What Is the Role of Sedating Antidepressants, Antipsychotics, and Anticonvulsants in the Management of Insomnia?
- 1.5k Downloads
- 27 Citations
Abstract
Psychiatric medications such as antidepressants, antipsychotics, and anticonvulsants are commonly prescribed by physicians for the off-label use of improving sleep. Reasons for preferential prescription of these medications over FDA-approved insomnia drugs may include a desire to treat concurrent sleep problems and psychiatric illness with a single medication, and/or an attempt to avoid hypnotic drugs due to their publicized side effects. However, there have been few large studies demonstrating the efficacy and safety of most off-label medications prescribed to treat insomnia. In addition, many of these medications have significant known side effect profiles themselves. Here we review the pertinent research studies published in recent years on antidepressant, antipsychotic, and anticonvulsant medications frequently prescribed for sleep difficulties. Although there have been few large-scale studies for most of these medications, some may be appropriate in the treatment of sleep issues in specific well-defined populations.
Keywords
Sleep disorders Insomnia Comorbid insomnia Slow wave sleep SWS Off-label Antidepressants Antipsychotics Anticonvulsants Hypnotics PsychiatryNotes
Disclosure
C. McCall: none; W. V. McCall: consultant for Sunovion.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Walsh JK, Schweitzer PK. Ten-year trends in the pharmacological treatment of insomnia. Sleep. 1999;22:371–5.PubMedGoogle Scholar
- 2.Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep. 2004;27:1441–2.PubMedGoogle Scholar
- 3.Owens J, Rosen C, Mindell J, et al. Use of pharmacotherapy for insomnia in child psychiatry practice: a national survey. Sleep Med. 2010;11:692–700.PubMedCrossRefGoogle Scholar
- 4.Mindell J, Emslie G, Blumer L, et al. Pharmacologic management of insomnia in children and adolescents: consensus statement. Pediatrics. 2006;117:1223–32.CrossRefGoogle Scholar
- 5.Poceta J. Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series. J Clin Sleep Med. 2011;7:632–8.PubMedGoogle Scholar
- 6.Rottach K, Schaner BM, Kirch M. Restless leg syndrome as side effect of second generation antidepressants. J Psychiatr Res. 2008;43:70–5.PubMedCrossRefGoogle Scholar
- 7.Schweitzer P, et al. Drugs that disturb sleep and wakefulness. In: Kryger M, Roth T, Dement, editors. Principles and practice of sleep medicine. 5th ed. St Louis: Elsevier Saunders; 2012. p. 542.Google Scholar
- 8.Weber J, Siddiqui M, Wagstaff A. Low-dose doxepin: in the treatment of insomnia. CNS Drugs. 2010;24:713–20.PubMedCrossRefGoogle Scholar
- 9.Kuntz R. Off-label prescribing of antidepressants and anxiolytics: an attorney's guide to psychoactive drugs. J Psychiatry Law. 1998;26:519–32.Google Scholar
- 10.Kramer S, McCall V. Off-label prescribing: 7 steps for safer, more effective treatment. Curr Psychiatry. 2006;5:15–28.Google Scholar
- 11.•• McCall W. Off-label use of prescription medications for insomnia: sedating antidepressants, antipsychotics, anxiolytics, and anticonvulsants. In: Sateia M, Buysse D, editors. Insomnia: diagnosis and treatment. London: Informa Healthcare; 2010. p. 397–409. This chapter presents a comprehensive review of the literature regarding the off-label use of psychiatric medications in treating sleep difficulties.Google Scholar
- 12.Dording C, Mischoulon D, Petersen T, et al. The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists. Ann Clin Psychiatry. 2002;14:143–7.PubMedGoogle Scholar
- 13.Montgomery I, Oswald I, Morgan K, et al. Trazodone enhances sleep in subjective quality but not in objective duration. Br J Clin Pharmacol. 1983;16:139–44.PubMedCrossRefGoogle Scholar
- 14.Yamadera H, Nakamura S, Suzuki H, et al. Effects of trazodone hydrochloride and imipramine on polysomnography in healthy subjects. Psychiatry Clin Neurosci. 1998;52:439–43.PubMedCrossRefGoogle Scholar
- 15.Ware JC, Pittard JT. Increased deep sleep after trazodone use: a double-blind placebo-controlled study in healthy young adults. J Clin Psychiatry. 1990;51:18–22.PubMedGoogle Scholar
