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

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 mug/l (single placebo i.v.) to 7.5+/-1.6 mug/l (single doxepin i.v.) or 7.6+/-2.0 mug/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.