02. Trazodone for Insomnia and Comorbid Depression: Are the AASM Guidelines Relevant?

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Reconciling Trazodone’s Efficacy and Guidelines

A common explanation for trazodone’s perceived flop as an antidepressant is that no one can stay awake at the effective dose for major depression. It has even been suggested that if trazodone was discovered today, it would be marketed as a sleep medication.

Yet the guidelines of the American Academy of Sleep Medicine (AASM) do not recommend trazodone for patients with primary insomnia. They state that the modest improvements in sleep quality are offset by side effects including headache and somnolence.

How can we reconcile our perception of efficacy in our patients with the guidelines from the American Academy of Sleep Medicine?

Meta-Analysis Differentiates Patient Populations

Luckily, a new meta-analysis sheds light on this discrepancy. For starters, the authors conjecture that patients with primary insomnia alone might be fundamentally different than patients with insomnia and depression.

In the latter group, major depression exacerbates insomnia and insomnia exacerbates depressive symptoms. From an initial search of almost 1000 studies, the authors identified 10 randomized controlled trials.

These trials focused on the safety and efficacy of trazodone for sleep problems in patients with depression.

Trazodone Improves Sleep in Depression

Four of those studies included the Pittsburgh Sleep Quality Index (PSQI). This index combines various measures of sleep quality including sleep latency and frequency of middle or early morning awakenings.

The trazodone group demonstrated significant improvements in sleep quality compared to placebo with a standardized mean difference of 0.827. An effect size of almost 1 is an impressive result when you consider the next outcome measure, improvement in depressive symptoms.

Trazodone Reduces Depressive Severity

Eight of the studies included the Hamilton Depression Rating Scale. Trazodone significantly reduced severity of depression compared to controls with a standardized mean difference of 0.365.

Although trazodone is often likely regarded as an antidepressant, this effect size from the eight included trials compares favorably with other data. Specifically, it aligns with the effect size of 0.3 commonly seen in regulatory trials of antidepressants as a group.

Common Trazodone Side Effects Profile

As for side effects, the authors identified specific risks compared to placebo.

• Blurred vision was most common with an odds ratio of 18.
• Next most common were somnolence and sedation, both seven times more likely.
• Dizziness, constipation and dry mouth were three to four times more likely.
• Finally, headache was twice as likely with trazodone than placebo. All were statistically significant. Although data were extracted on dose range from each study, the authors did not include an analysis of the relationship between dose and side effect profile or between dose and efficacy.

Trazodone Restores Restorative Sleep

Of interest, one of the studies from Turkey included polysomnographic recordings in addition to the PSQI. Trazodone increased total sleep time as well as the percentage of stage 3 and 4 sleep, considered the most restful stage of sleep.

It also decreased stage 1 sleep in which awareness of having been asleep is often absent upon awakening. Reduced slow-wave sleep is considered part of the core pathophysiology of major depression.

This suggests that trazodone might ameliorate a fundamental deficit in patients with major depression.

Evidence Quality Versus Guidelines

Finally, the authors performed a structured GRADE assessment of level of evidence and strength of recommendation. This enables a comparison with the guidelines from the American Academy of Sleep Medicine.

Their highest recommendation, that of strong, is for the use of cognitive behavioral therapy for insomnia (CBT-I) as a first-line treatment for patients with insomnia. The Academy’s recommendation against trazodone for patients with primary insomnia is based on a single randomized controlled trial and carries a GRADE assessment of moderate.

Based on four studies, the authors of the current meta-analysis also classified the level of evidence as moderate for the efficacy of trazodone to improve sleep quality in patients with major depression.

Clinical Takeaways for Comorbid Insomnia

My takeaway is that trazodone has efficacy for insomnia in our patient population. Most of these patients do not have uncomplicated primary insomnia but more often have concurrent major depression.

The optimum dose should be determined on a case-by-case basis to balance efficacy for depression and insomnia with side effects. Both patients with primary insomnia and insomnia comorbid with depression should be offered CBT-I as a first-line treatment.

This includes its components of cognitive therapy, stimulus control, relaxation therapy and sleep hygiene.

Additional References

• Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(2):255–262.
• Khan A, Fahl Mar K,  & Brown WA  Consistently Modest Antidepressant Effects in Clinical Trials: the Role of Regulatory Requirements. Psychopharmacology Bulletin. 2021 Jun 1;51(3):79–108. doi: 10.64719/pb.4412