1 Boring Old Man

Experimental Medicine
NIMH Director’s Blog
By Thomas Insel
June 12, 2012

In previous posts I have described the crisis of medication development for mental disorders. Medications developed over the past five decades have been prescribed widely but have not been sufficient for reducing the morbidity and mortality of mental disorders. Yet there is diminishing activity in research and development for new medications within either the biotech or pharmaceutical industries. While the development of psychosocial interventions and devices, including the use of mobile technologies, is promising, the absence of a robust development pipeline for more effective medications would be worrisome in any area of medicine and should be a grave concern to the mental health community.

What can we do? Medication development is slow, expensive, and high risk. Indeed, the most recent data suggest that creating small molecule medications across disease areas is, on average, a 15 year endeavor that costs over $2 B and fails more than 95% of the time [see figure below]. No wonder that industry has reduced their investments. Can NIMH afford to invest its public funds in medication development? Can we afford not to? The answer to both questions is complicated. To ignore the need would essentially write off “hope” for those not responding to current medications, not only in the short term but over a 15 year time frame. One approach is to improve the pipeline, making it more efficient. The new NIH National Center for Accelerating Translational Sciences [NCATS] will be developing resources, such as rescuing and repurposing existing medications, to reduce the time and cost of medication development. Some of these efforts, such as the recently announced, and rapidly expanding, initiative to make existing compounds available to academic scientists, may be helpful for research on mental disorders.

But the problem for new therapies for mental disorders is not only lack of compounds but lack of understanding of the targets for treatment development. Existing antidepressants and antipsychotics have many proposed molecular targets, but none that have been shown to be necessary or sufficient for their clinical effects. Amazingly, after three decades of broad use of these medications, we still don’t know how they work when they are effective…

As a result, NIMH is shifting from large clinical trials that promise an incremental improvement to a model called “experimental medicine.” In experimental medicine, drugs are used as clinical probes and the immediate goal is not to develop a treatment but to identify or verify a target. Using proof of concept studies we can determine the ability of the drug to act on a target and affect a biological process or endpoint related to a clinical disorder, such as demonstrating that the new compound occupies relevant neural receptors or produces relevant changes in brain activity. This approach acknowledges that animal studies, while critical for neuroscience, are not consistently predictive of how medications will work in humans, homo veritas. Experimental medicine focuses on human studies rather than rodent research. Clinical studies can be small but they include biomarkers and neurocognitive outcomes to determine mechanisms of action…

Experimental medicine is an experiment. Its success depends on identifying tractable targets. Given that over 95% of compounds fail during the clinical phases of development [a fact not appreciated by looking at the published literature which is biased towards positive results], success may require rapid failures in order to conserve resources by moving quickly to the next candidate [“fast-fail”]. Success will also be determined by how others get involved, from industry to the academic community to patient advocates. We will need public-private partnerships, clinical trial networks, and creation of a new “pre-competitive” culture to change the face of medication development and have more alternatives for people with mental illness.

• the salad days of 2005…
• not for me to say…
• neuroscience has increasingly become the royal road to the unconscious?…
• the first Lemming…

^{"There’s all of that plus he is not the director of the National Institute of Psychiatry but of Mental Health. His direction for psychiatry is certainly problematic but he seems to forget the psychologists and other clinicians who are part of mental health organizations and treatment."}