FDA Approves Ketamine Nasal Spray as First and Only Standalone Therapy for Treatment-Resistant Depression

In January, the US Food and Drug Administration (FDA) approved the Johnson & Johnson brand nasal spray, Spravato®, as the world’s first and only monotherapy for addressing treatment-resistant cases of major depressive disorder (MDD). In 2019, the FDA approved Spravato to treat treatment-resistant depression (TRD), with optional uses alone or alongside oral antidepressant medication (both required if suicidal). Now, patients affected by TRD – who didn’t respond to at least two other antidepressants – no longer need to use an antidepressant in order to benefit from ketamine-based therapy. 

According to the World Health Organization (WHO), approximately 280 million people are affected by depression globally, and it is estimated that about 30% of these people with depression meet the criteria for TRD. Thus, the FDA approved Spravato as a standalone ketamine therapy drug, marking a pivotal shift that provides an alternative depression treatment for millions of individuals with MDD who either don’t respond to or can’t tolerate other antidepressant medications.

If you are curious about ketamine therapy for depression, you may still have questions, such as: How is ketamine different from other antidepressants? What’s in the ketamine-derived nasal spray, and how do people use it? This article will provide some general answers by giving an overview of recent findings on how ketamine affects depression and information about the therapeutic uses of esketamine nasal spray to produce a clearer image of what the FDA acceptance of this type of depression treatment entails for potential patients curious to learn more about the therapeutic applications of ketamine.

How Ketamine is Used to Treat Depression

Ketamine is a dissociative anesthetic with a history of approved uses in various hospital and veterinary settings. Clinicians typically use ketamine as a general anesthetic, but they also use it to alleviate treatment-resistant chronic pain and seizures.

In the mental health field, the therapeutic effects of ketamine are researched in numerous clinical studies over the past decade, which have found the drug to be a promising potential treatment for individuals affected by a variety of psychological conditions, including post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and social anxiety disorder (SAD), as well as TRD. 

With the FDA approval of the brand-name Spravato nasal spray as a standalone therapy for individuals with TRD, patients can now obtain a prescription to be treated in a clinical setting with a nasal spray containing a kind of ketamine molecule called esketamine (as in the “S form” of the ketamine molecule—S-ketamine). However, doctors do not consider esketamine a first-line treatment for depression. To be eligible for esketamine nasal spray treatment, an individual must have tried at least two different antidepressant medications without experiencing improvements, despite taking an adequate dose for a reasonable duration. 

Ketamine works differently from many traditional antidepressants by targeting different neurochemical systems. While SSRIs (selective serotonin reuptake inhibitors) primarily act upon serotonin receptors, ketamine instead influences the brain’s glutamate system. It’s currently believed that via this neurochemical system, ketamine functions primarily as an NMDA (N-methyl-D-aspartate) receptor antagonist that can modulate synaptic plasticity and neural connections, which may explain its reported antidepressant effects. 

However, scientists are overall still uncertain about how to understand the mechanism of ketamine’s antidepressant effects, as ketamine also interacts with other neurotransmitter systems, which may contribute to its uniquely profound mitigating effects on depression.

Ketamine is also different from other antidepressants in its rapid onset of effects, producing noticeable benefits sometimes within hours, whereas SSRIs can take weeks to work. This is likely because ketamine directly boosts glutamate signaling in the brain, rather than relying on gradual changes in serotonin levels over time. 

Two forms of ketamine therapy for mental health conditions have been studied: intravenous (IV) infusions and a brand-name nasal spray containing esketamine called Spravato. While the FDA has approved Spravato for TRD and doctors can prescribe it to treat depression, providers still use IV ketamine infusions as an off-label treatment for many pain-related syndromes. This means that, although many clinics offer IV ketamine therapy based on emerging research, its use is subject to inconsistent medical guidelines, safety standards, and insurance restrictions.

What is Ketamine Nasal Spray?

The FDA-approved Spravato nasal spray provides a dose of one version of the ketamine molecule called esketamine (S-ketamine). The ketamine molecule comes in two different mirror-image orientations, and esketamine makes up half of what is found in the commonly used anesthetic form of the drug (R, S-ketamine, aka racemic ketamine). 

The FDA notes how racemic ketamine (R, S-ketamine) is quite different and not approved nor safe for nasal use. Researchers single out the esketamine structure for use in a nasal spray because the other orientation of the ketamine molecule is unsafe in animals, binds poorly with the skin, and is less predictable when taken orally. Moreover, since the chemical makeup of esketamine allows it to bind more tightly to the NMDA glutamate receptors, esketamine is two to four times more potent than ketamine at this receptor, so patients require a lower dose of esketamine than they do ketamine. 

The body absorbs ketamine nasal spray through the richly vascularized nasal membranes, allowing it to quickly enter the bloodstream. The drug then acts on certain receptors in the brain, leading to changes in mood and perception. Healthcare providers consider the nasal spray a more convenient and less invasive option for administration in the outpatient setting compared to IV treatments. Using ketamine via nasal spray also makes the process less painful than IV infusions, since patients must return for multiple rounds of treatment to experience the full benefits. 

A four-week clinical trial found that Spravato, when combined with an oral antidepressant, led to greater reductions in depression symptoms compared to a placebo with an oral antidepressant. Following this trial, some participants whose depression symptoms improved significantly during the first study chose to enroll in a year-long follow-up study. This extended research finds that Spravato continued to alleviate depression symptoms, and individuals who received the treatment were less likely to experience a relapse into severe depression compared to those using a placebo nasal spray.

