Ketamine-derived nasal spray provides new option for resistant depression

Spravato (esketamine) works in a different way to existing antidepressants, and has been shown to lessen symptoms as early as 24 hours after dosing.

Patients who have not responded to at least 2 different antidepressants in the current depressive episode are considered to have treatment-resistant depression. | GETTY IMAGES
Patients who have not responded to at least 2 different antidepressants in the current depressive episode are considered to have treatment-resistant depression. | GETTY IMAGES

Spravato is indicated in combination with an SSRI or SNRI for adults with major depressive disorder who have not responded to at least two different antidepressants in the current moderate to severe depressive episode.

The nasal spray is a single-use device that delivers a total of 28mg esketamine in two sprays (one spray per nostril).

The recommended starting dose is one or two sprays in each nostril on the first day. This is followed by 1, 2 or 3 sprays in each nostril twice a week for 4 weeks. Afterwards, if the patient’s depression improves, Spravato should be used once a week for the next 4 weeks and then once every 1 or 2 weeks for at least 6 months.

Esketamine is a stereoisomer of ketamine. It acts as an antagonist at the NMDA receptor, producing a transient increase in glutamate release and thereby boosting neurotrophic signalling, which may contribute to the restoration of synaptic function in brain regions involved in the regulation of mood and emotional behaviour.

Because of the risks of sedation and dissociation and the potential for abuse, Spravato is intended to be self-administered by the patient under the direct supervision of a healthcare professional. Blood pressure should be monitored 40 minutes after dosing as transient increases are common. 

Short-term studies

Esketamine was evaluated in five phase III studies in patients with treatment-resistant depression: three short-term (4-week) randomised double-blind studies (TRANSFORM-1, -2 and -3), one randomised double-blind relapse prevention study, and one long-term safety study. 

In all short-term studies, the primary efficacy endpoint was change in Montgomery–Åsberg Depression Rating Scale (MADRS) total score from baseline to day 28.

In the flexible dosing study TRANSFORM-2 (n=227), esketamine plus a newly initiated oral antidepressant demonstrated clinical and statistical superiority compared with placebo nasal spray plus a newly initiated oral antidepressant, and symptom reduction was observed as early as 24 hours post-dose.  

In the TRANSFORM-1 study (n=346), a clinically meaningful treatment effect was observed favouring esketamine plus newly initiated oral antidepressant compared with placebo nasal spray plus a newly initiated oral antidepressant, although the treatment effect for esketamine 84mg plus oral antidepressant compared with placebo plus oral antidepressant was not statistically significant. 

Similarly, TRANSFORM-3, a flexible dosing study involving adults ≥65 years (n=138), showed a clinically meaningful but not statistically significant treatment effect in change in MADRS total scores from baseline at the end of the 4-week induction phase was observed favouring esketamine plus newly initiated oral antidepressant compared with placebo nasal spray plus a newly initiated oral antidepressant.

In all three short-term studies, rates of response (defined as a ≥50% reduction in MADRS total score from induction baseline) and remission (defined as a MADRS total score ≤12) were significantly higher among patients who received esketamine in addition to an oral antidepressant than among those who received placebo nasal spray plus an oral antidepressant. 

Relapse prevention

In the relapse prevention study (n=297), continuous treatment with esketamine plus an oral antidepressant reduced the risk of relapse by 51% in patients who achieved stable remission, and by 70% among patients who achieved stable response, compared to switching from esketamine to placebo. 

Side-effects

In trials, the most common side-effects of esketamine were dizziness, nausea, dissociation, headache, somnolence, vertigo, dysgeusia, hypoaesthesia and vomiting, all of which were very common (affecting at least 10% of patients) but generally transient.

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