Overview. Optimizing Treatment in Schizophrenia: An Update. Illness Phases. First Episode

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1 Overview Optimizing Treatment in : An Update Christoph U. Correll, MD Professor of Psychiatry, Hofstra Northwell School of Medicine Hempstead, New York Medical Director, Recognition and Prevention Program The Zucker Hillside Hospital Glen Oaks, New York Treatment Goals First Episode Chronic Maintenance Treatment Treatment Resistance Adverse Effects Medications in Development Conclusions Illness Severity 10% 45% (FES: 5% 10%) Resistance Exacerbation Acute 18% 65% (FES: 40% 87%) Response Remission: 6 mo: 44% 12 mo: 52% 24 mo: 47% > 24 mo: 49% Stabilization Illness Phases Any duration : 57.3% Relapse Any duration: 44% (7% 52%) (FES: 17% 81%) Remission 13.5% [8% 20%] (FES: 16.6% ) Recovery Maintenance Treatment Phase FES = first-episode schizophrenia. Median [interquartile range]; In antipsychotic discontinuation studies. Carbon M, et al. Dialogues Clin Neurosci. 2014;16(4): Illness Severity 10% 45% (FES: 5% 10%) Resistance Exacerbation Acute 18% 65% (FES: 40% 87%) Response Stabilization Illness Phases Any duration : 57.3% Relapse Any duration: 44% (7% 52%) (FES: 17% 81%) Remission Relapse (placebo ): 3 mo: 37% 4 6 mo: 50% 7 12 mo: 64% mo: 79% Relapse (FES): 12 mo: 16% 24 mo: 54% 36 mo: 63% 48 mo: 75% 60 mo: 82% 13.5% [8% 20%] (FES: 16.6% ) Recovery Maintenance Treatment Phase FES = first-episode schizophrenia. Median [interquartile range]; In antipsychotic discontinuation studies. Carbon M, et al. Dialogues Clin Neurosci. 2014;16(4): Randomized Trials of SGAs vs FGAs in First-Episode First Episode N = 13, n = CGI-S = Clinical Global Impression Severity; FGA = first-generation antipsychotic; SGA = second-generation antipsychotic. Zhang JP, et al. Int J Neuropsychopharmacol. 2013;16(6):

2 A Randomized Comparison of Aripiprazole and Risperidone for the Acute Treatment of FES and Related Disorders: 3-Month Outcomes First large scale, double-masked, randomized comparison of aripiprazole (5 30 mg/day) vs risperidone (1 6 mg/day) in FES 198 patients, years old, with schizophrenia, schizophreniform disorder, schizoaffective disorder, or psychosis NOS Antipsychotic treatment 2 weeks lifetime 12-week RCT yielded no difference in: Positive symptom response rate (ARI = 62.8% vs RIS = 56.8%, P =.61) Time to response (8.0 vs 8.2 weeks) Change in total (P =.32) or positive symptoms (P =.96) or CGI-S (P =.57) Body weight gain Superiority of risperidone (mean dose: 3.2 mg/day) for Less akathisia (P =.03), but only early on in the trial (weeks 1 4) Superiority of aripiprazole (mean dose: 14.8 mg/day) for Negative symptoms: Avolition-apathy (P =.03) Depressed mood (P =.02) Total cholesterol (P =.003), LDL-cholesterol (P <.01), fasting glucose (P =.03) Prolactin levels (P <.0001). ARI = aripiprazole; RIS = risperidone; LDL = low-density lipoprotein; NOS = not otherwise specified; RCT = randomized controlled trial. Robinson DG, et al. Schizophr Bull. 2015;41(6): Recovery after an Initial Episode Early Treatment Program (RAISE-ETP) N = 404 (394 with cardiometabolic data) Age: years Diagnoses: Schizophreniform disorder, schizophrenia, schizoaffective disorder, psychotic disorder NOS, acute psychotic disorder < 6 months antipsychotic treatment Cluster randomized assignment of 34 centers to integrated care (NAVIGATE) or community care Treatment and follow-up for 2 years Primary outcome: Quality of life Secondary outcomes: Service utilization, cost, subjective well-being, relapses, hospitalization, recovery, cardiometabolic health Kane JM, et al. J Clin Psychiatry. 2015;76(3): NAVIGATE Team-based Shared decision making Strength and resiliency focus Psychoeducational teaching skills Motivational enhancement teaching skills Collaboration with natural supports 4 components 1. Psychopharmacology COMPASS 2. Individual Resiliency Training (IRT) 3. Family psychoeducation 4. Supported employment/education Demographics Adjusted for Cluster Design NAVIGATE Community Care P value Age and Gender Age (mean) Males (%) Race White (%) African American (%) Other (%) Role Functioning In school (%) Working (%) Prior Hospitalization (%) Kane JM, et al. J Clin Psychiatry. 2015;76(3): NAVIGATE Participants Stayed in Treatment Longer Time to Last Mental Health Visit (P =.009) Quality of Life Scale Fitted Model Group by Time Interaction (P =.015) DUP by Time Interaction (P =.003) DUP = duration of untreated psychosis; QLS = Quality of Life Scale.

