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Exploring the Sleep-Depression Connection

Drug Benefit TrendsDrug Benefit Trends Vol 20 No 12
Volume 20
Issue 12

Sleep disturbance, especially insomnia, is common, with up to 25% of the population in industrialized countries reporting severe chronic insomnia.1 Medications to improve sleep patterns are plentiful but are not always effective. New research on sleep disturbance focuses on the role of the hypothalamic-pituitary-adrenal (HPA) axis.


Sleep disturbance, especially insomnia, is common, with up to 25% of the population in industrialized countries reporting severe chronic insomnia.1 Medications to improve sleep patterns are plentiful but are not always effective. New research on sleep disturbance focuses on the role of the hypothalamic-pituitary-adrenal (HPA) axis.

The HPA Axis

The HPA axis begins with the amygdala, a bilateral, almond-shaped group of neurons within the medial temporal lobes of the brain that is involved in the processing of emotional reactions, particularly anxiety and conditioned fear. The amygdala, which is part of the limbic system, appears to recognize stressors and alerts the paraventricular nuclei of the hypothalamus. The hypothalamus, in turn, secretes corticotropin-releasing hormone (CRH), which triggers the pituitary gland to release corticotropin (ACTH, formerly adrenocorticotropic hormone), which then stimulates the adrenal gland to secrete cortisol.

The connection between the HPA axis and insomnia derives from the fact that CRH, ACTH, and cortisol are secreted not only in response to stressors but also in the normal daily rhythm. Because cortisol secretion in the HPA cycle typically peaks just before a person awakens, it can be thought of as a pattern that helps the body prepare to deal with the “stress” of being awake.2

Insomnia, Depression, and Stress: A Vicious Cycle

Insomnia that occurs comorbid with clinical depression may result, in part, from increased activity of the HPA axis (elevated ACTH and cortisol levels found in persons with severe depression, as detected by the dexamethasone/corticotropin-releasing hormone test3). Stress, too, may similarly cause sleep disturbance by overstimulating the HPA cycle.

However, findings of a recent study confirm that chronic insomnia, even without comorbid stress or depression, is also associated with elevated cortisol levels. Rodenbeck et al4 investigated hourly evening and nocturnal plasma cortisol secretion and sleep patterns in 7 men who had severe chronic primary insomnia and in age- and gender-matched controls. Evening and nocturnal cortisol levels were significantly higher in the 7 patients than in the controls. Evening cortisol levels correlated with the number of nocturnal awakenings in patients and in controls. Thus, the elevated evening and nocturnal cortisol secretion levels may be the physiological counterpart of a postulated hyperarousal in primary insomnia.

Persons with primary insomnia may set off a secondary HPA stress response simply by anticipating another night of disturbed sleep, resulting in a higher number of nocturnal awakenings.4 Consequently, HPA system activity is increased by depression and stress-which themselves cause sleep disturbance-as well as by the mere presence of insomnia, thereby setting into motion a vicious cycle. Sleep disturbance derives from stress and depression and adds to the severity of both conditions.

This relationship can be exploited clinically because the combined treatment of insomnia and major depression often proves very beneficial. For example, researchers found that when persons with comorbid insomnia and major depression received a morning SSRI (fluoxetine) and a nightly hypnotic (eszopiclone) or a nightly placebo, those in the eszopiclone group experienced improved sleep quality, a faster onset of the antidepressant response, and a greater magnitude of the antidepressant effect.5

Obstructive Sleep Apnea and the HPA Axis: A Complex Relationship

In contrast to the straightforward findings discussed above, recent research about the role of the HPA axis in obstructive sleep apnea (OSA) revealed a complex picture. OSA is characterized by episodes of apnea caused by upper airway constriction, secondary hypoxemia, and consequent mental arousal sufficient to clear the airway and reverse the asphyxia, followed by subsequent relaxation of the airway and an additional constriction.

In a 2005 study, Buckley and Schatzberg6 argued that because nocturnal awakenings are associated with pulsatile cortisol release and autonomic activation (which is also associated with CRH and cortisol release), OSA may trigger the HPA axis through this same mechanism of autonomic activation, awakening, and arousal. More recently, however, Vgontzas and colleagues7 showed that this line of reasoning may not have valid clinical implications. In a 4-night sleep-laboratory study, the researchers obtained serial 24-hour plasma measures of cortisol in 45 obese men with and without OSA. The team found that the nonpsychologically distressed men without OSA had low cortisol secretion levels. Cortisol secretion levels were only slightly elevated among obese men who had OSA and returned to normal with continuous positive pressure treatment. As a result of their findings, the researchers suggested that there may be 2 different phenotypes of obesity: one subtype that is associated with depression and/or anxiety, HPA axis hyperactivity, and less sleep, and another subtype that is associated with HPA axis normalcy or hypoactivity, normothymia, and more sleep.


The HPA axis seems to be intertwined with insomnia in a fairly complex way. In some persons with insomnia, increased HPA axis activity may be paramount. However, in other persons with insomnia (predominantly those without depression and/or stress), the HPA axis may be less involved. An even more complex relationship exists between the HPA axis and persons with special sleep disturbances, such as OSA.

Researchers and clinicians face the challenge of identifying groups of patients with different types of insomnia in order to treat them more effectively. Whether it is possible to find a medication that selectively targets the HPA axis to improve sleep quality remains an open question. In the meantime, treating persons who have presumed HPA overactivity with appropriate anxiolytics and antidepressants may be the most effective approach.

On the other hand, treating persons who have insomnia but do not have depression and/or anxiety with either a melatonin agonist or an agent that selectively blocks the γ-aminobutyric acid (GABA) A-benzodiazepine complex may be the appropriate first choice. The situation is not always clear. Some persons with primary insomnia who are agitated by the lack of sleep may present with anxiety and depression secondary to the sleep disturbance. In such persons, a combination of agents may be necessary.

Although we are making some progress in understanding the various types of insomnia and tailoring treatment accordingly, applying this understanding to individual patients remains something of an art form.



  • 1. Hajak G; SINE Study Group. Epidemiology of severe insomnia and its consequences in Germany. Eur Arch Psychiatry Clin Neurosci. 2001;251:49-56.
  • 2. Stahl SM, Wise DD. The potential role of a corticotropin-releasing factor receptor-1 antagonist in psychiatric disorders. CNS Spectr. 2008;13:467-483.
  • 3. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23:477-501.
  • 4. Rodenbeck A, Huether G, Ruther E, Hajak G. Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia. Neurosci Lett. 2002;324:159-163.
  • 5. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59:1052-1060.
  • 6. Buckley TM, Schatzberg AF. On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J Clin Endocrinol Metab. 2005;90:3106-3114.
  • 7. Vgontzas AN, Pejovic S, Zoumakis E, et al. Hypothalamic-pituitary-adrenal axis activity in obese men with and without sleep apnea: effects of continuous positive airway pressure therapy. J Clin Endocrinol Metab. 2007;92:4199-4207.
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