Therapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-making

Ketamine reduces the unpleasantness of negative outcomes without changing how gains are evaluated, according to a computational analysis of rhesus macaques making token-based decisions. The drug's effect on aversion was separable from side effects like fixation errors, which could be overcome with strong motivation to avoid mistakes. The authors propose that ketamine's acute dampening of negative events' impact might produce longer-term antidepressant effects by reducing the cumulative burden of slowly decaying memories of those events. They note that disruption-resistant affective memory could pose challenges in treating depression and call for further research on ketamine's action across diverse mood states and time scales.

Study at a glance

Abstract

The discovery of rapid-acting antidepressant, ketamine has opened a pathway to a new generation of treatments for depression, and inspired neuroscientific investigation based on a new perspective that non-adaptive changes in the intrinsic excitatory and inhibitory circuitry might underlie the pathophysiology of depression. Nevertheless, it still remains largely unknown how the hypothesized molecular and synaptic levels of changes in the circuitry might mediate behavioral and neuropsychological changes underlying depression, and how ketamine might restore adaptive behavior. Here, we used computational models to analyze behavioral changes induced by therapeutic doses of ketamine, while rhesus macaques were iteratively making decisions based on gains and losses of tokens. When administered intramuscularly or intranasally, ketamine reduced the aversiveness of undesirable outcomes such as losses of tokens without significantly affecting the evaluation of gains, behavioral perseveration, motivation and other cognitive aspects of learning such as temporal credit assignment and time scales of choice and outcome memory. Ketamine’s potentially-antidepressant effect was separable from other side effects such as fixation errors, which unlike outcome evaluation, was readily countered with strong motivation to avoid errors. We discuss how the acute effect of ketamine to reduce the initial impact of negative events could potentially mediate longer-term antidepressant effects through mitigating the cumulative effect of those events produced by slowly decaying memory, and how the disruption-resistant affective memory might pose challenges in treating depression. Our study also invites future investigations on ketamine’s antidepressant action over diverse mood states and with affective events exerting their impacts at diverse time scales.