Translational Research: From Research Findings to Transformative Treatments

Last month, I wrote about some fascinating basic science discoveries presented at the Society for Neuroscience (SfN) annual meeting. Hard on the heels of SfN is another annual meeting—that of the American College of Neuropsychopharmacology (ACNP). ACNP focuses on the next phase of neuroscience research—research which translates basic neuroscience findings into novel treatments. Here too, there was a lot of excitement as scientists presented their latest findings (which I’ll elaborate on below), presaging tomorrow’s transformative treatments.

Translating genetic knowledge into psychiatric treatments

One of the key questions in translational psychiatry today is how to take the explosion in knowledge about the genetic underpinnings of psychiatric disorders and use it to develop novel treatments. An important first step is to understand how psychiatric risk genes affect the brain. Emerging methodological approaches hold promise for providing such insight. The ACNP President’s Plenary at this year’s meeting addressed approaches such as using advanced stem cell technologies and other model systems to test neurobiological hypotheses around psychiatric risk genes; combining careful, precise behavioral phenotyping in cohorts of healthy volunteers, individuals with psychiatric illnesses, and carriers of specific high-risk alleles; and, comparing and contrasting the effects of risk genes on multiple illnesses.

Particularly compelling for me was a novel approach described by Alan Anticevic, Ph.D., a researcher conducting work funded by the NIMH at Yale University Medical School. He and his collaborators have used sophisticated computational methods to combine gene expression data, genetic risk information, and neuroimaging findings in individuals with schizophrenia and other psychotic disorders. Besides providing a platform to investigate the neural circuits affected by genetic risk, these methods can also be used to point out potential molecular targets for new therapies within those circuits.

The role of animal models in translational research

Animal models play important roles in basic neuroscience, helping to uncover the molecular, cellular, and circuit-level substrates underlying the development and function of the brain. Animal models have also played crucial roles in translation, helping establish the safety and potential efficacy of novel therapeutics, including drugs and devices. In addition, animal models have provided a theoretical framework for psychotherapies.

Yet, as we understand more and more about the complexity of psychiatric illnesses, legitimate questions have been asked about the use of animal models in translational neuroscience. One panel, in which I was fortunate enough to participate, focused on this issue. Panel moderator Tracy Bale, Ph.D. , of the University of Maryland School of Medicine, led a robust discussion on the use of such models in translational psychiatry—a discussion that spilled out of the packed hall and into the Twittersphere (take a look at my Twitter feed (@NIMHDirector ) from December 11^th and beyond).

As part of this panel, Eric Nestler, M.D., Ph.D. , of the Icahn School of Medicine at Mount Sinai, discussed novel approaches to demonstrate relevance of these models to human illnesses, including comparing molecular changes across a variety of animal models to those seen in humans, in order to capture both the heterogeneity of human illness and also the core features that are conserved in other species. Panel member Huda Akil, Ph.D., of the University of Michigan, made the important point that work in animals lays a basic science foundation that can inform translation more broadly. Kerry Ressler, M.D., Ph.D. , of McLean Hospital, emphasized the need to focus on behavioral measures that are conserved across species where possible, and on outcome measures that reflect conserved brain mechanisms.

In my comments, I noted that animal models cannot, by definition, capture the full complexity of mental illnesses as seen in humans. Accordingly, we cannot claim that animals are models of diseases, but rather they are models for the study of disease. This small semantic difference is nonetheless an important one since it signals a change in approach. To progress towards a greater understanding of, and new treatments for, mental illnesses, researchers should focus on making hypotheses about illness mechanisms and designing the most useful models—animal or otherwise—that will allow us to test these hypotheses.

Novel pharmaceutical therapies for mental illnesses

What about treatments for mental illnesses? Two exciting threads presented at ACNP suggest that some truly novel therapies may be just around the corner. Early in the meeting, a symposium presentation focused on a novel approach to the treatment of postpartum depression. Steven Paul, M.D., is a former NIMH intramural researcher and the founder of Sage Therapeutics, a pharmaceutical company focused on drug development for mental illnesses. Dr. Paul presented a historical perspective on the development of brexanolone, an analog of the naturally-occurring neurosteroid allopregnanolone. He described how early NIMH-supported basic science studies and groundbreaking translational and clinical work led to an FDA application for the use of brexanolone in women suffering from postpartum depression.

Later, Anthony Loebel, M.D., of Sunovion Pharmaceuticals, presented a poster on a clinical trial of SEP-363856, a novel antipsychotic that works by a completely different mechanism than other drugs that help those with schizophrenia. Working in conjunction with Psychogenics, a company that received early support from NIMH through our Small Business Innovation Research (SBIR) program, Dr. Loebel’s colleagues developed SEP-363856 by looking for compounds that produced similar behavioral effects as traditional antipsychotics in animal models, but were not antagonists to the D2-type dopamine receptor (all current antipsychotic medications exert their effects through D2-receptor antagonism). The clinical trial described by Dr. Loebel showed that this novel drug reduced psychosis symptoms in individuals with schizophrenia. Planning is underway for a larger trial of the drug to confirm the effect.

If approved, these two agents would be the first new psychiatric medications with truly novel mechanisms of action in decades. But even more importantly, they would demonstrate the potential for translating basic neuroscience research, including molecular pharmacology and animal behavior, into transformative treatments for those suffering from mental illnesses. And that is what translational research in psychiatry is all about.