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-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor 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-HT3 receptors in eliciting these differences. The 5-HT3 receptor antagonist ondansetron significantly reduced paroxetine's acute effects on ROL, while the 5-HT3 receptor agonist SR57227A significantly increased vortioxetine's 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-HT3 receptor antagonism in mitigating these differences.

Keywords: Sleep; antidepressant; serotonin; vortioxetine.

Figure 1.

Time spent in rapid eye movement (REM) (min) for vortioxetine and paroxetine before and after acute drug administration on day 1 and for 24 h on days 3 and 7. Data shown reflect mean±standard error of the mean (SEM) of the sum of time spent in REM for each 30-minute epoch after drug administration (marked with a red triangle on x-axis at 3 h after lights on) for day 1 or the whole light phase for all other days. The x-axis is plotted using zeitgeber time, which refers to the time relative to the light/dark schedule with time 0 corresponding to lights on and 12 to lights off. Paroxetine and its respective control, n=8 for all days; vortioxetine chow group had n=7, 7, 6, and 5, and control group had n=7, 6, 6, and 5 for days 1, 3, 7, and 10 respectively due to electroencephalographic (EEG) device failure. High variance on Day 10 (d) in the vehicle group is due to this lower animal number, however no change was noted in the vortioxetine group compared to day 7 (c). Significance was determined by multifactorial analysis of variance (ANOVA) with a Fisher LSD post-hoc test for multiple timepoint comparisons (*p<0.05; Figure 1(a), Day 1: vortioxetine (VOR) vs vehicle (VEH) F(46, 595)=3.0618, p<0.001; paroxetine (PAR) F(46, 754)=4.0164, p<0.001; Figure 1(b), Day 3: VOR vs VEH F(46, 595)=0.85, p=0.75; PAR vs VEH F(46, 754)=1.9986, p<0.001; Figure 1(c), Day 7: VOR vs VEH F(46, 542)=1.5352, p=0.016; PAR vs VEH F(46, 754)=1.8757, p<0.001; Figure 1(d), Day 10: VOR vs VEH F(46, 436)=1.3977, p=0.05; PAR vs VEH F(46, 754)=1.8572, p<0.001).

Figure 2.

Effect of vortioxetine and paroxetine on rapid eye movement (REM), non-rapid eye movement (NREM), wake (quiet wake and active wake), and REM/NREM ratio during 12-hour light phase (06:00–18:00). Data shown reflect mean±standard error of the mean (SEM) of the sum of time spent in each stage for each 30-minute epoch after drug administration for day 1 or the whole light phase for all other days. Each treatment group was compared to its respective vehicle control for each day separately (*p<0.05; **p<0.01; ***p<0.005).

Figure 3.

Effect of vortioxetine and paroxetine on rapid eye movement (REM), non-rapid eye movement (NREM), wake (quiet wake and active wake), and REM/NREM ratio during 12-hour dark phase (18:00–06:00). Data shown reflects mean± standard error of the mean (SEM) of the sum of time spent in each stage for each 30-minute epoch after drug administration for day 1 or the whole light phase for all other days. Each treatment group was compared to its respective vehicle control for each day separately (*p<0.05; **p<0.01; ***p<0.005).

Figure 4.

The mean (±standard error of the mean (SEM)) number of transitions from non-rapid eye movement (NREM) to wake during days 1, 3, 7 and 10 and calculated for 24 h after drug administration for day 1 and the time-matched 24-hour period for all other days. Each treatment group was compared to its respective vehicle control for each day separately (*p<0.05; **p<0.01; ***p<0.005).

Figure 5.

Rapid eye movement (REM) onset latency following acute administration of paroxetine alone and in combination with ondansetron shows that the 5-HT₃ antagonist reduced REM onset latency (*p<0.05, unpaired t-test). Ondansetron alone was not different than vehicle (p=0.331). Paroxetine was significantly greater than vehicle (p<0.001). Ondansetron in combination with paroxetine did not reach vehicle control levels (p<0.01, unpaired t-test), but did significantly reduce REM onset from paroxetine alone (p=0.004, unpaired t-test).

Figure 6.

Rapid eye movement (REM) onset latency following acute administration of vortioxetine alone and in combination with SR57227A shows that the 5-HT₃ agonist increased REM onset latency (*p<0.05, unpaired t-test). SR57227A alone induced a significant delay in REM onset compared to vehicle (p<0.001). Vortioxetine alone was not different than vehicle (p=0.228), however SR57227A in combination with vortioxetine significantly delayed (increased) REM onset compared to vortioxetine alone (p=0.003, unpaired t-test).