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Long-term Ketamine Treatment for Depression May Reduce Risk of Relapse

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Long-term Ketamine Treatment for Depression May Reduce Risk of Relapse

Giving ongoing, regular ketamine treatment to patients with treatment-resistant depression could be an effective and safe way to keep them from relapsing, according to a first-of-its-kind study.

Dutch researchers conducted the first ever systematic review of the evidence for the safety and effectiveness of long-term, regular ketamine treatments. They analyzed the results of many other clinical trials, case reports and open label trials, to get a picture of the overall state of the evidence for ketamine maintenance. The results are published in The Lancet Psychiatry, and suggest clinicians may want to cautiously consider long-term ketamine therapy — known as ketamine maintenance — for select patients with treatment-resistant depression. 

“There is great therapeutic potential of maintenance ketamine treatment,” Sanne Smith-Apeldoorn, a psychiatric physician-scientist at the University Medical Center Groningen in the Netherlands and lead author of the study, told Lucid News. “The available data show sustained efficacy in the majority of initial responders while severe adverse events seem uncommon.” 

Although ketamine has a long history of use as a veterinary and pediatric anesthetic — along with illicit use as a club drug — mounting evidence suggests the drug can rapidly relieve depression. The strength of the evidence was enough for the FDA to approve esketamine, a modified form of ketamine, for the treatment of depression in 2019. 

But the antidepressant effects of ketamine are fleeting, and many patients relapse within two to three weeks of a single dose of the drug. Researchers have tried different strategies to extend the effects of short term ketamine treatment, including giving other medications such as lithium, and providing cognitive behavioral psychotherapy to patients, but with limited success. 

Ketamine maintenance, defined by Smith-Apeldoorn and her colleagues as regular ketamine doses given for at least four months after initial treatment, is an obvious strategy to try to extend the benefits of initial ketamine therapy. However, it wasn’t known if this would be safe and effective. Although ketamine relieves depression with relative safety in the short term, it doesn’t mean problems won’t crop up with long term use. Recreational ketamine use, the researchers note in their paper, has been associated with liver damage and addiction. 

To assess the state of the evidence for ketamine maintenance, the researchers examined 45 different studies of different types, including randomized controlled trials and patient case reports ultimately encompassing 1,495 patients with depression. Of those, 1,272 were diagnosed with unipolar depression, 43 were diagnosed with bipolar depression and one patient was diagnosed with schizoaffective depression. Seven studies examining another 179 patients did not distinguish between diagnoses. 

They found that ketamine or esketamine treatment was, overall, very effective at lifting people out of depression and keeping them from relapsing during maintenance. Only between 0 to 9% of patients in the examined studies relapsed during ketamine maintenance, a rate that compares favorably to the 23% of patients with depression who relapse while taking traditional antidepressant therapies. 

At the same time, adverse reactions such as cognitive impairment, addiction and kidney problems were uncommon and generally temporary. 

Is this the evidence physicians have been waiting for in order to adopt wider use of ketamine to treat depression over the long term? Not quite, according to Elias Dakwar, a Columbia University psychiatrist whose own research focuses on the potential role of ketamine in treating addiction. 

For one, the study comes with a number of limitations, primarily the limitations of the studies which the researchers reviewed, said Dakwar. Many of those studies contained small numbers of patients or had no control groups, and such methodological limitations do not disappear when comparing multiple studies with multiple issues. 

“It provides a comprehensive overview so that is something,” Dakwar told Lucid News. “But can one conclude from this paper that the use of ketamine for maintenance treatment is safe and effective, or even what proper maintenance treatment looks like? No.”

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Moreover, it’s not a paper that will single handedly lead the FDA to approve ketamine — and not just esketamine — as a treatment for depression, Dakwar said. That means ketamine can only be used off-label, and that insurers will not cover the treatments. 

“It’s not a matter of low clinician buy-in, but because there is no insurance-amenable way to do so currently,” Dakwar said. “It is unlikely that yet another paper on ketamine will change people’s minds which haven’t been changed already.”

Smith-Apeldoorn and her colleagues readily acknowledge the limitations of their study, and do not conclude that ketamine maintenance therapy should be adopted as a mainstream depression treatment on the strength of their study alone. More long term studies with large numbers of patients and control groups are necessary to really advance knowledge around ketamine maintenance treatments, she said. 

But at the same time, the severity of the problem, the degree with which small numbers of patients with treatment-resistant depression suffer for lack of treatment alternatives, suggests a minimally expanded role for ketamine in the near future, according to Smith-Apeldoorn.

“Undoubtedly, there is a need for caution given the many unknowns regarding the long-term effects of ketamine treatment,” Smith-Apeldoorn said. “But we feel with the current evidence that for a select subset of patients, it is justifiable to offer maintenance ketamine treatment despite these unknowns, as there is no reasonable treatment alternative.”

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