REVIEW OF: Kheirabadi D et al, J Clin Psychopharm 2020;40(6):588–593

STUDY TYPE: Randomized controlled trial

Electroconvulsive therapy (ECT) has long been the gold standard for severe or treatment-refractory depression (TRD). However, it has two major drawbacks: it involves anesthesia and it may be associated with memory impairment. Ketamine has emerged as a possible alternative to ECT both for TRD and for acute suicidal ideation. Given ketamine’s advantage of working quickly, it is of great interest to know how these two very different treatments compare with each other.

In this study, investigators recruited 39 patients with severe depression, TRD, or acute suicidal ideation who were referred for ECT. These patients were then randomized to receive either ECT (n = 12), oral R-ketamine (n = 12), or IM ketamine (n = 15). All three treatments were offered for 6–9 sessions.

Depression scores improved over the course of three weeks in all three groups by about 40%–50% on the Hamilton Depression Rating Scale without significant differences between the groups. Several other differences did emerge, however: 1) Scores on suicidality ratings dropped significantly faster in patients receiving both versions of ketamine—as early as day 1—and remained lower through week 2; 2) The benefits of ECT and ketamine were apparent even one month post-treatment, though ECT appeared to display gains that were enduring yet not statistically significant; 3) Overall, patients receiving ketamine reported significantly higher levels of satisfaction, while patients receiving ECT were more likely to report significantly more cognitive complaints (58% of patients) one month post-treatment.

Ketamine is available in three forms: S-ketamine, R-ketamine, and ketamine (a 50/50 mixture of the two isomers). This study, which took place in Iran, used oral R-ketamine. In the US, intranasal S-ketamine (esketamine) is FDA approved for depression treatment as Spravato. The R- and S-isomers are not interchangable, and there is some evidence that the R-isomer may be even more effective than S-ketamine. The other ketamine arm in this study is identical to the racemic mixture of R- and S-ketamine that is used off-label for depression, except that it was delivered IM, whereas IV is the typical route in the US. Thus, we can’t be sure that these results would be the same for the kinds of ketamine used in the US.

TCPR’s Take
Given their small sample sizes, pilot studies should always be taken with a grain of salt. Nevertheless, these results are in line with prior research. Ketamine works more quickly than ECT especially for suicidal ideation and appears to be better tolerated, though ECT’s benefits may be more enduring. Larger studies will clarify ketamine’s optimal dosing, delivery route, and long-term safety, and for now ketamine remains on track to be the best alternative to ECT for severe depression, with a unique role in acutely suicidal ­patients.