Ketamine Demonstrates Rapid Improvement in Patients With Post-traumatic Stress Disorder

Certain regions of the brain, such as the hippocampus, prefrontal cortex, and amygdala are involved in the stress response.

Ketamine, an anesthetic found to help individuals with treatment resistant depression at lower doses, has now shown additional promise in easing the symptoms of post-traumatic stress disorder (PTSD), according to researchers at the Icahn School of Medicine at Mount Sinai. Their study, published in The American Journal of Psychiatry, highlights the first randomized controlled trial to demonstrate that repeated intravenous infusions of ketamine are effective and safe for the treatment of chronic PTSD.

“We found a rapid improvement in PTSD symptoms, including a reduction in the intensity and number of memory intrusions and nightmares, decreased avoidance of trauma reminders, and increased ability to enjoy activities and feel closer to others,” says the study’s corresponding author, Adriana Feder, MD, Associate Professor of Psychiatry at the Icahn School of Medicine. “Some individuals in the trial had an amazing response and others had a very clear response.”

Adriana Feder, MD

The randomized controlled trial involved 30 participants, with half receiving ketamine and half receiving midazolam, the psychoactive placebo control. Participants in the trial who were administered six infusions of intravenous ketamine over two consecutive weeks reported feeling less panic, more at peace, and better able to handle negative thoughts.

Ketamine’s potential efficacy for PTSD was first outlined in 2014, in a proof-of-concept study led by Dennis S. Charney, MD, 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. Participants in the 2014 study received a single infusion of either ketamine or the psychoactive placebo control, midazolam.

Dr. Charney says, “The data presented in our current study replicates and builds upon our initial findings about ketamine for PTSD and indicates that in addition to being rapid, ketamine’s effect can be maintained over several weeks.”

Mount Sinai’s research into an effective treatment for PTSD is particularly relevant now, during this time of heightened societal “trauma associated with the COVID-19 pandemic,” says Dr. Feder. Front-line medical workers face unprecedented emotional challenges in treating scores of severely ill patients with COVID-19, and people have experienced the sudden and unexpected loss of a loved one to the disease. Domestic violence is also on the rise.

PTSD affects roughly 6 percent of the U.S. population. Severity of trauma ranges by type and cumulative exposure, with the highest PTSD burden occurring among survivors of interpersonal violence. Only two medications—the selective serotonin reuptake inhibitors sertraline and paroxetine—are approved for the treatment of PTSD by the U.S. Food and Drug Administration (FDA) and at least one-third of people with the disorder do not respond to them. For many others, these medications, which can take weeks or months to work, often result in partial improvement in symptoms.

Dennis S. Charney, MD

Participants in Mount Sinai’s study had moderate to severe PTSD and had experienced the disorder an average of 15 years. Almost half reported sexual assault or molestation as their primary trauma. Others reported physical assault or abuse, witnessing a violent assault or death, having experienced the terrorist attacks of 9/11, or combat exposure.

Ketamine has been approved by the FDA for use as an anesthetic since 1970. In 2019, esketamine—one of the two mirror-image molecules or enantiomers of ketamine—was FDA-approved for administration in the form of nasal spray (Spravato®) in conjunction with an oral antidepressant for treatment-resistant depression, and more recently for major depressive disorder with acute suicidal ideation or behavior.

While the mechanism of action underlying its rapid-onset effect is incompletely understood, ketamine acts as an NMDA (N-methyl-D-aspartate) glutamate receptor antagonist in the brain, triggering a series of complex biological processes. Ketamine-induced changes in glutamate signaling are thought to increase neuroplasticity by reversing atrophied connections between neurons in the brain, resulting in more effective responses to stress.

“Now that we’ve shown that repeated infusions of ketamine can rapidly improve PTSD symptoms, a response maintained for several weeks, we would like to study how to maintain this robust response over a longer period of time, such as months or potentially years,” says Dr. Feder. Findings from preclinical studies suggest that ketamine might enhance the use of fear extinction learning and Dr. Feder and colleagues plan to evaluate the efficacy of adding trauma-focused psychotherapy to a course of ketamine infusions in their next phase of research.

Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) shows significantly better improvement in PTSD symptoms with ketamine compared with midazolam, the placebo.