Cortisol response to intramuscular desipramine in patients with major depression and normal control subjects: A replication study

doi:10.1016/0165-1781(92)90027-Z

Psychiatry Research

Volume 44, Issue 3, December 1992, Pages 237-250

https://doi.org/10.1016/0165-1781(92)90027-Z Get rights and content

Abstract

The authors conducted a double-blind study evaluating the cortisol response to 75 mg of desipramine (DMI), administered intramuscularly to 20 patients with major depressive disorder (MDD) and 20 age- and sex-matched normal control subjects. A blunted placebo-corrected cortisol response to DMI was found in MDD patients in comparison with the normal control subjects. Since the behavioral/side effect and pharmacokinetic profiles of DMI were similar for patients with MDD and normal control subjects, these findings suggest that patients with MDD have an underlying biological insensitivity of the hypothalamic-pituitary-adrenal axis to DMI. It is hypothesized that these findings are consistent with a norepinephrine deficit, an α₁-adrenergic receptor insensitivity, or both. Further use of DMI as a neuroendocrine probe for the noradrenergic system is indicated.

References (40)

G.M. Asnis et al.
Plasma dexamethasone and cortisol levels in depressed outpatients
Journal of Affective Disorders
(1989)
G.M. Asnis et al.
The cortisol response to desipramine in endogenous depressive and normal control subjects: Preliminary findings
Psychiatry Research
(1985)
G.M. Asnis et al.
The relationship of the dexamethasone suppression test (1 mg and 2 mg) to basal plasma cortisol levels in endogenous depression
Psychoneuroendocrinology
(1987)
G.M. Asnis et al.
Prolactin responses to haloperidol in normal young women
Psychoneuroendocrinology
(1988)
J.I. Javaid et al.
Inhibition of biogenic-amines uptake by imipramine, desipramine, 2 OH-imipramine and 2 OH-desipramine in man
Life Sciences
(1979)
E. Richelson et al.
Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: Most antidepressants selectively block norepin ephrine
European Journal of Pharmacology
(1984)
R.M. Rose
Endocrine response to stressful psychological events
J.W. Stewart et al.
Cortisol response to dextroamphetamine stimulation in depressed outpatients
Psychiatry Research
(1984)
R.L. Trestman et al.
Cortisol responses to mental arithmetic in acute and remitted depression
Biological Psychiatry
(1991)
S. Al-Damluji
Adrenergic mechanisms in the control of corticotrophin secretion
Journal of Endocrinology
(1988)

S. Al-Damluji et al.

Alpha-adrenergic stimulation of corticotropin secretion by a specific central mechanism in man

Neuroendocrinology

(1987)

G.W. Arana et al.

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

American Journal of Psychiatry

(1984)

G.M. Asnis et al.

Cortisol secretion in psychiatric disorders

G.M. Asnis et al.

The desipramine cortisol test—A selective noradrenergic challenge

Psychopharmacology Bulletin

(1986)

W.E. Bunney et al.

Norepinephrine in depressive reactions

Archives of General Psychiatry

(1965)

A.E. Calogero et al.

Regulation of rat hypothalamic corticotropin-releasing hormone secretion in vitro: Potential clinical implications

Advances in Experimental Medical Biology

(1988)

D.S. Charney et al.

Abnormal regulation of noradrenergic function in panic disorders: Effects of clonidine in healthy subjects and patients with agoraphobia and panic dis order

Archives of General Psychiatry

(1986)

D.S. Charney et al.

Noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agorophobia and panic disorder

Archives of General Psychiatry

(1984)

S.A. Checkley et al.

Hormonal responses to methylamphetamine in depression: A new approach to the noradrenaline depletion hypothesis

British Journal of Psychiatry

(1977)

T.D. Cooper et al.

A sensitive GLC method for the determination of imipramine and desmethylimpramine using a nitrogen detector

Psychopharmacology Communications

(1975)

Cited by (25)

