Chronic Imipramine Is Associated with Diminished Hypothalamic-Pituitary-Adrenal Axis Responsivity in Healthy Humans

Abstract

The hypercortisolism of melancholic depression is thought to reflect hypothalamic hypersecretion of CRH and may be related to the hyperarousal associated with this syndrome. Although chronic administration of imipramine to experimental animals significantly decreases CRH messenger RNA levels in the paraventricular nucleus, it is generally thought that resolution of hypercortisolism following recovery from depression is related to the improvement in mood and decrease in anxiety that accompanies recovery rather than an intrinsic effect of imipramine. The present study was designed to explore whether chronic imipramine administration to healthy, nondepressed volunteers is associated with effects on hypothalamic-pituitary-adrenal (HPA) axis function. We studied basal and provocative measures of HPA axis function in 14 healthy volunteers before and after 6 weeks of imipramine treatment at therapeutic doses. Imipramine was associated with decreased responses in peak ACTH and cortisol to ovine CRH and in peak ACTH to arginine vasopressin (P = 0.02, P = 0.003, and P = 0.02, respectively) without changes in indices of basal HPA axis function. These data are consistent with preclinical findings and support the hypothesis that imipramine has an intrinsic effect on central components of HPA axis function, potentially related to its therapeutic effects.

Chronic Antidepressant Treatments Decrease Pro‐Opiomelanocortin mRNA Expression in the Pituitary Gland: Effects of Acute Stress and 5‐HT1A Receptor Activation

“…However, there are deviating reports on the effects of chronic antidepressant treatments on basal and stimulated concentrations of ACTH and corticosterone/cortisol. In humans, chronic imipramine treatment reduced CRF‐ and vasopressin‐induced release of ACTH and cortisol (33). In rats, long‐term moclobemide treatment reduced the ACTH and corticosterone response to novel environment stress, but did not alter basal levels (15).…”

Combined pharmacotherapy and cognitive-behavioral therapy for anxiety disorders: Medication effects, glucocorticoids, and attenuated treatment outcomes.

“…In animals, these agents appear to not only reduce general levels of glucocorticoids (Badawy & Morgan, 1991), but also to attenuate stress‐induced increases in cortisol in some (Reul, Stec, Soder, & Holsboer, 1993), but not all, paradigms (Duncan, Knapp, Carson, & Breese, 1998). In humans, this general (Schule, Sighart, Hennig, & Laakmann, 2006) and stress‐induced (Michelson et al., 1997) attenuation of cortisol is also noted, and reduced levels of cortisol and reduced cortisol reactivity have been documented clinically in treatment of posttraumatic stress disorder (PTSD) with paroxetine (Vermetten et al., 2006). Moreover, a variety of antidepressant agents, including imipramine, amitriptyline, desipramine, fluoxetine, tianeptine, mianserin, moclobemide reboxetine, venlafaxine, citalopram, and mirtazapine, can attenuate some of the effects of glucocorticoids by inhibition of their action on gene transcription (Augustyn et al., 2005; Budziszewska, Jaworska‐Feil, Kajta, & Lason, 2000).…”

Pharmacogenetics of Antidepressant Response

“…310,311 Imaging studies on patients with MDD and suicidal behaviour, together with animal studies on models of depression and human studies, confirmed the primary role of CRH in the psychiatric field. [312][313][314][315][316] There are 2 primary receptor subtypes for the CRH in the CNS: corticotropinreleasing hormone receptors CRHR1 and CRHR2. The CRHR1 subtype is considered to play a key role in mediating the CRH-elicited effects in depression and anxiety.…”