INSIGHTS INTO ADDRESSING EARLY SCHIZOPHRENIA: PRODROME AND FIRST EPISODE

INSIGHTS INTO ADDRESSING EARLY SCHIZOPHRENIA: PRODROME AND FIRST EPISODE S. Charles Schulz, MD Professor & Head Donald W. Hastings Endowed Chair Department of Psychiatry University of Minnesota Medical School Minneapolis, MN

INSIGHTS INTO ADDRESSING EARLY SCHIZOPHRENIA: PRODROME AND FIRST EPISODE Jeffrey A. Lieberman, MD Chairman, Department of Psychiatry College of Physicians and Surgeons, Columbia University Director, New York State Psychiatric Institute Director, Lieber Center for Schizophrenia Research Psychiatrist-in-Chief at New York Presbyterian Hospital and Columbia University Medical Center New York, NY

S. CHARLES SCHULZ, MD Disclosures Research/Grants: AstraZeneca Pharmaceuticals LP; Otsuka America Pharmaceutical, Inc.; Rules-Based Medicine, Inc. Speakers Bureau: None Consultant: Biovail Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Lilly USA, LLC Stockholder: None Other Financial Interest: None Advisory Board: None

JEFFREY A. LIEBERMAN, MD Disclosures* Research/Grants: Allon Therapeutics; F. Hoffmann-La Roche LTD; GlaxoSmithKline; Lilly USA, LLC; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Sepracor Inc.; Targacept, Inc. Speakers Bureau: None Consultant: Bioline; GlaxoSmithKline; Intra-Cellular Therapies, Inc.; Lilly USA, LLC; Pierre Fabre Laboratories; PsychoGenics, Inc. Stockholder: None Other Financial Interest: Patent from Repligen Corporation Advisory Board: None * Receives no personal financial remuneration for these activities

LEARNING OBJECTIVE Improve recognition and management of early-onset schizophrenia.

SCHIZOPHRENIA PRODROME: COMPELLING DATA, EMERGING INSIGHTS

EARLY REFLECTIONS ABOUT THE PRODROME From Dr. H.S. Sullivan as retrieved by Dr. Patrick McGorry I feel certain that many incipient cases might be arrested before the efficient contact with reality is completely suspended, and a long stay in institutions made necessary. the long[er] psychotic collapse is escaped, the less the chance of a grave disorder, and the less typical any illness which ensues. In other words a psychosis occurring in a psychopathic youth under, say, the age of 22, is in all likelihood frankly schizophrenic; but an initial psychosis occurring at, say, 30 will probably be a brief excitement. Zipursky RB and Schulz SC. In: The early stages of schizophrenia. 2002.

EARLY-ONSET SCHIZOPHRENIA COURSE Normal Early-Onset Schizophrenia Course Premorbid Prodromal Deterioration Chronic/Residual Severity of Symptoms and Disability Gestation/ Birth Puberty Adolescence Adult Middle Age Developmental Stage Senescence Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884-897.

PRODROMAL HOT TOPICS Can the prodrome be accurately identified using symptoms, biomarkers, family history (or genes)? Are there ways to specify the direction of prodromal symptoms in order to apply specific treatments? Are there adequate data to recommend treatment approaches to the prodrome? In other branches of medicine, there are concerns of overdiagnosis of early stages of illness; how can such concerns be dealt with in the prodrome?

ON PREDICTING FUTURE PSYCHOSIS Prediction of Psychosis in Youth at High Clinical Risk: A Multisite Longitudinal Study in North America. Cannon TD, et al. Arch Gen Psychiatry. 2008;65(1):28-37. Cannon TD, et al. Arch Gen Psychiatry. 2008;65(1):28-37.

CANNON ET AL, 2008 Overview and Methods Clinical question under investigation Can algorithms be constructed to maximize predictive power of conversion to psychosis in a high-risk sample? Methods N = 291 Treatment-seeking patients at 8 sites in the North American Prodrome Longitudinal Study (NAPLS) Followed for 2.5 years Cannon TD, et al. Arch Gen Psychiatry. 2008;65(1):28-37.

