RESEARCH MONOGRAPH · KDC-MN-210
Mirtazapine
Mirtazapine (Remeron) does not work like an SSRI at all. Rather than blocking the serotonin pump, it blocks a brake on the nerve cells that release serotonin and norepinephrine, which causes those neurons to fire more freely. It also strongly blocks the histamine receptor that controls sleep and appetite, which is why patients on it tend to sleep deeply and gain weight. Organon brought it to market in 1996. Clinicians often reach for it when a patient needs sleep restoration or has lost weight from depression, since both effects can be therapeutic in that context. The trade-off is that the same antihistamine action makes morning grogginess common at low doses, and the appetite stimulation is unwelcome for some. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Tetracyclic atypical antidepressant (NaSSA)
A noradrenergic and specific serotonergic antidepressant; a tetracyclic with strong H1 antihistamine activity producing pronounced sedation and appetite stimulation.
Abstract
Mirtazapine ((R/S)-1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine; CAS 85650-52-8; molecular formula C17H19N3; molecular weight 265.36) is a tetracyclic NaSSA (noradrenergic and specific serotonergic antidepressant) developed at Organon and approved by the FDA in 1996 under the trade name Remeron. Mechanism distinguishes the compound from the SSRI/SNRI class: rather than inhibiting transporters, mirtazapine antagonizes presynaptic alpha-2 adrenergic autoreceptors and heteroreceptors, increasing both norepinephrine and serotonin release. Concurrent 5-HT2A and 5-HT2C antagonism redirects the released serotonin preferentially to 5-HT1A receptors. Strong H1 histamine antagonism (Ki approximately 0.14 nM, comparable to first-generation antihistamines) produces sedation and weight gain, often dose-limiting at higher doses. The compound has minimal activity at muscarinic, dopaminergic, or transporter sites. Plasma half-life is 20 to 40 hours; metabolism is via CYP2D6, CYP3A4, and CYP1A2. Approved for major depressive disorder; widely used off-label for insomnia and as an appetite stimulant. Used as a reference compound in alpha-2 adrenergic and 5-HT2 receptor pharmacology.
Mechanism of action
Alpha-2 adrenergic auto/heteroreceptor antagonism increasing 5-HT and NE release; 5-HT2A/2C and H1 antagonism redirecting serotonin to 5-HT1A. No transporter inhibition.
Reported research dose ranges
Reported research dose ranges in the literature.
References
- de Boer T. The pharmacologic profile of mirtazapine. J Clin Psychiatry 1996.
- Anttila SAK, Leinonen EVJ. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001.
- Croom KF, et al. Mirtazapine: a review of its use in major depression. Drugs 2009.
Read the full monograph
Available as a research-use-only PDF download. Note: PDFs for newly added compounds may take a few hours to propagate after this article was published.
The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.