Pharmacogenetics didn’t predict who got better. Psychotherapy did.
STUDY: Krivosova M et al, Front. Pharmacol. 2026;
STUDY TYPE: Retrospective cohort study
FUNDING: EU NextGenerationEU / Recovery and Resilience Plan for Slovakia
Background
Esketamine (Spravato) is metabolized by liver enzymes CYP-3A4 and -2B6, with minor contributions from CYP-2C9 and -2C19. But do genetic alterations in those enzymes affect treatment? This study tested that, and came to a very different conclusion.
The Study
- 32 adults with treatment-resistant depression in Italy.
- All received intranasal esketamine over 2 months (12 administrations). Researchers tracked depression scales along with CYP2B6, CYP2C9, and CYP3A4 metabolizer status, plus BDNF and OPRM1 gene variants.
Results
No genetic variant predicted response. Metabolizer status for CYP2B6, CYP2C9, and CYP3A4 showed no meaningful association with outcomes. BDNF and OPRM1 genotypes were similarly uninformative.
Dose didn’t predict response either. Most patients ended up at 84 mg, and higher doses didn’t produce better results.
The one factor tied to remission: Adjunctive psychotherapy. All eight patients receiving concurrent psychotherapy reached remission. None of the non-remitters were in therapy (p = 0.0002).
Limitations
Small, retrospective, uncontrolled, no blinding or randomization. It is possible those in psychotherapy were more resilient to begin with.
Practice Implications
- Pharmacogenetic testing did not influence results, likely because it is metabolized by multiple enzymes. Also, genes are not entirely responsible for drug metabolism, with up to 40% of the effects due to environment, diet, gender, age, and other causes.
- The psychotherapy finding is striking, and supported by recent controlled trials suggesting therapy can sustain ketamine’s benefits.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
