Despite early promise, this trial disappoints
STUDY: Zhukovsky P et al, Nature Mental Health 2026
STUDY TYPE: Randomized controlled trial
FUNDING: National Institute of Mental Health, Wellcome Leap
Background
Earlier this year, a video of Dr. Daniel Amen went viral. The usually polished psychiatrist was unable to explain why he charges over $5,000 for unproven biomarkers like SPECT brain scans.
Dr. Amen claims he doesn’t need randomized trials to test his methods, but the researchers in today’s paper are not above that. Let’s take a look, starting with the early promise.
The Biomarkers
Earlier, the team identified two unique fingerprints that predicted response to sertraline and bupropion, antidepressants with very different actions:
- Sertraline response predicted by: Higher neuroticism, more severe depression, older age, less impairment in cognitive control (Flanker task), and being employed.
- Bupropion response predicted by: Higher reward sensitivity (from Probabilistic Reward Task) and, on fMRI, more connectivity between the nucleus accumbens and rostral anterior cingulate cortex.
The New Study
- 48 unmedicated adults with major depressive disorder underwent fMRI and cognitive testing to generate two biomarker scores based on the putative fingerprints for sertraline and bupropion above.
- Patients were randomized for 8 weeks to a medication that was either consistent or inconsistent with their own marker profile.
Results
Getting the “right” drug didn’t matter response rates were nearly identical whether the assigned drug matched the biomarker (61.5%) or didn’t (66.7%).
The study did generate a secondary signal, worthy of further study. Patients who were negative for both biomarker fingerprints had the lowest response rates (43% vs 66-71%). Maybe a larger sample will tell us more.
Practice Implications
- From phrenology to genetics, biomarkers are hard to resist, but proof is even harder to find.
- In Difficult to Treat Depression, I arrived at only one biomarker with some utility: a low-cost test for inflammation (hs-CRP).
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
