REVIEW OF: Palagini L et al, World J Biol Psychiatry 2026
STUDY TYPE: Expert consensus review
CONFLICTS: Review is independently funded but author has industry ties
Background
When people don’t sleep well, they are more likely to develop depression, bipolar, and anxiety. But surprisingly, most sleep medications don’t prevent these problems, with one exception: Eszopiclone (Lunesta). Approved in the US in 2004, this sleep med is a more concentrated “enantiomer” of zopiclone, a popular sleep medication used outside the US since the 1990s.
The Results
This Italian task force systematically reviewed 12 randomized trials examining eszopiclone in psychiatric populations.
The strongest data are in major depression. Adding eszopiclone 3mg to fluoxetine in a 545-patient randomized trial produced faster antidepressant onset, better sleep, and greater overall depression response than fluoxetine alone. A response rate of 55.6% versus 42.0% for placebo was seen in a post-hoc analysis of over 1,000 patients with anxious depression. Importantly, stopping eszopiclone didn’t trigger rebound insomnia or rebound depression.
In GAD, eszopiclone added to escitalopram improved anxiety scores week by week in a large, placebo-controlled trial. In PTSD, eszopiclone improved insomnia and PTSD symptoms in a 3-week double-blind, placebo-controlled trial that was limited by its small size and cross-over design.
In schizophrenia, two randomized trials found improvements in insomnia and — unexpectedly — working memory, with one study linking eszopiclone to increased sleep spindle density.
In contrast, similar trials did not find benefits for depression with zolpidem (Ambien).
How it Works
Mechanistically, eszopiclone differs from zolpidem by binding α1, α2, α3, and α5 GABA-A subunits with similar affinity, which may explain its anxiolytic properties alongside its hypnotic ones. Animal data suggest it doesn’t impair sleep-dependent plasticity and may even be mildly pro-neurogenic.
My own take is that this effect is similar to adding a short-term benzodiazepine to accelerate response to antidepressants. Eszopiclone is metabolized into desmethylzopiclone, a compound with benzodiazepine properties. This metabolite is not sedating, but lingers during the day, relieving anxiety.
Practice Implications
- Eszopiclone is FDA-approved, has long-term efficacy data out to 12 months, and shows short-term benefits in major depression, generalized anxiety, and possibly PTSD and schizophrenia.
- Consider it in those disorders when patients also have insomnia, starting 1–2mg in the elderly, 3mg in adults.
- Start with behavioral strategies for sleep (eg, CBT-insomnia or the Sleep Coach app) and plan to taper off after 1-3 months
- The side effect of metallic taste can be relieved by taking it with a citrus drink
- Eszopiclone is covered in more detail in the chapter on rapid antidepressant therapies in Difficult to Treat Depression and a 2021 Carlat Podcast.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- What have you seen with eszopiclone? Problems? Benefits?
