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New research appears to show that a ketamine-based nasal spray can outmatch a standard option for people with treatment-resistant depression. The large clinical trial found that people taking the spray in combination with other antidepressants were more likely to experience a sustained remission of their symptoms than those taking an antipsychotic instead.

Ketamine has been used as both a sedative and a recreational drug with dissociative effects for decades. More recently, it’s emerged as a promising depression treatment. People taking ketamine for depression often receive low doses of it through IV infusions provided at specialized clinics, though this is considered an off-label use of the drug. But in 2019, the Food and Drug Administration officially approved a nasal spray developed by Johnson & Johnson, called Spravato. This spray uses a chemical sibling of ketamine known as esketamine (ketamine is composed of two molecular forms, one of which is esketamine).

Spravato was initially approved for people with clinical depression who haven’t responded to other treatments. In 2020, the FDA also approved it for people with depression expressing acute suicidal thoughts or behaviors, based on evidence showing it could quickly reduce ideation.

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Ketamine is meant to be prescribed alongside other conventional antidepressants. And in the pivotal trials that led to its approval, the spray plus these drugs performed better than taking the other drugs alone with a placebo spray. But there have historically been other treatments given to people with hardy depression, and it’s not yet completely clear how ketamine-based therapies compare to these alternatives. One of these options is the antipsychotic drug quetiapine, often sold as Seroquel.

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An extension of J&J’s clinical trials of Spravato, called the ESCAPE-TRD study, directly pitted their spray against quetiapine. The preliminary results of this trial were released last November, and the data was formally published on Wednesday in the New England Journal of Medicine.

The study involved over 650 adults with treatment-resistant depression, who were randomized to either receive quetiapine or the nasal spray, both in combination with typical antidepressants.

By week eight, about 28% of patients on the spray experienced a remission of their depression, based on a standard measuring scale, compared to 18% of those on quetiapine. This was the primary endpoint of the study, but the remission rate remained higher in those taking esketamine up to 32 weeks later (55% vs 37%). And the percentage of people who experienced no relapse of their symptoms at all through 32 weeks was higher as well (22% vs 14%).

The findings are the first of their kind to compare esketamine to a standard drug therapy for treatment-resistant depression, according to study author Allan Young, director of the Center for Affective Disorders at King’s College London. A study this May also found that ketamine performed as well as and possibly even better than electroconvulsive therapy—another common alternative—for these tough cases of depression.

Given these results, Young believes that ketamine should be considered a front-line therapy for treatment-resistant depression. And it might even be able to outshine traditional treatments for depression in general, at least for some people.

“There is an argument for using ketamine first if we can identify the characteristics of those who would respond well,” he told Gizmodo in an email.

At the same time, he notes that only a minority of people showed a complete response to esketamine. So while scientists are genuinely excited about the future of this drug and others like it, we still need a variety of treatment strategies to truly help everyone with depression.

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