RECEPTOR TARGETS IN SCHIZOPHRENIA: LINKING RECEPTORS TO SYMPTOMS. Jeffrey A. Lieberman, MD Columbia University

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2 RECEPTOR TARGETS IN SCHIZOPHRENIA: LINKING RECEPTORS TO SYMPTOMS Jeffrey A. Lieberman, MD Columbia University

3 JEFFREY A. LIEBERMAN, MD Disclosures Research/Grants: Allon Therapeutics; Forest Laboratories, Inc.; Merck & Co., Inc.; Pfizer Inc.; Sepracor, Inc. Speakers Bureau: None Consultant: None Stockholder: None Other Financial Interests: Holds a patent from Repligen Corporation Advisory Board: Bioline; GlaxoSmithKline; Intracellular Therapies, Inc; Eli Lilly and Company; Pierre Fabre Laboratories; PsychoGenics, Inc.; Wyeth Pharmaceuticals Dr. Lieberman receives no direct compensation or salary support for participation in these research, consulting, or advisory board activities

4 LEARNING OBJECTIVE Analyze data related to receptor targets to individualize treatment plans for patients with schizophrenia

5 ASYLUM INMATES Effects of Schizophrenia Without Treatment Kraepelin E

6 NATURAL HISTORY OF SCHIZOPHRENIA: STAGES OF ILLNESS Healthy Worsening Severity of Signs and Symptoms Premorbid Prodromal Onset/ Progression First Break Chronic/Residual Puberty Deterioration Negative Symptoms Cognitive Deficits Functional Impairment Gestation/ Birth Years Lieberman JA, et al. Biol Psychiatry 2001;50:

7 EVOLUTION OF TREATMENTS FOR PSYCHOTIC DISORDERS 30s 40s 50s 60s 70s 80s 90s Reserpine First Generation (Typical) Antipsychotics Later Generation (Atypical) Antipsychotics Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Amisulpride Paliperidone Iloperidone Asenapine Lurasidone

8 COMPARATIVE EFFECTIVENESS OF ANTIPSYCHOTIC DRUGS How do different antipsychotic drugs (APDs) compare clinically? NIMH CATIE (Lieberman J, et al 2005) 1 UK NHS - CUtLASS (Jones P, et al 2006) 2 NIMH TEOSS (Sikich L, et al 2008) 3 EUFEST (Kahn R, et al 2009) 4 Meta-Analyses Leucht S, et al Crossley N, et al Lieberman JA, et al. N Engl J Med 2005;353: ; 2. Jones PB, et al. Arch Gen Psychiatry 2006;63: ; 3. Sikich L, et al. Am J Psychiatry 2008;165: ; 4. Kahn RS, et al. Lancet 2008;371: ; 5. Leucht S, et al. Lancet 2009;373:31-41; 6. Crossley NA, et al. Br J Psychiatry 2010:196:

9 COMPARATIVE EFFECTIVENESS OF APDs Conclusions APDs are more similar than different Side effects SGAs an incremental advance Greater therapeutic differences in severely ill

10 WHAT TREATMENTS CAN AND CANNOT DO FOR SCHIZOPHRENIA Refractory psychosis Negative symptoms Cognitive symptoms Rehabilitate and regenerate Suppress symptoms Prevent recurrence Prevent progression

11 NOVEL TREATMENTS AS MONOTHERAPIES Non-Dopamine Antipsychotics Where are the new novel drugs for schizophrenia? 5-HT 2A antagonists (M100907) Sigma antagonists N-desmethyl clozapine (ACP-104) Neurokinin NK3 antagonists (alnetant) 5-HT 2C antagonists (vabicaserin) Muscarinic agonists (xanomeline) mglu2/3 receptor agonist (LY404039) Phosphodiesterase inhibitors

12 DOPAMINE D 2 RECEPTOR ANTAGONISM AS A UNIFYING PROPERTY OF ALL ANTIPSYCHOTIC DRUGS IN CLINICAL USE Karam CS, et al. Trends Pharmacol Sci 2010;31:

