Early identification of neurobiological markers of remission Michael Bodnar, PhD Ashok K. Malla, MD Martin Lepage, PhD
Outline Why study remission? Defining remission Data collection Results neurocognition neuroimaging: smri & fmri Conclusions & Future Direction
Why study remission? heterogeneity of outcome (Emsley et al, 2011, Curr Opin Psychiatry) inability to predict response early on (Menezes et al, 2006, Psychol Med) trial-and-error treatment strategy ongoing assessments careful monitoring of response and side-effects (Tandon et al, 2010, Schizophr Res) the challenge: to better understand the heterogeneity of outcome following a first-episode of psychosis identify markers of remission
Remission in schizophrenia PANSS level : mild or less 1 Absent 2 Minimal 3 Mild 4 Moderate 5 Moderately Severe 6 Severe 7 Extreme on all 8 core symptoms delusions hallucinatory behavior unusual thought content blunted affect passive or apathetic social withdrawal lack of spontaneity & flow of conversation mannerisms & posturing conceptual disorganization sustained for at least 6 months (Andreasen et al, 2005, Am J Psychiatry)
Data Collection Symptom evaluations Month 6 Month 12 Month 24 Neurocognition Neuroimaging structural MRI functional MRI DTI Neurocognition Neuroimaging structural MRI Since 2003 500+ clients treated Since 2004 smri: 135 initial, 68 fup1, & 47 fup2 Neuroimaging structural MRI DTI
Remission Rates Early Remission Month 6 Month 12 Remitted Non-Remitted FES sample Neuroimaging Neurocognition n=39, 20% n=16, 23% n=25, 23% n=157, 80% N=55, 77% n=83, 77% Percentages in line with other studies (Emsley et al, 2011, Curr Opin Psychiatry) rates varied from 19% to 88%
Neurocognition 0,0 z score -0,5-1,0 p=0.006-1,5-2,0 Verbal Memory Visual Memory Working Memory Speed of Processing (adapted from Bodnar et al, 2008, Br J Psychiatry) Reasoning/Problem Solving Non-Remitted (n=83) Remitted (n=25) Control (n=49) FES (n=108) Attention MATRICS Measurement and Treatment Research to Improve Cognition in Schizophrenia (Nuechterlein et al, 2004, Schizophr Res)
Automated whole-brain analysis (VBM8) right parahippocampal gyrus left hippocampus Areas with lower grey matter in non-remitted (n=41) compared to remitted (n=17) (p<0.001, uncorrected) (adapted from Bodnar et al, 2011, Clin Schizophr Related Psychoses)
Parahippocampus & Hippocampus Parahippocampal Entorhinal Perirhinal Tail Head Body Amygdala (Pruessner et al, 2002, Cereb Cortex) (Pruessner et al, 2000, Cereb Cortex) (Bodnar et al, 2010, Schizophr Res)
Verifying the VBM results... 3000 Parahippocampal Cortex 900 Hippocampus Tail 2800 800 2600 700 2400 600 2200 p=0.031 Left p=0.005 Right 500 p=0.001 Left p=0.027 Right (adapted from Bodnar et al, 2012, Psychiatry Res) Correlation, No significant Right differences Side in Social Withdrawal: -0.351, p=0.008 entorhinal or perirhinal cortices. Verbal Memory: 0.349, p=0.009 (adapted from Bodnar et al, 2010, Schizophr Res) No There significant were no differences significant in body or or head trend-level subregions correlations. amygdala. Non-Remitted (n=41) Remitted (n=17)
fmri Behavioral Task + + Which Alive or one not is bigger? alive? Encoding Strategy Semantic Relatedness 2x2 design Related Unrelated Associative Associativerelated Associativeunrelated (Achim et al, 2007, JAMA Psychiatry) Item-Oriented Item-related Item-unrelated
Related > Unrelated: Non-Remitted > Remitted 2.00 Posterior cingulate in schizophrenia: 1.50 remains overactive when mentally engaged 1.00 0.00-0.50 1.49-1.00-1.35 memory (Broyd et al, 2009, Neurosci Biobehav Rev; Mannell et al, 2010, Hum Brain Mapp) -1.50 Non-Remitted Remitted (Bodnar et al, 2012, Br J Psychiatry) left posterior cingulate peak voxel: x=-10, y=-57, z=12 cluster size: 130 voxels; t-value: 4.91 (Garrity et al, 2007, Am J Psychiatry; Meda et al, 2009, PLoS One; Whitfield-Gabrieli et al, 2009, Proc Natl Acad Sci USA) 0.50 hyper-activity worse memory (Meda et al, 2009, PLoS One; Whitfield-Gabrieli et al, 2009, Proc Natl Acad Sci USA) No significant differences for: associative > item-oriented or successful > unsuccessful PCC fails to turn off leading to over-sampling and unfocused attention poorer
Summary of results Non-Remitted: poorer verbal memory smaller hippocampus tail & parahippocampal cortex abnormal activity in posterior cingulate Posterior memory-related neural network differences between remitted & non-remitted FES patients Markers identified may be related to either positive or negative symptoms or both
Conclusions & Future Directions A better understanding of clinical outcome and of schizophrenia Highlight specific areas for future clinical research developing newer, target-specific treatments Negative (and positive) symptoms should be explored in further detail to determine specificity of markers related to remission
Thank you All personnel at PEPP Dr. Srividya Iyer Dr. Ridha Joober Dr. Ashok Malla All current and former lab members Hazel Sutton Audrey Benoit Jennifer Dell Elce Dr. Amelie Achim Dr. Philippe-Olivier Harvey Dr. Martin Lepage All of the clients and especially those who have kindly given their time to take part in our research.
