Peter M. Stoll

Pituitary-adrenal function in depressed patients: Resistance to dexamethasone suppression

Abstract Hypothalamic-pituitary-adrenocortical function is activated by physical stress and anxiety. This laboratory and others have reported elevated plasma cortisol levels in depressed patients. We report here the response to 48 hr and overnight dexamethasone suppression tests in markedly depressed patients. In twenty-seven 48-hr tests, 0·5 mg dexamethasone was given orally every 6 hr for 8 doses (4 mg total). 0900 plasma cortisol level was determined after 24 and 48 hr. In 55 overnight tests, 1, 2, or 8 mg dexamethasone was given at 2300 hr and 0900 plasma sampled 10 hr later. Seventy-four % of patients showed marked resistance to suppression in the 48 hr tests (second 0900 plasma > 5 μg/ 100 ml). Eighteen of 22 patients did not suppress to

Adrenocortical hyperactivity in depression: Effects of agitation, delusions, melancholia, and other illness variables

In an attempt to determine the relative contributions to adrenocortical hyperactivity in depression of agitation, delusions, and melancholic subtype, we measured cortisol levels before and after dexamethasone in 93 unipolar major depressed inpatients. Stepwise multiple regression showed that agitation predicted 22% of the variance in a.m. cortisol level after dexamethasone. Addition of the variables melancholia and delusionality to the regression model accounted for 27% and 34%, respectively, of the variance in the same cortisol variable. Age, illness severity, and weight loss added no further significant predictive value. Age, weight loss, and illness severity did affect cortisol levels when examined separately from the other variables. Rate of nonsuppression on the dexamethasone suppression test (DST) differed between the nonmelancholic major depressive group and any other group with melancholia. These results suggest why some discrepancies may exist between studies of the DST in delusional depression and indicate that agitation merits careful assessment in future studies of DST response.

Adrenocortical function and suicidal behavior in depressive disorders

In order to examine the hypothesis that abnormal adrenocortical function is associated with suicidal behavior, morning and afternoon plasma cortisols and 1-mg dexamethasone suppression tests (DSTs) were performed in 65 patients with primary major depressive disorder. Patients with recent suicide attempts (within 28 days before DST) were compared to patients who had made past attempts and those who had never made suicide attempts with respect to age, gender, severity of depression, and plasma cortisol levels. Plasma cortisol levels did not differ significantly among the three groups. Nonsuppression on the DST was associated with presence of delusions, increasing age, and global severity of depression, but not with suicide attempts.

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.

Increased extrapyramidal symptoms with addition of lithium to neuroleptics.

To explore whether lithium exacerbates neuroleptic-induced extrapyramidal symptoms (EPS), the authors prospectively rated 10 patients on neuroleptics before and after the addition of lithium. EPS ratings increased steadily after the initiation of lithium and were significantly elevated compared with baseline. Individual items that increased significantly were: gait, shoulder shaking, elbow rigidity, and tremor. These findings indicate that usual therapeutic levels of lithium may significantly worsen neuroleptic-induced EPS. Potential mechanisms for this interaction are discussed.

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.

Hypercortisolemia decreases dexamethasone half-life in rabbit

The pharmacokinetics of dexamethasone have been found to be related to endogenous hypothalamic-pituitary-adrenal (HPA) axis activity. Lower plasma dexamethasone levels in psychiatric patients (especially depressed) who are dexamethasone suppression test (DST) nonsuppressors have previously been reported. Since DST nonsuppression is one measure of HPA axis hyperactivity and is usually associated with relatively increased plasma cortisol levels and lower post dose plasma dexamethasone levels, we hypothesized that hypercortisolemia can induce a more rapid disappearance of dexamethasone from plasma. We therefore studied the kinetics of dexamethasone in rabbits before and after a period of sustained hypercortisolemia produced by administration of IM hydrocortisone acetate, a slowly absorbed salt of cortisol. Mean dexamethasone half-life decreased significantly from baseline of 1.92 h on day zero in seven rabbits to 1.17 h on experimental day 17 of induced hypercortisolemia (P < 0.001), while there was no significant change in saline treated controls (n = 3). Dexamethasone half-life had returned to the baseline levels when retested 88 days later on experimental day 105. The results indicate that pronounced hypercortisolemia decreases dexamethasone half-life in rabbits, and support the concept that increased circulating cortisol levels induce hepatic enzymes that metabolize dexamethasone. Thus, the lower postdexamethasone plasma dexamethasone levels and decreased dexamethasone half-life in DST nonsuppressors may in part reflect the effect of prior or coincident hypercortisolemia.