13 GLUTAMATERGIC AND GABAERGIC SIGNALING 1. Adapted with permission from Lewis DA, Moghaddam B. Arch Neurol 2006;63: ; 2. Karam CS, et al. Trends Pharmacol Sci 2010;31:

14 GLUTAMATERGIC TREATMENTS FOR SCHIZOPHRENIA Glycine Cycloserine D-Serine Sarcosine Lamotrigine Memantine Ampakine LY GLY-T inhibitor

15 CHOLINERGIC SIGNALING Karam CS, et al. Trends Pharmacol Sci 2010;31:

16 THE 22q11 LOCUS This 1.5-megabase region is flanked by low-copy repeat sequences (yellow boxes), making it prone to nonhomologous recombination. Approximately 30% of all individuals with 22q11.2 microdeletions develop symptoms of schizophrenia. Three schizophrenia candidate genes in this region are highlighted in bold font: proline dehydrogenase (PRODH), catechol-omethyltransferase (COMT) and a palmitoyltransferase (ZDHHC8). PRODH-P and DGRC6- like are pseudogenes. Adapted with permission from Dr. Alexander Arguello and Dr. Joseph Gogos, Dept of Physiology and Cellular Biophysics, Columbia University, New York, NY. Karam CS, et al. Trends Pharmacol Sci 2010;31:

17 NEUREGULIN (NRG1) ISOFORMS AND ERBB (EGF RECEPTOR TYROSINE KINASE) SIGNALING PATHWAYS Karam CS, et al. Trends Pharmacol Sci 2010;31:

18 DISRUPTED IN SCHIZOPHRENIA 1 (DISC1) DISC1 is a gene locus originally identified in a Scottish family, many of whom carried a balanced translocation between chromosomes 1 and 11 and who had a high frequency of psychiatric disorders, including schizophrenia, bipolar disorder, and recurrent major depression. Linkage and association studies have also supported a role for the DISC1 locus in schizophrenia. DISC1 associates with important cellular components, including the centrosome, microtubules, terminals and neurite growth cones, enabling it to play a part in various cellular functions, such as neuronal migration and axonal elongation, as well as microtubule transport and organization. DISC1 can also inhibit GSK-3 activity, and thus potentially overlaps with dopaminergic signaling and NRG1/ERB4 signaling. Adapted with permission from Macmillan Publishers: Chubb, et al. Mol Psych 2008;13: Karam CS, et al. Trends Pharmacol Sci 2010;31:

19 THERE IS NO INSULIN FOR SCHIZOPHRENIA Rational polypharmacy will be the state of the art

20 (RATIONAL) ADJUNCTIVE AND POLYPHARMACY Benzodiazepines Antidepressants Mood stabilizers Lithium, anticonvulsants (valproate, lamotrigine) Alzheimer s medications Cholinomimetics Memantine Combined antipsychotics

21 ADJUNCTIVE TREATMENTS FOR SCHIZOPHRENIA Neuroprotectants DHEA Pregnenolone N-acetyl cysteine Omega-3 fatty acid

22 NATURAL HISTORY OF SCHIZOPHRENIA: STAGES OF ILLNESS Healthy Worsening Severity of Signs and Symptoms Premorbid Prodromal Onset/ Progression First Break Chronic/Residual Puberty Deterioration Negative Symptoms Cognitive Deficits Functional Impairment Gestation/ Birth Years Lieberman JA, et al. Biol Psychiatry 2001;50:

23 GRAY MATTER THICKNESS CHANGES IN SCHIZOPHRENIA

24 NATURAL HISTORY OF SCHIZOPHRENIA: STAGES OF ILLNESS Healthy Worsening Severity of Signs and Symptoms Premorbid Prodromal Onset/ Deterioration Deterioration Chronic/Residual Margin of Prevention Gestation/ Birth 10 Puberty Years Lieberman JA, et al. Biol Psychiatry 2001;50:

