Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism

Steven C. Leiser, Deborah Iglesias-Bregna, Ligia Westrich, Alan L. Pehrson, Connie Sanchez

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT 5-HTand 5-HTreceptor antagonism, 5-HTreceptor partial agonism, and 5-HTreceptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80-90% SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HTreceptors in eliciting these differences. The 5-HTreceptor antagonist ondansetron significantly reduced paroxetines acute effects on ROL, while the 5-HTreceptor agonist SR57227A significantly increased vortioxetines acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HTreceptor antagonism in mitigating these differences.

Original languageEnglish
Pages (from-to)1092-1105
Number of pages14
JournalJournal of Psychopharmacology
Volume29
Issue number10
DOIs
StatePublished - 24 Oct 2015

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Receptors, Serotonin, 5-HT3
Paroxetine
Antidepressive Agents
Rodentia
Sleep
Pharmacology
REM Sleep
Electroencephalography
Serotonin
Eye Movements
vortioxetine
Ondansetron
Sleep Stages
Electromyography
Locomotion
Healthy Volunteers

Keywords

  • Sleep
  • antidepressant
  • serotonin
  • vortioxetine

Cite this

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title = "Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism",
abstract = "Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT 5-HTand 5-HTreceptor antagonism, 5-HTreceptor partial agonism, and 5-HTreceptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80-90{\%} SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HTreceptors in eliciting these differences. The 5-HTreceptor antagonist ondansetron significantly reduced paroxetines acute effects on ROL, while the 5-HTreceptor agonist SR57227A significantly increased vortioxetines acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HTreceptor antagonism in mitigating these differences.",
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Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture : Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism. / Leiser, Steven C.; Iglesias-Bregna, Deborah; Westrich, Ligia; Pehrson, Alan L.; Sanchez, Connie.

In: Journal of Psychopharmacology, Vol. 29, No. 10, 24.10.2015, p. 1092-1105.

Research output: Contribution to journalArticle

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