CNS Drugs

, Volume 4, Supplement 1, pp 1–12 | Cite as

Mechanisms of Action of Antidepressants

  • B. E. Leonard


The need to develop new antidepressants has been motivated by the frequency and potential severity of the adverse effects of the tricyclic and monoamine oxidase inhibitor antidepressants. This search for new classes of antidepressants has led to the development of selective inhibitors of noradrenaline (norepinephrine) or serotonin (5-hydroxytryptamine; 5-HT) reuptake, reversible inhibitors of monoamine oxidase, and noradrenergic and specific serotonergic antidepressants. While such novel antidepressants have different pharmacological profiles, there is no evidence that their therapeutic efficacy is superior to that of the tricyclic antidepressants. This raises the question of whether there is a common mechanism of antidepressant effect that may be activated via different neurochemical processes. Some of the possible mechanisms whereby chronic administration of antidepressants may elicit adaptive changes in serotonergic, noradrenergic and other neurotransmitter systems are discussed against the background of the biochemical basis of depression. Finally, the need to improve the efficacy of antidepressants, possibly by utilising mechanisms other than those involving direct modulation of monoamine neurotransmitters (e.g. by changes in prostaglandins, cytokines and neuropeptides such as corticotropin-releasing factor), is discussed.


Glucocorticoid Receptor Mirtazapine Serotonin Receptor Mianserin Milnacipran 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Leonard BE. Biochemical strategies for the development of antidepressants. CNS Drugs 1994; 1: 285–304CrossRefGoogle Scholar
  2. 2.
    Norman TR, Leonard BE. Fast-acting antidepressants — can the need be met? CNS Drugs 1994; 2: 120–31CrossRefGoogle Scholar
  3. 3.
    Åsberg M, Ringberger V-A, Sjoqvist F, et al. Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with chlorimipramine. Clin Pharmacol Ther 1977; 21(2): 2012–7Google Scholar
  4. 4.
    Emrich HM, Hollt V, Kissling W, et al. Beta endorphin like immunoreactivity in cerebrospinal fluid and plasma of patients with schizophrenia and other neuropsychiatric disorders. Pharmacopsychiatry 1979; 12: 269–76CrossRefGoogle Scholar
  5. 5.
    Leonard BE. Stress and the immune system: immunological aspects of depressive illness. In: Leonard BE, Miller K, editors. Stress, the immune system and psychiatry. Chichester: John Wiley and Sons, 1994: 114–36Google Scholar
  6. 6.
    Tuomisto J, Tukiainen E, Ahlfors UG. Decreased uptake of 5-hydroxytryptamine in blood platelets from patients with endogenous depression. Psychopharmacology 1979; 65: 141–7PubMedCrossRefGoogle Scholar
  7. 7.
    Healy D, Carney PA, Leonard BE. Monoamine related markers of depression. J Psychiatr Res 1983; 7: 251–8Google Scholar
  8. 8.
    Healy D, Carney PA, O’Halloran A, et al. Peripheral adrenoceptors and serotonin receptors in depression. J Affect Disord 1985; 17: 285–92CrossRefGoogle Scholar
  9. 9.
    Butler J, Leonard BE. The platelet serotonergic system in depression and following sertraline treatment. Int Clin Pychopharmacol 1988; 3: 343–7CrossRefGoogle Scholar
  10. 10.
    Leonard BE. Neurotransmitter receptors, endocrine responses and the biological substrates of depression: a review. Human Psychopharmacol 1986; 1: 3–18CrossRefGoogle Scholar
  11. 11.
    van Praag HM, Korf J, Puite J. 5-Hydroxyindole acetic acid levels in the cerebrospinal fluid of depressive patients treated with probenecid. Nature 1970; 225: 827CrossRefGoogle Scholar
  12. 12.
    van Praag HM, de Hahn S. Central serotonin deficiency is a factor which increase depression vulnerability? Acta Psychiatr Scand 1979; 61Suppl. 280: 86–96Google Scholar
  13. 13.
    van Praag HM. Depression, suicide and the metabolism of serotonin in the brain. J Affect Disord 1982; 4: 275–82PubMedCrossRefGoogle Scholar
  14. 14.
