1. Development and Utilization of Drug For Treating Psychotic Disorders: How Well Have US Federal and State Policies/ Laws Served Individual and Societal Needs And Rights? Herbert Meltzer MD Northwestern University Feinberg School of Medicine Psychotropic Medications and the Law

2. Disclosure of Commercial Interests Grantee: DaiNippon Sumitomo (Sunovion) Janssen, Novartis, Otsuka, EnVivo, Alkemese,Eli Lilly Consultant: Alkamese, EnVivo, BioLine, ACADIA, Merck, Novartis, Roche, Teva Shareholder: ACADIA, Astra Zeneca, SureGene

3. Outline Introduction:Better psychotropic drugs, fewer legal problems Antipsychotic drugs for psychotic disorders: –Typical and atypical antipsychotic drugs\ –Strongest effects of a beneficial nature –Modest but still significant benefits –Greatest limitations in efficacy –Prospects for developing better treatments Current status of antipsychotic drug discovery and development Laws and policies affecting research necessary for: –The development of psychotropic medications for treating psychotic disorders –The utilization of psychotropic medications for treating psychotic disorders

4. Introduction The Psychotic Spectrum Brain disorders: etiology genes, environment, experience Medication: symptom control, restoration of function, primary prevention and prevention of recurrences. Many of the legal issues which affect people with psychotic disorders, their significant others, and society would be solved with more effective and tolerable drug treatments integrated with non-treatment modalities Research is essential of discover these treatments and to effectively introduce them to clinical practice

5. Typical and Atypical Antipsychotic Drugs TYPICAL APDs (First generation drugs) Discovery : 1952-1980 Prototypical agents: chlorpromazine, haloperidol Mechanism of action: blockade of dopamine D 2 receptors Principal side effects: mechanism based parkinsonism, tardive dyskinesia, neuroleptic malignant syndrome, prolactin elevations ATYPICAL APDs (Second generation APDs Discovery: 1955, 1989-present Prototypical agents:clozapine, risperidone, olanzapine Mechanism of action: more potent blockade of serotonin 2A receptors than D 2 receptors but other actions also contribute to their action Principal side effects:non- mechanism based –Weight gain, lipid increases, hyperglycemia ; Clozapine: agranulocytosis

6. Antipsychotic drugs for Psychotic Disorders: Greatest Contributions Long term control of delusions and hallucinations in 70% of patients with schizophrenia, with some breakthrough episodes Control by clozapine of delusions and hallucination in ~60% of the treatment resistant schizophrenia patients Reduction of suicide rate by 70-80% in schizophrenia

7. 7-17 Year Clozapine Treatment Followup: BPRS Psychosis Subscale (N=95) *p<0.05 between baseline and last clinic evaluation ***p<0.001 between baseline and current evaluation * *** 2-7yrs 7-17 yrs * ***

8. Jari Tiihonen University of Eastern Finland 8 All-Cause MortalitySuicide Risk of Death Reference: Perphenazine Tiihonen J et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009;374:620-627.

9. 11 Year Follow Up Mortality in Patients with Schizophrenia Risk of death due to all causes was significantly lower in patients with long-term (7-11years) antipsychotic drug treatment than in those who had not used any APD during follow up Hazzard ratio = 0.81, 0.77-0.84; p<0.0001 Lowest risk was for clozapine: HR = 0.52 Jari Tiihonen Lancet 2009 9

10. Diffusion of Worst and Best Practices in Public Health Poor practices for treatment resistant schizophrenia, such as polypharmacy diffuse rapidly-rates as high as 50% in some studies Most underused evidence-based practices for schizophrenia:: clozapine and supported employment. –“Strikingly, its diffusion and use were not boosted by the FDA approval in Deember 2002 of the indication to reduce the risk of suicidal behavior.” Horvitz-Lennon et al., Health Affairs 2009

11. Antipsychotic drugs for psychotic disorders: modest but still significant benefits Improvement in some domains of cognition: verbal fluency, speeded motor pursuit, declarative memory, attention Improvement in negative symptoms Improvement in work and social function

12. Clozapine Improves Some Domains of Cognition Hagger et al Biological Psychiatry 1994 Verbal Flu Motor Pur Work Mem Vbl Long Term Mem Executive Function

13. ≥0.5SD Improvement in Speeded Motor Pursuit and Working Memory with Clozapine and Typical Neuroleptic Drugs Meltzer and Sumiyoshi in preparation, 2012

14. Wisconsin Card Sort:Categories Before and After Risperidone LAI in Treatment Resistant Schizophrenia Meltzer HY, ACNP 2011, in preparation

15. Antipsychotic drugs for psychotic disorders: Greatest limitations in efficacy Minimal improvement in executive function, working memory Minimal improvement in negative symptoms Minimal mprovement in work and social function

16. Major Issues Preventing Good Outcome in Schizophrenia Underfunded and poorly managed care in the public sector –Insufficient numbers of skilled prescribers and excessive productivity requirements –Hospital stays of insufficient length –Poorly supported housing programs –Underfunded job support programs –Poor continuum of care from inpatient to out patient care –Unjustified attacks on ‘atypical’antipsychotic drugs and barriers to their utilization Decreased life span: suicide, cardiovascular and metabolic disorders, smoking Non-adherence Limited availability of psychoeducational and psychosocial treatments Side effects of antipsychotic drugs Ineffective treatments for co-morbid substance abuse and other types of symptoms, e.g. anxiety, obsessive-compulsive disorders Refusal of treatment Limited utilization of ECT for treatment resistant patients Absence of biomarkers for choice of medication Cost of antipsychotic drugs