Effects of escitalopram/quetiapine combination therapy versus escitalopram monotherapy on hypothalamic-pituitary-adrenal-axis activity in relation to antidepressant effectiveness
2014, Journal of Psychiatric Research
Citation Excerpt :
Furthermore, depressive symptoms were also reduced under ESC monotherapy, which was not accompanied by significant HPA axis modulation. It has previously been suggested that several antidepressants such as reboxetine, SSRIs or tricyclic antidepressants acutely stimulate cortisol secretion in healthy subjects (Schule, 2007) as well as in depressive patients (Asnis et al., 1992). These compounds may slowly normalize HPA system hyperactivity when administered for several weeks via up-regulation of mineralocorticoid receptor and glucocorticoid receptor mRNA (Brady et al., 1991; Seckl and Fink, 1992) and decrease of CRH gene expression and CRH mRNA synthesis in the paraventricular nucleus (Mori et al., 1998; Stout et al., 2002).
The hypothalamic–pituitary–adrenocortical (HPA) system is believed to play an important role in the pathophysiology of major depressive disorder. In this context, the atypical antipsychotic quetiapine (QUE) has been shown to inhibit HPA system activity in healthy subjects. In this study we investigated whether the putative inhibitory effects of QUE on HPA system activity may contribute to its antidepressant efficacy. We analyzed the effects of QUE as an augmentation to the selective serotonin reuptake inhibitor (SSRI) escitalopram (ESC) on HPA system activity in comparison to a monotherapy with ESC in relation to the antidepressant effectiveness. HPA axis activity (cortisol and ACTH) was measured by means of the dexamethasone/corticotropin-releasing hormone (DEX/CRH) test which was performed before (week 0) and during (week 1, week 5) antidepressant psychopharmacotherapy. The combination therapy, but not the ESC monotherapy showed significantly inhibiting effects on HPA system activity leading to stepwise down-regulation. ACTH concentrations were reduced in the ESC/QUE group during five weeks of treatment. The inhibitory effect of QUE maybe involved in its antidepressant effects as an augmentation strategy.
Impact on cortisol and antidepressant efficacy of quetiapine and escitalopram in depression
2014, Psychoneuroendocrinology
Citation Excerpt :
This study supports the general assumption, that a long-term normalization of the HPA axis hyperactivity is a correlate of clinical improvement (response), regardless of the mechanism of action of the antidepressant drug and regardless of the initial changes of the HPA axis during week 1. Regarding the underlying mechanisms, it can by hypothesized that reuptake inhibiting antidepressants such as reboxetine, SSRIs or tricyclic antidepressants acutely stimulate COR secretion both in healthy subjects (Laakmann, 1988; Schule, 2007) and in depressed patients (Asnis et al., 1992) after single administration and may gradually normalize HPA axis hyperactivity in depressed patients when administered daily for several weeks via up-regulation of mineralocorticoid receptor and glucocorticoid receptor mRNA levels (Brady et al., 1991; Seckl and Fink, 1992), down-regulation of pro-opiomelanocortin mRNA expression in the pituitary gland (Jensen et al., 2001), and decrease of CRH gene expression and CRH mRNA synthesis in the paraventricular nucleus (Mori et al., 1998; Stout et al., 2002), thereby enhancing mineralocorticoid receptor and glucocorticoid receptor function and restoring the disturbed feedback control (“reset” mechanism). It can also be assumed that these effects of antidepressants on gene expression represent physiological adaptive mechanisms which are triggered by the primarily acute stimulatory effects of reuptake inhibitors on the ACTH and COR release and take several weeks to become effective.
In this study, the impact of quetiapine fumarate extended release (QXR) and escitalopram (ESC) on HPA axis activity was investigated in depressed patients in relationship to antidepressant efficacy.
In a randomized, open-label 5-week trial 60 inpatients suffering from major depression (DSM-IV criteria) were treated for 5 weeks with either QXR (300 mg/day) or ESC (10 mg/day). The dexamethasone/CRH (DEX/CRH) test was performed before treatment, after 1, and after 5 weeks of treatment. Cortisol (COR) AUC values were used to assess HPA axis function. The Hamilton Depression Rating Scale was used weekly to estimate antidepressant efficacy.
QXR and ESC showed comparable antidepressant effects but strongly differed in their impact on HPA axis activity. In the QXR group, a marked inhibition of COR AUC levels was observed which was most pronounced after one week of treatment but showed a partial re-increase after 5 weeks of treatment. In contrast, ESC transiently stimulated COR AUC values (week 1) whereas COR AUC levels at week 0 and week 5 were comparable. COR improvement at week 1 (defined as COR peak value reduction between DEX/CRH test 1 and 2) was significantly associated with better clinical outcome.
Apparently, different effects on HPA axis activity reflect distinct pharmacoendocrinological properties of psychotropic drugs.
Depressive Behavior in Mice Due to Immune Stimulation is Accompanied by Reduced Neural Activity in Brain Regions Involved in Positively Motivated Behavior
2006, Biological Psychiatry
Immune stimulation inhibits positively motivated behavior and induces depressive illness. To help clarify the mechanism of these effects, neural activity in response to a positive stimulus was examined in brain regions associated with positively motivated activity defined on the basis of prior behavioral studies of central α₁-adrenoceptor action.
Mice pretreated with either lipopolysaccharide or, for comparison, reserpine were exposed to a motivating stimulus (fresh cage) and subsequently assayed for fos expression and mitogen-activated protein kinase (MAPK) phosphorylation, two measures associated with α₁-adrenoceptor-dependent neural activity, in several positive-activity-related (motor, piriform, cingulate cortex, nucleus accumbens, locus coeruleus) and stress-related brain regions (paraventricular hypothalamus, bed nucleus stria terminalis).
Both lipopolysaccharide and reserpine pretreatment abolished fresh cage-induced fos expression and MAPK activation in the positive activity-related brain regions but enhanced these measures in the stress-related areas.
The results support the hypothesis that immune activation reduces α₁-adrenoceptor-related signaling and neural activity in brain regions associated with positive activity while it increases these functions in stress-associated areas. It is suggested that neural activities of these two types of brain regions are mutually antagonistic and that a reciprocal shift toward the stress regions is a factor in the loss of positively motivated behaviors in sickness behavior and depressive illness.
Influence of mirtazapine on urinary free cortisol excretion in depressed patients
2003, Psychiatry Research
Mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on urinary free cortisol (UFC) excretion was investigated in depression. Twenty patients (six men, 14 women) suffering from major depression according to DSM-IV criteria were treated with mirtazapine for 3 weeks. The patients received 15 mg mirtazapine on day 0; 30 mg mirtazapine on day 1; and 45 mg mirtazapine per day from day 2 to the end of the study (day 21). UFC excretion was measured before treatment (day 1), at the beginning (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Urine samples were collected from 08:00 to 08:00 h the following day. On the days of urine sampling, the severity of depressive symptoms was assessed using the 21-item version of the Hamilton Rating Scale for Depression (21-HAMD). There was a significant reduction of UFC excretion during 3-week mirtazapine therapy, which was already obvious after the first day of treatment (day 0). However, there were no significant across-subjects correlations between UFC reduction and decrease in 21-HAMD sum scores. Apparently, the mirtazapine-induced rapid reduction of cortisol secretion in depressed patients is not necessarily correlated with a favorable therapeutic response.
Stress-induced subsensitivity to modafinil and its prevention by corticosteroids
2002, Pharmacology Biochemistry and Behavior
Brain α₁-adrenoceptors are known to be necessary for motor activity in rodents and have been shown to be altered by stress and corticosteroids but only in biochemical experiments. To determine if the behaviorally coupled receptors are also affected by stress, the present study examined the effect of stress and corticosteroids treatment on the motor activity response to modafinil, a putative α₁-adrenoceptor agonist, which is unique in that it elicits extremely high levels of activity via these receptors. Mice were subjected to various schedules of restraint stress for 1–6 days and were subsequently tested for either modafinil-induced or dopaminergically induced behavioral activity in the home cage using videotape recording. In experiments on corticosteroid treatment, mice received exogenous corticosterone or dexamethasone in the drinking water before and during the stress and were tested for modafinil-induced activity as above. It was found that the stress significantly reduced the response to the drug by the third daily session. Motor responses to dopaminergic agents including apomorphine, amphetamine, dihydrexidine and quinpirole were either not altered or were increased at this time. Treatment of animals with corticosterone or dexamethasone prior to and during stress prevented the behavioral subsensitivity to modafinil. Corticosterone pretreatment markedly suppressed the plasma corticosterone response to the stress. The present results provide further support for the hypothesis that stress produces a selective desensitization or inhibition of motor-related brain α₁-adrenoceptors and that this effect can be prevented by corticosteroid treatment.
Glucocorticoids and depression
1999, Bailliere's Best Practice and Research in Clinical Endocrinology and Metabolism
Depression has been associated with impaired mineralocorticoid receptor function, restrained glucocorticoid receptor feedback at the level of the hypothalamic–pituitary–adrenal (HPA) axis, raised cortisol level and increased corticotropin-releasing factor activity, which may act in concert to induce the signs and symptoms of the disorder. Pre-clinical and clinical evidence suggests that both genetic and environmental factors contribute to the development of these HPA axis abnormalities in depressed patients. Support for this view derives from models using genetically modified animals and/or chronic stress exposure at different developmental stages, although all of the current approaches have to be viewed within their limitations to model the disease. However, both animal and human studies challenging the HPA system show at least some neuroendocrine and behavioural changes comparable to those seen in depression, suggesting that some of the depressive symptoms can be attributed to HPA axis hyperactivity. Moreover, normalization of the neuroendocrine function following chronic antidepressant drug treatment seems to be a prerequisite for stable remission of depressive psychopathology, i.e. that normalization of HPA function is critical for relief of the clinical symptomatology of this disorder.

