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Post by Former NIMH Director Thomas Insel: Treatment Development: The Past 50 Years

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Where have treatments for mental disorders come from? Over the past 50 years, innovative treatments of mental disorders have emerged from research in both public (often NIH-funded) and private (pharmaceutical and biotech) sectors. In general, publicly funded research has generated knowledge about the basic biology of mental disorders, leading to the identification of treatment targets that may be explored further by the private sector. For instance, NIMH funding has been essential for identifying the serotonin transporter as a target for the development of antidepressants and dopamine receptors as targets for antipsychotic medications.

While public funding has built the scientific foundation for medication development, most medication research and development (R&D) has been the domain of the private sector. This is true for diabetes and heart disease, as well as mental disorders. Until recently, some of the most critical steps in R&D, such as libraries of compounds, medicinal chemistry, and the transition from “preclinical” (non-human animal and laboratory studies) to “clinical” (human) studies, have been almost uniquely supported by pharmaceutical companies, perhaps with the exception of rare diseases.

In the past decade, NIH has spawned some new programs, such as the Molecular Libraries Program, to allow academic scientists access to some of the tools previously owned only by the pharmaceutical industry. But pharmaceutical R&D is an expensive enterprise that is beyond the budget of most NIH institutes. Most analysts estimate that the cost of developing a single drug is $1-2 billion over a 15- year period. In contrast, the entire annual NIH budget is $31 billion, about half of what the private sector invests in R&D per year.

Nevertheless, within our budget of roughly $1.5 billion, NIMH has supported several small but important programs to develop medications, often at the early stages (see figure below). For instance, the National Cooperative Drug Development Groups are investigating new potential compounds for depression and psychosis. And we have identified and validated new targets for treatment development, such as the cognitive deficits in schizophrenia.

Historically, in addition to discovery science, NIMH has invested heavily in clinical trials. Some of these trials have tested the effectiveness of medications, providing a public sector perspective without the perceived bias of the economic interests of a company that has a patent for the drug being studied. The practical trials of the past decade, such as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), included nearly 10,000 patients with schizophrenia, depression, or bipolar disorder, to compare the effectiveness of current medications.

This is the traditional picture of treatment development: public sector support of scientific discovery, and private sector investment in specific compounds and early phase clinical trials, followed mostly by private and some public funding of clinical trials (see figure). This traditional picture is about to change. NIH has announced plans to create a new institute—the National Center for Advancing Translational Science (NCATS). Pending Congressional approval, NCATS should enable the development of innovative methods and technologies to enhance the development, testing, and implementation of diagnostics and therapeutics important for a wide range of human diseases and conditions, including mental disorders. NCATS would also support studies of the process of R&D, including a collaboration with the Food and Drug Administration to help identify barriers to progress and provide science-based solutions to reduce costs and the time required to develop new drugs and diagnostics. This should help reduce the “bottleneck” that occurs in the treatment development pipeline.

But change is coming from another direction as well, especially for psychiatric medications. Over the past year, several companies, including Astra Zeneca, Glaxo-Smith-Kline, Sanofi Aventis, and recently Novartis, have announced either a reduction or a re-direction of their programs in psychiatric medication R&D. Some of these companies (such as Novartis) are shifting from clinical trials to focus more on the early phases of medication development where they feel they can identify better targets for treating mental disorders. Others are shifting from psychiatry to oncology and immunology, which are viewed by some as lower risk.

There are multiple explanations for these changes. For instance, many of the blockbuster psychiatric medications are now available in inexpensive generic form. In addition, there are few validated new molecular targets (like the dopamine receptor) for mental disorders. Moreover, new compounds have been more likely to fail in psychiatry compared to other areas of medicine. Studying the brain and the mind has proven to be much more difficult than the liver and the heart. Most experts feel the science of mental disorders lags behind other areas of medicine. The absence of biomarkers, the lack of valid diagnostic categories, and our limited understanding of the biology of these illnesses make targeted medication development especially difficult for mental disorders.

Given the industry’s lack of innovation over the past three decades and the history of aggressive marketing of psychiatric medications, some might understandably say, “good riddance.” But by almost any measure we need better treatments, both medications and psychotherapies, for the entire range of mental disorders. It is never a positive sign for those with mental illness when thousands of scientists and millions of dollars are shifted away from research on these disorders.

