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?

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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?
Psychotropic Medications and the Law

• Herbert Meltzer MD
• Northwestern University Feinberg School of
  Medicine

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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

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Outline

• IntroductionBetter 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

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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

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Typical and Atypical Antipsychotic Drugs

• TYPICAL APDs (First generation drugs)
• Discovery 1952-1980
• Prototypical agents chlorpromazine, haloperidol
• Mechanism of action blockade of dopamine D2
  receptors
• Principal side effects mechanism
  based parkinsonism, tardive dyskinesia,
  neuroleptic malignant syndrome, prolactin
  elevations

• ATYPICAL APDs (Second generation APDs
• Discovery 1955, 1989-present
• Prototypical agentsclozapine, risperidone,
  olanzapine
• Mechanism of action more potent blockade of
  serotonin 2A receptors than D2 receptors but
  other actions also contribute to their action
• Principal side effectsnon-mechanism based
• Weight gain, lipid increases, hyperglycemia
  Clozapine agranulocytosis

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Antipsychotic drugs for Psychotic
DisordersGreatest 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

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7-17 Year Clozapine Treatment Followup BPRS
Psychosis Subscale (N95)




2-7yrs
7-17 yrs
plt0.05 between baseline and last clinic
evaluation plt0.001 between baseline and
current evaluation
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Risk of Death
All-Cause Mortality
Suicide
Reference Perphenazine
Tiihonen J et al. 11-year follow-up of mortality
in patients with schizophrenia a
population-based cohort study (FIN11 study).
Lancet 2009374620-627.
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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 plt0.0001
• Lowest risk was for clozapine HR 0.52

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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
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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

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Clozapine Improves Some Domains of Cognition
Verbal Flu Motor Pur Work Mem Vbl
Long Term Mem Executive Function
Hagger et al Biological Psychiatry 1994
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0.5SD Improvement in Speeded Motor Pursuit and
Working Memory with Clozapine and Typical
Neuroleptic Drugs
Meltzer and Sumiyoshi in preparation, 2012
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Wisconsin Card SortCategories Before and After
Risperidone LAIin Treatment Resistant
Schizophrenia
Meltzer HY, ACNP 2011, in preparation
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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

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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 atypicalantipsychotic
  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

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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

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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 commonIt 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. 2008192161-163.
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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.
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Biotech Funding Gets Harder to Find
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 cant find new ways to
secure seed money.
Whats the new paradigm, or are we going to see
the biotech industry wither away. Kevin
Collins, Jenner Bloch
Wall Street Journal Monday, March 19,2012
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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

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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

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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

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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

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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

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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