Structure-Guided Drug Design Could Yield Fast-Acting Remedies for Complex Neuropsychiatric Conditions

Focused Pharma program will pursue new drugs that work quickly and deliver lasting remedies for conditions such as chronic depression and post-traumatic stress

Neuropsychiatric Conditions

In the wake of the Iraq and Afghanistan wars, the mental health crisis among U.S. military veterans remains unrelenting, despite the best efforts of healthcare researchers and providers to confront the scale and scope of the problem. According to a 2018 report from the Department of Veterans Affairs, an average of twenty U.S. veterans commit suicide each day.

To address the acute need for improved treatment options, DARPA today announced Focused Pharma, a program that seeks to revolutionize mental healthcare by developing completely new psychotherapeutic drugs to quickly remedy prevalent neuropsychiatric conditions such as post-traumatic stress, depression, anxiety, and substance abuse. While the neurophysiology underlying these conditions may be distinct, an aspect in common is the presence of a deleterious, repetitive thought process that negatively impacts an individual’s ability to function. For someone with post-traumatic stress, it involves re-experiencing trauma and the feelings associated with it; for depression it can take the form of a recurrent internal editor that attaches negative connotations to normal life events; for addiction it is the preoccupation with acquiring and using the substance of choice.

The goal of the Focused Pharma program is to develop novel compounds that directly affect specific neurotransmitter signaling processes that are often implicated in neurophysiological dysfunction, while overcoming limitations of current approaches. The envisioned drugs would selectively target and bind to specific neurotransmitter receptors, and activate only specific neural signaling pathways that may impact the conditions of interest.

“Focused Pharma will work to develop fast-acting drugs that have lasting impact, going beyond treating the symptoms of mental illness to tackle its underlying neurochemical roots,” said Dr. Tristan McClure-Begley, the DARPA program manager.

At present, psychotherapy, psychopharmacology, and direct brain stimulation are the most effective means of treating the symptoms of neuropsychiatric conditions. While valuable, these approaches also have substantial drawbacks that make them less than ideal for treating a challenge on the scale of mental healthcare for the military community. Existing medications exhibit variable effectiveness from one individual to another, can lead to undesirable side effects, can take weeks to months to observe therapeutic benefits even when paired with counseling, and do nothing to prevent relapse once a patient stops taking them. In the case of psychotherapy and direct brain stimulation, finite availability of treatment makes it difficult to meet high demand over wide areas, and direct brain stimulation requires surgery.

In creating Focused Pharma, DARPA examined evidence from privately funded human clinical studies demonstrating that certain Schedule 1 controlled drugs that engage serotonin receptors show promise of rapid and long-lasting therapeutic effect in treating neuropsychiatric conditions such as chronic alcohol dependence, post-traumatic stress, and treatment-resistant depression following only limited doses. However, because such drugs act on many neurotransmitter receptors and receptor subtypes in the brain without specificity and indiscriminately activate numerous signaling pathways, they produce significant side effects, including hallucination. These effects, coupled with their unpredictable consequences, render the drugs unusable in a military healthcare setting.

Researchers supporting the program will have to address a series of challenges, innovating beyond the state of the art in molecular pharmacology and functional chemical neurophysiology. Additionally, they will be responsible for validating the effectiveness of their compounds in animal models that are robust and accepted as preclinical models. DARPA has scheduled a review at the mid-point of the program to validate the hypothesis that the efficacy of these drugs can be de-coupled from side effects, and will terminate the effort if research does not support that hypothesis. Focused Pharma will not include human clinical trials, but at the end of the scheduled four-year program researchers must have an Investigational New Drug application ready for submission to the U.S. Food and Drug Administration.

“Our fundamental hypothesis is that drugs with biased activation of specific signaling pathways downstream of the receptor may be sufficient to induce a therapeutic effect that is uncoupled from deleterious neurological effects. Recent advances in neurotransmitter receptor structure-guided drug design are allowing us to generate the tools we need to test that hypothesis,” McClure-Begley said. “It is research we need to undertake given the scale of the mental health crisis our veterans face, and if it works, the payoff is a completely new, safe, and effective therapeutic option that transforms complex and previously intractable mental conditions into something more acutely treatable.”

DARPA is hosting a Proposers Day on October 1, 2019, in Arlington, Virginia, to provide additional information about Focused Pharma to interested researchers. Please visit https://go.usa.gov/xVRry for details. The registration deadline is September 24, 2019.

The Broad Agency Announcement includes full program details, as well as instructions on how to submit research abstracts and proposals. It is available at https://go.usa.gov/xVPVZ.