Clinical biomarkers for drug development in schizophrenia. Donald C. Goff, MD Nathan Kline Institute NYU School of Medicine

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1 Clinical biomarkers for drug development in schizophrenia Donald C. Goff, MD Nathan Kline Institute NYU School of Medicine

2 Strategies Biomarkers traditionally reflect specific drug targets or drug pharmacokinetics Illness models increasingly posit complex network dysregulation or impairment of plasticity

3 Potential roles for biomarkers Target engagement CNS activity Markers of drug mechanism: monitoring response Subtyping subjects: responder vs nonresponder

4 Commercial biomarker development in schizophrenia AmpliChip CYP 450 Test Predictor of clozapine response Predictor of iloperidone response (CNTF) PGxPredict: Clozapine (agranulocytosis) PhyzioType System (metabolic syndrome)

5 Increased amphetamine-induced dopamine release in striatum predicts antipsychotic response Laruelle et al, 2003 Abi-Dargham et al, PNACS 2000

6 GWAS discovery & replication of SNP associated with antipsychotic-induced weight gain Malhotra et al, Arch Gen Psychiatry 2012

7 No effect of folate on negative symptoms (n=28) Hill et al, Schizophrenia Research 2011

8 But folate supplementation improves negative symptoms in MTHFR T carriers T MTHFR C677T Genotype Estimate 1 95% CI F ES P-value CC 6.83 (-2.17, 18.82) T-carrier (-17.8, 0.18) T- vs CC (-27.46, -3.79) * Hill et al, Schizophrenia Research, 2011

9 Genetic variants in the folate metabolic pathway that predict negative symptoms Roffman et al, Schiz Bull 2011

10 Relationship between negative symptoms and allelic risk score, using either 4 single nucleotide polymorphism (SNP) score (a) or 5 SNP score (b) models. Low folate High folate Roffman et al. Schiz Bull 2011

11 Folate genes predict response of negative symptoms to folate supplementation (n=140) Roffman et al, JAMA Psychiatry 2013

12 Percent treated with clozapine by BDNF genotype 279 subjects 74 candidate genes from CATIE Clozapine a proxy for treatment resistance Zhang et al, Schiz Res 2013

13 Cognitive Enhancement Therapy Prevents Brain Volume Loss in Early-stage Schizophrenia Eack, S. M. et al. Arch Gen Psychiatry 2010;67:

14 The Blood-Brain Barrier

15 Blood Brain Barrier Active transport: maintains homeostasis influx/efflux transport, protects from harm Modified by inflammation, oxidative stress

16 What can peripheral measures tell us about the brain? 1. Equilibrium of substances that readily cross the BBB 2. Leakage between blood and CSF 3. Environmental factors may similarly affect periphery and CNS 4. Peripheral cells (lymphocytes or fibroblasts) may mirror CNS cells

17 Plasma & CSF BDNF concentrations: First episode psychosis vs controls (n=18) Plasma CSF Plasma: CSF r=0.51, p=0.03 Pillai et al, Int J Neuropsychopharm 2010

18 Blood biomarkers reported in schizophrenia 103 biomarkers 75 inflammatory BDNF ranked #1 Chan et al, Int Review Neurobiology Vol 101, 2011

19 Stress & inflammatory biomarkers and pathways linked to schizophrenia Chan et al, Int Rev Neurobiol 2011

20 Proteomics 250 Medication naïve first episode psychosis subjects 181 proteins screened 34 analytes identified 75% of cases: inflammation hormonal metabolic neurotrophic Schwarz et al, Molecular Psychiatry 2012

21 Methylome-wide association study in Aberg et al, JAMA Psychiatry 2014 schizophrenia 1. Neuronal differentiation/da 3. Hypoxia 2. Inflammation 4. Reelin 1497 subjects 68 million reads/subject Independent replication

22 Peripheral cytokine concentrations in schizophrenia by stage of illness Miller et al, Biol Psychiatry 2011

23 Correlates of serum CRP levels in 200 medication-free schizophrenia subjects Fawzi et al, Psychiatry Res 2011

24 Brain and serum cytokine levels in offspring exposed to maternal immune activation Garay et al Brain Behav & Immun 2013

25 BDNF, IL6 expression & cortisol levels predict left hippocampal volume in first episode schizophrenia Mondelli et al, J Clin Psychiatry 2011

26 Summary Traditional approaches to biomarkers have found little clinical application Recent advances in PET ligands, fmri, DTI will improve early drug development Big data is driving more complex models of illness and identifying potential biomarkers New biomarkers driving drug development in early intervention.