Distinct trajectories of antidepressant response to intravenous ketamine

This open-label study (n=328) found that people who were depressed, for those with childhood physical abuse responded best to ketamine (48mg/70kg) treatment. This analysis was done retrospectively and the analysis consisted of breaking the group in three parts (responders, non-responders, responders with lower initial depression scores).

Abstract

“Background: The N-methyl-D-aspartate receptor antagonist ketamine is potentially effective in treatment resistant depression. However, its antidepressant efficacy is highly variable, and there is little information about predictors of response.

Methods: We employed growth mixture modeling (GMM) analysis to examine specific response trajectories to intravenous (IV) ketamine (three infusions; mean dose 0.63 mg/kg, SD 0.28, range 0.30 – 2.98 mg/kg over 40 min) in 328 depressed adult outpatients referred to a community clinic. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) assessed depression severity at baseline and before each infusion, up to three infusions for four total observations.

Results: GMM revealed three QIDS-SR response trajectories. There were two groups of severely depressed patients, with contrasting responses to ketamine. One group (n=135, baseline QIDS-SR=18.8) had a robust antidepressant response (final QIDS-SR=7.3); the other group (n=97, QIDS-SR=19.8) was less responsive (final QIDS-SR=15.6). A third group (n=96) was less severely depressed at baseline (QIDS-SR=11.7), with intermediate antidepressant response (final QIDS-SR=6.6). Comparisons of demographic and clinical characteristics between groups with severe baseline depression revealed higher childhood physical abuse in the group with robust ketamine response (p=0.01).

Limitations: This was a retrospective analysis on a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. Information pertaining to traumatic events occurring after childhood and pre-existing or concurrent medical conditions that may have affected outcomes was not available.

Conclusions: Overall, ketamine’s effect in patients with severe baseline depression and history of childhood maltreatment may be consistent with ketamine-induced blockade of behavioral sensitization.“

Authors: Brittany O’Brien, Marijn Lijffijt, Jaehoon Lee, Ye Sil Kim, Allison Wells, Nicholas Murphy, Nithya Ramakrishnan, Alan C. Swann & Sanjay J. Mathew

Summary

In this study, patients with major depressive disorder received repeated IV ketamine.

1. Introduction

We identified three distinct patterns of treatment response among depressed, real-world patients receiving intravenous (IV) ketamine treatment. The SD-RI group reported a more severe history of childhood maltreatment than the SD-MI group.

The current study examined patterns of response to IV ketamine in patients with major depressive disorder and suicidality. It hypothesized that childhood trauma would be associated with improved response for severely depressed individuals.

We conducted a latent class analysis in 298 patients who received an acute course of IV ketamine in an outpatient community clinic. We hypothesized that maltreated individuals would respond more robustly to ketamine than nonmaltreated individuals.

2.1. Study sample and procedures

A de-identified database of 785 patients who received treatment through an IV ketamine clinic in Chicago, IL was obtained from January 2018 to December 2020. 298 patients who received an acute induction course of thrice weekly (M-W-F) ketamine infusions were included in the study.

2.2. Administration of IV ketamine

Ketamine infusions were administered over 40 – 60 min by a board-certified physician. The initial dose was 0.50 mg/kg, and the dose was maintained or adjusted over the course of treatment for each individual patient.

2.3.1. Quick Inventory of depressive symptomatology – self report (QIDS-SR)

The QIDS-SR is a 16-item self-report scale that is reliable and has a high correlation with scores on other depression scales.

The CHRT-SR is a 14-item self-report questionnaire that measures suicidal propensity and risk as well as impulsivity. It has excellent internal consistency and good reliability.

2.3.3. Childhood Trauma Questionnaire-Short Form (CTQ-SF)

The CTQ-SF is a 28-item self-report scale measuring childhood maltreatment. It has robust psychometric properties and was administered during the initial clinic visit before the first infusion.

2.4. Data analysis

Data analysis proceeded in two stages: first, growth mixture modeling (GMM) was conducted to determine the number of patient groups, and second, demographic and clinical characteristics were examined as possible antecedents or consequences of responses to treatment. Statistical tests and fit indices were utilized to identify the best solution (i.e., optimal trajectory groups), including entropy, Bayesian Information Criterion, adjusted Lo-Mendell-Rubin, likelihood-ratio test, and Bayesian LRT.

In the second stage, demographic and clinical profiles, primary diagnosis, childhood maltreatment history, and suicidality were compared between trajectory groups. A chi-square test of independence, independent-samples t-test, or analysis of variance were used for statistical analyses.

3.1. Subjects

About 60 % of patients were male, with mean age of 40.36 years (SD = 14.11), and most had a primary diagnosis of major depressive disorder (MDD). Over a third reported a childhood history of clinically significant emotional abuse.

3.2. Trajectories of depression during ketamine treatment

We hypothesized four classes of linear or quadratic growth in depressive symptoms during ketamine treatment, and found that the 3-class model of quadratic growth produced the lowest BIC (i.e., best fit) across all eight models.

The 3-class quadratic growth model identified three distinct patterns of QIDS-SR score change over six clinic visits. The largest group showed moderate depression at baseline and modest improvement over time, while the second largest group demonstrated severe depression at baseline with substantial improvement during treatment.

3.3. Demographic and clinical characteristics related to depression trajectories

The mean QIDS-SR and CHRT-SR scores of the SD-MI group were significantly higher than those of the MD-GI group across all visits, while the mean QIDS-SR and CHRT-SR scores of the SD-RI group were significantly higher than those of the MD-GI group after three ketamine infusions.

Table 3 presents demographic profiles and clinical characteristics of the three trajectory groups at baseline, with group comparisons. The SD-RI group had a significantly higher CTQ total score than the MD-GI group.

4. Discussion

A sample of patients receiving IV ketamine showed three distinct trajectories of antidepressant response. These findings are consistent with other studies that have demonstrated pretreatment characteristics and early treatment change patterns are associated with differential responses to treatment.

Membership in groups with severe depression pre-treatment was associated with higher CTQ total scores, but we did not replicate our previous study’s findings that a history of childhood physical abuse predicted better outcomes for patients presenting for treatment with severe depression.

Sensitization may be one mechanism underlying the development of PTSD. Ketamine and other glutamate antagonists have been shown to block the development and expression of sensitization to stress/trauma or analogous stimuli.

Cross-sensitization between traumatic, addictive, and similar physiological stimuli suggests that ketamine may be effective in people with psychiatric disorders associated with those characteristics. This finding is also consistent with reports of reduced suicidality after ketamine administration.

Ketamine response may be related to stress sensitization. Suicidality may be responsive to ketamine, and the potential for distinct trajectories of response, recovery, and relapse in suicidality relative to MDD remains to be investigated.

The researchers found that there were more females than males in the SD-MI group compared to the other groups. This finding is inconsistent with their previous report.

Our findings should be considered in light of several limitations, including the fact that only approximately two thirds of the current sample had available CTQ data, that we had limited information on the race and ethnicity of the sample, and that we used a retrospective analysis on a naturalistic sample.

In summary, treatment with ketamine was associated with distinct clinical trajectories in depressed patients, and greater childhood maltreatment was associated with a greater response to treatment.

CRediT authorship contribution statement

All authors contributed to the conceptualization, data collection, analysis, and writing of the manuscript.

Conflict of Interest

The authors of this article are supported by the Michael E. Debakey VA Medical Center.

Dr. Mathew has served as a consultant to many pharmaceutical companies.