Esketamine (SPRAVATO) Nasal Spray for Treatment-Resistant Depression

In March 2019 the Food and Drug Administration (FDA) approved the Schedule III controlled substance esketamine (SPRAVATO), a derivative of the intravenous anesthetic drug ketamine (KETALAR and generics) that the agency approved in 1970.[1]

Initially, the FDA approved esketamine as an adjunctive therapy alongside an oral antidepressant for adults with treatment-resistant depression, defined as those who have not benefited from oral antidepressants. Since then, the FDA extended esketamine’s approval for two additional indications in adults: as a monotherapy (standalone drug) for treatment-resistant depression and as an adjunctive therapy for depressive symptoms in individuals with major depressive disorder who have acute suicidal ideation or behavior.[2]

Esketamine is available in a spray device that delivers two self-administered single-use nasal sprays. Its labeled dosage intervals for treatment-resistant depression are twice weekly in the first month, weekly for the second month, and either once weekly or biweekly thereafter. Because of its immediate serious risks, esketamine can only be dispensed and used under the supervision of a clinician in a certified medical office or clinic.

In February 2019 Public Citizen’s Health Research Group strongly urged the FDA not to approve esketamine due to the lack of substantial evidence for its benefit.[3] In fact, there is clear evidence that esketamine causes serious adverse events.

We are now designating esketamine as Do Not Use because the evidence continues to show that it has an unfavorable benefit-risk profile.

Uncertain efficacy

Of the four placebo-controlled efficacy trials conducted by esketamine’s manufacturer to support its initial approval for treatment-resistant depression, two failed to meet their primary efficacy endpoints.

The third trial, which enrolled 223 participants, found minimal benefit for esketamine. After 28 days of follow-up, esketamine-treated participants had an average improvement of only four points over those who received a placebo nasal spray on a 60-point scale called the Montgomery-Åsberg Depression Rating Scale (MADRS).

The MADRS is an instrument that measures mood-related symptoms based on the following 10 items: sadness, apparent sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts. Notably, an improvement of seven to nine points on this scale corresponds to minimal clinical improvement.[4] Moreover, the MADRS is less comprehensive than the Hamilton Depression Rating Scale, which evaluates various aspects of depressive symptoms but has not been used in esketamine’s trials.[5]

The fourth trial examined remission in a highly selective group of 176 participants who had demonstrated a so-called “stable remission” following a 16-week esketamine treatment (open-label phase). Afterwards, the participants were randomly assigned to either continue esketamine therapy or switch to a placebo nasal spray (participants in both groups also took an oral antidepressant throughout the trial).

Although participants who continued esketamine treatment had a longer time to relapse in their depressive symptoms than those who were switched to a placebo, these effects were likely biased. In fact, half of the relapses in the placebo group occurred in the first month after esketamine discontinuation, which strongly suggests that there is a withdrawal effect for esketamine that may account for the early relapse, a serious limitation noted by FDA reviewers.[6]

Another limitation is that the “positive effect” for esketamine was driven by a single site in which all placebo users experienced relapse in their depressive symptoms compared with just 33% of placebo users across the other sites. Moreover, there were no statistically significant differences between the two groups when the outlier site was removed from the data.

A well-conducted meta-analysis published in 2025 in the American Journal of Psychiatry that analyzed data from esketamine’s randomized, controlled clinical trials found no robust evidence for the efficacy of esketamine as an add-on therapy for depression, including treatment-resistant depression.[7] There seems to be a “weak early” effect for esketamine and, at best, the effect is similar in magnitude to that of augmentation with atypical antipsychotics for depression. However, esketamine “virtually [has] no beneficial effect over placebo on suicidality” at any point, according to the meta-analysis.

The monotherapy indication of esketamine for treatment-resistant depression was based on a single trial.[8] This trial enrolled 378 treatment-resistant depression participants who, after discontinuing prior antidepressant therapy if applicable, were randomized to receive a low or high dose of esketamine or a placebo. After 28 days of follow-up, the mean differences in the change from the baseline in the MADRS between the esketamine and placebo groups were five and seven points for the low- and high-dose esketamine groups, respectively. Although these modest short-term differences were statistically significant, their clinical relevance is uncertain, as discussed earlier.

Serious risks

According to the FDA, six participants (all of whom received esketamine) died during the preapproval trials. Of those, three died by suicide within the first 20 days of their last esketamine dose. The remaining deaths involved a motorcycle accident 26 hours after the participant’s last dose of esketamine, a participant with high blood pressure (hypertension) who died of a heart attack six days after the last dose of esketamine, and another participant with hypertension who died suddenly on study day 113. Disturbingly, the FDA seems to have inappropriately discounted esketamine’s potential role in these deaths.

