Probabilistic Reinforcement Schedules in Neuropsychiatric Medications Development

Abstract

Anhedonia, the loss of pleasure from previously rewarding activities, is a core symptom of several diverse neuropsychiatric conditions, including major depressive disorder, bipolar disorder, post‐traumatic stress disorder, schizophrenia, and substance use disorders. Unfortunately, despite its transdiagnostic prevalence, no effective therapeutics exist to treat anhedonia. This is due, in part, to inconsistent assays across clinical populations and laboratory animals, which hamper treatment development. To bridge this gap, recent work has capitalized on exposing humans, rodents, and nonhuman primates to identical asymmetric probabilistic schedules of reinforcement to objectively quantify their responsivity to reward. In these computerized tasks, subjects make visual discriminations and probabilistic contingencies are arranged such that correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Under these conditions, both healthy humans and laboratory animals consistently develop a response bias in favor of the rich alternative. However, patients with neuropsychiatric disorders often exhibit blunted biases, which correlate with current, and predict future, anhedonia. Likewise, laboratory animals exposed to early‐life adversity or chronic stress have been shown to be less sensitive to asymmetric probabilistic contingencies. In addition, pharmacological challenges with candidate therapeutics known to enhance hedonic tone have produced similar desirable outcomes across species. Taken together, this quantitative framework offers a highly translational approach to assaying reward responsiveness to accelerate treatment development for neuropsychiatric disorders involving anhedonia.