Now, I’d like to speak to the efficacy of ketamine in studies of major depressive disorder, treatment-resistant depression or bipolar depression. Now, the first study that led to the current wave of excitement about ketamine as an antidepressant was published in 2000 by Berman and colleagues. In this very small crossover trial, patients with depression experienced a rapid improvement in mood within just a few hours after exposure to ketamine. This was not seen after these same participants were exposed to saline or placebo. These infusions were performed a week apart and there was some minimal but non-significant carryover effects when ketamine was the first drug administered. Following ketamine, there was an average of 13-point mean decrease in depression severity when measured by the Hamilton Depression Rating Scale.
It is important to note that the significant improvements in depression were noted within four hours of treatment even when baseline scores for neurovegetative symptoms such as sleep and appetite were assumed not to have changed because it was unreasonable to expect changes in these symptoms in a four-hour period. Now, this point highlights the limitations of assessing rapid change in depression with somewhat antiquated scales that were designed to measure changes over one week. Nevertheless, the observed rapid changes in mood following low-dose ketamine were dramatic and potentially revolutionary. It is also interesting to note that antidepressant effects of ketamine were temporally disconnected from and occurred later than the high and schizophrenia-like symptoms that subsided by the two-hour time point.
The positive findings of the Berman study were first replicated by researchers at the National Institutes of Health utilizing a similar crossover trial design. After being washed out of all medications, patients with major depressive disorder who have failed to respond to at least two antidepressant trials were given either ketamine or saline placebo and then crossed over to the opposite treatment after one week. A rapid antidepressant effect was seen within two hours in the group receiving ketamine compared to the same group when they received the placebo and a very large effect was seen after 24 hours with still a moderate effect seen after about one week.
It is important to note the blinded nature of placebo-controlled studies reviewed thus far is difficult to maintain because of the dose used ketamine reliably produces dissociative effects which peak about 15 to 30 minutes after infusion start. These effects generally subside within 30 minutes following the completion of the infusion. In an effort to improve blinding, some investigators have used midazolam, a benzodiazepine, as an active comparator. Midazolam was chosen because like ketamine it has noticeable effects on perception and cognition. It has a short half-life and a rapid onset of action and it can be delivered intravenously.
Murrough and his colleagues were the first to conduct a parallel randomized trial of ketamine versus midazolam in patients with treatment-resistant depression. At a two-site study, patients with treatment-resistant depression who were free from medications were randomized to either receive ketamine or midazolam. Ketamine produced a response in a greater proportion of patients than midazolam at 24 hours. And while ketamine was superior to midazolam in producing antidepressant effects, the magnitude of the difference seemed to be attenuated when compared with earlier studies that used saline as a placebo.
The key points to the early efficacy trials of ketamine are that ketamine has emerged as a prototypical rapid-acting antidepressant. Early efficacy studies showed a high rate of response in the range of 64% to 71% to a single dose of ketamine among individuals with treatment-resistant depression. Later clinical reports of the effectiveness of ketamine in clinical samples have demonstrated generally a lower response rate in the range of 50%. Now, this discrepancy between efficacy and effectiveness is not entirely unexpected and can frequently be seen as new treatments are taken from clinical trials to real world settings.
References:
- Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000). Antidepressant effects of ketamine in depressed patients. Biological psychiatry , 47(4), 351-354.
- Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., … & Manji, H. K. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression . Archives of general psychiatry, 63(8), 856-864
- Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., … & Charney, D. S. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial . American Journal of Psychiatry, 170(10), 1134-1142.