3 PANSS Total Score Change over 2 Years Group by Time Interaction : P =.016 DUP by Time Interaction: P =.043 % With Any Work or School Days / Month (Group by time interaction: P =.044) Median DUP = 74 weeks. PANSS = Positive and Negative Syndrome Scale. Months Time to First Psychiatric Hospitalization (Difference between treatments, P =.75) First-Episode : Key Points First-episode patients are generally more treatment responsive They require lower doses (~ 50%) They are more sensitive to side effects Relapse is very common While acute efficacy might be similar with FGAs and SGAs, relapse and treatment discontinuation seem to be higher with FGAs Multidisciplinary interventions focusing on engagement, treatment continuation, relapse prevention, physical health, and functional recovery are paramount Multiple Treatments Meta-Analysis Multi-episode / Chronic Aim Create hierarchy for 15 antipsychotic drugs Efficacy and major side effects Direct and indirect comparisons Includes some treatments without a European Union license for schizophrenia (sertindole, iloperidone, zotepine, ziprasidone, asenapine) Data set 212 RCTs Acute schizophrenia 43,049 participants Mean illness duration: 12.4 years Mean age: 38.4 years Network of comparisons for efficacy Leucht S, et al. Lancet. 2013;382(9896):

4 Forrest Plot: Efficacy of Antipsychotics vs Placebo The differences in efficacy between non-clozapine, firstline antipsychotics were small: Standardized mean differences: , median = 0.11 Magnitude PANSS Total Change on Placebo over Time in Trials of Acute Antipsychotics differed substantially in side effects: Standardized mean differences: , median = 0.34 (body weight) and 0.49 (prolactin) 1, 2, or 3 asterisks: Significant separation from placebo; **Significant separation from agents with 1 asterisk; ***Significant separation from all other agents; a: Only superior to lurasidone and iloperidone; b: Only superior to iloperidone; SMD +/- 95% CIs. Leucht S, et al. Lancet. 2013;382(9896): Alphs L, et al. Int J Neuropsychopharmacol. 2012;15(7): What is the Importance of Relapse Prevention? Maintenance 1. Harrison G, et al. Br J Psychiatry. 2001;178: Herings RM, et al. Pharmacoepidemiol Drug Saf. 12(5): Lieberman JA, et al. Neuropsychopharmacology. 1996;14(Suppl 3):13S-21S. 4. Lieberman JA, et al. Psychiatr Serv. 2008;59(5): Kane JM. J Clin Psychiatry. 2007;68 Suppl 14: Clinical Predictors of Poor Outcomes in the Long-Term Course of FES* Antipsychotics vs Placebo for Relapse Prevention in *Based on longitudinal first-episode samples. Carbon M, et al. Dialogues Clin Neurosci. 2014;16(4): Depot antipsychotics reduced relapse (RR 0.31, 95% CI ) more than oral drugs (0.46, ; P =.03). In a metaregression, drug-placebo advantages decreased with study length. Leucht S, et al. Lancet. 2012;379(9831):

5 Antipsychotics vs Placebo for Relapse Prevention in Antipsychotics vs Placebo for Relapse Prevention in Depot antipsychotics reduced relapse (RR 0.31, 95% CI ) more than oral drugs (0.46, ; P =.03). In a metaregression, drug-placebo advantages decreased with study length. Leucht S, et al. Lancet. 2012;379(9831): Depot antipsychotics reduced relapse (RR 0.31, 95% CI ) more than oral drugs (0.46, ; P =.03). In a meta-regression, drug-placebo advantages decreased with study length. Leucht S, et al. Lancet. 2012;379(9831): Indirect Comparison: LAIs and Oral Antipsychotics Compared with Placebo for Relapse Prevention Characteristics of Selected FGA and SGA LAIs Test for subgroup differences: P =.03, I 2 = 77.9% LAI = long-acting injectable antipsychotic. Leucht S, et al. Lancet. 2012;379(9831): Correll CU, et al. J Clin Psychiatry. 2016;77(suppl 3):1-24. No Differences in Study-Defined Relapse/All-Cause Discontinuation between LAIs and Oral Antipsychotics N studies Total RR P value Fluphenazine LAIs Were Not Superior to Oral Antipsychotics Regarding Adherence Meta-analysis of 10 RCTs in schizophrenia followed for 6 months Relapse Haloperidol Olanzapine LAI Risperidone LAI Zuclopenthixol Total All-cause Haloperidol Olanzapine LAI Risperidone LAI Zuclopenthixol discontinuation Fluphenazine Total Favors LAI Risk ratio (95% CI) Favors oral APs No difference in adherence between pooled LAIs and oral APs (only measured in 2 studies) ; 21 RCTs, N = 5176; > 6 months follow-up, in- and outpatients. AP = antipsychotic. Kishimoto T, et al. Schizophr Bull. 2014;40(1): Kishimoto T, et al. Schizophr Bull. 2014;40(1):

