The study of brain-based intermediate phenotypes in psychiatry is conceptually appealing and biologically compelling. It is a “no brainer” that genes do not encode for psychiatric symptoms but for simpler molecular processing in cells and information processing in brain. However, the intermediate phenotype approach has to be undertaken with considerable caution and attention to detail. A number of caveats need to be recognized in the literature as it currently exists, including inconsistencies in directionality of findings (hypo- or hyper-activation), biases in criteria for selection of relatives (offspring versus siblings or parents, and the presence of other psychiatric diagnoses in the relatives but not in the comparison groups), small sample sizes not powered to detect small effect sizes, and the relative independency of the different intermediate phenotypes, still not explored for any of them.
