The Selective Norepinephrine Reuptake Inhibitor Antidepressant Reboxetine: Pharmacological and Clinical Profile (original) (raw)

ABSTRACT

Reboxetine is the first commercially available norepinephrine reuptake inhibitor developed specifically as a first line therapy for major depressive disorder. In vitro and in vivo pharmacological studies indicated that reboxetine methanesulphonate has high affinity and selectivity for the human norepinephrine transporter over the serotonin and dopamine transporters. Pharmacological specificity is further demonstrated by the absence of affinity for 45 transmitter receptors and CNS targets.

Pharmacokinetic studies demonstrated that reboxetine is suitable for twice daily administration (8–10 mg/day) and that it exhibits minimal drug‐drug interactions. The starting dose of reboxetine should be reduced in the elderly, in patients with renal or hepatic impairment, or in patients receiving potent CYP3A inhibitors. A total of 20 phase II/III clinical studies comprising placebo‐controlled, active comparator‐controlled and open‐label uncontrolled studies in both short‐term and long‐term treatment of major depression have been conducted. In the treatment of major depression, reboxetine was superior to placebo in 5 of 12 short‐ or long‐term placebo‐controlled studies and was comparable in efficacy to active comparators in 3 out of 3 active‐controlled studies. Unlike conventional tricyclic antidepressants (TCAs), reboxetine had only minimal sedative and cardiovascular liabilities, probably due to increased pharmacological specificity of reboxetine as compared with TCAs. Unlike serotonin reuptake inhibitors, this selective and specific norepinephrine reuptake inhibitor demonstrated a distinct side‐effect profile with diminishing sexual dysfunction and GI side effects. The availability of this agent has afforded patients suffering from major depressive disorder a new class of agents to combat the debilitating consequence of this psychiatric disease. The demonstrated pharmacological specificity of this compound has provided the psychopharmacology community with a tool to elucidate the role of norepinephrine in brain functions. Testing this agent in different animal models has enabled the exploration of the role of modulation of norepinephrine tone in the therapy of CNS disorders beyond depression.

Keywords: Antidepressants, Depression, Norepinephrine, Reboxetine, Transporter

Full Text

The Full Text of this article is available as a PDF (132.9 KB).

REFERENCES

• 1.Andreoli V, Caillard V, Deo RS, Rybakowski JK, Versiani M. Reboxetine, a new noradrenaline selective antidepressant, is at least as effective as fluoxetine in the treatment of depression. J Clin Psychopharmacol 2002;22:393–399. [DOI] [PubMed] [Google Scholar]
• 2.Aston‐Jones G, Rajkowski J, Cohen J. Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 1999;46:1309–1320. [DOI] [PubMed] [Google Scholar]
• 3.Avenoso A, Facciolà G, Scordo MG, _et al._No effect of the new antidepressant reboxetine on CYP2D6 activity in healthy volunteers. Ther Drug Monit 1999;2:577–579. [DOI] [PubMed] [Google Scholar]
• 4.Ban TA, Gaszner P, Aguglia E, _et al._Clinical efficacy of reboxetine: A comparative study with desipramine, with methodologic considerations. Hum Psychopharmacol 1998;13:S29–S39. [Google Scholar]
• 5.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. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 6.Berridge CW: Modulation of forebrain electroencephalographic activity and behavioral state by the locus coeruleus‐noradrenergic system: Involvement of the medial septal area. Adv Pharmacol 1998;42:744–748. [DOI] [PubMed] [Google Scholar]
