Evaluating endophenotypes for psychiatric disorders

Avaliação de endofenótipos em transtornos psiquiátricos Studies on the etiology and pathophysiology of psychiatric disorders and studies on factors associated with treatment response have both been limited by clinical and genetic heterogeneity. The validity of diagnostic criteria based on clinical symptoms has been difficult to achieve because the psychiatric disorders, as defined by current classification schemas including DSM, likely encompass a group of disorders that are heterogeneous with respect to etiology and pathophysiology. In fact, without knowledge of the underlying etiological processes the diagnostic criteria for a disorder based on clinical characteristics cannot be evaluated adequately. The use of more indirect indicators of disease validity including family history, treatment response, longitudinal course and stability, patterns of comorbidity, and social consequences led to circularity in validating clinical diagnostic criteria. The evaluation of endophenotypes (i.e., intermediate phenotypes bridging the gap between available descriptors and the elusive underlying etiology) has been proposed as a strategy to overcome the methodological difficulties in psychiatric nosology and has already been a successful strategy in the elucidation of genetic factors in schizophrenia and medical diseases. The multifactorial threshold model of complex genetic disease assumes that many factors contribute to a disorder in an individual, that the effects of each single factor may be small but small effects may accumulate, and that once the combined effects of the factors pass some critical value the disorder may become manifest. This model also can be applied to both macro phenotypes and endophenotypes since we assume that multiple genetic and non-genetic factors contribute to a complex phenotype that becomes manifest when the combined effects of the factors pass the phenotype-specific threshold. The endophenotype approach assumes that the underlying liability of endophenotypes representing basic biological phenomena is less complex and easier to elucidate than the liability of complex behaviors, such as psychiatric diseases, irrespective of the magnitude of the total genetic risk of the phenotypic definition. Genetic factors for intermediate traits that are closer to the genotype in the developmental scheme may generally be easier to identify because of the improved signal-to-noise ratio in the fraction of variance explained by any single factor. Although the endophenotype concept has been specifically developed to improve the power of genetic studies, the identification of endophenotypes will also lead to improvements of diagnostic methods, disease classification, the development of animal models, and the development of better treatments. For example, assuming that neurologists would not know the different etiologies and pathophysiologies of tremor, they might define a ‘major tremor disorder’ based on clinical characteristics. As a result, they would include patients with conditions as dissimilar as classic Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, and frontotemporal dementia in the same trial testing the effect of a dopamine agonist in major tremor disorder. Although clinicians may recognize that some patients (i.e., those with Parkinson’s disease) experience considerable symptom reductions under treatment, the treatment effect across the whole heterogeneous sample would not reach statistical significance, and the effective drug would not be allowed Editorial 91