Despite decades of research, we lack objective diagnostic or prognostic biomarkers of mental health problems. A key reason for this limited progress is a reliance on the traditional case–control paradigm, which assumes that each disorder has a single cause that can be uncovered by comparing average phenotypic values of patient and control samples. Here, we discuss the problematic assumptions on which this paradigm is based and highlight recent efforts that seek to characterize, rather than minimize, the inherent clinical and biological variability that underpins psychiatric populations. Embracing such variability is necessary to understand pathophysiological mechanisms and develop more targeted and effective treatments.