• 7.Berzewski H, Van Moffaert M, Gagiano CA. Efficacy and tolerability of reboxetine compared with imipramine in a double‐blind study in patients suffering from major depressive episodes. Eur Neuropsychopharmacol 1997;7(Suppl 1):S37–S47. [DOI] [PubMed] [Google Scholar]
• 8.Beyer CE, Boikess S, Luo B, Dawson LA. Comparison of the effects of antidepressants on norepinephrine and serotonin concentrations in the rat frontal cortex: An in vivo microdialysis study. J Psychopharmacol 2002;16:297–304. [DOI] [PubMed] [Google Scholar]
• 9.Bolden‐Watson C, Richelson E. Blockade by newly‐developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci 1993;52:1023–1029. [DOI] [PubMed] [Google Scholar]
• 10.Borsini F, Meli A.):Is the forced swimming test a suitable model for revealing antidepressant activity Psychopharmacology (Berl) 1988;94:147–160. [DOI] [PubMed] [Google Scholar]
• 11.Bragin A, Jando G, Nadasdy Z, Hetke J, Wise K, Buzsáki G. Gamma frequency (40–100 Hz) patterns in the hippocampus of the behaving rat. J Neurosci 1995;15:47–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 12.Brown RE, Sergeeva OA, Eriksson KS, Haas HL. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci 2002;22:8850–8859. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 13.Brunello N, Mendlewicz J, Kasper S, _et al._The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharmacol 2002;12:461–475. [DOI] [PubMed] [Google Scholar]
• 14.Buzsaki G. Theta oscillations in the hippocampus. Neuron 2002;33:325–340. [DOI] [PubMed] [Google Scholar]
• 15.Bymaster FP, Katner JS, Nelson DL, _et al._Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 2002;27:699–711. [DOI] [PubMed] [Google Scholar]
• 16.Carra S, Blom J, Tascedda F, Brunello N, Labbe M, Barden N. Region‐specific BDNF expression modulation by chronic antidepressant treatment in a transgenic mouse model of depression. Soc Neurosci Abstr 2001;27:Program No. 564.7. [Google Scholar]
• 17.Chen B, Dowlatshahi D, MacQueen GM, Wang J, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001;50:260–265. [DOI] [PubMed] [Google Scholar]
• 18.Chergui K, Charlety PJ, Akaoka H, _et al._Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo. Eur J Neurosci 1993;5:137–144. [DOI] [PubMed] [Google Scholar]
• 19.Cocchiara G, Battaglia R, Pevarello P, _et al._Comparison of the disposition and of the metabolic pattern of reboxetine, a new antidepressant, in the rat, dog, monkey and man. Eur J Drug Metab Pharmacokinet 1991;16:231–239. [DOI] [PubMed] [Google Scholar]
• 20.Connor TJ, Kelliher P, Harkin A, Kelly JP, Leonard BE. Reboxetine attenuates forced swim test‐induced behavioral and neurochemical alterations in the rat. Eur J Pharmacol 1999;379:125–133. [DOI] [PubMed] [Google Scholar]
• 21.Coulomb F, Ducret F, Fiorentini F, _et al._Pharmacokinetics of single‐dose reboxetine in volunteers with renal insufficiency. J Clin Pharmacol 2000;40:482–487. [DOI] [PubMed] [Google Scholar]
• 22.Cryan JF, Dalvi A, Jin SH, Hirsch BR, Lucki I, Thomas SA. Use of dopamine‐β‐hydroxylase‐deficient mice to determine the role of norepinephrine in the mechanism of action of antidepressant drugs. J Pharmacol Exp Ther 2001;298:651–657. [PubMed] [Google Scholar]
• 23.Dannon PN, Iancu I, Grunhaus L. The efficacy of reboxetine in the treatment‐refractory patients with panic disorder: An open label study. Hum Psychopharmacol 2002;17:329–333. [DOI] [PubMed] [Google Scholar]
• 24.Davies DS, Murray S, Edwards RJ, _et al._Inhibitory potential of reboxetine on major drug metabolizing forms of P450 in humans [abstract]. American College of Neuropsychopharmacology 36th Annual Meeting, December 812, 1997, Waikoloa (Hawaii).
