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.     

Lithium augmentation in treatment-resistant depression: clinical evidence, serotonergic and endocrine mechanisms

For now more than 50 years, lithium has been the gold standard for the pharmacologic treatment of bipolar disorder. However, its utility is not restricted to acute mania and prophylactic treatment of bipolar disorder. A relatively new indication for its use is the addition to an antidepressant in the acute treatment phase of unipolar major depression. To date, this treatment approach called lithium augmentation is the best-documented approach in the treatment of refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment. In a recent double-blind, placebo-controlled trial, lithium augmentation has demonstrated to also be effective in the continuation treatment phase to prevent early relapses. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. In contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants, neuroendocrine studies on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined DEX/CRH test. Here we review new data on the efficacy and mechanism of action of lithium augmentation.     

The dexamethasone suppression test: its relationship to diagnoses, severity of depression and response to treatment

1. The dexamethasone suppression test (DST) was applied to 40 depressed patients, 40 healthy volunteers and 40 patients with other psychiatric disorders. 2. The post-dexamethasone cortisol level, adopted as the non-suppression criterion and established locally, was 3.0 micrograms/dl. 3. The DST sensitivity in depression was 45%, with a specificity of 95% and a positive predictive value of 90%. 4. There was a significant correlation (r = 0.38, p less than 0.05) between HDRS scores of depressed patients and their post-dexamethasone cortisol levels. 5. A prospective study of the depressed group, which was assessed with three depression rating scales, showed differences between non-suppressors and suppressors regarding to the symptoms severity and response to the treatment. It suggests that an abnormal DST result could have a prognostic value to antidepressant drugs and ECT. 6. The DST specificity in depression was also calculated from its performance in the group with other psychiatric disorders, and their diagnoses as well as the abnormal DST results were critically discussed.     

Hypothalamo-pituitary-adrenal activity in endogenously depressed post-traumatic stress disorder patients

We studied the hypothalamo-pituitary-adrenal (HPA) system in Vietnam veterans with post-traumatic stress disorder (PTSD) who also met Research Diagnostic Criteria for endogenous depression (MDD-ED). Over half also abused alcohol, and many complained of pain-confounding factors usually associated with increased HPA activity. Nonetheless, not even one patient had elevated basal plasma cortisol concentrations or an abnormal dexamethasone suppression test (DST); the subjects' post-dexamethasone cortisol values and plasma cortisol per ng plasma dexamethasone were in the low-normal range. These results highlight the biological heterogeneity of endogenous depression and its possible influence by past psychological trauma, and they raise questions about the use of current typological criteria for research purposes.     

Morning and Evening Adrenocortical Responses to ACTH Stimulation in Endogenously Depressed Patients: A Preliminary Report

Abstract: Adrenocortical stimulation with ACTH both in the morning (M-test) and in the evening (Etest) and the dexamethasone suppression test were carried out in patients suffering from endogenous depression (DEP) and normal controls (NOR). A greater cortisol release in DEP was recognized than in NOR in the M-test, an earlier peak response of DEP was shown in the M-test than in the Etest, and a lack of association between hypersecretion of cortisol during depression and cortisol output after ACTH administration was noted. These findings, together with the results of DST, suggest that excessive activity of the hypothalamic-pituitary-adrenal (HPA) axis in depression may result, partly, from adrenocortical hyperresponsiveness.     

Age effects in serial hypothalamic-pituitary-adrenal monitoring

To evaluate age effects on hypothalamic-pituitary-adrenal (HPA) regulation in depressives, we studied 65 patients with major depressive disorder, endogenous subtype. With each patient serving as his or her own control, we compared weekly dexamethasone suppression test (DST) results among three age subgroups (less than 40 years, n = 18; 40-70 years, n = 40; greater than 70 years, n = 7). The oldest patient group had higher mean post-dexamethasone plasma cortisol concentrations both before and after treatment, and more were DST nonsuppressors. Life table analyses revealed that elderly patients who were DST nonsuppressors had significantly slower patterns of normalization during treatment and that fewer elderly patients ever achieved normal suppression. The results indicate that age effects on HPA function may be confounded with other aspects of depression, such as severity, chronicity and number of previous episodes.     