    Åsberg MM, Bertilsson L, Tuck D, et al. Indolelamine metabolites in the cerebrospinal fluid of depressed patients before and during treatment with nortriptyline. Clin Pharmacol Ther 1973; 14: 277–86PubMedGoogle Scholar
  15. 15.
    Åsberg M, Traskman L, Toren P. 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor. Arch Gen Psychiatry 1976; 33: 1193–7PubMedCrossRefGoogle Scholar
  16. 16.
    Montgomery SA. The non-selective effects of selective antidepressants. Adv Biochem Psychopharmacol 1982; 31: 49–56Google Scholar
  17. 17.
    Veith RC, Bielski RE, Bloom V, et al. Urinary MHPG excretion and treatment with desipramine or amitriptyline prediction of response, effect of treatment and methodological hazards. J Clin Psyhopharmacol 1983; 3: 18–27Google Scholar
  18. 18.
    Potter WZ, Scheinin M, Golden RN, et al. Selective antidepressants on cerebrospinal fluid: lack of specificity on norepinephrine and serotonin metabolites. Arch Gen Psychiatry 1985; 42: 1177–7CrossRefGoogle Scholar
  19. 19.
    Leonard BE. Effect of antidepressants on neurotransmission: a common mechanism of action? In: Osborne NN, editor. Current aspects of the neurosciences. United Kingdom: MacMillan Press, 1992: 205–37Google Scholar
  20. 20.
    Leonard BE. Effect of antidepressants on specific neurotransmitters: are such effects relevant to their therapeutic action? In: den Boer JA, Sitzen JMA, editors. Handbook of depression and anxiety - a biological approach. New York: Marcel Dekker Inc., 1994: 379–404Google Scholar
  21. 21.
    Potter WZ, Grossman F, Rudorfer MV. Noradrenergic function in depressive disorders. In: Mann JJ, Kupfer DJ, editors. Biology of depressive disorders. Part A. A systems perspective. New York: Plenum Press, 1993: 1–28Google Scholar
  22. 22.
    Malone K, Mann JJ. Serotonin and major depression. In: Mann JJ, Kupfer DJ, editors. Biology of depressive disorders. Part A. A systems perspective. New York: Plenum Press, 1993: 29–50Google Scholar
  23. 23.
    Meyerson LR, Wennogle LP, Abel MS, et al. Human brain receptor alteration in suicide victims. Pharmacol Biochem Behav 1982; 17: 159–63PubMedCrossRefGoogle Scholar
  24. 24.
    Stanley M, Mann JJ. Increased serotonin binding sites in frontal cortex of suicide victims. Lancet 1983; 1: 214–6PubMedCrossRefGoogle Scholar
  25. 25.
    Kaufmann CA, Gillin JC, Hill B, et al. Muscarinic binding in suicides. Psychiatry Res 1984; 12: 47–55PubMedCrossRefGoogle Scholar
  26. 26.
    Risch SC, Kalin NH, Janowsky DS, et al. Co-release of ACTH and beta endorphin immunoreactivity in human subjects in response to central cholinergic stimulation. Science 1983; 222: 77PubMedCrossRefGoogle Scholar
  27. 27.
    Janowsky DS, Risch SC. Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorders in stress. Drug Dev Res 1984; 4: 125–42CrossRefGoogle Scholar
  28. 28.
    Janowsky DS, Risch SC, Gillin JC. Adrenergic-cholinergic balance and the treatment of affective disorders. Prog Neuropsychopharmacol Biol Psychiatry 1983; 7: 297–307PubMedCrossRefGoogle Scholar
  29. 29.
    Earley B, Glennon M, Lally M, et al. Autoradiographic distribution of cholinergic muscarinic receptors and serotonin2 receptors in olfactory bulbectomized rats after chronic treatment with mianserin and desipramine. Human Psychopharmacol 1994; 9: 397–407CrossRefGoogle Scholar
  30. 30.
