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Selective Serotonin/Noradrenal Reuptake Inhibitors (SNRIs)

Pharmacology and Therapeutic Potential in the Treatment of Depressive Disorders

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Summary

In recent years, potential new antidepressants have been developed that inhibit serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake in a selective manner. Examples of these serotonin/noradrenaline reuptake inhibitors (SNRIs) are duloxetine, milnacipran and venlafaxine

All 3 compounds effectively inhibit the serotonin and noradrenaline transporter, as judged from in vitro and in vivo tests. However, potency and selectivity differ between them. The concentration of drug that inhibits uptake by 50% (IC50) for serotonin and noradrenaline, respectively, in rat brain preparations are 2.6 and 7 nmol/L for duloxetine, 203 and 100 nmol/L for milnacipran and 210 and 640 nmol/L for venlafaxine. Duloxetine and venlafaxine are extensively metabolised to demethylated compounds that also inhibit serotonin and noradrenaline uptake, whereas milnacipran lacks active metabolites. Venlafaxine, but not milnacipran, downregulates β-adrenoceptor-mediated responses after single dose and repeated administration. This has been suggested to contribute to a rapid antidepressant action of the former agent. However, since other established antidepressants, such as several selective serotonin reuptake inhibitors and milnacipran, do not cause this effect on β-adrenoceptors after single dose and repeated administration, the relationship between changes in these receptors and antidepressant action is unclear.

Controlled studies in depressed patients have shown an efficacy of milnacipran and venlafaxine superior to placebo and comparable to that of reference antidepressants. Furthermore, SNRIs are devoid of some of the undesirable adverse effects common to first generation antidepressants (i.e. tricyclics and monoamine oxidase inhibitors). This may be due to a lack of interaction with aminergic receptors, and results in better compliance (although the incidence of adverse events of SNRIs, mainly gastrointestinal, increases with dose). The rapid onset of antidepressant effects has been reported in patients with major depression who were treated with venlafaxine and, to a lesser extent, with milnacipran. Although promising, these results need to be interpreted with caution, given the methodological difficulties in measuring appropriately the onset of antidepressant action and the few studies specifically addressing this issue.

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References

  1. Eccleston D, editor. The economic evaluation of antidepressant drug therapy. Br J Psychiatry 1993; 163 Suppl. 20: 5–42

    Google Scholar 

  2. National Advisory Mental Health Council. Health care reform for Americans with severe mental illnesses: report of the National Advisory Mental Health Council. Am J Psychiatry 1993; 150: 1447–65

    Google Scholar 

  3. Cookson J. The economic evaluation of antidepressant drug therapy. Side-effects of antidepressants. Br J Psychiatry 1993; 163 Suppl.: 20–4

    Google Scholar 

  4. Möller HJ, Fuger J, Kasper S. Efficacy of new generation antidepressants: meta-analysis of imipramine-controlled studies. Pharmacopsychiatry 1994; 27: 215–23

    Article  PubMed  Google Scholar 

  5. Montgomery SA, Henry J, McDonald G, et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994; 9: 47–53

    Article  PubMed  CAS  Google Scholar 

  6. Rudorfer MV, Potter WZ. Antidepressants: a comparative review of the clinical pharmacology and therapeutic use of the ‘newer’ versus the ‘older’ drugs. Drugs 1989; 37: 713–38

    Article  PubMed  CAS  Google Scholar 

  7. Song F, Freemantie N, Sheldon TA, et al. Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. BMJ 1993; 306: 683–7

    Article  PubMed  CAS  Google Scholar 

  8. Richelson E. Tricyclic antidepressants block histamine HI receptors of mouse neuroblastoma cells. Nature 1978; 274: 176–7

    Article  PubMed  CAS  Google Scholar 

  9. Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 1984; 230: 94–102

    PubMed  CAS  Google Scholar 

  10. Wong DT, Bymaster FP, Mayle DA, et al. LY248686: a new inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology 1993; 8: 23–33

    PubMed  CAS  Google Scholar 

  11. Moret C, Charveron M, Finberg JPM, et al. Biochemical profile of midalcipran (F2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology 1985; 24: 1211–9

    Article  PubMed  CAS  Google Scholar 

  12. Yardley JP, Husbands GE, Stack G, et al. 2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity. J Med Chem 1990; 33: 2899–905