CANNON ET AL, 2008 Results Conversion rate was 35% 5 variables uniquely predictive of psychosis 1. Significant prediction of genetic risk of schizophrenia 2. Higher levels of unusual thought content 3. Higher levels of paranoia 4. Greater social impairment 5. History of substance abuse Algorithms combining 2 or 3 of these variables resulted in dramatic increases in positive predictive power (PPP) of 68% to 80% 81% PPP for 1, 2, and 4 and 1, 2, 3, 4 Cannon TD, et al. Arch Gen Psychiatry. 2008;65(1):28-37.

CANNON ET AL, 2008 Conclusions Authors conclusions Prospective prediction of patients as high risk for psychosis is feasible The level of predictive accuracy is at a level of other areas of preventive medicine Cannon TD, et al. Arch Gen Psychiatry. 2008;65(1):28-37.

ON ABNORMAL NEUROANATOMY AND SYMPTOM ONSET Neuroanatomical Abnormalities Before and After Onset of Psychosis: A Cross-Sectional and Longitudinal MRI Comparison Pantelis C, et al. Lancet. 2003;361(9354):281-288. Pantelis C, et al. Lancet. 2003;361(9354):281-288.

PANTELIS ET AL, 2003 Overview and Methods Clinical question under investigation Do the neuroanatomical abnormalities in the brain predate symptoms in patients with schizophrenia? Methods Subjects with prodrome, N = 75 MRI scan at baseline and at 1 year Pantelis C, et al. Lancet. 2003;361(9354):281-288.

PANTELIS ET AL, 2003 Results and Conclusions 31% (n = 23) developed psychosis At baseline: Significant reductions in grey matter were seen between the subjects who became psychotic and those who did not After 12 months: More areas of grey matter reduction were noted Authors conclusions Some of the grey matter abnormalities associated with psychotic disorders predate the onset of frank symptoms, whereas others appear later Pantelis C, et al. Lancet. 2003;361(9354):281-288.

ON INTERVENING DURING THE PRODROME Randomized Controlled Trial of Interventions Designed to Reduce the Risk of Progression to First-episode Psychosis in a Clinical Sample with Subthreshold Symptoms McGorry PD, et al. Arch Gen Psychiatry. 2002;59(10):921-928. No pharmacotherapy agent is FDA approved for reduction in risk of progression to frank psychosis. McGorry PD, et al. Arch Gen Psychiatry. 2002;59(10):921-928.

MCGORRY ET AL, 2002 Overview and Methods Clinical question under investigation Can pharmacotherapy interventions during the prodrome alter risk of progression to psychosis? Methods Initial phase of the trial was 6 months N = 59 subjects at ultra high risk for progression to first-episode psychosis Treatment arms RIS + CBT (mean dose 1.3 mg/day) Needs-based intervention McGorry PD, et al. Arch Gen Psychiatry. 2002;59(10):921-928.

MCGORRY ET AL, 2002 Results and Conclusions At 6 months, progression to first-episode 3/31 RIS + CBT p =.03 10/28 Needs-based intervention After another 6 months: Groups were no longer different Protection against progression extended for 6 months after cessation of RIS use Authors conclusions There was a reduction in early transition to psychosis with more specific treatment McGorry PD, et al. Arch Gen Psychiatry. 2002;59(10):921-928.

ON INTERVENING DURING THE PRODROME Randomized Controlled Trial of Interventions For Young People at Ultra High Risk for Psychosis: 6-Month Analysis Yung AR, et al. J Clin Psychiatry. 2011;72(4):430-440. No pharmacotherapy agent is FDA approved for reduction in risk of progression to frank psychosis. Yung AR, et al. J Clin Psychiatry. 2011;72(4):430-440.

YUNG ET AL, 2011 Overview and Methods Clinical question under investigation Can CBT and/or pharmacotherapy employed during the schizophrenia affect outcomes? Methods 6-month RCT N = 115 randomized subjects into one of three groups CBT + RIS CBT + PBO Supportive + PBO N = 78 additional nonrandomized subjects who agreed to undergo assessment Yung AR, et al. J Clin Psychiatry. 2011;72(4):430-440.

