NIMH Shifts Focus to Molecular Origins of Mental Illness

NIMH Shifts Focus to Molecular Origins of Mental Illness

To accelerate the development of personalized and preemptive treatments for those living with mental illness, the NIMH is shifting away from current-generation treatments and toward preclinical drug development and early-phase clinical pharmacology, according to the institute’s director and a workgroup co-chair.

In a recent blog, Thomas Insel, MD, NIMH director, explained: “For existing treatments, we want to shift from trials studying group differences or adapting these treatments to yet another sub-population to support trials that identify reliable predictors (eg, biomarkers) of individual response, including who may benefit from and who may experience adverse effects of a particular treatment. We are also searching for preemptive treatments—interventions that can be used early in the course of a disorder to prevent disability.”

As the NIMH changes direction, Insel has relied on guidance from the National Mental Health Advisory Council’s Interventions Workgroup, made up of 20 experts from academia, private industry, nonprofit foundations and the NIH. It is co-chaired by David Lewis, MD, medical director and director of research at the Western Psychiatric Institute and Clinic, Pittsburgh, and John March, MD, MPH, director of the Division of Neurosciences Medicine at Duke Clinical Research Institute, Durham, NC.

Recently, the workgroup published a report, From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illness.1 March describes it as a “policy infrastructure document” that builds on an earlier council report on transformative neurodevelopmental research in mental illness.2

In the new report, the workgroup makes several observations—that mental illnesses are brain disorders and that virtually all of them are developmental disorders; that nearly all drugs approved for mental illness have been incremental changes of compounds available 4 decades ago; that the NIMH’s practical trials, such as Clinical Antipsychotic Trials of Interventions Effectiveness (CATIE), have documented the limited effectiveness of current medications; that the NIMH receives relatively few applications proposing to translate basic findings into the development of novel interventions; and that several major pharmaceutical companies have announced plans to “deprioritize” psychiatric drug development.

The NIMH’s challenge, says Insel, is to develop “far more effective strategies for prevention and treatment in a rational way and to do so with a limited budget.”

Financial constraints are a major barrier, according to the workgroup’s report. The cost of bringing 1 neuroscience-specific drug to market has been estimated at $1.8 billion—nearly the entire yearly extramural NIMH budget. So the focus is on how to best use and leverage the funds the NIMH does have.

Target identification

The NIMH spends the majority of its resources on discovery and translational neuroscience, but most of this work has yet to produce new novel druggable targets. According to March, however, epigenetic changes, brain circuit activation, intracellular signaling pathways modifications, structural brain changes, neuroplasticity, changes in RNA expression, and proteomic and metabolomic markers all hold great promise for understanding early disease processes and, by extension, may reveal novel treatment targets.

For that reason, the report recommends that more money be spent both on the preclinical side and on the early-phase clinical pharmacology side. The hope is that this investment in translational neuroscience can be moved rapidly into interventions that are better for patients, said March, a professor of psychiatry and behavioral sciences at Duke.

The NIH has already established a full continuum infrastructure for drug development, according to March. It includes target identification, assays, large-scale screening capacity, medicinal chemistry, animal testing, genetic toxicology, and reproductive toxicology. In addition, phase 1 unit capabilities for pharmacokinetic and pharmacodynamic studies are available through the NIH Rapid Access to Interventional Development (NIH-RAID) Program mechanism.

Through its report, the workgroup sought to highlight such NIH resources for researchers as the Molecular Libraries Probe Production Centers Network (MLPCN) and the National Cooperative Drug Discovery and Development Group (NCDDDG) Program. The workgroup also called for increased sharing of resources and data.

“NIMH could leverage its investment in clinical trials by requiring standard collection of clinical, cognitive and laboratory data that can be integrated across diagnostic groups, across sites and across trials,” the workgroup said.

According to March, “NIH is moving as fast as possible toward a model, already in place in physics, in which everything is shared as it happens, including raw data. So for NIH-funded research, the goal will be to have all of the data up on the Web in these large shared databases.”

As an example, March cited the National Database for Autism Research (NDAR), a biomedical informatics system and research data repository developed by the NIH to support and accelerate the advancement of research on autism spectrum disorders (ASD). Recently, NDAR made available the data from more than 10,000 participants enrolled in ASD studies. The NDAR research portal provides tools to define and standardize data as well as to ensure a collaborative approach and open data access to the whole ASD research community.

Pharma’s involvement

Asked about the report’s warnings of decreasing industry investments in psychiatric drug discovery and development, March said, “It is not a universal phenomenon, but in general, large pharma has backed away from psychiatry until the probability of success goes up—new mechanisms, new targets, new compounds, biologics that have real promise—then companies will come back in.”

So who is doing that work? March responded that it is small pharma and biotech companies, often spin-offs of academic laboratories frequently funded by disease-specific foundations, venture capital, venture philanthropy, and government grants.

“It is not as though industry is not involved; it is just restructuring where the effort lies. . . . Like the NIMH, industry is increasingly focused on phase 1 and 2 trials that should identify the next generation of compounds that are going to change lives of mentally ill patients,” he said.

March said that industry is being forced by revenue declines from patent expirations, increased regulatory scrutiny, and strained health care budgets to devise new strategies for improving research and development productivity. Those strategies have been outlined in an article by psychiatrist Steven Paul, MD, former president of the Lilly Research Laboratories, who now leads the Helen & Robert Appel Institute for Alzheimer’s Research at Weill Cornell Medical College, New York.3

And despite rhetoric in the press suggesting that industry-academic collaborations by definition are unethical, March said there is clear movement toward what some have called the “new biotech,” a conjunction of academia, industry, and the NIH, dedicated to bringing forth novel drugs or devices to help patients. At Duke, for example, March said his institute is collaborating with industry on phase 1 and 2 trials of innovative treatments for both neurological and psychiatric diseases.

Bright spots

While the challenges ahead are many, March and the workgroup cited some bright spots. Trials are under way with metabotropic glutamate receptor 5 antagonists, which hold promise for those with fragile X syndrome who have intellectual deficits. Also, a new focus on glutamate receptors as a target for antidepressant action has yielded early evidence for rapidly acting antidepressants with effects evident in hours rather than weeks. The NIMH will shortly issue a request for proposals entitled “Rapidly Acting Treatments for Treatment-Resistant Depression (RAPID)” with a response date of January 12, 2011.

In the area of nonpharmacological treatments, studies of cognitive remediation promise a new approach to the prodrome of schizophrenia based on principles of neuroplasticity.

March describes the NIMH’s new direction as “incredibly exciting.”

“I have reached a point in my life where I realize that science is like an organism made up of ideas, and those ideas morph and change,” he said. “Those of us who do research are custodians of the organism; we get to feed it, pet it, take care of it, and watch it grow and develop. These Council workgroup reports are part of the care and feeding of the organism that we call the science of mental illness. The workgroup report on transformative developmental neuroscience points the field toward the molecular origins of mental illness in early development; From Discovery to Cure pivots the field toward early-phase clinical pharmacology. Put the 2 together, and it becomes possible for the first time to envision preemptive treatments, a world without mental illness. How wonderful is that?”



1. From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses. Report of the National Advisory Mental Health Council’s Workgroup. August 2010. Accessed December 2, 2010.
2. Transformative Neurodevelopmental Research in Mental Illness: Report of the National Advisory Mental Health Council’s Workgroup. 2008. Accessed December 2, 2010.
3. Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9:203-214.

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