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

Ketamine, a rapid-acting antidepressant, reduces how aversive negative outcomes feel without changing how gains are evaluated, motivation, or other learning processes. In rhesus macaques making token-based decisions, ketamine lowered the impact of losses when given intramuscularly or intranasally. This effect was separate from side effects like fixation errors, which could be countered by strong motivation. The acute reduction in negative event impact may lead to longer-term antidepressant effects by preventing the cumulative buildup of negative memories. The findings suggest that disrupting affective memory could pose challenges in treating depression and invite further study across different 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.