REVIEW OF: Reif A et al, N Engl J Med 2023;389:1298–1309

STUDY TYPE: Randomized, single-blind controlled trial

In treatment-resistant depression (TRD), should you augment a selective serotonin reuptake inhibitor (SSRI) or serotonin/norepinephrine reuptake inhibitor (SNRI) with quetiapine or esketamine? Quetiapine, an oral medication, poses potential metabolic side effects. Esketamine requires in-office monitoring but is FDA approved for TRD after at least two antidepressant failures—a criterion not met by all studies on quetiapine. A recent head-to-head study compared these medications.

A total of 676 adults with major depressive disorder were drawn from 171 sites across 24 countries. Their average age was about 45. All participants had TRD, defined as an insignificant response to two to six treatments from at least two antidepressant classes, including their current SSRI or SNRI. Upon entering the trial, participants continued their current medication, but all augmenting agents were discontinued. Those on low-dose quetiapine underwent a seven-day washout period before the researchers randomized them to receive adjunctive open-label esketamine (n=336) or extended-release quetiapine (n=340), with doses adjusted to 50–300 mg over three weeks. The study’s primary goal was remission at week eight, defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 10 or less. A secondary endpoint was ongoing remission up to week 32. Janssen, the maker of esketamine, funded the study.

At week eight, the esketamine group was 1.5 times more likely to achieve remission than the quetiapine group (27.1% vs 17.6%, p=0.003). Approximately 50% of the esketamine group reached remission by week 32, compared to 30% in the quetiapine group. However, the difference in MADRS scores between the groups was marginal: 2.8 points out of 60 at week eight and 2.2 points at week 32, bringing the clinical significance of these findings into question.

Adverse effects led to higher discontinuation rates in the quetiapine group compared to the esketamine group (11% vs 4.2%), with both groups experiencing high rates of side effects (93% vs 78%). One patient in the esketamine group developed acute coronary syndrome and one developed dizziness, both attributed to the medication. No serious adverse events were linked to quetiapine.

CARLAT TAKE

This study suggests esketamine may be somewhat more effective than quetiapine for augmentation in TRD. However, the study’s funding source, Janssen, raises concern for potential biases, particularly in study design. Notably, all participants in the esketamine group were naive to this treatment, unlike some in the quetiapine group, who may have previously tried and not responded to atypical antipsychotics. This discrepancy could disadvantage the quetiapine arm. Despite these concerns, the direct comparison offered by this clinical trial is valuable.