Aticaprant shows symptom improvement as adjunctive treatment in MDD

Key takeaways:

• The study included 166 adults with major depressive disorder randomized to receive aticaprant or placebo.
• At 6 weeks, there was a greater difference in MADRS score in the group that received aticaprant.

MIAMI BEACH, Fla. — Adjunctive treatment with aticaprant for those with major depressive disorder and history of antidepressant failure resulted in greater symptom improvement compared with placebo after 6 weeks, a presenter said.

“Why test aticaprant in major depressive disorder? The opiate system in general is designed for measurement of pain,” Mark E. Schmidt, MD, senior director in experimental medicine at Janssen Pharmaceuticals, said in his presentation at the American Society of Clinical Psychopharmacology annual meeting. “It’s an important component of the stress-response system.”

Schmidt and fellow researchers sought to examine the therapeutic benefit of aticaprant — a small molecule, high-affinity, selective kappa opioid receptor antagonist — as an adjunctive therapy for those with depression.

They conducted a multicenter, double-blind, placebo-controlled, randomized study of 184 individuals aged 18 to 64 years with major depressive disorder. The participants had an inadequate response to their current antidepressants (taken for at least 6 weeks but no more than 12 months prior to study entry)  as measured by a Montgomery Åsberg Depression Rating Scale (MADRS) score of greater than or equal to 25 and anhedonia as defined by a Snaith-Hamilton Pleasure Scale (SHAPS) score of 20 or higher.

 Participants underwent a 5-week screening phase followed by an 11-week treatment phase, the latter consisting of a placebo lead-in period of up to 3 weeks, a 6-week treatment period. Patients who completed treatment underwent a withdrawal period in which they received only placebo for the remaining time.

All were randomized 1:1 to receive either once daily 10 mg aticaprant or to continue placebo during the treatment period while keeping up their SSRI/SNRI, without change, throughout the study interval.

A total of 169 participants were included in the safety analyses and 166 were included in the full intent to treat (fITT) analyses.

Improvement in MADRS total score at week 6 for aticaprant was significant compared with placebo in the fITT analysis set (-3.1 [1.05] with one-sided 80% CI upper limit of -2.21).

Among patients with high anhedonia at treatment baseline (defined by SHAPS 38), the researchers found larger differences between aticaprant and placebo at week 6 (effect size: 0.51 fITT) than in those with low anhedonia level (treatment baseline SHAPS 20 and <38) (effect size: 0.29 fITT).

Data showed treatment was well-tolerated overall, with few patients in either treatment group recording adverse events that led to discontinuation. The most common adverse events reported for aticaprant and placebo were headache (11.8% vs. 7.1%, respectively), diarrhea (8.2% vs. 2.4%), pruritus (5.9% vs. 0%), and nasopharyngitis (5.9% vs. 2.4%). One serious adverse event (acute cholecystitis in the placebo group) and no deaths were reported.

“Adjunct aticaprant treatment in participants with major depressive disorder and incomplete response to standard care resulted in significantly greater reduction in MADRS compared to placebo,” Schmidt noted. “The safety profile of aticaprant is favorable, supporting further investigation in larger trials.”

Editor's Note: This article was updated on June 21, 2023 to better clarify study participants' response to antidepressants. Healio regrets the error.