Repeated intravenous (IV) ketamine infusions significantly reduce symptom severity in individuals with chronic post-traumatic stress disorder (PTSD) and the improvement is rapid and maintained for several weeks afterwards, according to a study conducted by researchers from the Icahn School of Medicine at Mount Sinai. The study is the first randomised, controlled trial of repeated ketamine administration for chronic PTSD and suggests this may be a promising treatment for PTSD patients.
"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," says Dr Adriana Feder, associate professor of psychiatry at the Icahn School of Medicine at Mount Sinai and lead author of the study. "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."
Previous to the current study, Mount Sinai researchers conducted the first proof-of-concept, randomised, controlled trial of a single dose of intravenous ketamine for PTSD, which showed significant and rapid PTSD symptom reduction 24-hours post-infusion.
First approved by the US Food and Drug Administration as an anaesthetic agent in 1970, ketamine 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 to even months to work. These drugs are considered ineffective in at least one third of cases, and only partially effective in an additional 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. 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," said Dr Dennis S Charney, Anne and Joel Ehrenkranz dean of the Icahn School of Medicine at Mount Sinai and president of academic affairs for the Mount Sinai Health System and senior author of the paper.
For the current study, participants were randomly assigned to receive six infusions of ketamine, administered three times per week over two consecutive weeks, compared to six infusions of the psychoactive placebo control midazolam (chosen because its pharmacokinetic parameters and nonspecific behavioural effects are similar to those of ketamine) administered and evaluated over the same schedule. Individuals in this study had severe and chronic PTSD from civilian or military trauma, with median duration of 14 years and nearly half of the sample taking concomitant psychotropic medications. The primary traumas reported by participants included sexual assault of molestation, physical assault or abuse, witnessing violent assault or death, having survived or responded to the 9/11 attacks, and combat exposure.
All study participants were assessed at baseline, at week 1 and week 2, as well as on each infusion day by teams of trained study raters who administered the Clinician Administered PTSD Scale for DSM-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%) attained at least 30% or more reduction in symptoms from baseline at week two than those in the midazolam group (20%). Furthermore, ketamine infusions were associated with marked improvements across three of the four PTSD symptom clusters – intrusions, avoidance, and negative alterations in cognitions and mood.
In the subsample of ketamine responders, improvement in PTSD symptoms was rapid, observed 24 hours after the first infusion, and was maintained for a median of 27.5 days following the primary outcome assessment day. In addition to PTSD symptom improvement, the ketamine group exhibited markedly greater reduction in comorbid depressive symptoms than the midazolam group, which is notable given the high comorbidity of depression in individuals 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," added Feder. "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 are named co-inventors on an issued patent in the US, and several issued patents outside the US, filed by the Icahn School of Medicine at Mount Sinai for the use of ketamine as a therapy for PTSD.
A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder.
Adriana Feder, Sara Costi, Sarah B Rutter, Abigail B Collins, Usha Govindarajulu, Manish K Jha, Sarah R Horn, Marin Kautz, Morgan Corniquel, Katherine A Collins, Laura Bevilacqua, Andrew M Glasgow, Jess Brallier, Robert H Pietrzak, James W Murrough, Dennis S Charney
Published in the American Journal of Psychiatry on 5 January 2021
Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors’ previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.
Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale–Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.
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). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. 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.
This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine’s full potential as a treatment for chronic PTSD.
The Mount Sinai Hospital / Mount Sinai School of Medicine material
American Journal of Psychiatry study (Open access)