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Desmopressin Normalizes the Blunted Adrenocorticotropin Response to Corticotropin-Releasing Hormone in Melancholic Depression: Evidence of Enhanced Vasopressinergic Responsivity

Departments of Psychological Medicine (T.G.D., E.L., L.V.S.) and Endocrinology (J.N.-P., S.M., A.B.G.), St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom

Address all correspondence and requests for reprints to: Prof. Ted Dinan, Department of Psychiatry, Royal College of Surgeons in Ireland, St. Stephen’s Green, Dublin 2, Ireland. E-mail: tdinan{at}indigo

	Abstract

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Major depression is associated with significant disturbance in hypothalamic-pituitary-adrenal axis functioning, including blunted release of ACTH in response to CRH infusion. Eight melancholic depressives and eight matched healthy comparison subjects underwent, in random order, the following challenges: placebo, CRH, CRH+DDAVP. Blood for ACTH and cortisol estimation was drawn at -15, 0, 15, 30, 45, 60, 90, and 120 min. A blunted release of ACTH, in response to CRH challenge, was observed in depression (P < 0.01), whereas maximal cortisol responses in both groups were similar, despite elevated baseline levels in depression (P < 0.05). The combined CRH/DDAVP infusion produced similar ACTH and cortisol release in both groups. These results suggest that melancholic depression is associated with enhanced pituitary vasopressinergic responsivity.

	Introduction

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DISTURBANCES in hypothalamic-pituitary-adrenal axis (HPA) function are the most consistently demonstrated neuroendocrine abnormalities in major depressive illness, especially in those with melancholic features (1). Hypercortisolism (2) and the relative failure to suppress with an overnight dose of dexamethasone are frequently seen (3). Elevated CSF levels of CRH- immunoreactivity (4), together with blunted CRH-stimulated ACTH release, have also been reported (5, 6). In addition, constant infusions of either ovine or human CRH seem to reproduce the abnormal HPA axis rhythm seen in depressed patients (7). These changes occur in a setting of adrenal hyperplasia, demonstrable either by computed tomography or magnetic resonance imaging (8, 9), with a reduction in adrenal gland volume in excess of 50%, documented after successful treatment of the depressive episode (9).

Though CRH secreted from the hypothalamic paraventricular nucleus is the dominant regulator of the HPA axis, in recent years the role of AVP as a cosecretagogue has been increasingly recognized (10). It has been suggested that dysregulation of the hypothalamic CRH-containing neurons may result from genetic or environmental factors that lead to CRH hypersecretion with a concomitant elevation in serum cortisol and down-regulation of hypophysial CRH receptors (11, 12, 13); this model explains many of the neuroendocrine changes. However, the sustained hypercortisolism is difficult to understand if the pituitary CRH receptors undergo significant adaptive down-regulation, and it has therefore been speculated that the continued overactivation of the axis is sustained by concomitant hypersecretion of AVP.

To further investigate this hypothesis, we have therefore studied the effects of the vasopressin analogue, desmopressin, on the pituitary-adrenal responses to CRH in a group of depressed patients, as compared with matched control subjects. In healthy subjects, desmopressin significantly potentiates ACTH release when coadministered with CRH (14). We hypothesized that the coadministration of desmopressin with CRH would overcome the blunted ACTH response observed in depressed individuals when CRH is administered alone.

	Subjects and Methods

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Subjects

Eight patients (five female) with major depression and with melancholic symptoms (DSM-1V) were recruited. All gave fully informed written consent to take part in the study, which had Ethics Committee approval. They ranged in age from 34–56 yr, were within 10% of ideal body weight, and were drug-free for at least 4 weeks before study entry. Hamilton depression scores ranged from 21–28. Physical examination and routine laboratory investigation revealed no evidence of any other illness.

Eight healthy subjects were carefully matched for gender, age, and body weight; none had a personal or family history of depression.

