The Impact of Childhood Maltreatment on Intravenous Ketamine Outcomes for Adult Patients with Treatment-Resistant Depression

This open-label study (n=115) found that ketamine improved depression (TRD) symptoms and especially for those with childhood trauma. It is hypothesized that the ability of ketamine to block trauma-associated behavioral sensitization is the mechanism through which this happens.

Abstract

“Childhood maltreatment is associated with a poor treatment response to conventional antidepressants and increased risk for treatment-resistant depression (TRD). The N-methyl-D-aspartate receptor (NDMAR) antagonist ketamine has been shown to rapidly improve symptoms of depression in patients with TRD. It is unknown if childhood maltreatment could influence ketamine’s treatment response. We examined the relationship between childhood maltreatment using the Childhood Trauma Questionnaire (CTQ) and treatment response using the Quick Inventory of Depressive Symptoms–Self Report (QIDS-SR) in TRD patients receiving intravenous ketamine at a community outpatient clinic. We evaluated treatment response after a single infusion (n = 115) and a course of repeated infusions (n = 63). Repeated measures general linear models and Bayes factor (BF) showed significant decreases in QIDS-SR after the first and second infusions, which plateaued after the third infusion. Clinically significant childhood sexual abuse, physical abuse, and cumulative clinically significant maltreatment on multiple domains (maltreatment load) were associated with better treatment response to a single and repeated infusions. After repeated infusions, higher load was also associated with a higher remission rate. In contrast to conventional antidepressants, ketamine could be more effective in TRD patients with more childhood trauma burden, perhaps due to ketamine’s proposed ability to block trauma-associated behavioral sensitization.”

Authors: Brittany O’Brien, Marijn Lijffijt, Allison Wells, Alan C. Swann & Sanjay J. Mathew 

Summary

Article

Childhood maltreatment was associated with a poor treatment response to conventional antidepressants and increased risk for treatment-resistant depression. Ketamine was shown to rapidly improve symptoms of depression in patients with TRD, and higher childhood maltreatment load was associated with a higher remission rate.

1. Introduction

Approximately 12.2% of US residents 13 years and older have a lifetime history of major depressive episodes, and 35% of depressed patients have treatment resistant depression.

Ketamine is a promising treatment option for patients with TRD. It works by blocking the N-methyl-D-aspartate receptor (NMDAR), enhancing prefrontal and hippocampal glutamate concentrations, and activating the AMPAR and mTOR signaling pathways.

Childhood maltreatment is a risk factor for treatment-resistant depression in adulthood. In this study, we examined the influence of childhood maltreatment on ketamine treatment response in moderate to severely depressed adults receiving treatment at an outpatient ketamine clinic.

2.1. Patient Characteristics

The demographics, treatment and clinical features of 115 patients who received ketamine IV are summarized in Table A1. All patients had moderate to severe levels of depression at pre-treatment baseline and received 0.62 or 0.70 mg/kg of IV ketamine per infusion.

2.2. Single Infusion

Ketamine treatment significantly decreased depressive symptoms in 115 patients (mean SD; baseline 18.63 3.70; post-infusion: 13.12 5.13)

Childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ), which provides total scores and subscale scores for five distinct domains of childhood maltreatment. About two-thirds of the sample had a maltreatment load of 1 or higher.

We correlated the QIDS-SR change score with maltreatment load, SA, PN, total CTQ and PA, but not with EA or EN, and tested the effects of these variables on treatment response using two separate RM-GLM analyses.

The effect of time and load on QIDS-SR was significant. Patients with load 5 had a larger reduction in QIDS-SR scores from baseline than patients with loads 0, 1 or 3.

Subscale RM-GLM analysis showed that those with SA 8 had a mean decrease in QIDS-SR of 8.08 points compared to 4.82 points of those with SA 8 (n = 91), but this difference was only 2 points at post-infusion.

Table A2 shows that maltreatment load only affected CTQ total and subscale scores. RM-GLM showed that the interaction between maltreatment load and treatment response remained significant after controlling for demographic, clinical and treatment variables.

2.3. Repeated Infusions

The demographics, treatment variables and diagnostic characteristics of 63 clinic patients who received at least four repeated ketamine infusions are summarized in Table A1.

