The discovery of potentially many hundreds of risk genes for schizophrenia does not resolve the mystery of the illness at the level of an individual. The diversity of implicated gene functions has encouraged speculation that there are convergent biological pathways that mediate risk at the systems level, perhaps represented in gene coexpression patterns. The authors emphasize that gene coexpression varies across development, with some molecular elements related to schizophrenia risk losing importance or gaining momentum over time. The systems biology of risk and environmental exposures associated with risk are both time-dependent. The authors propose that the dynamic gene-environment interplay subtended by shifting coexpression patterns may explain variable expressivity of genetic risk during development. In particular, gene-environment correlations provide a mechanism for the individual-hence for their genes-to affect the environment and thus individual experience, promoting chains of life events. The authors envision the paired study of molecular and behavioral patterns over time as a way to identify novel treatments and preventive strategies to change the course of schizophrenia.

The design, conduct, and interpretation of double-blind randomized placebo-controlled clinical trials in major depressive disorder (MDD) are complicated by determinants of nonspecific response to treatment (NSRT). This narrative review provides a comprehensive overview of the determinants of NSRT in randomized controlled trials (RCTs) for MDD, including the placebo effect, factors related to measurement of the primary endpoint, the inclusion of misdiagnosed patients, the relapsing-remitting course of MDD, and factors related to functional unblinding. Potential strategies to reduce the impact of the determinants of NSRT and to improve the interpretation of RCT outcomes in MDD are also summarized. These strategies include use of centralized rating and standardized rater training, independent diagnostic confirmation, optimized site selection, minimizing financial incentives, exclusion of subjects participating in multiple clinical trials, exclusion of patients with unstable major depressive episode trajectories, and use of active placebo and alternative trial designs. Uniformity among experts in the definitions of determinants of NSRT and related concepts, as well as in strategies to address them, may facilitate progress in the development of novel treatments for MDD.