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European Union: Spravato, Esketamine nasal spray, approved for adults with treatment-resistant major depressive disorder

European Commission ( EC ) has approved Spravato ( Esketamine ) nasal spray, in combination with a selective serotonin reuptake inhibitor ( SSRI ) or serotonin and norepinephrine reuptake inhibitor ( SNRI ), for adults living with treatment-resistant major depressive disorder ( TRD ).
According to the approval, patients are considered to have TRD depression if they have not responded to at least two different treatments with antidepressants in the current moderate-to-severe depressive episode.

The approval of Esketamine is based on data from a clinical trial programme in patients with TRD depression, including over 1,600 patients treated with Esketamine.
The five phase 3 trials included three short-term studies, one randomised withdrawal and maintenance of effect study, and one long-term safety study.
These data have demonstrated that treatment with Esketamine nasal spray plus a newly initiated oral antidepressant was associated with a greater reduction in depressive symptoms compared to a newly initiated oral antidepressant plus placebo nasal spray, in adult patients ( 18-64 years ), with the onset of efficacy as early as day 2.
Approximately 70% of Esketamine-treated patients responded to treatment, with a greater than or equla to 50% symptom reduction.
Furthermore, approximately half of all treated patients achieved remission at the end of the 4 week studies.
Continued treatment with Esketamine nasal spray plus oral antidepressant reduced the risk of relapse by 70% among patients with stable response and by 51% in patients in stable remission, compared to continuing treatment with oral antidepressant alone.

Across the five phase 3 and one phase 2 clinical trials, Esketamine nasal spray has demonstrated a favourable benefit-risk profile, with sustained efficacy and no new safety concerns were observed over a period of up to one year.
The most commonly observed adverse events in TRD depression patients treated with Esketamine were dizziness, nausea, dissociation, headache, somnolence, vertigo, dysgeusia, hypoaesthesia, and vomiting.
These side effects were generally mild-to-moderate, transient ( typically resolving within 2 hours ) and occurred on the day of dosing.

Esketamine is an antagonist of the N-methyl-D-aspartate ( NMDA ) glutamate receptor, and is understood to work differently than other currently available therapies for major depressive disorder. It is thought to help restore synaptic connections between brain cells in people with TRD depression, allowing for more activity and communication between specific regions of the brain. Based on results from clinical trials, this increase in activity and communication is thought to help improve the symptoms of depression.

Major depressive disorder affects nearly 40 million people of all ages in Europe and is the leading cause of disability worldwide. Individuals with depression, including major depressive disorder, experience continuous suffering from a serious, biologically-based disease, which has a significant negative impact on all aspects of life, including quality of life and function.
Although currently available antidepressants are effective for many patients, their onset of effect takes between four to six weeks.
Furthermore, about one third of patients do not respond to currently available treatments, and are considered to have treatment-resistant depression or TRD. ( Xagena )

Source: Janssen Cilag, 2019