Perseverative behavior under uncertainty is enhanced by tryptophan depletion but diminished with subclinical obsessive–compulsive symptoms

Serotonin is critically involved in flexible decision-making, yet the preponderance of evidence comes from non-human studies. Many insights about the serotonin’s function have come from the technique of dietary acute tryptophan depletion (ATD). However, it is unclear whether ATD modulates choice behavior during probabilistic reversal learning (PRL), a widely used model of behavioral flexibility with significant translational and clinical value. To determine whether ATD affects latent choice tendencies, we applied computational models of reinforcement learning to PRL data from healthy human volunteers (n = 62; 29 females) who had received either ATD or placebo in a randomized, double-blind, placebo-controlled procedure. A secondary objective was to ascertain how model parameters related to clinically relevant self-report questionnaires. ATD did not affect the updating (“learning rates”) or deployment (“reinforcement sensitivity”) of value representations driving choice. However, ATD increased “stimulus stickiness”, the tendency to choose a previously chosen visual stimulus again, regardless of reinforcement—a pattern seen in stimulant use disorder (SUD). Greater subclinical obsessive–compulsive symptoms were associated with lower stimulus stickiness, a pattern seen in clinically diagnosed obsessive–compulsive disorder (OCD). Low reinforcement sensitivity was instead related to intolerance of uncertainty and symptoms of depression and anxiety. Individuals with higher trait impulsivity showed lower reward and higher punishment learning rates, which parallels findings in SUD. Collectively, these results point to a role for serotonin in compulsive tendencies. They underscore the utility of computational modelling in illuminating the microstructure of behavior, which could point towards new markers of vulnerability to psychopathology. ### Competing Interest Statement T.W.R. discloses consultancy with Cambridge Cognition, Arcadia, Greenfield Bioventures, Heptares, Shionogi and Takeda. Royalties with Cambridge Cognition. Research grants with Shionogi and GlaxoSmithKline and editorial honoraria with Elsevier and Springer-Nature. R.N.C. consults for Campden Instruments and receives royalties from Cambridge Enterprise, Routledge, and Cambridge University Press. B.J.S discloses consultancy with Cambridge Cognition and Greenfield BioVentures, and receives royalties for CANTAB from Cambridge Cognition. All other authors declare no conflicts of interest. J.W.K. was supported by a Gates Cambridge Scholarship and an Angharad Dodds John Bursary in Mental Health and Neuropsychiatry, and T.W.R. by a Wellcome Trust Senior Investigator Grant 104631/Z/14/Z. R.N.C.'s research is funded by the UK Medical Research Council (MC\_PC\_17213). Q.L. was supported by the National Key Research and Development Program of China (grant 2018YFC0910503), the National Natural Science Foundation of China (grant 81873909), the Natural Science Foundation of Shanghai (grant 20ZR1404900), the Shanghai Municipal Science and Technology Major Project (grant 2018SHZDZX01), and the Zhangjiang Lab. B.J.S. receives funding from the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (Mental Health Theme); the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.