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  • Original Research Article
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Delayed pharmacological effects of antidepressants

Abstract

Although antidepressants may not be primary mood stabilizers, they are efficacious in the prophylaxis of recurrent depressive illnesses, as well as in the treatment of acute episodes. Pharmacological effects that may contribute to the prophylactic effects of these drugs are not understood. Studies have been carried out in which antidepressants have been given to laboratory animals, such as rats, for periods of up to 3–4 weeks. Data obtained in such studies are thought to be important for their beneficial effects in depressive episodes, but also may be relevant to their prophylactic effects. Results are presented showing that when selective inhibitors of serotonin or norepinephrine uptake are given for such time periods, they still produce selective effects on serotonergic or noradrenergic parameters. For example, long-term administration of selective norepinephrine reuptake inhibitors causes a down-regulation of β1 adrenoceptors. Selective serotonin reuptake inhibitors do not produce this effect. Long-term administration of selective serotonin reuptake inhibitors causes down-regulation of the serotonin transporter, but not the norepinephrine transporter. In contrast, selective norepinephrine reuptake inhibitors down-regulate the norepinephrine transporter but not the serotonin transporter. Substantial loss of serotonin transporter binding sites takes 15 days to occur and is accompanied by a marked reduction of serotonin transporter function in vivo.

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References

  1. Solomon DA, Keller MB, Leon AC et al. Multiple recurrences of major depressive disorder Am J Psychiatry 2000 157: 229–233

    Article  CAS  Google Scholar 

  2. Keller MB, Lavori PW, Lewis CE et al. Predictors of relapse in major depressive disorder JAMA 1983 250: 3299–3304

    Article  CAS  Google Scholar 

  3. Montgomery SA . Efficacy in long-term treatment of depression J Clin Psychiatry 1996 57 (Suppl 2): 24–30

    Google Scholar 

  4. Weiss JM, Cierpial MA, West CH . Selective breeding of rats for high and low motor activity in a swim test: toward a new animal model of depression Pharmacol Biochem Behav 1998 61: 49–66

    Article  CAS  Google Scholar 

  5. Willner P . Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation Psychopharmacology 1997 134: 319–329

    Article  CAS  Google Scholar 

  6. Gelenberg AJ, Chesen CL . How fast are antidepressants? J Clin Psychiatry 2000 61: 712–721

    Article  CAS  Google Scholar 

  7. Quitkin FM, Rabkin JG, Ross D et al. Identification of true drug response to antidepressants Arch Gen Psychiatry 1984 41: 782–786

    Article  CAS  Google Scholar 

  8. Stassen HH, Angst J, Delini-Stula A . Fluoxetine versus moclobemide: cross-comparison between the time courses of improvement Pharmacopsychiatry 1999 32: 56–60

    Article  CAS  Google Scholar 

  9. Katz MM, Koslow SH, Frazer A . Onset of antidepressant activity: reexamining the structure of depression and multiple actions of drugs Depress Anxiety 1996/1997 4: 257–267

    Article  Google Scholar 

  10. Popoli M, Brunello N, Perez J et al. Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs J Neurochem 2000 74: 21–33

    Article  CAS  Google Scholar 

  11. Duman RS, Malberg J, Thome J . Neural plasticity to stress and antidepressant treatment Biol Psychiatry 1999 46: 1181–1191

    Article  CAS  Google Scholar 

  12. Mongeau R, Blier P, de Montigny C . The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments Brain Res Rev 1997 23: 145–195

    Article  CAS  Google Scholar 

  13. Frazer A . Norepinephrine involvement in antidepressant action J Clin Psychiatry 2000 61: 25–30

    CAS  PubMed  Google Scholar 

  14. Delgado PL, Miller HL, Salomon RM et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action Biol Psychiatry 1999 46: 212–220

    Article  CAS  Google Scholar 

  15. Miller HL, Delgado PF, Salomon RM et al. Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression Arch Gen Psychiatry 1996 53: 117–128

    Article  CAS  Google Scholar 

  16. Banerjee SP, Kung LS, Chanda SK . Development of beta-adrenergic receptor subsensitivity by antidepressants Nature (Lond) 1977 268: 455–456

    Article  CAS  Google Scholar 

  17. Frazer A, Pandey G, Mendels J et al. The effect of triiodothyronine on [3 H]-cyclic AMP production in slices of rat cerebral cortex Neuropharmacology 1974 13: 1131–1140

    Article  CAS  Google Scholar 

  18. Ordway GA, Gambarana C, Tejani-Butt SM et al. Preferential reduction of binding of 125I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments J Pharmacol Exp Ther 1991 257: 681–690

