On a Quest for the Elusive Schizophrenia Biomarker

Abstract

f l l g t b t F r d T here is a desperate need to identify biomarkers for psychiatric illness. Biomarkers facilitate the development of etiologic rather than symptom-based diagnostic methods, foster early dentification and treatment, and advance our understanding of he complex genetic and neurobiological mechanisms involved in sychiatric disorders. Biomarkers also reflect a genetic predisposiion to a disorder with or without phenotypic evidence for the isorder (1). Schizophrenia is one of the most severe neuropsychitric disorders, the diagnosis of which remains symptom-based, not tiologically based. Moving to more etiologically based diagnostic ethods is preferable for disorder identification compared with the tatus quo of relying on subjective symptom reports and observaion. True biomarkers should also facilitate identification and treatent of a population at high risk for the disorder, which may ltimately translate into prevention in a subset of individuals. Furhermore, biomarkers also provide an entry point from which to tudy the molecular mechanisms underlying schizophrenia that ay lead to new treatments. Lastly, although the heritability of chizophrenia has been estimated to be as high as 80% (2), it is now lear that the genetics of schizophrenia are complex, with many usceptibility genes and epigenetic, stochastic, and nongenetic i.e., environmental) influences. Biomarkers may uncover further ariants in the structural genome by avoiding the heterogeneity hat exists when relying exclusively on clinical presentation. Endophenotypes are heritable biomarkers of psychiatric disorers. To be considered as an endophenotype, a biomarker must eet certain criteria (3). These criteria include: 1) heritability (i.e., he proportion of genotypic variance that contributes to biomarker ariance); 2) trait stability (e.g., a biomarker that is unrelated to llness duration or pharmacological treatments); 3) test–retest relibility; 4) diagnostic specificity (i.e., a biomarker is present in the isease of interest but not present is other disorders); and 5) coegregation of biomarker and illness within families. A final criterion hat should also be considered is simplicity. A biomarker should be imple enough to be understood, applied, and interpreted by a iverse group of health care professionals while being sophistiated enough to reflect the key neurobiological underpinnings of he disorder. One such example is blood glucose level as a diagnosic biomarker for diabetes. Blood glucose levels are not a symptom f diabetes, and symptoms in diabetic patients do not often reflect lood glucose levels. Rather than symptoms, it is blood glucose evels that are diagnostic of disease, directly targeted by treatment nd strongly predicting clinical outcome. Dysfunction of -aminobutyric acid (GABA) inhibitory interneuons represents one of the most established neurobiological findngs in schizophrenia and, by extension, is a promising mechanism hrough which to develop a biomarker for this disorder. Benes et al. 4) first demonstrated that patients with schizophrenia have morhologic changes in cortical GABA interneurons. A decreased denity of nonpyramidal cells (i.e., interneurons) in anterior cingulate ayers II through VI and in prefrontal cortex layer II among patients