6 LAIs Reduce Risk of Hospitalization Compared with Oral Antipsychotics in Mirror Image Studies Study RR P value Girardi et al Beauclair et al <0.001 Arato & Erdos <0.001 Devito et al <0.001 Denham & Adamson <0.001 Morritt <0.001 Lam et al <0.001 Lindholm <0.001 Peng et al <0.001 Gottfries & Green Rosa et al Chang et al <0.001 Johnson & Freeman <0.001 Crivera et al <0.001 Ren et al <0.001 Svestka et al Total (16 studies) (n = 4066) < ; 25 mirror-image studies; N = 5940; > 6 months follow-up Kishimoto T, et al. J Clin Psychiatry. 2013;74(10): MPR (%) Medication Possession Ratio Improved following Initiation of LAIs Commercially Insured (n = 394) P <.001 In an analysis of US databases, patients* who initiated LAI antipsychotics demonstrated an improvement in MPR *Patients 13 years old were identified using an ICD-9 diagnosis of schizophrenic disorders (295.xx) on administrative claims, which includes schizophrenia, schizophreniform disorder, and schizoaffective disorder. MPR = medication possession ratio. Offord S, et al. J Med Econ. 2013;16(2): MPR (%) Medicare Insured (n = 147) P <.001 LAIs Significantly Improve Treatment Outcomes in Patients with 33% vs 5% Relapse in 86 FES Patients Randomized to Oral RIS vs RIS LAI Risk of discontinuation or rehospitalization after a first hospitalization for schizophrenia, by antipsychotic treatment (n = 2588) ; nationwide register study; follow-up after first admission for schizophrenia. Tiihonen J, et al. Am J Psychiatry. 2011;168(6): Excellent adherence: RIS = 33%, RIS LAI = 95%. Subotnik KL, et al. JAMA Psychiatry. 2015;72(8): Management of Treatment-Resistant Patients Treatment Resistance Kane JM, et al. UptoDate Accessed June 5, 2017.

7 Network Meta-Analysis of Head-to-Head Trials of APs vs Clozapine in Treatment-Resistant : Total Symptoms Psychopharmacologic Augmentation of Any AP: Total Symptoms Samara MT, et al. JAMA Psychiatry. 2016;73(3): Correll CU, et al. JAMA Psychiatry. 2017;[Epub ahead of print]. AMSTAR-Plus Content Score Items A. AMSTAR-Plus Content Score 1. Was the majority of all meta-analyzed Can t answer/ Double-blind studies: < 84% of all studies double-blind? included studies Double-blind studies: 85% 94% of all included studies Double-blind studies: 95% 100% of all included studies 2. Was the total number of participants in the Can t answer / Total n < 500 meta-analysis sufficiently large? Total n = Total n Point 2 Points 1 Point 2 Points Adverse Effects 3. Was the meta-analytically derived primary outcome result confirmed in at least 1 large study with approximately 100 patients/arm? Can t answer/not confirmed in study with n 200 Confirmed in a 2-arm study with n 200 Confirmed in a 3-arm study with n Point 2 Points 4. Were studies with observed cases analyses included in the meta-analysis? Can t answer/ Yes No 1 Point 5. Was the primary outcome result Can t answer/yes heterogeneous? No (Q statistic = P >.05 and I 2 < 50%) 1 Point 6. Was there significant publication bias Can t answer/yes regarding the primary outcome result? No (Egger s test P >.05, symmetrical funnel plot) 1 Point AMSTAR= A MeaSurement Tool to Assess systematic Reviews. Shea BJ, et al. BMC Med Res Method. 2007;7:10. Correll CU, et al. JAMA Psychiatry. 2017;[Epub ahead of print]. Adverse Effects Considered by Patients Relatives to Have Most Negative Effects on Quality of Life Written survey of relatives of patients with schizophrenia, N = 320 Sedation Weight gain Anxiety Parkinsonism Anticholinergic effects Acute dystonia Insomnia Hypersalivation Akathisia Sexual dysfunction Angermeyer MC, et al. Psychiatr Prax. 1999;26(4): Relatives Listing Adverse Effect (%) Adverse Events Considered by Patients to Have Most Negative Effect on Quality of Life Patients rated metabolic consequences of medication to contribute to morbidity, low quality of life, and low satisfaction with care Weight gain Somnolence/insomnia Concentration difficulties Memory loss Disorganized thoughts UNITE survey was an Internet-based multinational survey with 1155 respondents with schizophrenia and 1300 respondents with bipolar disorder from 11 countries. McIntyre RS. J Clin Psychiatry. 2009;70 Suppl 3: Patients Reporting Adverse Event Prevalence (%)