• 25.Dekeyne A, Gobert A, Auclair A, Girardon S, Millan MJ. Differential modulation of efficiency in a food‐rewarded “differential reinforcement of low‐rate” 72‐s schedule in rats by norepinephrine and serotonin reuptake inhibitors. Psychopharmacology (Berl) 2002;162:156–167. [DOI] [PubMed] [Google Scholar]
• 26.Denolle T, Pellizzoni C, Jannuzzo MG, _et al._Hemodynamic effects of reboxetine in healthy male volunteers. Clin Pharmacol Ther 1999;66:282–287. [DOI] [PubMed] [Google Scholar]
• 27.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. [DOI] [PubMed] [Google Scholar]
• 28.Delgado PL, Moreno FA. Role of norepinephrine in depression. J Clin Psychiatry 2000;61(Suppl 1):5–12. [PubMed] [Google Scholar]
• 29.Delgado PL, Moreno FA, Onate L, Gelenberg AJ. Sequential catecholamine and serotonin depletion in mirtazapine‐treated depressed patients. Int J Neuropsychopharmacol 2002;5:63–66. [DOI] [PubMed] [Google Scholar]
• 30.Dubini A, Bosc M, Polin V. Do noradrenaline and serotonin differentially affect social motivation and behaviour Eur Neuropsychopharm 1997;7(Suppl 1):S49–S55. [DOI] [PubMed] [Google Scholar]
• 31.Dubini A, Bosc M, Polin V. Noradrenaline‐selective versus serotonin‐selective antidepressant therapy: differential effects on social functioning. J Psychopharmacol 1997;11(4, Suppl):S17–S23. [PubMed] [Google Scholar]
• 32.Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997;54:597–606. [DOI] [PubMed] [Google Scholar]
• 33.Edwards DM, Pellizzoni C, Breuel HP, _et al._Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding. Biopharm Drug Disp 1995;16:443–460. [DOI] [PubMed] [Google Scholar]
• 34.El‐Giamal N, de Zwaan M, Bailer U, _et al._Reboxetine in the treatment of bulimia nervosa: A report of seven cases. Int Clin Psychopharmacol 2000;15:351–356. [DOI] [PubMed] [Google Scholar]
• 35.Ferguson JM, Mendels J, Schwartz GE: Effects of reboxetine on Hamilton Depression Rating Scale factors from randomized, placebo‐controlled trials in major depression. Int Clin Psychopharmacol 2002;17:45–51. [DOI] [PubMed] [Google Scholar]
• 36.Ferguson JM, Wesnes KA, Schwartz GE. Reboxetine versus paroxetine versus placebo: Effects on cognitive functioning in depressed patients. Int Clin Psychopharmacol 2003;18:9–14. [DOI] [PubMed] [Google Scholar]
• 37.Fiorentini F, Poggesi I, Januzzo MG, _et al._Effect of lorazepam on the pharmacokinetics of reboxetine in healthy volunteers [abstract]. Eur Neuropsychopharmacol 1995;5:300. [Google Scholar]
• 38.Fleishaker JC, Francom SF, Herman BD, Knuth DW, Azie NE. Lack of effect of reboxetine on cardiac repolarization. Clin Pharmacol Ther 2001;70:261–269. [DOI] [PubMed] [Google Scholar]
• 39.Fleishaker JC, Herman BD, Pearson LK, _et al._Evaluation of the potential pharmacokinetic/pharmacodynamic interaction between fluoxetine and reboxetine in healthy volunteers. Clin Drug Invest 1999;18:141–150. [Google Scholar]
• 40.Fleishaker JC, Mucci M, Pellizzoni C, _et al._Absolute bioavailability of reboxetine enantiomers and effect of gender on pharmacokinetics. Biopharm Drug Disp 1999;20:53–57. [DOI] [PubMed] [Google Scholar]
• 41.Frazer A, Benmansour S. Delayed pharmacological effects of antidepressants. Mol Psychiatry 2002;7(Suppl 1):S23–S28. [DOI] [PubMed] [Google Scholar]
• 42.Frazer A. Norepinephrine involvement in antidepressant action. J Clin Psychiatry 2000;61(Suppl 10):25–30. [PubMed] [Google Scholar]
• 43.Friedman JI, Adler DN, Davis KL. The role of norepinephrine in the pathophysiology of cognitive disorders: Potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease. Biol Psychiatry 1999;46:1243–1252. [DOI] [PubMed] [Google Scholar]
• 44.Garcia R. Stress, synaptic plasticity, and psychopathology. Rev Neurosci 2002;13(3):195–208. [DOI] [PubMed] [Google Scholar]
• 45.Gartside SE, Umbers V, Hajos M, Sharp T. Interaction between a selective 5‐HT1A receptor antagonist and an SSRI in vivo: Effects on 5‐HT cell firing and extracellular 5‐HT. Br J Pharmacol 1995;115:1064–1070. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 46.Grant MM, Weiss JM. Effects of chronic antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiologic activity. Biol Psychiatry 2001;49:117–129. [DOI] [PubMed] [Google Scholar]
