How effective is ketamine for depression? 

First synthesized in 1962, the dissociative anesthetic ketamine is rapidly growing in popularity for its off-label use in treating depression and mood disorders. In recent years, hundreds of clinics across the U.S. have begun offering ketamine for depression, anxiety and other mood disorders.  

The surge in interest has also attracted startups such as Mindbloom and Field Trip Health. At the same time, Janssen (NYSE:JNJ) scored FDA approval for the ketamine enantiomer Spravato (esketamine) for depression in 2019. 

Impressive but limited data

While evidence is building that indicates that ketamine is effective against depression, the level of evidence is frequently limited to small clinical trials, case reports and anecdotes. “It’s really difficult to tease apart what’s happening in these [ketamine] studies because there’s no standard protocol,” said Linnea Butler, a marriage and family therapist with a background in the pharma industry. 

In some studies, patients may have a quick screen with a medical doctor before receiving a ketamine infusion. In other studies, patients may receive more preparation and discussion before a ketamine infusion.  

A two-site randomized controlled study involving 68 patients found that ketamine offered statistically significant antidepressant effects for up to seven days following a single infusion. 

Another randomized clinical trial found that six ketamine infusions resulted in a more than 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores over 12 days. In addition, more than 70% of patients had a therapeutic response to ketamine therapy. 

A 2021 article published in Frontiers in Psychiatry concludes that an integrative approach to ketamine therapy may improve outcomes in treatment-resistant treatment. 

Promising case reports

When asked how ketamine-assisted psychotherapy compares to traditional psychotherapy, Butler stresses that it is hard to compare the two but notes that ketamine appears to have helped drive substantial improvements in some of her patients. 

While the evidence is anecdotal, it is often striking. “For example, one person I worked with for seven years very intensely — sometimes meeting two or three times a week — did six ketamine sessions together,” Butler recalled. After the patient concluded those ketamine-assisted psychotherapy treatments, the patient’s trauma scores dropped by roughly 70%. “His depression scores dropped by 50%,” she said. “It was huge.” 

Before the ketamine-assisted therapy, there had been “basically no movement,” Butler said. “I was sort of keeping him afloat.” 

Another patient of her receiving ketamine-assisted psychotherapy had significant improvements in anxiety and PTSD symptoms. 

While there are limited data showing how ketamine compares to traditional antidepressants for treating depression, the latter drug class has limited effectiveness for many patients. One analysis of antidepressants published in Nature found the efficacy of antidepressants to range from 42% to 53%. A separate study found that half of patients are likely to relapse after five years. 

While data are lacking comparing ketamine against SSRIs, one analysis concluded that ketamine’s efficacy in treating depression made “all other treatments pale in comparison.”

“I think that ketamine-assisted psychotherapy has the potential to be remarkable, but it’s not a magic pill,” Butler said. 

An unclear upside for pharma companies

The analyst firm GlobalData predicts that Spravato will generate global sales of roughly $383 million by 2029. 

Other drug developers are aiming to create unique ketamine-inspired offerings. They include HMNC Brain Health, which is trying to tap ketamine’s antidepressant effects while limiting its dissociative symptoms. Another company, Bexson Biomedical, is working on developing a wearable low-dose ketamine patch that provides an alternative for opioids in managing post-operative pain.

Making money off of ketamine could be tricky for pharmaceutical companies. “How do you as a pharma make money with a molecule that has been out there for a very long time?” asked Butler. 

While Janssen’s esketamine-based nasal spray has won patent protection and the support of insurers, the drug is available through a restricted distribution program known as Spravato Risk Evaluation and Mitigation Strategies (REMS).  

A catalyst for psychotherapy

Experts have diverging opinions on how ketamine should be used. Some clinics administer the drug to depressed patients with little to no psychotherapeutic therapeutic support. 

Conversely, a growing number of therapists such as Butler back the use of ketamine as a catalyst for psychotherapy. 

The drug can help patients to make behavior changes while resulting in immediate changes in mood. “There’s nothing out there as fast acting as ketamine,” Butler said. 

While ketamine’s ability to lift mood may be swift, it is a “transient effect,” Butler said. 

Butler has provided ketamine-assisted psychotherapy (KAP) for more than two years. 

Ketamine is a N-methyl-D-aspartate (NMDA) receptor antagonist, but it also interacts with other neurotransmitter systems, including the mu, delta and kappa opioid receptors. In addition, the ketamine metabolite norketamine is also an NMDA receptor antagonist. 

Ketamine also spurs an increase in brain-derived neurotrophic factor (BDNF), which may promote neural plasticity in depression. 

“With ketamine psychotherapy, we’re making use of the increase in BDNF,” Butler said. “Ketamine acts as a psychological lubricant for the process of psychotherapy.” 

While ketamine may offer transient relief from depression symptoms when used on its own, “I personally think there’s a missed opportunity,” Butler said. “When you couple it with psychotherapy, you get a longer-lasting effect.”