A common gene variant linked to higher blood levels of oral esketamine

The question

Do common genetic differences in liver enzymes explain why blood levels of oral esketamine vary so much between people taking it for depression?

What they did

Researchers looked at 18 patients who were part of a placebo-controlled trial of repeated low-dose oral esketamine for treatment-resistant depression. Blood was drawn four hours after a dose. The team measured esketamine and its breakdown products in plasma, and tested each person for three variants in cytochrome P450 enzymes (CYP2B6 516 G > T, CYP3A422 and CYP3A53) that help the body break the drug down.

What they found

People carrying the CYP2B6 516 G > T variant had higher esketamine blood levels (median 5.1 µg/L) than non-carriers (median 2.1 µg/L), a statistically significant difference (p = 0.032). No significant link was found for CYP3A422 carriers (n = 2) or for people with one copy of CYP3A53 (n = 2). The gene variants were also not significantly linked to levels of esketamine’s breakdown products.

The fine print

Only 18 people were tested, and just two carried each of the two CYP3A variants, so those comparisons were far too small to show anything. This was a sub-analysis of a larger trial, not a study designed to answer this question. Blood levels were measured at a single time point, and the study did not report whether higher levels meant better or worse depression outcomes or more side effects. This summary is based on the abstract only.

What it means

Genetics may partly explain why oral esketamine reaches very different blood levels in different people, but this sample is too small to guide any clinical decisions.

Evidence grade: Very low. A small genetic sub-analysis of 18 people drawn from a larger placebo-controlled trial, with only two carriers of some variants, so findings are preliminary.

This summary is based on the study’s published abstract.