Cortisol and corticosterone response after syn-corticotropin in relationship to dexamethasone suppressibility of cortisol

The current study was designed to investigate whether glucocorticoid output after syn-ACTH stimulation is different in depression associated with dexamethasone suppression test (DST) nonsuppression from the euthymic state and DST suppression. We gave 28 depressives a DST and an adrenocortical challenge with synthetic ACTH. Fourteen patients were nonsuppressors on the DST. After successful drug treatment, the subjects were reinvestigated by both tests; all DSTs revealed plasma cortisol concentrations below the criterion value of 50 ng/ml. Cortisol and corticosterone responses after syn-ACTH tended to be higher during depression. After clinical remission, higher cortisol and corticosterone responses occurred in those patients who were DST nonsuppressors during depression. This finding suggests that patients who suffer from a depression which is linked to an abnormal pituitary--adrenocortical regulation develop an enhanced sensitivity of the adrenal cortex to ACTH.     

Salivary, total plasma and plasma free cortisol in panic disorder

Summary. Background. Research on basal HPA axis activity in patients with panic disorder showed inconsistent results. Methods. Basal total plasma, plasma free and salivary cortisol levels were compared in patients with panic disorder (n = 47) and in healthy individuals (n = 23). Correlations between these fractions were calculated. Results. All three basal cortisol fractions were significantly elevated in patients compared to controls. There were significant correlations between all three cortisol fractions. Conclusions. Nonsignificant differences between cortisol levels of patients and healthy controls in previous studies may have been due to inclusion of less severely ill patients or to small sample sizes (96 words). Received July 28, 1999; accepted October 26, 1999     

Serial dexamethasone suppression tests in simultaneous panic and depressive disorders

Recent work suggests that the simultaneous occurrence of major depressive disorder (MDD) and panic disorder (PD) may be of relevance for clinical findings, therapeutic outcome, and prognosis. It is of interest to know whether or not this relevance extends to biological findings. We addressed this question through comparison of serial Dexamethasone Suppression Test (DST) results in patients who had either MDD alone or simultaneous MDD and PD. We were unable to describe differences between the groups.     

Association between low plasma levels of dexamethasone and elevated levels of cortisol in psychiatric patients given dexamethasone

In psychiatric inpatients, positive results on 40 dexamethasone suppression tests (elevated cortisol levels) were strongly associated with low plasma levels of dexamethasone. Bioavailability or pharmacokinetic factors may contribute importantly to the outcome of the dexamethasone suppression test.     

Judgement of the hypothalamic-pituitary-adrenocortical function in psychiatric patients by betamethasone-induced cortisol suppressibility

Summary Betamethasone induced cortisol suppressibility was examined in 62 drug free consecutively admitted psychiatric inpatients. Betamethasone was choosen instead of the commonly used dexamethasone, because its double half-life compared to dexamethasone and its higher tissue availability. After a base-line evaluation with blood samples drawn at 8 a.m., 4 p.m., and 11 p.m., 0.5 mg or 1.0 mg betamethasone was given orally at 11 p.m. Postbetamethasone cortisol as well as betamethasone blood levels were then measured at the same time points as on the baseline day. In the groups receiving 1.0 mg betamethasone non-depressed patients had significantly (p<0.05) lower postbetamethasone cortisol levels than depressed patients for each time point measured whereas 0.5 mg betamethasone did not differentiate depressed from non-depressed patients. Patients with other depressions like schizoaffective psychosis -depressive subtype- or organic brain syndrome with depressive symptomatology demonstrated similar postbetamethasone cortisol profiles as the group of patients with major depression. Betamethasone plasma concentrations differed significantly (p< 0.001) with respect to the oral dosage with higher values for the 1.0 mg betamethasone groups.     

Platelet serotonin, plasma cortisol, and dexamethasone suppression test in schizophrenic patients.

