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Esketamine Nasal Spray Eases Depression Quickly

Esketamine Nasal Spray Eases Depression Quickly

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Action Points

  • Note that this small randomized trial demonstrated that an intranasal formulation of the s-enantiomer of ketamine had strong anti-depressant effects compared to placebo.
  • Be aware that individuals with psychotic symptoms or a history of psychosis were excluded as the drug could potentiate these symptoms.

An intranasal formulation of ketamine quickly diminished depressive symptoms in patients with treatment-resistant depression, researchers found.

In a phase II study, those taking one of three doses of esketamine (28 mg, 56 mg, or 84 mg) had significantly greater improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores compared with placebo over 8 days, Ella Daly, MD, of Janssen, and colleagues reported online in JAMA Psychiatry.

Those improvements persisted despite reduced dosing frequency in a subsequent open-label phase that lasted about two months, the researchers said.

Several studies have shown ketamine to have antidepressant effects, and there’s been growing interest in this and other NMDA receptor antagonists, in the class of glutamate receptor modulators, to treat depression and suicidality — especially since about a third of patients don’t respond to current treatment options.

A limitation of ketamine, however, is that it needs to be delivered intravenously. So researchers at Janssen developed an intranasal formulation called esketamine, which is the S-enantiomer of ketamine. This version has a higher affinity for the NMDA receptor than the ketamine R-enantiomer, the researchers explained, adding that nasal delivery will also boost bioavailability of the compound. (The chirally pure molecule can also be patented separately from the racemic form.)

The current study enrolled patients at multiple outpatient referral centers from January 2014 to September 2015. It involved four phases: screening; double-blind treatment (days 1-15) composed of two one-week periods; optional open-label treatment (days 15-74); and post-treatment follow-up (8 weeks).

This design allowed for a smaller sample size to assess efficacy, dose-response, and safety than a standard parallel-group design, while preserving a low chance of type 2 error to avoid missing the efficacy signal, the researchers said.

A total of 67 patients (mean age 45) were randomized, and 60 completed both double-blind periods. All had treatment-resistant depression, which was defined as a lack of clinically meaningful improvement after treatment with at least two different oral antidepressants taken at adequate doses. All of them continued to take their oral antidepressants during the study, and esketamine nasal spray was delivered under the supervision of a healthcare professional.

In the first period, participants were randomized to placebo or to one of the three doses of esketamine. In the second phase, 28 placebo-treated patients with moderate-to-severe symptoms were re-randomized to one of the four treatment arms, while those with mild symptoms continued to receive placebo. Finally, during the open-label phase, dosing frequency was reduced from twice weekly to weekly, then to every two weeks.

The primary efficacy endpoint was change from baseline to 8 days on the MADRS scale.

Overall, Daly and colleagues found that the anti-depressant effect was rapid in onset, evident as early as two hours post-dose, and was dose-related. Mean MADRS scores fell in all groups, with significantly greater improvement in all esketamine dose groups compared with placebo, as well as a dose-response relationship.

  • 28 mg: −4.2, P=0.02
  • 56 mg: −6.3, P=0.001
  • 84 mg: −9.0, P<0.001

These improvements persisted over 8 weeks of follow-up without additional esketamine doses in those who remained in the study, the researchers added. Responses “appeared to persist for more than two months with a lower dosing frequency,” they wrote.

During the double-blind phase, the most common treatment-emergent adverse events in esketamine-treated patients were dizziness, headache, and dissociative symptoms. (The latter has been a problem with racemic ketamine; the quasi-hallucinatory effect has made it a drug of abuse, with street names such as Special K.)

Three of 56 esketamine-treated patients discontinued the study during the blinded phase, as did one of 57 patients during the open-label phase. These included one event each of syncope, headache, dissociative syndrome, and ectopic pregnancy. None of the placebo-treated patients discontinued.

Most esketamine-treated patients had transient elevations in blood pressure and heart rate on dosing days, which returned to normal within two hours of the dose. Perceptual changes or dissociative symptoms began shortly after the start of intranasal dosing, peaked at 30 to 40 minutes, and similarly resolved by two hours. These effects attenuated in all dose groups with repeated dosing, and there was no psychosis.

Daly and colleagues concluded that the results support further investigation in larger trials, and the drug is currently being evaluated in phase III trials in treatment-resistant depression and for patients with major depressive disorder who are at immediate risk for suicide.

In an accompanying editorial, Ole Andreassen, MD, PhD, of Oslo University, and colleagues said the significant effects at just one week are “substantially faster than current treatments.”

While esketamine is a good candidate for intranasal delivery, they wrote, some potential barriers include mucosal inflammation, nasal polyps, and septal deviation. Poor self-administration practices can also reduce efficacy, they noted.

Although there was no psychosis in the trial, patients with psychotic disorders or major depressive disorder with psychosis were excluded, Andreassen and colleagues cautioned. They also urged that “the potential for addiction” be evaluated in future studies.

Still, they said the results demonstrate “considerable promise of combining a compound with rapid antidepressant effects with intranasal delivery” and await results from phase III results.

Several authors are employees of Janssen, which funded the study.

The editorialists disclosed financial relationships with Lundbeck and being co-inventors on an intranasal oxytocin delivery device.

  • Reviewed by
    F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner


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