Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression

In this open-label study (n=42) participants with treatment-resistant depression (TRD) received eight ketamine infusions (0.5 mg/kg) over four weeks while continuing their conventional treatment regimes. Ketamine significantly reduced participants level of anhedonia (inability to feel pleasure) and these effects lasted longer in patients who were not using benzodiazepines.

Abstract

“Anhedonia constitutes one of the main symptoms of depressive episode. It correlates with suicidality and significantly effects the quality of patient’s lives. Available treatments are not sufficient against this group of symptoms. Ketamine is a novel, rapid acting strategy for treatment resistant depression. Here we report the change in symptoms of anhedonia measured by Snaith-Hamilton Pleasure Scale as an effect of eight ketamine infusions as an add-on treatment in 42 patients with treatment resistant depression. We also determined the effect of this change on the severity of depressive symptoms measured by Inventory for Depression Symptomatology-Self Report 30-Item (IDS-SR 30). We have observed statistically significant decrease in the level of anhedonia during ketamine treatment. After adjusting for potential confounders we have found that significant reduction in Snaith-Hamilton Pleasure Scale (SHAPS) after each infusion and 1 week post treatment was observed only among patients who did not use benzodiazepines. The reduction in symptoms of anhedonia mediates the antidepressive effect of ketamine. The results need replication in a larger randomized placebo controlled trial.”

Authors: Alina Wilkowska, Mariusz Stanislaw Wiglusz, Maria Galusko-Wegielink, Adam Wlodarczyk & Wieslaw J. Cubala

Summary

INTRODUCTION

Ketamine is a novel, effective, and rapid-acting antidepressant in unipolar patients and bipolar treatment resistant depression. It works through the inhibition of presynaptic and postsynaptic NMDARs in GABAergic interneurons, leading to a disinhibition of glutamate transmission and the subsequent glutamate release, increasing synaptic plasticity.

Ketamine increases dopamine levels in the brain and increases dopaminergic neuron activity in rodent models of depression. It may also increase glutamate levels, which may be one potential route of the antianhedonic efficacy of ketamine in both unipolar and bipolar treatment resistant depression.

In this study, eight intravenous ketamine infusions improved depressive symptoms and anhedonia in patients with treatment-resistant depression.

Patients

The study population included 41 patients with treatment resistant mood disorders (TRD) who received intravenous ketamine. The patients had an inadequate response to two or more antidepressants or a clinically unsatisfactory response to at least two approved dissimilar medications.

Adults 65 years or older who were medically stable were enrolled in the study. Exclusion criteria included pregnancy, breastfeeding, an active history of uncontrolled diseases, and previous adverse effects while on ketamine.

Study Design

The study followed an observational design; all patients continued baseline psychotropic treatment and necessary treatment of chronic somatic diseases during ketamine infusions. Ketamine was administered at a dose of 0.5 mg/kg based on the actual body weight of the patient.

Psychometric Measures

A 14-item self-reported measure of anhedonia was used to assess the effect of the treatment on the severity of the measured depressive symptoms. The results were assessed before treatment, at the third, fifth, and seventh infusions, and 1 week after treatment.

Statistical Analysis

Data were analyzed by using the IBM SPSS Statistics package ver. 26. The following methods were used: one-way ANOVA with repeated measures, general linear models with repeated measures, Friedman’s test, and moderated mediation model for the relationship between ketamine infusions and depression severity.

Snaith–Hamilton Pleasure Scale

At baseline, 97.5% of patients met the criteria for clinically significant anhedonia (i.e., SHAPS 2). After adjusting for potential confounders, a significant decrease in the SHAPS total score was observed across infusions and during the post-infusion visit in patients not using benzodiazepines.

30-Item Inventory for Depressive Symptomatology—Self Report

The IDS-30 total scores decreased significantly as ketamine was administered, and the difference between the baseline and third infusion was significant at p = 0.013. There were no significant interaction effects.

30-Item Inventory for Depressive Symptomatology—Self Report 30 Item No. 18

The results showed that the intensity of suicidal ideation decreased as a result of ketamine infusions, but this change was observed only after the fifth and seventh infusions.

Mediation Model

Mediation analysis with moderation was conducted to determine if there was an indirect effect of anhedonia on the relationship between the number of infusions and the severity of depression. The results indicate a significant unstandardized indirect effect of anhedonia.

DISCUSSION

This study found that ketamine treatment significantly decreased the level of anhedonia, reduced the severity of depression, and reduced suicidal ideation. The decrease in anhedonia explained 42% of the variance in the improvement of the IDS-SR 30 score.

One study showed that ketamine had a rapid antianhedonic effect after a single infusion in 36 patients with treatment-resistant bipolar depression, and a subsequent open label study included 52 participants with TRD who received one infusion of 0.5 mg/kg ketamine after a 2-week washout period.

Ketamine had no significant effect on anhedonia in the subgroup of patients using benzodiazepines compared with the rest of patients. There is some evidence that ketamine is attenuated by concomitant benzodiazepines. A post-hoc analysis of data of 10 TRD patients treated with ketamine showed that the responder group had a significantly smaller dose of BDZ used than a non-responder group, and a recent post-hoc analysis of data of 47 MDD patients treated with ketamine showed significantly worse outcomes in the subgroup receiving BDZ. Ketamine blocks NMDA receptors and causes glutamatergic activity, which in turn increases BDNF. Benzodiazepines counteract this effect.

Ketamine and benzodiazepines have a common target, which is the reward system. Regular benzodiazepine use is a strong correlate of treatment resistance in patients with treatment-resistant depression, suggesting a possible coexistence of anxiety disorder, suppression of feelings as an effect of BDZ, and negative influence of BDZ on cognitive functions.

The study was conducted without a placebo control, randomization, and blinding, and had several limitations. It also included unipolar and bipolar patients in the same group, and the present level of evidence is insufficient for scientific recommendation.

Ketamine had an antianhedonic effect in patients with treatment-resistant depression in unipolar and bipolar disorder, but this effect was attenuated by benzodiazepines.

ETHICS STATEMENT

The studies involving human participants were reviewed and approved by the Institutional Ethics Committee of Medical University of Gdansk.

AUTHOR CONTRIBUTIONS

All authors contributed to the conceptualization, methodology, funding acquisition, formal analysis, writing, investigation, data curation, and project administration of this paper.