A neglected strategy for increasing antidepressants?

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1. Natural treatments: omega-3 fatty acids, L-methylfolate or light therapy

2. Antipsychotics: aripiprazole, risperidone or quetiapine

3. Antidepressants: bupropion, imipramine or mirtazapine

4. Lithium

5. Liothyronine (T3)

When rapid relief is the priority, an antipsychotic medication may be the best choice. For favorable tolerance, there is bupropion or natural therapy, and lithium has strong anti-suicide effects, if that is a concern. But what if insomnia is the main complaint? Mirtazapine is tempting here, but this drug carries a risk of weight gain and has not performed well in several recent and well-designed augmentation trials.2 Instead, a standard hypnotic may be a good option when patients continue to experience depression and insomnia on an antidepressant, but not just any hypnotic.

Eszopiclone: ​​the science behind its potential effect on depression

In the early 2000s, a group of sleep researchers set out to determine whether hypnotics could improve the mood of patients with depression and insomnia. The results didn’t go exactly as expected, but they pave the way for a drug with unique potential for depression.

But first, investigators had to overcome an obstacle. At the time, it was believed that hypnotics could induce depression through their sedative effects. This concern was partially addressed in a 1999 study that tested whether zolpidem could alleviate the selective serotonin reuptake inhibitor [SSRI]- induced insomnia in patients who had otherwise recovered on antidepressants. Sleep problems improved with zolpidem and, much to the relief of the investigators, the sedating drug did not worsen the depression.3

Based on this result, the manufacturer of eszopiclone funded a large trial to see if depression could actually improve with its hypnotic. Five hundred and forty-five patients with depression and insomnia were randomized to receive either 3 mg eszopiclone or placebo while simultaneously starting a fluoxetine trial. As expected, the hypnotic improved sleep, but it also improved mood symptoms that were unrelated to sleep. Compared to placebo, those who received eszopiclone experienced a faster and more complete recovery from depression.4

The same group repeated the study with zolpidem ER in a large trial of a similar design. Once again, the hypnotic improved sleep, but this time there was no change in mood.4 Replication in China gave the same negative results, and last year zolpidem again failed to improve mood or reduce suicidal tendencies when added to an SSRI in a randomized trial involving patients with depression, insomnia and suicidal tendencies.4.5

Meanwhile, eszopiclone repeated its success, improving mood and insomnia in 2 additional trials, including 1 involving peri- and postmenopausal women with insomnia and depressive symptoms.6.7 Generalized anxiety disorder also improved when eszopiclone was added to an SSRI in a large manufacturer-supported trial that replicated the pivotal depression trial design of eszopiclone.8

The studies of zolpidem and eszopiclone involved many of the same researchers, who had continued this work with the idea that any sleep-enhancing hypnotic would indirectly improve mood. But to this day, eszopiclone remains the only hypnotic with distinct antidepressant effects (ramelteon has slight preventative benefits in bipolar disorder but is not known to treat depression).9 It’s hard to say if this is a statistical fluke or a real difference, as eszopiclone has not clashed with other hypnotics in depression. However, eszopiclone has a unique mechanism of action that may explain its antidepressant effects. To understand this, we have to look to the GABAA receiver.

Compared to benzodiazepines, z hypnotics have more limited effects on GABAA, which would explain why they treat sleep but not anxiety. Specifically, z hypnotics are selective for the sleep-inducing GABAA -1 subunit, while benzodiazepines have additional effects on the α-2 and -3 subunits which are involved in anxiety and depression. . But eszopiclone is an exception. It works on all subunits, and may in fact be a bit more selective for anti-anxiety drugs -2 and-3.ten This effect is enhanced by the active metabolite of eszopiclone, desmethylzopiclone, which is a selective -2 and -3 partial agonist with very little α-1 activity (this is a good thing, as it would otherwise cause a lot daytime sedation).11 In animal models, desmethylzopiclone reduced anxiety without causing sedation or motor impairment.12 Its effects in humans are not well described, but the above trials give us a clue, and the company that launched eszopiclone has patented this metabolite as a potential anxiolytic.

In this way, eszopiclone resembles benzodiazepines, which have been used to treat depression and speed up response to antidepressants in more than 3 dozen controlled trials.13 In most of these trials, their antidepressant effects were independent of their anxiolytic effects, just as eszopiclone treated symptoms of depression that were unrelated to sleep.