    Article  PubMed  CAS  Google Scholar 

  13. Lilly Research Laboratories. Duloxetine.HCl (LY248686). Clinical investigation brochure. March 1994

  14. Puozzo C, Filaquier C, Briley M. Plasma levels of F 2207, midalcipran, a novel antidepressant after single oral administration in volunteers [abstract]. Br J Clin Pharmacol 1985; 20:291P

    Google Scholar 

  15. Wyeth-Ayerst Research. Venlafaxine. Investigational Drug Brochure. August 1994

  16. Howell SR, Husbands GE, Scatina JA, et al. Metabolic disposition of 14C-venlafaxine in mouse, rat, dog, rhesus monkey and man. Xenobiotica 1993; 23: 349–59

    Article  PubMed  CAS  Google Scholar 

  17. Howell SR, Hicks DR, Scatina JA, et al. Pharmacokinetics of venlafaxine and O-desmethylvenlafaxine in laboratory animals. Xenobiotica 1994; 24: 315–27

    Article  PubMed  CAS  Google Scholar 

  18. Klamerus KJ, Maloney K, Rudolph RL, et al. Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite. J Clin Pharmacol 1992; 32: 716–24

    PubMed  CAS  Google Scholar 

  19. Muth EA, Haskins JT, Moyer JA, et al. Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative. Biochem Pharmacol 1986; 35:4493–7

    Article  PubMed  CAS  Google Scholar 

  20. Bolden Watson C, Richelson E. Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain syn-aptosomes. Life Sci 1993; 52: 1023–9

    Article  PubMed  CAS  Google Scholar 

  21. Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl) 1994; 114: 559–65

    Article  CAS  Google Scholar 

  22. Fuller RW, Hemrich-Luecke SK, Snoddy HD. Effects of duloxetine, an antidepressant drug candidate, on concentrations of monoamines and their metabolites in rats and mice. J Pharmacol Exp Ther 1994; 269: 132–6

    PubMed  CAS  Google Scholar 

  23. Engleman EA, Perry KW, Mayle DA, et al. Simultaneous increases of extracellular monoamines in microdialysates from hypothalamus of conscious rats by duloxetine, a dual serotonin and norepinephrine uptake inhibitor. Neuropsycho-pharmacology. In press

  24. Kihara T, Ikeda M. Effects of duloxetine, a new serotonin and norepinephrine uptake inhibitor on extracellular monoamine levels in rat frontal cortex. J Pharmacol Exp Ther 1995; 272: 177–83

    PubMed  CAS  Google Scholar 

  25. Adell A, Artigas F. Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex. An in vivo microdialysis study. Naunyn Schmiedebergs Arch Pharmacol 1991; 343: 237–44

    Article  PubMed  CAS  Google Scholar 

  26. Invernizzi R, Belli S, Samanin R. Citalopram’s ability to increase the extracellular concentrations of serotonin in the dorsal raphe prevents the drug’s effect in the frontal cortex. Brain Res 1992; 584: 322–4

    Article  PubMed  CAS  Google Scholar 

  27. Romero L, Celada P, Artigas F. Reduction of in vivo striatal 5-hydroxytryptamine release by 8-OH-DPAT after inactivation of Gj/Go proteins in dorsal raphe nucleus. Eur J Pharmacol 1994; 265: 103–6

    Article  PubMed  CAS  Google Scholar 

  28. Tanda G, Carboni E, Frau R, et al. Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential? Psychopharmacology (Berl) 1994;115: 285–8

    Article  CAS  Google Scholar 

  29. Carboni E, Tanda GL, Frau R, et al. Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem 1990; 55: 1067–70

    Article  PubMed  CAS  Google Scholar 

  30. Stenger A, Couzinier JP, Briley M. Psychopharmacology of midalcipran, 1 -phenyl-1 -diethyl-amino-carbonyl-2-aminomethyl-cyclopropane hydrochloride (F 2207), a new potential antidepressant. Psychopharmacology (Berl) 1987; 91: 147–53

    Article  CAS  Google Scholar 

  31. Moret C, Briley M. Effect of antidepressant drugs on monoamine synthesis in brain in vivo. Neuropharmacology 1992; 31:679–84

    Article  PubMed  CAS  Google Scholar 

  32. Blier P, De Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994; 15: 220–6

    Article  PubMed  CAS  Google Scholar 

  33. Assie MB, Charveron M, Palmier C, et al. Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat. Neuropharmacology 1992; 31: 149–55

