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Drugs which influence serotonin transporter and serotonergic receptors: Pharmacological and clinical properties in the treatment of depression

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Abstract

Depression is nowadays a major contributor to global burden of disease. The most commonly prescribed drugs influence monoaminergic pathways, mainly concentrating on serotonin. Unfortunately, there are several drawbacks associated with these drugs, namely late onset of action, risk of suicide and adverse effects: mainly nausea, vomiting and sexual dysfunction. Therefore there is still need for new drugs with possibly high efficacy and fewer side effects.

In this paper selected compounds which inhibit serotonin reuptake by acting on the serotonin transporter (SERT) and various serotoninergic receptors are presented. We also discuss the ways in which their mechanism of action can be modified to improve pharmacological profile.

Here, we focus on describing drugs’ potency, efficacy and adverse effects. Additional applications, apart from depression, are also discussed.

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References

  1. Elhwuegi AS. Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:435–51.

    Article  CAS  PubMed  Google Scholar 

  2. Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 2008;33:2080–92.

    Article  CAS  PubMed  Google Scholar 

  3. Ribeiro P, Patocka N. Neurotransmitter transporters in schistosomes: structure, function and prospects for drug discovery. Parasitol Int 2013;62:629–38.

    Article  CAS  PubMed  Google Scholar 

  4. Lau T, Schloss P. Differential regulation of serotonin transporter cell surface expression. Wiley Interdiscip Rev Membr Transp Signal 2012;1:259–68.

    Article  CAS  Google Scholar 

  5. Ramamoorthy S, Shippenberg TS, Jayanthi LD. Regulation of monoamine transporters: role of transporter phosphorylation. Pharmacol Ther 2011;129:220–38.

    Article  CAS  PubMed  Google Scholar 

  6. Blakely RD, Bauman AL. Biogenic amine transporters: regulation in flux. Curr Opin Neurobiol 2000;10:328–36.

    Article  CAS  PubMed  Google Scholar 

  7. Abraham G, Milev R. Stuart lawson J: T3 augmentation of SSRI resistant depression. J Affect Disord 2006;91:211–5.

    Article  CAS  PubMed  Google Scholar 

  8. Brunton L, Chabner B, Knollman B. Goodman and Gilman’s the pharmacological basis of therapeutics. 12th ed. McGraw-Hill Education; 2011.

  9. Katzung B, Trevor A. Basic & clinical pharmacology. 13th ed. McGraw-Hill Education; 2014.

  10. Artigas F. Serotonin receptors involved in antidepressant effects. Pharmacol Ther 2013;137:119–31.

    Article  CAS  PubMed  Google Scholar 

  11. Romero L, Bel N, Artigas F, de Montigny C, Blier P. Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: in vivo microdialysis and electrophysiological studies in the rat brain. Neuropsychopharmacology 1996;15:349–60.

    Article  CAS  PubMed  Google Scholar 

  12. Artigas F, Celada P, Laruelle M, Adell A. How does pindolol improve antidepressant action? Trends Pharmacol Sci 2001;22:224–8.

    Article  CAS  PubMed  Google Scholar 

  13. Kimura S, Ohi Y, Haji A. Effects of cholinesterase inhibitors and serotonin-1A receptor agonists on morphine-induced ventilatory depression and antinociception in rats. Eur J Pharmacol 2013;703:33–41.

    Article  CAS  PubMed  Google Scholar 

  14. Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 2006;311:77–80.

    Article  CAS  PubMed  Google Scholar 

  15. López-Figueroa AL, Norton CS, López-Figueroa MO, Armellini-Dodel D, Burke S, Akil H, et al. Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry 2004;55:225–33.

    Article  PubMed  CAS  Google Scholar 

  16. Davidson C, Stamford JA. Effect of chronic paroxetine treatment on 5-HT1B and 5-HT1D autoreceptors in rat dorsal raphe nucleus. Neurochem Int 2000;36:91–6.

    Article  CAS  PubMed  Google Scholar 

  17. Cooke HJ, Sidhu M, Wang YZ. Activation of 5-HT1P receptors on submucosal afferents subsequently triggers VIP neurons and chloride secretion in the guinea-pig colon. J Auton Nerv Syst 1997;66:105–10.

    Article  CAS  PubMed  Google Scholar 

  18. Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog Neuropsychopharmacol Biol Psychiatry 2013;45:54–63.