    Leonard BE. Serotonin receptors - where are they going? Int Clin Psycopharmacol 1994; 9Suppl. 1: 7–18CrossRefGoogle Scholar
  31. 31.
    Ogren SO, Fuxe K. Effects of antidepressant drugs on cerebral serotonin receptors. In: Green AR, editor. Neuropharmacology of serotonin. Oxford: Oxford University Press, 1985: 131–80Google Scholar
  32. 32.
    Johnson AM. The comparative pharmacological properties of selective serotonin re-uptake inhibitors in animals. In: Feighner JP, Boyer WF, editors. Selective serotonin re-uptake inhibitors. Chichester, UK; John Wiley & Sons, 1991: 37–70Google Scholar
  33. 33.
    De Montigny C, Chaput Y, Blier P. Modification of serotonergic neuron properties by long-term treatment with serotonin reuptake blockers. J Clin Psychiatry 1990; 51Suppl. B: 4–8PubMedGoogle Scholar
  34. 34.
    Hamon M, Emerit MB, Mestiakawa S, et al. Pharmacological, biochemical and functional properties of 5-HTIA binding sites labelled by 8-0H-DPAT in the rat brain. In: Dourish T, Ahlenius S, Hudson PH, editors. Brain 5HTIA receptors. Chichester: Ellis Horwood, 1987: 34–51Google Scholar
  35. 35.
    Goodwin GM, De Sousa RJ, Green AR. Presynaptic serotonin receptor mediated response in mice attenuated by antidepressant drugs and electroconvulsive shock. Nature 1985; 317: 531–3PubMedCrossRefGoogle Scholar
  36. 36.
    Aghajanian GK, De Montigny C. Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin. Science 1978; 202: 1303–6PubMedCrossRefGoogle Scholar
  37. 37.
    Blier P, De Montigny C, Chaput Y. A role for the serotonin system in the mechanism of action of antidepressant treatment: preclinical evidence. J Clin Psychiatry 1990; 51Suppl. 4: 14–20PubMedGoogle Scholar
  38. 38.
    Chaput Y, De Montigny C, Blier P. Effects of a selective 5HT reuptake blocker, citalopram, on the sensitivity of 5HT autoreceptors: electrophysiological studies in the rat. Naunyn-Schmiedebergs Arch Phamacol 1986; 33: 342–9CrossRefGoogle Scholar
  39. 39.
    De Montigny C, Chaput YU, Blier P. Classical and novel targets of antidepressant drugs. In: Mendlewicz J, Brunello N, Langer SZ, Racagni G, editors. New pharmacological approaches to the therapy of depressive disorders. Basel: Karger, 1993: 8–17Google Scholar
  40. 40.
    Peroutka SJ, Synder SH. Long-term antidepressant treatment decreases spiroperidol-labelled serotonin receptor binding. Science 1980; 210: 88–90PubMedCrossRefGoogle Scholar
  41. 41.
    Stolz JF, Marsden CA, Middlemiss DM. Effect of chronic antidepressant treatment and subsequent withdrawal on 3H-5-HT and 3H-spiperone binding in rat frontal corex and serotonin receptor mediated behaviour. Psychopharmacology 1983; 80: 150–5PubMedCrossRefGoogle Scholar
  42. 42.
    Nelson DR, Thomas DR, Johnson AM. Pharmacological effects of paroxetine after repeated administration to animals. Acta Psychiatr Scand Suppl. 1989; 350: 21–3PubMedCrossRefGoogle Scholar
  43. 43.
    Sanders-Bush E, Breeding M, Knoth K, et al. Sertraline induced desensitization of the serotonin 5HT2 receptor transmembrane signalling system. Psychopharmacology 1992; 99: 64–9CrossRefGoogle Scholar
  44. 44.
