Improvements in Treatment-Resistant Depression With Esketamine

Esketamine nasal spray (Spravato) combined with an oral antidepressant for treatment-resistant depression reduced depression severity and led to numerically more remissions during maintenance, post-hoc analyses of three phase III trials suggested.

Pooled data from TRANSFORM-1 and TRANSFORM-2 -- both 4-week, randomized studies -- demonstrated reductions on the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS) total score from days 2-28 for patients receiving a newly initiated oral antidepressant plus esketamine versus those assigned to an oral antidepressant plus placebo, reported Jennifer Kern Sliwa, PharmD, of Janssen Scientific Affairs.

Significant reductions in depression severity were seen with esketamine at days 15 and 28 both on MADRS and the 9-item Patient Health Questionnaire (PHQ-9), according to a poster presented at Psych Congress 2021, held virtually and in-person in San Antonio.

Between the pooled esketamine and placebo groups, respectively, the least-squares mean change from baseline at these time points were:

• MADRS, day 15: -13.2 vs -10.1, P=0.002
• MADRS, day 28: -21.6 vs -17.2, P<0.001
• PHQ-9, day 15: -9.0 vs -7.2, P=0.001
• PHQ-9, day 28: -12.8 vs -10.3, P<0.001

A higher proportion of patients in the pooled esketamine group achieved a clinically substantial change in depressive symptoms on the PHQ-9 as well -- defined as a drop from baseline of 6 points or more -- at day 15 (64.4% vs 52.8% for the pooled placebo group, P=0.005) and day 28 (77.1% vs 64.7%, P<0.001).

In an analysis of SUSTAIN-1 -- a relapse prevention study of oral antidepressants with either esketamine or placebo in adults who achieved stable remission following esketamine optimization -- Kern Sliwa reported that a numerically higher number of patients on maintenance esketamine achieved remission from treatment-resistant depression, defined as ≤4 on the PHQ-9 (57.3% vs 44.2% in the placebo group, P=0.083).

Researchers also found that significantly more patients from the placebo group had clinical worsening based on total PHQ-9 scores in the maintenance phase than the esketamine group (increase of 6 or more points):

• Week 2: 16.7% vs 3.5%, P=0.004
• End point: 38.4% vs 21.4%, P=0.014

"[In] this post-hoc analysis of TRANSFORM-1, TRANSFORM-2, and SUSTAIN-1, treatment with esketamine nasal spray and an oral antidepressant, versus treatment with an oral antidepressant plus placebo nasal spray, resulted in significant benefit from the patient-rated PHQ-9, a measure of depression severity that is relevant to routine clinical practice," Kern Sliwa said.

Still, scores on MADRS, or even PHQ-9, may not always tell the whole story. As MedPage Today reported at the 2019 American Psychiatric Association annual meeting, three suicides were reported among patients with treatment-resistant depression treated with esketamine during clinical trials -- occurring 4, 12, and 20 days after the patients' last dose -- while none were reported from the respective placebo groups. In two of those three cases, patients' MADRS scores seemed to be improving prior to their deaths. Since its approval, esketamine has continued to stir debate among clinicians and researchers.

TRANSFORM-1 and TRANSFORM-2 included a total of 565 patients, with 343 randomized to oral antidepressants plus esketamine and 222 to oral antidepressants plus placebo. SUSTAIN-1 had 176 participants, with 90 in the antidepressant-esketamine arm and 86 in the antidepressant-placebo arm. Across the studies, a majority of participants were women (64-69%), white (86-90%), and were taking serotonin and norepinephrine reuptake inhibitors (61-69%) as their form of oral antidepressant, as opposed to selective serotonin reuptake inhibitors (31-39%).

That the trials included in these analyses were not designed to specifically address the endpoints in the current post hoc analysis was named as a major limitation to its findings. Additionally, the researchers noted, TRANSFORM-1 and TRANSFORM-2 involved fixed dosing and flexible dosing, respectively, which may have contributed to some skewed data. The self-report nature of the PHQ-9 was also cited as a limitation, due to its inherent variability and dependence on patient recall over time.