Thinking clearly about the endophenotype-intermediate phenotype-biomarker distinctions in developmental psychopathology research

Abstract

The endophenotype is central to modern developmental psychopathology studies. It is used in studies seeking to connect the genetic substrates of the panoply of major mental disorders with processes, tapped by laboratory and other assessment measures, in the genotype to a behavior/psychopathology pathway. Proposed originally by Gottesman and Shields (1972; Shields & Gottesman, 1973) 41 years ago, the endophenotype concept has gained widespread traction in psychopathology research since the Gottesman and Gould (2003) review. Other concepts broadly related to the endophenotype notion have also generated discussion in experimental and developmental psychopathology research. One is the intermediate phenotype, a concept proffered as a putative alternative formulation to the endophenotype. Another concept in this intellectual vein is biomarker. The terms endophenotype, intermediate phenotype, and biomarker have often been used interchangeably in the psychiatric literature, yielding conceptual confusion. However, these three terms are not fungible. The recent Research Domain Criteria proposal from the National Institute of Mental Health has emphasized selected underlying processes thought to be of developmental etiologic significance to psychopathology. These selected processes will be the focus of energetic future research efforts, many of which will make use of the endophenotype and biomarker research paradigms. In this context, the concepts of endophenotype, intermediate phenotype, and biomarker are examined critically and contrasted in terms of meaning, intention, clarity, and intellectual history. This analysis favors use of the endophenotype concept in genetically informed laboratory and neuroscience studies of psychopathology. The term intermediate phenotype is perhaps best restricted to its originally defined meaning in genetics. Biomarker is used to denote objectively measured biological antecedents or consequences of normal or pathogenic processes or a physiologic response to a therapeutic intervention.