National Sleep Foundation

Chapter 2: Insomnia

Pharmacology – Anti-depressants

Sedating Antidepressants

Concerns about tolerance, dependence, and abuse with Benzodiazepine receptor agonist (BZD) use have led to an increase in off-label use of sedating antidepressants to treat insomnia — although these concerns are highly exaggerated and, in many cases, unfounded. i, ii  

The U.S. Food and Drug Administration has not approved MOST antidepressants for insomnia (other than low-dose doxepin) and their use is not recommended by National Institutes of Health guidelines. There is a lack of efficacy data on their success in treating insomnia, and these antidepressants have various side effects that are often more substantial than those observed with hypnotics. iii

Antidepressants’ efficacy in treating insomnia depends on the individual patient and the specific drug itself. Improving depression may itself improve insomnia, although certain antidepressants can promote wakefulness (i.e., secondary tricyclics and some serotonin and norepinephrine reuptake inhibitors).

Antidepressants may be preferable to hypnotics in some patients with insomnia that is comorbid with depression, anxiety, or fibromyalgia; in patients who fail hypnotics; in cases of untreated sleep apnea; and in patients with a history of substance abuse. All the caveats for these drugs (e.g., possible coronary side effects, induction of mania, and/or increased suicide risk) must be considered when they are used off-label for insomnia.

The antidepressants often used include trazodone, tertiary tricyclic antidepressants, and mirtazapine, which are described in more detail below.

Trazodone

Trazodone (50, 100, 150, 300 mg) is the most frequently prescribed antidepressant for treating insomnia, despite the scarcity of supportive data about its efficacy. iv

In the only placebo-controlled, double-blind, large-scale trial, treatment with trazodone 50 mg was significantly more effective than placebo, in subjectively reducing sleep latency in patients with insomnia, but was less effective than zolpidem 10 mg. This effect was not significant beyond the first week of the 14-day study, however.v Additionally, patients with insomnia treated for one night with trazodone 100 mg experienced increased slow wave sleep (SWS), but no improvements in sleep latency, total sleep time, or nighttime awakenings.

Trazodone’s side effects include increased risk of daytime sedation, orthostatic hypotension, lightheadedness and weakness, and the rare (but serious) risk of priapism. Trazodone should be used with caution in patients with cardiac disease.vi  

Tertiary tricyclic antidepressants

Tertiary tricyclic antidepressants (e.g., amitriptyline, doxepin, imipramine) improve sleep continuity, sleep quality, and slow wave sleep (SWS), but may aggravate preexisting restless legs syndrome and periodic limb movement in sleep (see Chapter 8).vii The use of tertiary tricyclic antidepressants to improve overall sleep is limited by their side effects, including cardiovascular (e.g., tachycardia and orthostatic hypotension), sedation, dry mouth, urinary retention, and weight gain.

Low-dose doxepin has been approved by the FDA for treatment of insomnia (specifically to treat insomnia characterized by difficulties in maintaining sleep) as well as depression.viii

Mirtazapine

Mirtazapine (15, 30, 45 mg) is an antidepressant to treat Major Depressive Disorder, and is used off-label to treat insomnia, particularly because it does not inhibit REM sleep. It has not been evaluated in placebo-controlled studies of insomnia.ix

A randomized, double-blind study in patients with insomnia and Major Depressive Disorder demonstrated that mirtazapine significantly decreased sleep latency and wakefulness after sleep onset and increased sleep efficiency, and had no effect on REM or slow wave sleep. Its use is limited, however, because it can cause considerable weight gain.x

References

  1. Mendelson WB, Roth T, Cassella J, et al. The treatment of chronic insomnia: drug indications, chronic use and abuse liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting symposium. Sleep Med Rev. 2004;8:7-17.
  2. Walsh JK, Schweitzer PK. Ten-year trends in the pharmacological treatment of insomnia. Sleep. 1999;22:371-375.
  3. Krystal A, “Pharmacologic Treatment: Other Medications,” In Kryger M, Roth T, Dement WC (eds.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, pages 916-930.
  4. Krystal A, “Pharmacologic Treatment: Other Medications,” In Kryger M, Roth T, Dement W C (eds.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, pages 916-930.
  5. Krystal A, “Pharmacologic Treatment: Other Medications,” In Kryger M, Roth T, Dement W C (eds.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, pages 916-930.
  6. Krystal A, “Pharmacologic Treatment: Other Medications,” In Kryger M, Roth T, Dement W C (eds.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, pages 916-930.
  7. Krystal A, “Pharmacologic Treatment: Other Medications,” In Kryger M, Roth T, Dement W C (eds.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, pages 916-930.
  8. Weber J, Siddiqui MA, Wagstaff AJ, McCormack PL, “Low-dose doxepin: in the treatment of insomnia,” CNS Drugs. 2010 Aug;24(8):713-20. doi: 10.2165/11200810-000000000-00000.
  9. Krystal A, “Pharmacologic Treatment: Other Medications,” In Kryger M, Roth T, Dement WC (eds.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, pages 916-930.
  10. Krystal A, “Pharmacologic Treatment: Other Medications,” In Kryger M, Roth T, Dement WC (eds.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, pages 916-930.