6.1. Mirtazapine: The greatest lie of all?

These commentaries are based on Dr Gillman’s peer reviewed scientific papers, see Publications

I wrote my criticism of this drug decades ago, and nothing has changed, except that the evidence for my initial opinions has become more substantial — people are still using it as an ‘antidepressant’ when it is just an anti-histamine.  Observing current marketing conventions for new drugs, it would be valid to refer to this drug as a highly specific H1 antagonist, since that property is 100 times more potent than any other property it possesses, and a thousand times more potent than its supposed beneficial alpha-2 antagonism.

Frankly, the psychopharmacology community were both negligent and naïve in accepting so readily the utter guff that was promulgated about this drug when it was marketed.

This overlaps a bit with the other commentary on Mirtazapine, but it is worth preserving anyway.

Old note (with minor emendations)

Mirtazapine is a drug whose mechanism and potency of action is elucidated by serotonin toxicity data.  It is also an example of how drugs become approved as an antidepressant when there is no plausible putative mechanism for their actions and no quality scientific evidence of efficacy.  Since it is being promoted to doctors as a dual action drug (one proposed to raise both serotonin and noradrenaline) it is instructive to consider this question in detail because it illustrates aspects of current debates concerning pharmaceutical companies, scientific integrity, bias in academia, refereeing standards of journals and related issues* (see ‘Mirtazapine, a paradigm of mediocre science in a deficient regulatory environment’).

*I have written various other commentaries pertinent to this issue since

Mirtazapine has been advertised to doctors as a ‘dual-action’ drug.  The spin doctors’ acronym is NaSSA: ‘noradrenergic (Na) and specific serotonergic (SS) antidepressant’ — pure bullshit.  One of my papers examines the evidence relating to possible serotonergic effects of mirtazapine specifically [1], another looks at how serotonin toxicity data can be used to help us understand the serotonin related effects of all drugs [2].

Mirtazapine (MIRT) and its analogue mianserin (MIAN), have mechanisms and potency of action that have never been clear.  Data concerning serotonin toxicity (ST) clarifies the picture, especially about supposed dual-action in humans, which has always been heavily promoted, often by the usual well remunerated KOLs [3-13].

Recent work establishes the association between serotonergic effects and elevation of serotonin in experiments with rats.  There is also good evidence to extrapolate that to ST in humans [2].  Increasing levels of serotonin are associated with increasing serotonergic side effects, and as they become further elevated, with toxicity, culminating in hyperthermia and death.  The degree to which different drugs exhibit these effects in humans correlates well with their capacity to elevate serotonin levels in rats.

The clinical efficacy of particular drugs in specific conditions, e.g. serotonin reuptake inhibitors (SRIs) in obsessive compulsive disorder (OCD), has been used to correlate alterations in serotonin levels induced by amitriptyline and clomipramine (CMI) with clinical efficacy, and the ability to induce ST [1, 14].

MIRT is not effective in obsessive compulsive disorder (OCD) or cataplexy, does not affect platelet serotonin, does not cause serotonergic side effects, or toxicity in over-dose, and does not cause ST if mixed with MAOIs.  This indicates clearly that MIRT is not altering serotonin levels in the brain to a clinically significant or meaningful extent.

Possible differences between mianserin and its 6-aza analogue, mirtazapine, may be demonstrated by examining affinity data from more recent research.  MIRT is less, rather than more, potent as an A2 antagonist than MIAN.  The most potent property of both drugs is histamine receptor H1 antagonism, which is strongly associated with sedation and weight gain [15].  The main significant difference is for noradrenaline reuptake inhibitor (NRI) potency, MIRT being even weaker than MIAN.  The key observation is that, paradoxically, MIRT is less potent at A2 receptors.  This is further substantiated by this result that was not available to me at the time of my review [16] which shows Mirt has Ki 20 vs 5 for mianserin!

These results directly contradict what is required by the key claimed difference between the drugs, that was supposed to justify the rationale for marketing mirtazapine as an improvement over mianserin.

Micro-dialysis studies in the rat have been adduced to support claims re 5-HT, [17-19] but again more recent independent research fails to corroborate the initial ‘Organon’ findings [20-22].

Systematic data from three case series of over-doses in humans all demonstrate neither serotonergic symptoms of any sort, nor ST.  All reported cases of MIRT over-dose or toxicity are referenced and analysed in my review, no adequately documented case report of ST with MIRT (or MIAN) alone exists.