• 47.Grenhoff J, Nisell M, Ferre S, Aston‐Jones G, Svensson TH. Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat. J Neural Transm Gen Sect 1993;93:11–25. [DOI] [PubMed] [Google Scholar]
• 48.Gross DW, Gotman J. Correlation of high‐frequency oscillations with the sleep‐wake cycle and cognitive activity in humans. Neuroscience 1999;94:1005–1018. [DOI] [PubMed] [Google Scholar]
• 49.Hajós M, Gartside SE, Sharp T. Inhibition of median and dorsal raphe neurones following administration of the selective serotonin reuptake inhibitor paroxetine. Naunyn Schmiedeberg's Arch Pharmacol 1995;351:624–629. [DOI] [PubMed] [Google Scholar]
• 50.Hajós M, Hoffmann WE, Robinson DD, Yu JH, Hajós‐Korcsok É. Norepinephrine but not serotonin reuptake inhibitors enhance theta and gamma activity of the septo‐hippocampal system. Neuropsychopharmacology 2003;28:857–864. [DOI] [PubMed] [Google Scholar]
• 51.Hajós‐Korcsok É, McTavish SF, Sharp T. Effect of a selective 5‐hydroxytryptamine reuptake inhibitor on brain extracellular noradrenaline: Microdialysis studies using paroxetine. Eur J Pharmacol 2000;407:101–107. [DOI] [PubMed] [Google Scholar]
• 52.Hajós‐Korcsok É, Robinson DD, Yu JH, Fitch CS, Walker E, Merchant KM. Rapid habituation of hippocampal serotonin and norepinephrine release and anxiety‐related behaviors, but not plasma corticosterone levels, to repeated footshock stress in rats. Pharmacol Biochem Behav 2003;1974:609–616. [DOI] [PubMed] [Google Scholar]
• 53.Harkin A, Kelly JP, McNamara M, _et al._Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression. Eur J Pharmacol 1999;364:123–132. [DOI] [PubMed] [Google Scholar]
• 54.Harkin A, Nally R, Kelly JP, Leonard BE. Effects of reboxetine and sertraline treatments alone and in combination on the binding properties of cortical NMDA and β1‐adrenergic receptors in an animal model of depression. J Neural Transm 2000;107:1213–1227. [DOI] [PubMed] [Google Scholar]
• 55.Hendershot PE, Fleishaker JC, Lin KM, Nuccio ID, Poland RE. Pharmacokinetics of reboxetine in healthy volunteers with different ethnic descents. Psychopharmacology 2001;155:148–153. [DOI] [PubMed] [Google Scholar]
• 56.Herman BD, Fleishaker JC, Brown MT. Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans. Clin Pharmacol Ther 1999;66:374–379. [DOI] [PubMed] [Google Scholar]
• 57.Herman JP, Renda A, Bodie B. Norepinephrine‐γ‐aminobutyric acid (GABA) interaction in limbic stress circuits: Effects of reboxetine on GABAergic neurons. Biol Psychiatry 2003;53(2):166–174. [DOI] [PubMed] [Google Scholar]
• 58.Hilger E, Willeit M, Praschak‐Rieder N, Stastny J, Neumeister A, Kasper S. Reboxetine in seasonal affective disorder: An open trial. Eur Neuropsychopharmacol 2001;11:1–5. [DOI] [PubMed] [Google Scholar]
• 59.Hindmarch I. Effect of antidepressants on cognitive and psychomotor function: The lack of effect of reboxetine. Hum Psychopharmacol 1998;13:S21–S27. [Google Scholar]
• 60.Invernizzi RW, Parini S, Sacchetti G, _et al._Chronic treatment with reboxetine by osmotic pumps facilitates its effect on extracellular noradrenaline and may desensitize α2–adrenoceptors in the prefrontal cortex. Br J Pharmacol 2001;132:183–188. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 61.Jacobs BL, Fornal CA. Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology 1999;21(2, Suppl):9S–15S. [DOI] [PubMed] [Google Scholar]
• 62.Jensen O, Tesche CD (2002): Frontal theta activity in humans increases with memory load in a working memory task. Eur J Neurosci 15:1395–1399. [DOI] [PubMed] [Google Scholar]
• 63.Jannuzzo MG, Ryde M, Karlmark B, _et al._Pharmacokinetics of reboxetine in healthy volunteers of different ages [abstract]. Eur Neuropsychopharmacol 1995;5:300. [Google Scholar]
• 64.Jannuzzo MG, Strolin Benedetti M, Duchene P, _et al._Pharmacokinetics of reboxetine in the elderly [abstract]. Advances in simultaneous pharmacokinetic/pharmacodynamic modeling. 2nd International symposium. Measurement and kinetics of in vivo drug effects. Noorwijkerhout, The Netherlands, 1416 April 1994. Book of abstracts; 94–96.