A per-protocol analysis using only patients who completed four infusions on a twice- or once-weekly schedule showed that repeated ketamine infusions improved depressive symptoms. The evidence for these improvements was strong, and the evidence for improvement after the fourth infusion was moderate.

We examined correlations between QIDS-SR change score and CTQ variables, and found that maltreatment load, PN, PA, and SA had significant effects on QIDS-SR change.

The RM-GLM analysis revealed that the time by load interaction was significant, and that the load groups did not differ in QIDS-SR score at any of the time points. However, the load groups had a trend for a higher QIDS-SR change score than the other groups.

The time by PA interaction was significant, as was the time by PN interaction, with those with higher scores on PA having a greater decline in QIDS-SR from baseline to visit five.

The relationship between maltreatment and response and remission rates was examined with X2 statistics. BF showed significant effects of maltreatment load and PN, and moderate effects of SA and PA.

The percentage of patients who met criteria for response and remission at visit 5 was higher for those with clinically significant maltreatment on at least four CTQ subscales.

Table A5 displays demographic, treatment and clinical variables divided by maltreatment load. Self-reported diagnosis and prescribed psychopharmacological treatment did not consistently relate to treatment effect.

We analyzed patients continuing with multiple infusions on a per-protocol basis, and found that maltreatment load was not associated with exclusion from the sample, but that patients with clinically significant physical neglect were less likely to be excluded.

Patients with more severe maltreatment were more likely to follow the fixed twice- and once-weekly treatment schedule and had a higher response rate and remission rate to ketamine infusion than patients with low maltreatment.

3. Discussion

This naturalistic study in TRD patients showed that those with childhood maltreatment benefit as much as those without clinically significant maltreatment history, and may benefit more from a single and repeated ketamine infusion.

Age, gender, and ketamine dose were minimally affected by outcomes, and psychiatric diagnosis and concurrent medication did not affect outcomes. Ketamine could benefit TRD patients with high maltreatment load across a variety of diagnoses and concurrent treatment, in particular for single infusion.

A relationship between more severe childhood maltreatment and a better treatment response to ketamine may be related to processes of trauma-induced behavioral sensitization. Development of validated markers of sensitization may make it possible to identify and treat “treatment-resistant” depression.

Childhood maltreatment may affect treatment response to ketamine. A twice weekly infusion schedule followed by weekly infusions for maintenance may maximize benefit and minimize patient burden.

The current study has several limitations, such as a small sample size, lack of demographic information, a retrospective measure, and a naturalistic study design which may bias clinical and treatment variables and therefore complicate the generalizability of the findings.

4.1. Study Samples

This study included adult patients with moderate to very severe depressive symptoms who had failed at least one trial of antidepressant medication. The study examined the effects of childhood maltreatment on ketamine’s antidepressant response after a single infusion of ketamine and after at least 4 repeated infusions of ketamine.

4.3. Data Set

Researchers collected de-identified information from patients who received treatment at ketamine treatment centers from April 2016 to April 2019.

4.4. Materials

The QIDS-SR is a 16-item self-report scale that assesses all the criterion symptom domains designated by the APA to diagnose a major depressive episode.

The CTQ is a 28-item self-report scale measuring childhood maltreatment prior to the age of 18. A patient’s “maltreatment load” score indicates the total number of domains a patient scored above threshold for clinically significant maltreatment.

4.5. Data Analysis

Ketamine treatment effects on the QIDS-SR and the possible influence of childhood maltreatment were tested with repeated measures general linear models (RM-GLM). Significant interactions were tested with appropriate follow-up analyses.

Data distributions for ketamine, SA, PA and PN were normalized with inverse transformations, and statistical analyses were performed in JASP 0.9.0.1.

5. Conclusions

This study suggests that ketamine treatment could be considered before other antidepressant medications in TRD populations with high self-reported childhood maltreatment.

Possible effects of diagnosis or medication on time by maltreatment interactions were tested with RM-GLM. Antipsychotics, hypnotics, and atypical antidepressant medication did not affect the time by load interaction.

Appendix H

We provide an example from the text of an interaction between time and maltreatment load. The interaction model was preferred over the main effects model by BF = 6.57.