The history of mianserin and mirtazapine: study of their neurochemical activity and determination of their position in the classification of antidepressants

The paper systematizes the history of studying the neurochemical activity of mianserin and mirtazapine. The concept of the development of the antidepressant effect of these drugs, by stimulating the release of norepinephrine into the synaptic cleft, is shown to have gained unanimously acceptance. The data on manifestation of their thymoleptic effect due to stimulation of the release of serotonin into the synaptic cleft have been disputed. Other neurochemical theories of the development of the antidepressant activity of mianserin and mirtazapine have been unproven or rejected. The history of identifying the position of mianserin and mirtazapine in the classification of antidepressants has been generalized. The paper shows the ambiguity of approaches to this issue. As turned out, the legality of using the term «noradrenalinergic and specific serotonergic antidepressant» has been criticized. Analysis of historical facts has identified that it is rational to assign mianserin and mirtazapine to one neurochemical group and its designation by the term «norepinephrine and (presumably) serotonin release stimulators – α2-adrenergic receptor and serotonin 5-HT2 receptor blockers».

mianserin, mirtazapine, α2-adrenergic receptors, serotonin 5-HT2 receptors, norepinephrine, serotonin, α2-adrenergic receptor blockers, noradrenalinergic and specific serotonergic antidepressants, norepinephrine and serotonin release stimulators – α2-adrenergic and serotonin 5-HT2 receptor blockers, history of antidepressants

1. Marshall RJ. The pharmacology of mianserin – an update. Br J Clin Pharmacol. 1983;15 Suppl 2:263S-268S.

2. Baldessarini R. Medikamentoznoe lechenie depressii i trevozhnykh rasstroistv. V kn.: Klinicheskaya farmakologiya po Gudmanu i Gilmanu. Moskva: Praktika; 2006. S. 350-82. In: Klinicheskaya farmakologiya po Gudmanu i Gilmanu [Clinical pharmacology by Goodman and Gilman]. Moscow: Praktika; 2006. P. 350-82.

3. Maj J. Serotoninergic mechanisms of antidepressant drugs. Gesundheitswesen. 2015 Nov; 77(11):880. doi: 10.1055/s-0035-1563376. Epub 2015 Nov 25.

4. Pettibone DJ, Pflueger AB. Effects of methiothepin and lysergic acid diethylamide on serotonin release in vitro and serotonin synthesis in vivo: possible relation to serotonin autoreceptor function. J Neurochem. 1984 Jul; 43(1):83-90.

5. Raiteri M, Maura G, Versace P. Functional evidence for two stereochemically different alpha-2 adrenoceptors regulating central norepinephrine and serotonin release. J Pharmacol Exp Ther. 1983 Mar;224(3):679-84.

6. de Boer TH, Nefkens F, van Helvoirt A, et al. Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan. J Pharmacol Exp Ther. 1996 May; 277(2):852-60.

7. Nagayasu K, Kitaichi M, Nishitani N, et al. Chronic effects of antidepressants on serotonin release in rat raphe slice cultures: high potency of milnacipran in the augmentation of serotonin release. Int J Neuropsychopharmacol. 2013 Nov; 16(10):2295-306. doi: 10.1017/S1461145713000 771. Epub 2013 Aug 7.

8. de Boer TH, Maura G, Raiteri M, et al. Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers. Neuropharmacology. 1988 Apr;27(4):399-408.

9. Westenberg HG. Pharmacology of antidepressants: selectivity or multiplicity? J Clin Psychiatry. 1999;60 Suppl 17:4-8.

10. de Boer T. The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission. Int Clin Psychopharmacol. 1995 Dec;10 Suppl 4:19-23.

11. de Boer T. The pharmacologic profile of mirtazapine. J Clin Psychiatry. 1996;57 Suppl 4:19-25.

12. Millan MJ, Gobert A, Rivet JM, 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. Eur J Neurosci. 2000 Mar;12(3):1079-95.

13. Bengtsson HJ, Kele J, Johansson 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 Nov;362(4-5):406-12.

14. Gillman PK. A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status. Hum Psychopharmacol. 2006 Mar;21(2):117-25.

15. Gillman PK. Mirtazapine, a paradigm of mediocre science in a deficient regulatory environment. https://psychotropical.com/mirtazapine-a-paradigm-of-mediocre-science/

16. Pinder RM. Designing a new generation of antidepressant drugs. Acta Psychiatr Scand Suppl. 1997;391:7-13.

17. Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999;60 Suppl 4:4-11.

18. Syunyakov TS. Affective disorders are an interdisciplinary problem. New opportunities in diagnostics, treatment and prevention (review of conference materials). Psikhiatriya i psikhofarmakoterapiya. 2012;14(1):69-72. (In Russ.).

19. Clinical use of modern antidepressants]. Saint-Petersburg: MIA; 1995. 564 p.

20. Yanichak FD, Devis DM, Preskorn ShKh, et al. Printsipy i praktika psikhofarmakoterapii [Principles and practice of psychopharmacotherapy]. Kiev: Nika-Tsentr; 1999. 728 p.

21. Montgomery S. Why do we need new and improved antidepressants? Medicographia. 2005;27(3):213-6.

22. Raevskii KS. Antidepressants: neurochemical aspects of the mechanism of action. Psikhiatriya i psikhofarmakoterapiya. 2001;3(5):162-6. (In Russ.)

23. Andrusenko MP. Antidepressants: correlation of neurochemical properties and clinical effects in the treatment of depression. Psikhiatriya i psikhofarmakoterapiya. 2005;7(5):273-9. (In Russ.)

24. Mosolov SN. Pharmacotherapy of mental disorders. In: Gofman AG, editor. Psikhiatriya: spravochnik prakticheskogo vracha [Psychiatry: a Handbook of a practical physician]. 2nd ed. Moscow: MEDpress-Inform; 2010. P. 371-445.

25. Aleksandrovskii YuA, Neznanov NG, editors. Psikhiatriya: natsional'noe rukovodstvo [Psychiatry: national guidelines]. Moscow: GEOTAR-Media; 2018. 1008 p.

26. Kozlovskii VL. Psikhotropnye preparaty: ot teorii k praktike [Psychotropic drugs: from theory to practice]. Saint-Petersburg: Spetslit; 2018. 175 p.

27. Akhapkin RV, Bukreeva ND, Vazagaeva TI, et al. The project of clinical recommendations «Depressive episode, Recurrent depressive disorder». Rossiiskoe obshchestvo psikhiatrov. 2019. 67 p.