As of this month, the U.S. Food and Drug Administration (FDA) has approved the use of esketamine nasal spray as an adjunctive treatment modality for a novel application in major depressive disorder (MDD: for patients with suicidal ideation with intent). While it had already been approved for treatment-resistant depression as of last year, research has now pointed to its use in an acute setting.
One such study was that by Papakostas et al. (2020), who conducted a meta-analysis of 241 studies, selecting randomized, double-blind trials comparing esketamine to placebo in MDD patients. Their evaluation of the drug was done based on the Montgomery-Asberg Depression Rating Scale (MADRS) results for the experimental groups. This scale was designed by Montgomery & Asberg (1977) to evaluate the most commonly occurring symptoms of primary depressive illness, and is used as an effective tool to assess response to treatment.
What Papakostas’ team found was that intranasal esketamine had a significant association with MADRS score changes for the better, indicating improvements in depressive symptoms when compared to the placebo group.
Other studies further corroborate the value of esketamine as an additional therapy to oral antidepressants in treating depression, with a favorable safety profile. Phase 3 trials such as that by Wajs et al (2020) indicate that esketamine, when used alongside an oral antidepressant for MDD, is safe, tolerable, and confers long-term improvements in depression.
Risks are Evident
However, there are some caveats which the FDA have noted. The primary caveat is that of esketamine’s side effects. For instance, there are boxed warnings for esketamine for the risk of sedation and risk of abuse and misuse. In such circumstances, there may be an increased risk of suicidal ideation in the pediatric population. There is also an increased risk, particularly at the commencement of the drug, of dissociative symptoms as well (Bahr, Lopez, & Rey, 2019).
With this in mind, the FDA have taken extra precautions in the administration of this drug, the primary one being that its availability is limited to a restricted distribution system, as part of its Risk Evaluation and Mitigation Strategy. This is a program of the FDA done to monitor medications with a risk of adverse effects and abuse.
The patient is to administer the intranasal spray when supervised by his/her health care provider in their office. They are not allowed to take the drug home with them. To add another step, the patient is to be monitored by their HCP for at least two hours upon administration of esketamine As expected, patients are also not allowed to drive or operate machinery.
One final thing to keep in mind going forward is the need to tailor the drug to each individual patient, based on their response to the drug over time. Literature in the past year has shown that patients evaluated for treatment every four weeks had a high probability of improvement or maintaining benefit.
By doing this (evaluation), one can gauge how the patient is responding based on his or her depression inventories, and either increase, decrease, or maintain the dose for a certain period of time to confer symptomatic improvement (Nijs et al., 2020).
Now that esketamine is FDA approved, we can further address the all too common prevalence of depression with a more effective treatment modality. As always, I emphasize that this is an effective adjunctive approach, much like all other pharmacological approaches to psychiatric conditions.
It will reap maximal benefit if supplemented to psychotherapy and a solid support group for each patient with depression. That said, the fact that a ketamine derivative is now a mainstream treatment modality shows how out-of-the-box thinking in science and medicine can give way to some wonderful discoveries and potentially groundbreaking treatments.
Bahr, R., Lopez, A., & Rey, J. A. (2019). Intranasal Esketamine (SpravatoTM) for Use in Treatment-Resistant Depression In Conjunction With an Oral Antidepressant. P & T : a peer-reviewed journal for formulary management, 44(6), 340–375.
Montgomery, S., & Åsberg, M. A. R. I. E. (1977). A new depression scale designed to be sensitive to change. Acad. Department of Psychiatry, Guy’s Hospital.
Nijs, M., Wajs, E., Aluisio, L., Turkoz, I., Daly, E., Janik, A., Borentain, S., Singh, J. B., DiBernardo, A., & Wiegand, F. (2020). Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data. The international journal of neuropsychopharmacology, 23(7), 426–433. https://doi.org/10.1093/ijnp/pyaa027
Papakostas, George I., et al. “Efficacy of Esketamine Augmentation in Major Depressive Disorder: A Meta-Analysis.” The Journal of Clinical Psychiatry 81.4 (2020).
Wajs, E., Aluisio, L., Holder, R., Daly, E. J., Lane, R., Lim, P., … & Kasper, S. (2020). Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2). The Journal of clinical psychiatry, 81(3).