BACKGROUND: Serotonin (5-HT) regulates hypothalamic-pituitary-adrenal (HPA) axis activity. Abnormal response to the dexamethasone suppression test (DST) and altered platelet 5-HT concentration have been shown in some schizophrenic patients. METHODS: Platelet 5-HT and plasma cortisol concentrations were determined simultaneously in 86 male schizophrenic patients before and after DST. Basal plasma cortisol and platelet 5-HT levels were also determined in 69 healthy male persons. RESULTS: Schizophrenic patients had higher plasma cortisol and platelet 5-HT concentrations than healthy persons. An abnormal escape from dexamethasone suppression was observed in 50% of patients. In these patients predexamethasone cortisol and platelet 5-HT concentrations were higher than in patients with normal DST. CONCLUSIONS: This study demonstrates that schizophrenic patients have the HPA axis dysregulation that could be connected with a disturbance in the 5-HT system.     

Circadian analysis of plasma cortisol levels before and after dexamethasone administration in depressed patients

Pituitary-adrenal regulation in healthy subjects and in depressed patients is very dynamic. Interpretation of results of the 1-mg dexamethasone suppression test has usually depended on the result of a single blood cortisol level measurement obtained in the morning or afternoon. We analyzed circulating cortisol concentrations by obtaining blood samples at 20-minute intervals for 24 hours before and after dexamethasone administration in depressed patients. The results illustrate the variability in patterns of escape from the effects of dexamethasone among depressed patients; they also indicate the influence of the sampling time on the test results and thus on the relationship of the test result to various clinical classifications. Finally, these results provide the basis for understanding the consequences of alternative sampling strategies.     

Baseline plasma cortisol and dexamethasone test in unselected psychiatric inpatients

The plasma cortisol (PC) level at 08.00 a.m. was assessed in 250 unselected psychiatric inpatients suffering from various disorders, assorted in 8 diagnostic groups. Endogenously depressive patients showed a significantly higher rate of cortisol hypersecretion (PC greater than 560 nmol/l = 20 micrograms/dl) than the neurotically or reactively depressed patients and than schizophrenics or paranoid psychotics. The PC level after the midnight dose of 1 mg dexamethasone was examined in 125 patients at 08.00 a.m. (group I) and in 125 patients at 04.00 p.m. (group II). There was no statistical difference in the rate of dexamethasone test (DST) nonsuppressors (PC greater than 140 nmol/l = 5 micrograms/dl) in the separate diagnostic groups between group I and II, but in the postdexamethasone blood samples at 04.00 p.m., significantly more DST nonsuppressors were detected than in the samples at 08.00 a.m. in the total number of all patients, regardless of their diagnosis. DST nonsuppressors were found in all of our diagnostic groups with the exception of manic syndrome, and their various rates will be discussed and compared with the results of previous studies. The DST shows a high sensitivity in endogenous depression, but its diagnostic value is limited as a result of its relative lack of specificity.     

HPA hyperactivity with increased plasma cortisol affects dexamethasone metabolism and DST outcome

Data suggests that dexamethasone bioavailability or pharmacokinetic factors contribute importantly to the outcome of the dexamethasone suppression test, and a relationship between plasma cortisol and plasma dexamethasone levels has been shown. To evaluate these data further, we studied plasma dexamethasone pharmacokinetics in 24 patients with major depression (15 suppressors and nine nonsuppressors) who received a 1 mg IV dexamethasone bolus at 09:00 h with blood samples collected at intervals over the next 14 h. We found that nonsuppressors had significantly shorter plasma dexamethasone half-life (P=0.003) as well as significantly lower dexamethasone levels 10 h (P=0.02) following IV dexamethasone administration. Moreover, upon clinical improvement of patients, the shortened dexamethasone half-life and lower dexamethasone levels disappeared in the five patients who switched from nonsuppression to suppression and were restudied by IV bolus. These 10-h post IV plasma dexamethasone level findings paralleled the results of the 1 mg overnight oral DST performed in these depressed patients (N=22) where we found significantly lower 10 h plasma dexamethasone levels in nonsuppressors on admission compared to suppressors (P=0.002) and again at discharge (P=0.007). Interestingly, in the few patients who switched from suppression to nonsuppression over the course of hospitalization, 10-h post dose plasma dexamethasone levels simultaneously dropped. No difference in dexamethasone half-life was observed in the patients studied by oral and IV dexamethasone administration. These findings support the concept that metabolism of dexamethasone is significantly related to the activity of the HPA axis (particularly by plasma cortisol levels), and that dexamethasone pharmacokinetics can be modified by state-dependent phenomena.     

