New research supports the effectiveness and safety of esketamine nasal spray in treating depression


New research supports the effectiveness and safety of esketamine nasal spray in treating depression in people who have not responded to previous treatment.

The research will be published online today in the American Journal of Psychiatry.

This study is one of the key studies that led to the recent Food and Drug Administration (FDA) approval of esketamine nasal spray, in conjunction with an oral antidepressant, for use in people with treatment-resistant depression.

Depression is common, and as many as one-third of people with depression are considered treatment resistant – not finding relief from symptoms even after trying several antidepressants.

Esketamine offers a new fast-acting treatment for people that have not responded to other depression treatments.

Ketamine and its enantiomer S-ketamine (esketamine) are promising candidates to produce a rapid-onset antidepressant effect in treatment-resistant depression.

Ketamine causes continued blockade of the glutamate N-methyl-D-aspartate (NMDA) receptor, though this might not primarily mediate the antidepressant effect.

Alternative hypotheses include selectivity for the NMDA receptor subtype containing the NMDA receptor subunit 2B (NR2B), inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase, increased expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrKB), and activation of the mammalian target of rapamycin (mTOR) signaling pathway, alongside other independent actions attributed to the ketamine metabolism to R-hydroxynorketamine (R-HNK).

The enantiomer S-ketamine (esketamine) displays approximately fourfold greater affinity for the glutamate NMDA receptor in vitro than R-ketamine.

Proof-of-concept single-dose and repeat-dose studies with intravenous ketamine show a significant antidepressant and probably antisuicidal effect in the short term, with response rates over 60% as early as 4.5 h after a single dose, with a sustained effect after 24 h, and over 40% after 7 days.

This response can be further sustained over several weeks with repeated doses (two to three doses per week).

Tolerability seems acceptable in the short term, with transient elevation of blood pressure and mild and transient dissociative and psychotomimetic effects.

Intranasal esketamine has shown a comparable antidepressant effect, which has resulted in the US FDA granting the drug a “breakthrough therapy” designation, and theoretically it may offer an improved tolerability profile.

However, major concerns remain regarding an effective protocol to maintain the clinical antidepressant effect of ketamine seen with acute administration and the safety of ketamine and esketamine in the long term, specifically related to potential neurocognitive and urologic toxicity, together with the potential induction of substance use disorders.

Ketamine and esketamine are not currently approved treatments for depression, but the clinical use of ketamine is increasing in a variety of practice settings internationally.

Michael Thase, M.D., one of the study authors, described the study during a briefing held during the Annual Meeting of the American Psychiatric Association.

The phase 3, double-blind, active-controlled study was conducted at 39 outpatient centers from August 2015 to June 2017 and involved nearly 200 adults with moderate to severe depression and a history of not responding to at least two antidepressants.

Participants were randomly assigned to one of two groups.

One group was switched from their current treatment to esketamine nasal spray (56 or 84 mg twice weekly) plus a newly initiated antidepressant (duloxetine, escitalopram, sertraline, or extended-release venlafaxine).

The other group was switched from their current treatment to a placebo nasal spray in combination with a new antidepressant.

The improvement in depression among those in the esketamine group was significantly greater than the placebo group at day 28.

Similar improvements were seen at earlier points in time.

Adverse events in the esketamine group generally appeared shortly after taking the medication and resolved by 1.5 hours later while patients were in the clinic.

The most common side effects included dissociation, nausea, vertigo, dysgeusia (distortion of the sense of taste) and dizziness.

Seven percent of patients in the esketamine group discontinued the study due to side effects.

“This trial of esketamine was one of the pivotal trials in the FDA’s review of this treatment for patients with treatment resistant depression.

Not only was adjunctive esketamine therapy effective, the improvement was evident within the first 24 hours,” Thase said.

“The novel mechanism of action of esketamine, coupled with the rapidity of benefit, underpin just how important this development is for patients with difficult to treat depression.”

In an accompanying commentary in the American Journal of Psychiatry, Alan Schatzberg, M.D., at Stanford University School of Medicine, highlights several areas where information about the best use of esketamine is lacking, such as how long and how often to prescribe it, and raises concerns about the potential for abuse.

While he notes that esketamine could be useful for many patients with depression, he cautions that “there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice.”

The commentary describes esketamine’s relationship to ketamine, an anesthetic in use for decades that has also been used recreationally as a party drug.

While ketamine administered intravenously at sub-anesthetic doses is an effective treatment being used for refractory depression, at present, intravenous ketamine for the treatment of depression has not been approved by the FDA, although it can be prescribed off-label. Ketamine is composed of molecules that are mirror images of each other (S-ketamine and R-ketamine).

It is the intranasal formulation of the S-ketamine molecule (i.e., esketamine) that received FDA approval.

More information:American Journal of Psychiatry (2019). DOI: 10.1176/appi.ajp.2019.19020172

Journal information: American Journal of Psychiatry
Provided by American Psychiatric Association


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