    Deakin JFDW, Guimaraes FS, Wang M, et al. Experimental tests of the 5HT receptor imbalance theory of affective disorders. In: Sandler M, Coppen A, Harnetts S, editors. 5-Hydroxytryptamine in psychiatry. Oxford: Oxford Medical Publications, 1991: 143–54CrossRefGoogle Scholar
  45. 45.
    Leysen JE, Awouters F, Kennis L, et al. Receptor binding profile of R 414687, a novel antagonist of 5HT2 receptors. Life Sci 1981; 20: 1015–8CrossRefGoogle Scholar
  46. 46.
    Leonard BE. A comparison of the pharmacological properties of the novel tricyclic antidepressant lofepramine with its major metabolite desipramine: a review. Int Clin Psychopharmacol 1987; 2: 281–97PubMedCrossRefGoogle Scholar
  47. 47.
    O’Connor WT, Leonard BE. Effect of chronic administration of the 6-aza analogue of mianserin (Org. 3770) and its enantiomers on behaviour and changes in noradrenaline metabolism of olfactory-bulbectomized rats in the ‘open field’ apparatus. Neuropharmacology 1986; 25(3): 267–70PubMedCrossRefGoogle Scholar
  48. 48.
    De Boer T, Nefkens F, van Helvoirt A. The alpha2 antagonist Org. 3770 enhances serotonin transmission in vivo. Eur J Pharmacol 1994; 253: R5–6PubMedCrossRefGoogle Scholar
  49. 49.
    Smith WT, Glaudin V, Pangides J, et al. Mirtazapine vs amitriptyline vs placebo in the treatment of major depressive disorders. Psychopharmacol Bull 1990; 26: 191–6PubMedGoogle Scholar
  50. 50.
    De Boer T, Ruigt GSF. The selective α2-adrenoceptor antagonist mirtazapine (Org 3770) enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission. CNS Drugs 1995; 4Suppl. 1: 29–38CrossRefGoogle Scholar
  51. 51.
    Pinder RM, Wieringa JH. Third generation antidepressants. Med Res Dev 1993; 13: 259–325Google Scholar
  52. 52.
    Zivkov M, De Jongh G. Org. 3770 vs amitriptyline: a 6 week randomized double-blind multicentre trial in hospitalized patients. Human Psychopharmacol 1995. In pressGoogle Scholar
  53. 53.
    Trallas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibits antidepressant actions. Eur J Pharmacol 1990; 185: 1–10CrossRefGoogle Scholar
  54. 54.
    Leonard BE. The comparative pharmacology of new antidepressants. J Clin Psychiatry 1993; 54Suppl.: 3–15PubMedGoogle Scholar
  55. 55.
    Skolnick P, Miller R, Young A, et al. Chronic treatment with 1-aminocyclopropanecarboxylic acid desensitizes behavioural responses to compounds acting at the N-methyl-D-aspartate receptor complex. Psychopharmacology 1992; 107: 489–96PubMedCrossRefGoogle Scholar
  56. 56.
    Maj J, Rogoz Z, Skuza G, et al. The effects of MK-801 and antidepressant drugs in the forced swimming test in rats. Eur J Neuropsychopharmacol 1992; 2: 37–41CrossRefGoogle Scholar
  57. 57.
    Papp M, Moryl E. Similar effects of chronic treatment with imipramine and the NMDA antagonists. CGP3784 and MK801 in a chronic mild stress model of depression in rats. Eur J Neuropsychopharmacol 1993; 3: 348–9CrossRefGoogle Scholar
  58. 58.
    Paul IA, Trullas R, Skolnick P, et al. Down regulation of cortical beta adrenoceptors by chronic treatment with functional NMDA antagonists. Psychopharmacology 1992; 106: 285–7PubMedCrossRefGoogle Scholar
  59. 59.
    Paul IA, Trullas R, Skolnick P, et al. Adaptation of the NMDA receptor complex in rat frontal cortex following chronic treatment with electroconvulsive shock or imipramine. Eur J Pharmacol 1993; 247: 305–12PubMedCrossRefGoogle Scholar
  60. 60.