View all citing articles on Scopus

View full text

Cortisol response to intramuscular desipramine in patients with major depression and normal control subjects: A replication study

Abstract

Journal of Affective Disorders

Psychiatry Research

Psychoneuroendocrinology

Psychoneuroendocrinology

Life Sciences

European Journal of Pharmacology

Psychiatry Research

Biological Psychiatry

Adrenergic mechanisms in the control of corticotrophin secretion

Journal of Endocrinology

Alpha-adrenergic stimulation of corticotropin secretion by a specific central mechanism in man

Neuroendocrinology

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

American Journal of Psychiatry

Cortisol secretion in psychiatric disorders

The desipramine cortisol test—A selective noradrenergic challenge

Psychopharmacology Bulletin

Norepinephrine in depressive reactions

Archives of General Psychiatry

Regulation of rat hypothalamic corticotropin-releasing hormone secretion in vitro: Potential clinical implications

Advances in Experimental Medical Biology

Abnormal regulation of noradrenergic function in panic disorders: Effects of clonidine in healthy subjects and patients with agoraphobia and panic dis order

Archives of General Psychiatry

Noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agorophobia and panic disorder

Archives of General Psychiatry

Hormonal responses to methylamphetamine in depression: A new approach to the noradrenaline depletion hypothesis

British Journal of Psychiatry

A sensitive GLC method for the determination of imipramine and desmethylimpramine using a nitrogen detector

Psychopharmacology Communications