The Essentials on Esketamine for Treatment-Resistant Depression

The recent FDA approval of esketamine (Spravato™) nasal spray, in conjunction with an oral antidepressant, for treatment-resistant depression brings new hope to patients who have failed to improve on traditional antidepressants.

“I believe esketamine will play a very important role in the short-term management of treatment-resistant depression because it can provide rapid relief,” says Amit Anand, MD, Vice Chair for Research in Cleveland Clinic’s Center for Behavioral Health. “Its other main advantage is a convenient mode of administration via nasal spray.”

Dr. Anand was a member of the team at Yale University in the 1990s that discovered that ketamine (the parent compound of esketamine) could effectively treat severe depression. The intravenously administered anesthetic agent has been used off-label, in subanesthetic doses, for treatment-resistant depression in clinics across the U.S. Esketamine is the first form or derivative of ketamine to receive U.S. marketing approval for depression.

In addition to his role in discovering ketamine’s antidepressant effects, Dr. Anand is now principal investigator of an ongoing four-center clinical trial (ELEKT-D) comparing the efficacy and safety of ketamine with electroconvulsive therapy (ECT) in patients with treatment-resistant depression. The trial, profiled in this earlier Consult QD post, is funded by the U.S. government-sponsored Patient-Centered Outcomes Research Institute (PCORI).

Targeting the glutamate signaling pathway for rapid relief

Esketamine is intended to be self-administered by the patient under close medical supervision in a doctor’s office or clinic, because of its potential adverse effects and risk of sedation and dissociation. Due to its addictive properties, and to prevent abuse and misuse, esketamine nasal spray is available only through a restricted distribution system, as part of an FDA Risk Evaluation and Mitigation Strategy (REMS) system.

As the s-enantiomer of ketamine, esketamine has a highly similar mode of action. “Both drugs act rapidly, within several hours of administration, and this is their main advantage when compared with the 4- to 6-week onset of action for traditional antidepressants,’’ Dr. Anand says. “Esketamine and ketamine both target the brain’s glutamate signaling pathway and cause a transient effect that lasts approximately 3 to 7 days.”

Esketamine is meant to be reserved for a selected group of patients who have not responded to currently available oral antidepressants. “Approval is for use only in patients who have failed to improve after adequate trials of at least two oral antidepressants,” Dr. Anand explains. Patients still have to take an oral antidepressant together with esketamine in a clinic setting, usually once or twice a week. After an observation period of at least two hours, the patient is released home but cannot drive or operate machinery for at least 24 hours.

Side effects of esketamine reported in clinical trials include dizziness, dissociation, nausea, sedation, anxiety, lethargy, vertigo, increased blood pressure, vomiting and hypoesthesia.

Differentiating between short- and long-term treatment

Dr. Anand points out that it is very important to differentiate between short- and long-term use of ketamine and esketamine for depression, noting that until now only limited treatment options were available for patients who experience severe, debilitating episodes of the disease.

“For the past 70 years, and before the use of ketamine, we’ve only had one option for fast, short-term treatment of depression, and that is ECT,” he says. “ECT is very effective but carries social stigma, requires anesthesia in a hospital setting and may cause memory problems. Another type of treatment, repetitive transcranial magnetic stimulation (rTMS), is usually reserved for less severely ill patients.”

Dr. Anand believes esketamine will be a major addition to the armamentarium of approved therapies for fast treatment of resistant depression if it proves to be as effective as ECT — a question his ELEKT-D trial should help clarify — because it lacks the side effects associated with ECT and is much easier to administer. However, its safety and effectiveness over the long term still need to be investigated.

“At this point we don’t know if esketamine will continue to have an effect when given over many years, and what is long-term side effects will be,” he says. “Because ketamine, also known as the party drug Special K, is a known drug of abuse, we also have to be very careful with esketamine over the long term.”

The question of cost

Another concern may be cost, which Dr. Anand says will be significantly higher than that of currently available oral antidepressants. Wholesale pricing ranges from about $4,700 to $6,700 for the initial month of treatment and approximately $2,300 to $3,500 monthly thereafter. “That’s before discounts,” he notes, “but on top of that there may be facility costs from the outpatient sites where the drug is administered.”

He is optimistic, however, that only a portion of these costs will be borne by patients as insurers increasingly start covering esketamine. Another option, he says, is to be treated with the much cheaper generic intravenous ketamine: “Insurers may be more likely to provide coverage for subanesthetic intravenous ketamine now that FDA has approved esketamine.”

Image at top courtesy of Janssen Pharmaceuticals.