Abstract
This study examined the presence of increased pharmacodynamic tolerance with reduced effectiveness following repeated antidepressant trials over the course of the affective illness in subjects with treatment-responsive bipolar II depression. Data were derived from the open-label phase of a prospective, randomized, placebo-controlled trial of long-term fluoxetine versus lithium monotherapy in 148 subjects >=18 years old with treatment-responsive bipolar II depression, who were initially administered open-label fluoxetine monotherapy for 12 weeks. Response was defined as >=50% reduction in baseline Hamilton Rating Scale for Depression (HRSD) score, and remission was defined as a final HRSD score =<8. Subjects reported a mean (SD) total of 1.61 (1.85) (range: 0-9) prior adequate, antidepressant trials over the course of their affective illness, before study enrollment. There was a 25% reduction in the likelihood of fluoxetine response (p < 0.01) and a 22% lower likelihood of remission (p = 0.02), respectively, with each increase in the number of prior antidepressant treatment trials over the illness course. There was no clinically meaningful correlation between fluoxetine response or remission and any other baseline clinical or demographic variable. Thus, only the number of prior antidepressant trials meaningfully impacted the likelihood of fluoxetine response or remission. Limitations. This was an exploratory study of post hoc, analyses, and the trial was not specifically powered to test the development of increased pharmacodynamic tolerance. Disease heterogeneity or inter-individual differences in antidepressant responsiveness may have influenced fluoxetine effectiveness. Conclusion. These results confirm prior observations of an increased pharmacodynamic tolerance after repeated antidepressant administration, resulting in a step-wise loss of antidepressant effectiveness over the course of the illness.
Highlights
An increase in pharmacodynamic tolerance of antidepressant drugs with a loss of effectiveness was first suggested by Lieb and Balter [1] and subsequently demonstrated by Amsterdam et al [2] in a prospective study of 149 fluoxetine-treated subjects with unipolar or bipolar II major depressive episode
The phenomenon has been reported in unipolar depression [2, 3, 5, 6] but may occur in bipolar disorder [3, 4, 7], and may be more common with repeated administration of selective serotonin reuptake inhibitor (SSRI) antidepressants [12,13,14], it may occur with other pharmacologic classes of antidepressants [3, 4, 8,9,10]
In the current exploratory analysis, we examined the phenomenon of increased pharmacologic tolerance after repeated exposure to antidepressant therapy administered at any time over the course of the affective illness, from data derived from a prospective randomized controlled trial of fluoxetine monotherapy of bipolar II major depressive episode
Summary
An increase in pharmacodynamic tolerance of antidepressant drugs with a loss of effectiveness was first suggested by Lieb and Balter [1] and subsequently demonstrated by Amsterdam et al [2] in a prospective study of 149 fluoxetine-treated subjects with unipolar or bipolar II major depressive episode. There is considerable debate as to whether step-wise loss of antidepressant effectiveness results from a genetic predisposition to non-response [13, 15, 16] or from oppositional tolerance with a persistant induction of monoamine receptor down-regulation by repeated antidepressant administration [17]. The latter possibility is disturbing because it would suggest that some cases of resistant depression may be iatrogenic in nature and result from repeated antidepressant administration per se, but not from the application of psychotherapy [6]
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