Study design

The study was a single-blind, randomized, placebo-controlled, cross-over design. Subjects were tested on three separate occasions with placebo, 100 µg ovine-sequence CRH (oCRH) alone, and 100 µg oCRH in combination with 10 µg desmopressin. The test order was randomized, with intervals of at least 3 days between tests.

After a fast, from 0800 h, an indwelling forearm cannula was inserted at 1330 h, and the subject remained supine for the duration of the test. At 1400 h (0 min), the infusion was injected iv, over 15 sec. Blood was taken, for estimation of plasma ACTH and serum cortisol, at -15, 0, 15, 30, 45, 60, 90, and 120 min. Blood pressure and pulse-rate were recorded at each time point. After testing, each subject was advised to restrict fluid intake to 2 L for the remainder of the day.

Hormone assays

Plasma cortisol was measured by an unextracted, nonchromatographic RIA. The coefficient of variation, at both 100 nmol/L and 1000 nmol/L, was 6%. Plasma ACTH was measured, using a two-site unextracted immunoradiometric assay, with a commercially available kit supplied by Nichols Institute Diagnostics (San Juan, Capistrano, CA). The sensitivity of the assay is 5 ng/L. Intraassay and interassay coefficients of variation were 3% and 6%, respectively.

Statistical analysis

All results are expressed as mean ± SEM. The responses were measured both as delta scores (maximum level, post infusion, relative to baseline) and areas under the curve (AUC) and were principally analyzed with a two-way repeated-measures ANOVA with Tukey comparisons; Student’s paired t tests and Pearson product-moment correlation coefficients were also used where appropriate.

	Results

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Baseline cortisol levels (mean of -15 and 0 samples) were higher in depression than in the healthy subjects on each of the test occasions: CRH test day (depressives vs. healthy volunteers), 446 ± 39 nmol/L vs. 206 ± 27 nmol/L (P < 0.05); CRH+desmopressin day, 435 ± 26 nmol/L vs. 214 ± 28 nmol/L (P < 0.05); and placebo day, 440 ± 43 nmol/L vs. 318 ± 16 nmol/L (P < 0.05). Baseline ACTH was also higher in the depressives: CRH test day, 13.3 ± 1.0 ng/L vs. 10.0 ± 1.4 ng/L (P = 0.06); CRH+desmopressin day, 13.6 ± 1.2 ng/L vs. 9.9 ± 1.2 ng/L (P = 0.05); and placebo day, 14.6 ± 1.2 ng/L vs. 10.9 ± 1.3 (P = 0.06) (Fig. 1).

View larger version (16K): [in this window] [in a new window]   Figure 1. ACTH response to oCRH (100 µg infusion at time 0). Results are expressed as mean ± SEM.

With regard to plasma ACTH, the AUC responses were significantly increased for both CRH alone (P < 0.01) and for CRH in combination with desmopressin (P < 0.01), whereas placebo caused no change in either group (Fig. 2). The addition of desmopressin caused a significantly greater stimulation, as compared with CRH alone, in the normal volunteers and also in the depressives, but the incremental change was greater in the depressed patients (P < 0.05). When comparing the two groups directly, depressed patients showed a significantly lower response, compared with the controls, when expressed as either AUC or deltas. However, for the combination of CRH and desmopressin, both AUC and delta values were not significantly different.

View larger version (16K): [in this window] [in a new window]   Figure 2. ACTH response to combined administration of oCRH (100 µg) and DDAVP (10 µg) at time 0. Results are expressed as mean ± SEM.

The two-way ANOVA on the cortisol responses to both CRH and CRH+desmopressin, with baseline cortisol entered as a covariate, was not significant. Maximal cortisol responses to CRH are similar in depressives and controls. The addition of desmopressin did not further increase the cortisol response to CRH in either depressed patients or normal controls.

No relationship was established between the severity of depression, family history, age, or previous psychotropic exposure and the endocrine responses. No adverse events were reported during the course of the study.