• 65.Januzzo MG, Bosc M, Renoux A, _et al._Effect of reboxetine on the pharmacokinetics of lorazepam in healthy volunteers [abstract]. Eur Neuropsychopharmacol 1995;5:300–301. [Google Scholar]
• 66.Jolly DC, Richards JB, Seiden LS. Serotonergic mediation of DRL 72s behavior: Receptor subtype involvement in a behavioral screen for antidepressant drugs. Biol Psychiatry 1999;45:1151–1162. [DOI] [PubMed] [Google Scholar]
• 67.Kasper S, el Giamal N, Hilger E. Reboxetine: The first selective noradrenaline reuptake inhibitor. Exp Opin Pharmacother 2000;1:771–782. [DOI] [PubMed] [Google Scholar]
• 68.Katona C, Bercoff E, Chiu E, Tack P, Versiani V, Woelk H. Reboxetine versus imipramine in the treatment of elderly patients with depressive disorders: A double‐blind randomized trial. J Affect Dis 1999;55:203–213. [DOI] [PubMed] [Google Scholar]
• 69.Keller M. Role of serotonin and noradrenaline in social dysfunction: A review of data on reboxetine and the Social Adaptation Self‐Evaluation Scale (SASS). Gen Hosp Psychiatry 2001;23:15–19. [DOI] [PubMed] [Google Scholar]
• 70.Kugaya A, Seneca NM, Snyder PJ, _et al._Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology 2003;28:413–420. [DOI] [PubMed] [Google Scholar]
• 71.Lam Y, Ereshefsky L, Toney G, _et al._The effects of reboxetine and nefazodone on the pharmacokinetics and pharmacodynamics of alprazolam. Annual Meeting of the American Psychiatric Association. Chicago, IL, USA, May 2000;13–18.
• 72.Larrosa O, de la Llave Y, Bario S, Granizo JJ, Garcia‐Borreguero D. Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: A pilot study. Sleep 2001;24:282–285. [DOI] [PubMed] [Google Scholar]
• 73.Lee AL, Ogle WO, Sapolsky RM. Stress and depression: Possible links to neuron death in the hippocampus. Bipolar Disord 2002;4:117–128. [DOI] [PubMed] [Google Scholar]
• 74.Lemke MR. Effect of reboxetine on depression in Parkinson's disease patients. J Clin Psychiatry 2002;63:300–304. [DOI] [PubMed] [Google Scholar]
• 75.Linner L, Endersz H, Ohman D, Bengtsson F, Schalling M, Svensson TH. Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex. J Pharmacol Exp Ther 2001;297:540–546. [PubMed] [Google Scholar]
• 76.Linner L, Wiker C, Wadenberg ML, Schalling M, Svensson TH. Noradrenaline reuptake inhibition enhances the antipsychotic‐like effect of raclopride and potentiates D2‐blockage‐induced dopamine release in the medial prefrontal cortex of the rat. Neuropsychopharmacology 2002;27:691–698. [DOI] [PubMed] [Google Scholar]
• 77.Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000;20:9104–9110. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 78.Massana J, Moller HJ. Reboxetine: A double‐blind comparison with fluoxetine in major depressive disorder. Int Clin Psychopharmacol 1999;14:73–80. [DOI] [PubMed] [Google Scholar]
• 79.Mateo Y, Fernandez‐Pastor B, Meana JJ. Acute and chronic effects of desipramine and clorgyline on α2‐adrenoceptors regulating noradrenergic transmission in the rat brain: A dual‐probe microdialysis study. Br J Pharmacol 2001;133:1362–1370. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 80.Meyer TE, Habener JF. Cyclic adenosine 3′,5′‐monophosphate response element binding protein (CREB) and related transcription‐activating deoxyribonucleic acid‐binding proteins. Endocrinol Rev 1993;14:269–290. [DOI] [PubMed] [Google Scholar]
• 81.Millan MJ, Gobert A, Lejeune F, _et al._S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 2001;298:565–580. [PubMed] [Google Scholar]
