Disentangling the association of depression on the anti-fatigue effects of ketamine

This analysis of earlier data investigated of ketamine’s (35mg/70kg) anti-fatigue effects (it significantly improves fatigue scores) could be separated from the anti-depressant (amotivation and depressed mood) effects. The study found that the effect was completely explained by this. In other words, the anti-depressant effects also caused the anti-fatigue effects.

Abstract

“Background Fatigue and depression are closely associated. The purpose of this secondary analysis was to understand the relationships between depression and improvements in specific depression domains on the anti-fatigue effects of ketamine, which we previously reported.

Methods This secondary analysis re-evaluated data collected longitudinally from 39 patients with treatment-resistant Major Depressive Disorder (MDD) enrolled in a double-blind, randomized, placebo-controlled, crossover trial using a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg over 40 minutes) or placebo. A mediation model assessed the effect of depression on the anti-fatigue effects of a single dose of intravenous ketamine versus placebo at Day 1 post-infusion. Fatigue was measured using the National Institutes of Health–Brief Fatigue Inventory (NIH-BFI), and depression was assessed by the Montgomery–Ǻsberg Depression Rating Scale (MADRS).

Results Compared to placebo, ketamine significantly improved fatigue (p = .0003) as measured by the NIH-BFI, but the anti-fatigue effects of ketamine disappeared (p = .47) when controlling for depression as measured by MADRS total score. In this study sample, the anti-fatigue effects of ketamine were mostly accounted for by the changes in amotivation and depressed mood scores.

Conclusions In this study, ketamine did not have a unique effect on fatigue outside of its general antidepressant effects in patients with treatment-resistant depression. Specifically, the anti-fatigue effects of ketamine observed in this study seem to be explained by the effects of ketamine on two symptom domains of depression: amotivation and depressed mood. The study findings suggest that the anti-fatigue effects of ketamine should be assessed by fatigue-specific measures other than the NIH-BFI or future studies should enroll fatigued patients without depression.“

Authors: Leorey N. Saligan, Cristan Farmer, Elizabeth D. Ballard, Bashkim Kadriu & Carlos A. Zarate Jr.

Summary

This secondary analysis re-evaluated data from 39 patients with treatment-resistant Major Depressive Disorder who received a single intravenous infusion of ketamine hydrochloride or placebo at Day 1 post-infusion. The results showed that the anti-fatigue effects of ketamine were mostly accounted for by the changes in amotivation and depressed mood scores.

Ketamine did not have a unique effect on fatigue in this study, but rather had an effect on two symptom domains of depression.

Fatigue and depression are complex constructs, but their association is well documented. However, some evidence suggests that depression and fatigue are distinct constructs, and separating one construct from the other continues to be a challenge.

Amotivation is a common symptom of depression and fatigue. A shared biological mechanism may explain the relationship between amotivation and fatigue in a subset of depressed patients.

Previous work from our team observed that ketamine had rapid and sustained anti-fatigue effects, lasting until 2 days post infusion. The effect size of the ketamine-placebo difference was greatest at day 2.

Our research team has incorporated independent measures of fatigue and depression in their clinical trials, and has found that ketamine has antidepressant and anti-fatigue effects. This information may be used to identify specific domains of depression that are related to anti-fatigue effects of ketamine.

This study investigated the association of depression with the rapid anti-fatigue effects of ketamine. The study identified specific symptom domains of depression that were related to the anti-fatigue effects of ketamine.

1.1. Design and subjects

This study explored the efficacy of ketamine as an intervention in reducing depressive symptoms in patients with Major Depressive Disorder. Informed consent was obtained from all study participants.

Men and women with a diagnosis of recurrent MDD without psychotic features were eligible to participate if they had a score of 20 on the MADRS at screening and before each infusion, and had failed to respond to at least one prior adequate antidepressant trial.

Fatigue was assessed using the seven-item NIH-BFI and the 10-item MADRS, both validated to measure fatigue separate from depression in the context of depressive disorders. Both questionnaires were administered in the mornings at baseline and Day 1 (24 h) post-ketamine infusion.

Specific symptom domains were assessed using the MADRS, the HAMD, the SHAPS, and the BDI. The anhedonia subscale was excluded from the analysis because it was obtained from only about half of the sample.

1.3. Data analyses

We generated a mediation model to determine whether the effect of ketamine on depression symptoms accounted for its effect on fatigue. We confirmed a significant effect of ketamine versus placebo on MADRS total score and NIH-BFI total score.

General linear mixed models were used to estimate the effect of ketamine on baseline assessments. Cohen’s d effect size was calculated using the estimated difference, standard error, and degrees of freedom from this contrast.

2.2. Depression as a mediator of the anti-fatigue effects of ketamine

The NIH-BFI score was significantly improved under ketamine compared to placebo, but this effect was completely mediated by the MADRS Total Score.

2.3. Specific depression symptom domains as mediators of the anti-fatigue effect of ketamine

Most specific symptom domains of depression accounted for only a small amount of the effect of ketamine on fatigue.

3. Discussion

Ketamine can improve fatigue symptoms in patients with treatment-resistant MDD, but its effects on amotivation and depressed mood fully explained the anti-fatigue effects of ketamine.

The findings of this study revealed that the anti-fatigue effect of ketamine was uniquely independent of the effect of ketamine on reduced sleep. The lack of association between fatigue and sleep impairment is intriguing and worth investigating.

The study findings raise the possibility that the NIH-BFI may not be a sufficient measure to capture fatigue as a separate construct from depression, and future studies should consider enrolling non-depressed patients with clinically significant fatigue to explore the unique anti-fatigue effects of ketamine.

4. Conclusions

This study revealed that ketamine did not have a unique effect on fatigue independent of its general antidepressant effects, and that its anti-fatigue effects were explained by its localized effects on amotivation and depressed mood.