Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients

This open-label between-subjects study (n=49) compared the antidepressant efficacy of serial R(-)ketamine treatment (35mg/70kg) versus electroconvulsive therapy (ECT) for patients with depression. Ketamine produced faster antidepressant effects and improved neurocognitive functioning, especially attention and executive functions, which implicate that it may be a more favorable treatment option in the short-term.

Abstract

“Background: While electroconvulsive therapy (ECT) is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients. Efficacy and onset of action are currently among the main factors that influence clinical decision making, however, the effect of these treatments on cognitive functions should also be a crucial point, given that cognitive impairment in depression is strongly related to disease burden and functional recovery. ECT is known to induce transient cognitive impairment, while little is known about ketamine’s impact on cognition. This study therefore aims to compare ECT and serial ketamine administration not only with regard to their antidepressant efficacy but also to acute neurocognitive effects.

Methods: Fifty patients suffering from depression were treated with either serial ketamine infusions or ECT. Depression severity and cognitive functions were assessed before, during, and after treatment.

Results: ECT and ketamine administration were equally effective, however, the antidepressant effects of ketamine occurred faster. Ketamine improved neurocognitive functioning, especially attention and executive functions, whereas ECT was related to a small overall decrease in cognitive performance.

Conclusions: Due to its pro-cognitive effects and faster antidepressant effect, serial ketamine administration might be a more favorable short-term treatment option than ECT. Limitations As this research employed a naturalistic study design, patients were not systematically randomized, there was no control group and patients received concurrent and partially changing medications during treatment.”

Authors: Laura Basso, Luisa Bönke, Sabine Aust, Matti Gärtner, Isabella Heuser-Collier, Christian Otte, Katja Wingenfeld, Malek Bajbouj & Simone Grimm

Notes

This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health‘

Summary

While ECT is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients.

1.Introduction

Depressive disorder causes the highest overall disease burden of mentalandneurologicaldisordersinEuropeaswellasworldwide. Despite several effective treatment options, a few unmet needs still remain, especially for patients who do not benefit sufficiently from pharmacological treatment with conventional antidepressants.

Depressive patients show wide ranging cognitive deficits, which are not a consequence of the depressive symptoms but rather a distinct feature of depression. Cognitive impairment is related to higher disability and disease burden, suicide risk, and treatment non-compliance.

ECT is the gold standard for the acute treatment of treatmentresistant depression, but has several limitations, especially causing transient cognitive impairments. Ketamine is a new antidepressant intervention with antidepressant responses within days. Although there are some studies on the neurocognitive effects of ketamine, such as impaired verbal memory, no negative short-term effects have been found in depressed patients.

This study aims to examine whether baseline cognitive functioning can predict treatment outcome of ECT or ketamine administration in depressed patients.

2.1. Participants

Patients with major depressive disorder were treated with ketamine infusions or ECT at the Department of Psychiatry, Charité – Universitätsmedizin Berlin. All patients gave written informed consent, and 31 patients met the inclusion criteria.

Thirty-one patients were selected who had received the standard treatment ECT in the period from August 2013 to June 2016. They were divided into two groups, 25 patients treated with ketamine and 25 patients treated with ECT, and their clinical data are described in the supplement.

2.2.1. Design

Clinical assessments were performed before the first treatment intervention, after 50% of the interventions had been administered, and after the last treatment intervention.

Cognitive assessments were performed routinely with patients receiving ECT and ketamine before the first ECT session, after the sixth and after the twelfth or last KETamine infusion. Post treatment neurocognitive testing was performed on the day after the last ECT or ketamine administration.

2.2.2. Treatment

A MECTA 5000Q device was used to deliver ultra-brief pulse stimuli for right unilateral ECT. Patients were anesthetized with propofol or etomidate and were given succinylcholine for muscle relaxation.

2.3. Statistical analyses

All analyses were conducted using SPSSstatisticalsoftware, version 24, for Mac OS X. Change scores were computed for clinical and neurocognitive data, and a 2 x 2 (Intervention [ECT,ketamine]Time[change inpercentagefromT0toT1,change inpercentagefromT0toT2]repeatedmeasuresANOVA) was conducted to compare reductions in MADRS scores between groups.

The effect size d was calculated for within-group t-tests and between-group ANOVAs/AN-COVAs, and absolute p-values were represented for all conducted tests.

3.1. Group differences in demographic and baseline clinical and neurocognitive data

The two treatment groups did not differ regarding age, gender, education, or other demographic variables, except for the duration of the current episode and baseline MADRS scores, which were not related to baseline cognitive performance.

3.2. Change in clinical data

A significant Treatment Group – Time interaction was found, with ketamine reducing symptoms more strongly from T0 to T1 than ECT (M = 34.86%, SD = 21.29, n = 22). However, treatment response could not be predicted by baseline MADRS scores.

3.3. Change in neurocognitive data

Changes in performance in different cognitive domains and the composite score were significant for both treatment groups. However, excluding MADRS baseline scores from the model increased the p-value for the composite score.

3.4. Relationship between clinical and neurocognitive data

MADRS baseline scores were not systematically associated with cognitive performance at baseline in any domain except for verbal memory. Moreover, baseline cognitive performance could not predict treatment response.

4.Discussion

Our study demonstrated that both ECT and ketamine are effective treatments for depression. However, ketamine showed a faster onset of action than ECT and showed stronger symptom reduction mid-treatment compared to patients treated with ECT (after 2 weeks).

Regarding neurocognitive functioning, results generally matched our expectations, yet some surprising findings were made. For patients treated with ECT, performance was expected to decline, yet only verbal memory was significantly reduced after ECT, with generally large effect sizes.

Results indicate that patients treated with ketamine showed significant improvements in the domains of attention, visual memory, and executive functions, but a decline in verbal memory performance was found. This finding might suggest that ketamine constitutes a more favorable treatment option over ECT for patients with preexisting cognitive impairments.

No association between baseline cognitive performance and treatment response was found in any of the three studies. Therefore, improvement in cognitive performance is likely to reflect direct effects of ketamine itself, and not secondary effects caused by the clinical improvement.

As the study employed a naturalistic design, patients could choose between ketamine and ECT. Ketamine might be perceived as a more effective treatment option, but this effect might also be confounded by the lack of a control group. The sample is very heterogeneous with regard to clinical characteristics such as severity of depression, diagnosis (unipolar, bipolar), psychiatric and medical co-morbidities, and the use of antidepressant medication. However, the results regarding efficacy and changes in the different cognitive domains were generally not affected by baseline symptoms severity.

Patients were assessed after treatment ended, and long-term cognitive performance improved again. However, relapse rates are high after 6 months without any continuation treatment, and a randomized controlled trial with a large sample including long-term follow up measurements seems advisable.

In conclusion, serial ketamine administration was related to a better short-term cognitive outcome than ECT treatment in depressed patients, while simultaneously achieving faster symptom reduction.