The acute and post-discontinuation effects of a glucocorticoid receptor (GR) antagonist probe on sleep and the HPA axis in chronic insomnia: a pilot study.
OBJECTIVE
Hypothalamic-pituitary-adrenal axis (HPA) hyperactivity has been reported in patients with chronic insomnia without depression. Aglucocorticoid receptor (GR) antagonist may re-regulate HPA axis activity even after discontinuation and may have clinical benefit.


METHODS
Ten subjects with chronic insomnia participated in a placebo controlled double-blinded prospective 30-day pilot study of the acute and post-discontinuation effects of a 5-day course of 600 mg of the glucocorticoid antagonist, mifepristone. Sleep outcome measures were polysomnogram and Insomnia Severity Index. Hormonal outcome measures were mean overnight cortisol and ACTH (23:00-07:00). We predicted sleep would improve and that overnight cortisol and ACTH would decrease at 2 weeks post-treatment discontinuation.


RESULTS
At 2 weeks post-discontinuation, Insomnia Severity Index (ISI) decreased by 4.0 points (effect size = 0.97). Polysomnogram findings were limited. Mean cortisol (0.84 microg/dL, effect size = 0.91) and ACTH (5.50 pg/mL, effect size = 0.96) were still mildly increased (23:00 to 07:00). Post hoc analysis revealed that, the ratio of cortisol/ ACTH decreased (-0.21, effect size = 1.15) as did mean cortisol from 18:00 to 23:00 (-0.47 microg/dL, effect size = 0.56).


CONCLUSIONS
This is the first study of a GR antagonist in chronic insomnia. Sleep improvement manifests in terms of decreased ISI post-treatment discontinuation. The decrease in cortisol in the early evening (18:00 to 23:00) in combination with the decrease in cortisol/ ACTH ratio may be an indicator of the longer-term biological mode of action of the drug.
Buckley
Theresa
T
Department of Psychiatry, Stanford University Medical School, Stanford, CA, USA. tbuckley@stanford.edu
Duggal
Vandana
V
Schatzberg
Alan F
AF
D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors* / Q000097:blood*; D000328:Adult; D002908:Chronic Disease; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004569:Electroencephalography; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006993:Hypnotics and Sedatives / Q000009:adverse effects* / Q000627:therapeutic use*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D015735:Mifepristone; D010865:Pilot Projects; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000503:physiopathology*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy* / Q000503:physiopathology*
D006993:Hypnotics and Sedatives; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone