This review (2020; 6 studies) compares ketamine with ECT as treatments for treatment-resistant depression (TRD). The authors preliminarily conclude that ketamine may show effects faster, but these effects seem to be less durable.
Abstract
“Objective: Ketamine has repeatedly shown to have rapid and robust antidepressant effects in patients with treatment resistant depression (TRD). An important question is whether ketamine is as effective and safe as the current gold standard electroconvulsive therapy (ECT).
Methods: The literature was searched for trials comparing ketamine treatment with ECT for depression in the Pubmed/MEDLINE database and Cochrane Trials Library.
Results: A total of 137 manuscripts were identified, 6 articles were included in this review. Overall quality of the included studies was diverse with relevant risk of bias for some of the studies. Results suggest that ketamine treatment might give faster but perhaps less durable antidepressant effects. Side effects differed from ECT, in particular less cognitive impairment was apparent in ketamine treatment.
Limitations: The included studies have limited sample sizes, use different treatment protocols and in most trials, longer term follow up is lacking. Furthermore, allocation bias appears likely in the non-randomized trials. Conclusions: Current available literature does not yet provide convincing evidence to consider ketamine as an equally effective treatment alternative to ECT in patients with TRD. There are indications for a more favourable short term cognitive side effect profile after ketamine treatment. Methodologically well-designed studies with larger sample sizes and longer follow up duration are warranted.”
Authors: Jolien K.E. Veraart, Sanne Y. Smith-Apeldoorn, Harm-Pieter Spaans, Jeanine Kamphuis & Robert A. Schoevers
Summary
Ketamine has been shown to have rapid and robust antidepressant effects in patients with treatment resistant depression. However, the current available literature does not yet provide convincing evidence to consider ketamine as an equally effective treatment alternative to ECT in patients with TRD.
- Introduction
Major depressive disorder (MDD) is a highly prevalent disorder accounting for a large proportion of disability worldwide. ECT is the gold standard treatment for TRD, but entails certain disadvantages, including repeated anesthesia and a risk of serious cognitive problems.
Ketamine has been shown to have rapid and robust antidepressant effects in patients with MDD and TRD. It may serve as an effective and acceptable alternative to ECT for TRD patients.
- Methods
This review included studies of patients with MDD who received ketamine in any form (racemic, S-ketamine or R-ketamine), at any dose and frequency and in any route of administration vs. ECT. The following information was retrieved: characteristics of the participants, intervention, comparison, outcomes, and study design.
The methodological quality of the included studies was assessed by two investigators using the Risk of Bias version 2 tool and the Risk Of Bias In Non-randomized Studies-of-Interventions tool.
- Results
A total of 137 articles were identified, of which 129 were excluded because there was no clinical trial or comparison between ketamine treatment and ECT.
Six articles were included in the review, three of which were single blind, randomized controlled trials, and three were naturalistic open label studies. The results of the methodological quality evaluation can be found in Tables 2 and 3.
In a single blind, randomized study, patients with MDD and ECT indication received three IV ketamine infusions of 0.5 mg/kg with brief pulse (BP) bilateral (BL) ECT on three test days every 48 h. Ketamine was associated with lower mean scores on the Beck Depression Inventory and Hamilton Depression Rating Scale-25.
A second single blind, randomized trial was performed in 32 patients with MDD and ECT indication. The results showed that both groups improved, with the ketamine group improving by 8.2 points and the ECT group by 11.4 points.
Although not significantly different, ketamine users seemed to recover a bit faster and ECT had a numerical benefit after 6 treatment sessions. The antidepressant effect in the ketamine group did not last, but the mean HDRS scores gradually returned to baseline values within 3 months post treatment.
The study did not report how many ECT sessions were performed, and the drop-out rate was high. There were also small sample sizes in the study groups.
Sharma et al. (2020) compared the effects of right unilateral ECT and 0.5 mg/kg IV ketamine infusion in 26 patients with bipolar or unipolar depression, with or without psychotic symptoms. The ECT group showed greater reduction in HDRS scores and achieved response and remission faster. Ketamine treatment improved cognitive functions in patients with ECT-related cognitive deficits when compared to baseline, whereas no significant difference was found in the ECT group. However, the study had several limitations, including the use of two different ECT methods.
In the open label trial of Allen et al. (2015), patients with unipolar TRD received up to 12 ECT sessions twice weekly or up to three 0.5 mg/kg IV ketamine infusions once a week. Most patients received all 3 infusions, and 50% showed response following the final ECT session. Seven patients discontinued ketamine sessions, and none discontinued ECT. Reasons for discontinuation included elevation of diastolic blood pressure during infusion, loss to follow-up, unpleasant experience, and work commitments.
The study was non-randomized, open label, and susceptible to selection bias. It followed a short period of time, and had a low baseline symptom severity.
Basso et al. (2020) treated 31 patients with TRD with ketamine infusions and 31 patients with ECT. They included 50 patients, of which 31 had ketamine infusions and 31 had ECT. At baseline, patients treated with ketamine had significantly lower MADRS scores than those treated with ECT, but their current episode was longer. The mean MADRS scores were more strongly reduced for patients treated with ketamine at the mid treatment time point. Patients treated with ketamine showed significantly better neurocognitive test performance than patients treated with ECT. The difference regarding change on the composite score had a small effect size favoring ketamine.
A third open label trial was performed in 44 MDD patients receiving either ECT (N = 17) or IV ketamine 0.5 mg/kg (N = 27). The patients’ HDRS scores decreased after both ECT (from 21.41 (SD 8.33) to 15.35 (SD 8.60)) and ketamine treatment (from 20.15 (SD 4.70) to 8.93 (SD 10.73).
- Discussion
Limited data is available on whether ketamine treatment may serve as a proper alternative to ECT in TRD treatment. However, one study found significantly more improvement after ECT, and two studies found no significant differences between ECT and ketamine treatment.
Ketamine showed a more favorable neurocognitive side effect profile than ECT, although the durability of ketamine’s antidepressant effects after treatment cessation was less than ECT. Ketamine treatment may also be useful as a relapse prevention strategy after ECT.
Currently available studies have considerable methodological limitations including small sample sizes and lack of longer term follow up assessments. Long term side effects of ketamine treatment should be investigated, including cognitive impairment, urinary tract problems and risk of abuse.
The studies included here used different ketamine treatment protocols and ECT treatment differed in terms of frequency, electrode placement, stimulus width, dose determination, medication used for anaesthesia, and time to relapse. This makes extrapolating the results to clinical practice difficult.
Three trials used a blind, randomized study design, but it seems likely that allocation bias causes differences between the two treatment groups. In addition, the included studies differed in terms of in- and exclusion criteria.
Three studies comparing ketamine to ECT treatment in patients with depression were identified through clinicaltrials.gov. These studies include the Canadian biomarker integration network in depression (CAN-BIND study), the Swedish study (A randomized controlled non-inferiority trial comparing ketamine with ECT in patients with MDD), and the ELEKT-D study.
The results of trials comparing ketamine treatment with ECT should be interpreted with caution considering the discussed methodological limitations of the studies.
Author statement
Harm-Pieter Spaans, Jeanine Kamphuis and Robert Schoevers contributed to the analysis and interpretation of data and gave final approval.
Declaration of Competing Interest
J. Veraart, MD, R. Schoevers, MD, PhD, S. Smith-Apeldoorn, MD, HP. Spaans, MD, PhD, J. Kamphuis, MD, have received speaker honoraria from Janssen outside the submitted work.