Psychopathology and plasma cortisol responses to dexamethasone in prepubertal psychiatric inpatients

This study of 51 prepubertal psychiatric inpatients evaluates plasma cortisol measurements at 8 AM, 4 PM, and 11 PM before and after dexamethasone was administered in counterbalanced order at doses of 0.5 mg and 1.0 mg. Approximately 76.5% of the children had an affective disorder. Major depressive disorder was associated with higher plasma cortisol levels than other disorders. Pre- and postdexamethasone plasma cortisol levels using 0.5 mg dexamethasone exhibited a circadian variation. The optimal criterion for cortisol nonsuppression was 5 micrograms/dl measured at 8 AM after administration of 0.5 mg dexamethasone.     

Plasma corticosterone and cortisol following dexamethasone in psychiatric patients

Radioimmunoassays of cortisol (F) and corticosterone (B) were carried out in 133 plasma specimens, obtained at 0800 or 1600 h on the day following administration of dexamethasone (1.0 mg), from 69 patients admitted to a psychiatric inpatient service, to test suggestions that assays of B might complement those of F in the dexamethasone suppression test (DST) in a psychiatric setting. The overall correlation between F and B was +0.80. Concentrations of B averaged 5-8% those of F. We found close agreement (80-85%) between positive (F greater than or equal to 4.5 micrograms/dl) and negative DST results for both steroids assayed by radioimmunoassay at a criterion of greater than or equal to 1.5 ng/ml for B, as well as a reasonable compromise between sensitivity and specificity of the B-DST at that criterion. Post-dexamethasone samples obtained at 1600 h showed somewhat closer agreement between the B-DST and the F-DST than at 0800 h. Inclusion of 0800 h samples added little to the rate of positive results with the F-DST but did add to those of the B-DST by about 10% or more, depending on the criterion selected for a positive B-DST. The rate of positive DSTs among 44 patients who had both steroids assayed at both times was approximately 61%, and the agreement between positive test results among these patients was 92%. In a mixed population of acutely ill, hospitalized patients with various DSM-III diagnoses, but excluding those with medical or pharmacologic contraindications to the DST, high rates of positive DST results were obtained in patients with major depressive disorders (47-58%), with little difference found among those with bipolar, non-bipolar or melancholic characteristics. High rates also were found among manic and other acutely psychotic patients, as well as others with neurotic or characterological diagnoses, but rarely in a small group of chronic schizophrenics. Thus, a positive DST as evaluated with B or F is evidently not specific for cases of major depression, but may be indicative of acute illness, possibly with affective features. The results support suggestions that a steroid suppression test based on corticosterone may be useful to aid in diagnosis of major psychiatric illnesses and might complement or substitute for the F-DST. It may be possible to avoid certain pharmacologic complications in the DST by use of a test based on suppression of B by F rather than by dexamethasone.     

Altered cingulate white matter connectivity in panic disorder patients

OBJECTIVE: Functional imaging studies of panic disorder subjects suggest an increased activation of the cingulate regions of the brain. Aim of the current study was to explore the white matter connectivity differences between subjects with panic disorder and healthy comparison subjects. METHOD: Structural white matter connectivity, as determined from fractional anisotropy (FA) values obtained by diffusion tensor imaging, was assessed for anterior and posterior cingulate regions in 24 panic disorder patients and 24 age and sex-matched healthy comparison subjects. RESULTS: Subjects with panic disorder exhibited significantly greater FA values in left anterior and right posterior cingulate regions (by 13.3% and 19.6%, respectively) relative to comparison subjects. White matter connectivity for these two cingulate regions was also positively correlated with clinical severity, as determined by Panic Disorder Severity Scale. FA values in left anterior cingulate region negatively correlated with the time of Trail Making Tests and positively with Digit Symbol Substitution Test. CONCLUSIONS: Findings suggest a potential 'enhancement' in white matter connectivity in left anterior and right posterior cingulate regions in panic disorder, and that these changes may play an important role in mediating clinical symptoms of panic disorder.     