	Discussion

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To our knowledge, this is the first study to report the combined CRH/desmopressin test in depression. Previous studies have examined the responses to vasopressin or desmopressin in depression, with inconsistent findings. Three studies found ACTH and cortisol responses similar in depressives and controls (15, 16, 17), whereas Gispen-deWied (18) found enhanced sensitivity to low-dose AVP in depression. However, AVP itself causes a variety of side-effects, and it can be difficult to dissociate specific ACTH-releasing effects from such changes. Desmopressin alone is relatively free of side-effects, but its ACTH-releasing ability is so poor that it may be difficult to identify the subtle changes in HPA axis activity seen in depression. We therefore used CRH coadministration to enhance any possible effect of desmopressin on ACTH release.

As in previous studies, we found the release of ACTH, in response to CRH infusion, to be blunted, confirming the robust nature of this finding in patients with major depression. However, when desmopressin was infused with CRH, the release of ACTH was similar in depressives and healthy subjects, and the augmentation of the ACTH response was greater in depression than in normal controls. This was in spite of the higher baseline levels of cortisol in depressed patients, suggesting that desmopressin is facilitated in its ACTH-releasing activity in depression. Taken together, we interpret these results as indicating that corticotrope vasopressin receptors are more in evidence in depression. Our results are in contrast to conditions of chronic inflammatory stress. In patients with multiple sclerosis for example, blunted ACTH response to AVP is reported (19).

The combined desmopressin/CRH stimulation test has been described in patients with Cushing’s syndrome. Following earlier studies on the use of desmopressin alone, we found that desmopressin potentiated the effect of CRH in some patients with ACTH-dependent Cushing’s syndrome and, in combination with CRH, was highly effective in the differential diagnosis of ACTH-dependent Cushing’s syndrome (14). We suggested that there may be abnormalities in vasopressin receptor number or function in these tumors.

The vasopressin 1b (V1b) receptors on the anterior pituitary respond to AVP in regulating ACTH release, although there may be a minor contribution from the V2 receptor. Desmopressin is known to be more potent at the V2 than the V1a receptor, but its action at V1b receptor sites is not known with any certainty. However, it has been shown to synergistically interact with CRH in bringing about ACTH release in vitro, an effect which is not antagonized by V2 receptor blockade. Our results are therefore most readily explicable as an increase in the population of V1b receptor affinity or number on the corticotropes of patients with major depression.

Postmortem studies on the brains of individuals with a known history of depression support the view that vasopressin may be involved in the pathophysiology of the disorder. The number of AVP-expressing neurons in the paraventricular nucleus was reported to be increased by 56% in depression, both unipolar and bipolar (20). This finding is consistent with the animal literature showing that many paraventricular neurons are capable of coexpressing both CRH and AVP and tend to increase the relative predominance of AVP production in times of stress (21).

The baseline ACTH was consistently elevated in depression, across all three tests. Such an elevation is consistent with the sustained adrenal overactivity seen in the disorder, as evidenced by the baseline hypercortisolism. The high levels of ACTH and cortisol may help explain the blunted response to CRH. Such elevated levels would enhance negative feedback and diminish the response to the secretagogue. The fact that desmopressin continues to exert a significant influence in the presence of high ACTH and cortisol suggests that AVP may be less sensitive to the impact of negative feedback.

In summary, we have found that the ACTH responsiveness to CRH is enhanced by desmopressin in depressed (more than in normal) subjects, suggesting a change in corticotrope vasopressin receptor responsivity in depressive illness.

Received October 10, 1998.

Revised February 12, 1999.