- 16.Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005;66:469–76.PubMedCrossRefGoogle Scholar
- 17.Haffmans PMJ. The effects of trazodone on sleep disturbances included by brofaromine. Eur Psychiatry. 1999;14:167–71.PubMedCrossRefGoogle Scholar
- 18.Nierenberg A, Adler LA, Peselow E, et al. Trazodone for antidepressant-associated insomnia. Am J Psychiatry. 1994;151:1069–72.PubMedGoogle Scholar
- 19.Burns M, Hoskowitz H, Jaffe J. A comparison of the effects of trazodone and amitriptyline on skills performance by geriatric subjects. J Clin Psychiatry. 1986;47:252–4.PubMedGoogle Scholar
- 20.Warrington SJ, Ankier SI, Turner P. An evaluation of possible interactions between ethanol and trazodone or amitriptyline. Br J Clin Pharmacol. 1984;18:549–57.PubMedCrossRefGoogle Scholar
- 21.Saletu-Zyhlarz G, Abu-Bakr M, Anderer P, et al. Insomnia related to dysthymia: polysomnographic and psychometric comparison with normal controls and acute therapeutic trials with trazodone. Neuropsychobiology. 2001;44:139–49.PubMedCrossRefGoogle Scholar
- 22.James S, Mendelson W. The use of trazodone as a hypnotic: a critical review. J Clin Psychiatry. 2004;65:752–5.PubMedCrossRefGoogle Scholar
- 23.• Roth A, McCall W, Vaughn, Liguori A. Cognitive, psychomotor and polysomnographic effects of trazodone in primary insomniacs. J Sleep Res. 2011;20:552–8. Although trazodone is one of the most frequently prescribed off-label medications for insomnia, few studies have investigated its efficacy and safety for this indication. In this study, trazodone 50 mg produced significant impairments of short-term memory, verbal learning, equilibrium, and arm muscle endurance across time-points. Relative to placebo, trazodone was associated with fewer night-time awakenings, minutes of Stage 1 sleep and self-reports of difficulty sleeping.PubMedCrossRefGoogle Scholar
- 24.Wichniak A, Wierzbicka A, Jernajczyk W. Patinets with insomnia and subthreshold depression show marked worsening of insomnia after discontinuation of sleep promoting medication. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1671–6.PubMedCrossRefGoogle Scholar
- 25.Sheehan D, Croft H, Gossen E, et al. Extended-release trazodone in major depressive disorder: a randomized, double-blind, placebo-controlled study. Psychiatry. 2009;6:20–33.PubMedGoogle Scholar
- 26.Calandre E, Morillas-Arques P, Molina-Barea R, et al. Trazodone plus pregabalin combination in the treatment of fibromyalgia: a 2-phase, 24-week, open-label uncontrolled study. BMC Musculoskelet Disord. 2011;12:95.PubMedCrossRefGoogle Scholar
- 27.Morillas-Arques P, Rodriguez-Lopez C, Molina-Barea R, et al. Trazodone for the treatment of fibromyalgia: an open-label, 12-week study. BMC Musculoskelet Disord. 2010;11:204.PubMedCrossRefGoogle Scholar
- 28.Camargos E, Pandolfi M, Freitas M, et al. Trazodone for the treatment of sleep disorders in dementia: an open-label, observational and review study. Arq Neuropsiquiatr. 2011;69:44–9.PubMedCrossRefGoogle Scholar
- 29.Stein M, Kurth M, Sharkey K, et al. Trazodone for sleep disturbance during methadone maintenance: a double-blind, placebo-controlled trial. Drug Alcohol Depend. 2012;120:65–73.PubMedCrossRefGoogle Scholar
- 30.Kupfer DJ, Spiker DG, Coble P, et al. Amitriptyline and EEG sleep in depressed patients: I. Drug effect Sleep. 1978;1:149–59.Google Scholar
- 31.Doerr J, Spiegelhalder K, Petzold F, et al. Impact of escitalopram on nocturnal sleep, day-time sleepiness, and performance compared to amitriptyline: a randomized, double-blind, placebo-controlled study in healthy male subjects. Pharmacopsychiatry. 2010;43:166–73.PubMedCrossRefGoogle Scholar
- 32.Ware M, Fitzcharles M, Joseph L, et al. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 2010;110:604–10.PubMedCrossRefGoogle Scholar
- 33.Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30:1555–61.PubMedGoogle Scholar
- 34.•• Krystal A, Lankford A, Durrence HH, et al. Efficacy and safety of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia. Sleep. 2011;34:1433–42. Five weeks of nightly administration of doxepin 3 mg and 6 mg to adults with chronic primary insomnia resulted in significant and sustained improvements in sleep maintenance and early morning awakenings.PubMedGoogle Scholar