    Paul IA, Nowak G, Layer RT, et al. Adaptation of the NMDA receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther 1994; 269: 95–102PubMedGoogle Scholar
  61. 61.
    Largent BL, Wikstrom H, Gundlach AL, et al. Structural determinants of sigma receptor affinity. Mol Pharmacol 1987; 32: 732–84Google Scholar
  62. 62.
    Itzhak Y, Kassin CO. Clorgyline displays high affinity for sigma binding sites in C57 BL 6 mouse brain. Eur J Pharmacol 1990; 176: 107–8PubMedCrossRefGoogle Scholar
  63. 63.
    Tam SW, Cook L. Sigma opiates and certain antipsychotic drugs mutually inhibit (+)− [3H] SKF 10047 and [3H] haloperidol binding in guinea pig membranes. Proc Nat Acad Sci USA 1984; 81(17): 5618–21PubMedCrossRefGoogle Scholar
  64. 64.
    Roman FJ, Pascaud XP, Duffy 0, et al. Neuropeptide Y and peptide YY interact with rat brain sigma and PCP binding sites. Eur J Pharmacol 1989; 174: 301–2PubMedCrossRefGoogle Scholar
  65. 65.
    Higuchi H, Costa E, Yang H-Y. Neuropeptide Y inhibits the nicotine mediated release of catecholamines from bovine adrenal chromaffin cells. J Pharmacol Exp Ther 1988; 244: 468–74PubMedGoogle Scholar
  66. 66.
    Paul IA, Nowak G, Young A, et al. In vitro modulation of sigma-1 receptors in mouse fore brain by antidepressant drugs. Eur J Pharmacol (Mol Pharmacol Sect) 1995. In pressGoogle Scholar
  67. 67.
    Leonard BE. Second generation antidepressants: chemical diversity but unity of action? In: Montgomery S, Corn TH, editors. Psychopharmacology of depression. Oxford: Oxford University Press, 1994: 19–31Google Scholar
  68. 68.
    Wong KL, Bruck RC, Farabman IA. Amitriptyline mediated inhibition of neurite outgrowth from chicks embryonic cerebral explants involves a reduction in adenylate cyclase activity. J Neurochem 1991; 57: 1223–30PubMedCrossRefGoogle Scholar
  69. 69.
    Racagni G, Tinelli D, Bianchi E, et al. cAMP-dependent binding proteins and endogenous phosphorylation after antidepressant treatment. In: Sandler M, Coppen A, Harnett S, editors. 5-Hydroxytryptamine in psychiatry. Oxford: Oxford Medical Publications, 1991: 116–23CrossRefGoogle Scholar
  70. 70.
    van Eekelen JAM, Kiss JZ, Westphal HM, et al. Immunocytochemical study on the intracellular localization of the type 2 glucocorticoid receptor in the rat brain. Brain Res 1987; 436: 120–8PubMedCrossRefGoogle Scholar
  71. 71.
    Burnstein XL, Cidlowski JA. Regulation of gene expression by glucocorticoids. Ann Rev Physiol 1989; 51: 683–99CrossRefGoogle Scholar
  72. 72.
    Kitayama I, Janson AM, Cintra A. Effects of chronic imipramine treatment on glucocorticoid receptor immunoreactivity in various regions of the rat brain. J Neural Trans 1988; 73: 191–203CrossRefGoogle Scholar
  73. 73.
    Dinan TG. Glucocorticoids and the genesis of depressive illness: a psychobiological model. Br J Psychiatry 1994; 164: 365–71PubMedCrossRefGoogle Scholar
  74. 74.
    Song C, Leonard BE. The effect of olfactory bulbectomy in the rat, alone or in combination with antidepressants and endogenous factors, on immune function. Human Psychopharmacol 1995; 10: 7–18CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • B. E. Leonard
    • 1
  1. 1.Department of PharmacologyUniversity CollegeGalwayIreland

Personalised recommendations