The selective serotonin reuptake inhibitor sertraline alters learning from aversive reinforcements in patients with depression: evidence from a randomized controlled trial

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for de- pression and anxiety. However, little is known about how pharmacological action is related to cognitive and affective processes. Here, we examine whether reinforcement learning processes mediate the treatment effects of SSRIs. Reinforcement learning provides a promising framework as both serotonin and depression have been linked to specific reinforcement learning processes such as automatic Pavlovian inhibition. The PANDA trial was a multicentre, double-blind, randomized clinical trial in UK primary care comparing the SSRI sertraline with placebo for depression and anxiety. Participants (N=655) performed an affective Go/NoGo reinforcement-learning task three times during the trial and computational models were used to infer reinforcement learning processes. There was poor task performance: only 54% of the task runs were informative, with more informative task runs in the placebo than the active group. There was no evidence for the preregistered hypothesis that Pavlovian inhibition was affected by sertraline. Exploratory analyses revealed that sertraline increased how fast participants learned from losses and faster learning from losses was associated with more severe generalised anxiety symptoms. Furthermore, in the sertraline group, early increases in Pavlovian inhibition were associated with improvements in depression after 12 weeks. In conclusion, sertraline was effective in treating anxiety, yet it increased learning from losses, and the rate of learning from losses was positively related to anxiety. Poor task performance limits the interpretability and likely generalizability of the findings, and highlights the critical importance of developing acceptable and reliable tasks for use in clinical studies. Trial registration: ISRCTN registry ISRCTN84544741 and EudraCT number 2013-003440-22 Funding: NIHR RP-PG-0610-10048