YUNG ET AL, 2011 Results and Conclusions Proportions developing psychosis: 8/115 randomized subjects 4/78 nonrandomized subjects No difference between the randomized groups Authors conclusions The authors discuss the power of the study The interventions may be equally effective Yung AR, et al. J Clin Psychiatry. 2011;72(4):430-440.

ON INTERVENING DURING THE PRODROME Long-Chain Omega-3 Fatty Acids for Indicated Prevention of Psychotic Disorders: A Randomized, Placebo-Controlled Trial Amminger GP, et al. Arch Gen Psychiatry. 2010;67(2):146-154. No pharmacotherapy agent is FDA approved for reduction in risk of progression to frank psychosis. Amminger GP, et al. Arch Gen Psychiatry. 2010;67(2):146-154.

AMMINGER ET AL, 2010 Overview and Methods Clinical question under investigation Can omega-3 fatty acids reduce rate of progression to psychosis in patients with subthreshold psychosis? Methods 12-month RCT 81 subjects at ultra-high risk of psychotic disorder Treatment arms Omega-3 fatty acids PBO Amminger GP, et al. Arch Gen Psychiatry. 2010;67(2):146-154.

AMMINGER ET AL, 2010 Results Amminger GP, et al. Arch Gen Psychiatry. 2010;67(2):146-154.

AMMINGER ET AL, 2010 Results and Conclusions 76/81 subjects completed the trial Converted to psychosis 2/41 11/40 Omega-3 fatty acids PBO Reduced symptoms with Authors conclusions Omega-3 fatty acids There was reduction of conversion to a psychotic disorder with omega-3 fatty acid therapy Omega-2 fatty acid therapy was safe Amminger GP, et al. Arch Gen Psychiatry. 2010;67(2):146-154.

ON OUTCOMES FOR NONCONVERTERS At Clinical High Risk for Psychosis: Outcome for Non-Converters Addington J, et al. Am J Psychiatry. 2011 Apr 15 [Epub ahead of print]. Addington J, et al. Am J Psychiatry. 2011 April 15 [Epub ahead of print].

ADDINGTON ET AL, 2011 Overview and Methods Clinical question under investigation What are outcomes for nonconverters? Methods Subjects 111 Nonconverters 139 Controls Nonconverters had at least one follow-up visit in the NAPLS group, did not become psychotic, and did not receive antipsychotic medication Controls were non-psychiatric comparison subjects Addington J, et al. Am J Psychiatry. 2011 April 15 [Epub ahead of print].

ADDINGTON ET AL, 2011 Results and Conclusions Nonconverters Did improve in ratings and function as a group during the first year 43% had an Axis II disorder Had poorer social and role function than control subjects Authors conclusions Some patients have the onset of a psychotic illness while some remit Some subjects who didn t convert continued to have symptoms and poor function Addington J, et al. Am J Psychiatry. 2011 April 15 [Epub ahead of print].

CLINICAL CONNECTIONS There may be a bipolar prodrome, but it may be difficult to distinguish it from SZ subjects Some of the grey matter abnormalities associated with psychotic disorders predate the onset of frank symptoms

CLINICAL CONNECTIONS In high-risk patients: Symptom characteristics during the prodrome can help predict risk of progression Emerging, investigational data are mixed Help-seeking prodromal patients who do not nonconvert to psychosis often have poor functioning and likely represent a group truly at high risk

PREVENTING DISABILITY FROM SCHIZOPHRENIA WITH EARLY INTERVENTION

CAN WE PREVENT THE PROGRESSION AND DISABILITY OF SCHIZOPHRENIA? Stages of Illness Premorbid Prodromal Onset/Progression Healthy Worsening Severity of Signs and Symptoms First Break Deterioration Chronic/Residual Puberty Gestation/Birth 10 20 30 40 50 Years Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884-897.

GRAY MATTER VOLUME CHANGES IN THE COURSE OF SCHIZOPHRENIA Courtesy of Jay Giedd and Paul Thompson.

CHEMICAL NEUROTRANSMISSION AND CONNECTIVITY Postmortem Brain Tissue Normal Control Dendrites Cell body Axon Person with Schizophrenia Person with Schizophrenia Glantz, Lewis. 1999.

