Clozapine - Health Sciences Center for Knowledge Management

Clozapine is underused in Ohio:
How can we address this?
Dale Svendsen, MD, MS
October 15, 2014
How I will Present This?
 Clozapine: Its Use, History, Indications, Efficacy,
Side Effects
 How might we at OSU address the utilization of
Clozapine in Ohio
Steps to address the utilization of Clozapine in Ohio
 Why: Clozapine is the Best Medication Treatment for the 30% of
people with Treatment Resistant Schizophrenia Spectrum
Disorder yet in Ohio only about 5.8 % of this population is
receiving it.
 How: Engage you, your feelings, thoughts, and ideas in what
this why message means for you
 What: Implemention approaches* to address the
underutilization of clozapine in Ohio
Svendsen, D., Hogan, M. & Worham-Wood, J., Transformational Leadership in Mental Health, pgs. 531-532 in Modern
Community Mental Health an Interdisciplinary Approach, edited by Yeager, K, . Cutler, D, Svendsen, D, & Sills, GM,
Oxford U. Press, 2013
Psychiatric Services, February 2014
What started the interest in clozapine at OSU Psychiatry?
State Variation in Clozapine Initiations
629,809 AP Tx episodes with 2.2% starts
79,934 TR with 5.5% starts
What Do Others @ OSU think in response to Stroup
Change Starts with US!
John Campo…..shares his interest in best medication practices by frequently forwarding articles
on Use of Psychiatric Medications such as Sroup’s, Andreason’s article on how first episode
psychosis people do better after 7 years on low dose or discontinuation and have more gray
matter, invites Sandy Steingard for Grand Rounds, leads Minds Matters studies with Cynthia
Fontenella, etc.
Sam Guirgis has strong regard for using clozapine, considers its use in early psychosis patients
and has published using sophisticated testing for a successful rechallenge. He begins a QI study
of clozapine use at OSU-Harding
Bob Kowatch: Clozapine very effective in adolescents when I used it in the 1990s. Wt. gain was a
problem as were petit mal seizures. Metformin helps if you add it early. Several other newer
approaches to consider for wt. gain
Maryann Murphy: Agree with Bob. Metformin kept a lid on wt. gain in a study
Gene Arnold: If there is a departmental push to prescribe more clozapine, it would be a good
opportunity to study both the effect on gut flora and/or the effect of concomitant probiotic and/or
metformin use
Jessica Hellings: Loxapine is a “poor main’s clozapine” without agranulocytosis and weight gain.
Joe Coyle recommended it as first line treatment in schizophrenia
What do Others Think in response to Stroup Article?
The major risk is agranulocytosis. It’s simply difficult to justify its use until a patient failed
multiple other atypicals
Katherine Brownlowe: As a younger psychiatrist....“those who need it most are unlikely to
follow up or continue meds after discharge…and a lack of outreach services in central Ohio
compared to Vermont”
Tracey Skale, Medical Director at Greater Cincinnati Behavioral Health Services: “I use LOTS
of clozapine and as an agency many of our folks are on clozapine. The residents coming out
have negligible experience with clozapine which is a shame. So, the newer docs tend not to
start clozapine. In addition, one of the hospitals has been taking our clozaril people OFF (!)
clozaril if the patient happens to go in...which is very frustrating to us”
Jay Carruthers, NY OMH Medical Director of clozapine initiative in NY. 2.5% is too low.
We’re trying to make clozapine more accessible to those that need it the most. But its culture
change—institution, provider and consumer...that’s needed.
Dale Svendsen: Clozapine use in Ohio’s State Hospitals….including a suggestion that OSU
could be a leader in addressing the underutilization of Clozapine… followed by several
suggestions for publication, a clozapine grand rounds by Herb Meltzer, me, etc.
Request from Dr. Campo for Clozapine Grand Rounds
• …”Given its relatively unique profile, inconvenience alone, at least from
the practitioner perspective, probably is not a good reason to avoid
recommending and trying the drug in the setting of an appropriate and
well informed patient.
• Your ideas about how we can mitigate the complexities of clozapine use
deserve attention and further discussion, and I am hopeful that our
burgeoning group of psychiatrists interested in psychosis will get together
and generate some practical and actionable ideas.”
Clozapine: It’s Use in Ohio’s State Hospitals
and in Ohio in the 1990s
 Sept, 1992-June, 1994: $1 M per year from the legislature for the only atypical
 Initially over 800 patients met criteria with average LOS of > 4 years...