READ: Could the Up-and-Coming Medicinal Ketamine Market Rival the Cannabis Industry?

How to Use Ketamine Nasal Spray

Esketamine nasal spray is self-administered by the patient under a doctor’s supervision in a medical facility. The supervised setting allows for precise dosing and close monitoring to minimize potential side effects and ensure the overall safety and efficacy of the treatment. Taking Spravato in a supervised administration setting also allows healthcare professionals to control the supply, quantity, frequency, provide support, answer questions, and monitor for any adverse reactions or improper use during the session.

The Spravato spray device contains 2 sprays (28 mg per spray), and a doctor determines how many sprays you will need, depending on your dose. It is recommended that patients not eat within two hours of treatment. Dosing will be different depending on the particular patient, medical condition, and treatment regimen involved. Because it can cause nausea, you’ll be asked to stop eating for 2 hours before the session, plus no liquids 30 minutes before taking it.

For TRD, healthcare providers typically start adults on a 56-milligram (mg) dose on the first day of treatment. They then administer 56 mg or 84 mg twice per week for the first four weeks, followed by 56 mg or 84 mg once a week for the next four weeks. Then, 56 mg or 84 mg doses are taken once a week for another four weeks. At 9 weeks and after, patients will return for 56 or 84 mg dosing sessions every two weeks or once a week. Timing Spravato administration effectively plays a critical role in its effectiveness. Following the prescribed schedule and avoiding missed doses helps maintain a consistent level of the medication in the body, which can maximize Spravato’s therapeutic benefits and improve treatment outcomes.

After administering a dose of esketamine, healthcare providers typically require patients to remain under medical supervision for at least two hours to monitor potential side effects. Doctors also advise patients not to drive on the day of treatment and to arrange transportation home after receiving esketamine nasal spray therapy.

What Does Ketamine Nasal Spray Feel Like?

The esketamine solution begins to take effect within 30–60 minutes after administration, with peak impact occurring around one to two hours later. Effects typically persist for several hours, and some individuals even experience residual effects for up to 24 hours after initial administration. 

Taking the nasal spray can produce a variety of initial sensations depending on the individual, due to factors such as dosage and personal tolerance. Some common effects experienced when taking ketamine nasal spray include:

• Altered Perception: Users may feel detached from their surroundings, which can create altered perceptions of time, space, and one’s own body.
• Euphoria: Including intoxication and impairment; users should not drive nor operate heavy machinery until the next day after restful sleep.

• Weightlessness: Users can experience a sense of floating or disconnecting from their physical body, with some individuals reporting having an “out-of-body” experience.
• Dizziness: Users can also experience dizziness, lack of coordination, or impaired motor skills. This medication may also increase blood pressure. Overall precautions for those at cardiovascular risk.

As for therapeutic effect, many individuals experience noticeable improvement in mood, energy levels, and outlook within hours or days of starting esketamine nasal spray. However, patients should continue consistent redosing visits, as maintaining the prescribed frequency is essential for achieving optimal and lasting results from the treatment. This medicine may also cause fetal harm, so it should not be taken by those who are planning, pregnant, or breastfeeding.

For most individuals, the full therapeutic effects of intranasal esketamine become most apparent after a few weeks of consistent treatment. Clinical trials show that patients begin experiencing significant shifts in their depression symptoms after four weeks of treatment. 

Final Thoughts

The approval of Spravato as a standalone therapy for TRD marks a significant step in expanding treatment options for individuals struggling to treat their depression, offering a new, fast-acting alternative to traditional antidepressants. 

Furthermore, the FDA’s movement to approve the use of Spravato for treating depression reflects a broader shift in psychiatry toward exploring the potential benefits of psychedelic medicines, which challenges long-held assumptions about mental health treatment and the medical utility of various psychedelic substances. As research into ketamine and other psychedelic compounds continues, such mental health therapies may become increasingly essential to the future of psychiatric care.

Frequently Asked Questions

Who is eligible for therapy with ketamine nasal spray?

The FDA has approved ketamine nasal spray to treat major depressive disorder in patients who haven’t responded successfully to at least two other antidepressant medications. It may be taken alone or in conjunction with other antidepressants; the latter is required if the patient is suicidal.

Is ketamine nasal spray better than IV?

The FDA has approved the nasal spray form of esketamine as the only ketamine treatment for depression. IV infusion ketamine therapies can be administered “off-label” to patients with treatment-resistant depression, but they have yet to receive FDA approval. 

How long does ketamine therapy with nasal spray take?

The immediate effects of ketamine nasal spray (intranasal ketamine) typically last for about 1 to 2 hours. You can typically achieve full therapeutic benefits after 4 to 8 weeks of routine treatments.

Is ketamine nasal spray addictive?

Ketamine and esketamine are potentially liable to abuse if not controlled, particularly in those who already have a greater risk for substance abuse. Using ketamine nasal spray at prescribed doses under medical supervision does not lead to withdrawal symptoms, according to clinical trials, even after 4 weeks.  However, tolerance may still occur because of reduced responses to prolonged treatment.

What are the negative side effects of ketamine nasal spray for depression?

In the clinical trials for Spravato, participants commonly reported side effects such as feeling dissociated, dizzy, nauseous, sedated, or drunk. They also experienced vertigo, decreased sensitivity, anxiety, lethargy, elevated blood pressure, and vomiting. These side effects typically occurred short term and lasted only for the duration of the drug’s immediate effects. Long-term side effects beyond one year are still unknown, as the drug is relatively new.