8 Relapse and Adverse Efffects Reduce Quality of Life in Patients with RAISE: Smoking, Lipid Abnormalities, Hypertension, Diabetes, and Metabolic Syndrome with Related Drug Rx Stable 0.92 Stable with Weight Gain Stable with Hyperprolactinemia Stable with Diabetes Stable with EPS Relapse 0.60 Mean Utility-Score* *The relevance of the different health states was assessed using a Time-Tradeoff instrument. Higher scores reflect better utility for the patient. EPS = extrapyramidal side effects. Briggs A, et al. Health Qual Life Outcomes. 2008;6:105. Dyslipidemia: TG 150 mg/dl, LDL-C or non-hdl-c: 130 mg/dl; HDL-C for males < 40 mg/dl, for females < 50 mg/dl. TG = triglyceride; HDL = high-density lipoprotein. Correll CU, et al. JAMA Psychiatry. 2014;71(12): Medical Risk Management Strategies of Antipsychotic-Treated Patients PREVENTION PRIMARY SECONDARY Treatment Initiation Healthy lifestyle counseling Healthy lifestyle intervention Start with lower-risk antipsychotic If Adverse Effect Is is Present Healthy lifestyle counseling/intervention Consider changing to lower-risk antipsychotic Consider weight loss intervention Medications in Development TERTIARY If Adverse Effect Progresses/Serious Healthy lifestyle counseling/intervention Considering changing to lower-risk antipsychotic Add targeted treatment for pathological values Consider referral to specialist Correll CU. CNS Spectr. 2007;12(10 Suppl 17):12-20, 35. Targets of Phase 2 and Phase 3 Agents for Targets of Phase 2 and Phase 3 Agents for (cont d) Köster LS, et al. Expert Opin Emerg Drugs. 2014;19(4):

9 Recently Approved and Active Phase 3 Agents Pursued by the Pharmaceutical Industry and Academia SCZ Target Neg. SXS Tardive dyskinesia Cannabis Use Neg. SXS, Cognition Neg. SXS, Cognition ITI-007 (Lumateperone) for Acute N = 335 N = 450 Garay RP, et al. Expert Opin Pharmacother. 2016;17(7): Weight Loss Neg. SXS Neg. SXS Vanover KE, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL. N = 696 ITI-007 (Lumateperone) for Acute MIN-101 for Negative Symptoms Vanover KE, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL. Davidson M, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL. MIN-101 for Negative Symptoms ALKS-3831 (Olanzapine + Samidorphan) (ALKS-33 μ Opioid Antagonist) for Davidson M, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL. Silverman B, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; June 22-25, 2015; Miami, FL.

10 ALKS-3831 (Olanzapine + Samidorphan) (ALKS-33 μ Opioid Antagonist) for Vesicular Monoamine Transporter Type 2 Silverman B, et al. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; June 22-25, 2015; Miami, FL. VMAT2 is a protein concentrated in the human brain that is primarily responsible for re-packaging and transporting monoamines (dopamine, norepinephrine, serotonin, and histamine) in pre-synaptic neurons Deutetrabenazine vs Placebo Deutetrabenazine significantly improved AIMS scores from baseline to Week 12 compared with placebo (-3.0 vs -1.6, P =.019) KINECT 3: Change in AIMS total Score from Baseline * N = 117. *P =.007; P =.019. AIMS = Abnormal Involuntary Movement Scale. Fernandez HH, et al. Neurology. 2017;88(21): Hauser RA, et al. Am J Psychiatry. 2017;174(5): Valbenazine for Tardive Dyskinesia: Phase 3 Trial (KINECT 3) AIMS Scores by Study Visit in Extension Phase (ITT) Grigoriadis D, et al. Presented at: 55th Annual Meeting of the American College of Neuropsychopharmacology; December 4-8, 2016; Hollywood, FL. Conclusions is a severe disorder that often has a chronic and debilitating course Early interventions are hoped to delay or prevent the onset of the disorder and to reduce morbidity Due to lack of reliable intra-individual response predictors, antipsychotic choice needs to be tailored to patient characteristics and needs Broadly similar efficacies of antipsychotics (except for clozapine) make optimization of safety and tolerability a significant goal in individualized drug selection Maintenance medication is essential to prevent relapses and nonadherence, often associated with adverse effects, is a leading cause of relapse Novel mechanisms, biomarkers, and personalized medicine are needed