 1177 eligible over the 22 months of the study...608 selected...
 37 % refusal....
 56 discontinued treatment...82% of these over the first 6 months
 21 DC’ed because of major adverse effects...9 for wbc, 1 agranulocytosis
 6 other medical reasons
 20 for refusing to continue treatment
 9 for failure to respond to treatment
 S/R: in 119 monitored and S/R reduced from 256 episodes and 33.6% of
individuals to 64 episodes in 15.1% of individuals
 Improvement slow...but enduring. No discharges after 6 months...12 readmits
 Over 80 % were responders (all 3) or partial responders ( 2 of 3)
 1. 20% reduction in BPRS
 2. Clinician rated improvement in mental and behavioral status
 3. Patient reporting benefits
 Celebrate the success…”Stepping Ahead”
 Mid 1990s: other atypical antipsychotics introduced and clozapine generic
 Effects on the system
After the Awakening, the
Real Therapy Must Begin
By James Willwerth/Cleveland Monday,
July 06, 1992
In Washington Irving's
classic folktale, Rip Van
Winkle awakes from a 20year nap to find his youth
behind him, the world
radically changed and his
assumptions hopelessly
Lori Schiller, “The Quiet
Room”, 1996
Diann Auld Reitelbach, “Catching
the Thief: A Story, A Search and
Clozapine: Historical Perspectives
 1952--Chlorpromazine (Thorazine) synthesized in Paris and observed to control
agitation, hallucinations and delusions. FDA approved in 1953. The first D2
blocker with neurologic side effects. Class termed neuroleptics.
 1956—Clozapine synthesized in Switzerland. Lacked neurologic side effects, termed
 1961—Clozapine developed by Sandoz
 1971- Clinical trials and then use in Europe
 1975- After deaths from agranulocytosis withdrawn from market although still used
in China without wbc monitoring
 1980s-studies showed it was effective for Treatment Resistant Schizophrenia
 1988--US Clozaril Study compared clozapine with chlorpromazine.
 1989- FDA approves for treatment resistant schizophrenia with requirements for
weekly white blood cell and absolute neutrophil counts
 1994-2002—Clozapine becomes generic and other atypical antipsychotics introduced
 2002—FDA approved for reducing the risk of suicide in patients with schizophrenia
 2005-- FDA approved criteria to allow reduced blood monitoring frequency.[61]
 2006—CATIE and CUtLASS demonstrate clozapine better than other atypical
antipsychotics for treatment resistant (TR) schizophrenia
Other Important Clozapine Perspectives
 Benefit for co-occurring substance use, tobacco cessation, reducing
aggression and longer life compared with other antipsychotics for
persons with schizophrenia.
 Usefulness for bipolar patients (Sue McIlroy @ UC)
 Effective in low doses in Parkinson patients for psychosis, tremor,
dystonia, etc.
 5 Black box warnings for agranulocytosis, seizures, myocarditis,
"other adverse cardiovascular and respiratory effects", and for
"increased mortality in elderly patients with dementia-related
What is the Evidence to support clozapine’s claim to be the gold
Kane JM, Honigfeld G, Singer J, Meltzer HY, the Clozaril Collaborative Study Group: Clozapine for
the treatment–resistant schizophrenic: a double-blind comparison with chlorpromazine, Arch Gen
Psychiatry 1988; 45:789–796
Essock SM, Hargreaves WA, Covell NH, Goethe J: Clozapine’s effectiveness for patients in state
hospitals: results from a randomized trial. Psychopharmacol Bull 1996; 32:683–697
Saveanu, TI, Wellage, L,& Roth, D, Evaluation of the Impact of Use of Clozapine Treatment in the
Ohio State Hospital System, New Research in Mental Health, Ohio Department of Mental Health,
1995, Volume, 12, 198-211
Rosenheck R, Cramer J, Xu W, Thomas J, Henderson W, Frisman L, Fye C, Charney D,
Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory
Schizophrenia: A comparison of clozapine and haloperidol in hospitalized patients with refractory
schizophrenia. N Engl J Med 1997; 337: 809–815
MCEVOY, LIEBERMAN, STROUP, ET AL, Effectiveness of Clozapine Versus Olanzapine,
Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond
to Prior Atypical Antipsychotic Treatment, Am J Psychiatry 163:4, April 2006 (Greater time to
all cause discontinuation)
Randomized Controlled Trial of the Effect on Quality of Life of Second- vs First-generation
Antipsychotic Drugs in Schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia Study (CUtLASS 1 Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP,
Murray RM, Markwick A, Lewis SW Archives of General Psychiatry October 2006; 63:1079 –1087
(Greater Reduction in PANNSS Scores after one year)
Leucht S1, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR,
Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM, Comparative efficacy and
tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.
