Although psychotherapy and antidepressant medications (most notably selective serotonin reuptake inhibitors or SSRIs) have significantly improved treatment for depression, many people still do not find satisfactory remission after standard treatment. Labeled “treatment-resistant depression,” this debilitating disorder is experienced as a dark prison of suffering that contains no hope of ending. Until recently, electroconvulsive treatment (ECT) was the only method of last resort.

The use of enough electric current through the brain to cause a seizure was developed in 1938 as a treatment for severe schizophrenia. I personally witnessed ECT help a terrified mute patient who had to be constrained to prevent her from continually eating paint she scraped off the wall. A few treatments settled her terrors enough to no longer require restraints, to respond to simple commands, and to feed herself.

ECT has been refined over the decades to increase its safety and eventually became an embarrassingly effective treatment for resistant depression despite its seemingly barbaric nature. Patients today are sedated like during a colonoscopy, given a short-acting paralytic drug to prevent musculoskeletal injury during their seizure, and then shocked with the minimum effective electric current. After a few treatments, many patients can resume much of their normal pre-depression lives, though the impact on memory can persist for a while and is often quite troubling.

What Ketamine Is

Recently, the drug ketamine has begun to rival ECT as a potentially effective treatment for treatment-resistant depression. Ketamine was first synthesized in 1962 and found to be a safe and effective dissociative anesthetic. Dissociative drugs cause people to feel separated or detached from their body or physical environment. Ketamine’s use in humans began in 1970 for battlefield surgery in Vietnam. Soon afterward, it became known as “Special K” in party scenes around the world, leading to its being scheduled and its access restricted by the Drug Enforcement Administration in 1999. Then, from 2000 to 2008, studies established ketamine’s ability, when given intravenously in sub-anesthetic doses, to provide extremely quick and effective relief from depression.

In an article published May 24, 2023, in the New England Journal of Medicine, Amit Anand et al., reported the largest study to date comparing the effectiveness of ketamine and ECT for treatment of nonpsychotic treatment-resistant depression.^1,2 Five clinical centers contributed to this open-label, randomized, noninferiority study. Open studies do not blind patients or researchers to the treatment being used. A “noninferiority” study is simply a strange name for studies designed to determine whether one treatment is at least as effective as another. In this study, 195 randomly assigned patients received a subanesthetic dose of intravenous ketamine twice a week, and 170 other patients received ECT three times a week, both groups for three weeks.

New Study Findings

A total of 55.4 percent of the patients in the ketamine group and 41.2 percent of those in the ECT group had sustained improvement at 6-month follow-up as defined by a 50 percent or more decrease in depressive symptoms scored on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with adverse musculoskeletal side effects and decreased memory recall after three weeks of treatment that cleared by follow-up. Ketamine treatment was not associated with side effects other than an experience of transient dissociation at the time of treatment.

Patients with nonpsychotic treatment-resistant depression now have a legitimately proven alternative to ECT. Ketamine is soon likely to become the dominant choice for several reasons. Ketamine therapy does not require the level of specialized staff and equipment as ECT. It does not require full anesthesia. And, it does not carry the social stigma attached to ECT by movies such as One Flew Over the Cuckoo’s Nest. Ketamine can be administered in office settings and does not carry the risk of memory deficits caused by ECT.

Potential for Abuse

The potential downside of ketamine therapy is its potential for abuse. I once treated a physician who used ketamine recreationally to the gradual detriment of his marriage, risk to his medical license, and facial injuries when he crashed into a coffee table while under the influence. As psychedelics enjoy a new wave of popularity, Special K is likely to spread as a novel drug offering a novel experience. Abuse is also likely to occur on the treatment side as some physicians already prescribe microdosing and use it to treat unproven diagnoses. Nasal spray forms of ketamine are already available, and the age-old process of over-promising is upon us.

Bottom line, ketamine has been scientifically shown to relieve treatment-resistant depression quickly and safely. It may have other uses as well. But it will never be a panacea. And consumers should be careful to seek treatment from an experienced physician.