Current versions of the DSM and ICD have facilitated reliable clinical diagnosis and research. However, problems have increasingly been documented over the past several years, both in clinical and research arenas (eg, 1, 2). Diagnostic categories based on clinical consensus fail to align with findings emerging from clinical neuroscience and genetics. The boundaries of these categories have not been predictive of treatment response. And, perhaps most important, these categories, based upon presenting signs and symptoms, may not capture fundamental underlying mechanisms of dysfunction. One consequence has been to slow the development of new treatments targeted to underlying pathophysiological mechanisms.

History shows that predictable problems arise with early, descriptive diagnostic systems designed without an accurate understanding of pathophysiology. Throughout medicine, disorders once considered unitary based on clinical presentation have been shown to be heterogeneous by laboratory tests—eg, destruction of islet cells versus insulin resistance in distinct forms of diabetes mellitus. From infectious diseases to subtypes of cancer, we routinely use biomarkers to direct distinct treatments. Conversely, history also shows that syndromes appearing clinically distinct may result from the same etiology, as in the diverse clinical presentations following syphilis or a range of streptococcusrelated disorders.