Schizophrenia (SCZ) is a severe, chronic, and disabling psychotic illness that affects approximately 87,000 Veterans. Deficits in the performance of critical everyday functions are important and tragic consequences of SCZ. Rehabilitative treatment for disability reduction has the potential to benefit nearly every patient with SCZ. Cognition in SCZ has the potential to be enhanced by behavioral interventions. Brain changes have been shown to accompany enhanced cognition after cognitive training in SCZ, such as increases in a marker of brain plasticity (brain-derived neurotrophic factor, BDNF), and normalization of a measure that is dependent on the hippocampus. This hippocampal finding is important because of known hippocampal abnormalities in SCZ and their link to impaired cognition. Participants with SCZ are capable of participating in aerobic exercise (AE) training and making gains in fitness. One small study reported improved short-term memory with AE compared to a control non-aerobic exercise, but the sample size was limited to 8 per group. Importantly, this study found increased hippocampal volume that correlated with gains in aerobic fitness and with cognitive improvement. AE is known to confer many physical health benefits. The AE literature in animals and healthy aging populations is informative for this SCZ project. A number of recent studies indicate that AE is associated with cognitive gains in healthy aging subjects, and these gains correlate with hippocampal volume increases, that in turn correlate with increased BDNF and cardiovascular fitness. AE in rats increases BDNF mRNA, and this occurs prominently in the hippocampus. Taken together, these preclinical and clinical studies are consistent with the hypothesis that AE, via increases in fitness, induce BDNF increases that lead to brain changes, particularly (but not necessarily limited to) the hippocampus that subserve cognitive gains with AE. There are parallels between the reduced hippocampal volume in SCZ and the hippocampal volume loss seen with normal aging. It is possible that a similar mechanism may underlie potential cognitive gains with AE in SCZ. AE is a potentially important means to improve cognition in SCZ, but work on the cognitive effects of AE in SCZ is surprisingly sparse. This project will fill this important knowledge gap. The study will be a randomized rater blind parallel group clinical trial to compare twelve weeks of AE training with a control condition (CONT) consisting of stretching exercises in 40 participants aged 18-70 with SCZ or schizoaffective disorder.
Specific Aims of the project are:
Specific Aim 1 : Compare the feasibility and effectiveness of AE training to a CONT condition at the end of training (12 weeks) in VA participants with SCZ. We predict that completion of this training will be feasible in our VA population, and that the AE group will exhibit significantly greater cognitive improvement than the CONT group (measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery, MCCB). MCCB at 8 weeks post-training follow up will be a secondary outcome.
Specific Aim 2 : Evaluate whether increases in cardiovascular fitness mediate cognitive improvement. Cardiovascular fitness will be estimated with a reliable and valid measure of oxygen uptake (VO2max) prior to and after 12 weeks of the AE vs. CONT intervention and at 8 weeks post-training follow up. Estimated VO2max is the most appropriate test as it accounts for initial fitness level of the participant without the physically exhausting and frightening experience of a full V02max test. We predict that estimated VO2max improvement in the AE group will predict cognitive gain with training at 12 weeks and 8 weeks post-training follow up.
Specific Aim 3 : Compare changes in measures of everyday functional abilities (U. California San Diego Performance-Based Skills Assessment, UPSA) in the AE vs. CONT groups. We predict that the AE group will show greater gains in the UPSA than the CONT group at 12 weeks and 8 weeks post-training follow up.
Schizophrenia affects over two million Americans, many of whom are Veterans. Schizophrenia is generally a life-long condition: thus the disabilities with which these patients struggle will require treatment from the VA for the life of the patients. Improvements in cognitive function and skills of everyday living are highly resistant to treatment with our currently available medication. This proposal will investigate the feasibility and effectiveness of aerobic exercise (AE) to enhance the cognition and rehabilitation of our Veteran patients. If AE leads to enhanced cognitive functioning of these patients, AE could become a valuable treatment modality for the rehabilitation of our patients. AE could thus have dual benefits on both cognition and physical health. Hence this proposal is highly relevant to the VA mission of reducing impairments and rehabilitating our Veteran patients.
