Mood and neuropsychological effects of different doses of ketamine in electroconvulsive therapy for treatment-resistant depression

This randomized, double-blind, active placebo-controlled study (n=90) compared the antidepressant efficacy between ketamine (56mg/70kg), the anesthetic propofol (56mg/70kg), and the combination of ketamine (35mg/70kg) plus propofol (35mg/70kg), within the context of pretreatment for electroconvulsive therapy for patients with treatment-resistant depression (TRD). Compared to the others, the ketamine group exhibited earlier improvements in depression, better seizure parameters and seizure quality in electroconvulsive therapy, and a lower degree of executive cognitive impairment, which highlights the usefulness of ketamine-assisted electroconvulsive therapy for treating depression.

Abstract

“Background: Treatment-resistant depression (TRD) is a growing clinical challenge. Electroconvulsive therapy (ECT) is an effective tool for TRD treatment. However, there remains a subset of patients who do not respond to this treatment with common anesthetic agent. Ketamine, a noteworthy anesthetic agent, has emerged as an augmentation to enhance the antidepressant efficacy of ECT. Trials of i.v. ketamine in TRD indicated dose-related mood enhancing efficacy. We aimed to explore anesthetic and subanesthetic concentrations of ketamine in ECT for TRD with respect to their impact on mood and neuropsychological effects.

Methods: Ninety TRD patients (36 males, 54 females; average age, 30.6 years old) were randomly assigned to receive either ketamine (0.8mg/kg) (n=30), subanesthetic ketamine (0.5mg/kg) plus propofol (0.5mg/kg) (n=30) or propofol (0.8mg/kg) (n=30) as an anesthetic and underwent 8 ECT sessions. The primary outcome measures were the 17-item Hamilton Depression Rating Scale (HDRS-17), cognitive assessments and seizure parameters.

Results: The ketamine group had an earlier improvement in HDRS-17, longer seizure duration, lower electric quantity, a higher remission rate, and a lower degree of executive cognitive impairment compared to the ketamine+propofol and propofol groups. The ketamine+propofol group showed earlier improvement in the HDRS-17, a longer seizure duration and a different seizure energy index when compared to the propofol group.

Limitations: The postoperative dissociative side effect was not assessed.

Conclusions: Both anesthetic and subanesthetic concentrations of ketamine have rapid mood enhancing actions in ECT for TRD, while anesthetic concentrations results in larger magnitudes of antidepression and cognitive protection. ECT with ketamine anesthesia might be an optimized therapy for patients with TRD.”

Authors: Xiaomei Zhong, Hongbo He, Chunping Zhang, Zhijie Wang, Miaoling Jiang, Qirong Li, Minling Zhang & Xiong Huang

Summary

Treatment-resistant depression (TRD) is a growing clinical challenge. Ketamine, an anesthetic agent, has emerged as an augmentation to enhance the antidepressant efficacy of electroconvulsive therapy (ECT).

Ninety patients with TRD underwent 8 ECT sessions and were assessed for depression, cognitive abilities and seizure parameters.

Ketamine showed more improvement in HDRS-17, longer seizure duration, lower electric quantity, higher remission rate, and lower executive cognitive impairment compared to propofol.

Ketamine anesthesia enhanced mood and provided cognitive protection in patients with TRD.

Elsevier B.V.

1. Introduction

Major depressive disorder is a widespread psychiatric illness affecting 350 million people worldwide. ECT is the most effective treatment for major depressive disorder, but the response rate to ECT using a common anesthetic agent is approximately 50 – 60%.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor blocking agent, has emerged as a novel, rapid-acting antidepressant. Its antidepressant effect is due to the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Ketamine is a noteworthy anesthetic agent used mainly for starting and maintaining anesthesia. Several studies have tested the antidepressant effects of ketamine for ECT anesthesia in medication-free or antidepressant-antipsychotic drug combinations in patients with MDD or TRD, with inconsistent efficacy results.

A previous study indicated that ketamine administered with anesthetic concentrations increased the antidepressant effect of ECT for TRD, while subanesthetic concentrations showed no effect. The optimal mode of ketamine anesthesia for ECT remains unknown.

Ketamine, used as an anesthesia for ECT, may exhibit potential cognitive protection by inhibiting the NMDA-receptor activation, mediating beneficial changes in apoptosis-regulating proteins, and interfering with the inflammatory response to injury.

2.1. Subjects

The study was approved by the ethics committee of the Affiliated Brain Hospital of Guangzhou Medical University and all participants gave written informed consent. Patients with TRD were recruited from the wards of the Affiliated Brain Hospital of Guangzhou Medical University and ECT sessions were performed in the Department of ECT.

2.2. Research intervention

TRD patients were randomized to receive ketamine, ketamine – propofol or propofol as anesthesia for ECT. They received atropine sulfate, ketamine – propofol or propofol I.V. push, respectively, and succinylcholine as a muscle relaxant.

