Abstract
Electrophysiological studies suggest that α2-adrenoceptors profoundly affect monoaminergic neurotransmission by enhancing noradrenergic tone and serotonergic firing rates. Recent reports suggest that α2-antagonism may hasten and improve the response to antidepressant medications. To test this hypothesis, a randomized double-blind controlled trial was undertaken to determine if the combination of an α2-antagonist (yohimbine) with a selective serotonin reuptake agent (SSRI) (fluoxetine) results in more rapid onset of antidepressant action than an SSRI agent alone. In all, 50 subjects with a DSM-IV diagnosis of major depressive disorder confirmed by SCID interview were randomly assigned to receive either fluoxetine 20 mg plus placebo (F/P) or fluxetine 20 mg plus a titrated dose of yohimbine (F/Y). The yohimbine dose was titrated based on blood pressure changes over the treatment period, in a blind-preserving manner. Hamilton depression scale ratings (HDRS) and clinical global impression (CGI) ratings were obtained weekly over a period of 6 weeks. The rate of achieving categorical positive responses was significantly more rapid in the F/Y group compared to the F/P group using both the HDRS and the CGI scales as outcome measures in a survival analysis using a log-rank test (χ2(1)=5.86, p=0.016 and χ2(1)=5.29, p=0.021, respectively). At the last observed visit, 18 (69%) of the 26 F/Y subjects met the response criteria for CGI compared to 10 (42%) of 24 F/P subjects. Using the HDRS criteria, 17 (65%) of 26 F/Y subject vs 10 (42%) of 24 F/P subjects were responders. The addition of the α2-antagonist yohimbine to fluoxetine appears to hasten the antidepressant response. There is also a trend suggesting an increased percentage of responders to the combined treatment at the end of the 6-week trial.
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References
Baraban JM, Aghajanian GK (1980). Suppression of firing activity of 5-HT neurons in the dorsal raphe by alpha-adrenoceptor antagonists. Neuropharmacology 19: 355–363.
Besson A, Haddjeri N, Blier P, de Montigny C (2000). Effects of the co-administration of mirtazapine and paroxetine on serotonergic neurotransmission in the rat brain. Eur Neuropsychopharmacol 10: 177–188.
Carpenter LL, Yasmin S, Price LH (2002). A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry 51: 183–188.
Cappiello A, McDougle CJ, Malison RT, Heninger GR, Price LH (1995). Yohimbine augmentation of fluvoxamine in refractory depression: a single-blind study. Biol Psychiatry 38: 765–767.
Charney DS (1998). Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry 59: 11–14.
Charney DS, Price LH, Heninger GR (1986). Desipramine–yohimbine combination treatment of refractory depression. Implications for the beta-adrenergic receptor hypothesis of antidepressant action. Arch Gen Psychiatry 43: 1155–1161.
Dam J, Ryde L, Svejso J, Lauge N, Lauritsen B, Bech P (1998). Morning fluoxetine plus evening mianserin versus morning fluoxetine plus evening placebo in the acute treatment of major depression. Pharmacopsychiatry 31: 48–54.
Feuerstein TJ, Mutschler A, Lupp A, Van Velthoven V, Schlicker E, Gothert M (1993). Endogenous noradrenaline activates alpha 2-adrenoceptors on serotonergic nerve endings in human and rat neocortex. J Neurochem 61: 474–480.
First M, Spitzer R, Gibbon M, Williams J (2001). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition. (SCID-I/NP). Biometrics Research, New York State Psychiatric Institute: New York.
Frankhuyzen AL, Mulder AH (1980). Noradrenaline inhibits depolarization-induced 3H-serotonin release from slices of rat hippocampus. Eur J Pharmacol 63: 179–182.
Freedman JE, Aghajanian GK (1984). Idazoxan (RX 781094) selectively antagonizes alpha 2-adrenoceptors on rat central neurons. Eur J Pharmacol 105: 265–272.
Guy W (1976). ECDEU Assessment Manual. National Institute of Mental Health, Rockville, MD.
Haddjeri N, Blier P, de Montigny C (1996). Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain. J Pharmacol Exp Ther 277: 861–871.
Hamilton M ed. (1969). Diagnosis and Rating of Anxiety, Br J Psychiatry Spec Publ.
Hollander E, McCarley A (1992). Yohimbine treatment of sexual side effects induced by serotonin reuptake blockers. J Clin Psychiatry 53: 207–209.
Hopwood SE, Stamford JA (2001). Noradrenergic modulation of serotonin release in rat dorsal and median raphe nuclei via alpha(1) and alpha(2A) adrenoceptors. Neuropharmacology 41: 433–442.
Krystal JH, McDougle CJ, Woods SW, Price LH, Heninger GR, Charney DS (1992). Dose–response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine. Psychopharmacology 108: 313–319.
Mazure C, Nelson JC, Price LH (1986). Reliability and validity of the symptoms of major depressive illness. Arch Gen Psychiatry 43: 451–456.
McGahuey CA, Gelenberg AJ, Laukes CA, Moreno FA, Delgado PL, McKnight KM et al (2000). The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther 26: 25–40.
Michelson D, Kociban K, Tamura R, Morrison MF (2002). Mirtazapine, yohimbine or olanzapine augmentation therapy for serotonin reuptake-associated female sexual dysfunction: a randomized, placebo controlled trial. J Psychiatric Res 36: 147–152.
Mongeau R, Blier P, de Montigny C (1993). In vivo electrophysiological evidence for tonic activation by endogenous noradrenaline of alpha 2-adrenoceptors on 5-hydroxytryptamine terminals in the rat hippocampus. Naunyn-Schmiedebergs Arch Pharmacol 347: 266–272.
Nierenberg AA (2001). Do some antidepressants work faster than others? J Clin Psychiatry 62: 22–25.
Price J, Grunhaus LJ (1990). Treatment of clomipramine-induced anorgasmia with yohimbine: a case report. J Clin Psychiatry 51: 32–33.
Quitkin FM, Taylor BP, Kremer C (2001). Does mirtazapine have a more rapid onset than SSRIs? J Clin Psychiatry 62: 358–361.
Stahl SM (1998). Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord 51: 215–235.
Starke K, Montel H (1973). Involvement of alpha-receptors in clonidine-induced inhibition of transmitter release from central monoamine neurones. Neuropharmacology 12: 1073–1080.
Svensson TH, Bunney BS, Aghajanian GK. (1975). Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist clonidine. Brain Res 92: 291–306.
Thase ME (2001). Methodology to measure onset of action. J Clin Psychiatry 62: 18–21.
Acknowledgements
This work was supported by NIMH K08 MH01715-01 (GS), and the Mental Health Clinical Research Center at Yale MH30929-21 (GS, DSC), VA Research Enhancement Award Program (GS, AK). We would also like to thank Lisa Roach and Matthew Wachen for their assistance.
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Previous Presentations: Portions of this study were previously presented at 57th meeting of The Society of Biological Psychiatry, Philadelphia PA, May 2002 and the 2002 American College of Neuropsychopharmacolgy meeting, San Juan, PR, December 2002.
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Sanacora, G., Berman, R., Cappiello, A. et al. Addition of the α2-Antagonist Yohimbine to Fluoxetine: Effects on Rate of Antidepressant Response. Neuropsychopharmacol 29, 1166–1171 (2004). https://doi.org/10.1038/sj.npp.1300418
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DOI: https://doi.org/10.1038/sj.npp.1300418
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