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Director’s Blog: Who Will Develop the Next Generation of Medications for Mental Illness?

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In 2007 NIMH completed a series of practical trials to assess the effectiveness of currently available medications.  With the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial for schizophrenia, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, roughly 10,000 patients were studied at nearly 200 sites.  None of these studies was perfect, but in aggregate they told us what we might have surmised from several worrisome public health indicators: the medications we have today, even when optimized within a research study, help some people get better, but too few  completely recover.  It is undeniable that we can improve outcomes for people with mental illness if we provide comprehensive evidence-based care.   But, if we are honest with ourselves and our patients, we need to admit that today’s treatments, both medications and psychosocial interventions, may be good but they are not good enough. 

Clearly, developing a new generation of medications of truly novel compounds with far greater efficacy and greater effectiveness will require a new, rational basis for therapeutic development based on understanding mechanisms responsible for disease, identifying targets through which these mechanisms can be altered, and building the pipeline to create innovative medications. The good news is that research elucidating the neurobiological bases of disorders is revealing new targets for drug development for depression, schizophrenia, bipolar disorder, anxiety, and autism. 

A commentary this week in Science, co-authored by three Nobel laureates and several other distinguished scientists, trumpets the opportunities to revolutionize our approach to mental disorders.(1)  The pathway from understanding disease mechanisms, to identifying targets, to developing novel medications has been worked out in cancer and immunology and can be applied to psychiatric drugs to develop agents that are not simply “me too” drugs, but innovative, effective medications.

Who will develop this new generation of medications for people with mental illness?  Traditionally drug development has been mostly the role of industry.  The model has been that NIH supports  early phase target identification in academic labs, with the subsequent stages including early phase trials conducted  by scientists in biotech or pharmaceutical companies, followed by later phase clinical trials either in pharmaceutical or NIH-supported academic studies leading to FDA approval.

This figure portrays the different phases of drug development from “Target Availability” to “High Throughput Screen” to “Probe to Lead Compound” to “Preclinical Optimization” to “Phase I, II and III Trials” in terms of Industry vs. NIH contributions for three select years, 2005, 2010 and 2015.  In 2005, NIH’s involvement was primarily at the beginning phase of “Target Availability” and at the very final stage of “Phase I, II and III Trials.”  In 2010, NIH’s role is expanded to include more of the beginning phases of “Target Availability” and preliminary work in “High Throughput Screen”, along with its contribution at “Phase I, II and III Trials.”  In 2015, it is projected that NIH will be involved in all phases of drug development as an equal partner with Industry.

This traditional model appears to be in trouble.  Over the past year, biotech has gradually moved away from central nervous system (CNS) targets, citing the difficulty of creating new drugs in this area.  In the past couple months, two of the major pharmaceutical companies for antidepressants and antipsychotics, GlaxoSmithKline (GSK) and AstraZeneca, have announced termination of their psychiatric medication development programs.  There are worrisome indications that other companies may soon follow.  Several forces have been cited for leading industry away from psychiatric medication development: the market has many generics; novel agents (such as those targeting receptors for neuropeptides) have failed; there is an absence of predictive animal models or cell models; and the expense and long time-frame for developing CNS drugs.   A recent review of the economic challenges of drug development from the industry perspective called for a shift to investments on early phases of discovery (target validation and proof of concept), a so-called “quick win-fast fail” approach. (2)

Paradoxically, while companies are making business decisions to shift away from CNS targets, the scientific opportunities for progress have never been better.  And the public health mandate is clear: we cannot condemn millions of people with mental illness to a future without better treatments.  What can NIMH do to facilitate the next generation of medications for mental illness? 

Some initiatives are already underway.   NIMH co-leads the Molecular Libraries Program, an NIH-wide effort to enable academic researchers to screen for molecules that could become lead compounds for drug development.  To move this lead compound into a drug, NIH has developed programs for medicinal chemistry, toxicology, pharmacokinetics, and pharmacodynamics leading up to early phase clinical trials.  The recently signed Healthcare Reform law includes the Cures Acceleration Network which authorizes NIH to increase these kinds of efforts to bring better treatments to the public.

Drug development is costly.  And, according to industry figures, it is usually unsuccessful.  Current figures estimate a cost of nearly $1.8 billion across 25 separate projects to successfully launch a single drug.(2)  With an annual budget of $1.4 billion, NIMH will not be able to replace pharma.  Short of replacing pharma, can we feed the pipeline at various points to ensure that drug development does not grind to a halt? Could a few key discoveries from NIMH-supported science yield the “quick win-fast fail” tools that would re-incentivize industry to invest in innovation?

We are already supporting development of new classes of medications for Fragile X syndrome and for depression.  NIMH- supported research could identify lead compounds for rapidly acting antidepressants or cognitive deficits in schizophrenia or social deficits in autism, building a pipeline for transformative treatments in each of these areas of high public health need.  And with new NIH-wide priority on accelerating cures, NIMH should be able to support more early phase clinical trials. 

If industry continues to abandon medication development for those with mental illness, NIMH, either alone or in a partnership, will need to fill the gap by investing in the next generation of treatments. Conducting clinical research more efficiently may free up some of the resources required to make a major investment. But limits in NIMH’s funding clearly indicate that, as we set priorities, hard choices will need to be made between investing in new medications and attempting to optimize the use of existing ones.  Our mission,  “transforming the understanding and treatment of mental illness” requires nothing less.


  1. Huda Akil, Sydney Brenner, Eric Kandel, Kenneth S. Kendler, Mary-Claire King, Edward Scolnick, James D. Watson, and Huda Y. Zoghbi; The Future of Psychiatric Research: Genomes and Neural Circuits. Science 26 March 2010: 1580-1581.
  2. Steven M. Paul, Daniel S. Mytelka, Christopher T. Dunwiddie, Charles C. Persinger, Bernard H. Munos, Stacy R. Lindborg, Aaron L. Schacht ; How to improve R&D productivity: the pharmaceutical industry's grand challenge  .Nature Reviews Drug Discovery 9, 203-214 (19 February 2010)