Recurrence in bipolar disorder unlikely the result of “antidepressant tolerance”

While a preponderance of studies of antidepressant-treated bipolar depression have observed equivocal long-term outcomes characterized by non-robust antidepressant response and insufficient reprise of quality of life, a recent English-language study, published in a Polish medical journal by University of Pennsylvania researcher Jay Amsterdam and Indiana University colleague L. Lorenzo-Luaces (JD. Amsterdam and L. Lorenzo-Luaces, Psychiatria Polska 52(6):957-969, 2019), attributes diminishing antidepressant responsivity in persons with bipolar disorder to antidepressant tolerance.

The authors retrospectively studied148 adult patients with bipolar II disorder (listed erroneously as bipolar I disorder in the article title) whose most recent depressive recurrences had responded or remitted during 12 weeks of open-label treatment with fluoxetine monotherapy. Likewise having shown response or remission during antidepressant treatment of prior bipolar depressive episodes (adjunctive medications unspecified), the patients withal showed diminishing rates of response and remission over the course of illness. (The authors define response and remission in standard fashion (the former as fifty-percent or greater reduction of Hamilton Depression Rating Scale total score) and the latter as a final total Hamilton depression rating of eight or lower).

Having examined their patients’ rates of response and remission during prior consecutive trials of (unspecified) antidepressants, the authors observed rates of response and remission that had declined by means of 25 and 22 percent, respectively, per episode. Declining antidepressant response and remission rates were unrelated to (unspecified) baseline clinical or demographic variables.

The authors attribute what they call “step-wise loss of antidepressant effectiveness” over the course of their patients’ depressive recurrences to pharmacodynamic tolerance (diminishing pharmacologic activity at equivalent bioavailability) to repeated therapeutic exposures to antidepressants. (Obiter: Pharmacokinetic interactivity is not ruled out, since patients’ fluoxetine (or other antidepressant) blood concentrations during current and prior treatment are not reported. The authors concede that diminishing antidepressant responsiveness may have devolved from other causes, such as features of experimental design during analysis of patients’ most recent episodes (retrospective analysis of antidepressant response in a patient sample under-powered for testing pharmacodynamic tolerance, interindividual differences among patients in prior trials, and time–related increased heterogeneity of syndromes diagnosed as bipolar disorder over the duration between patients’ first and most recent depressive episodes. Moreover, they do not discuss potential contribution to their results of studies reporting 20 to 80 percent of patients initially diagnosed with bipolar depressive episodes subsequently have been re-diagnosed as having dysphoric hypomania or depressive mixed state, documented unresponsive to or exacerbated by antidepressant exposure. Robust and consistently reported, those findings and that of treatment-resistance to antidepressant monotherapy are increasingly regarded as potential “markers” of missed diagnosis of a bipolar spectrum disorder in patients initially diagnosed with (unipolar) major depressive disorder or “true” bipolar depression. Moreover, randomized, double-blind studies by one of the authors (J.D.A.), of patients with bipolar II disorder, have not reported pharmacodynamic tolerance (to acute or prophylactic antidepressant effects) during long-term treatment.)




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