Addressing heterogeneity (and homogeneity) in treatment mechanisms in depression and the potential to develop diagnostic and predictive biomarkers

It has been 10 years since machine learning was first applied to neuroimaging data in psychiatric disorders to identify diagnostic and prognostic markers at the level of the individual. Proof of concept findings in major depression have since been extended in international samples and are beginning to include hundreds of samples from multisite data. Neuroimaging provides the unique capability to detect an acute depressive state in major depression, while we would not expect perfect classification with current diagnostic criteria which are based solely on clinical features. We review developments and the potential impact of heterogeneity, as well as homogeneity, on classification for diagnosis and prediction of clinical outcome. It is likely that there are distinct biotypes which comprise the disorder and which predict clinical outcome. Neuroimaging-based biotypes could aid in identifying the illness in individuals who are unable to recognise their illness and perhaps to identify the treatment resistant form early in the course of the illness. We propose that heterogeneous symptom profiles can arise from a limited number of neural biotypes and that apparently heterogeneous clinical outcomes include a common baseline predictor and common mechanism of treatment. Baseline predictors of clinical outcome reflect factors which indicate the general likelihood of response as well as those which are selective for a particular form of treatment. Irrespective of the mechanism, the capacity for response will moderate the outcome, which includes inherent models of interpersonal relationships that could be associated with genetic risk load and represented by patterns of functional and structural neural correlates as a predictive biomarker. We propose that methods which directly address heterogeneity are essential and that a synergistic combination could bring together data-driven inductive and symptom-based deductive approaches. Through this iterative process, major depression can develop from being syndrome characterized by a collection of symptoms to a disease with an identifiable pathophysiology