Predictive value of heart rate in treatment of major depression with ketamine in two controlled trials

This open-label study (n=51) found that a large increase in heart rate (HR) and -variability (HRV) predicted better outcomes for those suffering from depression (MDD) after administration of ketamine.

Abstract

“Objective: Ketamine has been shown to be effective in treatment of episodes of major depressive disorder (MDD). This controlled study aimed to analyse the predictive and discriminative power of heart rate (HR) and heart rate variability (HRV) for ketamine treatment in MDD.

Methods: In 51 patients, HR and HRV were assessed at baseline before and during ketamine infusion and 24 hours post ketamine infusion. Montgomery–Åsberg Depression Rating Scale (MADRS) was used to assess changes of depressive symptoms. A 30% or 50% reduction of symptoms after 24 hours or within 7 days was defined as response. A linear mixed model was used for analysis.

Results: Ketamine infusion increased HR and HRV power during and after infusion. Responders to ketamine showed a higher HR during the whole course of investigation, including at baseline with medium effect sizes (Cohen’s d = 0.47–0.67). Furthermore, HR and HRV power discriminated between responders and non-responders, while normalized low and high frequencies did not.

Conclusion: The findings show a predictive value of HR and HRV power for ketamine treatment. This further underlines the importance of the autonomous nervous system (ANS) and its possible malfunctions in MDD.

Significance: The predictive power of HR and HRV markers should be studied in prospective studies. Neurophysiological markers could improve treatment for MDD via optimizing the choice of treatments.”

Summary

Ketamine has been shown to be effective in the treatment of episodes of major depressive disorder. This controlled study aimed to analyse the predictive and discriminative power of heart rate and heart rate variability for ketamine treatment in MDD.

1. Introduction

Ketamine has been shown to be effective in treatment resistant depression, but more knowledge is needed about how to select patients that might benefit from this treatment option.

Research has focused upon the characteristics of responders to ketamine treatment, including genetic polymorphism, functional neuroimaging, baseline Glx/Glutamate ratio, and baseline delta sleep ratio. Although these findings contribute to our understanding of the neurobiological mechanisms of ketamine action, objective clinical predictors remain elusive.

Ketamine’s impact on the autonomous nervous system and its anesthetic properties on the central nervous system has been repeatedly demonstrated. This study aimed to evaluate the predictive power of heart rate and heart rate associated measures for ketamine treatment in MDD.

Reduced heart rate variability (HRV) in patients with depression reflects sympathovagal dysbalance accompanying the disorder. Drugs for depression reduce HRV values, but the impact of other medication remains controversial. Baseline HRV changes in response to emotional stimuli were associated with the reduction of depressive symptoms after fluoxetine treatment. Additionally, an increased sympathetic tone as it can be reflected in higher HR, larger HRV power and larger Low Frequency power was associated with a more pronounced decrease of symptoms after ketamine infusion.

2. Methods

Fifty-one patients were recruited into two consecutive controlled trials between 2010 and 2015. The trials were double-blind and randomized, and the second trial was single-blind and one-arm, fixed sequence design without randomization. These studies aimed to identify clinical, electrophysiological, and biological predictors of response to a single intravenous dose of ketamine as treatment for depression in patients with MDD. Inclusion criteria were suicidal risk, current psychiatric comorbidity, serious unstable medical illness or neurological disorder, as well as lifetime history of psychotic symptoms and psychotic disorders in first- or second-degree relatives. Patients continued their psychopharmacological treatment in unchanged dose over duration of the study.

Ketamine was infused into the subjects’ forearms using an infusion pump. The total dose was 0.54 mg/kg within 30 min, and the subjects’ blood levels were assessed 10 minutes and 30 minutes after starting the infusion.

Depression ratings were obtained at baseline, 24 h, 72 h and 7 days post infusion. A modified response criterion was used to evaluate treatment response, which was defined as a decrease of depressive symptoms by means of MADRS > 30% at 24 h after infusion.