What can NIMH do about this? Without the large budget and the scientific expertise for medication development, how can NIMH compensate for the pharmaceutical industry’s shift in focus? Is it appropriate for NIMH to invest public dollars in an area that many pharmaceutical companies have deemed too risky for investment? In the next blog, I will suggest that what many are calling a “crisis in medication development” may be an opportunity for NIMH innovation.

NIMH Drug and Device Development Pipeline
NIMH-specific Resource    
Multiple NIH Institutes/Centers
Target ID

Target ID: Identification of molecules that play a role in a disease processes.

Assay Development

Assay Development: Development of an experimentally controlled biochemical or biological system used for the quantitative analysis of test samples.


HTS: High throughput screening - a method in which a large number of assays (1000-1M) are performed and assessed in a relatively short time period, using automated technologies.

Hit to Lead

Hit to Lead: Progression from discovery of a compound whose activity exceeds a predefined threshold, to the identification of a compound within a series with sufficient pharmacological and biological characteristics to progress to a full drug development program.

Lead Optimization

Lead Optimization: Process in which the drug-like properties of an initial lead or lead series are improved and compounds with favorable chemical, pharmacological, and toxicological profiles are identified for progression to the clinic.


Pre-Clinical: Testing of compounds in experimental systems for their biological and toxic effects and potential clinical applications.

Phase I

Phase I: Assessment of drug safety and tolerability. Drugs are tested in a small group of healthy volunteers to determine the drug's activity. Related “first-in-human” studies may also assess target engagement and pharmacological effects.

Phase II

Phase II: Typically double-blinded, placebo-controlled studies designed to continue Phase I safety assessments, to determine how well the drug works in patients, and to identify the optimal dose to be used in Phase III clinical trials.


Provides screening of novel psychoactive compounds for pharmacological and functional activity at cloned human or rodent CNS receptors, channels, and transporters. Assays also available for bioavailability predictions and cardiovascular toxicity predictions.

Synthesizes and distributes novel research chemicals, psychoactive drugs, and compounds including support for radiochemistry, and limited medicinal chemistry and GMP synthesis.


Supports the identification and evaluation of neurophysiological measures as potential assays that bridge between preclinical and first in human studies in treatment development research.


Supports experimental medicine-based first-in-human and proof-of-concept studies of novel mechanism of action investigational drugs or devices to attract private funding for further clinical development as FDA-approved treatments. Also supports testing of novel drugs for use in pediatric populations with psychiatric disorders.


Supports pilot testing of novel interventions for mental disorders in adults and children through an experimental therapeutics approach. Under this FOA, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support “go/no-go” decisions about further development or testing of the intervention.

Supports small businesses/biotechnology companies in the development of high throughput tools for compound screening, target identification, novel technologies for evaluating compounds in clinical trials, and drug discovery/development.

National Cooperative Drug Discovery and Development Groups (NCDDG) ( U19, U01)

Advancing the discovery, preclinical development, and proof of concept testing of new candidate medications to treat mental disorders or drug or alcohol addiction, and to develop novel ligands as tools to further characterize existing or to validate new drug targets.

Supports development of novel, robust analytical platforms, using in vitro assays to measure neurobiological endpoints and build a pipeline to be used in the context of target identification and drug discovery.


Bridging Interventional Development Gaps: provides access to government-funded contract resources for generating data and clinical material that investigators need to file an IND application with the FDA.


Supports development of assays for specific biological targets and disease mechanisms with intent to screen for small molecule compounds that show potential as probes for use in advancing knowledge about the known targets, identifying new targets, or as pre-therapeutic leads.


The program creates a drug development pipeline within the NIH to stimulate research collaborations with academic scientists, non-profit organizations, and pharmaceutical and biotechnology companies working on rare and neglected illnesses.

Drug Discovery for Nervous System Disorders ( R01, R21)

Supports studies aimed at translating basic science findings into the conceptualization, discovery, and preclinical evaluation of innovative therapeutics for nervous system disorders, with the goal of accelerating the development of new treatments.

Discovery of in vivo ( R01) and cell-based ( R21) Chemical Probes

Supports optimization of hits using integrated biological and chemical examination of structure activity relationships to develop novel in vivo chemical probes.

The Network bridges the gap in drug development between academic and industry research, offering researchers a “virtual pharma” to develop promising hit compounds from chemical optimization through Phase I clinical testing.