Symptomatic profiles Positive Symptom Total Negative Symptom Total 35 30 25 20 15 * * * 35 30 25 20 15 * * * * * 10 10 5 5 0 First Assessment Month 3 Month 6 Month 9 Month 12 0 First Assessment Month 3 Month 6 Month 9 Month 12 * p<0.01 * p<0.001 Non-Remitted (n=83) Remitted (n=25)
Negative symptoms in remission Non-Remitted n=83, 77% n=33 Psychoticism Negative n=16 n=2 n=32 Disorganization Mixed Correlation: Parahippocampal Cortex and Social Withdrawal Right, -0.351, p=0.008 Left, -0.297, p=0.026 Individual symptoms for not achieving remission: 1 delusions; 3 hallucinations 2 conceptual disorganization 7 blunted affect; 12 social withdrawal; 2 lack of spontaneity
Remitted vs. Non-Remitted 1 year 2 year Non-Remitted n=157, 80% Remitted N=39, 20% Non-Remitted Remitted n=113, 72% N=53, 32% R NR: 9 NR R: 14
Cortical Thickness right Medial left parahippocampal gyrus posterior cingulate Red = areas with less thickness in non-remitted (p<0.01, corrected) 56 FES: 39 non-remitted & 17 remitted
Parahippocampal Gyrus mm 3 3500 3000 Non-Remitted (n=41) Remitted (n=17) Controls (n=5) 2500 2000 1500 1000 p=0.031 Parahippocampal Perirhinal Entorhinal Parahippocampal Perirhinal Entorhinal Left p=0.005 Right Comparison between non-remitted and remitted patients only. No significant [group x region x side] interaction: F=0.36, df=2,54, p=0.70
Hippocampus Tail
Parahippocampal Cortex mm 3 Non-Remitted (n=41) Remitted (n=17) 3000 * Correlation: 2800 Social Withdrawal Right, -0.351, p=0.008 Left, -0.297, p=0.026 2600 2400 2200 p=0.031 Left p=0.005 Right No significant differences in entorhinal or perirhinal cortices (adapted from Bodnar et al, 2012, Psychiatry Res)
Hippocampus Tail mm 3 900 800 Non-Remitted (n=41) * Remitted (n=17) No significant correlations 700 600 500 p=0.001 Left p=0.027 Right No significant differences in body or head subregions or amygdala (adapted from Bodnar et al, 2010, Schizophr Res)
Hippocampus Tail 1 year follow-up 900 850 800 p=0.009 p=0.163 p=0.137 p=0.006 750 700 650 First Assessment Follow-Up Left Right Non-Remitted (n=26) Remitted (n=12)
DTI: posterior cingulum bundle 0.400 Non-Remitted (n=14) Remitted (n=9) 0.380 FA Value 0.360 0.340 0.359 0.360 0.351 0.349 0.320 Right Posterior Cingulum Left Posterior Cingulum posterior cingulum bundle: hippocampus to cingulate
Defining remission Consensus definition of remission in schizophrenia published in 2005 (Andreasen et al, Am J Psychiatry, 2005, 162:441-449). Measured with PANSS, SAPS & SANS, or BPRS & SANS. Easily implemented in clinical trials and clinical practice. Can easily and directly compare studies of outcome and across cultures. (van OS et al, Acta Psychiatr Scand, 2006, 113:91-95).
Defining remission Negative symptoms equally important: higher baseline levels related to a poorer outcome (White et al, Psychol Med, 2009, 39: 1447-1456) necessary to properly assess remission (Cassidy et al, Schizophr Bull, 2010, 36: 1001-1008). 6-month time component as symptoms tend to fluctuate 3-month equally valid (Cassidy et al, Schizophr Bull, 2010, 36: 1001-1008). (Moller, Eur Psychiatry, 2007, 22:380-386)