    Article  PubMed  CAS  Google Scholar 

  34. Matsubara R, Matsubara S, Koyama T, et al. Effect of chronic treatment with milnacipran (TN 912), a novel antidepressant, on beta adrenergic receptor adenylate cyclase system and serotonin2 receptor in the rat cerebral cortex. Jpn J Neuro-psychopharmacol 1993; 15: 119–26

    CAS  Google Scholar 

  35. Moret C, Briley M. Serotonin autoreceptor subsensitivity and antidepressant activity. Eur J Pharmacol 1990; 180: 351–6

    Article  PubMed  CAS  Google Scholar 

  36. Artigas F. 5-HT and antidepressants: new views from micro-dialysis studies [letter]. Trends Pharmacol Sci 1993; 14: 262

    Article  PubMed  CAS  Google Scholar 

  37. Baraban JM, Aghajanian GK. Suppression of firing activity of 5-HT neurons in the dorsal raphe by alpha adrenoceptor antagonists. Neuropharmacology 1980; 19: 355–63

    Article  PubMed  CAS  Google Scholar 

  38. Weiss M, Blier P, de Montigny C. Effects of the sustained administration of milnacipran on the activity of noradrenaline and serotonin neurons [abstract]. International Symposium on the role of 5-HT in Psychiatric Diseases: 1992 Jun 24-26; Castres, France, P8

    Google Scholar 

  39. Moret C, Briley M. Effect of milnacipran and desipramine on noradrenergic alpha(2)-autoreceptor sensitivity. Prog Neuro-psych Biol Psychiatry 1994; 18: 1063–72

    Article  CAS  Google Scholar 

  40. Melikian HE, Moore KR, Qian Y, et al. Structure and function of plasma membrane serotonin transporters [abstract]. Soc Neurosci Abs 1993; 19:494

    Google Scholar 

  41. Thompson RG, Heiligenstein JH, Birkett MA. Dual serotonin (5-HT) and norepinephrine (NE) uptake inhibitors. Clinical results in major depression [abstract]. Neuropsychopharma-cology 1994; 10 Suppl. 3 (Pt 1): 652S

    Google Scholar 

  42. Serre C, Clerc G, Escande M, et al. An early clinical trial of midalcipran, 1. phenyl-1-diethyl aminocarbonyl-2-aminomethyl cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant. Curr Ther Res 1986; 39: 156–64

    Google Scholar 

  43. Ansseau M, von Frenckell R, Gerard MA, et al. Interest of a loading dose of milnacipran in endogenous depressive inpatients. Comparison with the standard regimen and with fluvoxamine. Eur Neuropsychopharmacol 1991; 1: 113–21

    Article  PubMed  CAS  Google Scholar 

  44. von Frenckell R, Ansseau M, Serre C, et al. Pooling two controlled comparisons of milnacipran (F2207) and amitriptyline in endogenous inpatients. A new approach in dose ranging studies. Int Clin Psychopharmacol 1990; 5: 49–56

    Article  Google Scholar 

  45. Ansseau M, von Frenckell R, Mertens C, et al. Controlled comparison of two doses of milnacipran (F 2207) and amitriptyline in major depressive inpatients. Psychopharmacology (Berl) 1989; 98: 163–8

    Article  CAS  Google Scholar 

  46. Macher JP, Sichel JP, Serre C, et al. Double-blind placebo-controlled study of milnacipran in hospitalized patients with major depressive disorders. Neuropsychobiology 1989; 22: 77–82

    Article  PubMed  CAS  Google Scholar 

  47. Khan A, Fabre LF, Rudolph R. Venlafaxine in depressed outpatients. Psychopharmacol Bull 1991; 27: 141–4

    PubMed  CAS  Google Scholar 

  48. Schweizer E, Weise C, Clary C, et al. Placebo-controlled trial of venlafaxine for the treatment of major depression. J Clin Psychopharmacol 1991; 11: 233–6

    Article  PubMed  CAS  Google Scholar 

  49. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed rev. Washington DC: American Psychiatric Association, 1987

    Google Scholar 

  50. Mendels J, Johnston R, Mattes J, et al. Efficacy and safety of b.i.d. doses of venlafaxine in a dose-response study. Psychopharmacol Bull 1993; 29: 169–74

    PubMed  CAS  Google Scholar 

  51. Benkert O, Hackett D, Realini R, et al. A randomised, double blind comparison of rapidly scalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia [abstract]. Neuropsychopharmacology 1994; 10 Suppl. 3(Pt 2): 165S

