Effects of the Addition of Metyrapone to Antidepressant Therapy in Depression With Dexamethasone Suppression Test Non-suppression.

Summary

The hypothesis of a link between depression and Hypothalamic-Pituitary Axis (HPA) dysfunction is now experienced. Since a first description in 1949 this link has made the HPA one of the most investigated hormonal axis in depression. Many studies have demonstrated quantitative variations of circulating cortisol in situation of depression including increasing of basal concentration of blood cortisol or Adrenocorticotropic Hormone (ACTH). Furthermore there is an attenuated negative feedback performance of the blood cortisol on the release of ACTH and cortisol. This attenuation seems to be a consequence of a bluntness of sensibility of the hypothalamic cells and their Glucocorticoids Receptors type 2. Actually it seems that these phenomena are included in a diversion of the cortisol's action. From a function of acute stress management, with short-time exposures, the cortisol become one of the factors increasing an allostatic load, or resulting of this increase, maintaining a permanent state of stress, an inertia delay to adaptation and facilitating the emergence of psychiatric disorders. This lack of function can be estimated by the Dexamethasone Suppression Test (DST) which, by stimulation attempting of feedback mechanisms by Dexamethasone (which has cortisol-like properties), can show a non-suppressor population with HPA bluntness. If this biological feature isn't a biological marker of depression, because of a lack of specificity and sensibility, is notably associated with a poor outcome and higher risks of suicidal behaviors and pharmacological resistance. Many studies have explored possibilities of action on the HPA to treat depression or improve antidepressant specific therapeutics, with inconstant results. One of the most promising molecule seems to be Metyrapone, a reversible inhibitor of the 11ß-hydroxylase enzyme which transform desoxycorticosterone and 11deoxycortisol to respectively corticosterone and cortisol. There have been several open label studies which aim to explore the possibility of an effect of the combination between Metyrapone and antidepressant molecules. This led to two randomized double blind controlled versus placebo studies whose conclusions are divergent. These conclusions and their heterogeneity lead to think that there is a sub-population which could be better responder to this type of association. Physiopathological knowledges and preliminary observations in DST non-suppressor population by using anti-glucocorticoids therapies , makes it possible to consider possible that responsive sub-population can be defined by the feature " DST non-suppressor ".

Timeline

Start

2018-12-22

Primary completion

2022-06

Completion

2022-09

Publications

• Background Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001 Mar;178:234-41. doi: 10.1192/bjp.178.3.234.
• Background Cowen PJ. Not fade away: the HPA axis and depression. Psychol Med. 2010 Jan;40(1):1-4. doi: 10.1017/S0033291709005558.
• Background Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med. 2011 Feb-Mar;73(2):114-26. doi: 10.1097/PSY.0b013e31820ad12b. Epub 2011 Jan 21.
• Background Linkowski P. Neuroendocrine profiles in mood disorders. Int J Neuropsychopharmacol. 2003 Jun;6(2):191-7. doi: 10.1017/S1461145703003407.
• Background Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry. 2001 Mar 1;49(5):391-404. doi: 10.1016/s0006-3223(00)01088-x.
• Background Gray JD, Kogan JF, Marrocco J, McEwen BS. Genomic and epigenomic mechanisms of glucocorticoids in the brain. Nat Rev Endocrinol. 2017 Nov;13(11):661-673. doi: 10.1038/nrendo.2017.97. Epub 2017 Sep 1.
• Background Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ. Epigenetic programming by maternal behavior. Nat Neurosci. 2004 Aug;7(8):847-54. doi: 10.1038/nn1276. Epub 2004 Jun 27.
• Background Herbert J, Goodyer IM, Grossman AB, Hastings MH, de Kloet ER, Lightman SL, Lupien SJ, Roozendaal B, Seckl JR. Do corticosteroids damage the brain? J Neuroendocrinol. 2006 Jun;18(6):393-411. doi: 10.1111/j.1365-2826.2006.01429.x.
• Background McEwen BS. Mood disorders and allostatic load. Biol Psychiatry. 2003 Aug 1;54(3):200-7. doi: 10.1016/s0006-3223(03)00177-x.
• Background Carroll BJ, Feinberg M, Greden JF, Tarika J, Albala AA, Haskett RF, James NM, Kronfol Z, Lohr N, Steiner M, de Vigne JP, Young E. A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Arch Gen Psychiatry. 1981 Jan;38(1):15-22. doi: 10.1001/archpsyc.1981.01780260017001.
• Background Ribeiro SC, Tandon R, Grunhaus L, Greden JF. The DST as a predictor of outcome in depression: a meta-analysis. Am J Psychiatry. 1993 Nov;150(11):1618-29. doi: 10.1176/ajp.150.11.1618.
• Background Gallagher P, Malik N, Newham J, Young AH, Ferrier IN, Mackin P. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD005168. doi: 10.1002/14651858.CD005168.pub2.
• Background Maric NP, Adzic M. Pharmacological modulation of HPA axis in depression - new avenues for potential therapeutic benefits. Psychiatr Danub. 2013 Sep;25(3):299-305.
• Background Murphy BE, Ghadirian AM, Dhar V. Neuroendocrine responses to inhibitors of steroid biosynthesis in patients with major depression resistant to antidepressant therapy. Can J Psychiatry. 1998 Apr;43(3):279-86. doi: 10.1177/070674379804300307.
• Background Rogoz Z, Skuza G, Wojcikowski J, Daniel WA, Wrobel A, Dudek D, Zieba A. Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression. Pol J Pharmacol. 2004 Nov-Dec;56(6):849-55.
• Background Jahn H, Schick M, Kiefer F, Kellner M, Yassouridis A, Wiedemann K. Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry. 2004 Dec;61(12):1235-44. doi: 10.1001/archpsyc.61.12.1235.
• Background McAllister-Williams RH, Anderson IM, Finkelmeyer A, Gallagher P, Grunze HC, Haddad PM, Hughes T, Lloyd AJ, Mamasoula C, McColl E, Pearce S, Siddiqi N, Sinha BN, Steen N, Wainwright J, Winter FH, Ferrier IN, Watson S; ADD Study Team. Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial. Lancet Psychiatry. 2016 Feb;3(2):117-27. doi: 10.1016/S2215-0366(15)00436-8. Epub 2015 Dec 23.
• Background Duval F, Mokrani MC, Erb A, Gonzalez Opera F, Calleja C, Paris V. Relationship between chronobiological thyrotropin and prolactin responses to protirelin (TRH) and suicidal behavior in depressed patients. Psychoneuroendocrinology. 2017 Nov;85:100-109. doi: 10.1016/j.psyneuen.2017.07.488. Epub 2017 Jul 28.

Drugs

Indications