Step‐wise loss of antidepressant effectiveness with repeated antidepressant trials in bipolar II depression

Abstract

Objective This study examined the relationship between the number of prior antidepressant treatment trials and step-wise increase in pharmacodynamic tolerance (or progressive loss of effectiveness) in subjects with bipolar II depression. Methods Subjects ≥ 18 years old with bipolar II depression (n = 129) were randomized to double-blind venlafaxine or lithium carbonate monotherapy for 12 weeks. Responders (n = 59) received continuation monotherapy for six additional months. Results After controlling for baseline co-variates of prior medications, there was a 25% reduction in likelihood of response to treatment with each increase in the number of prior antidepressant trials [odds ratio (OR) = 0.75, B = −0.29, SE = 0.12; χ2 = 5.70, p < 0.02], as well as a 32% reduction in the likelihood of remission with each prior antidepressant trial (OR = 0.68, B = −0.39, SE = 0.13; χ2 = 9.71, p = 0.002). This step-wise increase in pharmacodynamic tolerance occurred in both treatment conditions. Prior selective serotonin reuptake inhibitor (SSRI) therapy was specifically associated with step-wise increase in tolerance, whereas other prior antidepressants or mood stabilizers were not associated with pharmacodynamic tolerance. Neither the number of prior antidepressants, SSRIs, or mood stabilizers, were associated with an increase in relapse during continuation therapy. Conclusions The odds of responding or remitting during venlafaxine or lithium monotherapy were reduced by 25% and 32%, respectively, with each increase in the number of prior antidepressant treatment trials. There was no relationship between prior antidepressant exposure and depressive relapse during continuation therapy of bipolar II disorder.

Effectiveness and safety of monoamine oxidase inhibitor treatment for bipolar depression versus unipolar depression: An exploratory case cohort study

“…These findings are consistent with prior reports by Amsterdam et al 38 and Rush et al, 39 whereby repeated exposure to prior antidepressant therapy over the course of unipolar depression resulted in a stepwise loss of antidepressant responsiveness. This phenomenon has also been reported for patients receiving antidepressants for bipolar II major depressive episode, in the acute and maintenance phase of treatment 40–42 …”

More Treatment, but Not Less Anxiety and Mood Disorders: Why? Seven Hypotheses and Their Evaluation

“…How frequently these adverse effects occur and outbalance the benefits of treatment is less clear. In particular, medication has been associated with a variety of adverse effects: paradoxical effects, manifestations of tolerance (loss of clinical effect, refractoriness), withdrawal symptoms and disorders [78][79][80][81]. Significant adverse effects of psychological treatments have been noted as well [82,83].…”

Antidepressant treatment response in bipolar II disorder

“…In a recent article, Amsterdam et al . conducted secondary analyses of study data assessing the efficacy of lithium versus venlafaxine monotherapy over a 12‐week period for 129 outpatients meeting criteria for the depressed phase of bipolar II disorder, as well as relapse prevention therapy in a 6‐month continuation study of 59 of those subjects .…”

“…The reader is referred back to the published figure for his or her own inspection and interpretation. Amsterdam et al . provide possible explanations for the finding: in essence, inter‐individual differences in response to different drugs, perhaps the result of genetic predisposition, and physiological adaptation over time leading to progressive tolerance.…”

“…Amsterdam et al . report that the increase in pharmacodynamic tolerance related to past antidepressant exposure occurred with both the lithium and venlafaxine treatments.…”