Lancet. 2013 Sep 14;382(9896):940.
CATIE Phase 2E: Time to Discontinuation
Overall p-value= 0.028*
McEvoy et al, AJP 2006
Leucht et al. Lancet 2013
Balancing the Risks and Benefits of clozapine
 Agranulocytosis...<1.0 % 1st 6 months; .o1% after 6 months
 Cardiovascular risks…myocarditis and cardiomyopathy…and tachycardia
 Metabolic side Effects…similar to olanzapine…insulin resistance
 Wt Gain
 Glucose dysregulation
 Lipid increases
 Seizures and myoclonic jerks
 Hypersalivation
 Obstipation
 Anticholinergic side effects
 Sedation
Clozapine Agranulocytosis Risk
 Overall Risk of agranulocytosis or granulocytopenia is
 Most risk occurs between six weeks and six months.
 Risk: second six months 0.70/1000 patient yrs
 Risk: after first year is 0.39/1000 patient yrs
Mandatory monitoring results in very few cases of full
Five year data found 382 cases of aganulocytopenia
among 99,502 patients (0.38%) and 12 deaths (0.01%)
Described in Meltzer article in references
Weight gain
Leucht et al. Lancet 2013
Leucht et al. Lancet 2013
Extrapyramidal symptoms
Leucht et al. Lancet 2013
How to mange the side effects of clozapine?
Clozapine and Cardiovascular risk
Myocarditis Symptom Checklist for Patients on Clozapine
Complete before starting clozapine and then weekly for the first 8 weeks of clozapine
Date of clozapine initiation __________________
Today’s Date __________________
Heart Rate __________________
Blood Pressure __________________
Temperature __________________
Complaints of:
Chest pain/pressure
Peripheral edema
Persistent palpitations
Fatigue or decreased exercise capacity
Fever or flu-like symptoms
Myocarditis Myocarditis is a very low risk of clozapine use. It almost always occurs in the first 2
months of clozapine treatment. Reasonable estimates of its incidence in patients started on
clozapine range from 2/1000 to 1/1000. Consequences can include death (25%) and disability.
Guidelines: Managing Adverse Effects of Clozapine
 Do not panic.
 Always consider the rare but serious problems associated with clozapine:
e.g. Agranulocytosis, Myocarditis, Neuroleptic Malignant Syndrome(NMS)
 Always consider other drugs as a potential cause.
 Do not stop clozapine unless it is absolutely necessary.
 Lowering the dose is fine:
 Unless it is absolutely necessary (i.e. Myocarditis, agranulocytosis, NMS),
clozapine should be gradually lowered and not just stopped. Abrupt
discontinuation can often lead to rapid relapse that is worse than the initial
 Ask for help. (See “Clozapine Phone Consultation Service” link at
Clozapine Resource Center webpage) OSU Role?
J. Nielsen, et al, Termination of Clozapine Treatment Due to Medical Reasons: When Is it Warranted and
How Can It be Avoided?, J Clin Psychiatry, 2013: 74 (6): 603-613
What is the Use of Clozapine in Ohio?
Ohio: Total population (adults with Medicaid who had at least two service claims in 2011 with a
diagnosis of schizophrenia spectrum disorder)* and had at least one pharmacy claim for an
antipsychotic medication): 14,801
Clozapine includes those that were identified on clozapine, Clozaril or FazaClo.
Total number of patients on clozapine alone:
Total number of patients on clozapine plus at
least one other antipsychotic:
All patients on clozapine (alone or in combination):
Franklin County: Total number of patients from Franklin county
with a diagnosis of schizophrenia spectrum disorder: 1474
- All patients on clozapine (alone or in combination):
Ohio new clozapine starts: Stroup, et al, 2001-2005 of all antipsychotic starts
*Schizophrenia spectrum disorder (schizophrenia, schizoaffective, schizophreniform, delusional disorder, psychosis
October 10th, 2014: Data courtesy of NEOMED Dept. of Psychiatry : Mark Munetz, Chris Ritter, Sara Dugan and
OHMAS Carol Karstens
New York OMH Clozapine Utilization
 denominator: patients with 295.x diagnosis receiving antipsychotic
 numerator: 295.x patient receiving clozapine
Q4 2011
Q4 2013
 Inpatient range: 8.45% - 45.66%
 Clinic range: 0% - 40.1%
 New starts in NY in 2002-2005, 1.8-2.6% (Stroup et al)
Courtesy of Jay Carruthers, MD, Director of clozapine initiative in NY OMH
Clozapine: perspectives so far in the 21st Century
 Underused….