    CAS  PubMed  Google Scholar 

  19. Yang HY, Tae J, Seo YW, Kim YJ, Im HY, Choi GD, et al. Novel pyrimidoazepine analogs as serotonin 5-HT(2A) and 5-HT(2C) receptor ligands for the treatment of obesity. Eur J Med Chem 2013;63:558–69.

    Article  CAS  PubMed  Google Scholar 

  20. Mbaki Y, Gardiner J, McMurray G, Ramage AG. 5-HT 2A receptor activation of the external urethral sphincter and 5-HT 2C receptor inhibition of micturition: a study based on pharmacokinetics in the anaesthetized female rat. Eur J Pharmacol 2012;682:142–52.

    Article  CAS  PubMed  Google Scholar 

  21. Cavero I, Safety Guillon J-M. Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy. J Pharmacol Toxicol Methods 2014;69:150–61.

    Article  CAS  PubMed  Google Scholar 

  22. Li X, Ma Y, Wu X, Hao Z, Yin J, Shen J, et al. Serotonin acts as a novel regulator of interleukin-6 secretion in osteocytes through the activation of the 5-HT2B receptor and the ERK1/2 signalling pathway. Biochem Biophys Res Commun 2013;441:809–14.

    Article  CAS  PubMed  Google Scholar 

  23. Cervantes-Durán C, Rocha-González HI, Granados-Soto V. Peripheral and spinal 5-HT receptors participate in the pronociceptive and antinociceptive effects of fluoxetine in rats. Neuroscience 2013;252:396–409.

    Article  PubMed  CAS  Google Scholar 

  24. Bharti S, Singh R, Chauhan SS, Hussain T, Al-Attas OS, Arya DS. Phosphorylation of Akt/GSK-3b/eNOS amplifies 5-HT 2 B receptor blockade mediated anti-hypertrophic effect in rats. FEBS Lett 2012;586:180–5.

    Article  CAS  PubMed  Google Scholar 

  25. Hutcheson JD, Ryzhova LM, Setola V, Merryman WD. 5-HT2B antagonism arrests non-canonical TGF-b1-induced valvular myofibroblast differentiation. J Mol Cell Cardiol 2012;53:707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Moss N, Choi Y, Cogan D, Flegg A, Kahrs A, Loke P, et al. A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties. Bioorg Med Chem Lett 2009;19:2206–10.

    Article  CAS  PubMed  Google Scholar 

  27. Löfdahl A, Rydell-Törmänen K, Müller C, Martina Holst C, Thiman L, Ekström G, et al. 5-HT2B receptor antagonists attenuate myofibroblast differentiation and subsequent fibrotic responses in vitro and in vivo. Physiol Rep 20164:.

  28. Janssen W, Schymura Y, Novoyatleva T, Kojonazarov B, Boehm M, Wietelmann A, et al. 5-HT2B receptor antagonists inhibit fibrosis and protect from RV heart failure. Biomed Res Int 2015;2015:1–9.

    Google Scholar 

  29. Fletcher PJ, Rizos Z, Noble K, Soko AD, Silenieks LB, Lê AD, et al. Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement. Neuropharmacology 2012;62:2288–98.

    Article  CAS  PubMed  Google Scholar 

  30. Kondaurova EM, Naumenko VS, Popova NK. Effect of chronic activation of 5-HT3 receptors on 5-HT3, 5-HT(1A) and 5-HT(2A) receptors functional activity and expression of key genes of the brain serotonin system. Neurosci Lett 2012;522:52–6.

    Article  CAS  PubMed  Google Scholar 

  31. Ohno Y, Imaki J, Mae Y, Takahashi T, Tatara A. Serotonergic modulation of extrapyramidal motor disorders in mice and rats: role of striatal 5-HT3 and 5-HT6 receptors. Neuropharmacology 2011;60:201–8.

    Article  CAS  PubMed  Google Scholar 

  32. Ortega JE, Mendiguren A, Pineda J, Meana JJ. Regulation of central noradrenergic activity by 5-HT(3) receptors located in the locus coeruleus of the rat. Neuropharmacology 2012;62:2472–9.

    Article  CAS  PubMed  Google Scholar 

  33. Kovac AL. Comparative pharmacology and guide to the use of the serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting. Drugs 2016;76:1719–35.

    Article  CAS  PubMed  Google Scholar 

  34. Lennertz L, Wagner M, Grabe HJ, Franke PE, Guttenthaler V, Rampacher F, et al. 5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option. Eur Neuropsychopharmacol 2014;24:86–94.

