Co-chairs: Hank Riordan, PhD; Steven Potkin, MD
The fall dinner session was hosted by Henry Riordan, Paul Song and Steve Potkin. Dr. Riordan began the session by recounting the reasons for the formation of the BWG including the need to ensure that the interests and expertise of the International Society for CNS Clinical Trials and Methodology are thoughtfully considered and communicated to the Society’s members updating attendees regarding the mission and activities of the BWG. By way of background he reasserted the important role of various biomarkers in informing clinicians about the relative safety, tolerability and efficacy of a range of CNS drugs and products. In addition, biomarkers can aid in the development of novel therapeutic agents, identify susceptible populations, provide endpoints for clinical trials and even serve as predictor variables. As such an emphasis of the BWG is to determine which imaging biomarkers are predictive of treatment response.
Dr. Riordan briefly reviewed the process and methodology utilized by the BWG to offer support for imaging biomarkers in future schizophrenia trials. He then briefly summarized the qualitative evaluation of the utility of imaging biomarkers in schizophrenia as a measure of treatment response. Schizophrenia treatment studies that included the structural or functional imaging modalities, including vMRI, fMRI, FDG-PET, receptor occupancy PET & SPECT, and DTI were identified, categorized, and evaluated with strongest evidence being in support of volumetric MRI which exhibited the highest overall qualitative rating. Therefore, this imaging modality was chosen for more quantitative analyses. Brain regions examined included whole brain, lobar volumes, basal ganglia and ventricular volumes, as well as grey and white matter. Analysis of intervention effects on brain volume revealed a moderate but non-significant overall effect size. However, significant decreases in brain volume were associated with treatment were noted for a total white matter that was seen early in treatment and grew in response to study duration. Interestingly some evidence was also noted for an increase in grey matter for two atypical antipsychotic medications. An analysis of homogeneity including all studies revealed no significant variance among effect sizes that would support examining the effects of moderator variables While these initial results did not fully support the qualitative evidence grading they did suggest that it is
Paul Song then reviewed the process and services offered by Dr. Evidence that could potentially be utilized by the BWG in future activities. The mission of Dr. Evidence is to improve clinical outcomes by finding, delivering, and making relevant and readable medical evidence that enables clinicians to support informed decisions. This is accomplished through a suite of evidence based medicine methodologies and analytic tools that are unified in a singular technology platform. The services most likely to be utilized by the BWG include a comprehensive library management system equipped with a robust search engine, data extraction and quality control with accompanying QUOROM charts to identify why studies are not chosen for evaluation, automated evidence tables, and meta analysis complete with funnel and forest plots. Importantly, once data is extracted the meta analysis tool is customizable so that effect sizes can be obtained for subsets of studies and even types. Corroboration of the prior quantitative results via meta analysis with a QUOROM Flow diagram of rejected references is planned.
Finally Steve Potkin reviewed the literature suggesting the power of an integrated approach to biomarkers by assessing brain imaging and genetic factors simultaneously to provide new targets fordrug development, enrich study populations for Proof of Mechanism and Target Engagement studies. The function of genes on behavior can be determined by brain imaging. Brain function is strongly influenced by genetic factors; therefore, studying the integration of imaging and genetics offers the possibility of greater understanding that studying each independently.