It has been hypothesized that mirtazapine may be less sedating at doses of 30 mg/day or more compared to doses of 15 mg or less. This belief has become widespread–among patients, prescribing clinicians, and authors of review articles and textbooks. But, is this just a myth that keeps getting propagated? Let’s answer that here.
Proposed reason for this hypothesis of paradoxical sedation
Fact: Mirtazapine has a very high affinity for histamine-1 receptors, which it blocks. So, even at low doses, it is quite sedating.
Fact: At doses greater than 15 mg/day, its alpha-2 antagonism leads to increased noradrenergic activity.
Speculation: One review article (Kent, 2000) states what all the others say as well: “At higher doses, the stimulating effect of increased noradrenergic transmission counteracts some of the sedating antihistaminic effect, which results in the paradoxical clinical observation of less sedation at higher doses.
Many patients and their clinicians believe it
A quick Google search shows that this is a belief widely held by patients and prescribing clinicians.
An example of an online post by a patient: “I have read a few posts on here that 15 mg is more sedative than higher doses. My doctor also mentioned this to me…”
Many, if not most, readers were probably told in their training about this paradoxical decreased sedation at higher doses. I certainly was.
Textbook/ review article authors believe it
Here are just a few examples:
1. The American Psychiatric Association Publishing Textbook of Psychopharmacology, Fifth Edition, agrees that 30 mg/day or more of mirtazapine is less sedating than 15 mg or less. In support of this, it quotes a clinical trial (Claghorn and Lesem 1995) and a review article (Kent, 2000). More on these references below.
2. Stahl’s Essential Psychopharmacology. Prescriber’s Guide, Fifth Edition states (p. 443):
“Sedation may not worsen as dose increases. Breaking a 15-mg tablet in half and administering 7.5 mg dose may actually increase sedation.” But, no reference is provided to support this particular statement.
3. A review article (Preskorn, 2000) states: “There is some suggestion that sedation is more pronounced on low rather than high dose mirtazapine therapy (15 versus 30 mg/day or more)….Thus, mirtazapine most likely causes sedation at low doses (i.e., concentrations) by preferentially blocking the histamine-1 receptor, while at higher doses (i.e., concentrations), mirtazapine blocks the alpha-2 adrenergic receptor, which theoretically could reduce its sedating effects to some degree.
4. The review article cited by the Textbook of Psychopharmacology mentioned above (Kent 2000) states the hypothesis as if it were fact, but does not provide any evidence or references for the claim.
Why do people believe this?
1. The hypothesis regarding greater noradrenergic activity at higher doses, etc certainly sounds plausible! But, that doesn’t necessarily mean it is true.
2. Patients get used to the sedation from histamine blockade. So, if the dose is titrated up to 30 mg/day and the sedation is getting better, one may jump to the conclusion that the 30 mg dose is less sedating.
3. One review article (Preskorn, 2000) noted that, “This suggestion is principally based on the fact that there was a higher incidence of sedation in the American trials, which used lower doses, than in the European trials, which used higher doses of mirtazapine” but acknowledged that, “There may be other reasons for this finding….”
As of July 2018, I have yet to find a book or a review article that disagreed with this belief. But is it really true?
Is there ANY research evidence at all to support this idea?
I looked up the study (Claghorn and Lesem 1995) cited by the Textbook of Psychopharmacology noted above, but I found that this study did NOT show that a higher dose of mirtazapine was less sedating. Instead, what it found was that:
“Somnolence…generally appeared during the 1st week of treatment and decreased in intensity during the further course of the study while the dose of (mirtazapine) was increased.”
In my opinion, an equally likely alternative explanation for this may be that the participants got used to the sedative effect.
What kind of data would we need to authoritatively answer the question of whether or not mirtazapine is less sedating at higher doses (more than 15 mg/day)? A fixed-dose study where patients were started directly (without any titration) on either a lower or a higher dose of mirtazapine.
Unfortunately, almost all the clinical trials of mirtazapine either started at 15 mg with a possible increase in dose later OR started directly at 30 mg, but not both in the same study.
But, after much effort, I did find a study that compared single doses of mirtazapine 5 mg, mirtazapine 15 mg, mirtazapine 30 mg, diazepam 10 mg, and placebo (Sørensen et al., 1985).
A summary of the study is available below for optional reading in case you are bored and looking for something to do. For the others, my conclusion from the findings is that if you look at the different outcome measures like sleep onset/ maintenance/ duration and next day sedation, there was no clear difference between the three doses of mirtazapine.