    Google Scholar 

  52. Schweizer E, Feighner J, Mandos LA, et al. Comparison of venlafaxine and imipramine in the acute treatment of major depression in outpatients. J Clin Psychiatry 1994; 55: 104–8

    PubMed  CAS  Google Scholar 

  53. Danjou P. A randomised, double-blind, comparison of venlafaxine and fluoxetine in inpatients with major depression and melancholia [abstract]. Neuropsychopharmacology 1994; 10 Suppl. 3 (Pt 2): 222S

    Google Scholar 

  54. Norman TR, Leonard BE. Fast-acting antidepressants: can the need be met? CNS Drugs 1994; 2: 120–31

    Article  Google Scholar 

  55. Van Praag HM. In search of the mode of action of antidepressants. 5-HTP/tyrosine mixtures in depressions. Neuropharmacology 1983; 22: 433–40

    Article  PubMed  Google Scholar 

  56. Danish University Antidepressant Group. Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology 1986; 90: 131–8

    Google Scholar 

  57. Danish University Antidepressant Group. Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Disord 1990; 18: 289–99

    Article  Google Scholar 

  58. Anderson IM, Tomenson BM. The efficacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants. J Psychopharmacol 1994; 8: 238–49

    Article  PubMed  CAS  Google Scholar 

  59. Nelson JC, Mazure CM, Bowers MB, et al. A preliminary open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 1991; 48: 303–7

    Article  PubMed  CAS  Google Scholar 

  60. Goodnough DB, Baker GB. 5-Hydroxytryptamine(2) and betaadrenergic receptor regulation in rat brain following chronic treatment with desipramine and fluoxetine alone and in com-bination. J Neurochem 1994; 62: 2262–8

    Article  PubMed  CAS  Google Scholar 

  61. Dechant KL, Clissold SP. Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness. Drugs 1991; 41: 225–53

    Article  PubMed  CAS  Google Scholar 

  62. Hyttel J, Overo KF, Arnt J. Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-up-take inhibitor, Citalopram. Psychopharmacology (Berl) 1984; 83: 20–7

    Article  CAS  Google Scholar 

  63. Pälvimäki EP, Laakso A, Kuoppamaki M, et al. Up-regulation of beta(1)-adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments. Psychopharmacology (Berl) 1994; 115: 543–6

    Article  Google Scholar 

  64. Nalepa I, Vetulani J. Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor Citalopram. J Neurochem 1993; 60: 2029–35

    Article  PubMed  CAS  Google Scholar 

  65. Koe BK, Koch SW, Lebel LA, et al. Sertraline: a selective inhibitor of serotonin uptake, induces subsensitivity of betaadrenoceptor system of rat brain. Eur J Pharmacol 1987; 141: 187–94

    Article  PubMed  CAS  Google Scholar 

  66. Bel N, Artigas F. Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse 1993; 15: 243–5

    Article  PubMed  CAS  Google Scholar 

  67. Ferrer A, Artigas F. Effects of single and chronic treatment with tranylcypromine on extracellular serotonin in rat brain. Eur J Pharmacol 1994; 263: 227–34

    Article  PubMed  CAS  Google Scholar 

  68. Invernizzi R, Bramante M, Samanin R. Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors. Eur J Pharmacol 1994; 260: 243–6

    Article  PubMed  CAS  Google Scholar 

  69. Göthert M, Huth H, Schlicker E. Characterization of the receptor subtype involved in alpha-adrenoceptor-mediated modulation of serotonin release from rat brain cortex slices. Naunyn Schmiedebergs Arch Pharmacol 1981; 317: 199–203

    Article  PubMed  Google Scholar 

  70. Mongeau R, De Montigny C, Blier P. Effects of long-term alpha-2 adrenergic antagonists and electroconvulsive treatments on the alpha-2 adrenoceptors modulating serotonin neurotransmission. J Pharmacol Exp Ther 1994; 269: 1152–9

    PubMed  CAS  Google Scholar 

  71. Tao R, Hjorth S. α2-Adrenoceptor modulation of rat ventral hippocampal 5-hydroxytryptamine release in vivo. Naunyn Schmiedebergs Arch Pharmacol 1992; 345: 137–4

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neurochemistry, Centro de Investigaciön y Desarrollo, C.S.I.C., Jordi Girona 18–26, E-08034, Barcelona, Spain

    Francesc Artigas

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Artigas, F. Selective Serotonin/Noradrenal Reuptake Inhibitors (SNRIs). CNS Drugs 4, 79–89 (1995). https://doi.org/10.2165/00023210-199504020-00001

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