title: Metyrapone in treatment-resistant depression.
abstract: Depression affects a significant proportion of the population, with 1-year and lifetime prevalence of 3-5% and 10-30% respectively. Full remission is achieved in only a third of patients following treatment with first-line antidepressant. There is a need for novel treatments for treatment-resistant depression (TRD). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been described in patients with depression. There is persistent rise in the levels of cortisol (end product of the HPA axis) and impairment of the negative feedback inhibition mechanism of the HPA axis. Dysregulation of the HPA axis has been found to be linked to nonresponse to antidepressants and relapse following successful treatment. The efficacy of pharmacological agents that intervene with the mechanisms involved in dysregulation of cortisol synthesis and release are being explored in depression, particularly in TRD. Studies have been carried out with these drugs as augmenting agents for antidepressants or as monotherapy. The strongest evidence has come from studies using metyrapone, a cortisol synthesis inhibitor, and this has been described in detail in this review. The most robust evidence for its antidepressant efficacy in depression comes from a double-blind, randomized, placebo-controlled study of augmentation of serotonergic antidepressants with metyrapone. A 3-week augmentation of serotonergic antidepressants with 1 g metyrapone daily was shown to be superior to placebo in reducing the Montgomery-Asberg Depression Rating Scale by 50%, 5 weeks following initiation of treatment. The mechanism of the antidepressant action of metyrapone is not clear but the evidence for various potential mechanisms is discussed.
authors: Institution of Neurosciences - Academic Psychiatry, Campus for Ageing and Vitality, Westgate Road, Newcastle NE4 6BE, UK.
authors: Paul David
authors: PD
authors: Sigalas
authors: Himanshu
authors: H
authors: Garg
authors: Stuart
authors: S
authors: Watson
authors: Richard Hamish
authors: RH
authors: McAllister-Williams
authors: I Nicol
authors: IN
authors: Ferrier
keywords: antidepressant; antiglucocorticoid; depression; hypothalamic–pituitary–adrenal axis; metyrapone; treatment resistant
references: Cochrane Database Syst Rev. 2008 Jan 23;(1):CD005168
references: 18254070
references: Psychopharmacology (Berl). 1998 Jul;138(2):124-32
references: 9718281
references: Biol Psychiatry. 2006 Dec 15;60(12):1343-9
references: 16889757
references: Neuroendocrinology. 1987 Aug;46(2):143-6
references: 2819759
references: Fundam Clin Pharmacol. 1997;11(3):206-14
references: 9243251
references: J Psychiatr Res. 2007 Apr-Jun;41(3-4):290-4
references: 16956623
references: Biol Psychiatry. 1995 Mar 15;37(6):364-8
references: 7772644
references: Neuropsychopharmacology. 2006 Mar;31(3):628-36
references: 16160710
references: J Clin Endocrinol Metab. 1997 Jan;82(1):234-8
references: 8989265
references: Ann Intern Med. 1991 Jan 15;114(2):143-4
references: 1984391
references: Psychoneuroendocrinology. 2003 Feb;28(2):121-37
references: 12510008
references: Arch Gen Psychiatry. 2004 Dec;61(12):1235-44
references: 15583115
references: Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):325-30
references: 10618417
references: Psychoneuroendocrinology. 2004 Oct;29(9):1198-204
references: 15219644
references: Am J Psychiatry. 1993 May;150(5):810-2
references: 8480829
references: J Nerv Ment Dis. 1979 Apr;167(4):229-36
references: 438794
references: J Clin Psychiatry. 1990 Apr;51 Suppl:14-20; discussion 21
references: 2157700
references: Psychoneuroendocrinology. 1997;22 Suppl 1:S125-32
references: 9264159
references: Naunyn Schmiedebergs Arch Pharmacol. 1995 Aug;352(2):141-8
references: 7477436
references: Arch Intern Med (Chic). 1950 Feb;85(2):199-258
references: 15405892
references: Psychopharmacology (Berl). 1994 Mar;114(2):360-4
references: 7838929
references: J Psychiatr Res. 2003 Nov-Dec;37(6):525-33
references: 14563384
references: J Clin Psychiatry. 1990 Dec;51 Suppl B:4-8
