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Director’s Blog: Treatment Development: Where do we go from here?


In the previous blog post, I described the unprecedented reduction in the pharmaceutical industry’s research and development programs for psychiatric medications. Given that we need a next generation of safe, effective treatments across nearly all mental disorders, this news is worrisome.

What can be done? NIMH does not have the human or financial resources to develop the next generation of medications. We can, however, support science that can catalyze innovation and discovery in both the public and private sectors. Here are a few opportunities to “turn the herd.”

First, we can identify new targets for new treatments. Over the past four decades, nearly all medications for depression and psychosis have been “me too” drugs based on serendipitous discoveries of drugs that influence dopamine and serotonin. Genetic studies of autism, bipolar disorder, and schizophrenia are revealing novel molecular pathways including some that could be targets for treatment development.iBrain imaging studies have revealed critical circuits that can follow the effects of treatments with great precision.ii iii iv v And cognitive science is helping us define new targets for clinical treatment, such as “social motivation” in autism and “anhedonia” (inability to experience pleasure) in Simply put, better treatments will require better science. Genetics, neuroscience, and cognitive science are giving us the tools to understand mental disorders so the next generation of treatments can be developed by design rather than serendipity.

But serendipity is sometimes a great thing. Clinical experience can yield the best clues to new treatments, for instance when someone treated for inflammatory bowel disease notes the resolution of their chronic depression or a cancer therapy proves helpful for schizophrenic symptoms. An important opportunity for discovery comes from empowering patients and providers to crowd-source these experiences. Indeed, this may be the most rapid path to a new treatment. Websites such as Patients Like Me  are harnessing the power of social networking to empower people with neurological and psychiatric disorders to discover what works. This approach can also yield insights into new, unexpected treatment effects.

In the drug development world, the new use of a currently approved treatment is called “repurposing.” Ketamine, an anesthetic that has been off-patent for decades, appears to have profound, rapid antidepressant effects.vii Ketamine could be repurposed as a next generation treatment for depression, but there are concerns about its safety. NIMH has launched a new program, the Rapidly-Acting Treatments for Treatment-resistant Depression  project, to follow up on this finding by identifying other potential rapid treatments for depression.

Some repurposed drugs, like ketamine, are available for research. But others that have been under development by a pharmaceutical company may not be accessible for rigorous testing. Paradoxically, as pharmaceutical companies shift their investments away from treatments for mental disorders, there may be a unique opportunity for non-industry scientists if companies are willing to share their compounds that are being shelved. To that end, Astra Zeneca and the Medical Research Council in the United Kingdom recently announced a new public-private partnership  to make compounds available for academic research. If a model like this could be developed with several companies here in the United States, it seems possible that university scientists could push forward progress on potential treatments that will not be developed by industry.

Finally, we can alter the process of treatment development. By most estimates, more than 90 percent of compounds that go into clinical development will fail, either because of high toxicity or low efficacy. The proposed new NIH National Center for Advancing Translational Science (NCATS)  will be designed to speed the delivery of new drugs, diagnostics, and medical devices to patients. NCATS can also develop resources for the scientific community, such as a “medicine cabinet” of compounds for non-industry scientists, or a “chip” to predict toxicology of new compounds. It can also be a leader in a new area of research called regulatory science, which will help us understand how policies may facilitate or inhibit translation of research into practice.

For NIMH, the problem is clear. Research over the past decade has shown that our current medications are not good enough. Industry has had blockbusters but very few breakthroughs in the past forty years. There was always hope that the billions of dollars invested in this area by the pharmaceutical industry would result in more effective treatments for our most disabling disorders. Now, however, we face the possibility that there will be no “next generation” of mental disorder treatments emerging from industry. We need to catalyze both the public and private sectors to ensure that the same innovation being applied to cancer and heart disease research will also serve those with severe mental illness.

 i Elia et al. Nature Genetics. In press.

 ii Forbes et al. Reward-related brain function as a predictor of treatment response in adolescents with major depressive disorder. Cogn Affect Behav Neurosci. 2010 Mar;10(1):107-18.

 iii Kumari et al. Beyond dopamine: functional MRI predictors of responsiveness to cognitive behaviour therapy for psychosis.Front Behav Neurosci. 2010 Feb 12;4:4.

 iv Borairi S, Dougherty DD, The use of neuroimaging to predict treatment response for neurosurgical interventions for treatment-refractory major depression and obsessive-compulsive disorder. Harv Rev Psychiatry. 2011 May-Jun;19(3):155-61

 v Victor TA et al Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder.Arch Gen Psychiatry. 2010 Nov;67(11):1128-38.

 vi Roiser, Elliott, Sahakian, Cognitive mechanisms of treatment in depression. Neuropsychopharmacology, 2012 Jan;37(1): 117-36.

 vii Charney, Nature Med, Cracking the moody brain: lifting the mood with ketamine. 2010 Dec;16(12):1384-5.