Which Antidepressant is the Right One for Medication Augmentation? A Journal Review With Rakesh Jain, MD

Psych Congress Steering Committee Member, Rakesh Jain, MD, MPH, discusses the question: When augmenting an antidepressant with another antidepressant, which one should I choose? For this installment of 7 in 7, Dr Jain presents his takeaways from the article, "Combining antidepressants vs antidepressant monotherapy for treatment of patients with acute depression: a systematic review and meta-analysis," recently published in JAMA Psychiatry​​​​​​.

Read the transcript:

Dr Rakesh Jain:  One of the most pressing questions in contemporary psychiatry is this one. When augmenting an antidepressant with another antidepressant, which one do I choose? Do I even do it?

Therefore, this topic is very worthy of our conversation during this journal article review, where my goal is to review 7 journals and then find 1 article that is worthy of spending some time looking at.

The question we are going to be examining in some depth is, is bupropion augmentation appropriate, or is mirtazapine or trazodone augmentation appropriate, and which one might be better? Is it time to look at this issue differently?

My name is Rakesh Jain. Hello, everyone. I'm a clinical professor in the Department of Psychiatry at Texas Tech University, School of Medicine in Permian Basin, Midland, Texas, and in private practice in Austin, Texas. My favorites 7 journals, which I consider essential in my development as a mental health clinician are the following:

I love the American Journal of Psychiatry, Molecular Psychiatry, Translational Psychiatry—The Lancet Psychiatry is a great international journal—The Journal of Positive Psychology, The Child and Adolescent Psychiatry's main journal, which we often call “The Orange Journal,” and then, of course, The Journal of Wellness.

Today's featured article is this one. It appears in the February issue of JAMA Psychiatry, and the very title of it should intrigue us, "Combining Antidepressants Versus Antidepressant Monotherapy for Treatment of Patients With Acute Depression." This is a systemic review and a meta‑analysis.

I will be reporting on the results of an original investigation from researchers from Germany, from the University of Cologne Medical School, led by Jonathan Henssler. If you would like to read the article for yourself, the entire citation is provided here for you, and I'll be providing it one more time at the end of this journal review.

The goals of this study, this systematic review and meta‑analysis of randomized clinical trials compared combinations of 2 antidepressants with antidepressant monotherapy alone in adults with acute depression primarily to ask and try and answer 3 questions.

Number 1, what is the efficacy of this combination treatment relative to monotherapy, both as first‑line treatment and as treatment for nonresponders? Goodness me, that first goal is spectacular. Number 2, are combination treatments that include mirtazapine or bupropion particularly effective?

Number 3, what is the comparative tolerability of combination therapies? You folks ready to dive into it?

They reviewed well over 5000‑plus records, and they, of course, found 39 randomized controlled trials, which included 6751 patients who were eligible for this analysis. It's a pretty spectacularly large, wonderful meta‑analysis.

The results. As you can see just from looking at it, there is some random spread to study results favoring monotherapy or favoring combination. Overall, including the confidence intervals, the combination therapies are favored.

Hold on. There's more depth and nuance to it that we'll be examining right now. First of all, why don't we focus on bupropion? Surprise, surprise, combination therapy that included bupropion was not associated with superior outcomes compared with monotherapy. Wow, this flies in the face of what many of us clinicians have been doing.

Though I must tell you, amongst nonresponder populations, bupropion combination was superior. These combinations were superior to monotherapy with a standard mean deviation of about 0.17. Starting out with bupropion did not produce any superior results, but in nonresponders, we did see positive results.

On the other hand, if alpha‑2 autoreceptor antagonists—examples would be mirtazapine, trazodone—if they were used, guess what? Combination of SSRIs, SNRIs with one of these antagonists of presynaptic alpha‑2 autoreceptors were associated with superior outcomes relative to monotherapy.

Amongst all 18 randomized controlled trials, amongst the nonresponder population, and also in particular when applied as first‑line treatment, guess what? That particular combination of SSRIs, SNRIs with mirtazapine and trazodone were actually significant.

What about effect sizes with these 2 very popular interventions? For antidepressants plus alpha‑2s, the alpha‑2 antagonists, the effect size was actually pretty good. It varied between 0.32 and 0.43. For bupropion, the effect sizes were considerably lower, 0.06 and 0.15. Already, this study is making some waves in the field of psychiatry, as you can see why that would be the case.

What about tolerability? With respect both to patients dropping out of treatment for any reason and to dropouts due to adverse reactions, guess what? Data for combination and monotherapy were similar, both for starts at the very beginning as well as for combinations later.

Alpha‑2 adrenergic receptor antagonists, bupropion, who won? Clearly, the alpha‑2 adrenergic receptor antagonists do win the battle. By the way, on the tolerability front, interestingly, despite widely held beliefs that bupropion might be superior to alpha‑2 adrenergic receptor antagonists, that did not prove to be the case in these studies.

What this article teaches us, I'll offer you this in 3 parts. Part 1, for clinical practice, physicians should be aware that combinations of our reuptake inhibitors with alpha‑2 autoreceptor antagonists—remember, the 2 main ones are mirtazapine and trazodone—are a potent treatment option associated with superior outcomes relative to monotherapy.

What's lesson number 2 we can learn? Clinicians can inform patients that, on average, this advantage does not come at the cost of lower tolerability. How fascinating. Of course, part 3, the lesson we could learn is that these authors believe combination treatment particularly suggests itself in severe cases of depression right off the bat and for patients resistant to standard treatment.

Three very important teachings from this article, and that's why it was worthy of inclusion in my Journal Club Review. You want to read this article in its entirety? I suspect, after having given you these results, you would want to. Here is the citation that'll allow you to read this original research from our colleagues in Germany.

Folks, thank you so much for joining me in this issue of "7 Journals in 7 Minutes." I hope you found it useful, and I will see you at the next issue. Goodbye for now.