Mirtazapine is classified as a noradrenergic and specific serotonergic antidepressant. This study aims at objectively investigating the effects of single-dose mirtazapine on sleep of healthy volunteers.
We studied the effect of acute administration of mirtazapine (30 mg) on the sleep polysomnogram, using a double-blind, placebo-controlled design. Subjects spent 3 consecutive nights in the laboratory. First night allowed for adaptation to the laboratory and application of electroencephalogram electrodes, while the second and third nights were reserved for recording baseline sleep and studying the effects of drug treatment, respectively.
Young healthy volunteers (n=20), with a mean age of 24 years, were randomly separated into two groups: placebo (n=10) and mirtazapine (n=10).
On the third night, subjects received either placebo or mirtazapine. Comparisons were made between sleep variables from baseline values in both groups. Independent samples t-test was utilized to evaluate the differences between the two groups.
Mirtazapine improved the variables related to sleep continuity when compared with placebo. It increased the sleep efficiency index, while decreasing the number of awakenings and their duration. The slow wave sleep time was increased, while the stage 1 sleep time was decreased significantly. There was no significant effect on rapid eye movement sleep variables.
Our findings suggest that mirtazapine has considerable effects on slow wave sleep. Further studies are recommended to investigate the efficiency of antidepressants, in respect to the effects of 5-HT2 blockade on slow wave sleep.
"j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p antidepressant effects, mirtazapine also has sleep-promoting properties, both in preclinical models  and in healthy volunteers , and in patients with depression ; these effects are thought to result from high-affinity binding at 5-HT2 and histamine-1 (H1) receptors (affinity at H1 is approximately six times greater than that at 5-HT2) . Esmirtazapine maleate (Org 50081), which was in development for the treatment of insomnia, is the maleic acid salt of the S(+) enantiomer of mirtazapine. "
[Show description][Hide description] DESCRIPTION: Objective: Esmirtazapine (Org 50081), a medication that binds with high affinity to serotonin 5-HT2A and
histamine-1 receptors, was evaluated as a potential treatment for insomnia.
Methods: Adults with primary insomnia were treated with esmirtazapine (3.0 or 4.5 mg) or placebo in
this 6-week, double-blind, randomized, polysomnography (PSG) study. The end points included wake
time after sleep onset (WASO) (primary), latency to persistent sleep, and total sleep time. Patientreported
parameters were also evaluated, including sleep quality and satisfaction with sleep duration.
Residual daytime effects and rebound insomnia (sleep parameters during the single-blind placebo runout
week after treatment ended) were also assessed.
Results: Overall, 419 patients were randomized and 366 (87%) completed treatment. The median decrease
in PSG WASO (double-blind average) was 20.5 min for placebo, and 52.0 min and 53.6 min for
the 3.0- and 4.5-mg esmirtazapine groups, respectively (P < 0.0001 vs. placebo for both doses). Changes
in the other PSG parameters and in all patient-reported parameters were also statistically significant with
both doses versus placebo. Overall, 35–42% of esmirtazapine-treated patients had adverse events (AEs)
versus 29% in the placebo group. AEs were mild or moderate in most esmirtazapine-treated patients.
Furthermore, the incidence of AEs leading to discontinuation was low (<8%).
Conclusions: Six weeks of treatment with esmirtazapine was associated with consistent improvements
in objective and patient-reported parameters of sleep onset, maintenance, and duration. It was generally
well tolerated, and residual daytime effects were minimal and no rebound insomnia was observed.
"In this condition, reduction in REM sleep was associated with stronger expectations of pain relief and stronger placebo effects the next morning. Consistently, placebo responders specifically exhibited the greatest reduction in REM sleep (and correspondingly longer REM sleep latency) compared with nonresponders and compared with the normal sleep architecture generally observed in young healthy subjects, as described previously in our laboratory and others (Aslan et al., 2002; Shaw et al., 2005). Moreover, the decrease in REM sleep not only reflected individual expectations but also predicted concurrent pain unpleasantness reductions and remembered relief in the morning placebo test. "
[Show abstract][Hide abstract] ABSTRACT: The experience of a sensory event is extensively shaped by past experience and expectations. Placebo analgesia, one of the most studied models of expectation-mediated effects, can be induced by suggestion of analgesia and conditioning. The present study examined the possibility that sleep might contribute to the consolidation of new expectations and consequently influence the generation of expectation-mediated placebo effects. Strong expectations of analgesia were generated before sleep by conditioning manipulations wherein the intensity of thermal pain stimulation was surreptitiously reduced after the application of a topical placebo cream. Expectations and placebo analgesic effects were measured the following morning and compared with those of a control daytime group without sleep. Although placebo effects were observed in both groups, correlation analysis suggests that the mediating effect of expectations on placebo responses was strongest in the overnight group. Moreover, after exposure to a convincing analgesia experience, the relative duration of rapid eye movement (REM) sleep decreased in subjects showing higher analgesic expectations and placebo responses the next morning. In a third group exposed to less consistent analgesic experiences before sleep, expectations reported in the morning were comparable with other groups. However, expectations were positively correlated with REM sleep and did not emerge as a significant mediator of the analgesic effect. Together, these findings show that sleep-related processes may influence the association between expectations and placebo analgesia and that REM sleep can predict placebo-induced expectations of pain relief. However, equivocal previous experience with treatments may significantly alter the relationship between relief expectation, REM sleep, and placebo effects.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2009; 29(38):11745-52. DOI:10.1523/JNEUROSCI.1224-09.2009 · 6.34 Impact Factor
"The increase in SWS did not relate to any changes in daytime performance (van Laar et al., 2001). Similar to the findings with ritanserin, the noradrenergic, specific serotonergic drug mirtazapine also promotes subjective (Ridout et al., 2003) and objective measures of sleep such as the duration of SWS (Aslan et al., 2002), possibly via a 5-HT 2A receptor-mediated mechanism. One study reported that selfrated sleep duration in the first night following evening intake of 30 mg mirtazapine increased by 58 min (Wingen et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Serotonin [5-hydroxytryptamine (5-HT)] and 5-HT receptors are involved in sleep and in waking functions such as cognition and mood. Animal and human studies support a particular role for the 5-HT2A receptor in sleep, which has led to renewed interest in this receptor subtype as a target for the development of novel pharmacological agents to treat insomnia. Focusing primarily on findings in healthy human volunteers, a review of the available data suggests that antagonistic interaction with 5-HT2A receptors (and possibly also 5-HT2C receptors) prolongs the duration of slow wave sleep and enhances low-frequency (< 7 Hz) activity in the sleep electroencephalogram (EEG), a widely accepted marker of sleep intensity. Despite certain differences, the changes in sleep and the sleep EEG appear to be remarkably similar to those of physiologically more intense sleep after sleep deprivation. It is currently unclear whether these changes in sleep are associated with improved vigilance, cognition and mood during wakefulness. While drug-induced interaction with sleep must be interpreted cautiously, too few studies are available to provide a clear answer to this question. Moreover, functional relationships between sleep and waking functions may differ between healthy controls and patients with sleep disorders. A multimodal approach investigating subjective and objective aspects of sleep and wakefulness provides a promising research avenue for shedding light on the complex relationships among 5-HT2A/2C receptor-mediated effects on sleep, the sleep EEG, cognition and mood in health and various diseases associated with disturbed sleep and waking functions.
European Journal of Neuroscience 06/2009; 29(9-9):1795-1809. DOI:10.1111/j.1460-9568.2009.06718.x · 3.18 Impact Factor
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