Number of cortisol time-points and dexamethasone suppression test sensitivity for major depression

Failure to suppress cortisol secretion after administration of dexamethasone has been reported to be a diagnostic marker for major depression and to have prognostic implications when repeated after antidepressant treatment. The pulsatile pattern of cortisol secretion suggested to us that increasing the number of post-dexamethasone cortisol determinations might significantly increase the sensitivity of the dexamethasone suppression test (DST) for major depression. With a conventional two-point DST (1600 h and midnight), 5% of 20 normal volunteers, 8% of 13 inpatients with non-major depressions, and 31% of 65 inpatients with primary major depression failed to suppress. With six post-dexamethasone points (0800 h, 1200 h, 1600 h, 2000 h, 2200 h, midnight), the respective percentages were 10, 15 and 44%. The additional points increased the sensitivity from 31 to 44%, mostly by identifying more major depressives with a "late escape" pattern. If a clinician is using the DST to establish a marker for major depression that can be repeated to monitor response to treatment and the likelihood of relapse, then perhaps the increased sensitivity of the six-point DST would be helpful, despite a modest decrease in specificity from 94 to 88%.     

Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder

Although lithium augmentation is the foremost and most well-documented treatment strategy for treatment resistant depression, knowledge of factors related to response remains scanty. Findings with the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test are associated with response to treatment with a tricyclic antidepressant. This study investigated the potential predictive value of the DEX/CRH test for lithium augmentation response in major depressive disorder. The DEX/CRH test was conducted prior to lithium augmentation in 30 patients with a major depressive episode who had not responded to an antidepressant monotherapy trial of at least 4 weeks. Response status was assessed weekly using the Hamilton Rating Scale for Depression. For multivariate prediction, a logistic regression analysis was performed. Eleven (37%) patients responded to lithium augmentation within 4 weeks. Responders showed higher ACTH response and lower cortisol response in the DEX/CRH test, but results were not statistically significant. However, non-responders had a statistically significant higher cortisol/ACTH peak ratio (3.43+/-1.75) compared to responders (2.18+/-1.38) (P=0.027). This ratio is an indicator for the sensitivity of the adrenal cortex to ACTH. A cortisol/ACTH peak ratio of 1.8 was identified as the best cutoff point to differentiate responders from non-responders. In conclusion, results suggest a more sensitive adrenal cortex in non-responders to lithium augmentation. The findings would be in line with the assumption of a more chronic course of depression with more pronounced biological alterations in the non-responder group, because chronic depression is known to cause enlargement of the adrenal gland with a subsequent hypersensitivity to ACTH. Results of this study should be confirmed in a larger study group.     

HPA-axis hyperactivity and mortality in psychotic depressive disorder: preliminary findings

BACKGROUND: The excess mortality associated with depressive disorders has been most often attributed to risks for suicide but diverse findings indicate that depressive disorders also increase risks for cardiovascular (CV) mortality. Among the possible mediators is the hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity that characterizes many cases of relatively severe depressive disorder and severity is characteristic of psychotic depressive disorder. METHODS: The following describes a 17-year mortality follow-up of 54 patients with Research Diagnostic Criteria (RDC) psychotic major depression or schizoaffective, mainly affective, depression. All had baseline assessments that included a 1mg dexamethasone suppression test with post-dexamethasone samples at 8 a.m., 4 p.m. and 11 p.m. RESULTS: Regression analyses showed that both greater age and higher maximum post-dexamethasone cortisol concentrations predicted deaths due to CV causes (t=4.01, p<0.001 and t=3.03, p=0.004, respectively). The 4 who died from CV disease had a mean (SD) post-dexamethasone cortisol concentration of 18.0 (6.0)microg/dl while the mean (SD) value for the remaining 50 patients was 7.6 (6.6)microg/dl (t=3.03, df=53, p=0.004). Regression analyses showed the 11 p.m. post-dexamethasone value to be predictive of suicide (t=2.05, p=0.048). CONCLUSIONS: Conclusions should be tentative because an earlier follow-up of a more heterogeneous, but larger, sample did not find a relationship between DST results and CV mortality, and because only 4 CV deaths occurred in the present study. HPA-axis hyperactivity is probably only one of a number of factors that link depressive disorder to CV mortality.     

