Schizophrenia, a devastating mental illness afflicting 1% of people, is clinically heterogeneous in course, symptoms, and treatment response. Multiple lines of enquiry point to a complex underlying neurobiology with disturbances in neurotransmitter and membrane phospholipid expression. Metabolomics, the study of metabolism at """"""""global"""""""" level, can elucidate neurobiological phenotypes to provide new biochemically-based insights into schizophrenia pathogenesis, individual variation in clinical presentation and also drug response. Metabolomics studies the """"""""metabolome"""""""", the entire repertoire of small molecules present in cells and/or tissues- with concentrations/changes of these compounds representing the final product of interactions extending from gene sequence to gene expression- protein expression and total cellular environment. We have developed platforms and identified initial metabolic signatures for CNS diseases and drug response in schizophrenia, depression, motor neuron disease, Alzheimer's and Parkinson's disease, In this entirely revised study application, we will now build on our initial work mapping lipidomic signatures to now replicate and extend further these lipidomic profiles as well as to incorporate neurotransmitter platforms of relevance to schizophrenia pathophysiology and treatment. In order to establish a robust scientific platform to later study the effects of antipsychotic treatment, we will first innovatively examine neurotransmitter and signatures in unmedicated patients with schizophrenia and in a healthy and carefully matched comparison group. We hypothesize that there will be metabolomic signatures associated with (1) glutamate-dopamine-serotonin neurotransmitter dysfunction, and (2) membrane phospholipid dysfunction. Phospholipids play an important role in regulating membrane structure and function and perturbations in these lipids impact proper neuro transmission. Characterizing these metabolic signatures is an important first step towards understanding disease pathogenesis in advance of studying putative metabolic signatures associated with treatment response.
This project takes important steps toward understanding the biochemical expression of schizophrenia by examining for metabolic signatures that are associated with the illness. If we succeed in discovering a disease signature for schizophrenia, this could provide an external validating measure that will improve clinical and may offer leads to the underlying pathophysiology of schizophrenia.
|McEvoy, Joseph; Baillie, Rebecca A; Zhu, Hongjie et al. (2013) Lipidomics reveals early metabolic changes in subjects with schizophrenia: effects of atypical antipsychotics. PLoS One 8:e68717|
|Yao, Jeffrey K; Condray, Ruth; Dougherty Jr, George G et al. (2012) Associations between purine metabolites and clinical symptoms in schizophrenia. PLoS One 7:e42165|
|Condray, Ruth; Dougherty Jr, George G; Keshavan, Matcheri S et al. (2011) 3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia. Int J Neuropsychopharmacol 14:756-67|