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Synergy in Action

ISCTM 2012 Scientific Meeting – Biomarkers Summary

Biomarkers Working Group Dinner
22 Feb 2012
Chair: H Riordan

The dinner session presented a good opportunity for Henry Riordan and Nathen Chen to update the ICTM membership regarding the mission and activities of the BWG by. Dr. Riordan began the session with an overview of the origins of the BWG as well as a review of the BWG mission statement and deliverables.  Dr. Chen then provided updates on the qualitative grading data presented at the fall session in addition to the major findings in his poster. Dr. Riordan followed by reviewing the quantitative data and analyses conducted to date and introduced the ISCTM membership to the services offered by Dr. Evidence who have been invited to next ISCTM meeting.

By way of background Dr. Riordan noted that as CNS drug development advances toward an increasingly personalized approach to treatment, the role of various biomarkers has become ever more important for 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.  The growing interest in biomarkers raises many challenges for diverse stakeholders regarding both the structure and elements of clinical trials that are needed to establish valid scientific data in support of these biomarkers. Unfortunately, CNS drug developers currently lack sufficient data and many of the tools necessary to successfully implement the use of biomarkers in the drug development process. Given this, and the burden of development and qualification of biomarkers in terms of both time and cost, the formation of collaborative international groups to undertake these biomarker related challenges is essential.  These challenges also provide a unique opportunity for meaningful industry-academia-government collaboration; and the BWG was formed to help meet these challenges while ensuring that the interests and expertise of the International Society for CNS Clinical Trials and Methodology are both thoughtfully considered and communicated to the Society’s members.

Dr. Chen then 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. The following table summarizes his report on the results of this qualitative grading of evidence evaluation for these putative imaging biomarkers.

  Paper Identified Abstract Reviewed Articles on Target Key Findings Evidence Level

sMRI

265
 
100
 
35
 

– Volume loss of frontal grey matter in schizophrenia at various stage

– Loss of both grey and while matter vs treatment by typical antipsychotics

– Loss of grey matter but increase of while matter vs treatment by atypical antipsychotics

A

fMRI

1881 15+ 15

– Evidence for psychopharmacological effects on cerebral physiology (e.g., percent signal change in frontal lobe regions).

– Evidence for psychopharmacological effects on functional connectivity

B

DTI

250 16 10

– No prospective study prospectively examined between group treatment effects

– Anisotrophy in pts generally lower than healthy controls; lower still in pts with “poor outcomes

– Anisotrophy reductions in pts take place earlier in the course of illness, closer to the time of first psychotic episode and stabilize in its chronic phase, but inconsistent findings and confounded by age and illness duration.

D

FDG-PET

7 7 7

– Resting rCBF was significantly lower in schizophrenia compared to normal controls

– Schizophrenics has significantly higher right and left contrast enhancement compared to normal controls

– Antipsychotics was associated with greater change toward normal values & away from the values found in the unmedicated comparison group for dorsolateral prefrontal cortex gray matter and white matter underlying medial prefrontal and cingulate cortex.

C+ – B

PET

184 40 22

– Model to characterized dose –occupancy relationship

– Striatal D2/D3 occupancy predicted both improvement of positive symptoms and occurrence of EPS

B+ – A

SPET

50 25+ 25

– See PET

– Limited 5HT2A blockade in antipsychotic action

– Confirm neurotransmitter dysfunction of D2, 5-HT2A, NMDA, GABA, muscarinic receptors

– Regional Cerebral  Blood Flow (rCBF) analysis suggested hypofrontality

– Evidence of differential rCBF related to antipsychotic efficacy and cognitive improvements

B+ – A

By way of follow up and in order to determine the quality of evidence to support the application of imaging biomarkers in clinical trials of schizophrenia Dr. Riordan reviewed the relevant sMRI literature – the area that had the highest overall qualitative rating.  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 (across different types medication) revealed a moderate but non-significant overall effect size  (g=0.452, 95% CI= -0.56, 0.17)). An analysis of homogeneity including all studies revealed no significant variance among effect sizes that would support examining the effects of moderator variables (QB[133]=133.299 12, p<0.45). Significant decreases associated with treatment were noted for a total white matter volume 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 antipsychotics.  While these initial results did not fully support the qualitative evidence grading they did suggest that it is possible to more confidently select specific brain regions that are more likely to be sensitive to antipsychotic medication effects. Further work is needed relating these ESs to changes in schizophrenia symptoms and outcomes.

Key Outcomes of the BWG Dinner Session:
 
•Provided a summary of the qualitative grading data for imaging biomarkers (sMRI, fMRI, DTI, FDG/receptor PET & SPECT) suggesting highest rating for sMRI.
 
•Reviewed the quantitative data and meta analytic procedures for sMRI changes in various ROIs associated with treatment effects with largest ES for white matter decreases over time.
 
•Introduced the process and services offered by Dr. Evidence that could potentially be utilized by the BWG in future activities.   A formal presentation by Dr. Evidence on replication of meta analyses at the Fall 2012 meeting is anticipated. 
 
•Explored the possibility of registering schizophrenia imaging biomarkers meta analysis on Cochrane Collaboration as well as approach to publication supporting the utility of key biomarkers (cognition, ERP, imaging etc.) in a proof of concept setting.