A recent clinical trial found that esketamine nasal spray used alone — without other antidepressants — significantly reduced symptoms of treatment-resistant depression in as little as 24 hours for some people.

What Is Esketamine and How Does It Work?

Esketamine is a fast-acting medication approved by the U.S. Food and Drug Administration (FDA) for treatment-resistant depression under the brand name Spravato. It is delivered as a nasal spray and typically used along with an oral antidepressant.

Unlike most antidepressants, which affect serotonin or other neurotransmitters, esketamine targets a different brain receptor — the NMDA receptor — and is believed to help reset brain connections involved in mood.

Study Shows Esketamine Works on Its Own

In this new phase 4 clinical trial, researchers tested esketamine as a standalone treatment in 378 adults with treatment-resistant depression. Participants received either a smaller or larger dose of the drug or a placebo (inactive treatment) twice a week for four weeks. None were taking oral antidepressants during this time.

Both esketamine dosage levels led to significantly greater improvements in depression scores compared to placebo by day 28. Some people experienced relief as early as 24 hours after their first dose. Among participants who took esketamine, more people finished the course of treatment and had up to three times higher improvements in depression symptoms than people who took the placebo.

Common side effects of esketamine included:

• Nausea — Affected about 1 in 4 people taking the drug
• Dissociation (a feeling of disconnection) — Affected nearly 1 in 4 participants
• Dizziness — Affected 21.7 percent of participants
• Headache — Affected 19 percent of participants

Most of these side effects were mild and went away quickly, according to the study.

Importantly, prescribing information for the drug notes the potential for severe side effects, including:

• Sedation, dissociation, and respiratory depression after administration
• Potential for misuse or abuse
• Increased risk of suicidal thoughts or behaviors, especially in young adults

Note: If you or someone you know needs help, you can contact the 988 Suicide & Crisis Lifeline by calling or texting 988 or chatting online.

The drug must be administered in a certified healthcare setting, and safety monitoring remains essential.

Why This Matters for People With Depression

Treatment-resistant depression affects about one-third of people with major depressive disorder, and many struggle to find relief with standard antidepressants. Esketamine nasal spray was first approved by the FDA in 2019 — but only for use alongside an oral antidepressant.

In early 2025, the FDA expanded that approval, making it the first and only esketamine-based treatment approved as a standalone option for adults with treatment-resistant depression.

The new study offers evidence that esketamine on its own may provide rapid relief and could fill a critical treatment gap. This matters for people who can’t tolerate oral antidepressants or haven’t benefited from them.

If you’re living with depression and have not found relief from your current treatment plan, speak with your doctor. Together, you can determine whether alternative treatments may be a good choice, weighing the potential benefits and drawbacks.

Learn more about the various types of treatment available for depression.

Join the Conversation

On MyDepressionTeam, people share their experiences with depression, get advice, and find support.

Have you tried esketamine or other treatments for treatment-resistant depression? What was your experience with them? Let others know in the comments below.