Development and Psychopathology 25 (2013), 1347–1357 # Cambridge University Press 2013 doi:10.1017/S0954579413000655 Thinking clearly about the endophenotype–intermediate phenotype–biomarker distinctions in developmental psychopathology research MARK F. LENZENWEGERa,b aState University of New York at Binghamton; and bWeill Cornell Medical College 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. Development and Psychopathology is celebrating 25 years of widely in any informed consideration of developmental psy- shaping the field of inquiry in developmental psychopathol- chopathology. Methodological approaches to data that are es- ogy, and the scholarship that fills the pages of this unique sential to unraveling pathways of pathogenesis have been de- journal has impacted the field well beyond the borders of scribed here in detail and adopted by many. Consider the the developmental psychopathology vantage point. For ex- explication of multilevel modeling by Willett, Singer, and ample, one might only think of the concept of resilience Martin (1998) and the wide use this approach now enjoys. and how this concept (a legacy of Norman Garmezy; Gar- In short, this journal has consistently hosted the cutting- mezy, 1996), which has been well represented in the pages edge theoretical and methodological discussions, as well as of Development and Psychopathology, has become nearly data-driven empirical studies, in developmental psychopa- universal in our thinking about psychological adjustment in thology for a quarter of a century. the face of adversity (see Hanson & Gottesman, 2012; Mas- I can still recall looking through the inaugural issue of De- ten, 2011); or consider the powerful theoretical constructs of velopment and Psychopathology in the reading room of the equifinality and multifinality (Cicchetti & Rogosch, 1996), Department of Human Development at Cornell University which appeared first in these pages and are now adopted in 1989. As I perused the first issue I remember thinking that this journal would be a unique place where rich discus- Portions of this essay are extensively amended and extended versions of prior sion would occur on any number of developmental psychopa- discussions of these concepts by the author (Lenzenweger, 2010), and they are thology topics. I imagined the journal as a forum in which the used here with my permission of the author, who holds copyright. Some of the principles of developmental psychopathology as a vantage ideas presented in this paper with regard to anxiety and depression are dis- point could be imparted, debated, proposed, and refined. I cussed in a highly abbreviated form in Lenzenweger (in press). I thank Irving think this potential has been more than realized, and the pre- I. Gottesman for useful discussions of the endophenotype concept. Address correspondence and reprint requests to: Mark F. Lenzenweger, dictions Dante Cicchetti made in 1989 (Cicchetti, 1989)have Department of Psychology, State University of New York at Binghamton, Sci- come to be born out in what continues to be a vigorous ence IV, Binghamton, NY 13902-6000; E-mail: [email protected]. scholarly venue. Professor Cicchetti is to be saluted by the 1347 1348 M. F. Lenzenweger community of psychopathology research scholars for his vi- targets for even more intense scrutiny in the coming years, sion and energy in founding and sustaining Development with the hope that illuminating these basic processes will fur- and Psychopathology. ther illuminate our understanding of the development of psy- chopathology. Central to the study of the selected processes in the RDoC approach is the implicit assumption that research Orienting Remarks efforts will depart from a traditional focus on signs and symp- This paper concerns the concepts of endophenotype, inter- toms of illness. A further implicit assumption is that an ener- mediate phenotype, and biomarker. Each of these terms is getic, wholesale research effort focused on the processes of currently in active use in developmental psychopathology. greatest interest in the RDoC framework will make ample For example, in this journal alone there have been 68 articles use of the concepts of endophenotype, intermediate pheno- that mentioned endophenotype, 51 articles that mentioned type, and biomarker in the coming years. biomarker, and 11 articles that mentioned intermediate phe- The traditions of laboratory research in psychopathology notype. The 2012 Special Issue of this journal that focused (cf. Maher, 1966; Lenzenweger & Hooley, 2003), the entirely on the contributions of the genetic/genomic sciences RDoC initiative, the forthcoming DSM-5, and an ever-chang- to developmental psychopathology (Volume 24, Issue 4) con- ing array of genetic and epigenetic research strategies will all tained many papers referring to one of more of these con- shape future psychopathology discourse. The concepts of en- cepts. The papers in this special issue highlighted the central- dophenotype, intermediate phenotype, and biomarker have ity of genetic factors acting in concert with epigenetic factors, all played roles in discussions regarding gene–illness path- environmental factors, and other forces in the pathogenesis of way models in contemporary experimental and developmen- psychopathology (Grigorenko & Cicchetti, 2012), an as- tal psychopathology research. The concepts of biomarker, sumption that embraces the concepts of endophenotype, in- intermediate phenotype, and endophenotype have been termediate phenotype, and biomarker. Moreover, Beau- used increasingly to frame research questions, particularly chaine, Neuhaus, Brenner, and Gatzke-Kopp (2008) outline those efforts seeking to identify RDoC-defined dimensions an approach to research on prevention that incorporates con- and the associated homogenous systems underlying those di- cepts such as endophenotypes and biomarkers. mensions, and these concepts will continue to serve such a Over the past 20 years we have seen an increased focus on framing function. However, there are critical issues surround- the process/systems approach to understanding the causes of ing the use of these concepts that are largely ignored by those psychopathology. Kagan (in Schwartz, Snidman, & Kagan, using the concepts without intellectual vigor. Whereas some 1999) described anxiety psychopathology emanating from investigators have used these concepts interchangeably (sy- deviations in the fear system. Recall that the core assessments nonymously), the terms are actually not fungible. An under- of the children in Kagan’s landmark studies were done in the standing of their individual meanings and implications for laboratory when the children were 4 months old, thus tapping psychopathology research is essential (on conceptual clarity, early indicators of behavioral inhibition. Davidson (1998) de- see Meehl, 1977). Although there is a dawning awareness that scribed affective disorder, particularly depression, in terms of these concepts are not equivalent (see footnote 1 in Fornito & the approach (positive emotion) and the withdrawal (negative Bullmore, 2012), there has not been a comparative conceptual emotion) systems. This work was done largely in the context analysis of them. Given the prominence of these concepts in of psychophysiological assessments. Depue and Lenzenwe- current discussions in developmental psychopathology, it ger (2005) have proposed a model that describes personality seems the time is ripe for a critical examination of these ideas. disorders as emergent products of the agentic approach,