Central and peripheral molecular profiling of sex differences in schizophrenia, major depressive disorder, and controls

Schizophrenia and major depressive disorder (MDD) are disabling, poorly understood conditions with inadequate diagnostic and therapeutic technologies. They are characterized by clinical and epidemiological heterogeneity between male and female patients. Females have a higher prevalence of MDD, and in schizophrenia males have a higher incidence, earlier onset, more negative symptoms, and a worse prognosis and response to antipsychotic medication in schizophrenia. A better understanding of sex differences in these patients is needed to provide insight into biological mechanisms in these conditions and develop better diagnostic tools and therapies for males and females. This thesis sought to examine molecular sex differences in control subjects and in schizophrenia and MDD patients by profiling serum and prefrontal cortex (PFC) brain tissue. Multiplex immunoassay and microarray technologies were used to measure concentrations of proteins and small molecules in serum and gene expression in brain, respectively. Extensive differences in serum molecular concentrations were found between males and females experiencing a menstrual cycle, using oral contraceptives, and after menopause. These were involved in immune, metabolic, and endocrine processes and may play a role in driving sex differences in susceptibility and other characteristics of mental disorders. Furthermore, the hypothalamic-pituitary-gonadal (HPG) axis was altered in MDD and first onset, antipsychotic naive schizophrenia patients. Biological processes involving response to steroid hormone stimulus and estradiol were enriched among differentially expressed genes in the PFC in schizophrenia. However, investigation of sex-dependent differences in PFC gene expression in schizophrenia was limited by the small number of female samples available. Finally, higher serum concentrations of a number of immune and inflammatory molecules were associated with MDD and schizophrenia in males only and this may have consequences for immune hypotheses of these disorders. The research undertaken in this thesis has advanced the understanding of the mechanisms potentially involved in schizophrenia and MDD in males and females. Furthermore, sex and female hormonal status should routinely be taken into account during design and analysis of psychiatric molecular data to increase the reproducibility of such studies. This research shows that failing to consider these in biomarker studies can result in a high proportion of false positive findings and obscure important sex-dependent markers of mental disorders