Despite this research, benzodiazepines are not used routinely for depression because of their risk of tolerance and abuse. These risks may also apply to eszopiclone, but the above trials are somewhat reassuring. In several of them, eszopiclone was replaced by a placebo after 2 months of treatment without loss of antidepressant and anxiolytic gains. There was also no rebound insomnia, and in some studies it stabilized sleep patterns in a way that continued after the hypnotic was stopped.4.8

Does all of this elevate eszopiclone to the level of antidepressant augmentation? May be. It has more positive results than some augmentation strategies that are endorsed by evidence-based guidelines.1 But there are 2 caveats. Firstly, eszopiclone has only been studied in patients with comorbid insomnia, but this is not a major obstacle as it is the rare patient with depression who has no difficulty sleeping (approximately 15%).14 More importantly, eszopiclone was started in tandem with an antidepressant in these augmentation trials, so we don’t know if it might make a difference when added later, after a few antidepressant failures.

The bottom line

When selecting a hypnotic in depression or generalized anxiety disorder, eszopiclone should be on the list. Treatment does not need to be long term. Most patients were able to reduce the hypnotic gradually after recovery. To enhance these chances, first expect short-term use and guide the patient to behavioral interventions for long-term sleep maintenance.

Dr Aiken is the editor of the Mood Disorders section for Psychiatric schedulesMT, editor of the Carlat Psychiatry Report and director of the Mood Treatment Center. He has written several books on mood disorders, most recently The Depression and Bipolar Workbook. It can be heard in the weekly Carlat Psychiatry Podcast with his co-host Kellie Newsome, PMH-NP. The author does not accept fees from pharmaceutical companies but receives royalties from PESI for The Depression and Bipolar Workbook and from WW Norton & Co. for Bipolar, not so much.

The references

1. Giakoumatos CI, Osser D. The Harvard South Shore Program Psychopharmacology Algorithm Project: An Update on Unipolar Nonpsychotic Depression. Harv Rev Psychiatry. 2019; 27 (1): 33-52.

2. Jordan T, Aiken C. Mirtazapine increased: Running out of rocket fuel. The Carlat Psychiatry Report. September 2019. Accessed August 27, 2021.

3. Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in depressed patients treated with SSRIs. J Clin Psychiatry. 1999; 60 (10): 668-676.

4. Kishi T, Matsunaga S, Iwata N. Efficacy and tolerability of the addition of Z drugs to antidepressant therapy for major depressive disorder: a systematic review and meta-analysis of randomized controlled trials. Eur Arch Psychiatry Clin Neurosci. 2017; 267 (2): 149-161.

5. McCall WV, Benca RM, Rosenquist PB, et al. Reducing suicidal ideation through treatment of insomnia (rest-it): a randomized clinical trial. Am J Psychiatry. 2019; 176 (11): 957-965.

6. McCall WV, Blocker JN, D’Agostino R Jr, et al. Treatment of insomnia in depressed insomniacs: effects on health-related quality of life, objective and self-reported sleep, and depression. J Clin Sleep Med. 2010; 6 (4): 322-329.

7. Joffe H, Petrillo L, Viguera A, et al. Eszopiclone improves insomnia and depressive and anxiety symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blind, placebo-controlled crossover trial. Am J Obstet Gyneco. 2010; 202 (2): 171.e1-171.e11.

8. Pollack M, Kinrys G, Krystal A, et al. Eszopiclone co-administered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Arch Gen Psychiatry. 2008; 65 (5): 551-562.

9. Kishi T, Nomura I, Sakuma K, et al. Melatonin receptor agonists – ramelteon and melatonin – for bipolar disorder: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials. Neuropsychiatrist Dis Treat. 2019; 15: 1479-1486.

10. Nutt DJ, Stahl SM. In Search of Perfect Sleep: The Continuing Evolution of GABAA Receptor Modulators as Hypnotics. J Psychopharmacol. 2010; 24 (11): 1601-1612.

11. Fleck MW. Molecular actions of (S) -desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone. J Pharmacol Exp Ther. 2002; 302 (2): 612-618.

12. Carlson JN, Haskew R, Wacker J, et al. Sedative and anxiolytic effects of the enantiomers and metabolite of zopiclone. Eur J Pharmacol. 2001; 415 (2-3): 181-189.

13. Benasi G, Guidi J, Offidani E, et al. Benzodiazepines as monotherapy in depressive disorders: a systematic review. Psychother Psychosom. 2018; 87 (2): 65-74

14. Sunderajan P, Gaynes BN, Wisniewski SR, et al. Insomnia in Patients with Depression: A STAR * D Report. CNS spectrum. 2010; 15 (6): 394-404.


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