“Most psychiatric diseases are, in all likelihood, heterogeneous diseases with multiple different causes.”

I received my M.D. from University of Virginia. This was followed by fellowship training at the National Institute of Mental Health intramural program. I am now an Assistant Professor of Psychiatry at the University of Maryland School of Medicine in Baltimore.

My lab uses molecular, cellular, and behavioral approaches to study the pharmacology of psychotropic medications in rodents in the hope of illuminating their translation to the underlying pathophysiology of psychiatric illness. Our research has a particular focus on the study of novel antidepressants and mood stabilizers. We are also interested in the development of improved animal models for applications to psychiatry as well as the functional consequences of mood disorder susceptibility genes.

Most psychiatric diseases are, in all likelihood, heterogeneous diseases with multiple different causes. This heterogeneity is in many ways encouraged by the current mechanisms used to categorize these diseases, which do not allow much precision in defining relevant phenotypes. In psychiatry, categorizing patients with quantitative measures is described as an endophenotype strategy or approach. These quantitative measures may be neurophysiological, biochemical, endocrine, neuroanatomical, cognitive, or neuropsychological. Heritability (indexed by parent to offspring transmission) and stability (independent of state) are key components of any useful endophenotype, especially those that will lead to the discovery of underlying susceptibility genes.

Importantly, the endophenotype strategy reduces the complexity of symptoms and multifaceted behaviors resulting in units of analysis that are more amenable to being modeled in the laboratory—for example, cell culture or animal studies. It is similar to how we study other complex human diseases. For example, a blood test for high glucose to diagnose diabetes, rather than looking solely at a compilation of symptoms such as weight gain and fatigue. Why should psychiatry be any different?

I wrote this review article with Professor Irving Gottesman, a behavioral geneticist now at the University of Minnesota, whom I had met when we were both at the University of Virginia. He, along with the late James Shields at the Medical Research Council (London), Psychiatric Genetics Unit, had actually introduced the concept to psychopathology research in 1972!

Our commentary was part of a resurgence of the endophenotype concept, stimulated by an invitation to write a thought-piece for the American Journal of Psychiatry by editors David Lewis and Nancy Andreasen. In the past few years many in the field of psychiatric neuroscience have really caught on to the idea. This emergence is due to many factors, including the increasing recognition of the limited reproducibility of genetic and neurobiological studies directed toward etiologies of the disorders in the current psychiatric diagnosis system, and an improved appreciation for the complex relationships between genes and behavior.

This manuscript was a collaborative effort that included Haim Einat, Guang Chen, and Husseini Manji at the National Institutes of Mental Health. The purpose of this article was to determine the extent to which the ERK MAP kinase signaling pathway was activated by the mood stabilizers lithium and valproate. Following chronic administration, both drugs increased activation of this signaling pathway in the brains of rats. Further, chronic lithium administration to rats prevented behavioral changes associated with ERK pathway activation. It is hypothetically possible that activation of ERK signaling may result in more rapid antidepressant response in patients.

  Where do you see this research going in five to ten years?

I hope, and I believe, that this research will lead to improved prevention, diagnosis, and treatment of psychiatric disease. Furthermore, as we continue to appreciate the biological nature of psychiatric diseases and their treatment, it is likely that societal stigma associated with these diseases will decrease.

First, that in the future it may be possible to define psychiatric disease by more quantitative measures related to neurobiological function, rather than asking a series of questions during an interview. These endophenotypes may assist in diagnosis, as well as tailoring treatments for individual cases of psychiatric illnesses. Second, novel medications are being developed for the treatment of psychiatric disease based upon understanding both direct and indirect targets of existing medications. There are a number of people who are refractory to current treatments and who may be helped by both of these experimental approaches.

Todd Gould, M.D.
Department of Psychiatry
School of Medicine
University of Maryland
Baltimore, MD, USA
  

Dr. Todd Gould's most-cited paper with 414 cites to date: Gottesman II and Gould TD, "The endophenotype concept in psychiatry: Etymology and strategic intentions," Amer. J. Psychiat. 160(4): 636-45, April 2003. Source: Essential Science Indicators.