Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
Insomnia is defined as difficulty initiating sleep (falling asleep), difficulty maintaining sleep (waking during the night), or nonrestorative sleep (not feeling refreshed during the day). Sleep disturbances are almost always present in individuals with depression. A number of studies have demonstrated that insomnia increases the risk of new-onset depression, as well as the risk of recurrence of depression (Manber & Chambers, 2009). Depressed patients who experience insomnia are more likely to have suicidal thoughts than depressed patients without significant insomnia. Disturbed sleep is also associated with a less-than-optimal response to antidepressant medication. Sleep disturbance is a common residual symptom in depressed patients who have otherwise responded to treatment with antidepressant agents, and the presence of insomnia is a risk factor for a subsequent depressive relapse.
Benzodiazepine Receptor Agonist (BzRA) Drugs
The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). GABA receptor systems are the target of a wide range of drugs active on the CNS, including anti-anxiety, sedative-hypnotic, general anesthetic, and anticonvulsant drugs. GABA also modulates the activity of the neurotransmitters serotonin, norepinephrine, and dopamine. Studies have found reduced plasma, spinal fluid, and brain GABA levels in depression (Krystal et al., 2002). Animal studies have also found that chronic stress can reduce or deplete GABA levels.
The main GABA receptor complexes are referred to as GABA-A, GABA-B, and GABA-C. The GABA-A receptor complex is the most clinically important and is composed of at least five subunits (each of which may have various isoforms). BzRA drugs work by binding to GABA-A receptors in the brain. The two BzRA drug classes are referred to as benzodiazepine and non-benzodiazepine drugs (Becker & Sattar, 2009). The benzodiazepine drugs bind nonspecifically to the GABA-A receptor complex and are related by their similar central chemical structure but have different chemical side chains that result in important pharmacokinetic differences (influencing their elimination half-lives and whether they have active or inactive metabolites).
Eight benzodiazepine drugs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of anxiety: alprazolam (Xanax®), chlordiazepoxide (Libritabs®), clonazepam (Klonopin®), clorazepate (Tranxene®), diazepam (Valium®), halazepam (Paxipam®), lorazepam (Ativan®), and oxazepam (Serax®). These drugs are also commonly used for insomnia.
Five benzodiazepine drugs are approved by the FDA specifically for the short-term treatment of insomnia: estazolam (ProSom®), flurazepam (Dalmane®), quazepam (Doral®), temazepam (Restoril®), and triazolam (Halcion®). These are not usually used for treating anxiety. They have a rapid onset of effect for initiating sleep but differ in their elimination half-lives.
Three non-benzodiazepine BzRA drugs are FDA approved for insomnia: zolpidem (Ambien®; Ambien CR®; Edluar™ sublingual tablets; Zolpimist™ oral spray), zaleplon (Sonata®), and eszopiclone (Lunesta®). These drugs, which are chemically unrelated to the benzodiazepines (Becker & Sattar, 2009), have a rapid onset of effect for initiating sleep. They bind more selectively to specific subunits on the GABA-A receptor complex, which may explain why they have hypnotic effects without significant anti-anxiety or anticonvulsant effects. This subunit selectivity may also explain the relatively better tolerability and lower risk for abuse of non-benzodiazepines compared with benzodiazepines.
Several studies have found that the co-administration of various benzodiazepine drugs or zolpidem improve the sleep of depressed patients without impairing the antidepressant response (Jindal & Thase, 2004). A placebo-controlled study found that augmentation of fluoxetine with eszopiclone not only improved sleep but also led to a significantly greater antidepressant remission rate (Fava et al., 2006). The benzodiazepine drugs alprazolam and clonazepam alone have also been demonstrated in placebo-controlled studies to have significant antidepressant effects (Morishita, 2009; Warner, Peabody, Whiteford, & Hollister, 1988). Hence, the judicious use of benzodiazepines or other sedative-hypnotic agents can be beneficial for treating insomnia in depressed patients, and they may enhance the overall effectiveness of antidepressant drugs.
Melatonin Receptor Drugs
Melatonin, a hormone synthesized from serotonin and secreted by the pineal gland, regulates sleep-wake cycles. It is effective for circadian rhythm sleep disturbances (e.g., associated with jet lag) but is only modestly effective in the treatment of insomnia unrelated to circadian rhythm sleep disturbances (Pandi-Perumal, Srinivasan, Spence, & Cardinali, 2007). Disturbances in circadian rhythms have been demonstrated in depression, and melatonin may improve sleep in depressed patients, but it does not appear to have inherent antidepressant effects (Dalton, Rotondi, Levitan, Kennedy, & Brown, 2000). Agomelatine (Valdoxan®) is a synthetic analog drug of the hormone melatonin (Howland, 2009). It stimulates the activity of melatonin MT1 and MT2 receptors and inhibits the activity of serotonin 5HT-2C receptor subtypes. It is an approved antidepressant drug in Europe but is not yet available in the United States. Ramelteon (Rozerem®) is also a synthetic analog of melatonin (Rajaratnam, Cohen, & Rogers, 2009). It is a MT1 and MT2 receptor agonist drug currently FDA approved for the treatment of insomnia characterized by difficulty falling asleep. Unlike agomelatine, it does not bind to any serotonin receptors and has not been investigated as an antidepressant agent. It is structurally unrelated to BzRA drugs and does not bind to any GABA receptor.
