NEW YORK—Research from the Icahn School of Medicine at Mount Sinai (ISMMS) has shown that repeated intravenous (IV) ketamine infusions significantly — and rapidly — reduce symptom severity in people with chronic post-traumatic stress disorder (PTSD). The improvement was also maintained for several weeks after treatment. This study, published today in the American Journal of Psychiatry, is the first randomized, controlled trial of repeated ketamine administration for chronic PTSD, and the data suggests that ketamine infusions could be a promising treatment for PTSD.
Mount Sinai researchers previously conducted a proof-of-concept trial of a single dose of intravenous ketamine for PTSD, which showed significant and rapid PTSD symptom reduction 24 hours post-infusion. Ketamine, which was first approved by the FDA as an anesthetic, acts as an antagonist of the N-methyl-d-aspartate (NDMA) receptor, an ionotropic glutamate receptor in the brain. In contrast, widely used antidepressants target different neurotransmitters — serotonin, norepinephrine, and dopamine — and can take weeks or even months to become effective. These drugs are considered ineffective in at least one third of cases, and only partially effective in another third.
“The data presented in our current study not only replicates, but also builds on our initial findings about ketamine for PTSD, indicating that in addition to being rapid, ketamine’s effect can be maintained over several weeks,” noted Dr. Dennis S. Charney, Anne and Joel Ehrenkranz Dean of ISMMS, president of Academic Affairs for the Mount Sinai Health System, and senior author of the paper. “PTSD is an extremely debilitating condition and we are pleased that our discovery may lead to a treatment option for so many who are in need of relief from their suffering.”
In the current study, participants were randomly assigned to receive six IV infusions of ketamine administered three times per week over two consecutive weeks. This was compared to six infusions of the psychoactive placebo control midazolam — chosen because its pharmacokinetic parameters and nonspecific behavioral effects are similar to those of ketamine — administered and evaluated over the same schedule.
The people chosen for this study had severe and chronic PTSD from either civilian or military trauma, with a median duration of 14 years. Nearly half of the sample population was taking concomitant psychotropic medications. The primary traumas reported by participants included sexual assault or molestation, physical assault or abuse, witnessing violent assault or death, combat exposure, and having responded to or survived the 9/11 attacks.
All study participants were assessed at baseline, at weeks 1 and 2, and on each infusion day, by teams of trained study raters who administered the Clinician-Administered PTSD scale for DSM-5 (CAPS-5) and the Montgomery-Asberg Depression Rating Scale (MADRS), standard rating scales for the assessment of PTSD and depression. Significantly more participants in the ketamine group (67 percent) had at least a 30 percent or more reduction in symptoms from baseline at week two than those in the midazolam group (20 percent). Ketamine infusions were associated with marked improvements across three of the four PTSD symptom clusters — intrusions, avoidance, and negative alterations in cognition and mood. In the subsample of ketamine responders, the improvement in PTSD symptoms was rapid, observed 24 hours after the first infusion.
“The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91),” states the article abstract. “Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.”
“Our findings provide insight into the treatment efficacy of repeated ketamine administration for PTSD — an important next step in our quest to develop novel pharmacologic interventions for this chronic and disabling disorder, as a large number of individuals are not sufficiently helped by currently available treatments. The data suggests repeated IV ketamine is a promising treatment for people who suffer from PTSD and provides evidentiary support to warrant future studies to determine how we can maintain this rapid and robust response over time,” pointed out Dr. Adriana Feder, associate professor of Psychiatry at ISMMS, and lead author of the study.
In addition to PTSD symptom improvement, the ketamine group exhibited markedly greater reduction in comorbid depressive symptoms than the midazolam group. This is notable, given the high comorbidity of depression in people with PTSD. Study findings further suggested that repeated ketamine infusions are safe and generally well-tolerated in individuals with chronic PTSD.
“Future studies may include administering additional doses over time and examining repeated ketamine infusions combined with trauma-focused psychotherapy, to help us determine how we can maintain this robust response over the long term,” Feder added. “We want people suffering with PTSD to know that hope is on the horizon and we are working diligently to collect the information that will help bring them the relief they so desperately need.”
Charney and Feder have been named co-inventors on an issued patent in the US, and several issued patents outside the US, filed by the ISMMS for the use of ketamine as a PTSD therapy.