After going through textbooks, review articles, and clinical trials, I cannot find ANY research evidence at all for the hypothesis that mirtazapine is less sedating at higher doses (more than 15 mg/day).
I also spoke to two top psychopharmacology experts who, unlike many other “experts” are also clinicians, and they both agreed that the idea that mirtazapine is less sedating at higher doses is a myth.
So, it seems to be one of the many ideas that seem plausible based on reasoning from pharmacological effects but turn out to not be supported by the (limited) empirical evidence available.
We should officially declare this hypothesis dead. R.I.P. (Rajnish Mago, MD. July 27, 2018)
Also, I propose that we use a new term–psychopharmythology–for such beliefs. 🙂 What are others? Post your views at
(Rajnish Mago, MD. July 27, 2018)
Optional to read
Summary of findings of the study by Sørensen et al. (1985)
This was a double blind, placebo-controlled clinical control of patients who were expected to be anxious or have insomnia prior to gynecological surgery. Yes, not a study in persons with a mental disorder. But, that didn’t matter, since I was only trying to find data on a specific issue.
Participants (n=250) were randomized to one of five groups and each group got a single dose of the study drug on the night before the surgery. The five groups were: mirtazapine 5 mg, mirtazapine 15 mg, mirtazapine 30 mg, diazepam 10 mg, and placebo. Sleep was measured using a sleep questionnaire and also by a visual analog scale. So, what did they find?
1. Visual analog scale for sleep
The visual analog scale for sleep involved rating from the extremes of “slept very badly” to “slept extremely well”. Mirtazapine 5 mg/ 15 mg/ 30 mg and diazepam 10 mg all improved sleep statistically significantly more than placebo did. But, there were no statistically significant differences between any of the four active drug groups.
Sometimes there can be differences in treatment groups but we may not be statistically confident that these are “real” differences (type II error). So, when no statistically significant difference is found, we should also look at the actual numbers. The improvement in sleep was very similar in the four active treatment groups, but the scores were in the following order: mirtazapine 5 mg < mirtazapine 15 mg < mirtazapine 30 mg < diazepam 10 mg. This means that even the raw numbers did not support the idea that lower doses of mirtazapine are more sedating than higher doses.
2. Sleep questionnaire
Sleep onset: Those who received mirtazapine 5 mg or 15 mg had statistically significantly less difficulty falling asleep than those who received placebo. But, the difference was not statistically significant for those who received mirtazapine 30 mg versus those who received placebo. These data could support the idea that lower doses (5 mg or 15 mg) are more sedating than higher doses (30 mg), but read on.
Sleep maintenance: Those who received mirtazapine 15 mg or 30 mg were statistically significantly less likely to wake up during the night than those who received placebo. Those who received mirtazapine 5 mg did not have this benefit compared to placebo. So, this seems to support the opposite of what we saw above for sleep onset.
Sleep duration: All three doses of mirtazapine were associated with sleeping longer compared to placebo with no statistically significant difference between the three doses So, this doesn’t go either way.
Oversleeping/ morning sedation: Only persons who received mirtazapine 30 mg were more likely than those who received placebo to need to be woken up in the morning, to wake up less refreshed, and to feel more sleepy. This supports the idea that the 30 mg dose was the most sedating.
The number of patients reporting side effects was greater in those who received mirtazapine 30 mg than those who received 5 mg or 15 mg.
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Claghorn JL, Lesem MD. A double-blind placebo-controlled study of Org 3770 in depressed outpatients. J Affect Disord. 1995 Jun 8;34(3):165-71. PubMed PMID: 7560544.
Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet. 2000 Mar 11;355(9207):911-8. Review. Erratum in: Lancet 2000 Jun 3;355(9219):2000. PubMed PMID: 10752718.
Preskorn SH. Imipramine, Mirtazapine, and Nefazodone: Multiple Targets. J Psychiatr Pract 2000 Mar;6(2):97–102. Free full-text available at http://www.preskorn.com/columns/0003.html
Sørensen M, Jørgensen J, Viby-Mogensen J, Bettum V, Dunbar GC, Steffensen K. A double-blind group comparative study using the new anti-depressant Org 3770, placebo and diazepam in patients with expected insomnia and anxiety before elective gynaecological surgery. Acta Psychiatr Scand. 1985 Apr;71(4):339-46. PubMed PMID: 4003099.
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