Other Sleep-Promoting Drugs
Sedating antidepressant drugs, such as amitriptyline (Elavil®), doxepin (Sinequan®), trazodone (Desyrel®), nefazodone (Serzone®), and mirtazapine (Remeron®), are commonly used for treating primary insomnia. Their sleep-promoting effects have been demonstrated primarily in depressed patients. With the exception of doxepin (Silenor®), antidepressant drugs have not been well studied in nondepressed patients with primary insomnia. The brand-name drug Silenor is a low-dose formulation (3 to 6 mg per day) of doxepin that is FDA approved as a treatment for primary insomnia.
The second-generation antipsychotic drugs olanzapine (Zyprexa®) and quetiapine (Seroquel®) are sometimes used in low doses to promote sleep, but they also have inherent antidepressant effects. For this reason, quetiapine is FDA approved as an add-on therapy together with another antidepressant drug for treatment-resistant depression (Bauer et al., 2009). Similarly, the proprietary combination of fluoxetine and olanzapine (olanzapine-fluoxetine combination; Symbyax®) is FDA approved for treatment-resistant depression (Trivedi et al., 2009).
Psychotherapy for Insomnia and Depression
Cognitive-behavioral therapies and pharmacotherapy are similarly effective for the short-term treatment of primary insomnia (Smith et al., 2002). A number of controlled trials investigating the use of various kinds of cognitive-behavioral therapies (alone versus in combination with antidepressant medication) among depressed patients with comorbid insomnia have been completed or are still in progress (see http://www.clinicaltrials.gov, trials NCT00620789, NCT00610259, NCT00255905, and NCT00767624). Only one such study has been published. In this small, randomized, controlled pilot study of 30 participants with depression and comorbid insomnia, adding cognitive-behavioral therapy for insomnia to the antidepressant medication escitalopram (Lexapro®) resulted in higher rates of remission of depression and remission from insomnia compared with escitalopram plus a control condition (Manber et al., 2008).
Sleep Deprivation for Depression
Disturbed sleep is a common symptom of depression but may also reflect abnormal underlying biological processes that regulate sleep-wake cycles and are relevant to the pathophysiology of depressive disorders (Wirz-Justice, 1995). Approximately 30% to 50% of depressed patients have a significant but transient antidepressant effect from total sleep deprivation, but this positive benefit is often lost with a full night of sleep (Giedke & Schwarzler, 2002). Serial partial sleep deprivation, whereby patients stay awake daily from 2:00 a.m. to 10:00 p.m., has been used to achieve a more sustained antidepressant response, but this has not been especially effective. Sleep deprivation followed by pharmacotherapy may be more effective (Benedetti & Smeraldi, 2009). In addition, some evidence suggests that sleep deprivation may accelerate the response to antidepressant drugs and may be a useful augmentation strategy for partial responders to antidepressant agents (Thase & Rush, 1995).
Patients with seasonal depression or bipolar depression may be somewhat more sensitive to the antidepressant effects of sleep deprivation, and sleep deprivation may precipitate mania in patients with bipolar disorder (Colombo et al., 2000). A positive response to sleep deprivation predicts a positive response to light therapy, and the combination has been used to obtain a more sustained antidepressant effect (Fritzsche, Heller, Hill, & Kick, 2001).
The biological processes that regulate sleep-wake cycles are relevant to the pathophysiology and treatment of depression. Although antidepressant medications that effectively treat depression can also improve sleep, targeted therapies for insomnia may be helpful for treating residual sleep disturbances that are associated with poor outcomes. Somewhat paradoxically, sleep deprivation can also be associated with a transient antidepressant effect. Sleep deprivation would be difficult to use in routine clinical practice but might be an appropriate strategy to try for treatment-resistant forms of depression. Because sleep disturbances are common among depressed patients, nurses should be familiar with the potential role of specific sleep interventions in the treatment of depression.