    Article  CAS  PubMed  Google Scholar 

  35. Berthouze M, Rivail L, Lucas A, Ayoub MA, Russo O, Sicsic S, et al. Two transmembrane Cys residues are involved in 5-HT4 receptor dimerization. Biochem Biophys Res Commun 2007;356:642–7.

    Article  CAS  PubMed  Google Scholar 

  36. Licht CL, Knudsen GM, Sharp T. Effects of the 5-HT(4) receptor agonist RS67333 and paroxetine on hippocampal extracellular 5-HT levels. Neurosci Lett 2010;476:58–61.

    Article  CAS  PubMed  Google Scholar 

  37. Grailhe R, Grabtree GW, Hen R. Human 5-HT(5) receptors: the 5-HT(5A) receptor is functional but the 5-HT(5B) receptor was lost during mammalian evolution. Eur J Pharmacol 2001;418:157–67.

    Article  CAS  PubMed  Google Scholar 

  38. McCorvy JD, Roth BL. Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther 2015;150:129–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ferrero H, Solas M, Francis PT, Ramirez MJ. Serotonin 5-HT6 receptor antagonists in Alzheimer’s disease: therapeutic rationale and current development status. CNS Drugs 2017;31:19–32.

    Article  CAS  PubMed  Google Scholar 

  40. Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H. Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders. Pharmacol Ther 2008;117:207–31.

    Article  CAS  PubMed  Google Scholar 

  41. Monti JM, Jantos H, Schechter LE. The effects of systemic and local microinjection into the central nervous system of the selective serotonin 5-HT6 receptor agonist WAY-208466 on sleep and wakefulness in the rat. Behav Brain Res 2013;249:65–74.

    Article  CAS  PubMed  Google Scholar 

  42. Monti JM, Jantos H. Effects of the 5-HT6 receptor antagonists SB-399885 and RO-4368554 and of the 5-HT(2A) receptor antagonist EMD 281014 on sleep and wakefulness in the rat during both phases of the light-dark cycle. Behav Brain Res 2011;216:381–8.

    Article  CAS  PubMed  Google Scholar 

  43. de Bruin NMWJ, McCreary AC, van Loevezijn A, de Vries TJ, Venhorst J, van Drimmelen M, et al. A novel highly selective 5-HT6 receptor antagonist attenuates ethanol and nicotine seeking but does not affect inhibitory response control in Wistar rats. Behav Brain Res 2013;236:157–65.

    Article  PubMed  CAS  Google Scholar 

  44. Horisawa T, Nishikawa H, Toma S, Ikeda A, Horiguchi M, Ono M, et al. The role of 5-HT7 receptor antagonism in the amelioration of MK-801-induced learning and memory deficits by the novel atypical antipsychotic drug lurasidone. Behav Brain Res 2013;244:66–9.

    Article  CAS  PubMed  Google Scholar 

  45. Nikiforuk A, Popik P. Amisulpride promotes cognitive flexibility in rats: the role of 5-HT7 receptors. Behav Brain Res 2013;248:136–40.

    Article  CAS  PubMed  Google Scholar 

  46. Ulugol A, Oltulu C, Gunduz O, Citak C, Carrara R, Shaqaqi MR, et al. 5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice. Pharmacol Biochem Behav 2012;102:344–8.

    Article  CAS  PubMed  Google Scholar 

  47. Albayrak A, Halici Z, Cadirci E, Polat B, Karakus E, Bayir Y, et al. Inflammation and peripheral 5-HT7 receptors: the role of 5-HT7 receptors in carrageenan induced inflammation in rats. Eur J Pharmacol 2013;715:270–9.

    Article  CAS  PubMed  Google Scholar 

  48. Yang Z, Liu X, Yin Y, Sun S, Deng X. Involvement of 5-HT7 receptors in the pathogenesis of temporal lobe epilepsy. Eur J Pharmacol 2012;685:52–8.

    Article  CAS  PubMed  Google Scholar 

  49. Barbanti P, Aurilia C, Egeo G, Fofi L, Palmirotta R. Serotonin receptor targeted therapy for migraine treatment: an overview of drugs in phase I and II clinical development. Expert Opin Investig Drugs 2017;1-9.

