By Mark Gold, MD
Ketamine was discovered by chemist Calvin Stevens in 1962 and its anesthetic effect was confirmed during testing with human prisoners in 1964. Ketamine was approved by the FDA in 1970 as Ketalar®, an injectable, rapid-acting general anesthetic. Because Ketamine does not cause respiratory depression or hypotension, it was released as a safer alternative to phencyclidine (PCP) that also provided excellent analgesia (pain relief).
Ketamine produces an intense dissociative state during which patients appear to be awake and are safely breathing, but do not respond to sensory input. It was found particularly useful in the emergency room, the military, and acute trauma situations, favored by many physicians due to its impressive safety profile. Ketamine continues to be used primarily for analgesia and sedation in clinical settings--both alone and in combination with other medications. More recently, it has been used to manage chronic pain and to treat asthma. Excitement about the expanded possibilities of using ketamine for depression was tempered by it’s well-known potential for diversion and misuse.
In 2000, a group of researchers led by John Krystal and Dennis Charney at the Yale University Department of Psychiatry reported a significant and surprisingly acute antidepressant effect when treating depressed patients with intravenous ketamine. Ketamine is a racemic mixture--containing equal amounts of esketamine and arketamine. Esketamine binds approximately four times tighter to the NMDA-glutamate receptor than arketamine. Yale research labs found that ketamine triggers the production of glutamate in the brain, allowing the brain to form new neural pathways. This can help patients develop more positive thought patterns and behaviors, something not seen before in traditional antidepressants.
After more than a decade of study with over 1,000 patients, esketamine has been developed as an intranasal spray for treatment-resistant depression and was approved by the FDA as Spravato® in early March of 2019. Its unique intranasal delivery system reduces the likelihood of abuse or diversion but is able to achieve the same effective blood concentrations as ketamine.
Recent research has been met with excitement about the possibility of using ketamine to treat major depression comorbid with addiction, but some preliminary research conducted at Stanford had suggested that naltrexone might lessen the effectiveness of the ketamine therapy. Yoon, Krystal, and Pertrakis found that this wasn’t always the case.
Ketamine and Naltrexone
To study the effects of ketamine and naltrexone in combination, Drs. Yoon, Petrakis, and Yale Chairman of Psychiatry John Krystal recruited five individuals with alcohol use disorder and major depressive disorder to participate in their 2018 study “Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case Series of Patients With Depression and Alcohol Use Disorder”. Patients first received injectable naltrexone, and began ketamine infusions two days later. Over an 8-week period, the patients received a total of four ketamine infusions, with promising results. Three out of the five patients reported significant relief from their depressive symptoms after the first dose, and all of the patients reported relief after multiple doses. Importantly, this study contradicts previous research from Stanford that suggests opiate receptor stimulation medications like naltrexone lessen the antidepressant effect of ketamine when administered as a pre-treatment to the ketamine therapy.
Looking to the Future
Despite the small study size, all of the patients tolerated the treatment well and reported no serious adverse effects. This means that there is a possibility that people who are being treated with naltrexone for a substance use disorder and ketamine for depression can be treated for both depression and addiction at the same without their medications interfering with one another. While the findings are encouraging, the authors urge a cautious interpretation of the study and call for larger randomized clinical trials. This study was a preliminary experiment funded primarily by the Department of Veterans Affairs. In order to address increased alcohol misuse among veterans and the potential mental health effects of deployment, like depression, a robust array of treatment options is needed to treat this population.
Citation: Yoon, G., Petrakis, I. L., & Krystal, J. H. (2019). Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder. JAMA psychiatry.
Dr. Mark S. Gold is a teacher of the year, translational researcher, author, mentor and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine and food. Read more by Dr. Gold here.