- 35.•• Krystal A, Durrence HH, Scharf M. Efficacy and safety of doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient trial of elderly subjects with chronic primary insomnia. Sleep. 2010;33:1553–61. Doxepin 1 mg and 3 mg administered nightly to elderly chronic insomnia patients for 12 weeks resulted in significant and sustained improvements in most endpoints, without evidence of next-day residual sedation or other significant adverse effects. Doxepin also demonstrated improvements in both patient- and physician-based ratings of global insomnia outcome.PubMedGoogle Scholar
- 36.•• Lankford A, Rogowski R, Essink B, et al. Efficacy and safety of doxepin 6 mg in a 4-week outpatient trial of elderly adults with chronic primary insomnia. Sleep Med. 2012;13:133–8. Elderly adults meeting DSM-IV-TR criteria for primary insomnia were randomized to 4 weeks of nightly treatment with either doxepin 6 mg or placebo. Doxepin 6 mg produced significant improvements in sleep maintenance, sleep duration, and sleep quality endpoints that were sustained throughout the trial.PubMedCrossRefGoogle Scholar
- 37.Ruigt GSF, Kemp B, Groenhout CM, et al. Effect of the antidepressant Org 3770 on human sleep. Eur J Clin Pharmacol. 1990;38:551–4.PubMedCrossRefGoogle Scholar
- 38.Aslan S, Isik E, Cosar B. The effects of mirtazapine on sleep: a placebo controlled, double-blind study in young healthy volunteers. Sleep. 2002;25:677–9.PubMedGoogle Scholar
- 39.Perez D, Loprinzi D, Barton DL. Pilot evaluation of mirtazapine for the treatment of hot flashes. J Support Oncol. 2004;2:50–6.PubMedGoogle Scholar
- 40.Wingen M, Bothmer J, Langer S, et al. Actual driving performance and psychomotor function in healthy subjects after acute and subchronic treatment with escitalopram, mirtazapine, and placebo: a crossover trial. J Clin Psychiatry. 2005;66:436–43.PubMedCrossRefGoogle Scholar
- 41.Shen J, Hossain N, Streiner D, et al. Excessive daytime sleepiness and fatigue in depressed patients and therapeutic response of a sedating antidepressant. J Affect Disord. 2011;134:421–6.PubMedCrossRefGoogle Scholar
- 42.Shen J, Moller H, Wang X, et al. Mirtazapine, a sedating antidepressant, and improved driving safety in patients with major depressive disorder: a prospective, randomized trial of 28 patients. J Clin Psychiatry. 2009;70:370–7.PubMedCrossRefGoogle Scholar
- 43.Dolev Z. Case series of perimenopausal women with insomnia treated with mirtazapine followed by prolonged-release melatonin add-on and monotherapy. Arch Womens Ment Health. 2011;14:269–73.PubMedCrossRefGoogle Scholar
- 44.Cohrs S, Rodenbeck A, Guan Z, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology. 2004;174:421–9.PubMedGoogle Scholar
- 45.Wiegand M, Landry F, Bruckner T, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology. 2008;196:337–8.PubMedCrossRefGoogle Scholar
- 46.Nanda F, Singer C. Placebo-Controlled Trial of Quetiapine for Sleep Disturbance in Dementia and MCI. 16 ed. 2008;A126.Google Scholar
- 47.Cates M, Jackson C, Feldman J, et al. Metabolic consequences of using low-dose quetiapine for insomnia in psychiatric patients. Community Ment Health J. 2009;45:251–4.PubMedCrossRefGoogle Scholar
- 48.Dolder C, McKinsey J. Quetiapine for sleep in patients with dementia. Consult Pharm. 2010;25:676–9.PubMedCrossRefGoogle Scholar
- 49.Tassniyom K, Paholpak S, Tassniyom S, et al. Quetiapine for primary insomnia: a double blind, randomized controlled trial. J Med Assoc Thai. 2010;93:729–34.PubMedGoogle Scholar
- 50.Golubchik P, Sever J, Weizman A. A low-dose quetiapine for adolescents with autistic spectrum disorder and aggressive behavior: open-label trial. Clin Neuropharmacol. 2011;34:216–9.PubMedCrossRefGoogle Scholar
- 51.Stein D, Bandelow B, Merideth C, et al. Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder: an analysis of pooled data from 3 8-week placebo-controlled studies. Hum Psychopharmacol. 2011;26:614–28.PubMedCrossRefGoogle Scholar
- 52.Bauer M, El-Khalili N, Datto C, et al. A pooled analysis of 2 randomized, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. J Affect Disord. 2010;127:19–30.PubMedCrossRefGoogle Scholar
