Proceedings of UCLA Healthcare

-VOLUME 19 (2015)-

CLINICAL VIGNETTE

Dose-Dependent Sedating and Stimulating Effects of Mirtazapine

Case Report

A 90-year-old woman was hospitalized for failure to thrive, low plasma concentrations and increased sedation at low doses
deconditioning, fatigue, and chronic intractable lower of mirtazapine.6 At higher doses, the antihistamine activity is
extremity pain from a leg wound. She complained of insomnia offset by increased noradrenergic transmission, which reduces
and received different sleeping pills on different days and was its sedating effect.4,7 This was confirmed in a German study,
finally given a dose of mirtazapine 7.5 mg. She subsequently which noted negative correlations between plasma mirtazapine
became somnolent and was barely arousable the next day. concentration and both sedation and duration of sleep in the
Workup for delirium was non-revealing. Mirtazapine was first week of treatment.8
discontinued, and her sedation progressively resolved.
In our case, 7.5 mg of daily mirtazapine was excessively
Discussion sedating to our 90-year-old hospitalized patient. At the 15 mg
dose, the norepinephrine effects of mirtazapine would have
Mirtazapine is a widely used antidepressant for major likely reduced the sedating effects of histamine and serotonin.
depressive disorder and has a unique pharmacologic profile. In a comparison of clinical trials of mirtazapine in Europe
Its well-known ability to promote sleep, and occasionally versus the United States, less sedation was seen in the
cause weight gain, makes it a good option to address the European studies that used higher initial doses of mirtazapine
insomnia, anorexia, and weight loss that often accompany (15-20 mg) than in the US studies that used lower initial doses
depression in older adults. (5-10 mg).9 Therefore in order to reduce sedation, it has been
suggested that mirtazapine be initiated at higher doses as high
Mirtazapine has multiple pharmacological actions that as 30 mg or more daily in younger patients.4,10,11
contribute to its effects on sleep. It produces its antidepressant
effects primarily by antagonizing alpha 2 adrenergic receptors It should be noted, however, that although sedation is an
on both norepinephrine and serotonin (5-HT) presynaptic expected effect of the agent, it is usually most noticeable in
axons, while also antagonizing post-synaptic 5-HT subtype 2 the first few weeks of therapy and diminishes with continued
and 3 receptors, which leads to increased release of treatment.12 Tolerance to mirtazapine’s histaminic effects
norepinephrine and enhanced specific (5-HT1 only) serotonin develops 7-10 days after beginning treatment.4 This was
activity.1 Although pre-synaptic activity on serotonin axons confirmed in a placebo-controlled study with severe long-term
increases serotonin release, the antagonizing of type 2 and 3 sedation occurring in only 1 of 49 treated patients.13
post-synaptic serotonin receptors leads to selective
enhancement of only the type 1 receptor activity. Unlike other A recent systematic review of studies of mirtazapine’s
antidepressants, mirtazapine does not employ serotonin or sustained effects on sleep in major depressive disorder found
norepinephrine reuptake blockade as its main pharmacologic mirtazapine to consistently improve sleep efficiency, total
action. sleep time and sleep quality.4 In addition, specific
improvements in sleep in patients treated with mirtazapine
Serotonin has a complex effect on sleep and its array of were better than those on other antidepressants.4
receptor subtypes are involved in different effects. 5-HT 2a
and 5-HT 2c receptors play a role in reducing REM and slow Mirtazapine effects on sleep quality include shortened time-to-
wave sleep; thus, antagonism of these receptors promotes onset of sleep, reduced stage I sleep, increased deep sleep,
sleep.2-4 Mirtazapine at low doses also has a high affinity for increased latency of REM sleep, reduced nighttime
the histamine-1 receptor.5 Both the histaminic and awakening,14 and improved sleep continuity while preserving
serotonergic effects contribute to increased sedation. sleep architecture.15 These sleep-promoting effects of
However, the dose of mirtazapine is critical to its effects on mirtazapine have to be balanced against its risk for excessive
sleep. At low doses, mirtazapine preferentially blocks the sedation; the latter is more pronounced at lower doses and in
histamine receptor, since at lower plasma concentrations it has the first weeks of therapy.
a higher affinity to histamine receptors than to serotonergic
receptors. Consequently, there is increased duration of sleep at
In contrast to the risk of excessive sedation at low doses, 5. Anttila SA, Leinonen EV. A review of the
mirtazapine at higher doses can be over-stimulating in older pharmacological and clinical profile of mirtazapine. CNS
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