 Generic and little marketing
 Younger psychiatrists lack experience with its use and don’t get to see
benefits that may take time
 Side effects are significant and practice settings are often not conducive
to safe use
 As BH/PH care integration is occurring, now seems like a good time
to safely prescribe and monitor.
 OSU could be a leader with others in addressing the underuse of
clozapine and could advance the science (?wt. gain) if we begin an
 Clozapine would likely reduce hospital readmissions for persons with
TR Schizophrenia....ACA payment reform looks at hospital readmission
 Families and persons with a lived experience are not advocating as in
 Awareness of the benefits and risks of clozapine is essential for
increasing the use of this lifesaving agent (Meltzer)
What are the Special Benefits of Clozapine? (NY)
Clozapine is Underutilized: How Can We Address this?
Transformational Leadership
Keep your eye upon the star
“Taking care of business” is job one
Share the vision and develop it further with others.
When the problem seems impossible to resolve, try reframing the issues.
Mental health leadership is a team sport.
Mental health leadership focus includes consumer, clinical, and administrative
“Do the right thing”: A value-based approach leads to trust.
You can’t do just one thing. Change takes action on many fronts at the same time.
Lead, follow, or get out of the way.
Seek outside consultation to assist.
Partner with your best resources
Schedule time to consider, gather input, and set direction
Measure and improve...Improvement Science
Svendsen, D., Hogan, M. & Worham-Wood, J., Transformational Leadership in Mental Health Care, in Modern Community
Mental Health: An Interdisciplinary Approach, edited by Yeager, Cutler, Svendsen & Sills, Oxford U. Press, 2013
Keep your eye upon the star
"Start With Why”
The golden circle
Simon Sinek, author & speaker
Simon O. Sinek is an author best known for popularizing the concept of "the
golden circle" and to "Start With Why",described by TED as "a simple but powerful model for
inspirational leadership all starting with a golden circle and the question "Why?"‘
Lloyd Sederer,MD, Huffington Post,[
“Keep your eye upon the star”
“Do the right thing”
"Start With Why”
 Clozapine is the Best Medication Treatment for the
30% of people with Treatment Resistant
Schizophrenia Spectrum Disorder. However in Ohio
only 5.8 % of the Medicaid population with
Schizophrenia Spectrum Disorder is receiving it
 If the diagnosis were cancer would “we” not be
offering and encouraging the best known treatment
despite side effects and difficulties with
Clozapine: The why is clear...but some barriers
25 years later… a challenge for the mental health system
Remains the most effective antipsychotic for
TR psychosis:
• FDA Indicated for treatment refractory psychosis, suicide
• Other: violence/aggression, co-morbid substance
Vastly underutilized for a number of reasons:
• Fragmented system of care
• Demands more work of everyone: prescriber, ancillary staff,
and patient
• Prescriber bias: poly-pharmacy
• Consumer bias?: Side effects “front loaded” and benefits
“back loaded” in some instances
Should be considered after 2 failed
antipsychotic trials
• Delay in trial of 5-10 years, if given at all
The quintessential science to service gap in behavioral
HOW: To Address this?
“You can’t do just one thing”
“How do you think about this?
 Systems Based...How can we change the system?
 Population based medicine... and patient centered care
 Culture change….change starts with us….our clinical services...
our use of clozapine....our medical faculty and residents...our
handoffs and partnerships
 Relationship, Relationship, Relationship
 Transformational leadership... and processes...a team sport
 Business Plan…put your resources where your mouth is….win/win
relationships….Access new resources and approaches...MEDAPP, State,
 Key Driver Diagram…global aims and smart aims
 Improvement Science
 Improve patient care by reducing the gap between what is actual and possible (Yeager)
 Clinical and Translational research
 Find a Parade and Get in Front of it
 Tipping Point, …Malcolm Gladwell…Law of the Few (Connectors, Mavens, and
Salesmen), the Stickiness Factor, and the Power of Context...
