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J Affect Disord. 2009 May;115(1-2):234-40. doi: 10.1016/j.jad.2008.07.007. Epub 2008 Aug 9.

Does tachyphylaxis occur after repeated antidepressant exposure in patients with Bipolar II major depressive episode?

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  • 1Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-3309, United States.



Tachyphylaxis often refers to the loss of antidepressant efficacy during long-term treatment. However, it may also refer to the gradual loss of efficacy after repeated antidepressant exposures over time. The aim of this study was to examine the phenomenon of tachyphylaxis in patients with Bipolar II major depression treated with either venlafaxine or lithium. We hypothesized that a greater number of prior antidepressant exposures would result in a reduced response to venlafaxine, but not lithium, therapy.


83 patients were randomized to treatment with either venlafaxine (n=43) or lithium (n=40). The primary outcome was a >or= 50% reduction in baseline Hamilton Depression Rating score. A detailed history of prior drug therapy was obtained. Logistic regression was used to test the hypothesis that prior antidepressant exposure was associated with reduced response to venlafaxine therapy.


The mean number of prior antidepressant and mood stabilizer exposures was significantly higher in venlafaxine non-responders versus responders (p=0.02). There was no significant association between response to lithium and the number of prior antidepressant and mood stabilizer exposures (p=0.38). The odds of responding to venlafaxine or lithium therapy decreased with an increasing number of prior antidepressant exposures (p=0.04). Response was not significantly affected by the number of prior mood stabilizer exposures (p=0.30). Adjustment for clinical and demographic covariates sharpened the estimated impact of prior antidepressant exposure on treatment outcome.


This study was a post hoc exploratory analysis. The study was not specifically powered to test the hypothesis of an association between number of prior antidepressant drug exposures and response to venlafaxine or lithium therapy.


These observations support earlier findings suggesting the presence of tachyphylaxis occurring after repeated antidepressant drug exposures. Possible mechanisms of tachyphylaxis may include genetic predisposition for non-response, physiological adaptation after repeated antidepressant exposures, and inherent illness and pharmacokinetic heterogeneity.

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