New Discoveries in the Use of Ketamine for Post-Traumatic Stress Disorder

Mount Sinai continues to gain global recognition for its groundbreaking work with ketamine and post-traumatic stress disorder (PTSD), publishing studies in 2021 which showed for the first time the effectiveness of repeat ketamine infusions for treating PTSD, and changes in the brain’s  neurocircuitry that may be at the root of the improvement. That seminal work is paving the way for additional research to determine if the robust response seen in patients with chronic PTSD can be maintained over longer periods, such as months or potentially years.

“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 Adriana Feder, MD, first author of the study in The American Journal of Psychiatry. “Some individuals in our trial had an amazing response and others had a very clear response.”

The randomized trial included 30 participants with chronic and severe PTSD who were administered six infusions of intravenous ketamine over two consecutive weeks. Researchers found a clinical improvement in PTSD symptoms compared to the group that received the psychoactive placebo midazolam, an improvement that was maintained for nearly 28 days. The ketamine cohort reported feeling less panic, greater peace, and an enhanced ability to handle negative thoughts. Participants had experienced their disorder for an average of 15 years, with almost half reporting sexual assault or molestation as their primary trauma.

While ketamine has been used as an anesthetic for over 50 years, it was not until 2014 that its efficacy for PTSD was described in a 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. “The data presented in our current study replicates and builds on our initial findings about ketamine for PTSD and indicates that in addition to being rapid, ketamine’s effect can be maintained over several weeks,” notes Dr. Charney.

PTSD is estimated to affect about 6 percent of this country’s population. Only two medications have been approved by the U.S Food and Drug Administration (FDA) to treat the disorder: the selective serotonin reuptake inhibitors sertraline and paroxetine. At least one-third of people with the disorder do not response to these medications, however, and for others they can take weeks or months to produce even a partial improvement in symptoms.

The mechanism by which ketamine alleviates mood and stress-related psychopathology is not fully understood, but a new study authored by Drs. Feder and Charney sheds light for the first time on changes in neurocircuit functioning that are believed to play a pivotal role. The study, published in The Journal of Neuropsychopharmacology, found that the most reliable
predictor of symptom improvement was increased functional connectivity between the amygdala, the part of the brain’s limbic system involved in the processing of emotions and memories associated with fear, and the prefrontal cortex. The changes were observed while participants with severe and chronic PTSD were processing socio-emotional stimuli when shown faces that could be considered threatening.

Findings like these have set the stage for further research to determine how the encouraging improvements seen in PTSD patients on ketamine can be sustained over longer periods -- no small challenge given the fact most patients eventually experience a loss of response and a return of their symptoms. Underway at Mount Sinai is a study to determine the synergistic effects of a course of six ketamine infusions with trauma-focused psychotherapy. “Pre-studies have suggested that ketamine might enhance the use of fear extinction learning,” says Dr. Feder, “and our team is now working hard to advance this promising new pathway.”