Nancy A. Melville

June 06, 2017

MIAMI – As the off-label use of ketamine for the treatment of severe depression continues to soar, two new studies provide insight into the way clinicians are using it in the field, away from the research setting.

In the first of the two studies presented here at the American Society of Clinical Psychopharmacology (ASCP) 2017 Annual Meeting, researchers compared a range of doses of ketamine, an N-Methyl-D-aspartate (NMDA) antagonist drug, with placebo.

The drug is commonly provided via intravenous infusion of 0.5 mg/kg, administered over approximately 45 min. Studies assessing the balance between efficacy and the notable side effects of dissociative symptoms and blood pressure changes are lacking.

In a double-blind study, patients with treatment-resistant depression were randomly assigned to groups of approximately 20 patients each to receive either intravenous ketamine, provided over 45 min, at single doses of either 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, and 1.0 mg/kg, or a single IV dose of midazolam 0.045 mg/kg, representing an active placebo.

Safety and efficacy assessments were conducted at days 0, 1, 3, 5, 7, 14, and 30.

The primary outcome measure was improvement on the six-item Hamilton Depression Rating Scale (HAMD-6). Improvement from baseline was significant in the various dose groups combined (P = .02) as well as individually with respect to both low and high doses, compared to the placebo group. The effect largely reflected differences at day 1 following the infusion; none of the effects were sustained at day 3.

After adjustment for variables, the .05-mg/kg and 1.0-mg/kg groups had the highest improvement in HAMD-6 scores (reductions of 4.79 and 3.76; P = .00 and P = .04, respectively).

The 0.1-mg/kg group demonstrated a trend toward improvement, with HAMD-6 reductions of 3.18 and an unadjusted improvement of P = .02, but improvement was nonsignificant after adjustment (P = .14).

As expected, the side effects of dissociative symptoms and elevations in blood pressure were significantly lower with lower doses compared to higher doses.

Similar findings were observed in other measures, including the Montgomery–Åsberg Depression Rating Scale, the Symptoms of Depression Questionnaire, and others.

"The results indicate that the doses that do seem to have the highest effects of dissociative and blood pressure effects have the highest clinical effect," study investigator George Papakostas, MD, director of treatment-resistant depression studies, Depression Clinical and Research Program, Massachusetts General Hospital, Boston, told meeting delegates.

"However, I do think there is a signal for efficacy in the 0.1-mg/kg dose, even though it just misses statistical significance."

Patterns of Use

In a second study, researchers investigated current ketamine treatment patterns among clinicians who prescribe the drug for severe depression.

The study was conducted by investigators at Yale School of Medicine, New Haven, Connecticut, and was led by Samuel Wilkinson, MD. The researchers identified ketamine prescribers nationwide and sent them a Web-based survey.

The survey was distributed to 76 physicians across the United States. Of these, 57 (75%) responded.

Among the respondents, 66.7% were trained in psychiatry, 22.8% were trained in anesthesiology, 3.5% in emergency medicine, 3.5% in family medicine, and 1.8% in physical medicine or rehabilitation.

The majority of providers (87.7%) treated patients with IV ketamine; 22.8% used an oral formulation, and 19.3% used an intranasal formulation.

Of those treating with IV ketamine, 44% reported using the standard dose of 0.5 mg/kg, infused over 40 to 45 min; 12% reported using doses ranging from 0.5 to 1.0 mg/kg, and 14% reported using doses between 0.5 and 3.0 mg/kg.

Anesthesiologists were most likely to use higher doses of the drug.

Overall, the clinicians reported efficacy rates of approximately 60% to 80%, which Dr Wilkinson noted was consistent with research.

"This is not the same quality of official rating scales, but in terms of meaningful response, most said between 60% and 80%, which is close to the efficacy we see in most clinical trials."

Off-Label Use Continues to Grow

Approximately 80% of clinicians reported using some form of vital sign monitoring at least every 15 minutes. "This was somewhat reassuring," he said.

Nearly 90% of clinicians reported offering patients ketamine on a continual or maintenance basis for a period of more than 1 month; 29.8% reported administering monthly treatments; 21.1% reported administering treatments once every 3 weeks; 12.3% reported giving treatments once every 2 weeks; and 15.8% reported treatments of less than once 1 month's duration.

On the basis of survey responses, the authors speculate that at least 3670 patients have been treated with ketamine for psychiatric disorders in the United States.

"This is the first attempt to characterize practice patterns among physicians providing ketamine outside of research protocols as a treatment for psychiatric disorders," the investigators note.

"We identified a rapidly growing number of physicians of a variety of specialties and geographic locations offering ketamine treatment for psychiatric disorders," they add.

Dr Wilkinson said that the off-label use of ketamine is not slowing.

"While there is controversy regarding the use of ketamine for depression outside of the realm of research, I am arguing that this train has left the station," he said.

"There is clearly excitement over the real and rapid effect, combined with the desperation of patients who are not responsive to conventional treatments."

It is unlikely that the US Food and Drug Administration will grant approval of ketamine for the treatment of depression in the near future, said Dr Wilkinson. Therefore, he called for the establishment of a ketamine registry, which he describes as being "the next best thing.

"If we partner with each other and with community providers who are offering ketamine for depression, we can learn more about it. There are clearly a large number of patients being treated with this, and we need to be able to pool our data and learn something," he said.

The dosing study was funded by the National Institute of Mental Health.

American Society of Clinical Psychopharmacology (ASCP) 2017 Annual Meeting. Abstracts 3001031 and 3000858, presented June 1, 2017.

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