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Ketamine Nasal Spray Sees Success in Trial for Treatment-Resistant Depression

A nasal spray bottle.
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A new clinical trial has shown that ketamine nasal spray treatment in patients with treatment-resistant depression led to higher rates of remission than standard intervention with the antipsychotic drug quetiapine. The research is published in the New England Journal of Medicine.

Options for treatment-resistant depression

Treatment-resistant depression is defined as having unsuccessful responses to two or more consecutive treatments and affects up to 30% of patients with major depressive disorder (MDD). The condition profoundly impacts the lives of those affected and represents one of the highest economic burdens of any psychiatric disorder.

Quetiapine – an antipsychotic drug – is commonly used to tackle treatment-resistant depression, but additional treatments to target the condition specifically are sorely needed.

In Europe, esketamine nasal spray – a version of ketamine that is thought to activate some brain receptors more strongly – is the only therapy specifically approved for treatment-resistant depression and is given alongside antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs). However, there is little data comparing esketamine to quetiapine.

In the current trial, researchers compared the efficacy of the eskatamine nasal spray Spravato® to quetiapine, both in combination with SSRIs or SNRIs.

Increased remission rates

The researchers recruited 336 patients in the esketamine group and 340 to the quetiapine group in this randomized, open-label Phase 3b clinical trial funded by Spravato’s manufacturer, Johnson & Johnson.

The main goal was to measure the number of patients that achieved remission – i.e., a substantial improvement in depressive symptoms – defined as a score of ≤ 10 on the Montgomery–Åsberg Depression Rating Scale (MADRS).

After eight weeks of treatment, significantly more esketamine-treated patients achieved remission (27.1%) compared to the quetiapine group (17.6%).

Furthermore, esketamine-treated patients were 1.55 times more likely to remain relapse-free with continued treatment after achieving remission compared to quetiapine (21.7% and 14.1%, respectively).

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Side effects and limitations

Nevertheless, esketamine treatment was also associated with a high rate of side effects such as sedation and dissociation. 92% of patients experienced adverse events, leading to 4.2% discontinuing treatment, while 78% in the quetiapine group experienced adverse events and 11% discontinued.

Furthermore, the study design was also somewhat limited as patients were not blinded to their treatment, though it was single-blinded, as raters determining MADRS scores were unaware of the patient grouping.

"This large head-to-head trial gives physicians important data to consider in the management of treatment-resistant depression by comparing the short- and long-term effectiveness of Spravato to an oral antipsychotic,” said Dr. Reina Benabou, vice president and head of medical affairs at Johnson & Johnson Neuroscience. “Spravato offers patients an additional important option. It is critical that those living with this difficult-to-treat condition have choices to consider for their personal treatment plans, in discussion with their healthcare providers.”

Reference: Reif A, Bitter I, Buyze J, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. NEJM. 2023;389(14):1298-1309. doi: 10.1056/NEJMoa2304145


This article is a rework of a press release issued by Johnson & Johnson. Material has been edited for length and content.