For years, ketamine has served as a powerful anesthetic, and in recent decades, it has gained popularity as a recreational drug. However, recent advances have transformed its role: ketamine has emerged as an effective tool for treating severe, treatment-resistant conditions depression which traditional medicines fail to treat.
A recent expanded study published in the prestigious journal New England Journal of Medicine He revealed that ketamine therapy provides similar benefits for those with unresponsive depression, matching the efficacy of the most advanced treatment available today – ECT – while offering fewer side effects. Ketamine and its derivatives are crucial in facing an epidemic that kills several people in Israel annually and more than a million people worldwide.
This groundbreaking, most comprehensive and significant study to date reveals that ketamine therapy is on par with the most powerful treatment available for refractory depression. Investigating the potential of this substance – originally a narcotic, then a street drug, and recently re-evaluated as a treatment for unresponsive depression – against ECT, the current leading treatment for severe depression.
What the research showed
The research showed that ketamine matches the effectiveness of electric shocks. Close examination of the study highlights that ketamine therapy is often superior to electric shock, especially with regard to side effects.
It is expected that between 15 and 30 percent of the world’s population will experience major depression during their lifetime. In Israel alone, the number reaches two to three million people. Although various classes of antidepressants developed since the 1950s can help many patients, a problem arises when about 20% of patients fail to respond to these conventional medications or show only partial improvement. Some patients who do not respond to medication-based treatment find relief in targeted psychotherapeutic approaches such as cognitive behavioral therapy and IPT, which, while important, also present limitations. This translates into prolonged depression, immense suffering for patients and their families, and significant disruption to the daily lives of hundreds of thousands of Israelis. Moreover, depression takes a deadly toll, with nearly a million people globally succumbing to suicide each year because of depression.
At present, the most effective treatment for refractory depression entails ECT under general anesthesia. Although psychiatrists highly appreciate the effectiveness of this approach, it carries three significant drawbacks:
- It carries a societal stigma, which prevents many patients from pursuing it.
- Side effects such as memory impairment, although usually temporary, present challenges.
- Since refractory depression is a chronic condition, the complexities associated with the frequent administration of ECT treatments make them insufficient to treat this widespread disease.
For decades, after the advent of first- and second-generation antidepressants, psychiatry has grappled with treatment-resistant depression. The search for alternatives has driven the development of innovative technologies such as electromagnetic stimulation (TMS) therapy. However, these approaches tend to be quite expensive and are unlikely to serve as the required comprehensive solution. As such, efforts to explore innovative drug therapies and overcome historical stigma have intensified, leading to a re-evaluation of familiar substances – including those once considered street drugs – and a consequent neglect of research on their therapeutic potential.
In the past decade, the effectiveness of ketamine in treating depression has received attention. While the substance has faced disqualification due to its potential to induce psychosis and psychedelic experiences—similar to the “trip” and immediate highs it popularized as a street drug—recent findings have revealed its usefulness in cases where conventional treatments falter. Ketamine has been significantly recognized by the medical community since the mid-20th century as an anesthetic, and is still used in short-term pediatric sedation and veterinary treatments. Despite early skepticism due to the negative reputation of such drugs, accumulating evidence has shed light on ketamine’s ability to treat treatment-resistant depression. Contrary to initial concerns, the risk of addiction and psychosis appears to be less serious.
The use of ketamine has gained acceptance and has secured a place in the official psychiatry toolkit in many countries. To provide a comprehensive picture, a recent study enrolled nearly 400 patients with refractory depression at five US medical centers. This comprehensive study represents the most significant clinical comparison conducted to date. The researchers deliberately targeted the most complex cases, with 40% of the participants having previously explored other avenues.
The research team divided the participants into two groups: one receiving electroconvulsive therapy and the other receiving ketamine. After three weeks of the interventions, 55% of the ketamine-treated participants reported significant relief of depressive symptoms, exceeding the 41% improvement seen in the ECT participants. Follow-up evaluations conducted six months later showed near-identical indicators of quality of life for both groups.
One of the drawbacks of ketamine therapy is that it needs to be injected, which hinders its application and efficacy in this widespread problem. Thus, efforts are being made to develop more user-friendly methods of using ketamine or its analogues, while maintaining their effectiveness. An effective approach involves distillation of ketamine to produce esketamine, a molecule suitable for administration by nasal spray. Absorbed through the nasal capillaries, this innovation eliminates the need for intravenous injection. Esketamine has been shown to be effective against depression, and its easy use led to FDA approval in 2019 as a “breakthrough drug” for the treatment of resistant depression. It has also received the approval of the European Medicines Agency (EMA) and the Israeli Ministry of Health, to be included in the list of Israeli medical medicines since 2020.
An additional advantage of ketamine and esketamine treatment is the rapid response often experienced by those with refractory depression. At present, treatment with esketamine is done in specialized clinics, which requires patients to remain under observation for two hours after treatment. Although the process remains complex, this effort has proven worthwhile for individuals with severe depression in the long term, as evidenced by the improvement seen under the new treatments.
Sometimes, these treatments work like miracles. Substances such as ketamine and esketamine indicate a major leap forward in the management of depression. For Life, a group devoted to suicide prevention, sees these drugs as promising tools in tackling the continuing and deadly suicide epidemic. The author, Professor Hagai Hermesh, respected psychiatrist and member of the Executive Board of the For Life Association, stresses the high potential of these drugs in combating this tragic scourge.