17. Current status of antipsychotic drug discovery and development Views of Eric Kandel, Tom Insel: only advance in drug treatment of schizophrenia in the last 60 years has been clozapine Major drug companies have stopped psychotropic drug discovery programs seeking new antipsychotics or through mergers have ceased to exist: e.g Zeneca, Glaxo, Novartis, Organon, Sanofi,Wyeth Antipsychotic drug discovery effort but often at much reduced levels: Eli Lilly, Otsuka, Merck, Pfizer –New formulations to extend patents and obtain new indications common Limited effort by National Institute of Mental Health: aftermath of CATIE study Decreased and very limited interest of venture capital to fund discovery and development of novel treatments by start ups, biotechs: ACADIA, EnVivo, etc Limited and/or much decreased funding by foundations for clinical research: Stanley Foundation, Brain and Behavior Research Foundation (BBRF), IMHRO

18. 18 “CATIE and CUtLASS: Can We Handle The Truth?”-I “It is worth reflecting on how crudely we often use antipsychotic drugs. Polypharmacy, the prescribing of two or more antipsychotics in parallel is widespread despite the lack of evidence to support it and that it doubles cost and multiplies safety risks. Off-label prescribing is common…It is the same sense of frustration that allowed to be ‘beguiled’, as Peter Jones [CUtLASS PI] said in the Washington Post by the promise of a new class of drugs. These trials [CATIE and CUtLASS] emphasize again the urgent need for discovering new, safe, effective medications, as well as knowing how best to use existing medications.” Lewis S et al. Br J Psychiatry. 2008;192:161-163.

19. 19 Cost-Effectiveness and Policy Implications With CATIE Atypicals – Cost $3600-$6000 more costly – Are no more effective – Incur greater weight gain but may have less TD risk This is as far as the science of CEA goes at present Whether this should shape formulary policy to discourage use of SGAs is a question of value and consensus – not a scientific question of fact From Rosenheck slides for National CATIE Education Program.

20. ‘Biotech Funding Gets Harder to Find’* *Wall Street Journal: Monday, March 19,2012 ‘Venture Capitalists Tighten Purse Strings, IPOSs Bring in Less, Larger Drug Makers Demand More’ ‘Fewer start-up biotechs are getting the investments needed to being their drug discovery work, thought those that manage to get funding are seeing average investment increase’ ‘Ultimately, some promising advances may go unexplored, if start-ups can’t find new ways to secure seed money.’ “What’s the new paradigm, or are we going to see the biotech industry wither away.” Kevin Collins, Jenner & Bloch

21. Laws and policies affecting research necessary for the development of psychotropic medications for treating psychotic disorders Market forces are not sufficient to provide adequate capital for research into new antipsychotic drugs Need for a national policy to direct capital and reward innovation to psychotropic drug development Need for long term support for infratructure of ethical, effective clinical trial sites to test novel drugs –Poor standards for clinical testing sites: failed studies Need for larger SBIR grants for innovative companies in the field of antipsychotic drug development Need for those who head public treatment agencies to embrace psychotropic drug research, including industry funded Need to revise some FDA policies, e.g. bipolar psychotic disorder and acute schizophrenia

22. Laws and policies affecting research on the utilization of antipsychotic drugs for treating psychotic disorders No requirements or rewards to practice evidence based medicine –clozapine for high suicide risk individuals Inadequate resources for effectiveness trials: the CATIE trial vs epidemiology Restored use of typical antipsychotic drugs because of CATIE trial, financial incentives Inadequate research on optimal organization of treatment services Laissez faire attitude towards clinical practice –Diffusion of worst practices, e.g. polypharmacy Inadequate electronic medical records to track treatment failures Inadequate requirements for continuity of care No linkage between payment for drugs and efficacy of the drugs: ‘a lemon law” vs ‘premium for premium outcome’ Limitations in FDA implementation of its oversite role

23. What Can Be Done to Increase The Use Of Clozapine? Education Algorithms Genetic test for agran and risk for suicide Alerting staff about recent suicide attempt Minimizing side effects of clozapine Discontinuation of monitoring at 12 months Law suits for failure to recommend use of clozapine after serious suicide attempt

24. What Can Be Done to Enhance Antipsychotic Drug Discovery Create a national fund for drug discovery based upon the income generated from sale of antipsychotic drugs Create more academic discovery units at major universities License discoveries to pharma marketing companies with requirements for profits to be reinvested in further research and support of better utilization Recognize the global nature of the need for more effective drugs and rise of science in China, in particular, and fund research programs that are most promising and cost-effective More attention to traditional medicines: stepholidine Increased support for translational research

25. What Can Be Done to Enhance Antipsychotic Drug Utilization? Education of patients and their families Better training of prescribers –better use of electronic tools to guide treatment decisions –pay for performance –enhanced understanding of multidimensional nature of the syndrome Use of algorithms: International Psychopharmacology Algorithm Project (IPAP ® ) –restrict polypharmacy –structure treatment for adequate dosage and duration –favor use of clozapine for its approved indications Increased pharmacogenomic effort

26. Conclusions Current antipsychotic drugs, for some patients, are dramatically effective but as used in practice only rarely achieve their full potential, e.g. the underutilization of clozapine for suicide and treatment resistance, polypharmacy Many of the medical and legal issues that adversely affect those with psychotic disorders, e.g. involuntary hospitalization, incarceration rather than hospitalization, comorbid substance abuse, inadequate support for needed services, would be lessened by optimal utilization of current medications and development of more effective treatments. However, various laws and policies at the federal, state, and local levels, coupled with underfunding of services and research have retarded the prospects for discovering novel mechanisms and developing more effective and safer drugs A well directed and fully funded basic, translational, and service-based research effort focused on antipsychotic and cognitive enhancing drugs, on a world wide scale, could dramatically cut the illness and societal burdens from psychotic disorders