Neuroendocrinological Mechanisms of Actions of Antidepressant Drugs

Abstract

Noradrenaline or serotonin (5-HT) reuptake-inhibiting antidepressants such as reboxetine or citalopram acutely stimulate cortisol and adrenocorticotrophic hormone (ACTH) secretion in healthy volunteers, whereas mirtazapine acutely inhibits the ACTH and cortisol release, probably due to its antagonism at central 5-HT(2) and/or H(1) receptors. These differential effects of antidepressants on cortisol and ACTH secretion in healthy subjects after single administration are also reflected by their different time course in the down-regulation of hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity in depressed patients as assessed by serial dexamethasone (DEX)/corticotrophin-releasing hormone (CRH) tests: Reuptake-inhibiting antidepressants such as reboxetine gradually normalise HPA axis hyperactivity in depressed patients during several weeks of treatment via up-regulation of mineralocorticoid and glucocorticoid receptor function and by step-by-step restoration of the disturbed feedback control. By contrast, mirtazapine markedly reduces HPA axis activity in depressed patients within 1 week, but there is a partial re-enhancement of HPA hormone secretion after several weeks of therapy. In all studies performed to date, the short-term effects of daily treatment with antidepressants on the DEX/CRH test results are comparable in responders and nonresponders. Moreover, a reduction in HPA axis activity is not necessarily followed by a favourable clinical response and some depressed patients keep on showing nonsuppression in the DEX/CRH test despite clinical improvement. Therefore, the importance of HPA axis dysregulation for the short-term efficacy of antidepressants continues to be a matter of debate. However, there are convincing data suggesting that persisting nonsuppression in the DEX/CRH test despite clinical remission predicts an enhanced risk for relapse of depressive symptomatology with respect to the medium- and long-term outcome.

A final common pathway for depression? Progress toward a general conceptual framework

“…Chronic stress and antidepressant treatment, which produce opposite changes in positively motivated behavior, have been shown also to produce a series of opposing changes in receptor and neuronal function in this system. These effects which include alterations in α 1 -adrenergic (Maj and Rogóz, 1999), 5HT1 (Ossowska et al, 2001;Srinivas et al, 2001), 5HT2A (Ossowska et al, 2001;Esposito, 2006), D1 (Ossowska et al, 2001;Huzarska et al, 2006), D2 (D'Aquila et al, 2000), GR and MR (Holsboer, 2001;Schule, 2007) as well as in neurotrophin release (Duman and Monteggia, 2006) and neuronal morphology McEwen, 2003). These multiple correlated effects appear to be the results of a combination of factors including altered neurotransmitter, cytokine, corticosteroid and neurotrophin release (Duman and Monteggia, 2006;Bisagno et al, 2000;McEwen, 2000).…”

Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study

“…Examples include anti-inflammatory treatments influencing immuno-inflammation such as cyclooxygensase-2 (COX-2) inhibitors, aspirin, minocycline and polyunsaturated fatty acids (Berk et al, 2013a, Fond et al, 2014, Muller, 2013 and antioxidant therapies to increase antioxidant defences and lower free radical damage such as n-acetyl cysteine, Ebselen, vitamin E and coenzyme-Q 10 (Berk et al, 2013b, Scapagnini et al, 2012. Interestingly, despite pharmaceutical antidepressants originally being heralded as targeting monoaminergic actions, there is also evidence that they can modulate immuno-inflammation, reduce oxidative stress, enhance neurotrophic factors and influence HPA activity (Abdel-Wahab and Salama, 2011, Andrade and Rao, 2010, Hannestad et al, 2011, Kocki et al, 2012, Schule, 2007.…”

Escitalopram affects spexin expression in the rat hypothalamus, hippocampus and striatum

“…There are many suggestions that SSRI treatment may affect the hypothalamic corticotropin-releasing factor (CRF) pathway [19,20] and hypothalamo-pituitary adrenal (HPA) axis [21]. Interestingly, 2 hours after escitalopram administration the level of TRH-like peptides was increased in the rat nucleus accumbens, striatum, cerebellum and medulla oblongata, while TRH concentration was decreased in the nucleus accumbens.…”