Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression: A Randomized, Open-Label, Non-Inferiority Trial (KetECT)

Abstract

Background: Ketamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared with electroconvulsive therapy (ECT), the most effective therapy for depression.

Methods: Hospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale score ≤10). Secondary outcomes included adverse events (AEs), time to remission, and relapse. Treatment sessions (maximum of 12) were administered until remission or maximal effect was achieved. Remitters were followed for 12 months after the final treatment session.

Results: In total 186 inpatients were included and received treatment. Among patients receiving ECT, 63% remitted compared with 46% receiving ketamine infusions (P = .026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of 6 treatment sessions to induce remission. Distinct AEs were associated with each treatment. Serious and long-lasting AEs, including cases of persisting amnesia, were more common with ECT, while treatment-emergent AEs led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within 12 months in the ketamine and ECT groups, respectively (P = .52).

Conclusion: Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.

Keywords: Electroconvulsive therapy; ketamine infusion; major depressive disorder; psychotic depression; racemic ketamine.

Figure 1.

Trial profile of a randomized controlled trial comparing electroconvulsive therapy (ECT) and multiple infusions with racemic ketamine for treatment of major depressive disorder in hospitalized patients. AE, adverse event; MADRS, Montgomery Åsberg Depression Rating Scale; SAE, serious adverse event.

Figure 2.

Montgomery Åsberg Depression Rating Scale (MADRS) scores at baseline and after completed treatment in hospitalized patient with major depressive disorder (MDD) randomized to electroconvulsive therapy or multiple infusions with racemic ketamine. Patients were administered between 1 and 12 treatment sessions on a per-need basis. Boxes enclose mean scores ± 1 SD. Midlines indicate median values. Vertical lines indicate 10th to 90th percentiles. Circles indicate individual MADRS scores for participants in the electroconvulsive therapy (ECT) (black) and ketamine (red) treatment groups, respectively. AE, adverse event.

Figure 3.

Mean Montgomery Åsberg Depression Rating Scale (MADRS) score and remission rate over successive treatment sessions in hospitalized patient with major depressive disorder (MDD) randomized to electroconvulsive therapy (ECT) or multiple infusions with racemic ketamine. (A) Mean MADRS scores over the 4-week treatment (thrice weekly) period. Boxes and lines indicate mean scores and 1-sided SD for ECT (black) and ketamine (red). Numbers on the x-axis denote the treatment session that preceded the rating. Baseline and acute indicate ratings done prior to receiving any treatment and 4–5 hours after receiving the first treatment, respectively. (B) Numbers indicate the accumulated percentage of remitters in the treatment groups over time. AE, adverse event; Ket, racemic ketamine.

Figure 4.

Kaplan-Meier curves of time to relapse during a 12-month follow-up period in patients with major depressive disorder (MDD) remitting following randomization to electroconvulsive therapy (ECT) or multiple infusions with racemic ketamine. Hospitalized patients with major depressive disorder were randomized to ECT (black line) or multiple infusions with racemic ketamine (red line). Remitters were followed-up at 1 week and at 3, 6, and 12 months after their last treatment session. Ket, racemic ketamine.