have produced inconsistent results, many of which may be attributable to methodological shortcomings and insufficient statistical power. The complex aetiology of PTSD, for which experiencing a traumatic event forms a necessary condition, makes it difficult to identify specific genes that substantially contribute to the disorder. Gene-finding strategies are difficult to apply. Interactions between different genes and between them and the environment probably make certain people vulnerable to developing PTSD. Gene-environmental studies are needed that focus more narrowly on specific, distinct endophenotypes and on influences from environmental factors.     

Cortisol, ACTH, and dexamethasone concentrations in a psychogeriatric population

Cortisol and adrenocorticotrophic hormone (ACTH) were measured at 2 time points before the administration of 1 mg of dexamethasone (day 1) and 1 time point on the following day (day 2). Thirteen severely depressed elderly patients, 15 patients with Alzheimer-type dementia (ATD), and 16 normal controls were studied. Cortisol was markedly elevated in depressed patients compared with the other subjects in day 1 samples. Following dexamethasone, both the depressed and ATD patients showed a similar elevation of cortisol compared with controls. ACTH concentrations were not significantly different between the groups before dexamethasone, but were significantly higher in both depressed and ATD patients after dexamethasone. More depressed patients than ATD patients exhibited hypersecretion of ACTH after dexamethasone. This implies that ACTH is less responsive to glucocorticoid feedback in elderly depressed patients, which may be a factor in causing hypercortisolemia.     

The dexamethasone suppression test and response to somatic treatment: a review

The dexamethasone suppression test (DST) has been primarily investigated as an aid in diagnosing endogenous depression; yet, its major clinical use has been as a predictor of treatment response. It is commonly held that 1) an abnormal DST predicts response to somatic (and not psychologic) therapies, 2) an abnormal DST predicts response to noradrenergic antidepressants, and 3) a normal DST predicts response to serotonergic agents. The DST predicted response to somatic therapies in only 6 of 16 published studies. No single methodologic factor, such as population variables, DST technique, or study design, can explain the marked discrepancy in study results. Only two of seven studies examining the DST and response to neurotransmitter-specific antidepressant groups found a positive relationship. The evidence that the DST predicts response to noradrenergic agents is weak. The DST does not predict acute response to somatic treatment in general or response to specific antidepressants. The selection of the appropriate treatment for depressed patients is still best made using clinical criteria.