Bitemporal ECT was performed using the Thymatron s IV device. Blood pressure was recorded just before anesthesia and 10 min after the ECT procedure.

2.3. Psychopathology and cognitive assessment

The Hamilton Depression Rating Scale (HDRS-17) was used to assess the severity of depressive symptoms and the treatment response, and the Brief Psychiatric Rating Scale (BPRS-18) was used to evaluate general psychopathology symptoms.

Cognitive tests were used to assess cognition at baseline and 48 – 72 h after the eighth treatment.

2.4. Statistical analysis

Statistical analyses were performed using SPSS 18.0 software. The Kruskal-Wallis H (K) test, Mann-Whitney U test, one-way analysis of variance (ANOVA) and post hoc least significant difference test with Bonferroni correction were used to analyze data.

3.1. Demographic and clinical characteristics

Ninety patients with TRD were enrolled. Ten patients in the ketamine group, 13 patients in the ketamine propofol group and 11 patients in the propofol group were diagnosed with bipolar disorder.

3.2. Antidepressant effect

Three anesthesia conditions were associated with depressive symptom improvement. There was a significant group-by-time interaction and significant group differences (ketamine).

Patients who received ketamine as an anesthesia versus those who received propofol had lower HDRS-17 scores after the first treatment, and this difference became greater after the second treatment, third treatment, fourth treatment, and sixth treatment, but receded after the eighth treatment.

We found no responders until the completion of the third treatment among the three groups. The ketamine group had a statistically significant higher response rate and a higher remission rate than the ketamine propofol group.

3.3. The effect on psychopathology symptoms

All three treatment groups had improved psychopathology symptoms. However, the ketamine group had significantly improved psychopathology symptoms compared to the propofol group, and the ketamine propofol group had significantly improved emotional symptoms compared to the propofol group.

3.4. Seizure parameters

A GLM repeated-measures analysis showed that the electric quantity required for ECT became higher with increasing treatment times. The electric quantity required in the ketamine group was lower than that in the propofol group or in the ketamine propofol group.

The main effect of group was higher in the ketamine group than in the propofol group or in the ketamine propofol group, and there was no significant group-by-time interaction for seizure duration or seizure energy index.

3.5. Cognitive function

After eight ECT treatments, the cognitive function of the propofol group was significantly worse than that of the ketamine group on the WCST and TMT. The degrees of cognitive impairment were not different among the three groups.

3.6. Side effects

The majority of patients reported minimal transient adverse events during ECT treatments, including headaches and nausea.

Systolic blood pressure was higher in the ketamine and ketamine propofol groups than in the propofol group after each ECT treatment, but there was no difference in the diastolic blood pressure between the ketamine and ketamine propofol groups at any time point.

4. Discussion

In this study, we compared the effects of ketamine and propofol on antidepressant efficacy, seizure parameters, cognitive function and side effects in patients with TRD. We found that ketamine had a more rapid antidepressant effect, higher remission rate, lower electric quantity, increased seizure duration, a higher seizure energy index and less cognitive impairment. Ketamine enhanced the speed of response to ECT, and the superiority of ketamine over propofol disappeared after the completion of the sixth and eighth ECT sessions. Ketamine increased the effectiveness of ECT when used as an adjuvant to propofol. The antidepressant efficacy of ketamine may be dose-related. In the present study, the patients in the ketamine group received a larger dose of ketamine than the patients in the ketamine propofol group, and this superiority lasted until the eighth ECT session. Our results suggest that ketamine enhances the antidepressant effect of ECT for treatment of TRD. Ketamine has superior antidepressive effects and cognitive protection compared to subanesthetic concentrations of ketamine.

A meta-analysis of 5 RCTs suggested that ketamine augmentation in ECT settings was ineffective, while we found high response and remission rates in TRD patients. There are three major explanations for this conflicting result.

Ketamine anesthesia was associated with longer seizure duration and more favorable central inhibition effects, with higher-quality seizures, than propofol. Ketamine required less electric quantity for ECT than propofol and ketamine propofol.

After a grand mal seizure, patients have a period of cognitive impairment. Ketamine is preferable to propofol or ketamine propofol in regards to the impairment of executive functioning following ECT, possibly due to the neuroprotection of ketamine and the low electrical dosage.

Ketamine increased central sympathetic activity and catecholamine reuptake inhibition, resulting in raised blood pressures. Although the increase was temporary and without clinical significance, ketamine anesthesia was safe and well tolerated for ECT.

Although the blinding wasn’t tested, the study’s outcomes may have been biased by guesses about treatment allocation. The study did not assess dissociative states, but future studies with large sample sizes are needed to provide evidence for clinical expansion.

Ketamine has been shown to improve depressive symptoms in patients with TRD, but its use is limited by cardiovascular side effects and dissociative symptoms. Ketamine ECT may be a potential future direction for TRD treatment.