 “Be a thought Leader”…and “Doer”…”Listen”…”THE” OSU Wexner Medical
Center…patient care, education and research”
Share the vision and develop it further with others
Mental health leadership is a team sport
Mental health leadership includes consumer, clinical, and
administrative perspectives.
(Regulation, Payment, Systems, Business Approach, etc.)
Persons & Family
Share the vision and develop it further with others.
 Today’s Grand Rounds
 The story of bringing clozapine to Ohio’s State
Hospitals and afterwards
 “Find a Parade and Get in Front of it”
“Taking care of business” is job one
Change starts with us
 OSU College of Medicine Mission, Vision and Values
 All areas of the Ohio State College of Medicine are driven by our
mission: to improve people’s lives through innovation in research, education
and patient care
 What is OSU Harding Use of clozapine and
antipsychotic polypharmacy? Waiting for results!
WHAT: Partner with your best resources
Thank you for coming to North Central.
We continue to enjoy our developing collegial relationship
with the Ohio State University Department of Psychiatry.
We have been working on the development of the clozapine
outpatient treatment team. We are thinking of starting
with the approximate 40 existing patients, two caseworkers
and one nurse. We would use this as the initial cohort and
build from that. We are wondering whether you have any
estimates about the number of additions to the team that
might be expected from OSU? Please let us know your
Don Wood
Find a Parade and Get in Front of It
Partner with your best resources
 OSU Psychiatry and Behavioral Health/NEOMED collaborate on
 BEST Practices in Pharmacotherapy
 In collaboration with the BeST Center……… (i.e. psychiatry and pharmacy staff
and consultants):
 1) Develop an implementation approach to promote the appropriate use of
 2) Clinical guidance for selection and dosing of pharmaceutical agents for:
Individuals experiencing an initial psychotic episode;
Potential changes/titration
Individuals having lived with a diagnosis of schizophrenia spectrum disorders over
A joint effort benefitting both Departments of Psychiatry
“Find a Parade and Get in Front of it”
 State of Ohio
“When the problem seems impossible to resolve try reframing it”
Polypharmacy & cost
Low dose
for FEP
clozapine use
?fund an
Project Name: Revisiting Pharmacotherapy in Schizophrenia
Increase the evidence based
utilization of antipsychotics for the
treatment of schizophrenia by:
1. Decreasing the extended
use of antipsychotic
polypharmacy by 20%
2. Increasing the use of
clozapine in appropriate
patients by 10%
3. Decrease mental health
hospitalizations due to nonadherence by 10%
4. Decrease rehospitalization
rates within 12 weeks of
previous mental health
discharge due to medication
related problems by 10%
5. Decrease emergency room
visits by 10%
6. Increase the number of
patients working or enrolled
in school by 10%
7. Increase documentation and
evaluation by 10%
•Increase the number of patients with
schizophrenia that take antipsychotics
who achieve functional recovery.
Public Relations/Outreach
Identification/Collaboration with
Partner institutions
Resource and supportive
Seek outside consultation to assist
NEW York has a clozapine initiative with a very thoughtful approach: Consult with Lloyd
Sederer, MD, Mike Hogan, PhD, Scott Stroup, MD, Jay Carruthers, MD
1) "Considering Clozapine" - a module that prepares consumers for talking to their doctor
about clozapine. (Available to all at )
2) "Motivating Clozapine Use- An Aid for Prescribers" - (Accessible to all at
tabid/252/Default.aspx )
3) Algorithm for identifying candidates for a clozapine trial
4) Prescribers' manual
5) Helpful recent article by Jimmi Nielsen and John Kane's group on discontinuation for
medical reasons: when it is indicated and when it's not
6) Resident Curriculum by Freudenreich et al
Share the vision and develop it further with others.
Schedule time to consider, gather input, and set direction
Develop an implementation approach to promote the appropriate use of Clozapine
 OSU Psychiatry
 Faculty and Residents...and new faculty?...and Clozapine Clinic Team
 State of Ohio, Office of Health Transformation, Ohio Medicaid, OHMAS, State
 NEOMED...develop the implementation approach further
 NY OMH...Scott Stroup, Feb. 25th, 2015
 Grand Rounds and Consultation
 Ohio Hospitals...e.g., OHA
 OHIO EMPOWERMENT COALITION and Consumer Operated Services
 Persons with a Lived Experience
 Other Universities, Disciplines, training programs
 Others
"Considering Clozapine“ if we have time
Thanks for listening
Please share your thoughts and ideas
[email protected]

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