The Neuropsychiatric Translational Revolution Still Very Early and Still Very Challenging

Advances in knowledge of mammalian neurobiology and genomics far outpace their application to common but complex human disorders, especially those impacting brain function. Recently, Karayiorgou et al1 argued for the almost exclusive use and funding of neuropsychiatric research using highly penetrant de novo mutations and selected animal models to illuminate the neural circuit and genomic network basis of neuropsychiatric disorders and to get Big Pharma back into central nervous system drug development. While their viewpoint reflects the great speed with which knowledge about mammalian genomics and neurobiology is proceeding, the translation of this kind of new basic science data to the bedside is proceeding at a much slower pace, making such prescriptive scientific pathways premature.2 Many therapeutic advances in medicine are concentrated in accessible tissue disorders, such as coagulopathies and oncology, where diseased tissue can be directly examined and manipulated. But we largely lack such direct approaches for the relatively inaccessible brain with its complex neural circuit imbalances compared with the more discrete mitotic dysfunctions seen in oncology. Furthermore, with an increasing basic science and genomic focus in psychiatric neuroscience, we often overlook treatment advances in the area of cognitive, psychosocial, and health services interventions, either alone or in conjunction with pharmacotherapies.3 To suggest that one translational approach to complex neuropsychiatric disorders be given almost absolute scientific and funding primacy1 is very premature indeed. The gap between basic and applied research is not specific to neuropsychiatry. Indeed, several years ago, Nobel Laureates Goldstein and Brown4 pointed out that “elite” basic science journals present research that is often disarticulated from the practical clinical realities in medicine. They explained why they published more than 30 articles in the Journal of Clinical Investigation: Because the importance of [these] papers went beyond basic science. Editors and readers of elite basic science journals such as Nature, Cell, and Science would have difficulty comprehending the importance of studying fat accumulation in smooth muscle cells and hepatocytes… By publishing in the JCI, we were able to reach a broad audience of medically oriented scientists.4 In fact, both the etiological and therapeutic implications of much published basic neurobiological research remains unclear. For example, the precise genomic etiology of common (≥1% prevalence) yet complex neuropsychiatric disorders continues to elude us. Based on a qualitative questionnaire administered at the 2011 Program and Executive Committees of the American College of Neuropsychopharmacology and Society of Biological Psychiatry, we found that the gap between basic science research and effective treatment—that is, between the bench and bedside—is of growing concern to senior neuropsychiatric thought leaders. Specifically, about 80% of the 60 thought leaders surveyed believe it is either important or essential for them, their colleagues, and students to see more than 30 patients who have the disorder that they are studying. Yet, nearly two-thirds of thought leaders believe that the research in high-impact basic science journals does not reflect this requisite level of knowledge of the actual neuropsychiatric disorders that are being modeled.5 We face some distinct research challenges in neuropsychiatry. A tissue slice of kidney or lungs or liver gives up its functional role quite easy (eg, in the lung, blood and bronchial structures are designed for gas exchange). In contrast, the brain is less accessible and is morphologically and genomically enigmatic and complex. Thus, we respectfully suggest a number of considerations for the field to create a more relevant translational research environment that narrows the gap between the bench and bedside, while broadening research foci.