The National Institute of Mental Health (NIMH) has made a major investment in short, early-stage clinical trials with the hope of jumpstarting psychiatric drug discovery in the next three years.
In late September, NIMH announced that it has awarded contracts, each amounting to $9 million over three years, to three academic institutions to conduct clinical trials in psychotic spectrum disorders, mood and anxiety disorders, and autism spectrum disorders. The three programs are named FAST-PS, FAST-MAS, and FAST-AS, respectively.
The FAST-PS program will be led by Jeffrey Lieberman, M.D., chair of the Department of Psychiatry at Columbia University, director of the New York State Psychiatric Institute and president-elect of APA. The principal investigator of FAST-MAS is Andrew Krystal, M.D., a professor of psychiatry and behavioral sciences at Duke University School of Medicine. The principal investigator of FAST-AS is James McCracken, M.D., a professor of child psychiatry at the NPI-Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles. The principal investigators will coordinate with several research sites around the country to carry out three to five clinical trials in each program.
“These [programs] are contracts rather than grants, so that NIMH is closely involved in how the trials are conducted,” Jill Heemskerk, Ph.D., deputy director of the Division of Adult Translational Research at NIMH, told Psychiatric News.
NIMH has convened a committee of experts, along with the investigators, to choose candidate drugs that will be tested in the clinical trials. The candidate drugs will include a mixture of novel compounds that have not been approved for clinical use and repurposed drugs that have been used for other indications.
One source for the novel compounds is a set of 58 compounds made available through collaboration between pharmaceutical companies and the National Institutes of Health’s newly established National Center for Advancing Translational Sciences. These compounds have already been tested for safety in humans, and their pharmacological properties have been studied in laboratories. The companies still own their patents but are not actively developing them for marketing approval.
NIMH will make public announcements soon to solicit suggestions on selecting promising candidate drugs.
Each FAST program hopes to conduct several phase 1 or phase 2a studies, according to the three investigators who will lead the programs. The study designs will depend on the properties of each selected drug, the scope of the research, and nature of the disease studied.
The studies will take a “fast-fail” experimental approach, seeking early physiological evidence of whether a drug is likely to be effective. Some of these studies will be as short as “one or two doses of the treatment, or at most one to four weeks,” said Lieberman. The sample size in each study will range from a handful of volunteers to dozens.
Although conventional clinical trials tend to last for weeks or months, researchers leading the rapid trials for these programs expect to observe rapid response to a drug in the living human brain by using cutting-edge technologies and biomarkers, thus directly connecting molecular manipulations in the brain to observed changes in brain activities in particular regions and to clinical symptoms.
“We plan to use PET scan, functional MRI [fMRI], magnetic resonance spectroscopy, and radioactive ligands, which will show [molecular] binding to target sites,” said Lieberman. For example, the FAST-PS program will study the effects of some drugs on cognitive impairment by observing changes in blood flood to the prefrontal cortex. Also, the antipsychotic effects of certain drugs may be reflected in brain scans as reduced glutamate binding, as glutamate is a neurotransmitter implicated in psychotic symptoms.
In the FAST-MAS program, Krystal and colleagues plan to use EEG and fMRI to study changes in the brain’s capacity to inhibit or regulate emotional responses such as fear and negative mood. They believe that this neurological pathway is a key aspect in both mood and anxiety disorders.
Autism spectrum disorders could be more difficult to study than psychotic or mood disorders, McCracken acknowledged, as the biomarkers and neurocircuits are less defined. The FAST-AS program will focus on the neurological effects of drugs acting on the GABA system using tools such as magnetic resonance spectroscopy. Correlations between autism symptoms and the brain’s reward system in the ventral striatum also will be studied.
In all three areas, the studies will help validate or establish biomarkers to help scientists “look inside the brain” and quantitatively measure neuropsychiatric dysfunctions.
Given the high rate of failures in psychotropic drug development, it is possible that none of the candidate drugs will “make it” into an effective new treatment for any of the disorders studied, Heemskerk acknowledged. However, even failures will generate valuable knowledge to advance research. If a drug fails, the results from brain scans and biomarker measurements will provide some direct explanation for why it fails, and the same goes for success. From this knowledge, researchers will have a clear idea about how to proceed.
In addition, the investigators noted that the studies will apply NIMH’s research domain criteria (RDoc) to focus on specific functional impairments that may cross-cut psychiatric diagnosis but share common neurocircuitry or genetic bases.
Beyond looking for promising new drugs, the FAST programs could “help the field improve methodology . . . and establish new ways to evaluate treatment in general,” said Krsytal. For the FAST-MAS studies, his team has proposed using adaptive design, which allows researchers to determine whether to continue with a study or terminate early in the middle of a trial.
“This is a unique investment by NIMH in the high-risk, high-reward type of research…and exploring the edge of our knowledge,” McCracken commented.
“We will generate examples of how these clinical trials should be conducted to guide future NIMH-funded trials,” said Heemskerk. The initiative can potentially establish a faster and more efficient drug discovery model that will benefit psychiatric research for years to come. ■