December 21, 2022
Dr. Alison McInnes, MD
Aticaprant is a result of a new initiative at the NIMH called Fast Fail Trials or FAST. FAST was developed to address the failure of current psychiatric treatments to adequately address symptoms and the growing costs and failure rate associated with central nervous system drug development that 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 cicumvent 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.
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 to name a few. The different behavioral manifestations of this single DAT Val559 variant, like depression, ADHD, or autism, likely result from other risk genetic variants present in the individual.
Now we can see how future editions of the DSM may evolve beyond syndromes without a biological basis category—to discrete transdiagnostic phenotypes with known neurocircuitries like reward regulation or hedonic drive. This is where we’re heading.
Based on the identification of anhedonia and dysfunctional reward processing as defined target symptoms 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 is the activation of the ventral striatum as measured by fMRI. The behavioral 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 anhedonia is currently underway.
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 activating KORs resulting in reduced stress-induced coping in animal models. Ketamine reverses this activity via downregulation of KORs—and this may well be how it leads to enhanced resilience.
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 demonstrated 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 transdiagnostic symptoms across a range of psychiatric disorders.
Future editions of the DSM will evolve beyond current categories to focus on discrete behavioral phenotypes based on known neurocircuitry. This should improve the success of drug development efforts to bring better options for patients.
There's also an opportunity here to address stigma. We need to educate the public that behavioral phenotypes are based on known biological causes just like other medical disorders.
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