Dissociative symptoms with intravenous ketamine in treatment-resistant depression exploratory observational study

This open-label study (n=49) investigated the relationship between dissociative and psychometric measures in course of intravenous ketamine (8x 35 mg/70kg infusions) as an add on treatment in inpatients with major depressive disorder (MDD) and bipolar disorder (BP) who were already using antidepressant medication. Significant differences in Clinician-Administered Dissociative States Scale (CADSS) scores of the course of the treatment were observed. No significant differences in the Brief Psychiatric Rating Scale (BPRS) were observed. Findings indicate a good safety profile for ketamine as an add-on intervention.

Abstract

“There is evidence for ketamine use in treatment-resistant depression (TRD). Several safety and tolerability concerns arise regarding adverse drug reactions and specific subpopulations. This paper aims to investigate the relationship between dissociative and psychometric measures in course of intravenous ketamine treatment in TRD inpatients with major depressive disorder and bipolar disorder. This study result represents safety data in a population of 49 inpatients with major depressive disorder and bipolar disorder subjects receiving eight 0.5 mg/kg of ketamine intravenous infusions, with a duration of 40 min each, as an add-on treatment to standard-of-care pharmacotherapy, registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963). The safety psychometrics assessed dissociation and psychomimetic symptomatology with the Clinician-Administered Dissociative States Scale (CADSS) the Brief Psychiatric Rating Scale (BPRS). The significant differences in CADSS scores between measurements in course of the treatment were observed (P = .003). No significant differences between BPRS measurements were made after infusions. In each case, both BPRS and CADSS values dropped to the “absent” level within 1 hour from the infusion. Neither CADSS nor BPRS scores were associated with the treatment outcome. The study demonstrates a good safety profile of intravenous ketamine as an add-on intervention to current psychotropic medication in TRD. The abatement of dissociation was observed in time with no sequelae nor harm. The study provides no support for the association between dissociation and treatment outcome. This study may be underpowered due to the small sample size. The protocol was defined as a study on acute depressive symptomatology without blinding.”

Authors: Adam Wlodarczyk, Wieslaw J. Cubala, Maria Galuszko-Wegielnik & Joanna Szarmach

Summary

Ketamine is used in treatment-resistant depression.

This paper investigates dissociative and psychometric measures in patients treated with intravenous ketamine.

This study result represents safety data in 49 patients with major depressive disorder and bipolar disorder receiving eight 0.5mg/kg of ketamine intravenous infusions. The CADSS and BPRS scores dropped to the “absent” level within 1 hour from the infusion.

outcome.

The study demonstrates good safety profile of intravenous ketamine as an add-on intervention to current psychotropic medication in TRD, with no sequelae or harm.

Bipolar depression, Clinician-Administered Dissociative States Scale, MADRS, SNRI, SSRI, MDD, CNS, SNRI, MDD, SSRI, BMI, BP, CADSS, CNS.

Treatment-resistant depression.

Keywords: dissociation, ketamine, psychosis, safety, tolerability, treatment-resistant depression

Jorddy Neves Cruz edited this work.

Dr. Adam Wodarczyk has received research support from several companies.

1. Introduction

Recent developments in rapid-acting antidepressant use in treatment-resistant depression provide robust evidence for ketamine use in major depressive disorder and bipolar disorder, with several concerns arising with regards to safety and tolerability of the drug. One of the major issues is the risk of adverse events associated with dissociative symptomatology.

2. Methods and population

The study population consisted of 35 patients with major depression or bipolar disorder, all of whom had an inadequate response to 2 or more antidepressants. The patients were examined using Mini-International Neuropsychiatric Interview by clinicians to verify the diagnosis using Diagnostic and Statistical Manual of Mental Disorders criteria.

The CADSS and BPRS were used to assess the acute psychoactive effects of ketamine administration.

2.1. Study design: ketamine infusions

The study followed an observational design with patients continuing baseline psychotropic standard-of-care and treatment of chronic somatic diseases during ketamine infusions.

Safety monitoring included periodic assessment of vital signs, mental status examination, and psychometric evaluation with Young Mania Rating Scale and MADRS before, during, and after each ketamine infusion. An on-site clinician evaluated potential behavioral risks after each session.

2.2. Statistical analysis

The analyzes were conducted using statistical software the IBM SPSS Statistics 25.0. Fisher exact test, Kruskal – Wallis test, Mann – Whitney U test, and Spearman rank correlation analysis were used.

The relationships between variables were determined using chain indexes and non-parametric tests, and in acuities among groups analyzed were used for the analysis for discrete and continuous variables.

3. Results

The clinical and demographic characteristic of the study group is presented in Table 1. The CADSS scores declined to an “absent” level within 1 hour after ketamine infusion in all patients at all times.

Table 2 shows that BPRS measurements after ketamine infusions declined to “absent” level within 1 hour in all patients.

3.1. Change over time in CADSS and MADRS scores

A post-hoc analysis of the results showed that the main effect of CADSS was present, and that the interaction effect of group membership and CADSS result was insignificant.

3.2. Change over time in BPRS and MADRS

Post-hoc analysis of the results showed that the main BPRS effect occurred after the division into groups, and that the interaction between the group and the BPRS result was insignificant.

4. Discussion

The research demonstrates good safety and tolerability profile of ketamine as an add-on treatment to current psychotropic medication in TRD. There was no association between CADSS score and treatment outcome with MADRS.

Our analysis showed that CADSS values were significantly higher after infusion than before infusion in 1 measurement, but that BPRS values were not significantly different before and after infusion.

The methodological strength of this study was to demonstrate the tolerability and general safety of the administration of ketamine to treatment-resistant patients. However, the study may be underpowered with regard to the small sample size and lack of long-term safety data.

Our study was in line with esketamine trials, as no harm was observed and all patients experienced persistent dissociative or psychotic symptoms during the follow-up visit.

Ketamine-induced central nervous symptomatology including dissociation and psychosis is believed to be associated with N-methyl-D-aspartate receptor blockade and surfeit ketamine activity. Although the intensity of the acute ketamine experience was higher than in esketamine nasal spray, it abated with time and had no sequelae.

The presented study provides no support for the intensity of dissociative symptomatology as being associated with an anti-depressive treatment effect of ketamine in TRD-BP. Ketamine is to be preferred in mood disorders treatment due to its safety and efficacy.

Short-term treatment with intravenous ketamine as an add-on intervention to current standard-of-care psychotropic medication in TRD demonstrated good safety and tolerability profile.