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Do you prescribe antidepressants for patients with bipolar depression? How much risk do they pose? This is a Quick Take on this crucial issue.
The good news is, with a new article from Cheniaux and Nardi, we have a remarkably deep dive into the literature on antidepressants and bipolar depression. The bad news is that there is no new news. After reading this masterful review, you will probably be right back where you started, though much more thoroughly informed. The ongoing debate is, antidepressants are not first line for bipolar depression, but are they second line? Are they farther down the list? Well, I instead focus here on 1 central line of thought. Is it possible that the more times we try an antidepressant, the more treatment resistant the patient becomes? In other words, the more antidepressants, the less likely the patient responds when the antidepressant is suspended and started on mood stabilizers with antidepressant effects.
That is the thrust of what the International Society for Bipolar Disorder has called the most important paper of 2016 by Jay Amsterdam and colleagues from the University of Pennsylvania in the U.S. This assertion, that more antidepressant exposure creates treatment resistance, comes from Amsterdam’s team after they produced a series of studies showing benefit from antidepressants in bipolar II. They even showed better outcomes with antidepressants than lithium, and yet they have raised this alarm. Do antidepressants create treatment resistance?
Now, you might think, maybe the nonresponders have just gotten more antidepressants over the years because they are nonresponders. That is logical. However, Amsterdam’s group carefully controlled as best they could for variables that were associated with inherent treatment resistance like baseline symptom severity, interepisode degree of recovery, and the number of prior depressive episodes. They have also shown that getting multiple antidepressants does not make you less likely to respond to psychotherapy, only to lithium, or even to another antidepressant. This is inconclusive, but if you are interested, check out the literature review that they provide in their full-text article online linked here from Psychopharmacology Institute.
Let’s back up and solidify what has not debated among 9 international treatment guidelines in the last 10 years. There is a review from the International Society for Bipolar Disorders with 60 coauthors. The consensus was, do not use antidepressants in bipolar I except with a mood stabilizer and only in pure bipolar depression. This includes not using antidepressants in rapid cycling, mixed states (even if there is more than 1 manic symptom), or if there is any evidence of a prior activation into hypomania or mania with an antidepressant. They mean just pure bipolar depression, preferably if there is evidence of a good prior response and combined with a mood stabilizer. For bipolar II, they offered no comment because of conflicts in the literature. However, that is half of all bipolar disorders, at least, and far more if we include the subthreshold bipolarity forms.
So, what are we supposed to do with those people? Well, that is where most of the debate continues. To be clear, the debate in bipolar I is about if you should turn to antidepressants as second line or later. The first line are quetiapine, lamotrigine, lithium, and, in the newer guidelines, lurasidone. Now, this is my personal view: After attending to the International Society for Bipolar Disorders meetings for 15 years, it looks to me that people who specialize in bipolar depression use fewer antidepressants than everybody else. Several studies back this up, including data from the STEP-BD research program.
I think the more confidence you have that you can control bipolar depression without antidepressants, the more you will avoid them because everyone agrees that antidepressants can make some patients worse. However, depending on how you define “worse”, it can be a small number if you count induction of mania or a significant number if you count cycle acceleration and mixed symptoms, like insomnia, agitation, and irritability. These new data from Amsterdam and colleagues suggest that you might be creating treatment resistance. So, why use an agent that can make things worse when we have multiple options that not only address the depression but decrease the likelihood of subsequent relapse? To emphasize, according to multiple international guidelines, quetiapine, lamotrigine, and lithium can be used, and if you are ready to spend a substantial amount of money, maybe lurasidone.
To conclude, it seems like the more skilled you become at treating bipolar disorders, the less you use antidepressants. Nevertheless, international guidelines support its use as second-line options after quetiapine, lamotrigine, and lithium. To learn more, check out this new review and the Amsterdam article linked from the Psychopharmacology Institute.
Abstract
Evaluating the Efficacy and Safety of Antidepressants in Patients With Bipolar Disorder
Elie Cheniaux, Antonio E Nardi
Introduction: The use of antidepressants (AD) in the treatment of bipolar depression is one of the most controversial issues in psychopharmacology. For some, AD are useful, but, for others, they should never be used in bipolar depression.
Areas covered: This review examines published clinical studies on the use of ADs in bipolar depression, addressing their clinical efficacy and the occurrence of side effects, manic switches, cycle acceleration, and suicidal behavior. Meta-analyzes and review articles on the subject are also discussed.
Expert opinion: Approved therapeutic options for bipolar depression are associated with not very high response rates and a high incidence of adverse effects. Patients with bipolar depression present very heterogeneous responses to the use of ADs. Some improve significantly, while others, especially those with concomitant manic symptoms, have had previous episodes of treatment-emergent mania or are rapid cyclers, exhibit manic switches or cycle acceleration. The authors conclude that the real question is not whether ADs should or should not be used in bipolar depression, but which patients benefit from these drugs and which ones are impaired. The concept of bipolar spectrum and a dimensional approach on bipolar/unipolar distinction may be useful for understanding the heterogeneity of responses to ADs.
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Reference
Cheniaux, E., & Nardi, A. E. (2019). Evaluating the efficacy and safety of antidepressants in patients with bipolar disorder. Expert Opinion on Drug Safety, 18(10), 893-913.
Related References
- Amsterdam, J. D., Lorenzo‐Luaces, L., & DeRubeis, R. J. (2016). Step‐wise loss of antidepressant effectiveness with repeated antidepressant trials in bipolar II depression. Bipolar Disorders, 18(7), 563-570.
- Amsterdam, J. D., & Kim, T. T. (2019). Prior antidepressant treatment trials may predict a greater risk of depressive relapse during antidepressant maintenance therapy. Journal of Clinical Psychopharmacology, 39(4), 344-350.
