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Neuropsychopharmacology (2004) 29, 11661171
& 2004 Nature Publishing Group All rights reserved 0893-133X/04 $25.00www.neuropsychopharmacology.orgAddition of the a2-Antagonist Yohimbine to Fluoxetine:
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[notdef]Gerard Sanacora*,1, Robert M Berman1,4, Angela Cappiello1, Dan A Oren1, Akira Kugaya1, Nianjun Liu1,
Ralitza Gueorguieva2, Donna Fasula1 and Dennis S Charney31Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; 2Department of Epidemiology and Public Health, YaleUniversity School of Medicine, New Haven, CT, USA;3National Institute of Mental Health, Bethesda, MD, USAElectrophysiological studies suggest that a2-adrenoceptors profoundly affect monoaminergic neurotransmission by enhancing
noradrenergic tone and serotonergic firing rates. Recent reports suggest that a2-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 thecombination of an a2-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 bySCID interview were randomly assigned to receive either fluoxetine 20 mg plus placebo (F/P) or fluxetine 20 mg plus a titrated dose ofyohimbine (F/Y). The yohimbine dose was titrated based on blood pressure changes over the treatment period, in a blind-preservingmanner. Hamilton depression scale ratings (HDRS) and clinical global impression (CGI) ratings were obtained weekly over a period of 6weeks. The rate of achieving categorical positive responses was significantly more rapid in the F/Y group compared to the F/P group usingboth the HDRS and the CGI scales as outcome measures in a survival analysis using a log-rank test (w2(1) 5.86, p 0.016 and
w2(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 wereresponders. The addition of the a2-antagonist yohimbine to fluoxetine appears to...