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Ketamine Has Potential Utility for Treating Treatment-Resistant Anxious Depression

Key findings

  • Overall, there was no significant interaction effect between treatment group assignment (ketamine vs. midazolam) and anxious/nonanxious status on depressive symptoms, as rated on multiple scales
  • On day 3, the nonanxious group responded significantly better to ketamine 0.1 mg/kg than the anxious group did, compared with midazolam
  • Subjects with anxious depression experienced a lower level of dissociative symptoms 40 minutes after the start of ketamine infusion, compared to subjects without anxious depression

Anxious depression is more difficult to treat than general major depressive disorder, and it seems to be particularly prevalent among patients suffering from treatment-resistant depression. Patients with anxious depression have higher rates of suicidal ideation, suicide attempts and treatment side effects.

The Rapidly-Acting Treatments for Treatment-Resistant Depression (RAPID) network, funded by the National Institute of Mental Health, recently conducted a multisite, randomized, double-blind, active placebo-controlled trial of four different dosages of intravenous ketamine in patients with unipolar treatment-resistant depression. When the ketamine groups were combined, the efficacy of ketamine was found to be superior to that of the active control, midazolam.

In light of what they term an "urgent need" for more effective treatments, a research team led by former research fellow Naji Salloum, MD, and George I. Papakostas, MD, director of Treatment-Resistant Depression Studies in the Depression Clinical and Research Program conducted a secondary analysis focused on trial participants who had anxious depression. As they report in Depression & Anxiety, ketamine was similarly effective in anxious and nonanxious patients with treatment-resistant depression.

Design of the Trial and Secondary Analysis

Subjects in the trial were 18 to 70 years old, had a primary psychiatric diagnosis of major depressive disorder and were currently experiencing a major depressive episode. Eligible patients also had to be experiencing treatment-resistant depression, defined as <50% response to at least two, but not more than seven, adequate treatment courses of antidepressants.

Of the 99 subjects randomized, 45 (45.5%) met the predefined criterion for anxious depression at baseline: a score of seven or more on the Hamilton Depression Rating Scale Anxiety–Somatization factor (HAMD-AS). Those 45 subjects included 35 (43.8%) of the 80 subjects randomized to ketamine and 10 (52.6%) of the 19 subjects randomized to midazolam. A single dose was administered of ketamine 0.1, 0.2, 0.5 or 1.0 mg/kg or midazolam 0.045 mg/kg.

In both the trial and the secondary analysis, the primary outcome measure was the score on the six-item Hamilton Depression Rating Scale (HAMD6) on Day 1 post-infusion. Ketamine works far more rapidly than traditional antidepressants; in previous studies, the difference in efficacy between ketamine and midazolam was most demonstrable at Day 1.

Pooled Ketamine Data

When data were combined from the four ketamine dosing groups, changes in HAMD6 score from baseline to Day 1 were not significantly different in subjects with anxious depression on ketamine or midazolam versus subjects without anxious depression on ketamine or midazolam. The results were similar for changes from baseline to Day 3.

Scores on other depression scales were consistent with the HAMD6 data. These included the Clinical Global Impression–Severity scale on Days 1 and 3 and the Montgomery–Åsberg Depression Rating Scale (MADRS) on Day 3. (The MADRS was not administered on Day 1.)

Analysis of Individual Ketamine Dosing Groups

With respect to both the HAMD6 and MADRS on Day 3, the nonanxious group responded significantly better to ketamine 0.1 mg/kg than the anxious group did, compared with midazolam. No similar relationships were found for the other ketamine doses.

The researchers note that these analyses were conducted with small numbers of subjects and without correcting-values for multiple comparisons.

Dissociative Symptoms

Ketamine is commonly used as a dissociative anesthetic, so the research team used the Clinician-Administered Dissociative States Scale (CADSS) to measure dissociative symptoms experienced by subjects in the ketamine arms of the trial. At 40 minutes after the start of the infusion, the average CADSS score was significantly lower in patients with anxious depression than in those without anxiety (8.26 vs. 14.25).

In this trial, subjects with anxious depression were significantly more likely than others to use benzodiazepines, which may have partially blunted dissociative symptoms, the researchers speculate.

The team warns that their results are exploratory. It will be worthwhile to continue examining whether ketamine is efficacious against anxious treatment-resistant depression, but larger trials that are designed and powered specifically to investigate that question will be required.

Learn more about the Depression Clinical & Research Program

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