NIMH Workgroup Lays Groundwork for Next Generation of Treatments

"Today's treatments [for mental illness] are not good enough. Based on results in other areas of medicine, we should be able to do better," concluded Thomas Insel, M.D., director of the National Institute of Mental Health (NIMH) in a recent blog. In 2009 he charged a workgroup to recommend steps for developing the next generation of treatments, taking advantage of scientific breakthroughs and new tools in order to maximize the public health impact of research investments. In its recent report, From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illness, the workgroup emphasizes the importance of personalization and preemption as the foundations for new treatments.

Personalized treatment is based on knowledge of an individual's genetic, physiologic, or behavioral characteristics that is precise enough to predict his or her response and guide treatment matching. A preemptive treatment arrests a disease process before it occurs or sufficiently early in its course to prevent devastating effects. Yet among the thousands of applications that NIMH receives each year, the report notes, very few propose development of personalized or preemptive treatments. The pathway to the discovery of such treatments, which are already used in oncology and cardiology, is not as clearly marked in psychiatry. Psychiatric genetics has not yielded a single validated target for any mental disorder, the report notes, and virtually all drugs approved for mental disorders have been incrementally changed versions—"me too" drugs—of compounds that have been available for the past 40 years. Preemption requires a basic understanding of a disease process, but the causes of mental disorders and their mechanisms are unknown. In addition, mental disorders are increasingly considered developmental brain disorders. By the time a diagnosis is made, causal factors may no longer be evident. In psychiatry, unlike oncology, diseased tissue cannot be removed for analysis and treatment development.

Because of these and other challenges, the report conveys a sense of urgency about the need for NIMH to deepen its involvement in new treatments. Recent announcements of decreasing industry investment in psychiatric drug development raise questions about who will provide support and momentum. The estimated cost of bringing a drug to market—$1 billion—represents nearly the entire annual NIMH extramural budget, the report notes. Thus the workgroup also considered where along the development pipeline NIMH can best catalyze efforts and how to optimize current treatments, develop productive partnerships, and use existing resources most effectively.

One resource that is currently underused by mental health researchers is the Molecular Libraries Probe Production Centers Network (MLPCN) ( mli.nih.gov/mli ), which is funded by the National Institutes of Health (NIH) Roadmap. After researchers pinpoint a specific target as relevant to a biological process or disease state, the next step is to identify small molecules that are able to modulate the target. Screening molecular libraries for such molecules has traditionally been the exclusive domain of industry. The MLPCN offers scientists in academia access to large-scale screening capacity, a large diverse chemical library, and the medicinal chemistry and informatics necessary to identify chemical probes to study the functions of genes, cells, and biochemical pathways. The program includes a network of centers—the NIH Chemical Genomics Center, an intramural component, and several extramural centers. Although researchers taking advantage of the program over the past five years have successfully identified more than 120 probes using 300,000 compounds, fewer than 10% are relevant to mental disorders.

Although drug development is the report's primary focus, the workgroup also addressed opportunities for designing new nonpharmacological treatments. Personalized treatments have been central to behavior therapy, the report notes. New findings from research on behavior, cognition, emotion, psychophysiology, and human development can be brought to bear on testing underlying mechanisms of pathology. As an example the report describes how recent insight into neuroplasticity along with findings from research on cognitive remediation have contributed to a new intervention for the prodrome of schizophrenia: intensive neuroplasticity-based computerized cognitive training exercises for ultra-high-risk adolescents and those with recent-onset schizophrenia.

The report emphasizes the importance of enhanced sharing of data, in particular the rich and underused data collected in NIH-funded and industry research. A sidebar describes "the exciting effort in data sharing" represented by the National Database for Autism Research ( ndar.nih.gov/ndarpublicweb ), a secure bioinformatics platform being developed by several NIH institutes, which later this year will make available data from more than 10,000 participants in autism research studies. The report also recommends that NIMH focus on partnership efforts, such as those undertaken by the Foundation for the National Institutes of Health ( www.fnih.org ), which works with government, academia, industry, and not-for-profit groups to share data and collaborate on projects.

In the final seven pages of the 30-page report, the workgroup lists current barriers to meeting four goals: develop novel interventions that prevent and cure mental illnesses, optimize current treatments and NIMH's treatment research, use existing resources effectively, and create partnerships. Tactical recommendations for overcoming each barrier are presented. For example, to address the scarcity of applications for funding to test personalized treatments, the workgroup encourages NIMH to support research on identification of baseline and early-response biomarkers and biosignatures, to identify a standard set of data or specimens (such as genetic, hormonal, or neurochemical) to be collected in appropriate clinical trials, to use adaptive trial designs that facilitate iterative evaluation of treatment effects and that incorporate identified biomarkers and known risk factors to predict treatment response, and to ensure that researchers account for patient preferences.

The workgroup was created by the National Advisory Mental Health Council. Its members represent NIH, academic institutions, small and large private industry, and nonprofit foundations; their areas of expertise span molecular biology to services research. From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illness is available on the NIMH Web site at www.nimh.nih.gov/about/advisory-boards-and-groups/namhc/reports/fromdiscoverytocure.pdf .