Last month, esketamine nasal spray became the first treatment for depression with a new mechanism of action approved by the Food and Drug Administration (FDA) since Prozac (fluoxetine hydrochloride) was approved in the late 1980s. Esketamine (sold as Spravato) has the potential to be extremely useful for people who have not responded to other treatments. Used in combination with an oral anti-depressant, it can take effect much faster than many common antidepressant medications. However, it comes with specific restrictions on its distribution and usage, potentially serious side effects, a high cost, and cautions from experts including the potential for misuse or dependence.

Research has found that among patients with treatment-resistant depression, esketamine led to significant improvement in symptoms and suicidal thinking in as little as four hours. Most antidepressant medications take four to six weeks to become fully effective.

However, the FDA approval comes with some specific requirements. Spravato is subject to a comprehensive Risk Evaluation and Mitigation Strategy program, which limits how it is distributed and administered. Pharmacies and health care settings must be certified to dispense Spravato.

Spravato is administered through a nasal spray under the supervision of a certified provider and is intended to be used in conjunction with another antidepressant medication. Patients receive Spravato once or twice and must be monitored for at least two hours after taking it and until the health care professional determines it is safe for the person to leave.

Among the potential side effects are the risk of sedation and dissociation (feeling of being detached or disconnected). Spravato also carries a “black-box warning” (information on a prescription drug label that calls attention to serious or life-threatening risks). Costs for the first month are between $4,720 and $6,785, and monthly maintenance costs are expected to be about half of that amount.

Spravato is indicated for people who have tried at least two other antidepressants, and not for those with mild depression. Gerard Sanacora, M.D., Ph.D., director of the Yale Depression Research Program, told Psychiatric News, “For those with mild depression, treatments like evidence-based psychotherapies that may take some time to work but have few risks and may provide more longer-term benefits may be a better choice.”

Esketamine is a purified form of ketamine, which has been used as an anesthetic for decades and as a party drug. It is administered in intravenous infusion at specialized clinics. This use of ketamine has not been approved for the treatment of depression but is legally prescribed off-label.

Both ketamine and esketamine have the potential for misuse. The APA’s current consensus statement on the issue says, “Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder.”