The main finding of my review is that reliable evidence for serotonergic effects of the analogues, MIRT and MIAN, is non-existent.  The evidence from the pharmaceutical company ‘Organon’, of insignificant changes, has not been replicated by independent researchers.  The key claimed difference between the two analogues in A2 potency never existed.  The initial claims are best described as ‘a triumph of hope over experience’: hope of what, is the key question.

There has been uncritical acceptance of the proposed mechanism of action of mirtazapine and never a foundation of independently replicated scientific evidence to support the ideas put forward.  In my opinion academics should be hanging their heads in shame over their role in this story and their passive collusion in not challenging this third-rate data.

In summary, the frequently repeated suggestions that mirtazapine has serotonergic action (and is therefore dual action) all rely on weak and un-replicated evidence.



1. Gillman, P.K., A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status. Human Psychopharmacology. Clinical and Experimental, 2006. 21(2): p. 117-25.

2. Gillman, P.K., A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biological Psychiatry, 2006. 59(11): p. 1046-51.

3. Nierenberg, A.A., Do some antidepressants work faster than others? J Clin Psychiatry, 2001. 62(Suppl 15): p. 22-5.

4. Schatzberg, A.F., Pharmacological principles of antidepressant efficacy. Hum Psychopharmacol, 2002. 17 Suppl 1: p. S17-22.

5. Norman, T.R., Mechanism of action of mirtazapine: dual action or dual effect? Australian and New Zealand Journal of Psychiatry, 2004. 38(4): p. 267-9.

6. Tran, P.V., et al., Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacol, 2003. 23(1): p. 78-86.

7. Blier, P., Possible neurobiological mechanisms underlying faster onset of antidepressant action. J Clin Psychiatry, 2001. 62(Suppl 4): p. 7-11; discussion 37-40.

8. Thompson, C., Mirtazapine versus selective serotonin reuptake inhibitors. Journal of Clinical Psychiatry, 1999. 60(Suppl 17): p. 18-22; discussion 46-8.

9. Nutt, D.J., Efficacy of mirtazapine in clinically relevant subgroups of depressed patients. Depression and Anxiety, 1998. 7(Suppl 1): p. 7-10.

10. Kasper, S., et al., A risk-benefit assessment of mirtazapine in the treatment of depression. Drug Safety, 1997. 17(4): p. 251-64.

11. Moller, H.J., Are all antidepressants the same? J Clin Psychiatry, 2000. 61(Suppl 6): p. 24-8.

12. Westenberg, H.G., Pharmacology of antidepressants: selectivity or multiplicity? Journal of Clinical Psychiatry, 1999. 60 (Suppl 17)( ; discussion 46-8): p. 4-8.

13. Gupta, R.K., J.W. Tiller, and G.D. Burrows, Dual action antidepressants and some important considerations. Australian and New Zealand Journal of Psychiatry, 2003. 37(2): p. 190-5.

14. Gillman, P.K., Amitriptyline: Dual-Action Antidepressant? Journal of Clinical Psychiatry, 2003. 64: p. 1391.

15. Kroeze, W.K., et al., H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology, 2003. 28(3): p. 519-26.

16. Fernandez, J., et al., Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents. J Med Chem, 2005. 48(6): p. 1709-12.

17. de Boer, T., F. Nefkens, and A. Van Helvoirt, The alpha 2-adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo. European Journal of Pharmacology, 1994. 253(1-2): p. R5-6.

18. Haddjeri, N., P. Blier, and C. de Montigny, Noradrenergic modulation of central serotonergic neurotransmission: acute and long-term actions of mirtazapine. International Clinical Psychopharmacology, 1995. 10 Suppl 4: p. 11-7.

19. Haddjeri, N., P. Blier, and C. de Montigny, Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission. Journal of Affective Disorders, 1998. 51(3): p. 255-66.

20. Millan, M.J., et al., Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram. European Journal of Neuroscience, 2000. 12(3): p. 1079-95.

21. Nakayama, K., T. Sakurai, and H. Katsu, Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation. Brain Research Bulletin, 2004. 63(3): p. 237-41.

22. Bengtsson, H.J., et al., Interaction of the antidepressant mirtazapine with alpha2-adrenoceptors modulating the release of 5-HT in different rat brain regions in vivo. Naunyn Schmiedebergs Arch Pharmacol, 2000. 362(4-5): p. 406-12.

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Dr Ken Gillman