• 82.Millan MJ, Dekeyne A, Papp M, _et al._S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 2001;298:581–591. [PubMed] [Google Scholar]
• 83.Miller DK, Wong EH, Chesnut MD, Dwoskin LP. Reboxetine: functional inhibition of monoamine transporters and nicotinic acetylcholine receptors. J Pharmacol Exp Ther 2002;302:687–695. [DOI] [PubMed] [Google Scholar]
• 84.Miller HL, Delgado PL, Salomon RM, _et al._Clinical and biochemical effects of catecholamine depletion on antidepressant‐induced remission of depression. Arch Gen Psychiatry 1996;53:117–128. [DOI] [PubMed] [Google Scholar]
• 85.Montminy M. Transcriptional regulation by cyclic AMP. Annu Rev Biochem 1997;66:807–822. [DOI] [PubMed] [Google Scholar]
• 86.Mucci M. Reboxetine: A review of antidepressant tolerability. J Psychopharmacology 1997;11(Suppl4):S33–S37. [PubMed] [Google Scholar]
• 87.Nestler EJ, Alreja M, Aghajanian GK. Molecular control of locus coeruleus neurotransmission. Biol Psychiatry 1999;46:1131–1139. [DOI] [PubMed] [Google Scholar]
• 88.Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34:13–25. [DOI] [PubMed] [Google Scholar]
• 89.Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995;15:7539–7547. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 90.Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996;16:2365–2372. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 91.Nyback HV, Walters JR, Aghajanian GK, Roth RH. Tricyclic antidepressants: Effects on the firing rate of brain noradrenergic neurons. Eur J Pharmacol 1975;32:302–312. [DOI] [PubMed] [Google Scholar]
• 92.O'Donnell JM, Seiden LS. Differential‐reinforcement‐of‐low‐rate 72‐second schedule: Selective effects of antidepressant drugs. J Pharmacol Exp Ther 1983;224:80–88. [PubMed] [Google Scholar]
• 93.Page ME, Lucki I. Effects of acute and chronic reboxetine treatment on stress‐induced monoamine efflux in the rat frontal cortex. Neuropsychopharmacology 2002;27:237–247. [DOI] [PubMed] [Google Scholar]
• 94.Page ME, Brown K, Lucki I. Simultaneous analyses of the neurochemical and behavioral effects of the norepinephrine reuptake inhibitor reboxetine in a rat model of antidepressant action. Psychopharmacology 2003;165:194–201. [DOI] [PubMed] [Google Scholar]
• 95.Parker G. “New” and “old” antidepressants: All equal in the eyes of the lore Br J Psychiatry 2001;179:95–96. [DOI] [PubMed] [Google Scholar]
• 96.Pellizzoni C, Poggesi I, Jørgensen NP, _et al._Pharmacokinetics of reboxetine in healthy volunteers. Single against repeated oral doses and lack of enzymatic alterations. Biopharm Drug Disp 1996;17:623–633. [DOI] [PubMed] [Google Scholar]
• 97.Pellizzoni C, Strolin Benedetti M, Poggesi I, _et al._Pharmacokinetics of reboxetine in healthy volunteers: Relative bioavailability and food effect [abstract]. Pharmacol Res 1995;31(Suppl):41. [Google Scholar]
• 98.Pencea V, Bingaman KD, Wiegand SJ, Luskin MB. Infusion of brain‐derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 2001;21:6706–6717. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 99.Poggesi I, Pellizzoni C, Fleishaker JC. Pharmacokinetics of reboxetine in elderly patients with depressive disorders. Int J Clin Pharmacol Ther 2000;38:254–259. [DOI] [PubMed] [Google Scholar]
• 100.Popoli M, Brunello N, Perez J, Racagni G. Second messenger‐regulated protein kinases in the brain: Their functional role and the action of antidepressant drugs. J Neurochem 2000;74:21–33. [DOI] [PubMed] [Google Scholar]
