IMPACT OF SELTOREXANT ON COGNITIVE PERFORMANCE OF ADULTS WITH MAJOR DEPRESSIVE DISORDER WITH INSOMNIA SYMPTOMS

Background

Many individuals with major depressive disorder (MDD) experience inadequate response to standard therapies and have residual symptoms, such as insomnia, and/or subsequent deficits in cognitive function. Cognitive deficits may contribute to negative short-and long-term functional outcomes in MDD1. Here we evaluated cognitive performance using a novel iPad-administered cognitive test battery in adults with MDD and insomnia symptoms (MDDIS). Data are from a 26-week randomized, double-blind study comparing adjunctive treatment with the selective orexin-2 receptor antagonist, seltorexant, versus quetiapine XR in adults with MDDIS with an inadequate response to current standard antidepressant therapy.

Methods

Participants with MDDIS received either seltorexant (20 mg; n=366) or flexibly dosed quetiapine XR (150/300 mg; n=390) administered adjunctively to their standard antidepressant (SSRI/SNRI) regimen. Cognition was evaluated using the ReVeRe.D cognitive test battery, based on classical neuropsychological tests spanning cognitive domains impacted in MDD2: Symbol Sorting Test (SST), Digit Span Forward Test (DSFT), Digit Span Backward Test (DSBT), Word List Recall Test (WLRT), Visuospatial Block Recall Test (VBRT), Symbol Digit Matching Test (SDMaT), Trail Making Test (TMT-B), and the Block Maze Test (BMT). For each test, a Reliable Change Index (RCI) was derived to distinguish clinical change from measurement error and to determine the percentage of participants exhibiting a meaningful improvement (RCI > 1.96) or meaningful decline (RCI < -1.96) at 26 weeks by treatment group. Nominal p-values were generated post-hoc to assess statistical significance, uncontrolled for multiplicity. P-values were derived from a generalized Cochran-Mantel-Haenszel (CMH) test for general association, adjusting for region, age group, and baseline rumination level.

Results

Participants in the seltorexant group had numerically greater improvements in executive functioning, verbal learning, and processing speed. On the SST number of categories completed (executive functioning), 12.4% of seltorexant participants showed meaningful improvement versus 6.5% for quetiapine XR (p=0.04), while meaningful decline occurred in 2.8% and 4.7% of patients (p=0.37), respectively. For SST perseverative errors, meaningful improvement was exhibited by 7.6% and 4.7% of the seltorexant and quetiapine XR groups (p=0.18), respectively. On the WLRT assessment (verbal learning) meaningful improvement was similar for seltorexant (1.7%) and quetiapine XR (1.4%; p=0.77). Lastly, on the SMDaT (processing speed), clinically meaningful improvement was noted in 21.1% of seltorexant-vs. 14.5% of quetiapine XR-treated participants (p=0.07).

Conclusions

RCI analyses support that the larger numerical gains in executive function observed at Week 26 with seltorexant compared with quetiapine XR were clinically meaningful and statistically significant. Similarly, seltorexant demonstrated clinically meaningful improvements in processing speed, with effects trending toward statistical significance. Meaningful decline was observed less frequently in each treatment group, with numeric differences in executive function favoring seltorexant. These data suggest that long-term improvements noted with seltorexant treatment in patients with MDDIS may have clinical relevance for functional cognitive impairments observed in MDDIS populations.