Towards precision medicine in psychiatry: investigating the contribution of cellular aging, pleiotropy and gender differences in psychiatric disorders and pharmacological response

Severe mental disorders such as bipolar disorder (BD), schizophrenia (SZ) and major depressive disorder (MDD) are characterized by a substantial socio-economic burden. Pharmacological treatment is the mainstay in the acute phase of severe mental disorders as well as in the prevention of recurrences. However, only one third of patients show excellent response to the first pharmacological treatment, while the other two thirds show partial or no response. The identification of reliable tools to stratify patients depending on the probability to respond to a specific treatment would allow to develop improved treatment strategies for these patients. In this regard, precision medicine aims to provide a more tailored treatment by integrating demographic, clinical, lifestyle and biological characteristics. Novel analytical approaches that allow to leverage pleiotropy to improve the yield of existing genome-wide summary statistics might also be of help to identify novel potential drug targets. In this thesis, we focus on the investigation of molecular markers related to cellular aging (telomere length) and inflammation in predisposition to severe mental disorders and response to psychotropic treatments. In addition, we present different studies aimed at identifying genetic loci shared between severe mental disorders and related traits (i.e. risk-taking propensity, telomere length and metabolic phenotypes). In the latter study we also focus on exploring gender differences in genetic determinants shared between mental disorders and metabolic phenotypes, highlighting the relevance of gender in the identification of pleiotropic loci and potential drug targets. Elucidating the shared genetic bases between severe mental disorders and genetically predicted markers of cellular aging, as well as age-related disorders such as metabolic disturbances, might allow us to discover novel drug targets and define subgroups of patients that might benefit of more tailored treatment strategies, moving toward precision medicine in severe mental disorders.