CAN RX ALTER THE COURSE OF SCZ? RCT of First-Episode Psychosis Outcomes Measured by Symptoms and Brain Morphology Cumulative Number of Remissions 100 80 60 40 20 p =.11 Remission Rate Haloperidol Olanzapine p =.08 0 N = 263 12 104 Weeks on Treatment Remission = Response for 4 consecutive weeks; Response = no ratings > 3 (mild) on PANSS items P1, P2, P3, P5, and P6 and CGI-Severity 4 Lieberman JA, et al. Arch Gen Psychiatry. 2005;62(4):361-370.

MR IMAGING BRAIN STRUCTURE AND TREATMENT EFFECTS IN SCHIZOPHRENIA cortex white matter 3D morphology ventricles

WHOLE BRAIN GRAY MATTER VOLUMES OVER 52 WEEKS ON MRI Volume (cc) 780 760 740 720 700 680 660 640 620 Healthy volunteers (n = 58) Patients (n = 75) Haloperidol Olanzapine 600 Relative Week of Therapy 580 0 12 52 Lieberman JA, et al. Arch Gen Psychiatry. 2005;62(4):361-370.

WHOLE BRAIN GRAY MATTER VOLUMES OVER 52 WEEKS ON MRI Volume (cc) 780 760 740 720 700 680 660 640 620 Healthy volunteers (n = 58) Patients (n = 75) Haloperidol Olanzapine 600 Relative Week of Therapy 580 0 12 52 Lieberman JA, et al. Arch Gen Psychiatry. 2005;62(4):361-370.

Lieberman JA, et al. Arch Gen Psychiatry. 2005;62(4):361-370.

CAUSAL ASSOCIATIONS AMONG MRI, SYMPTOMS, AND COGNITIVE RESPONSE TO TREATMENT Symptoms Treatment MRI brain changes Cognition Function

NATURAL HISTORY OF SCHIZOPHRENIA RATIONALE FOR EARLY DETECTION AND INTERVENTION Healthy Worsening Severity of Signs and Symptoms Premorbid Abnormal Brain Development Stages of Illness Chronic/ Residual End-Stage Deterioration Margin of Prevention Prodromal/Onset/ Deterioration Sensitization by dopamine Excitatory Neurotoxicity of glutamate Neurochemical Neurodegeneration? Dysregulation Gestation/Birth 10 Puberty 20 30 40 Years Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884-897. 50

LIMITATIONS OF EXISTING INTERVENTIONS FOR FEP Long Duration of Untreated Psychosis Inadequate Interventions High Attrition Rates

RISK OF REHOSPITALIZATION AFTER A FIRST HOSPITALIZATION FOR SCHIZOPHRENIA, BY ANTIPSYCHOTIC TREATMENT PATTERN (N = 2,588) Tiihonen J, et al. Am J Psychiatry. 2011;168(6):603-609.

EFFECTIVENESS OF ANTIPSYCHOTIC DRUGS IN FIRST-EPISODE SCHIZOPHRENIA Time to Treatment Discontinuation Kahn RS, et al. Lancet. 2008;371(9618):1085-1097.

Positive and Negative Syndrome Scale (PNSS) Total Score During 12-Month Follow-Up Clinical Global Impression (CGI) Global Assessment of Functioning (GAF) Kahn RS, et al. Lancet. 2008;371(9618):1085-1097.

GRAY MATTER VOLUME CHANGES IN SCHIZOPHRENIA Courtesy of Jay Giedd and Paul Thompson

TREATMENT EFFECTS ON BRAIN VOLUME TRAJECTORIES White Matter Ventricles Gray Matter Ho BC, et al. Arch Gen Psychiatry. 2011;68(2):128-137.

SUMMARY AND CLINICAL CONNECTIONS Schizophrenia is a progressive disorder that derives from a genetically mediated neurodevelopmental diathesis The clinical deterioration and enduring nature of its morbidity is due to structural pathology in frontal and temporal regions Antipsychotic drugs target psychosis and may prevent progression Early intervention and maintenance effective Other stages and symptom dimensions require new therapeutic strategies and targets Early detection and intervention requires better diagnostic methods, interventions and models of service delivery

QUESTIONS AND ANSWERS