#VisualAbstract: Esketamine augmentation therapy is superior to quetiapine for treatment-related depression

1. In this randomized controlled trial, in patients with treatment-resistant depression esketamine nasal spray as augmentation therapy was associated with higher rates of remission as compared to extended-release quetiapine.

2. Once remission was achieved, esketamine nasal spray was associated with lower risks of relapse at 32 weeks compared to extended-release quetiapine.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Treatment-resistant depression impacts approximately one-third of all patients with diagnosed major depressive disorder, and has implications for increased risk of hospitalization episodes and mortality. Within Europe, esketamine nasal spray is amongst the only treatments approved for treatment-resistant depression when used concurrently with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). However, evidence in support of its efficacy when compared directly against extended-release quetiapine is currently limited. This was a randomized controlled trial comparing the efficacy of esketamine nasal spray against extended-release quetiapine when used as an adjunct agent to an SSRI or SNRI. Results of the study found that esketamine nasal spray demonstrated a significantly higher rate of remission at eight weeks compared to extended-release quetiapine, and was associated with a lower risk of relapse 32 weeks after remission. The results of this study may be influenced by the open-label design, and have limited generalizability in the ‘real world’ given its specific comparator group of extended-release quetiapine. In summary, this study provided strong evidence in support of the use of esketamine nasal spray as an augmentation therapy to SSRI or SNRI amongst patients with treatment-resistant depression.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This was a single-blind randomized controlled trial investigating the efficacy and safety profile of esketamine nasal spray against extended-release quetiapine as a form of augmentation therapy alongside an SSRI or SNRI for patients with treatment-resistant depression. The primary outcome of interest was remission of depression as measured on the Montgomery-Asberg Depression Rating Scale after eight weeks. Adults with treatment-resistant depression, defined as meeting the Diagnostic and Statistical Manual of Mental Disorders criteria and who had received at least two consecutive treatments within the current episode from different medication classes, who scored 34 or above on the Inventory of Depressive Symptomatology-Clinician-Related scale were included. Overall, 676 participants were randomly assigned in a 1:1 ratio to receive esketamine as an augmentation (n=366), or quetiapine (n=340). Results of the primary analysis found that in comparison to quetiapine, participants receiving esketamine demonstrated a significantly higher rate of remission at week eight (p=0.003) and a significantly lower percentage of relapse at 32 weeks. There were no significant differences in the adverse events profile of esketamine and quetiapine compared to what has previously been established. Overall, this study provided strong evidence for the potential benefit of esketamine nasal spray for patients with treatment-resistant depression when used as an augmentation therapy to SSRIs or SNRIs.

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