- 53.Foldvary-Schaefer N, De Leon Sanchez I, Karafa M, et al. Gabapentin increases slow-wave sleep in normal adults. Epilepsia. 2002;43:1493–7.PubMedCrossRefGoogle Scholar
- 54.Karam-Hage M, Brower K. Open pilot study of gabapentin versus trazodone to treat insomnia in alcoholic outpatients. Psychiatry Clin Neurosci. 2003;57:542–4.PubMedCrossRefGoogle Scholar
- 55.Furieri F, Nakamura-Placios E. Gabapentin reduces alcohol consumption and craving: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68:1691–700.PubMedCrossRefGoogle Scholar
- 56.Arnold LM, Goldenberg D, Stanford S, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56:1336–44.PubMedCrossRefGoogle Scholar
- 57.Hahn K, Arendt G, Braun J, et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004;251:1260–6.PubMedCrossRefGoogle Scholar
- 58.Rice A, Maton S, Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomized, double blind, placebo controlled study. Pain. 2001;94:215–24.PubMedCrossRefGoogle Scholar
- 59.Backonja M. Gabapentin monotherapy for the symptomatic treatment of painful neuropathy: a multicenter, double-blind, placebo-controlled trial in patients with diabetes mellitus. Epilepsia. 1990;40(Suppl):S57–9.Google Scholar
- 60.Gordh T, Stubhaug A, Jenson T, et al. Gabapentin in traumatic nerve injury pain: a randomized, double-blind, placebo-controlled, cross-over, multi-center study. Pain. 2008;138:255–66.PubMedCrossRefGoogle Scholar
- 61.Lo H, Yang C, Lo H, et al. Treatment effects of gabapentin for primary insomnia. Clin Neuropharmacol. 2010;33:84–90.PubMedCrossRefGoogle Scholar
- 62.Yurcheshen M, Guttuso TJ, McDermott M, et al. Effects of gabapentin on sleep in menopausal women with hot flashes as measured by a Pittsburgh sleep quality index factor scoring model. J Womens Health. 2009;18:1355–60.CrossRefGoogle Scholar
- 63.Myrick H, Malcolm R, Randall P. A double-blind trial of gabapentin vs lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009;33:1582–8.PubMedCrossRefGoogle Scholar
- 64.Hindmarch I, Dawson J, Stanley N. A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep. 2005;28:187–93.PubMedGoogle Scholar
- 65.Arnold LM, Russell I, Diri E, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain. 2008;9:792–805.PubMedCrossRefGoogle Scholar
- 66.Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from 7 randomized, controlled trials across a range of doses. Diabetes Care. 2008;31:1448–54.PubMedCrossRefGoogle Scholar
- 67.Mease P, Russell I, Arnold LM, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol. 2008;35:502–14.PubMedGoogle Scholar
- 68.Siddall P, Cousins M, Otte A, et al. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006;67:1792–800.PubMedCrossRefGoogle Scholar
- 69.Russell I, Crofford L, Leon T. The effects of pregabalin on sleep disturbance symptoms among individuals with fibromyalgia syndrome. Sleep Med. 2009;10:604–10.PubMedCrossRefGoogle Scholar
- 70.• Pauer L, Winkelmann A, Arsenault P, et al. An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia. J Rheumatol. 2011;38:2643–52. This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with fibromyalgia to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary.PubMedCrossRefGoogle Scholar
- 71.• Montgomery S, Herman B, Schweizer E, et al. The efficacy of pregabalin and benzodiazepines in generalized anxiety disorder presenting with high levels of insomnia. Int Clin Psychopharmacol. 2009;24:214–22. Pooled data from 6 double-blind, placebo-controlled, 4- to 6-week trials of outpatients with generalized anxiety disorder found that pregabalin was well tolerated and improved overall anxiety symptoms, while specifically improving insomnia in patients with generalized anxiety disorder presenting with high levels of concurrent insomnia.PubMedCrossRefGoogle Scholar
- 72.Zammit GK, McNabb LJ, Caron J, et al. Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia. Curr Med Res Opin. 2004;20:1979–91.PubMedCrossRefGoogle Scholar
- 73.Roth T, Soubrane C, Titeux L, et al. Efficacy and safety of zolpidem-MR: a double-blind, placebo-controlled study in adults with primary insomnia. Sleep Med. 2006;7:397–406.PubMedCrossRefGoogle Scholar