  50. Fitzgerald KT, Bronstein AC. Selective serotonin reuptake inhibitor exposure. Top Companion Anim Med 2013;28:13–7.

    Article  PubMed  Google Scholar 

  51. Mourilhe P, Stokes PE. Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression. Drug Saf 1998;18:57–82.

    Article  CAS  PubMed  Google Scholar 

  52. Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE. Goldfrank’s toxicologic emergencies. 10th ed. McGraw-Hill Education; 2015.

  53. Thomas DE, Lee JA, Hovda LR. Retrospective evaluation of toxicosis from selective serotonin reuptake inhibitor antidepressants: 313 dogs (2005-2010). J Vet Emerg Crit Care (San Antonio) 2012;22:674–81.

    Article  Google Scholar 

  54. Woolf AD, Erdman AR, Nelson LS, Caravati EM, Cobaugh DJ, Booze LL, et al. Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007;45:203–33.

    Article  CAS  Google Scholar 

  55. Klint T, Helsdingen JT. Lack of typical SSRI-related adverse effects and sexual dysfunction with mirtazapine is related to specific blockade of 5-HT2 and 5-HT3 receptors. Eur Psychiatry 1996;11:347s.

    Article  Google Scholar 

  56. Nebhinani N. Sertraline-induced galactorrhea: case report and review of cases reported with other SSRIs. Gen Hosp Psychiatry 2013;35(576):e3–e35.

    Google Scholar 

  57. Ho HY, Kam K-WA, Young AL, Chan LK, Yu EC-S. Acute angle closure glaucoma after sertraline. Gen Hosp Psychiatry 2013;35(575):e1–2.

    Google Scholar 

  58. Uguz F, Sonmez EÖ. Neuroleptic malignant syndrome following combination of sertraline and paroxetine: a case report. Gen Hosp Psychiatry 201335:327. e7-327. e8.

    Article  PubMed  Google Scholar 

  59. Hogg S, Dalvi A. Acceleration of onset of action in schedule-induced polydipsia: combinations of SSRI and 5-HT1A and 5-HT1B receptor antagonists. Pharmacol Biochem Behav 2004;77:69–75.

    Article  CAS  PubMed  Google Scholar 

  60. Fagiolini A, Comandini A, Catena Dell’Osso M, Kasper S. Rediscovering trazodone for the treatment of major depressive disorder. CNS Drugs 2012;26:1033–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Papakostas GI, Fava M. 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;22:444–7.

    Article  PubMed  Google Scholar 

  62. Zaniewska M, McCreary AC, Wydra K, Filip M. Effects of serotonin (5-HT)2 receptor ligands on depression-like behavior during nicotine withdrawal. Neuropharmacology 2010;58:1140–6.

    Article  CAS  PubMed  Google Scholar 

  63. Tarantino P, Appleton N, Lansdell K. Effect of trazodone on hERG channel current and QT-interval. Eur J Pharmacol 2005;510:75–85.

    Article  CAS  PubMed  Google Scholar 

  64. Ghanbari R, El Mansari M, Blier P. Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain. Eur Neuropsychopharmacol 2012;22:518–26.

    Article  CAS  PubMed  Google Scholar 

  65. Schreiber S, Backer MM, Herman I, Shamir D, Boniel T, Pick CG. The antinociceptive effect of trazodone in mice is mediated through both mu-opioid and serotonergic mechanisms. Behav Brain Res 2000;114:51–6.

    Article  CAS  PubMed  Google Scholar 

  66. Roth BL, Lopez E, Patel S, Kroeze WK. The multiplicity of serotonin receptors: uselessly diverse molecules or an embarrassment of riches? Neuroscientist 2000;6:252–62.

    Article  CAS  Google Scholar 

  67. Fernández-Dueñas V, Poveda R, Fernández A, Sánchez S, Planas E, Ciruela F. Fentanyl-trazodone-paracetamol triple drug combination: multimodal analgesia in a mouse model of visceral pain. Pharmacol Biochem Behav 2011;98:331–6.

    Article  PubMed  CAS  Google Scholar 

  68. Stein MD, Kurth ME, Sharkey KM, Anderson BJ, Corso RP, Millman RP. Trazodone for sleep disturbance during methadone maintenance: a double-blind, placebo-controlled trial. Drug Alcohol Depend 2012;120:65–73.

    Article  CAS  PubMed  Google Scholar 

  69. Cheng W-M, Lin T-P, Lin ATL, Chen K-K, Chen T-J. A nationwide population study of trazodone use in urology patients. J Chin Med Assoc 2013;76:432–7.

