Schizophrenia (SZ) is a common and severe psychiatric disorder. There is emerging evidence that multiple structural and functional brain abnormalities develop early in the illness and outcomes can improve significantly with early intervention as opposed to reversal of morbidity. However, all currently available antipsychotics are effective on similar pathways; treatment failure is common and patients frequently suffer from side effects. Therefore, there is a critical need to identify new biological mechanisms that contribute to the pathology early in the illness and to develop novel treatments targeting these processes. Integrity of the high energy phosphate (HEP) metabolism is essential for providing energy required by myriad neuronal functions, including neurotransmission and plasticity -processes implicated in SZ pathology. While ATP is the primary energy source, creatine kinase (CK) enzyme reaction plays a central role in maintaining stable ATP concentrations by creating a HEP pool as PCr, and generating ATP from PCr during increased energy demand. Recent studies show abnormalities in several bioenergetic mechanisms in psychotic disorders, including reductions in CK rate at rest. However, CK has not been studied during neuronal activation in psychotic disorders. Identifying mediators of brain energy abnormalities will allow novel treatment approaches. Sleep, and specifically slow wave sleep (SWS), has a restorative role in brain energy homeostasis, and EEG power density at the slow wave frequency (slow wave activity, SWA) is the measure associated with the improvements in energy measures. SZ is characterized by pervasive sleep disturbances, including in the first episode (FE), and there is evidence for specific SWS deficits. However, the association of sleep characteristics and brain energy metabolism in this disorder has not been studied. Given this background, we propose to study the activity of CK enzyme during neuronal activation in patients with FE non-affective psychosis, and identify the role of reduced overnight accumulation of SWA in explaining CK modulation. For this purpose, we will collect overnight polysomnography data and use in vivo phosphorus magnetization transfer. Candidate is a psychiatrist with a background in neuroimaging research in psychotic disorders. Training objectives for this grant are for the candidate to gain 1. Training in sleep research; 2. Advanced training in cell biology and biochemical aspects of brain function; 3. Advanced training in statistics; 4. Training in data presentation and grant writing skills. These goals will be accomplished by mentorship, formal coursework, and the help of an exceptionally-qualified team of advisors and collaborators. The successful completion of this career development plan will assist the candidate in making the transition to an independent investigator with R01 level funding.
Outcomes in schizophrenia (SZ) may improve significantly with early intervention as opposed to reversal of morbidity, however, all currently available antipsychotics are effective on similar pathways, treatment failure or partial response is common. Therefore, there is a critical need to identify new biological processes that contribute to the pathology early in the illness. Proposed studies aim to identify a specific bioenergetic abnormality in early SZ and establish a mechanism that can be targeted for the treatment of this abnormality.