Esketamine can cause heart-related adverse effects. For example, according to esketamine’s label, up to 19% of esketamine users in clinical trials experienced a potentially serious increase in systolic or diastolic blood pressure at least once in the first 1.5 hours after receiving esketamine. Although the manufacturer says hypertension has occurred in the first weeks of treatment, it acknowledged that significant hypertension also can occur with any dose of esketamine, even in users with small prior increases in blood pressure related to the drug.

Esketamine also can cause breathing problems (respiratory depression or arrest). The FDA reviewers have suggested that more studies should be done to elucidate the long-term effect of esketamine use on cardiovascular endpoints.

Dissociation or perceptual changes (such as feeling disconnected from oneself, thoughts and feelings as well as distortion of space and time) have occurred in up to 84% of esketamine users in clinical trials. In addition, sedation (sleepiness) occurred in up to 61% of users. Esketamine also has been linked to anxiety, dizziness, fainting and spinning sensations. Furthermore, there are recent post-marketing reports of other adverse effects related to esketamine, such as impaired hand-eye coordination and feelings of guilt or worthlessness.[9]

As shown in an early clinical trial, esketamine can be abused because it has drug-liking characteristics, such as dissociation and euphoria (a feeling of intense excitement and happiness), similar to those of ketamine.[10] Therefore, esketamine carries a risk of abuse or misuse.

Importantly, it is too early to know all the serious long-term risks of esketamine. For example, there are concerns that the drug may impair cognitive function because of evidence that it slows reaction times in some patients. Another concern is that esketamine may cause inflammation and ulceration in the urinary bladder, a serious adverse effect that occurs in about 30% of regular ketamine users.[11]

What You Can Do

If you are struggling with persistent depression, do not use esketamine. Instead, start with psychotherapy and work with your clinician to identify and address the factors responsible for your condition. Use coping steps to control your condition, such as taking a walk or calling a loved one.

Improve your diet and sleep pattern, exercise regularly, manage stress, and get social support because such interventions have been shown to be effective for managing depressive symptoms.[12]

If you decide to take an oral antidepressant, work closely with your clinician to optimize the dose of your medication, allowing enough time or dose adjustments before switching to a different drug.
 

References

[1] Food and Drug Administration. News release: FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. March 5, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Accessed May 1, 2025.

[2] Janssen Pharmaceuticals, Inc. Label: esketamine (Spravato). January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf. Accessed May 1, 2025.

[3] Public Citizen. Letter to the FDA re. new drug application for esketamine single-use nasal spray for treatment of treatment-resistant depression. February 27, 2019. https://www.citizen.org/wp-content/uploads/2471.pdf. Accessed May 1, 2025.

[4] Horowitz MA, Moncrieff J. Are we repeating mistakes of the past? A review of the evidence for esketamine. Br J Psychiatry. 2021;219(5):614-617.

[5] Lan C-H, Wei JC-C. Esketamine nasal spray versus quetiapine for resistant depression. N Engl J Med. 2024;390(1):93-94.

[6] Horowitz MA, Moncrieff J. Are we repeating mistakes of the past? A review of the evidence for esketamine. Br J Psychiatry. 2021;219(5):614–617.

[7] Fountoulakis KN, Saitis A, Schatzberg AF. Esketamine treatment for depression in adults: A PRISMA systematic review and meta-analysis. Am J Psychiatry. 2025;182(3):259-275.

[8] Janssen Pharmaceuticals, Inc. Label: esketamine (Spravato). January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf. Accessed May 1, 2025.

[9] Liu R, Liu C, Feng D, et al. Pharmacovigilance of esketamine nasal spray: an analysis of the FDA adverse event reporting system database. Front Pharmacol. 2024;15(June 14):1414703.

[10] Food and Drug Administration. Joint supervisory review for regulatory action (summary review). Esketamine (Spravato), application number 211243Orig1s000. 03/05/2019. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000SumR.pdf. Accessed May 1, 2025.

[11] Horowitz MA, Moncrieff J. Are we repeating mistakes of the past? A review of the evidence for esketamine. Br J Psychiatry. 2021;219(5):614-617.

[12] Aguilar-Latorre A, Pérez Algorta G, Navarro-Guzmán C, et al. Effectiveness of a lifestyle modification programme in the treatment of depression symptoms in primary care. Front Med. 2022;9(July 26):954644.