Plasma L-tryptophan/neutral amino acid ratio and dexamethasone suppression in depression

We examined the ratio of plasma L-tryptophan (L-TRP) to other neutral amino acids (NAA) in normal controls and depressed patients undergoing a dexamethsone suppression test (DST). The L-TRP/NAA ratio discriminated controls from patients; however, there was no difference in the mean L-TRP/NAA ratio between DST suppressors and nonsuppressors. The cortisol level measured at 1600h postdexamethasone and the L-TRP/NAA ratio were positively correlated. The 1600h postdexamethasone cortisol levels accounted for 24% of the variance of Hamilton Depression Rating Scale ( HDRS ) scores. The inclusion of L-TRP/NAA ratios with 1600h postdexamethasone cortisol levels in a multiple regression equation resulted in an increase in this value and accounted for 65% of the variance in HDRS scores. The finding supports the use of multivariate biological models in depression.     

The dexamethasone suppression test: a study in a normal population

One hundred healthy, non-depressed volunteers were given a standard dexamethasone suppression test (DST) to determine the appropriate criterion values of plasma cortisol to define suppression or nonsuppression. By radioimmunoassay (RIA) of cortisol, the criterion value for 5% nonsuppression was plasma cortisol greater than 187 nmol/l, and for suppression less than 153 nmol/l, with an indeterminate range between these values. Use of the widely accepted pre-determined criterion value of 138 nmol/l gave a significantly greater frequency of nonsuppression. Values of cortisol measured by two RIAs in a subset of 43 volunteers were not equivalent. With the experimentally determined criterion value, no significant differences between nonsuppressors and suppressors were found for any measured physical or psychological parameters. Women taking oral contraceptives had significantly higher plasma cortisol pre-dexamethasone and post-dexamethasone. Their exclusion did not alter the calculated criterion value for the remainder, but their separately estimated criterion value was significantly higher. Caution should be exercised when classifying the DST status of women on oral contraceptives, particularly when values are at the lower end of the nonsuppressor range. Determination of a separate normal range for them may be warranted.     

Post-dexamethasone cortisol correlates with severity of depression before and during carbamazepine treatment in women but not men.

OBJECTIVE: Previous studies show a state-dependent relationship between depression and post-dexamethasone suppression test (DST) cortisol level, as well as differences in DST response with age and gender. METHOD: In this study, 74 research in-patients with affective disorders were given the DST on placebo and in a subgroup following treatment with carbamazepine. Depression was evaluated twice daily with the Bunney-Hamburg (BH) rating scale. Data were examined for the total subject population, by gender and by menopausal status in women. RESULTS: A robust positive correlation was observed between depression severity and post-DST cortisol in pre- and postmenopausal females, but not in males. This relationship persisted in women when restudied on a stable dose of carbamazepine (n=42). CONCLUSION: The pathophysiological implications of this selective positive relationship between severity of depression and post-DST cortisol in women, but not men, should be explored further.     

The central mechanism of hypothalamic-pituitary-adrenocortical system hyperfunction in depressed patients

While hypercortisolemia is commonly observed in depression, exactly where in the hypothalamic-pituitary-adrenocortical (H-P-A) axis this dysfunction arises remains undefined. In attempting to distinguish between central or peripheral locus of dysfunction, we studied in 12 patients (10 females, two males) with primary major depression and eight age-matched controls (six females, two males) in their adrenal cortisol response to infused adrenocorticotropic hormone (ACTH) (cosyntropin 0.05 microg/kg bodyweight) while endogenous ACTH was suppressed with 1 mg of dexamethasone. Compared with the control group, pre-dexamethasone plasma baseline cortisol level was significantly higher in depressed patients while ACTH level remained normal. Post-dexamethasone responses of both hormones were greatly non-suppressed in the depressed group. Exogenous cosyntropin-elicited rise in plasma cortisol was significantly lower in depressed patients while the ACTH response was not significantly different. These findings suggest that an adrenal cortisol response to ACTH was significantly decreased during depression as compared with normals in Chinese depressed patients. Therefore, the central mechanism of hyperfunctioning H-P-A axis causing hypercortisolemia should be emphasized.     

