Single doses of a highly selective inhibitor of phosphodiesterase 1 (lenrispodun) in healthy volunteers: a randomized pharmaco-fMRI clinical trial.
Document Type
Article
Publication Date
9-2022
Identifier
DOI: 10.1038/s41386-022-01331-3
Abstract
Lenrispodun is a potent and highly selective inhibitor of phosphodiesterase (PDE) type 1, which is thought to prolong intracellular second messenger signaling within cortical and subcortical dopaminergic brain regions. This is the first study of a PDE1 inhibitor in healthy volunteers using behavioral and neuroimaging approaches to examine its effects on neural targets and to provide a safety and tolerability assessment. The primary objectives were to determine whether lenrispodun induces changes in BOLD fMRI signals in the inferior frontal gyrus (IFG) during the stop signal task, and the dorsal anterior insula (dAI) during the extinction phase of a fear conditioning/extinction task. Using a double-blind, placebo-controlled, within-subjects design, 26 healthy individuals (22 completed all fMRI sessions) received in random order a single oral dose of placebo, lenrispodun 1.0 milligram (mg) or lenrispodun 10.0 mg and completed several tasks in the scanner including the stop signal (n = 24) and fear conditioning/extinction tasks (n = 22). Prespecified region-of-interest analyses for the IFG and dAI were computed using linear mixed models. Lenrispodun induced increases in IFG activity during the stop signal task at 1.0 mg (Cohen's d = 0.63) but not 10.0 mg (Cohen's d = 0.07) vs. placebo. Lenrispodun did not induce changes in dAI activity during fear extinction at either dose. Exploratory outcomes revealed changes in cardiac interoception. Lenrispodun administration was well-tolerated. These results provide evidence that 1.0 mg lenrispodun selectively improved neural inhibitory control without altering fear extinction processing. Future investigations should determine whether lenrispodun improves inhibitory control in target populations such as individuals with attention deficit hyperactivity disorder. Trial registration: ClinicalTrials.gov identifier: NCT03489772.
Journal Title
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Volume
47
Issue
10
First Page
1844
Last Page
1853
MeSH Keywords
Brain; Double-Blind Method; Extinction, Psychological; Fear; Humans; Magnetic Resonance Imaging; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases
Keywords
Brain; Double-Blind Method; Extinction, Psychological; Fear; Humans; Magnetic Resonance Imaging; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases
Recommended Citation
Khalsa SS, Victor TA, Kuplicki R, et al. Single doses of a highly selective inhibitor of phosphodiesterase 1 (lenrispodun) in healthy volunteers: a randomized pharmaco-fMRI clinical trial. Neuropsychopharmacology. 2022;47(10):1844-1853. doi:10.1038/s41386-022-01331-3
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