    Article  PubMed  Google Scholar 

  70. Chang J-C, Wu Y-T, Lee W-C, Lin L-C, Tsai T-H. Herb-drug interaction of silymarin or silibinin on the pharmacokinetics of trazodone in rats. Chem Biol Interact 2009;182:227–32.

    Article  CAS  PubMed  Google Scholar 

  71. Ren Z, Chen S, Zhang J, Doshi U, Li AP, Guo L. Endoplasmic reticulum stress induction and ERK1/2 activation contribute to nefazodone-induced toxicity in hepatic cells. Toxicol Sci 2016;154:368–80.

    Article  CAS  PubMed  Google Scholar 

  72. Horst WD, Preskorn SH. Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. J Affect Disord 1998;51:237–54.

    Article  CAS  PubMed  Google Scholar 

  73. Gelenberg AJ, Trivedi MH, Rush AJ, Thase ME, Howland R, Klein DN, et al. Randomized, placebo-controlled trial of nefazodone maintenance treatment in preventing recurrence in chronic depression. Biol Psychiatry 2003;54:806–17.

    Article  CAS  PubMed  Google Scholar 

  74. Núñez M. Effects of nefazodone on voluntary ethanol consumption induced by isolation stress in young and aged rats. Pharmacol Biochem Behav 2002;73:689–96.

    Article  PubMed  Google Scholar 

  75. Goldberg JF. A preliminary open trial of nefazodone added to mood stabilizers for bipolar depression. J Affect Disord 2013;144:176–8.

    Article  CAS  PubMed  Google Scholar 

  76. Rush AJ, Armitage R, Gillin JC, Yonkers KA, Winokur A, Moldofsky H, et al. Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder. Biol Psychiatry 1998;44:3–14.

    Article  CAS  PubMed  Google Scholar 

  77. Wiegand MH, Galanakis P, Schreiner R. Nefazodone in primary insomnia: an open pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:1071–8.

    Article  CAS  PubMed  Google Scholar 

  78. Freire-Garabal M, Varela M, Riveiro P, Balboa J, Liñares D, Mañá P, et al. Effects of nefazodone on the immune system of mice. Eur Neuropsychopharmacol 2000;10:255–64.

    Article  CAS  PubMed  Google Scholar 

  79. Agelink MW, Majewski T, Wurthmann C, Postert T, Linka T, Rotterdam S, et al. Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone. J Affect Disord 2001;62:187–98.

    Article  CAS  PubMed  Google Scholar 

  80. Brotto LA, Hanson LA, Gorzalka BB. Nefazodone attenuates the stress-induced facilitation of wet dog shaking behaviour but not the facilitation of sexual behaviour in female rats. Eur J Pharmacol 1999;381:101–4.

    Article  CAS  PubMed  Google Scholar 

  81. Przegaliński E, Lewandowska A. The effect of etoperidone, a new potential antidepressant drug, on the central serotonin system. J Neural Transm 1979;46:303–12.

    Article  PubMed  Google Scholar 

  82. Carruba MO, Parenti M, Ricciardi S, Picotti GB, Mantegazza P. Effect of etoperidone on the depletion of brain 5-hydroxytryptamine and catecholamines induced respectively by p-chloromethamphetamine and 6-hydroxydopamine in rats. Pharmacol Res Commun 1979;11:169–77.

    Article  CAS  PubMed  Google Scholar 

  83. Wu W, McKown LA. Hepatic in vitro metabolism of etoperidone, an antidepressant drug, in the rat and human. Chin Pharm J Taipei 2007;59:31.

    CAS  Google Scholar 

  84. Lisciani R, Baldini A, Benedetti D, Campana A, Barcellona PS. Acute cardiovascular toxicity of trazodone, etoperidone and imipramine in rats. Toxicology 1978;10:151–8.

    Article  CAS  PubMed  Google Scholar 

  85. Placheta P, Singer E, Kriwanek W, Mepiprazole Hertting G. a new psychotropic drug: effects on uptake and retention of monoamines in rat brain synaptosomes. Psychopharmacology (Berl) 1976;48:295–301.

    Article  CAS  Google Scholar 

  86. Cohen ML, Fuller RW, Kurz KD. Evidence that blood pressure reduction by serotonin antagonists is related to alpha receptor blockade in spontaneously hypertensive rats. Hypertension 1983;5:676–81.

