The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia. A placebo-controlled, double-blind, randomized, cross-over study followed by an open treatment over 3 weeks

Psychopharmacology (Berl). 2003 Dec;170(4):423-8. doi: 10.1007/s00213-003-1565-0. Epub 2003 Sep 10.


Rationale: In primary care, sedating antidepressants are often used for treating insomnia, although their underlying sleep-promoting mechanisms are only incompletely understood. Since enhanced evening and nocturnal plasma cortisol levels are supposed to maintain insomniac sleep complaints, a functional link between sleep and cortisol secretion in the mode of action of antidepressants in insomnia might be suspected.

Objectives: We therefore investigated the effects of the tricyclic antidepressant doxepin on nocturnal sleep and plasma cortisol concentration in ten patients (age 41.3+/-9.5 years) with chronic primary insomnia between 1700 hours and 0800 hours.

Methods: Single infusions of placebo and 25 mg doxepin were applied following a double-blind, randomized cross-over design. Afterward, all patients received 25 mg doxepin p.o. for 3 weeks in an open-study design.

Results: Both doxepin application forms improved sleep significantly and reduced mean cortisol levels from 9.0+/-1.7 microg/l (single placebo i.v.) to 7.5+/-1.6 microg/l (single doxepin i.v.) or 7.6+/-2.0 microg/l (subchronic doxepin p.o.). The duration of the quiescent period of the cortisol rhythm was significantly prolonged following both doxepin administrations compared with placebo.

Conclusions: The results implicate that the sleep-improving effects of doxepin are mediated at least in part by a normalization of hypothalamic-pituitary-adrenal axis functions. Although in some patients rebound insomnia and specific side effects must be considered, our findings give a further rationale for the use of antidepressants in the treatment of primary insomnia.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antidepressive Agents, Tricyclic / therapeutic use*
  • Cross-Over Studies
  • Double-Blind Method
  • Doxepin / therapeutic use*
  • Female
  • Humans
  • Hydrocortisone / blood
  • Hydrocortisone / metabolism*
  • Male
  • Polysomnography
  • Sleep / drug effects*
  • Sleep Initiation and Maintenance Disorders / blood
  • Sleep Initiation and Maintenance Disorders / drug therapy*


  • Antidepressive Agents, Tricyclic
  • Doxepin
  • Hydrocortisone