Mirtazapine is a topical example of a drug whose mechanism and potency of action may be elucidated by serotonin toxicity data. It is also an example of how drugs become approved as an antidepressants when there is no 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’).

Mirtazapine is advertised to doctors as a dual action drug. The spin doctors acronym is NaSSA: ‘noradrenergic (Na) and specific serotonergic (SS) antidepressant’. One of my a recent 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. Recently available data concerning serotonin toxicity (ST) may clarify the picture, especially whether it is a dual action NaSSA (‘noradrenergic and specific serotonergic antidepressant’) in humans, which is still heavily promoted (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 hyperpyrexia 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 ability to induce ST (2,14).

MIRT has not been shown to be 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.

Differences there might be 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 has been shown to be strongly associated with sedation and weight gain (15). The main significant difference is for noradrenaline reuptake inhibitor (NRI) potency, MIRT being weaker than MIAN. The key observation is that, paradoxically, MIRT is less potent at A2 receptors. This result contradicts what is required by the key claimed difference between the drugs that is supposed to justify the rationale for marketing mirtazapine as an improvement over mianserin.

Microdialysis studies in the rat have been adduced to support claims re 5-HT (16-18), but again more recent independent research fails to corroborate the initial ‘Organon’ findings (19-21).

Systematic data from three case series of over-doses in humans all demonstrate no serotonergic symptoms or ST. All reported cases of MIRT over-dose or toxicity are referenced and analysed in my review, no adequately documented case report of typical ST with MIRT alone exists.

The main finding of my review is that the evidence for serotonergic effects of the analogues, MIRT and MIAN, is inadequate and that initial evidence from the pharmaceutical company ‘Organon’, of rather small changes, has not been replicated by independent researchers. The key claimed difference between the two analogues in A2 potency never existed and has also not been replicated by independent researchers. The initial claims could be politly described as ‘a triumph of hope over experience’: hope of what is the key question. The weight of current evidence concerning the receptor affinity for A2 receptors is that it is the same for both drugs, or that MIRT is weaker, rather than stronger.

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 UK academics (especially) 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, frequently repeated assertions that mirtazapine has serotonergic action (and is therefore dual action) all rely on misinterpreted, weak, erroneous and unreplicated evidence. More bad science.

References

1. Gillman, PK, A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Human Psychopharmacology: Clinical and Experimental, 2006. 21: p. 117-25.

2. Gillman, PK, A Review of Serotonin Toxicity Data: Implications for the Mechanisms of Antidepressant Drug Action. Biological Psychiatry, 2006. 59: p. 1046-51.

3. Nierenberg, AA, Do some antidepressants work faster than others? Journal of Clinical Psychiatry, 2001. 62(Suppl 15): p. 22-5.

4. Schatzberg, AF, Pharmacological principles of antidepressant efficacy. Human Psychopharmacology: Clinical and Experimental, 2002. 17 Suppl 1: p. S17-22.

5. Norman, TR, 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, PV, et al., Dual monoamine modulation for improved treatment of major depressive disorder. Journal of Clinical Psychopharmacology, 2003. 23(1): p. 78-86.

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

8. Montgomery, SA, New developments in the treatment of depression. Journal of Clinical Psychiatry, 1999. 60(Suppl 14): p. 10-5.

9. Nutt, DJ, Efficacy of mirtazapine in clinically relevant subgroups of depressed patients. Depress 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, HJ, Are all antidepressants the same? Journal of Clinical Psychiatry, 2000. 61(Suppl 6): p. 24-8.

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

13. Gupta, RK, Tiller, JW, and Burrows, GD, Dual action antidepressants and some important considerations. Australian and New Zealand Journal of Psychiatry, 2003. 37(2): p. 190-5.

14. Gillman, PK, Amitriptyline: dual-action antidepressant? Journal of Clinical Psychiatry, 2003. 64: p. 1391.

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

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

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

19. Millan, MJ, 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.

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

21. Bengtsson, HJ, 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 Archives of Pharmacology, 2000. 362(4-5): p. 406-12.