Wednesday, December 31, 2014

Ketamine for PTSD

Feder et al. (2014) published one of the first studies looking at possible use of ketamine to treat PTSD. * In this study, ketamine (0.5 mg/kg IV over 40 minutes) was compared with midazolam, on a randomized, double-blind basis, to treat PTSD patients.   In a crossover design, each patient was scheduled to receive a second infusion, 2 weeks later, of the drug they had not received the first time. 

I think a particular strength of this study was the use of midazolam as an active placebo.  The study would have been strengthened even further if they asked subjects afterwards to guess which medication they had received (most patients would have been familiar with benzodiazepines, and would have known that they did not lead to lasting improvements in their symptoms--presumably most of the patients would have wanted to receive the ketamine, as a novel, hopeful treatment).

The results appear similar to other studies of using ketamine to treat depression:  significant improvement in the week following the infusion.  The acute dissociative effects of the drug wear off completely within a few hours, as ketamine levels go down to zero during this time, yet the symptom improvements are maximal after 24 hours, and continue to be significant over a one-week period. 

The overall effect was to reduce PTSD and depression symptom scores at least by half, with improvements in all PTSD domains.

Side effects were not a major problem; in the 24 hours following the infusion, ketamine patients reported more blurry vision, restlessness, and nausea, compared to the midazolam patients.  Only one ketamine patient dropped out during the infusion, because he felt uncomfortable with it. 

For the patients who had received ketamine first, 7 of 22 were still responders after 2 weeks, compared to only 1 of the midazolam group. 

Once again, I think it would be useful for more studies to explore oral or sublingual ketamine dosing, since this would be much more convenient and practical for a larger number of patients.  A gradual intravenous infusion over 40 minutes leads to a fairly similar change in serum levels compared to GI absorption.  Rapid bolus dosing is an advantage of using IV, but this has not been used for administering ketamine to psychiatric patients.   There are differences in the ratio of ketamine vs. metabolites with the oral vs. IV routes, but I do not see that the differences are so great as to obstruct the benefits.   Dose finding is less precise with oral dosing, but this is a technical matter which can be simply resolved through careful titration.    In any case, science may answer this question for us, through well-designed trials.  A study design I would suggest for this would be a double-blind crossover study comparing oral ketamine + IV saline infusion   vs. IV ketamine + oral placebo, with one treatment per week for 4 weeks.  Doses could be adjusted according to response and side effects on treatments 2, 3, and 4.

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