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Nasal esketamine spray is more effective than an extended-release antipsychotic, when both are taken in combination with SSRIs and SNRIs, in patients with depressive episodes that didn’t respond to two or more consecutive treatments, according to a study published Wednesday in the New England Journal of Medicine.

Research dating back to the early 2000s has shown that ketamine and esketamine — which is derived from ketamine — are effective in cases of so-called treatment-resistant depression, and the nasal spray version of the drug was specifically approved for this indication in 2019.


Yet most of the research so far has compared esketamine to placebo (a recent one compared it to electroconvulsive therapy, or ECT), while this latest head-to-head study — sponsored by Janssen, the maker of the esketamine spray, Spravato — compares its effectiveness against that of quetiapine, the generic version of Seroquel and a common treatment given in addition to SSRIs or SNRIs. (SSRIs and SNRIs, which increase serotonin and norepinephrine levels in the brain, are first-line treatments for depression.) The study was conducted in a fairly large group of 676 patients, out of whom 336 were administered esketamine weekly, while 340 were treated with quetiapine pills.

Ketamine outperformed quetiapine at all points of evaluation. At eight weeks, 27% of patients treated with ketamine were in remission, compared to 17% of those taking quetiapine. Furthermore, esketamine patients who were in remission at week eight were more than 50% more likely to still be in remission and relapse-free until week 32 compared to quetiapine patients.

“Quetiapine is not the most robust add-on treatment for treatment-resistant depression … and so I’m not surprised that ketamine would be a superior treatment,” said Joshua Berman, the medical director of the Interventional Neurotherapeutic Psychiatry Program in the Department of Psychiatry at Columbia University, who did not participate in the study.


The cumulative benefits of ketamine continued to be seen throughout the study, and more patients went into remission in the weeks following the eighth. By week 32, two-thirds of the patients were in remission. This, said Berman, is interesting both because it shows esketamine can have cumulative effects beyond the short-term, and because it builds on confidence about the long-term safety of the treatment.

Patients taking esketamine were also more likely to stick to the treatment; only 23% discontinued it, compared to 40% of the patients in the quetiapine group, who stopped taking the treatment due to its side effects (particularly sedation) and lack of efficacy.

“It’s good to see more data. And I’m happy to see that this is in a medical journal that’s general interest, because I think it’s good for physicians in general to be aware that these kinds of treatments are available. And not everybody has their depression treatment directed by a specialist,” said Berman.

The trial’s results may also lead to another treatment hypothesis, to be verified with further studies: that a longer initial course of esketamine treatment may be more effective than current protocols in giving conventional antidepressants, which are administered concomitantly, enough time to start working, said Berman.

“The research that would be up next in my opinion is to identify patients earlier who have a high likelihood to respond positively to ketamine,” said Andreas Reif, a professor of psychiatry at the University Hospital of Frankfurt, and the lead author of the paper. A third of patients don’t respond to the drug, he said, and current research lacks the insights to understand why.

“At the moment, we don’t know of any discriminating variable that helps us to guess which patients might benefit,” said Reif. “It would be really helpful to stratify patients according to any clinical parameter or biomarker.”

Esketamine can be prescribed in certain cases of psychiatric emergencies, but its main indication is for treatment-resistant depression, which means a patient needs to have tried at least two ineffective treatments during a depressive episode prior to being treated with esketamine. But waiting until two failed attempts with other drugs to start esketamine may unnecessarily delay access to effective treatment, and Reif even thinks treatment-resistant depression may be a misnomer, as it identifies the condition primarily by its response to available treatment.

“If you look at the literature, there are more than 220 definitions [of treatment-resistant depression]. The so-called consensus definition … usually says it’s an insufficient response to at least two consecutive treatments of antidepressants,” he said, but “insufficient response is somewhat vaguely defined.”

A better understanding of the effectiveness of esketamine as well as other treatments that can support SSRIs or SNRIs could allow definitions to be disentangled from treatment. “We can even get rid of the term ‘treatment-resistant depression,’ because if you look at the data, two-thirds of these patients were not resistant to treatment,” said Reif. The term, he said, “might have a negative effect on patients that are already kept in negative thinking.”

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