TRD increases the risk of comorbidity, suicide attempts and completions, all-cause mortality, and hospitalization, according to researchers from Goethe University in Frankfurt, Germany, and colleagues. The study was sponsored by Janssen Pharmaceutical Companies of Johnson & Johnson. The international randomized, phase IIIb study compared the drugs and dosage forms of two combination therapies: a group treated with SSRI/SNRIs in combination with esketamine nasal spray and another where SSRI/SNRIs were administered with extended-release quetiapine as recommended by the National Disease Management Guideline on Unipolar Depression.
The results showing superiority at achieving remission occurred at Week 8 (while still on study treatment) and in remaining relapse-free through Week 32 after remission at Week 8 (while still on study treatment) in patients who have TRD when both treatments were taken in combination with a continuing SSRI/SNRI.
“If a patient does not show any improvement after two different antidepressant therapies over several weeks, we call this treatment-resistant depression or TRD. Studies have shown that administering an additional drug can then be effective,” explained Principal Investigator Andreas Reif, MD, PhD, director of the department of psychiatry, psychosomatics, and psychotherapy at University Hospital Frankfurt. “In the first instance, such an added drug does not need to have an antidepressant effect, but it can often improve or enhance the effect in combination with the previous SSRI or SNRI therapy. This is what was done in the comparison arm, using quetiapine XR in addition to ongoing SSRI/SNRI treatment.”
Background information in the study noted that, in TRD—which is commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode—the percentage of patients with remission is low and the percentage with relapse is high.
The primary endpoint of the open-label, single-blind (with raters unaware of group assignments), multicenter, phase IIIb, randomized, active-controlled trial with assigned patients in a 1:1 ratio, was to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary endpoint was remission, defined as a score of 10 or less on the Montgomery–Åsberg Depression Rating Scale (MADRS), at Week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary endpoint was no relapse through Week 32 after remission at Week 8.
The researchers included all of the patients—336 assigned to the esketamine group and 340 to the quetiapine group—in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome.
The results indicated that more patients in the esketamine group than in the quetiapine group had remission at Week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = .003) and had no relapse through Week 32 after remission at Week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). “Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray,” the authors pointed out, adding that any adverse events were consistent with the established safety profiles of the trial treatments.
The authors concluded that, in patients with TRD, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at Week 8.
The authors explained that esketamine is known to have an analgesic effect at doses used in the study and with the kinetics of application through a nasal spray, “it also has a distinct antidepressant effect, which is thought to happen through counteraction of reduced neuronal plasticity in the brain, which is generally observed in patients with TRD. 27.1% of patients in the esketamine nasal spray arm, who had on average been ill for over a year, went into remission at Week 8 while on study treatment, that is, experienced improvement to an extent that their depression severity reached the non-depressed range. In the quetiapine extended-release study arm, only 17.6 percent who achieved remission at Week 8. Both treatments were taken in combination with a continuing SSRI/ SNRI.”
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