The GPR139 agonist TAK-041 produces time-dependent alterations to cerebral blood flow and reward system function in patients with schizophrenia: a randomised placebo-controlled trial.

Abstract

The negative and cognitive symptoms of schizophrenia are predictive of quality of life and functional recovery, but there are no approved drug options that target these symptoms directly. TAK-041 (also known as NBI-1065846) is a selective and potent small-molecule agonist of GPR139, an orphan G-protein-coupled receptor, which has been shown to reverse deficits related to negative and cognitive symptoms in animal models. In this proof-of-activity study to evaluate the effects of TAK-041 on motivational anhedonia, 23 adults with schizophrenia experiencing moderate to severe negative symptoms were administered a single 40 mg or 160 mg dose of TAK-041 in a randomised, double-blind, placebo-controlled, two-period crossover design. Functional magnetic resonance imaging (fMRI) assessment of reward function (monetary incentive delay [MID] task) and cerebral blood flow (CBF), as well as cognitive assessment with the Brief Assessment of Cognition in Schizophrenia (BACS) tool, were performed 3 h post dose and after 14 days. There was no significant effect of TAK-041 compared with placebo on BACS score at either timepoint. There was also no significant effect of TAK-041 on MID fMRI at day 1; however, at day 14, TAK-041 produced an increase in reward anticipatory activity in the ventral striatum compared with placebo. There was a significant decrease in CBF throughout the brain at day 1 that then reversed, resulting in a relative increase at day 14, compared with placebo. At day 14 there was a significant interaction between drug and CBF on reward anticipatory BOLD, indicating that drug-related changes to CBF may partially contribute to the observed BOLD effects (although the main effect of drug on the BOLD signal remained significant after including CBF as a covariate in the model). These data indicate that TAK-041 produces detectable changes in both CBF and reward task related fMRI signal in brain regions linked with symptoms and treatment response in schizophrenia. IND Number: 130074| EudraCT Number: 2017-001084-20| Clincaltrails.gov registry: NCT03319953.