Relationships between circulating hormones and brain abnormalities in schizophrenia and restoration of brain activity by raloxifene treatment

Schizophrenia is a severe neuropsychiatric disorder with marked deficits in cognitive and social functioning. Mounting evidence suggests that sex steroid hormones are strongly implicated in the pathophysiological underpinnings of schizophrenia. Moreover, grey matter deficits and abnormal brain function are integral components of disease neuropathology, a hypothesis that is supported by findings from postmortem and neuroimaging studies. This thesis used a multidisciplinary approach integrating structural neuroimaging, functional neuroimaging and molecular biology with the overall aim of determining how hormones may be associated with a number of core deficits and brain abnormalities routinely described in schizophrenia. In testing the hypothesis that some people with schizophrenia exhibit abnormal circulating hormone levels, I found that male patients had decreased testosterone levels and female patients had increased testosterone levels as compared with their respective healthy control groups, while DHEA levels were increased in both sexes of patients relative to controls. I showed for the first time that cortisol/DHEA ratios were inversely related to grey matter volume in the prefrontal cortex and hippocampus, suggesting that hypothalamicpituitaryadrenal axis dysfunction can contribute to key neuroanatomical deficits in schizophrenia. Further, endogenous testosterone levels were associated with neural activation during facial emotion recognition in male patients and not in male controls, suggesting that higher levels of testosterone may be beneficial for cortical processing during events key for healthy social functioning in patients. Since the beneficial effects of testosterone on cortical functions could be mediated by either androgen or estrogen action in the brain, I examined the extent to which adjunctive treatment with a brain estrogen receptor agonist, raloxifene, could enhance neural activation during facial emotion recognition in patients. Raloxifene increased prefrontal and hippocampal activation during emotion recognition in males and females with schizophrenia, demonstrating the drugs ability to alter neural activity associated with impairments in emotion processing of patients. The correlational and experimental studies from this thesis provide evidence that peripheral blood hormones may be informative of brain pathology in schizophrenia and further implicate the role of steroid hormones in disease neuropathology and possibly for treatment