The curse and opportunity of heterogeneity in the pursuit of psychiatric biomarkers.

271 other and which cluster with a target outcome, using replication to build confidence in an interpretation. Indeed, in the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) study, it was the entire biomarker battery which went into defining the final characteristics of the experimental biomarkerdefined entities, which were called “psychosis biotypes”. These biotype constructs have provided research with an alternative to phenomenologically defined entities, as a stage in developing final disease cate gories. Moreover, it is the full biomarker battery which can be ap plied to distinguishing and understanding defined features of the illness, such as negative symptoms. BSNIP researchers have developed several individual studies, now ongoing, to test the clinical applicability of the above biotype constructs. One such study tests the hypothesis that biotype 1, with its low intrinsic EEG activity, is a biomarker which indicates responsiveness to clozapine; specifically, we test the hypothesis that increasing intrinsic EEG activity with clozapine in biotype 1 will correlate with symptomatological improvement, using the attractor network model. A second study, designed to predict treatment response in early psychosis, hypothesizes that the biotypes will define good (biotype 3), moderate (biotype 2) or poor (biotype 1) response to standard coordinated specialty care (CSC). In each of these examples, a doubleblind trial of the biomarker observation (now ongoing) is necessary, and its application can only be supported if this is done with rigorous design. There is no doubt that considerable hard work will have to go into the study of biomarkers in psychiatry before we are able to bring them to a clinically useful place. Yet, the validation of biomarkers, as reviewed in AbiDargham et al’s paper, can be so decisive for the future of our field that these stud ies need to be conducted. Costs have to be born. Yes, wisely; but urgently.