Summary ACNP 2022 highlight: The Role of KORs in Mediating Stress-Related Deficits in Reward Processing: MOA of Ketamine and Aticaprant | Osmind www.osmind.org
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Dr. McInnes discussed the role of KORs in mediating stress-related deficits in reward processing and the potential for KOR antagonists like Aticaprant to treat anhedonia, as well as the possibility of the future DSM evolving beyond current categories to focus on discrete behavioral phenotypes.
Key Points
- Kappa Opioid Receptors (KORs) play a role in hedonic drive and reward processing, and can be modulated by drugs like Aticaprant and ketamine.
- The Fast Fail Trials (FAST) measure the activation of the ventral striatum as measured by fMRI, along with anhedonia and dysregulated reward processing as behavioral measures.
- Aticaprant is a KOR antagonist and may improve symptoms of dopamine dysregulation, such as anhedonia, stress-induced failure to cope, and attention deficits, irrespective of the diagnosis.
- A rare variant in the dopamine transporter (DAT Val559) was found in a small number of patients with diverse conditions, leading to abnormal dopamine efflux.
- Future editions of the DSM may evolve beyond syndromes without a biological basis to discrete transdiagnostic phenotypes with known neurocircuitries like reward regulation or hedonic drive.
- Mental health is a serious issue, and those in crisis should call 911 or the National Suicide Prevention Lifeline at 1-800-273-8255.
Summaries
182 word summary
At the American College of Neuropsychopharmacology (ACNP) meeting, Dr. Alison McInnes presented on the role of Kappa Opioid Receptors (KORs) in mediating stress-related deficits in reward processing. With the National Institute of Mental Health’s (NIMH) Fast Fail Trials (FAST) framework, Aticaprant, a KOR antagonist, was developed to treat anhedonia. KOR antagonists like Aticaprant may improve symptoms of dopamine dysregulation, such as anhedonia and attention deficits, irrespective of the diagnosis. Dynorphin, a KOR agonist, is often elevated due to stress and produces various symptoms. Animal models have shown that KOR antagonism normalizes dopamine neurons in the ventral striatum and relieves anhedonia and dysfunctional reward processing. Ketamine reverses KOR activity via downregulation, leading to enhanced resilience. A phase 3 study of Aticaprant as adjunctive therapy for patients with major depressive disorder (MDD) and moderate to severe anhedonia is currently underway. There is an opportunity to address mental health stigma by educating the public that behavioral phenotypes have biological causes, just like other medical disorders. The future DSM is expected to evolve beyond current categories and focus on discrete behavioral phenotypes based on known neurocircuitry.
438 word summary
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Mental health is a serious issue, and those in crisis should call 911 or the National Suicide Prevention Lifeline at 1-800-273-8255.
There is an opportunity to address mental health stigma by educating the public that behavioral phenotypes have biological causes, just like other medical disorders. The future DSM is expected to evolve beyond current categories and focus on discrete behavioral phenotypes based on known neurocircuitry.
KORs play a role in hedonic drive and reward processing by modulating dopamine release in the brain, and symptoms are present in several different psychiatric disorders. Antagonism of KORs has been demonstrated by the novel drug Aticaprant, which improves anhedonia and reward processing in clinical trials. Additionally, ketamine reverses KOR activity via downregulation, leading to enhanced resilience.
The FAST studies measure the activation of the ventral striatum as measured by fMRI, along with anhedonia and dysregulated reward processing as behavioral measures. A phase 3 study of Aticaprant as adjunctive therapy for patients with MDD and moderate to severe anhedonia is currently underway.
Overall, this research points toward the possibility of future editions of the DSM evolving beyond syndromes without a biological basis to discrete transdiagnostic phenotypes with known neurocircuitries like reward regulation or hedonic drive. KOR antagonists, such as Aticaprant, may improve symptoms of dopamine dysregulation, such as anhedonia, stress-induced failure to cope, and attention deficits, irrespective of the diagnosis. Dynorphin, a KOR agonist, is often elevated due to stress and produces various symptoms. A rare variant in the dopamine transporter (DAT Val559) was found in a small number of patients with diverse conditions, leading to abnormal dopamine efflux. Research in animal models showed that KOR antagonism normalizes dopamine neurons in the ventral striatum and relieves anhedonia and dysfunctional reward processing.
As DSM diagnoses are clinical syndromes with unclear etiology, the NIMH developed Fast Fail Trials (FAST) to use the RDoC framework to test drugs for discrete behavioral phenotypes associated with known neurocircuitry. Aticaprant is a result of FAST and is part of ketamine’s mechanism of action for depression. KOR antagonism is an exciting takeaway from ACNP 2022. I recently attended the American College of Neuropsychopharmacology (ACNP) meeting, where I was excited to learn about the promising new research on Anticaprant, a kappa opioid receptor antagonist, for treating anhedonia. This research is a major step forward in modernizing the DSM to focus on symptoms rather than syndromes.
At ACNP 2022, Dr. Alison McInnes, MD presented on the role of KORs (Kappa Opioid Receptors) in mediating stress-related deficits in reward processing, and the mechanism of action of ketamine and Aticaprant.