    CAS  PubMed  Google Scholar 

  19. Frazer A . Antidepressants J Clin Psychiatry 1997 58 (Suppl 6): 9–25

    Google Scholar 

  20. Blakely RD, Bauman AL . Biogenic amine transporters: regulation in flux Curr Opin Neurobiol 2000 10: 328–336

    Article  CAS  Google Scholar 

  21. Durand M, Berton O, Aguerre S et al. Effects of repeated fluoxetine on anxiety-related behaviors, central serotonergic systems, and the corticotropic axis in SHR and WKY rats Neuropharmacology 1999 38: 893–907

    Article  CAS  Google Scholar 

  22. Dean B, Pereira A, Pavey G et al. Repeated antidepressant drug treatment, time of death and frequency of handling do not affect [3H] paroxetine binding in rat cortex Psychiatry Res 1997 73: 173–179

    Article  CAS  Google Scholar 

  23. Gobbi M, Crespi D, Foddi MC et al. Effects of chronic treatment with fluoxetine and citalopram on 5-HT uptake, 5-HT1B autoreceptors, 5-HT3 and 5-HT4 receptors in rats Naunyn Schmiedeberg Arch Pharmacol 1997 356: 22–28

    Article  CAS  Google Scholar 

  24. Pineyro G, Blier P, Dennis T et al. Desensitization of the neuronal 5-HT carrier following its long-term blockade J Neurosci 1994 14: 3036–3047

    Article  CAS  Google Scholar 

  25. Hrdina PD, Vu TB . Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT2 receptors in rat brain Synapse 1993 14: 324–331

    Article  CAS  Google Scholar 

  26. Bauer ME, Tejani-Butt SM . Effects of repeated administration of desipramine or electroconvulsive shock on norepinephrine uptake sites measured [3H]nisoxetine autoradiography Brain Res 1992 582: 208–214

    Article  CAS  Google Scholar 

  27. Marcusson JO, Ross SB . Binding of some antidepressants to the 5-hydroxytryptamine transporter in brain and platelets Psychopharmacology 1990 102: 145–155

    Article  CAS  Google Scholar 

  28. Frazer A, Morilak DA . Drug for the treatment of affective (mood) disorders In: Brody TM, Larner J, Minneman KP (eds) Human Pharmacology: Molecular to Clinical, 3rd edn Mosby Year Book: St Louis 1998 pp 349–363

    Google Scholar 

  29. Owens MJ, Morgan WN, Plott SJ et al. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites J Pharmacol Exp Ther 1997 283: 1305–1322

    CAS  Google Scholar 

  30. Tremaine LM, Welch WM, Ronfeld RA . Metabolism and disposition of the 5-hydroxytryptamine uptake blocker sertraline in the rat and dog Drug Metab Dispos 1989 17: 542–550

    CAS  PubMed  Google Scholar 

  31. Fredricson Overo OK . Kinetics of citalopram in test animals: drug exposure in safety studies Prog Neuropsychopharmacol Biol Psychiatry 1982 6: 297–309

    Article  CAS  Google Scholar 

  32. Howell SR, Hicks DR, Scatina JA et al. Pharmacokinetics of venlafaxine and O-desmethylvenlafaxine in laboratory animals Xenobiotica 1994 24: 315–327

    Article  CAS  Google Scholar 

  33. Benmansour S, Cecchi M, Morilak DA et al. Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level J Neurosci 1999 19: 10494–10501

    Article  CAS  Google Scholar 

  34. Benmansour S, Cecchi M, Morilak DA et al. Effects of chronic antidepressant (AD) treatment on serotonin (SERT) and norepinephrine (NET) transporters Soc Neurosci 2000 Abstr 26: 400

    Google Scholar 

  35. Daws LC, Toney GM, Davis DJ et al. In vivo chronoamperometric measurements of extracellular serotonin clearance in the rat dentate gyrus J Neurosci Meth 1997 78: 139–150

    Article  CAS  Google Scholar 

  36. Daws LC, Toney GM, Gerhardt GA et al. In vivo chronoamperometric measures of extracellular serotonin clearance in rat dorsal hippocampus: contribution of serotonin and norepinephrine transporters J Pharmacol Exp Ther 1998 286: 967–976

    CAS  PubMed  Google Scholar 

  37. Gerhardt GA, Oke AF, Nagy G et al. Nafion-coated electrodes with high selectivity for CNS electrochemistry Brain Res 1984 290: 390–394

    Article  CAS  Google Scholar 

  38. Tejani-Butt SM . [3H]Nisoxetine: a radioligand for quantitation of norepinephrine uptake sites by autoradiography or by homogenate binding J Pharmacol Exp Ther 1992 260: 427–436

    CAS  Google Scholar 

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Frazer, A., Benmansour, S. Delayed pharmacological effects of antidepressants. Mol Psychiatry 7 (Suppl 1), S23–S28 (2002). https://doi.org/10.1038/sj.mp.4001015

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