• 101.Pozzi L, Invernizzi R, Cervo L, Vallebuona F, Samanin R. Evidence that extracellular concentrations of dopamine are regulated by noradrenergic neurons in the frontal cortex of rats. J Neurochem 1994;63:195–200. [DOI] [PubMed] [Google Scholar]
• 102.Raghavachari S, Kahana MJ, Rizzuto DS, _et al._Gating of human theta oscillations by a working memory task. J Neurosci 2001;21:3175–3183. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 103.Rammsayer TH, Hennig J, Haag A, Lange N: Effects of noradrenergic activity on temporal information processing in humans. Quart J Exp Psychol B 2001;54:247–258. [DOI] [PubMed] [Google Scholar]
• 104.Reneric JP, Lucki I. Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacology (Berl) 1998;136:190–197. [DOI] [PubMed] [Google Scholar]
• 105.Reuster T, Buechler J, Winiecki P, Oehler J. Influence of reboxetine on salivary MHPG concentration and cognitive symptoms among patients with alcohol‐related Korsakoff's syndrome. Neuropsychopharmacology 2003;28:974–978. [DOI] [PubMed] [Google Scholar]
• 106.Rey E, Dostert P, D'Athis Ph, _et al._Dose proportionality of reboxetine enantiomers in healthy volunteers. Biopharm Drug Disp 1999;20:177–181. [DOI] [PubMed] [Google Scholar]
• 107.Riva M, Brunello N, Rovescalli AC, _et al._Effect of reboxetine, a new antidepressant drug, on the central noradrenergic system: Behavioural and biochemical studies. J Drug Dev 1989;1:243–253. [Google Scholar]
• 108.Rocchetti M, Pellizzoni C, Poggesi I, _et al._Genetic polymorphism and reboxetine metabolism [abstract 80]. 1st Congress of the European Association for Clinical Pharmacology and Therapeutics. Therapie 1995(Suppl), Abstract 80.
• 109.Rogoz Z, Wrobel A, Krasicka‐Domka M, Maj J. Pharmacological profile of reboxetine, a representative of new class of antidepressant drugs, selective noradrenaline reuptake inhibitor (NARI), given acutely. Pol J Pharmacol 1999;51:399–404. [PubMed] [Google Scholar]
• 110.Saarelainen T, Hendolin P, Lucas G, _et al._Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant‐induced behavioral effects. J Neurosci 2003;23:349–357. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 111.Sacchetti G, Bernini M, Bianchetti A, Parini S, Invernizzi RW, Samanin R. Studies on the acute and chronic effects of reboxetine on extracellular noradrenaline and other monoamines in the rat brain. Br J Pharmacol 1999;128:1332–1338. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 112.Sacchetti G, Bernini M, Gobbi M, _et al._Chronic treatment with desipramine facilitates its effect on extracellular noradrenaline in the rat hippocampus: Studies on the role of presynaptic α2‐adrenoceptors. Naunyn Schmiedeberg's Arch Pharmacol 2001;363:66–72. [DOI] [PubMed] [Google Scholar]
• 113.Salomon RM, Miller HL, Delgado PL, Charney D. The use of tryptophan depletion to evaluate central serotonin function in depression and other neuropsychiatric disorders. Int Clin Psychopharmacol 1993;8(Suppl 2):41–46. [DOI] [PubMed] [Google Scholar]
• 114.Siepmann M, Muck‐Weymann M, Joraschky P, Kirch W. The effects of reboxetine on autonomic and cognitive functions in healthy volunteers. Psychopharmacology (Berl) 2001;157:202–207. [DOI] [PubMed] [Google Scholar]
• 115.Smith SL, Wu H, Merchant KM. The norepinephrine transporter selective antidepressant, reboxetine, blocks stress‐induced neuroendocrine and genomic responses [abstract]. Annual Meeting of American College of Neuropsychopharmacology, 1999.
