“Should such classification ultimately prove to have long-standing utility and validity,” Schneck offered, “it not only will enhance our care and treatment of patients but will be yet another acknowledgment of the remarkable insights of Kraepelin and his contemporaries more than a century ago.”
Treatment-emergent versus antidepressant-induced
The use of a mood stabilizer in this study did not appear to mitigate antidepressant treatment–emergent affective switching, although others have found protective effect from a concurrent mood stabilizer.4 The investigators note, however, that in addition to the study design limitations of modest effect size and absence of placebo control, the mood stabilizers and, to a lesser degree, the type of antidepressants were not standardized.
In discussing this further with Psychiatric Times, Frye considered the possibility that patients who manifest minimal manic symptoms also demonstrate less responsiveness to the mood stabilizer, with less protection against affective switching. “You could argue that the mood stabilizer was not fully optimal, because they would not have been coming in to our study—for bipolar depression—anyway, if it had been working,” Frye commented, “and specifically with the treatment-emergent manic group, you could argue that it wasn’t optimal from the other side either, that there was no mania prophylaxis.”
Frye and colleagues point out that their study does not address the question of whether antidepressants raise the risk of switching and indicate that larger studies with longer-term follow-up and monitoring for manic symptoms are necessary to distinguish antidepressant causality from the natural course of illness. This group has previously differentiated between antidepressants for relative risk of associated switching, however, and they emphasize in this report that “treatment-emergent mania is unequivocally an adverse outcome.”5
Frye commented that they had described this adverse outcome as treatment-emergent rather than antidepressant-induced because differences in patient susceptibility and between antidepressants in liability remain to be elucidated. “Maybe someone who does not have minimal manic symptoms and is on an SSRI for bipolar depression will do okay,” Frye explained, “but maybe someone who has minimal manic symptoms and then gets on more of a noradrenergic antidepressant . . . maybe that’s where there is compound risk.”
In an earlier study of adjunctive antidepressant treatment for bipolar depression, Gary Sachs, MD, and colleagues6 found neither an increased rate of treatment-emergent affective switch with addition of an antidepressant to a mood stabilizer nor evidence of increased efficacy. Frye cautioned against attempting to compare that study with his; he noted the differences in populations and designs, and pointed out that efficacy was not the primary outcome measure of his study.
Although the Sachs study data suggest that antidepressants are safe but ineffective for bipolar depression, Sachs and colleagues cautioned that longer-term studies are needed to fully assess the benefits and risks. While the role of antidepressant medication for bipolar depression continues to be debated, Frye offered his personal perspective that an antidepressant can be beneficial and safe for some patients with bipolar disorder.
“I would rather see us, as a field, not try to say, yes they work or they don’t, or they’re safe or they’re not, and really take more of an individualized, personalized approach,” Frye said. The focus should be on distinguishing between patients and defining individual optimal treatments, Frye argued.