The sleep-improving effects of doxepin are paralleled by a normalized plasma cortisol secretion in primary insomnia
- 374 Downloads
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.
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.
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.
Both doxepin application forms improved sleep significantly and reduced mean cortisol levels from 9.0±1.7 µg/l (single placebo i.v.) to 7.5±1.6 µg/l (single doxepin i.v.) or 7.6±2.0 µg/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.
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.
KeywordsInsomnia Antidepressant Cortisol Sedative
- American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DCGoogle Scholar
- American Sleep Disorders Association (1990) The international classification of sleep disorders. American Sleep Disorders Association, Rochester, MNGoogle Scholar
- Bhagwagar Z, Hafizi S, Cowen PJ (2002a) Acute citalopram administration produces correlated increases in plasma and salivary cortisol. Psychopharmacology 163:118–120Google Scholar
- Berlin I, Warot D, Legout V, Guilleminault S, Schollnhammer G, Puech AJ (1998) Blunted 5-HT1A-receptor agonist-induced corticotropin and cortisol responses after long-term ipsapirone and fluoxetine administration to healthy subjects. Clin Pharmacol Ther 63:428–436Google Scholar
- Götze U, Tölle R (1988) Circadian rhythm of free urinary cortisol, temperature and heart rate in endogenous depression and under antidepressant therapy. Neuropsychobiology 18:175–184Google Scholar
- Inder WJ, Prickett TCR, Mulder RT, Donald RA, Joyce PR (2001) Reduction of basal afternoon plasma ACTH during early treatment of depression with fluoxetine. Psychopharmacology 156:73–78Google Scholar
- Jarrett DB, Miewals JM, Kupfer DJ (1988) Acute changes in sleep-related hormone secretion of depressed patients following oral imipramine. Biol Psychiatry 24:541–554Google Scholar
- Jarrett DB, Pollock B, Miewald JM, Kupfer DJ (1991) Acute effect of intravenous clomipramine upon sleep-related hormone secretion in depressed outpatients and healthy subjects. Biol Psychiatry 29:3–14Google Scholar
- Linkowski P, Mendlewicz J, Kerkhofs M, Leclercq R, Goldstein J, Brasseur M, Copinschi G, van Cauter E (1987) 24-hour profiles of adrenocroticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment. J Clin Endocr Metab 64:141–152Google Scholar
- Nowell PD, Reynolds CF, Buysse DJ, Dew MA, Kupfer DJ (1999) Paroxetine in the treatment of primary insomnia: preliminary clinical and electroencephalogram sleep data. J Clin Psychiatry 60:89–95Google Scholar
- Ohayon MM, Caulet M, Piest RG, Guilleminault C (1998) Psychotropic medication consumption patterns in the UK general population. J Clin Epidemiol 51:273–283Google Scholar
- Rechtschaffen A, Kales A (1968) A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. U.S. Government Printing Office, WashingtonGoogle Scholar
- Riemann D, Voderholzer U, Cohrs S, Rodenbeck A, Hajak G, Rüther E, Wiegand MH, Laakmann G, Baghai T, Fischer W, Hoffmann M, Hohagen F, Mayer G, Berger M (2002) Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study. Pharmacopsychiatry 35:165–174CrossRefPubMedGoogle Scholar
- Rodenbeck A, Hajak G (2001) Neuroendocrine dysregulation in primary insomnia. Rev Neurol (Paris) 157:s57–s61Google Scholar
- Seifritz E, Baumann P, Müller MJ, Annen O, Amey M, Hemmeter U, Hatzinger M, Chardon F, Holsboer-Trachsler E (1996) Neuroendocrine effects of a 20-mg citalopram infusion in healthy males. A placebo-controlled evaluation of citalopram as 5-HT function probe. Neuropsychopharmacology 14:253–263Google Scholar
- Steiger A, von Bardeleben U, Guldner J, Lauer C, Rother B, Holsboer F (1993) The sleep EEG and nocturnal hormonal secretion studies on changes during the course of depression and on effects of CNS-active drugs. Prog Neuropsychopharmacol Biol Psychiatry 17:125–137Google Scholar
- Torpy DJ, Grice JE, Hockings GI, Crosbie GV, Walters MM, Jackson RV (1995) The effect of desipramine on basal and naloxone-stimulated cortisol secretion in human: interaction of two drugs acting on noradrenergic control of adrenocorticotropin secretion. J Clin Endocr Metab 80:802–806PubMedGoogle Scholar
- Van Cauter E, Leproult R, Kupfer DJ (1996) Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 81:2468–2473Google Scholar
- Vgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A, Kales A, Chrousos GP (2001) Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab 86:3787–3794Google Scholar
- Walsh AE, Hockney RA, Campling G, Cowen PJ (1993) Neuroendocrine and temperature effects of nefazodone in healthy volunteers. Biol Psychiatry 33:115–119Google Scholar
- Walsh JK, Schweitzer PK (1999) Ten-year trends in the pharmacological treatment of insomnia. Am J Psychiatry 22:371–375Google Scholar
- Wiegand M, Berger M (1989) Action of trimipramine on sleep and pituitary hormone secretion. Drugs 38[Suppl 1]:35–50Google Scholar
- World Health Organization (1991) Mental and behavioural disorders (including disorders of psychological development). Clinical descriptions and guidelines. In: International classification of diseases, 10th revn. World Health Organization, GenevaGoogle Scholar