Suppression of cortisol following dexamethasone in demented patients

Sixty-four nondepressed, carefully selected senile demented inpatients underwent two 1-mg overnight dexamethasone suppression tests (DSTs) separated by 7 days. These patients were in a clinically stable and drug-free state for at least 6 months before testing. The Modified Ischemic Score and ICD-9 criteria for Alzheimer's disease were used to dichotomize subjects into Alzheimer's and multi-infarct types of dementia. Patients with vascular dementias were significantly more likely to evidence DST nonsuppression. Furthermore, DSTs in this group were less reproducible from week to week than DSTs in Alzheimer's patients.     

Altered auditory processing in patients with panic disorder: A pilot study

Abstract

Objectives. Clinical and electrophysiological studies suggest that panic disorder (PD) patients show disturbed response inhibition to sensory stimuli. Thus, habituation of neuronal activation after repeated sine tone stimulation was assessed by functional magnetic resonance imaging (fMRI) in patients with PD. Methods. Twenty patients with PD and 20 age- and gender-matched healthy controls were assessed by 3T fMRI for auditory habituation. During three stimulation cycles of digitally generated pulsed (ν=5 Hz) 800-Hz sine tones alternating with silent periods, activation of the auditory cortex and other anxiety- or sensory integration-related regions was assessed. Brain activation was further analyzed dependent on functional serotonin transporter (5-HTT) gene variation (5-HTTLPR). Results. PD patients demonstrated an extended brain activity in the first stimulation block, which normalized during the second stimulation cycle. A positive correlation with anxiety measures (HAMA) and an increased activity of distinct anxiety- or sensory integration-related areas (e.g., BA 22, BA 10) were seen during the third block of auditory stimulation. There was a significant interaction of left amygdala activation and the 5-HTTLPR S allele. Conclusions. Our results support the hypothesis of an aberrant processing of sensory information in PD patients. This phenomenon may underlie an enhanced responsiveness to anxiety-relevant or irrelevant stimuli possibly increasing PD vulnerability.     

Salivary cortisol in panic attacks

OBJECTIVE: Documentation of hypothalamic-pituitary-adrenal (HPA) axis disturbance in panic disorder has been inconsistent. Increased cortisol levels have been associated with altered HPA function due to stress. The authors examined salivary cortisol levels in spontaneously occurring, unprovoked panic attacks. METHOD: Patients with panic disorder (N=25) collected saliva samples when panic attacks occurred. Levels of cortisol in the saliva samples were determined and were compared with levels in comparison samples of saliva obtained 24 hours after the panic attack occurred. RESULTS: During spontaneous panic attacks there was a subtle but significant elevation of cortisol levels, compared with levels obtained 24 hours later. No significant correlations were found between the cortisol elevations during panic attacks and the severity of the attack as measured by using the Acute Panic Inventory or the severity of illness as measured by using the Panic and Agoraphobia Scale. CONCLUSIONS: Saliva sampling may be a useful method for investigating neuroendocrine parameters during spontaneously occurring panic attacks.     

Alcohol use disorders in relatives of patients with panic disorder

OBJECTIVE: The aim of this study was to use data from a family study of anxiety disorders to examine the familial association between alcohol use disorders and panic disorder (PD), controlling for alcohol use disorders in the proband. METHOD: Data from a family study of anxiety disorders were used to compare rates of alcohol use disorders in the relatives of 3 proband groups (PD with lifetime alcohol use disorders, PD without lifetime alcohol use disorders, and not-ill controls). RESULTS: There was a significantly higher rate (12%) of alcohol use disorders among the relatives of PD probands compared with relatives of controls (5%), even in the absence of alcohol use disorders in the proband and after adjusting for differences in sociodemographic characteristics and lifetime drug use disorders (chi2 = 5.4; df = 1; P = .02). Anxiety symptoms were more frequent among the male relatives of panic probands who received an alcohol diagnosis, compared with those who did not have alcohol use disorders (10/25 vs 22/111; chi2 = 4.6; df = 1; P = .03). A similar pattern was found in women (8/11 vs 63/156; chi2 = 4.4; df = 1; P = .036). CONCLUSIONS: These findings suggest a familial association between PD and alcohol use disorders. Future studies with more refined alcohol diagnoses are needed to replicate and investigate the mechanism of this association.