Seeking the Optimal Dose for Ketamine’s Short-Term Rapid Antidepressant Effects

Seeking the Optimal Dose for Ketamine’s Short-Term Rapid Antidepressant Effects

Posted: November 27, 2018
Seeking the Optimal Dose for Ketamine’s Short-Term Rapid Antidepressant Effects

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In a trial involving 99 treatment-resistant patients, researchers sought to discover the optimal dose for the experimental drug ketamine, used as a rapidly acting antidepressant. They found that the two lowest doses tested were not reliably effective, while two higher doses were effective. The drug lost much of its effectiveness in most patients 3-5 days after a single IV infusion.


Although many studies in recent years have provided evidence that ketamine, an anesthetic drug, can provide rapid relief to people with deep depression, this research has not shed much light on what dose patients optimally should receive. And dosing is an important issue, since ketamine can generate serious side effects even at doses well below those used for anesthesia. The most important are the potential for addiction as well as dissociation, a disconcerting feeling of being detached from one’s surroundings.

Now, a team of researchers has reported results of a carefully controlled dosing trial of ketamine involving a group of 99 patients with treatment-resistant depression. The patients, who had not been helped in their current depressive episode by at least two conventional antidepressant treatments, were divided into five groups. One group received an “active placebo,” the drug midazolam, which generates drowsiness, while four groups received ketamine, each at a different dose ranging from very low to high. All of the participants remained on standard antidepressant medications they had previously been taking.

Publishing in Molecular Psychiatry on October 3, 2018, the team, led by Maurizio Fava, M.D., of Massachusetts General Hospital and Harvard University, a 1994 BBRF Young Investigator, and including 10 other investigators who have received support from the Foundation, concluded that there was “no clear or consistent evidence” that ketamine at the two lowest doses (0.1mg/kg and 0.2mg/kg) would generate a rapid antidepressant effect in treatment-resistant patients. But at the two higher doses tested – 0.5mg/kg and 1.0mg/kg – ketamine was found to “provide significant symptom amelioration within a few hours.”

Each participant in the trial, including the placebo group, received a single treatment, delivered via intravenous infusion. For those helped by ketamine, symptoms typically returned within a period of a few days. This result was consistent with other trials, which, said the researchers, typically delivered the drug at 0.5mg/kg. The team, which carefully monitored each of the trial participants for depression symptoms over a 30-day period following their infusion with either ketamine or placebo, noted that for those receiving ketamine there was “little evidence of meaningful therapeutic benefit after day 5,” although there was “a suggestion of greater sustained drug effect at the 1.0mg/kg dose as far out as days 15-30,” albeit “rather modest.”

The study, the researchers noted, was too small to answer the question of whether it made sense to raise ketamine doses in those who failed to respond at 0.5mg/kg. Nor could it resolve the question of whether those who could not tolerate that dose might nevertheless be helped by ketamine at lower dosages. These issues will have to be taken up by future studies.

The research team included two current grantees: 2015 Young Investigator Dawn F. Ionescu, M.D., and 2016 Young Investigator Samuel T. Wilkinson, M.D. It also included: 2004, 2000, and 1998 Young Investigator Marlene P. Freeman, M.D.; 2006 and 2001 Young Investigator Sanjay J. Mathew, M.D.; 2006 and 2001 Young Investigator Dan V. Iosifescu, M.D., Ph.D.; 2009 Young Investigator James Murrough, M.D.; 1998 Young Investigator Charles Debattista, M.D.; Foundation Scientific Council member and 2005 Falcone prizewinner Alan F. Schatzberg, M.D.; 1992 Yong Investigator and 2002 Independent Investigator Madhukar H. Trivedi, MBBS; and Foundation Scientific Council member and 2014 Distinguished Investigator, 2007 Independent Investigator, and 1999 Young Investigator Gerard Sanacora, M.D., Ph.D.

If you found this article interesting, you may find this Meet the Scientist Webinar interesting: Ketamine: Why Now? How? Where Do We Go from Here?