references: 2175309
references: Biol Psychiatry. 2007 Apr 15;61(8):952-6
references: 17336940
references: Neurochem Res. 2008 Apr;33(4):691-707
references: 17960478
references: J Clin Psychopharmacol. 1991 Apr;11(2):121-6
references: 1829098
references: J Psychiatr Res. 2000 May-Jun;34(3):171-81
references: 10867111
references: J Neurosci. 1989 Sep;9(9):3072-82
references: 2795152
references: J Psychiatr Res. 2010 Apr;44(6):339-46
references: 19909979
references: J Psychiatr Res. 2001 Mar-Apr;35(2):83-94
references: 11377437
references: Psychopharmacology (Berl). 1999 Aug;145(3):303-8
references: 10494579
references: Neuropharmacology. 2003 Dec;45(7):925-34
references: 14573385
references: Biol Psychiatry. 2002 Sep 1;52(5):386-92
references: 12242054
references: J Affect Disord. 1995 Feb 21;33(2):123-8
references: 7759660
references: Pol J Pharmacol. 2004 Nov-Dec;56(6):849-55
references: 15662100
references: Neuroendocrinology. 1987 Jun;45(6):492-7
references: 3039393
references: Neuroreport. 1998 Aug 3;9(11):2535-8
references: 9721928
references: Am J Psychiatry. 2002 Jul;159(7):1237-9
references: 12091208
references: Nihon Shinkei Seishin Yakurigaku Zasshi. 1996 Feb;16(1):33-6
references: 8640461
references: Brain Res. 2002 Oct 18;952(2):188-99
references: 12376179
references: Psychoneuroendocrinology. 1996 Apr;21(3):277-86
references: 8817726
references: Psychoneuroendocrinology. 2011 Aug;36(7):1053-61
references: 21316860
references: Psychol Med. 1998 May;28(3):573-84
references: 9626714
references: Psychol Med. 2010 Jan;40(1):1-4
references: 19335939
references: J Psychiatr Res. 2005 Mar;39(2):173-7
references: 15589565
references: Can J Psychiatry. 1998 Apr;43(3):279-86
references: 9561317
references: Pol J Pharmacol. 2003 Nov-Dec;55(6):993-9
references: 14730094
references: Am J Psychiatry. 2011 Oct;168(10):1107-16
references: 21865530
references: J Clin Psychopharmacol. 2001 Oct;21(5):516-21
references: 11593077
references: Biol Psychiatry. 2007 Dec 1;62(11):1228-35
references: 17651703
references: J Clin Psychiatry. 2005 May;66(5):598-602
references: 15889946
references: Psychoneuroendocrinology. 2009 Jan;34(1):19-26
references: 18805642
references: Q J Med. 1979 Jul;48(191):465-72
references: 542586
references: Arch Gen Psychiatry. 2005 Oct;62(10):1097-106
references: 16203955
references: J Psychiatr Res. 2000 Nov-Dec;34(6):383-92
references: 11165305
references: Mol Endocrinol. 1989 Nov;3(11):1886-94
references: 2558306
references: Am J Psychiatry. 1952 Mar;108(9):641-51
references: 14903192
references: J Clin Psychopharmacol. 2011 Aug;31(4):436-40
references: 21694614
references: Br J Pharmacol. 2000 Jun;130(4):797-804
references: 10864885
references: Neuroendocrinology. 1995 Oct;62(4):340-7
references: 8544947
references: J Psychiatr Res. 2004 Mar-Apr;38(2):129-36
references: 14757326
references: Psychoneuroendocrinology. 2011 Jan;36(1):19-27
references: 20646833
references: Neuropsychopharmacology. 2003 Sep;28(9):1572-8
references: 12784107
references: J Psychiatr Res. 1994 Jul-Aug;28(4):341-56
references: 7877114
references: Can J Psychiatry. 2004 Feb;49(2):124-38
references: 15065747
references: Am J Psychiatry. 2006 Nov;163(11):1905-17
references: 17074942
references: Biol Psychiatry. 2006 Apr 15;59(8):696-701
references: 16368077
references: Medicine (Baltimore). 1955 Feb;34(1):13-50
references: 14355368
references: J Psychopharmacol. 2007 Nov;21(8):826-32
references: 17715208
references: Lancet. 1997 May 24;349(9064):1498-504
references: 9167458
references: J Steroid Biochem Mol Biol. 1991 Aug;39(2):239-44
references: 1888684
references: Psychiatry Res. 1983 Mar;8(3):191-7
references: 6574538
references: Eur J Neurosci. 2002 Jun;15(12):2007-15
references: 12099906
references: Fundam Clin Pharmacol. 1996;10(1):16-27
references: 8900496
references: Psychopathology. 1998 Nov-Dec;31(6):302-6
references: 9780396
references: Arch Gen Psychiatry. 1990 Oct;47(10):963-8
references: 1977371
references: Am J Psychiatry. 1990 Oct;147(10):1297-303
references: 2399996