Electrocardiogram measurements, heart rate (HR) and heart rate variability (HRV) parameters provide information on the activity of the autonomous nervous system. The HRV-power is derived from the spectral analysis of changes of consecutive ECG R-peaks in milliseconds and is proportional to the ratio of the sympathetic and parasympathetic branches. Higher HRV power values reflect increased parasympathetic tone and decreased sympathetic activity. Recordings were taken before, during and 24 hours after ketamine infusion. Heart rate and heart rate variability measures were assessed using Kubios software, and RR-peaks were detected using an automatic RR detection algorithm.

Heart rate variability (HRV), normalized spectral power in the high frequency band (nHF) and normalized spectral power in the low frequency band (nLF) were computed as an overall estimator of the activity of the autonomous nervous system (ANS).

The data from the two controlled trials were pooled, and the baseline clinical data of responders and non-responders were compared using an unpaired t-test or Fisher’s exact test as appropriate. Linear mixed models were used to examine differences between responders and non-responders by means of HR and HRV measures before, at beginning of infusion, at end of infusion, and up to 24 hours after ketamine infusion as secondary outcome measures.

3. Results

ECG data from 47 out of 51 subjects was used in both trials. There were no unintended effects or important harms in either trial, and the mean % change of MDRS scores showed no significant differences between the two studies.

Heart rate, HRV power and nLF power increased significantly during ketamine infusion and decreased significantly after 24 hours. There was no significant difference between two separate studies.

The additional analysis with the response criterion revealed a significant group effect for HR and a significant effect for covariate sex but not for age.

A logistic regression analysis showed that pre infusion Heart Rate and Total HRV Power have a high predictive value for the outcome of ketamine infusions in major depression.

When all available HR and HRV measures were included in the logistic regression, the area under the curve increased to 0.96 with a sensitivity of 94% and a specificity of 93%.

Correlations between heart rate measures and ketamine/norketamine blood levels were significant. Ketamine levels were positively correlated with heart rate and negatively correlated with total HRV power.

4. Discussion

This study showed that responders and non-responders to ketamine infusion treatment in major depressive disorder had different profiles of the autonomous nervous system activity, suggesting a predictive value.

Ketamine increases sympathetic activity, which leads to increased heart rate and blood pressure, as well as bronchodilation, and the dissociative syndrome, which is defined by a decrease of central nervous system arousal whereas the activity of the autonomous nervous system is kept at high levels or even increases.

Ketamine treatment improves symptoms of MDD in parallel with a reduction of CNS arousal. A high ANS arousal was predictive of ketamine treatment outcome, possibly reflecting an overall hyperarousal of the ANS and CNS in those patients being responders.

Some evidence exists for decreased HRV in MDD, which is associated with a dysfunctional parasympathetic system and increased sympathetic activity. Ketamine increases heart rate and HRV power in depressive patients and is a predictive factor for treatment response.

In a small sample of 33 unmedicated subjects, a higher heart rate was predictive for response to SSRI or mirtazapine treatment. In the iSPOT-D study, an increasing heart rate over time in resting position was predictive for response to SNRI treatment.

There was a correlation between heart rate measures and ketamine/norketamine levels, but no significant difference by means of dosage between responders and non-responders. Therefore, subjects that are more sensitive to a sympathetic enhancement and that show higher excitation of the ANS before treatment, yield a larger response.

Patients were under drugs for depression in this study, and it is important to note that response prediction with a single parameter is a rather limited approach.

The response criterion with 50% decrease of MADRS after 24 h did not yield significant group differences between responders and non-responders for HRV measures. However, the results remained significant when lowering the threshold to 30% decrease after 24 h or increasing the time for response to 7 days.

5. Conclusion

These results encourage further research on autonomous nervous system regulation for determining treatment response to ketamine.

Acknowledgements

This work was supported by the Ministry of Health of the Czech Republic.