Using Biomarker Batteries

The biggest challenge for psychiatry today is the need toreveal and verify the essential pathologies of psychiatricsyndromes, including discovering relevant molecular, synap-tic, and circuit formulations of biologically based psychiatricdiseases. Any demonstrated pathology that reﬂects the biol-ogy of a facet or characterizes a subgroup of a psychiatricsyndrome would be an important target. Medical scientistsmust have asked this same question in the early 1900s whenthey were grasping for modern medicine handles on illnessmanifestations such as fever and dropsy (morbid edema).Psychiatric illness constructs today, as were fever and dropsyin the 1900s, are based on clinical constellations of symptomsand illness course. Multiple lines of evidence do not supportthe assumption that clinical phenomenological disease con-structs are congruent with biologically based disease entities.As Dr. Steve Hyman has opined, for psychiatry, “DSM was apoor mirror of nature (Steve Hyman, M.D. et al., personalcommunication, 2011).” The task of looking for biologicallydeﬁned disease characteristics of serious mental illness thatmay lie orthogonal to clinical diagnostic boundaries is achallenging one. One could ask, “If we eschew clinicalphenomenology as the gold standard, what brain character-istic(s) might optimally deﬁne a homogeneous disease groupwithin the schizophrenia syndrome?”Roalf et al. (1) address this issue by estimating the herit-ability of structural brain phenotypes in large extended familiescontaining multiple cases of schizophrenia. They quantiﬁedregional brain volumes and performed shape analyses forsubcortical and limbic brain regions, and they estimatedheritability for these variables. Not all variables on which theyreported differentiated healthy persons from probands/rela-tives. All of the structures that showed group differences(accumbens, caudate, hippocampus, putamen, and thalamus,but not amygdala and pallidum) also had signiﬁcant heritabilityestimates. Palaniyappan et al. (2) also contrasted regionalbrain deviations among schizophrenia spectrum relativeswithout schizophrenia itself versus brain deviations amongprobands with schizophrenia and reported that some altera-tions were associated with genetic propensity for illness andsome were peculiar to the disease. Findings from studies likethose of Roalf et al. and Palaniyappan et al. offer intriguingindications that sophisticated quantiﬁcations of brain morpho-logic deviations could aid understanding of essential ingredi-ents of the schizophrenia constitution versus deviations thatare consequences of disease. Although this work is animportant step forward, several caveats are worth considering.First, as Kendler and Neale (3) caution, estimating herit-ability from sibling-sibling and parent-offspring data alonedoes not provide the opportunity to distinguish genetic andfamilial-environmental sources of variance. However, perhapswe can at least conclude that Roalf et al. (1) demonstrate thattheir subcortical morphology measures are moderately tostrongly familial and are deserving of further intensive study.Also, heritability is a population metric, perhaps best esti-mated in large and varied samples (a point to which Roalf et al.allude), that does not tell us, for instance, that genes accountfor 70% of accumbens morphology for a single individual.Nevertheless, Roalf et al. at least show that measures ofsubcortical brain morphology are intriguing prospects forpsychosis biomarkers.Second, regional brain morphology is among the mostrational choices as a disease-related phenotype because it iseasily obtained, is moderately replicable across sites, and couldindicate alterations in regional pathology of a molecular orcellular nature. Many authors have reported a diagnosticdistinction based on brain anatomy within the psychosisdimension between the two major psychosis diagnoses, schizo-phrenia and bipolar disorders ( 4), despite the similarity in theirunderlying histopathology (5). However, as indirect measures ofregional neural activity, brain volume and shape are fundamen-tally limited biomarkers, despite their usefulness. This funda-mental limitation is true for any of the individual brain molecular,cellular, or activity biomarkers of human brain disease withunknown pathophysiology. How can we begin to identify keybiological characteristics of psychiatric syndromes?Third, to deﬁne pivotal biomarkers of schizophrenia orpsychosis generally, it may be important to consider theprobability that, rather than a single biomarker, a battery ofbiomarkers, integrated in multivariate space, may be requiredto deﬁne any single disease construct. Epigenetics, etiologicheterogeneity, pleiotropy, and variable expressivity inﬂuencephenotypic manifestations, making it difﬁcult for a singlelaboratory measure to be pathognomonic for complex psy-chiatric diseases. Multiple means for assessing the etiologiccomplexities that undergird complex psychopathologic dis-eases will be a requirement for advancing our ﬁeld. Roalf et al.have identiﬁed an important neuropathologic construct toconsider in such a multivariate enterprise. Other researchgroups are also beginning to examine the utility of extensivebiomarker batteries to create multivariate-based disease con-structs that are biologically, and perhaps etiologically, dis-tinctive (6,7). The value of a biomarker battery is to representmany aspects of brain function in a complex constellation,including cognition, regional neural activity, motor function,and brain shape and volume. Multiple variables would repre-sent many aspects of a disease entity, each with multiplemeasures, and use the resultant disease characteristics todeﬁne disease groupings—all biological-based—that distin-guish neurobiologically meaningful disease subgroups thatcut across conventional clinical groupings. The Bipolar-Schizophrenia Network for Intermediate Phenotypes hasinitiated such an approach to understanding and parsing90