Esketamine nasal spray for treatment-resistant depression
The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended the granting of a marketing authorisation for esketamine nasal spray (Spravato) for patients with treatment-resistant depression.
The recommended indication is for use in combination with an SSRI or an SNRI, for adults with treatment-resistant major depressive disorder. Patients are defined as treatment resistant if they have not responded to at least two different antidepressant treatments in the current moderate to severe depressive episode. The CHMP recommends that esketamine nasal spray should only be initiated by psychiatrists, to ensure a correct diagnosis of treatment-resistant depressive disorder.
Esketamine, a psychoanaleptic drug, is the S enantiomer of ketamine, and about twice as potent as standard ketamine and more quickly eliminated from the body. It acts as an antagonist at N-methyl-D-aspartate (NMDA) receptors – a novel mechanism of action for an antidepressant, producing a transient increase in glutamate release. It is believed to improve symptoms of depression by helping to restore synaptic connections between brain cells, allowing increased activity and communication between specific regions of the brain.
Each nasal spray device delivers two sprays (one for each nostril), delivering a total dose of 28mg esketamine. The recommended dose and frequency of administration should be individualised according to response, but during the maintenance phase, it should usually be administered either weekly or fortnightly, under the direct supervision of a healthcare professional.
The approval was based on data from five pivotal phase 3 clinical trials, including over 1600 patients with treatment-resistant depression, which showed that treatment with esketamine nasal spray plus a newly-initiated oral antidepressant was associated with a reduction in depressive symptoms compared with a newly-initiated antidepressant plus placebo nasal spray, as early as day two of treatment. In one short-term trial, approximately 70% of all esketamine-treated patients responded to treatment with a 50% or greater symptom reduction after one month, and approximately half of patients achieved remission. In a maintenance of effect study, continued esketamine treatment, in combination with an oral antidepressant, also reduced the risk of relapse compared with oral antidepressant alone. In trials, the most common side-effects of esketamine were dissociation, dizziness, nausea, sedation, headache, vertigo, dysgeusia, hypoaesthesia, blood pressure increase, anxiety and vomiting. These effects were generally transient and mild to moderate in severity.
The US Food and Drug Administration (FDA) approved esketamine nasal spray in March 2019, and it is currently marketed in the USA for use in conjunction with an oral antidepressant in adults with treatment-resistant depression. The US product contains a boxed warning about the risks of sedation, dissociation, abuse and misuse, and suicidal thoughts and behaviours.
A final decision on marketing authorisation is expected from the European Commission before the end of the year, and NICE is currently appraising esketamine for treatment-resistant depression (ID1414), with publication expected by March 2020.