Janssen's Spravato (Esketamine) Nasal Spray Approved by FDA as First Novel Treatment for Treatment-Resistant Depression in Nearly 50 Years

Arterial New Medicine (biobeat1) learned that on March 5, 2019, the FDA approved Johnson & Johnson's Janssen Spravato (esketamine) nasal spray, in conjunction with oral antidepressants, for the treatment of treatment-resistant depression. The approval of Spravato marks the first new approach in nearly 50 years for treating patients with treatment-resistant depression (major depressive disorder).

Janssen’s Spravato (esketamine) nasal spray is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator. Esketamine is the S-enantiomer of ketamine. Janssen posits that its therapeutic effect is achieved by restoring synaptic connections in the brain cells of patients with major depressive disorder. In the current disease stage, patients with major depressive disorder who have not responded to treatment despite receiving adequate doses of at least two antidepressant therapies are considered to have treatment-resistant depression. Given the risks associated with Spravato that may lead to serious adverse outcomes, as well as its potential for diversion and abuse, Spravato is currently available only through a restricted distribution system under the Risk Evaluation and Mitigation Strategy (REMS).

“For treatment-resistant depression, a serious and life-threatening condition, we have long been seeking appropriate therapeutic options to provide additional effective treatment,” said Dr. Tiffany Farchione, Acting Director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Controlled clinical trials evaluating the safety and efficacy of this drug, along with a thorough review under the FDA’s drug approval process—including extensive discussions with our external advisory committees—ultimately led to the decision to approve this medication. However, due to safety concerns, the drug will be available only through a restricted distribution system and must be administered in certified healthcare settings to ensure proper monitoring of patient use.”

Mathai Mammen, Global Head of Research and Development at Johnson & Johnson, stated that Spravato has the potential to transform the treatment landscape for major depressive disorder (MDD). He said, “This medication offers new hope for the estimated one-third of patients with depression who do not respond to existing treatment regimens.”

Some individuals have expressed opposition to the approval of Spravato. Dr. Indra Cidambi, MD, addiction specialist and medical director at the Center for Network Therapy (CNT), stated, “Ketamine is an inexpensive street drug (potentially much cheaper than obtaining it through legal channels) and can provide immediate symptom relief. The FDA’s approval of Spravato (esketamine) for the treatment of depression may lead patients who are unable or find it difficult to access esketamine therapy to seek out ketamine on the street for self-treatment of depressive symptoms. This could result in a significant increase in ketamine addiction.”

“Recall that when states began implementing restrictions on opioid analgesic prescriptions, many patients already prescribed opioids turned to street heroin to alleviate pain or withdrawal symptoms,” warned Dr. Cidambi.

The approval of Spravato was primarily based on a short-term (four-week) clinical trial and a long-term maintenance-of-efficacy trial. In the short-term study, patients were randomly assigned to receive either Spravato or a placebo nasal spray. Given the severe nature of treatment-resistant depression and patients’ need for therapy, all participants in these studies continued concomitant use of other oral antidepressants throughout the clinical trials. The primary efficacy endpoint was assessed based on changes from baseline in the severity of depressive symptoms as measured by a standardized rating scale. In one of the short-term studies, Spravato nasal spray demonstrated a statistically significant effect on depression severity compared with placebo, with some effects observable within two days. In the long-term maintenance-of-efficacy trial, the risk of relapse of depressive symptoms was reduced by 51% in patients who continued treatment with Spravato plus an oral antidepressant, compared with those who received placebo nasal spray plus an oral antidepressant.

However, the Spravato packaging also carries a warning alerting patients to the risk of sedation after taking the medication, as well as potential dissociation, impaired judgment and thinking, abuse and misuse of the drug, and suicidal thoughts and behaviors. Due to various adverse reactions, patients must be monitored by a physician for at least two hours after using Spravato. The REMS program requires prescribers and patients to sign a patient enrollment form. This form clearly indicates that the patient understands they should leave the healthcare facility safely to return home and should not drive or operate heavy machinery for the remainder of the day. Additionally, patients self-administer the Spravato nasal spray under the supervision of a healthcare provider in a certified physician’s office or clinic, but the spray cannot be taken home. Healthcare providers will instruct patients on how to use the nasal spray device. During and after each use of the nasal spray device, healthcare providers will continue to monitor the patient and determine when it is safe for them to leave.

In clinical trials, the most common side effects observed in patients treated with Spravato were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia or hypersensitivity, anxiety, somnolence, increased blood pressure, vomiting, and a feeling of intoxication. Patients with unstable or poorly controlled hypertension, as well as those with aneurysmal vascular disease, may be at additional risk for cardiovascular or cerebrovascular adverse reactions. Spravato may impair attention, judgment, thinking, reaction speed, and motor skills. Patients should not drive or operate machinery on the day following treatment, even after resting. Spravato may cause fetal harm; women of childbearing potential should consider pregnancy planning and contraception, and breastfeeding is not recommended during treatment.