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have discouraged pharmaceutical companies from investigating new drugs for mental health indications.

DSM diagnoses like depression are clinical syndromes and their etiology is unclear, which

makes it challenging to develop biological targets to reliably test proof of mechanism for a novel
drug. Hence many drugs for depression fail in development.

To circumvent this, FAST stipulates the use of the NIMH Research Domain Criteria Project (RDoC)

frame, rather than the DSM.
The RDoC framework allows the testing of drugs for discrete behavioral phenotypes associated with
measurable changes in known neurocircuitry.

Several lines of research lead to KOR antagonism as a potential drug target for anhedonia and adjunc-
tive treatment for depression.

Research in animal models showed that KOR antagonism relieves anhedonia and dysfunctional reward
processing by normalizing activity of dopamine neurons in the ventral striatum (a reward center of the

brain).

Separately, investigators observed a rare genetic variant in the dopamine transporter (DAT Val559) in a
small number of patients with disparate conditions such as attention-deficit hyperactivity disorder, bipolar
disorder, and autism spectrum disorder. This variant exhibits abnormal dopamine efflux, leading to

dysregulation of dopamine receptors in the brain and elevated synthesis of dynorphin.

Dynorphin is a KOR agonist and elevated levels, commonly as a result of stress, produce a variety of
discrete symptoms including but not limited to anhedonia, dysregulation of reward processing, and/or

reduction of stress-induced coping. The different behavioral manifestations of this single DAT Val559
variant, like depression, ADHD, or autism, likely result from other genetic risk variants present in a given

individual.

There's so much to learn from this example. These clinically distinct DSM disorders share abnormal
dopamine efflux and symptoms like anhedonia in common. KOR antagonists may improve these symp-
toms irrespective of the diagnosis!

Now we can see how future editions of the DSM may evolve beyond syndromes without a de-

fined biological basis —to discrete transdiagnostic phenotypes with known neurocircuitries like
reward regulation or hedonic drive. This is where I believe we’re heading.

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NORTHERN CALIFORNIA PSYCHIATRIC SOCIETY Page 17 January / February 2023