Ketamine Dosing for Depression May Not Be 'One-Size-Fits-All'

Megan Brooks

October 17, 2018

Results of a dose-ranging study of ketamine as adjunctive therapy for treatment-resistant depression confirms that a single intravenous dose of 0.5 mg/kg has a rapid and robust antidepressant effect.

The study also provides some evidence that a lower dose of 0.1 mg/kg — one that has been typically considered too low — may have some beneficial effect without blood pressure elevation or dissociative symptoms.

"This raises the possibility that lower doses may work for some patients, and this would be an important study to do. Nobody has really ever studied the 0.1 mg/kg dose before in depression," senior author Maurizio Fava, MD, executive director of the Clinical Trials Network and Institute, Department of Psychiatry, Massachusetts General Hospital, Boston, told Medscape Medical News.

The study was published online October 3 in Molecular Psychiatry.

Optimal Dose Unknown

Ketamine is an NMDA receptor antagonist that has long been used as a general anesthetic. It has been shown in several studies to induce rapid, albeit transient, antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown.

Fava and a team of ketamine researchers from six US centers compared four different doses of IV ketamine among 99 adult outpatients with treatment-resistant depression. The participants had failed to respond satisfactorily (ie, <50% improvement in depression symptoms) to at least two adequate courses of treatment during their current depressive episode.

Participants were randomly allocated to receive a single 40-min IV infusion of ketamine 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, or the active placebo midazolam (0.045 mg/kg).

The patients were assessed with the 6-item Hamilton Depression Rating Scale (HAM-D-6) on the day of infusion and 2, 3, 5, 7, 14, and 30 days later. Additional standard instruments measured aspects of mood and suicidal thought. Dissociative symptoms were assessed during and after ketamine infusion, and vital signs were measured after treatment and at all follow-up visits.

On the HAM-D-6 (primary outcome), there was a statistically significant day by group interaction effect (P = .0278) in the two-group analysis between ketamine and active placebo and in the five-group analysis (P = .0391) between ketamine (0.1, 0.2, 0.5 or 1.0 mg/kg) and active placebo.

In pairwise comparisons, after adjusting for multiple comparisons, antidepressant effects of standard-dose (0.5 mg/kg) and high-dose (1.0 mg/kg) ketamine were superior relative to active placebo. For most participants in these two-dose groups, the benefits of ketamine treatment began to decrease on the third day after treatment and were no longer detectable after 5 days.

The low 0.1 mg/kg dose showed significant antidepressant effect only before adjustment (P = .02). There was no clear or consistent evidence for clinically meaningful efficacy after adjustment (P-adj = .014), and most of the effect was due to differences on the first day.

The 0.2 mg/kg dose did not show any significant benefits. The researchers say it's possible that the lack of efficacy of that dose may be due to the fact that the treatment group was small and that participants in this group tended to be more treatment resistant to begin with.

Overall, ketamine infusions were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses.

"In our study, 1.0 mg/kg was no better than 0.5 mg/kg, and 0.5 mg was slightly better tolerated than 1.0 mg. On the other hand, 0.1 mg was extremely well tolerated and had an effect that was statistically significant, only without the adjustment, so it was not as robust as the 0.5, but there was an effect that was detectable," said Fava.

"These results support the clinical observation that one size — in this case, the most studied dose of 0.5 mg/kg — does not fit all, as some patients may require a lower-than-average dose; and each patient needs a tailored treatment plan that may include ketamine, together with other medications and talk therapy," coauthor Cristina Cusin, MD, who directs the ketamine clinic as Massachusetts General Hospital, said in a news release.

Short-Lived Benefit

Commenting on the results for Medscape Medical News, Bryan Bruno, MD, attending physician at Lenox Hill Hospital in New York City, noted that "most practitioners use 0.5 mg/kg, so it's good to see confirmation in this study that the 0.5 and 1.0 mg/kg doses appear to be the most effective doses, although the 1.0 mg dose does have slightly more side effects, dissociative effects during the infusion. It's also good to see, but not surprising, that lower doses are not particularly effective.

"Unfortunately," said Bruno, "all the studies of ketamine show that the benefit is very brief and wears off after a few days. And there are questions about the effects of a maintenance course of ketamine and whether or not there are longer-term side effects, so that still needs to be studied.

"I think ketamine is going to be most useful for patients who we really want a very rapid benefit while we are waiting for more traditional antidepressants to kick in, which can take about 4 to 6 weeks to work, and for people who are hospitalized with very severe symptoms and suicidal ideation who can be helped immediately with ketamine," said Bruno.

The study was supported by National Institute for Mental Health. Dr Fava has disclosed no relevant financial relationships. A complete list of the other authors' relevent financial relationships is available in the original article. Dr Bruno has disclosed no relevant financial relationships.

Mol Psychiatry. Published online October 3, 2018. Abstract

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