A novel, experimental design to assess rapid antidepressant action: Results from a phase 1b randomized trial of NV-5138

BACKGROUND: Assessment of rapid-acting antidepressants (RAADs) requires rating scales sensitive to symptomatic changes over short time frames (hours to days). An innovative trial design was employed in an exploratory, first-in-human, phase 1b trial assessing rapid-acting effects of NV-5138 (mefluleucine), an intracellular enhancer of mechanistic target of rapamycin 1 synaptic signaling, for treatment-resistant depression. METHODS: ) assessments (5 assessments within 24 h following dosing). RESULTS: response criteria (50 % score reduction; P = .04). At 24 h, the MADRS favored NV-5138 but was not statistically different from placebo. NV-5138 was well tolerated, with no psychotomimetic, severe, or serious adverse events reported. CONCLUSIONS: The innovative design of this exploratory study facilitated appropriate participant selection and rapid antidepressant response detection. These features may be useful in other trials evaluating RAADs (ClinicalTrials.gov, NCT03606395).