Each month, Editor-in-Chief Chris Aiken, MD, gives advice on a different practice challenge.

Dear Dr. Aiken: In the July/August 2018 issue, you wrote that ­bupropion (Wellbutrin) augmentation does not work in ­treatment-resistant depression (TRD). So why do we see it work so often in practice?

Dr. Aiken: When all of the studies are averaged together, bupropion augmentation does not seem to work, but it’s possible that something is lost in the averaging. What if there were two types of depressed patients—some who got worse with bupropion augmentation and others who got better? When lumped together, they would cancel out and give the impression that bupropion makes no difference. That’s what a new analysis of the large CO-MED trial suggests. This study randomized 665 depressed patients into three treatment arms:

1. Escitalopram + placebo


2. Escitalopram + bupropion


3. Venlafaxine + mirtazapine

Outcomes were similar for all three groups after 12 weeks and again after 7 months. That’s not a surprise, as our July/August issue suggested that none of those augmentation strategies perform much better than placebo. However, a different story ­emerges when the patients in that study are stratified by weight or inflammation. Compared to SSRI monotherapy, adding bupropion actually worsened outcomes when patients had a BMI ≤ 25 or low levels of C-reactive protein (CRP < 1 mg/L), a marker for inflammation. When CRP was ≥ 1 mg/L or BMI was ≥ 35, bupropion augmentation performed much better than SSRI monotherapy (remission rates were 1.75 times greater). For mild-moderate obesity (BMI 26–34), the three treatments did not differ (Jha MK et al, J Affect Disord 2018;234:34–37; Jha MK et al, Psychoneuroendo 2017;78:105–113).

These results need replication, but they did not come out of nowhere. Obesity is an inflammatory state, so it makes sense that BMI and CRP predicted similar outcomes. Bupropion is dopaminergic and noradrenergic, and has anti-inflammatory effects. Other research suggests that dopaminergic and noradrenergic antidepressants perform better in inflammatory states than the SSRIs.

Bottom line
Bupropion augmentation is not well-supported by the data, but if you use it, patients with obesity or inflammation may have the best outcomes. If combining bupropion with an SSRI, choose escitalopram or citalopram, as the others can alter its metabolism (see TCPR, Nov/Dec 2018). As for CRP, there’s growing evidence that this biomarker can predict medication response, so look for an update in a future issue.