Accepted February 22, 1999.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Dinan TG. 1994 Glucocorticoids and the genesis of depression: a psychobiological model. Br J Psychiatry. 164:365–371.[Abstract/Free Full Text]
2. Sachar EJ, Hellman L, Roffwarg HP, et al. 1970 Cortisol production in depressive illness. Arch Gen Psychiatry. 23:289–294.[Abstract/Free Full Text]
3. Carroll BJ. 1982 Use of the dexamethasone suppression test in depression. J Clin Psychiatry. 43:44–56.[Medline]
4. Nemeroff CB, Widerlov E, Bissette G, et al. 1984 Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science. 226:1342–1344.[Abstract/Free Full Text]
5. Holsboer F, Gerken A, Stalla GK, et al. 1985 ACTH, cortisol and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery. Biol Psychiatry. 20:276–286.[CrossRef][Medline]
6. Gold PW, Chrousos GP. 1985 Clinical studies with corticotropin releasing factor: implications for the diagnosis and pathophysiology of depression, Cushing’s disease and adrenal insufficiency. Psychoneuroendocrinology. 10:401–419.[CrossRef][Medline]
7. Ur E, Grossman AB, Besser MG. 1995 Continuous administration of human corticotropin-releasing hormone in the absence of glucocorticoid feedback in man. Neuroendocrinology. 61:191–197.[Medline]
8. Nemeroff CB, Krishnan KKR, Reed D, et al. 1992 Adrenal gland enlargement in major depression: a computed tomographic study. Arch Gen Psychiatry. 49:384–390.[Abstract/Free Full Text]
9. Rubin RT, Phillips JJ, Sadow TF, et al. 1995 Adrenal gland volume in major depression: increase during the depressive episode and decrease with successful treatment. Arch Gen Psychiatry. 52:213–218.[Abstract/Free Full Text]
10. Scott LV, Dinan TG. 1997 The role of vasopressin in the regulation of the hypothalamic-pituitary-adrenal axis. Life Sci. 62:1985–1998.
11. Holsboer F, Laurer CJ, Schreiber W, et al. 1995 Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology. 62:340–346.[Medline]
12. De Bellis MD, Chrousos GP, Burke L, et al. 1994 Hypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls. J Clin Endocrinol Metab. 78:249–258.[Abstract]
13. Ladd CO, Owens MJ, Nemeroff CB. 1996 Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology. 137:1212–1216.[Abstract]
14. Newell-Price J, Edwards R, Howes I, Perry L, Besser M, Grossman A Desmopressin causes ACTH and cortisol secretion in patients with Cushing’s disease and normal volunteers. Proc of the 77th Annual Meeting of The Endocrine Society, Washington DC, 1997 (Abstract OP39–5).
15. Meller WH, Kathol RC, Jaeckle RS, et al. 1987 Stimulation of the pituitary adrenal axis with arginine-vasopressin in patients with depression. J Psychiatr Res. 21:269–277.[CrossRef][Medline]
16. Kathol RG, Jaeckle RS, Lopez JF, et al. 1989 Consistent reduction of ACTH responses to stimulation with CRH, vasopressin and hypoglycemia in patients with major depression. Br J Psychiatry. 155:468–478.[Abstract/Free Full Text]
17. Malerbi DA, Fragoso M, Vieira-Filho AH, Brenlha EM, Mendonca B. 1996 Cortisol and adrenocorticotropin response to desmopressin in women with Cushing’s disease compared with depressive illness. J Clin Endocrinol Metab. 81:2233–2237.[Abstract]
18. Gispen-de Wied C, Westenberg H, Koppeschaar H, Thijssen J, Van Ree J. 1992 Stimulation of the pituitary-adrenal axis with a low-dose, arg-vasopressin in depressed patients and healthy subjects. Eur Neuropsychopharmacol. 2:411–419.[CrossRef][Medline]
19. Michelson D, Stone L, Gallive E, et al. 1994 Patients with multiple sclerosis showed normal ACTH response to oCRH and blunted response to AVP. J Clin Endocrinol Metab. 79:848–853.
20. Raadsheer FC, Hoogendijk WJG, Stam FC, Tilders FJH, Swaab DF. 1994 Increased number of corticotropin-releasing hormone neurons in the hypothalamic paraventricular nuclei of depressed patients. Neuroendocrinology. 60:436–444.[Medline]
21. Spinedi E, Hadid R, Gaillard RC. 1997 Increased vasopressinergic activity as a possible compensatory mechanism for a normal hypothalamic-pituitary-adrenal axis response to stress in BALB/c nude mice. Neuroendocrinology. 66:287–293.[Medline]

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