    Article  CAS  PubMed  Google Scholar 

  87. Maj J, Sypniewska M. Central action of mepiprazole. Pol J Pharmacol Pharm 1980;32:475–84.

    CAS  PubMed  Google Scholar 

  88. Fuxe K, Agnati LF, Ungerstedt U. The effect of mepiprazole on central monoamine neurons: evidence for increased 5-hydroxytryptamine and dopamine receptor activity. Eur J Pharmacol 1976;35:93–108.

    Article  CAS  PubMed  Google Scholar 

  89. Fong MH, Garattini S, Caccia S. 1-m-Chlorophenylpiperazine is an active metabolite common to the psychotropic drugs trazodone, etoperidone and mepiprazole. J Pharm Pharmacol 1982;34:674–5.

    Article  CAS  PubMed  Google Scholar 

  90. Pullar IA, Carney SL, Colvin EM, Lucaites VL, Nelson DL, Wedley S. LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone. Eur J Pharmacol 2000;407:39–46.

    Article  CAS  PubMed  Google Scholar 

  91. Wang S-J. Potential antidepressant LY 367265 presynaptically inhibits the release of glutamate in rat cerebral cortex. Synapse 2005;55:156–63.

    Article  CAS  PubMed  Google Scholar 

  92. Ozdemir E, Bagcivan I, Gursoy S, Altun A, Durmus N. Effects of fluoxetine and LY 367265 on tolerance to the analgesic effect of morphine in rats. Acta Physiol Hung 2011;98:205–13.

    Article  CAS  PubMed  Google Scholar 

  93. Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011;54:3206–21.

    Article  CAS  PubMed  Google Scholar 

  94. Zhu XY, Etukala JR, Eyunni SVK, Setola V, Roth BL, Ablordeppey SY. Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): a search for new dual-acting agents as potential antidepressants. Eur J Med Chem 2012;53:124–32.

    Article  CAS  PubMed  Google Scholar 

  95. Pessoa-Mahana H, González-Lira C, Fierro A, Zapata-Torres G, Pessoa-Mahana CD, Ortiz-Severin J, et al. Synthesis, docking and pharmacological evaluation of novel homo- and hetero-bis 3-piperazinylpropylindole derivatives at SERT and 5-HT1A receptor. Bioorg Med Chem 2013;21:7604–11.

    Article  CAS  PubMed  Google Scholar 

  96. Gomółka A, Ciesielska A, Wróbel MZ, Chodkowski A, Kleps J, Dawidowski M, et al. Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. Part 5. Eur J Med Chem 2015;98:221–36.

    Article  PubMed  CAS  Google Scholar 

  97. Stefanowicz J, Słowiński T, Wróbel MZ, Herold F, Gomółka AE, Wesołowska A, et al. Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile. Bioorg Med Chem 2016;24:3994–4007.

    Article  CAS  PubMed  Google Scholar 

  98. Ashby CR, Kehne JH, Bartoszyk GD, Renda MJ, Athanasiou M, Pierz KA, et al. Electrophysiological evidence for rapid 5-HT1A autoreceptor inhibition by vilazodone, a 5-HT1A receptor partial agonist and 5-HT reuptake inhibitor. Eur J Pharmacol 2013;714:359–65.

    Article  CAS  PubMed  Google Scholar 

  99. Heinrich T, Böttcher H, Gericke R, Bartoszyk GD, Anzali S, Seyfried CA, et al. Synthesis and structure-activity relationship in a class of indolebutylpiperazines as dual 5-HT(1A) receptor agonists and serotonin reuptake inhibitors. J Med Chem 2004;47:4684–92.

    Article  CAS  PubMed  Google Scholar 

  100. Hughes ZA, Starr KR, Langmead CJ, Hill M, Bartoszyk GD, Hagan JJ, et al. Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/ serotonin reuptake inhibitor, vilazodone. Eur J Pharmacol 2005;510:49–57.

    Article  CAS  PubMed  Google Scholar 

  101. Page ME, Cryan JF, Sullivan A, Dalvi A, Saucy B, Manning DR, et al. Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist. J Pharmacol Exp Ther 2002;302:1220–7.

    Article  CAS  PubMed  Google Scholar 

  102. Jain R, Chen D, Edwards J, Mathews M. Early and sustained improvement with vilazodone in adult patients with major depressive disorder: post hoc analyses of two phase III trials. Curr Med Res Opin 2014;30:263–70.