25 RECOVERY AFTER AN INITIAL SCHIZOPHRENIA EPISODE The RA1SE Project The current paradigm for treating schizophrenia in the U.S. focuses on managing end-stage illness and chronic disability RAISE is a NIMH-sponsored project that will test whether early, aggressive, and pre-emptive intervention can slow or halt clinical and functional deterioration in schizophrenia Increased recovery and reduced disability among individuals with schizophrenia may translate into significant cost savings for society National Institute of Mental Health. Information available at

26 CAN TREATMENT PREVENT THE ONSET AND PROGRESSION OF SCHIZOPHRENIA? Healthy Worsening Severity of Signs and Symptoms Premorbid Prodromal Onset/ Progression First Break Chronic/Residual Deterioration Negative Symptoms Cognitive Symptoms Functional Disability Gestation/ Birth 10 Puberty Years Lieberman JA, et al. Biol Psychiatry 2001;50:

27 PREDICTION OF PSYCHOSIS IN YOUTH AT HIGH CLINICAL RISK Outcomes Risk of conversion 35% during f/u period 5 clinical features improved prediction: genetic risk for schizophrenia + deterioration, higher severity of unusual thought content, suspicion/paranoia, greater social impairment, history of substance abuse Survival Distribution Function Major results Controls Prodromal patients Days Since Baseline Assessment Cumulative survival distribution function modeling time to conversion to psychosis in 291 clinical high-risk (prodromal) patients and 134 demographically comparable normal control subjects (dashed line). Cannon TD, et al. Arch Gen Psychiatry 2008;65:28-37.

28 RCTS OF INTERVENTIONS TO PREVENT PSYCHOSIS Randomized, unblinded comparison of risperidone + therapy vs. TAU 1 Randomized, double-blind comparison of olanzapine vs. PBO 2 Randomized double-blind comparison of omega-3-fatty acid vs. PBO 3 1. McGorry PD, et al. 2. McGlashan TH, et al. Am J Psychiatry 2006;163: Amminger GP, et al. Arch Gen Psychiatry 2010;67:

29 TIME TO CONVERSION TO PSYCHOSIS Cumulative Survival ω-3 Fatty Acids Placebo Time From Entry (Months) Kaplan-Meier estimates of risk transition from at-risk states to psychotic disorder in patients assigned to ω-3 fatty acids or PBO (p =.007) Amminger GP, et al. Arch Gen Psychiatry 2010;67:

30 KEY LIMITATIONS FOR EARLY INTERVENTION IN THE PRODROMAL PHASE Diagnostic criteria lack specificity and precision Unclear what is the best modality and treatment

31 WHY AREN T OUTCOMES BETTER FOR PATIENTS WITH SCHIZOPHRENIA? WHAT COULD IMPROVE OUTCOMES? Rx adherence Lack of psychosocial therapies Comorbidity Clozapine Long-acting meds Psychosocial therapies Early detection and intervention

32 WHAT HAS CHANGED? The biggest change in mental health from 1978 to today is that we now know that recovery is possible for any individual with a mental illness Rosalyn Carter

33 AN EVOLVING PERSPECTIVE ON RECOVERY A Meaningful Life Despite Disability the overarching message is that hope and restoration of a meaningful life are possible, despite serious mental illness. Instead of focusing primarily on symptom relief, as the medical model dictates, recovery casts a much wider spotlight on restoration of self-esteem and identity and on attaining meaningful roles in society. (Surgeon General, 1999) Mental Health: A Report of the Surgeon General, Available at

34 SCHIZOPHRENIA: COURSE OF ILLNESS AND POTENTIAL EFFECTS OF INTERVENTIONS Healthy Premorbid Prodromal Stages of Illness Onset and Progression Worsening Severity of Signs and Symptoms Prevention Recovery Deterioration Chronic/Residual Gestation/ Birth 10 Puberty Years Lieberman JA, et al. Biol Psychiatry 2001;50:

35 CLINICAL CONNECTIONS Antipsychotic differentiation related to side effect profiles Rational polypharmacy will be state of the art Increased recovery and reduced disability among individuals with schizophrenia may translate into significant cost savings for society

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