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Based on the identification of anhedonia and dysfunctional reward processing as defined target symp-

toms and dopamine activity in the ventral striatum as the biological target, Krystal and colleagues chose
to do a clinical trial of a KOR antagonist available from Janssen, Aticaprant.

The primary outcome measure was the activation of the ventral striatum as measured by fMRI. The be-

havioral measures include anhedonia and dysregulated reward processing. The trial was a success, and
a phase 3 study of Aticaprant as adjunctive therapy for patients with MDD and moderate to severe anhe-

donia is currently underway.

The FAST studies answered the following questions:

• Does the compound engage a target in the brain?
 Yes, KORs

• Does the compound measurably change a feature of brain function?
 Yes, it normalizes dopamine neurotransmission in the ventral striatum as measurable using
fMRI
• Is there a discrete behavioral phenotype linked to this neuronal circuitry?

 Yes, anhedonia
 Dysfunctional reward processing

Now here comes the grand finale: ketamine vs Aticaprant mechanism of action.

It turns out that ketamine administration causes enduring KOR desensitization lasting for 24 hours or
more. So ketamine is down-regulating KOR activity but in a different way than Aticaprant, which is a

direct KOR antagonist. Still, the downstream effects are the same, normalized dopamine transmission in
the ventral striatum and an increase in hedonic drive.

Additionally, dynorphins are released under stress and KORs resulting in reduced stress-induced coping

in animal models. Ketamine reverses this activity via downregulation of KORs—and this may well be
part of how it leads to enhanced resilience.

Summary and conclusion:

KORs play a role in hedonic drive and reward processing by modulating dopamine release in the brain.
These symptoms are present in several different psychiatric disorders. Antagonism of KORs, as demon-

strated by the novel drug Aticaprant, has been shown to improve anhedonia and reward processing in a
Phase 2 clinical trial. This suggests that targeting KORs may be a promising approach for treating trans-

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NORTHERN CALIFORNIA PSYCHIATRIC SOCIETY Page 18 January / February 2023