The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: a systematic review

This paper (2020) aimed to review the relationship between ketamine’s anti-depressant effect and its subjective effects and found that they were correlated in some studies (1/3 studies).

Abstract

“Objective: The relationship between ketamine’s hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder (MDD).

Methods: Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports.

Results: Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC’s one study found no correlation with the MADRS.

Conclusions: Ketamine’s dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies.”

Authors: David S. Mathai, Matthew J. Meyer, Eric A. Storch & Thomas R. Kosten

Summary

Research paper

Ketamine’s hallucinogenic- and dissociative-type effects are correlated with clinical outcomes in patients with Major Depressive Disorder.

1. Introduction

Ketamine is a high-affinity NMDAR antagonist with antidepressant effects thought to emerge from modulation of glutamate neurotransmission and AMPA receptor potentiation. It also has additional activity on opioid receptors, adrenergic receptors, and several serotonin and norepinephrine transporters.

Ketamine, a dissociative anesthetic, has also been classified as a hallucinogen. Its effects are mediated in part by activity at 5HT-2A receptors, though also by a glutamatergic pathway, to some extent.

Although formal investigation into the phenomenology of subjective ketamine experience has been limited, preliminary clinical data suggests that ketamine produces meaningful, transformative experiences that may help patients accept healthier values, behaviors and beliefs related to abstinence from drugs and alcohol.

Research into the subjective hallucinogenic experience is challenged by phenomenological and epistemic limitations, as well as by the potential unblinding of subjects in drug-facilitated subjective experiences. Several scales have been employed to measure various aspects of subjective experience in psychedelic experience, but none have been systematically analyzed to understand their potential contribution to antidepressant effects.

Here we conduct a systematic review of how ketamine’s hallucinogenic effects correlate with observed depression rating in patients with Major Depressive Disorder.

2.1. Search strategy and study eligibility

This review followed PRISMA guidelines and included peer-reviewed journal articles from 2000 to 2019 that discussed ketamine, esketamine, dissociation, mystical experience, psychotomimetic, altered states of consciousness, oceanic boundlessness, 5D-ASC, phenomenology of consciousness inventory, and peak experience.

Studies eligible for inclusion in the review met the following criteria: patients with MDD received ketamine, MDD symptoms were measured at regular intervals after ketamine use, and subjective changes in mental state were statistically correlated with data capturing post-injection MDD symptoms.

2.2. Study selection and data extraction

Database searches yielded 554 records, 213 records were screened, and 8 studies were included in the review. Two reviewers independently extracted data from eligible studies using a pre-piloted collection form.

3.1. Population and treatment

All patients were adults ranging from 18 to 70 years of age, and underwent a two-week washout period of all psychoactive drugs in three studies. Ketamine was administered intravenously at 0.5 mg/kg in five studies, and intranasally at 0.5 mg/kg in one study.

3.2. Test material

All studies measured depression using the MADRS or HAM-D, and two studies included secondary dissociation scales, the BDI or QIDS-SR. Depression symptoms were measured daily, and then at weekly or bimonthly intervals, until 1 month post-injection.

3.3. Subjective effects of ketamine

Ketamine produced marked dissociative effects in all five studies that measured CADSS, with significant separation from midazolam as active placebo beginning at a dose of 0.5 mg/kg and not evident at lower ketamine doses of 0.1 mg/kg and 0.2 mg/kg.

Ketamine infusion produced significantly greater total BPRS scores, with evident increases in positive symptoms that did not translate to statistical significance. Ketamine intranasal administration produced marginal increases in total BPRS scores at 40 min.

Subjective measures of altered states of consciousness include vigilance reduction, dread of ego dissolution, oceanic boundlessness, and auditory hallucinations.

3.4. Relationship between subjective effects and treatment response

Five studies explored correlations between CADSS scores and antidepressant responses, with significant variability between studies. No correlations were found between CADSS scores and HAM-D-25 scores at any time point, or between CADSS scores and HAM-D-6 scores at other timepoints. A study found a significant correlation between CADSS score and MADRS response at 24 h post-ketamine infusion. However, no relationship was found between CADSS score and antidepressant response in a study with intranasal ketamine.

Two of five studies found significant correlations between increased CADSS scores at 40 min and antidepressant responses at various timepoints after ketamine infusion. These correlations suggest moderately negative linear relationships, with change in CADSS score explaining no greater than 21% of the variance in antidepressant response.

Six studies included BPRS measurements, although correlations with depression scores were presented in five. No significant correlations were found when BPRS subscales were analyzed, and no relationship between BPRS symptoms and antidepressant response was found for intranasal ketamine.

One study found a moderately negative linear relationship between increased BPRS scores and antidepressant response, with change in BPRS score explaining 16% of the variance in antidepressant response.

One study did not find a correlation between 5D-ASC dimensions and MADRS percentage change on Day 0 (day of ketamine treatment).

3.5. Study quality and bias

Six of eight studies were placebo-controlled, and five were completed under double-blind conditions. One study included patients with bipolar depression, and one study used an active placebo of midazolam at doses of 0.03 mg/kg and 0.045 mg/kg.

4. Discussion

Three studies showed a weak to moderate association between antidepressant and dissociative effects of ketamine, and 12 – 21% of the variance in antidepressant response was explained by changes in BPRS and CADSS scores.

Several included studies did not provide correlations across all possible time-point scores, and thereby may have missed critical times for detecting such correlations. Overall, dissociation appears to be common, and greater intra-fusion dissociation is one of the strongest predictors of extended antidepressant response to ketamine. Data suggest that naltrexone blocks antidepressant effects but not dissociative effects, and that dissociation does not account for a significant proportion of treatment effect. Additional clarification of the relevance of dissociation seems essential for clinicians and researchers working with ketamine, as well as for patients, since treatment expectancies significantly mediate outcomes.

A study that analyzed CADSS data in ketamine treatment found that the depersonalization (“detachment from self”) subscale was most closely related to antidepressant response, but that other psychological activity was inadequately captured by the CADSS. The CADSS and BPRS were initially developed for patients with combat-related posttraumatic stress disorder and high levels of comorbid dissociative disorder, but may not be as useful for measuring ketamine-induced dissociation.

Ketamine’s short duration of effect has led to repeated ketamine infusions to extend time-to-relapse and increase rates of antidepressant response. If ketamine’s therapeutic effect is indeed mediated by psychoactive experience, repeated dosing of ketamine may improve outcomes.

Our review has several limitations, including a small number of relevant studies, small sample sizes within some studies, and an inability to conduct a robust meta-analysis. However, the findings presented here provide support for further consideration of ketamine-induced states of consciousness and investigation into the relevance of these states in treatment outcomes.

Author statement

This work was conceived and written by DSM, MJM, EAS and TRK without any funding source.