REVIEW OF: Price RB et al, Am J Psychiatry 2022;179(12):959–968

STUDY TYPE: Randomized, double-blind, parallel-arm trial

Ketamine can bring rapid relief in difficult-to-treat depression, but its benefits are unfortunately short-lived. Many medications have been tested, but none have helped patients stay well after ketamine treatment. So far, the only known intervention that prolonged ketamine’s antidepressant effects in a controlled trial was cognitive behavioral therapy. In the current study, researchers tested whether a different psychological intervention could prolong ketamine’s benefits.

The intervention, automated self-association training (ASAT), is a computerized system that pairs positive phrases (such as “sweet”) with self-referential stimuli (such as photos of the patient). The positive phrases are delivered both as rapid, subliminal messages on the screen as well as at a level of conscious perception. The device is under patent, and one of the study authors is the inventor. Patients viewed ASAT for 15–20 minutes a day over four days following ketamine infusion. A sham version of ASAT, which paired neutral traits with non-self-referential stimuli, was used as the placebo control.

This double-blind, parallel-arm study randomized 154 patients with major depression into three arms: ketamine/ASAT, saline/ASAT, and ketamine/sham ASAT. All patients had failed at least one antidepressant trial. The mean age was 34, and most subjects were White (75%) and female (63%). The primary outcome was severity of depression trended by the Montgomery-Åsberg Depression Rating Scale over 30 days.

Compared to the sham intervention, the group that received ketamine with ASAT stayed well longer. Over the 30-day follow-up period, depression scores increased gradually in the sham group but remained more stable and lower in the ASAT group. This difference was not detectable at 24 hours post-infusion, at which point the two ketamine-treated arms experienced similar improvements, and both ketamine arms were superior to the saline infusion arm.

While these findings were statistically significant, the 30-day effect size was small when looking at ketamine/ASAT compared to ketamine/sham (β = -0.31, 95% confidence interval [CI] = -0.75, 0.13), as well as for ketamine/ASAT compared to saline/ASAT (β = −0.38, 95% CI = -0.78, 0.027).

CARLAT TAKE

Ketamine’s long-term effects may depend on the psychological context in which it is delivered. While the psychological ­intervention tested here is not readily available, the results open the door to explorations of ketamine-assisted ­psychotherapy.