![]() 11 In animal models, desmethylzopiclone reduced anxiety without causing sedation or motor impairment. 10 This effect is furthered by eszopiclone’s active metabolite, desmethylzopiclone, which is a selective partial agonist at α-2 and -3 with very little α-1 activity (that is a good thing, as it would otherwise cause a lot of daytime sedation). It acts at all of the α subunits, and may actually be a little more selective for the anxiolytic α-2 and-3. Specifically, the z-hypnotics are selective for the sleep-inducing GABAA α-1 subunit, while benzodiazepines have additional effects on the α-2 and -3 subunits that are involved in anxiety and depression. To understand that we need to turn to the GABAA receptor.Ĭompared to the benzodiazepines, the z-hypnotics have more limited effects on GABAA, which is thought to explain why they treat sleep but not anxiety. However, eszopiclone does have a unique mechanism of action that might explain its antidepressant effects. 9 Whether this is a statistical fluke or a true difference is difficult to say, as eszopiclone has not gone head-to-head against other hypnotics in depression. But to this day eszopiclone remains the only hypnotic with distinct antidepressant effects (ramelteon has mild preventative benefits in bipolar disorder but is not known to treat depression). 8īoth the zolpidem and eszopiclone studies involved many of the same investigators, who had pursued this work with the idea that any hypnotic that improved sleep would indirectly improve mood. 6,7 Generalized anxiety disorder also improved when eszopiclone was added to an SSRI in a large manufacturer-supported trial that replicated the design of eszopiclone’s pivotal depression trial. ![]() Meanwhile, eszopiclone repeated its success, improving mood and insomnia in 2 additional trials, 1 of which involved peri- and postmenopausal women with insomnia and depressive symptoms. 4 Replication in China brought the same negative results, and last year zolpidem failed again to lift mood or reduce suicidality when added to an SSRI in a randomized trial of patients with depression, insomnia, and suicidality. Once again, the hypnotic improved sleep, but this time there was no change in mood. The same group repeated the study with zolpidem ER in a large trial of similar design. Compared to placebo, those who received eszopiclone experienced a more rapid and complete recovery from depression. As expected, the hypnotic improved sleep, but it also improved mood symptoms that were unrelated to sleep. Five hundred and forty-five patients with depression and insomnia were randomized to receive either eszopiclone 3mg or placebo while simultaneously starting a trial of fluoxetine. 3īuoyed by this result, the manufacturer of eszopiclone funded a large trial to see if depression might actually improve with their hypnotic. The sleep problems improved with zolpidem and, to the investigators’ relief, the sedating medication did not worsen depression. That concern was partly put to rest in a 1999 study that tested whether zolpidem could relieve selective serotonin reuptake inhibitor -induced insomnia in patients who had otherwise recovered on the antidepressant. At the time, it was thought that hypnotics might cause depression through their sedative effects. The results did not pan out exactly as expected, but they point the way toward a medication with unique potential in depression.īut first, investigators had to overcome a hurdle. In the early 2000s, a group of sleep researchers set out to investigate whether hypnotics could improve mood in patients with depression and insomnia. 2 Instead, a standard hypnotic may be a good option when patients continue to have depression and insomnia on an antidepressant, but not just any hypnotic.Įszopiclone: The Science Behind Its Potential Effect on Depression But what if insomnia is the chief complaint? Mirtazapine is tempting here, but this medication carries a risk of weight gain and did not perform well in several recent, well-designed augmentation trials. For favorable tolerability, there is bupropion or a natural therapy, and lithium has strong antisuicide effects, if that is a concern. When rapid relief is the priority, an antipsychotic might be the best choice. Antidepressants: bupropion, imipramine, or mirtazapine Antipsychotics: aripiprazole, risperidone, or quetiapineģ. Natural treatments: omega-3 fatty acids, L-methylfolate, or light therapyĢ. 1 In addition to psychotherapy and lifestyle approaches like aerobic exercise, they recommend augmentation with:ġ. The Psychopharmacology Algorithm Project recommends a menu approach that encourages patients to collaboratively choose an option that best fits their needs. Antidepressant augmentation is a common practice, and there are many strategies from which to choose.
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