- Bauer, M., Pretorius, H.W., Constant, E.L., Earley, W.R., Szamosi, J. & Brecher, M. (2009). Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: Results of a randomized, placebo-controlled, double-blind study. Journal of Clinical Psychiatry, 70, 540–549. doi:10.4088/JCP.08m04629 [CrossRef]
- Becker, P.M. & Sattar, M. (2009). Treatment of sleep dysfunction and psychiatric disorders. Current Treatment Options in Neurology, 11, 349–357. doi:10.1007/s11940-009-0039-z [CrossRef]
- Benedetti, F. & Smeraldi, E. (2009). Neuroimaging and genetics of antidepressant response to sleep deprivation: Implications for drug development. Current Pharmaceutical Design, 15, 2637–2649. doi:10.2174/138161209788957447 [CrossRef]
- Colombo, C., Lucca, A., Benedetti, F., Barbini, B., Campori, E. & Smeraldi, E. (2000). Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression: Replication of main effects and interaction. Psychiatry Research, 95, 43–53. doi:10.1016/S0165-1781(00)00164-5 [CrossRef]
- Dalton, E.J., Rotondi, D., Levitan, R.D., Kennedy, S.H. & Brown, G.H. (2000). Use of slow-release melatonin in treatment-resistant depression. Journal of Psychiatry and Neuroscience, 25, 48–52.
- Fava, M., McCall, W.V., Krystal, A., Wessel, T., Rubens, R., Caron, J. & Roth, T.,… (2006). Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biological Psychiatry, 59, 1052–1060. doi:10.1016/j.biopsych.2006.01.016 [CrossRef]
- Fritzsche, M., Heller, R., Hill, H. & Kick, H. (2001). Sleep deprivation as a predictor of response to light therapy in major depression. Journal of Affective Disorders, 62, 207–215. doi:10.1016/S0165-0327(00)00154-3 [CrossRef]
- Giedke, H. & Schwarzler, F. (2002). Therapeutic use of sleep deprivation in depression. Sleep Medicine Reviews, 6, 361–377.
- Howland, R.H. (2009). Critical appraisal and update on the clinical utility of agomelatine, a melatonergic agonist, for the treatment of major depressive disease in adults. Neuropsychiatric Disease and Treatment, 5, 563–576. doi:10.2147/NDT.S5453 [CrossRef]
- Jindal, R.D. & Thase, M.E. (2004). Treatment of insomnia associated with clinical depression. Sleep Medicine Reviews, 8, 19–30. doi:10.1016/S1087-0792(03)00025-X [CrossRef]
- Krystal, J.H., Sanacora, G., Blumberg, H., Anand, A., Charney, D.S., Marek, G. & Mason, G.F.,… (2002). Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Molecular Psychiatry, 7(Suppl. 1), S71–S80. doi:10.1038/sj.mp.4001021 [CrossRef]
- Manber, R. & Chambers, A.S. (2009). Insomnia and depression: A multifaceted interplay. Current Psychiatry Reports, 11, 437–442. doi:10.1007/s11920-009-0066-1 [CrossRef]
- Manber, R., Edinger, J.D., Gress, J.L., San Pedro-Salcedo, M.G., Kuo, T.F. & Kalista, T. (2008). Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep, 31, 489–495.
- Morishita, S. (2009). Clonazepam as a therapeutic adjunct to improve the management of depression: A brief review. Human Psychopharmacology: Clinical and Experimental, 24, 191–198. doi:10.1002/hup.1015 [CrossRef]
- Pandi-Perumal, S.R., Srinivasan, V., Spence, D.W. & Cardinali, D.P. (2007). Role of the melatonin system in the control of sleep: Therapeutic implications. CNS Drugs, 21, 995–1018. doi:10.2165/00023210-200721120-00004 [CrossRef]
- Rajaratnam, S.M.W., Cohen, D.A. & Rogers, N.L. (2009). Melatonin and melatonin analogues. Sleep Medicine Clinics, 4, 179–193. doi:10.1016/j.jsmc.2009.02.007 [CrossRef]
- Smith, M.T., Perlis, M.L., Park, A., Smith, M.S., Pennington, J., Giles, D.E. & Buysse, D.J. (2002). Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. American Journal of Psychiatry, 159, 5–11. doi:10.1176/appi.ajp.159.1.5 [CrossRef]
- Thase, M.E. & Rush, A.J. (1995). Treatment-resistant depression. In Bloom, F.E. & Kupfer, D.J. (Eds.), Psychopharmacology: The fourth generation of progress (pp. 1081–1097). New York: Raven Press.
- Trivedi, M.H., Thase, M.E., Osuntokun, O., Henley, D.B., Case, M., Watson, S.B. & Corya, S.A.,… (2009). An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression. Journal of Clinical Psychiatry, 70, 387–396. doi:10.4088/JCP.08m04064 [CrossRef]
- Warner, M.D., Peabody, C.A., Whiteford, H.A. & Hollister, L.E. (1988). Alprazolam as an antidepressant. Journal of Clinical Psychiatry, 49, 148–150.
- Wirz-Justice, A. (1995). Biological rhythms in mood disorders. In Bloom, F.E. & Kupfer, D.J. (Eds.), Psychopharmacology: The fourth generation of progress (pp. 999–1017). New York: Raven Press.