• 116.Sprouse J, Braselton J, Reynolds L, Clarke T, Rollema H. Consequences of 5‐HT re‐uptake blockade on postsynaptic 5‐HT1A receptor activation: An electrophysiological and neurochemical study in guinea pig dorsal raphe and hippocampus. Ann NY Acad Sci 1998;861:272–273. [DOI] [PubMed] [Google Scholar]
• 117.Steru L, Chermat R, Thierry B, _et al._The automated Tail Suspension Test: A computerized device which differentiates psychotropic drugs. Prog Neuropsychopharmacol Biol Psychiatry 1987;11:659–671. [DOI] [PubMed] [Google Scholar]
• 118.Svensson TH, Usdin T. Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants: Alpha‐receptor mediation. Science 1978;202:1089–1091. [DOI] [PubMed] [Google Scholar]
• 119.Szabadi E, Bradshaw CM, Boston PF, Langley RW. The human pharmacology of reboxetine. Hum Psychopharmacology Clin Exp 1998;13:S3–S12. [Google Scholar]
• 120.Szabo ST, Blier P. Effect of the selective noradrenergic reuptake inhibitor reboxetine on the firing activity of noradrenaline and serotonin neurons. Eur J Neurosci 2001;13:2077–2087. [DOI] [PubMed] [Google Scholar]
• 121.Szabo ST, de Montigny C, Blier P. Progressive attenuation of the firing activity of locus coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake inhibitors. Int J Neuropsychopharmacol 2000;3:1–11. [DOI] [PubMed] [Google Scholar]
• 122.Tanum L. Reboxetine: Tolerability and safety profile in patients with major depression. Acta Psychiatr Scand 2000;402(Suppl):37–40. [DOI] [PubMed] [Google Scholar]
• 123.Thomas DN, Holman RB. A microdialysis study of the regulation of endogenous noradrenaline release in the rat hippocampus. J Neurochem 1991;56:1741–1746. [DOI] [PubMed] [Google Scholar]
• 124.Tran A, Laneury JP, Duchene P, _et al._Pharmacokinetics of reboxetine in volunteers with hepatic impairment. Clin Drug Invest 2000;19:473–477. [Google Scholar]
• 125.Usher M, Cohen JD, Servan‐Schreiber D, Rajkowski J, Aston‐Jones G. The role of locus coeruleus in the regulation of cognitive performance. Science 1999;283:549–554. [DOI] [PubMed] [Google Scholar]
• 126.Valentino RJ, Curtis AL, Page ME, Pavcovich LA, Florin‐Lechner SM. Activation of the locus coeruleus brain noradrenergic system during stress: Circuitry, consequences, and regulation. Adv Pharmacol 1998;42:781–784. [DOI] [PubMed] [Google Scholar]
• 127.Versiani M, Cassano G, Perugi G, _et al._Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well‐tolerated treatment for panic disorder. J Clin Psychiatry 2002;63:31–37. [DOI] [PubMed] [Google Scholar]
• 128.Versiani M, Amin M, Chouinard G. Double‐blind, placebo‐controlled study with reboxetine in patients with severe major depressive disorder. J Clin Psychopharmacol 2000;20:28–34. [DOI] [PubMed] [Google Scholar]
• 129.Versiani M, Mehilane L, Gaszner P, Arnaud‐Castiglioni R. Reboxetine, a unique selective NRI, prevents relapse and recurrence in long‐term treatment of major depressive disorder. J Clin Psychiatry 1999;60:400–406. [DOI] [PubMed] [Google Scholar]
• 130.Vertes RP, Kocsis B: Brainstem‐diencephalo‐septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience 1997;81:893–926. [DOI] [PubMed] [Google Scholar]
• 131.Von Voigtlander PF, Triezenberg HJ, Losey EG. Interactions between clonidine and antidepressant drugs: A method for identifying antidepressant‐like agents. Neuropharmacology 1978;17:375–381. [DOI] [PubMed] [Google Scholar]
• 132.Wienkers LC, Allievi C, Hauer MJ, _et al._Cytochrome P450‐mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metab Disp 1999;27:1334–1340. [PubMed] [Google Scholar]
• 133.Wong EH, Sonders MS, Amara SG, _et al._Reboxetine: A pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor. Biol Psychiatry 2000;47:818–829. [DOI] [PubMed] [Google Scholar]
• 134.Wong EHF, Tinholt T, McFinton P, Cortes‐Burgos L, Amara S, Sonders M. Novel enantiomeric selectivity of reboxetine at the catecholamine transporters [abstact]. Soc Neurosci 2001;975 16. [Google Scholar]
• 135.Yamamoto BK, Novotney S. Regulation of extracellular dopamine by the norepinephrine transporter. J Neurochem 1998;71:274–280.3. [DOI] [PubMed] [Google Scholar]