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

Reviewer #1 (Public Review):

The modeling approaches are very sophisticated, and clearly demonstrate the selective nature of acute ketamine to reduce the impact of trial losses on subsequent performance, relative to neutral or gain outcomes. The authors then, not unreasonably, suggest that this effect is important in the context of the negative bias in interpreting events that is prominent in depression, in that if ketamine reduces the ability of negative outcomes to alter behavior, this may be a mechanism for its rapid acting antidepressant effects. However, there is a very strong assumption in this regard, as shown by the first sentence of the discussion which implies this is a systematic study of ketamine's acute antidepressant effects. In actuality, this is a study of the acute effects of ketamine on reinforcement learning (RL) modeled parameters. A primary concern here is that an effect presented as a "robust antidepressant-like behavioral effect" should be more enduring than just an alteration during the acute administration. As it is, the link to an "anti-depressant effect" is based solely on the selective effects on losses. This is not to say this is not an interesting observation, worthy of exploration. It is noted that a similar lack of enduring effects on outcome evaluation is observed in humans, as shown in supplemental fig. S4, but there is not accompanying citation for the human work. One question that comes to mind in terms of the selectivity observed is whether similar work has been done to examine the acute effects of any other drugs. If ketamine is unique in this regard, that would be quite interesting.

Reviewer #2 (Public Review):

Oemisch and Seo set out to examine the effects of low-dose ketamine on reinforcement learning, with the idea that alterations in reinforcement learning and/or motivation might inform our understanding of what alterations co-occur with potential antidepressant effects. Macaques performed a reinforced/punished matching pennies task while under effects of saline or ketamine administration and the data were fit to a series of reinforcement learning models to determine which model described behavior under saline most closely and then what parameters of this best-fitting model were altered by ketamine. They found a mixed effect, with two out of three macaques primarily exhibiting an effect of ketamine on processing of losses and one out of three macaques exhibiting an effect of ketamine on processing of losses and perseveration. They found that these effects of ketamine appeared to be dissociable from the nystagmus effects of the ketamine.
The findings are novel and the data suggesting that ketamine is primarily having its effects on processing of losses (under the procedures used) are solid. However, it is unclear whether the connection between processing of losses and the antidepressant effects of ketamine is justified and the current findings may be more useful for those studying reinforcement learning than those studying depression and antidepressant effects. In addition, the co-occurrence of different behavioral procedures with different patterns of ketamine effects, with one macaque tested with different parameters than the other two exhibiting effects of ketamine that were best fit with a different model than the other two macaques, suggests that there may be difficulty in generalizing these findings to reinforcement learning more generally.

1. First, the authors should be more explicit and careful in the connection they are trying to make about the link between loss processing and depression. The authors call their effect a "robust antidepressant-like behavioral effect" but there are no references to support this or discussion of how the altered loss processing would relate directly to the antidepressant effects.
2. It appears that the monkey P was given smaller rewards and punishers than the other two monkeys and this monkey had an effect of ketamine on perseveration that was not observed in the other two monkeys. Is this believed to be due to the different task, or was this animal given a different task because of some behavioral differences that preceded the experiment? The authors should also discuss what these differences may mean for the generality of their findings. For example, might there be some set of parameters where ketamine would only alter perseveration and not processing of losses?
3. The authors should discuss whether the plasma ketamine levels they observed are similar to those seen with rapid antidepressant ketamine or are higher or lower.
4. For Figure 4 or S3, the authors should show the data fitted to model 7, which was the best for one of the animals.