Psychotropic
Medications and the
Law
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
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
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
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
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 agents:clozapine,
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 effects:nonmechanism based
– Weight gain, lipid increases,
hyperglycemia ; Clozapine:
agranulocytosis
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
7-17 Year Clozapine Treatment Followup: BPRS
Psychosis Subscale (N=95)
14.00
12.00
Mean Score
10.00
8.00
**
6.00
***
***
4.00
2.00
0.00
Baseline
Last Clinic Evaluation
Current Evaluation
2-7yrs
7-17
*p<0.05 between baseline and last clinic evaluation
yrs
***p<0.001 between baseline and current evaluation
Risk of Death
All-Cause Mortality
Reference: Perphenazine
Suicide
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.
Jari Tiihonen
University of Eastern Finland
8
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
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
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
Clozapine Improves Some Domains of
Cognition
0
***
Z Score
-0.5
***
***
-1
-1.5
**
***
***
-2
-2.5
-3
CIGT
Verbal Flu
CWAT
DSST
PRIM
VLL-IR VLL-DR WISC- WCST- WCSTR-Maze
Cat
Prsvrn
Motor Pur Work Mem Vbl Long Term Mem
Executive Function
BASELINE
6 MONTHS
Hagger et al Biological
≥0.5SD Improvement in Speeded Motor
Pursuit and Working Memory with
Clozapine and Typical Neuroleptic Drugs
% Improvement From Baseline >= 0.05SD in PRIM
% Improvement From Baseline >= 0.05SD in DSST
70.0
70.0
Cloz
Cloz
TypNL
60.0
60.0
%>=
0.5SD
TypNL
50.0
50.0
%>=
0.5SD
40.0
40.0
30.0
30.0
20.0
20.0
10.0
10.0
0.0
0.0
6 Weeks
6 Months
12 Months
24 Months
6 Weeks
6 Months
Meltzer and Sumiyoshi in preparation, 2012
12 Months
24 Months
Wisconsin Card Sort:Categories Before and After
Risperidone LAI
in Treatment Resistant Schizophrenia
6
5
4
3
WCST CAT
2
1
0
base
WK6
WK12
Meltzer HY, ACNP 2011, in preparation
26
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
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
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
“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.
18
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.
19
‘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 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
*Wall Street Journal: Monday, March 19,2012
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
Laws and policies affecting research on the
utilization of antipsychotic drugs for treating
psychotic disorders
•
No requirements or rewards to practice evidence based medicine
–
•
•
•
•
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
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•
•
•
•
clozapine for high suicide risk individuals
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
What Can Be Done to Increase
The Use Of Clozapine?
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•
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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
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
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
Conclusions
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•
•
•
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