Lithium augmentation in the treatment of refractory depression in old age

A retrospective study of treatment and outcome is described in 59 consecutive referrals to a catchment psychogeriatric service meeting ICD9 criteria for manic depressive illness or depressive neurosis. Of 22 who failed to respond to tricyclic antidepressants, nine (of whom four had also failed to respond to ECT) were treated by lithium augmentation. Systematic comparisons between lithium-treated subjects, tricyclic responders and others failing to respond to tricyclics revealed no significant demographic differences. Lithium augmentation was successful in 6/9 subjects. Two ‘lithium failures’ were treated with tranylcypromine to good effect. At follow-up (median six months, range 3–20 months) 7/9 subjects in the lithium-treated group were well. This was similar to the follow-up status in tricyclic responders and significantly better than outcome in the other tricyclic non-responders. Lithium augmentation appears to be a relatively well-tolerated treatment manoeuvre in refractory depression in old age, with treatment response similar to that reported in younger subjects, and may be of particular use where ECT has failed.     

Dopaminergic function and the cortisol response to dexamethasone in psychotic depression

1. It has been hypothesized that psychotic symptoms in depression may be due to increased dopamine activity secondary to hypothalamic-pituitary-adrenal (HPA) axis overactivity. 2. To test this hypothesis, the authors examined the cortisol response to dexamethasone suppression test (DST, 1 mg orally) and multihormonal responses to apomorphine (APO, 0.75 mg s.c.)--a dopamine agonist--in 150 drug-free hospitalized patients with DSM-IV major depressive episode with psychotic features (MDEP, n=35), major depressive episode without psychotic features (MDE, n=74), or schizophrenia paranoid type (SCZ, n=41), and 27 hospitalized healthy controls (HCs). 3. MDEPs showed increased activity of the HPA system (i.e. higher post-DST cortisol levels) than HCs, SCZs and MDEs. However, there were no differences in adrenocorticotropic hormone (ACTH), cortisol, prolactin and growth hormone (GH) responses to APO between MDEPs and MDEs and HCs. On the other hand, SCZs showed lower APO-induced ACTH stimulation and a higher rate of blunted GH than HCs, MDEs and MDEPs, suggesting a functional alteration of the hypothalamic dopamine receptors in SCZs. 4. In the total sample and in each diagnostic group, DST suppressors and non-suppressors showed no differences in hormonal responses to APO. 5. These results suggest a lack of causal link between HPA axis hyperactivity and dopamine dysregulation. In contrast to schizophrenia, psychotic symptoms in depression seem not to be related to dopamine function dysregulation.     

Morning and evening adrenocortical responses to ACTH stimulation in endogenously depressed patients: a preliminary report

Adrenocortical stimulation with ACTH both in the morning (M-test) and in the evening (E-test) and the dexamethasone suppression test were carried out in patients suffering from endogenous depression (DEP) and normal controls (NOR). A greater cortisol release in DEP was recognized than in NOR in the M-test, an earlier peak response of DEP was shown in the M-test than in the E-test, and a lack of association between hypersecretion of cortisol during depression and cortisol output after ACTH administration was noted. These findings, together with the results of DST, suggest that excessive activity of the hypothalamic-pituitary-adrenal (HPA) axis in depression may result, partly, from adrenocortical hyperresponsiveness.     