    Article  CAS  PubMed  Google Scholar 

  103. BRINTELLIX (vortioxetine). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204447s000lbl.pdf (Accessed 17 July 2017).

  104. Riga MS, Celada P, Sanchez C, Artigas F. P. 2. e. 003 Role of 5-HT3 receptors in the mechanism of action of the investigational antidepressant vortioxetine. Eur Neuropsychopharmacol 2013;23:S393–4.

    Article  Google Scholar 

  105. Sanchez C. 863-Vortioxetine, an investigational antidepressant: implications of its multimodal mechanism of action in preclinical models of depression and cognitive function. Eur Psychiatry 2013;28:1.

    Google Scholar 

  106. Pehrson A, Li Y, Haddjeri N, Gulinello M, Sanchez C. P.1. g.014 Vortioxetine, a novel multimodal antidepressant, modulates GABA and glutamate neurotransmission via serotonergic mechanisms. Eur Neuropsychopharmacol 2013;23:S196–7.

    Article  Google Scholar 

  107. du Jardin KG, Jensen JB, Sanchez C, Pehrson AL. Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. Eur Neuropsychopharmacol 2014;24:160–71.

    Article  PubMed  CAS  Google Scholar 

  108. Mørk A, Montezinho LP, Miller S, Trippodi-Murphy C, Plath N, Li Y, et al. Vortioxetine (Lu AA21004), a novel multimodal antidepressant, enhances memory in rats. Pharmacol Biochem Behav 2013;105:41–50.

    Article  PubMed  CAS  Google Scholar 

  109. Jensen JB, du Jardin KG, Song D, Budac D, Smagin G, Sanchez C, et al. Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation. Eur Neuropsychopharmacol 2014;24:148–59.

    Article  CAS  PubMed  Google Scholar 

  110. Keefe RSE, Mahableshwarkar AR, Olsen CK. P.2. f.013 Clinical evidence for improvement in cognitive dysfunction in patients with major depressive disorder (MDD) after treatment with vortioxetine. Eur Neuropsychopharmacol 2013;23:S402–3.

    Article  Google Scholar 

  111. Angel I, Schoemaker H, Prouteau M, Garreau M, Langer SZ. Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties. Eur J Pharmacol 1993;232:139–45.

    Article  CAS  PubMed  Google Scholar 

  112. Andrews M, Brown A, Chiva J-Y, Fradet D, Gordon D, Lansdell M, et al. Design and optimization of selective serotonin re-uptake inhibitors with high synthetic accessibility. Part 1. Bioorg Med Chem Lett 2009;19:2329–32.

    Article  CAS  PubMed  Google Scholar 

  113. Stolerman IP. Encyclopedia of psychopharmacology. Springer; 2010.

  114. Dose Finding Study With Lu AA24530 in Major Depressive Disorder. https://clinicaltrials.gov/ct2/show/NCT00599911?term=Lu+AA24530&rank=1 (Accessed 17 July 2017).

  115. Efficacy and Safety of Lu AA34893 in Patients With Bipolar Depression, https://clinicaltrials.gov/ct2/show/results/NCT00622245 (Accessed 17 July 2017).

  116. Andreasen JT, Redrobe JP, Nielsen EØ. Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests: a comparison of SSR180711 and PNU-282987. Pharmacol Biochem Behav 2012;100:624–9.

    Article  CAS  PubMed  Google Scholar 

  117. Hayward A, Adamson L, Neill JC. Partial agonism at the α7 nicotinic acetylcholine receptor improves attention, impulsive action and vigilance in low attentive rats. Eur Neuropsychopharmacol 2017;27(4):325–35.

    Article  CAS  PubMed  Google Scholar 

  118. McClernon FJ, Hiott FB, Westman EC, Rose JE, Levin ED. Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial. Psychopharmacology (Berl) 2006;189:125–33.

    Article  CAS  Google Scholar 

  119. Papakostas G, Ionescu D. Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder. Mol Psychiatry 2015;20:1142–50.

    Article  CAS  PubMed  Google Scholar 

  120. Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov 2017;16(7):472–86.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Przemysław Paweł Taciak.

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Taciak, P.P., Lysenko, N. & Mazurek, A.P. Drugs which influence serotonin transporter and serotonergic receptors: Pharmacological and clinical properties in the treatment of depression. Pharmacol. Rep 70, 37–46 (2018). https://doi.org/10.1016/j.pharep.2017.07.011

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