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Mechanism of Action of Trazodone: a Multifunctional Drug

Abstract

Multifunctional drugs are those with more than one therapeutic mechanism. Trazodone is a multifunctional drug with dose-dependent pharmacologic actions. That is, it has hypnotic actions at low doses due to blockade of 5-HT2A receptors, as well as H1 histamine receptors and α1 adrenergic receptors. Higher doses recruit the blockade of the serotonin transporter (SERT) and turn trazodone into an antidepressant. Although trazodone has traditionally been used as a low dose hypnotic, a new controlled release formulation that has the potential to improve the tolerability of high doses may provide an opportunity to revisit this multifunctional drug as an antidepressant as well.

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2. DH Kim , MJ Maneen , SM Stahl . Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia. Neurotherapeutics. 2009;6:7885.

3. CJ Van der Schyf , MB Youdim . Multifunctional Drugs as Neurotherapeutics. Neurotherapeutics. 2009;6:13.

4. MJ Millan , Dual and triple acting agents for treating core and comorbid symptoms of major depression: novel concept, new drugs. Neurotherapeutics. 2009;6:5377.

6. B Cusack , A Nelson , E Richelson . Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology(Berl). 1994;114:559564.

7. M Tatsumi , K Groshan , RD Blakely , E Richelson . Pharmacological profile of anti-depressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340:249258.

8. E Richelson , T Souder . Binding of antipsychotic drugs to human brain receptors focus on newer generations compounds. Life Sci. 2000;68:2939.

11. AR Knight , A Misra , K Quirk , et al.Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004;370:114123.

12. MJ Millan . Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie. 2005;60:441460.

13. A Dekeyne , C Mannoury la Cour , et al.S32006, a novel 5HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology(Berl). 2008;199:549568.

14. S Rosenzweig-Lipson , A Sabb , G Stack , et al.Antidepressant like effects of the novel, selective 5HT2C receptor agonist WAY-163909 in rodents; Psychopharmacology(Berl). 2007;192:159170

15. SM Stahl . Novel mechanism of antidepressant action: norepinephrine and dopamine disinhibition (NDDI) plus melatonergic agonism. Int J Neuropsychopharmacol. 2007;10:575578.

16. M Maes , H Westenberg , E Vandoolaeghe , et al.Effects of trazodone and fluoxetine in the treatment of major depression: therapeutic pharmacokinetic and pharmacodynamic interactions through formation of meta-chlorophenylpiperazine. J Clin Psychopharmacol. 1997;17:358364.

17. RH Raffa , RP Shank , JL Vaught . Etioperidone, trazodone and mCPP: in vitro and in vivo identification of serotonin 5HT1A (antagonistic) activity. Psychopharmacology(Berl). 1992;108:320326.

18. P Schoeffter , D Hoyer . Interaction of arylpiperazines with 5HT1A, 5HT1B, 5HT1C and 5HT1D receptors: do discriminatory 5HT1B receptor ligands exist. Naunyn Schmiedebergs Arch Pharmacol. 1989;339:675683.

21. FC Cheng , TH Tsai , YS Wu , JS Kuo , CF Chen . Pharmacokinetic and pharmacodynamic analyses of trazodone in rat striatum by in vivo microdialysis. J Pharm Biomed Anal. 1999;19:293300.

22. K Mihara , N Yasui-Furukori , T Kondo , et al.Relationship between plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine, and its clinical effect in depressed patients. Ther Drug Monit. 2002;24:563566.

25. CB Saper , TC Chou , TE Scammell . The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001;24:726731.

26. Y Shigemoto , Y Fujii , K Shinomiya , C Kamei . Participation of histaminergic H1 and noradrenergic alpha 1 receptors in orexin A-induced wakefulness in rats. Brain Res. 2004;1023:121125.

27. M Pazzagli , MG Gionvannini , G Pepeu . Traodone increases extracellular serotonin levels in the frontal cortex of rats, Eur J Pharmacol. 1999;383:249257.

28. GJ Marek , LL Carpenter , CJ McDougle , LH Price . Synergistic action of 5HT2A antagonists and selectve serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology. 2003;28:402412.

29. T Cremers , K Rea , FJ Bosker , et al.Augmentation of SSRI effects on serotonin by 5HT2C antagonists: mechanistic studies. Neuropsychopharmacology. 2007;32:15501557.

31. V DiMatteo , A DeBlasi , C DiGiulio , E Esposito . Role of 5HT2C receptors in the control of central dopamine function. Trends Pharmacol Sci. 2001;22:229232.

32. P DeDeurwaerdere , S Navailles , KA Berg , WP Claarke , U Spampinato . Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci. 2004;24:32353241.

33. KD Alex , EA Pehek . Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther. 2007;113:296320.

34. KD Alex , GJ Yavanian , HG McFarlane , CP Pluto , EA Pehek . Modulation of dopamine release by striatal 5HT2C receptors. Synapse. 2005;55:242251.

35. G Porras , V DiMatteo , C Fracasso , et al.5HT2A and 5HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum. Neuropsychopharmacology. 2002;26:311324.

36. N Santana , A Bortolozzi , J Serrats , M Guadalupe , F Artigas . Expression of serotonin 1A and serotonin 2A receptor in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex. 2004;14:11001109.

37. RW Invemizzi , M Pierucci , E Calcagno , et al.Selective activation of 5HT2C receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulate: a combined in vivo electrophysiological and neurochemical study. Neuroscience. 2007;144:15231535.

38. WM Abi-Saab , M Bubser , RH Roth , AY Deutch . 5HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology. 1999;20:9296.

40. P Monteleone , G Gnocchi , G Delrio . Plasma trazodone concentrations and clinical response in elderly depressed patients: a preliminary study. J Clin Psychopharmacol. 1989;9:284287.

42. G Gartlehner , BN Gaynes , RA Hansen , et al.Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med. 2008;149:734750.

43. GI Papakostas , M Fava . A meta-analysis of clinical trials comparing the serotonin (5HT)-2 receptor antagonists trazodone and nefazodone with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. Eur Psychiatry. 2007;22:444447.

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CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
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