Attenuation of HPA Axis Hyperactivity and Simultaneous Clinical Deterioration in a Depressed Patient treated with Mirtazapine

It has been suggested that hypothalamic-pituitaryadrenal (HPA) system dysregulation plays an important role in the pathophysiology of depression and that normalization of HPA axis hyperactivity precedes successful treatment with antidepressants. We report the case of a 61-year-old patient suffering from a major depressive episode who underwent the combined dexamethasone suppression/CRH stimulation test (DEX/CRH test) before and again after one week of mirtazapine treatment. While the patient showed a marked decrease of cortisol and ACTH secretion during the DEX/CRH test within one week, a pronounced and ongoing deterioration of depressive symptoms with suicidal thoughts occurred that was resistant to antidepressant medication and had to be treated with electroconvulsive therapy. Apparently, mirtazapine rapidly attenuates HPA axis hyperactivity in depressed patients via direct pharmacoendocrinological effects. However, this amelioration of HPA system dysregulation is not necessarily accompanied by clinical improvement.     

Plasma 11-deoxycortisol and cortisol following dexamethasone in psychiatric patients

As it has been suggested that calculating the ratio of cortisol to its biosynthetic precursor, 11-deoxycortisol, may enhance the sensitivity of the dexamethasone suppression test (DST) for depression, cortisol and 11-deoxycortisol were measured in 90 subjects undergoing this test. Among these subjects, post-dexamethasone cortisol and 11-deoxycortisol levels were significantly correlated (r = 0.65, P less than 0.001) and evaluating the ratio of cortisol to 11-deoxycortisol decreased rather than enhanced sensitivity of the DST.     

Hypothalamic-pituitary-thyroid system activity during lithium augmentation therapy in patients with unipolar major depression

OBJECTIVE: Lithium augmentation is an established strategy in the treatment of refractory depression, but little is known about predictors of response and its mode of action. There is increasing evidence that low thyroid function indices within the normal range are associated with a poorer treatment response to antidepressants, but previous studies on the hypothalamic-pituitary-thyroid (HPT) system during lithium augmentation provide inconclusive results and have methodological limitations. This study aimed at exploring the role of thyroid function in lithium augmentation and used a prospective design that included a homogeneous sample of inpatients with unipolar major depressive disorder. METHODS: In 24 euthyroid patients with a major depressive episode who had not responded to antidepressant monotherapy of at least 4 weeks, we measured serum thyroid-stimulating hormone (TSH), total triiodothyronine (T3) and total thyroxine (T4) before (baseline) and during lithium augmentation therapy (follow-up). The time point of the endocrinological follow-up depended on the status of response, which was assessed weekly with the Hamilton Depression Rating Scale, 17-item version (HDRS17). Responders were reassessed immediately after response was determined, and non-responders after 4 weeks of lithium augmentation. RESULTS: There was a statistically significant change in thyroid system activity during lithium augmentation, with an increase of TSH levels and a decrease of peripheral T3 and T4 levels. However, there were no differences in any of the HPT hormones between responders and non-responders at baseline or at follow-up. CONCLUSIONS: The decrease of thyroid system activity during lithium treatment reflects the well-established "antithyroid" properties of lithium. However, it appears that thyroid status does not predict response to lithium augmentation in euthyroid patients before treatment.     

Plasma cortisol and 11-deoxycortisol activity in depressed patients and normal volunteers.

Plasma cortisol and 11-deoxycortisol were measured in 30 depressed patients and 110 normal volunteers before and after a 1.0 mg dexamethasone suppression test (DST). Post-dexamethasone plasma cortisol, 11-deoxycortisol and the cortisol/11-deoxycortisol ratio were significantly higher in the depressives compared to the controls, even when age and sex were taken into account. Pre-dexamethasone plasma cortisol, post-dexamethasone cortisol, 11-deoxycortisol and their ratio were significantly higher in the cortisol nonsuppressors than in the suppressors. The measurement of post-dexamethasone 11-deoxycortisol and the ratio did not differentiate between endogenous and reactive depression. Using the normative data, we explored several methods for determining a criterion value to define abnormal post-dexamethasone plasma 11-deoxycortisol and the cortisol/11-deoxycortisol ratio in depressed patients. All showed poor sensitivity and a low positive predictive value for depression. The measurement of 11-deoxycortisol thus does not enhance the clinical utility of the DST.