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Clozapine is underused in Ohio: How can we address this? Dale Svendsen, MD, MS October 15, 2014.

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Presentation on theme: "Clozapine is underused in Ohio: How can we address this? Dale Svendsen, MD, MS October 15, 2014."— Presentation transcript:

1 Clozapine is underused in Ohio: How can we address this? Dale Svendsen, MD, MS October 15, 2014

2 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

3 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

4 Comprehensive Reviews Clozapine: Balancing Safety with Superior Antipsychotic Efficacy Herbert Y. Meltzer, June, 2012  Clozapine is often referred to as the gold standard for the treatment of schizophrenia…yet the most underutilized treatment.  Concerns over side effects, especially 1) agranulocytosis; 2) metabolic side effects; and 3) myocarditis are responsible for much of the underutilization of clozapine. Nevertheless, two large epidemiologic studies has the lowest mortality of any antipsychotic drug and reduced...suicide.  Other reasons for limited use of clozapine include the extra effort entailed in monitoring for side effects and, possibly, minimal efforts to market it now that it is largely generic.  Awareness of the benefits and risks of clozapine are essential for increasing the use of this lifesaving agent.

5 Psychiatric Services, February 2014 What started the interest in clozapine at OSU Psychiatry?

6 State Variation in Clozapine Initiations 2002-2005: 629,809 AP Tx episodes with 2.2% starts 79,934 TR with 5.5% starts

7 What Do Others @ OSU think in response to Stroup Article? 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

8 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.

9 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.”

10 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 AP  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

11 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 20- year nap to find his youth behind him, the world radically changed and his assumptions hopelessly outmoded. Brendan Lori Schiller, “The Quiet Room”, 1996 Diann Auld Reitelbach, “Catching the Thief: A Story, A Search and Schizophrenia”

12 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 atypical  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] [61]  2006—CATIE and CUtLASS demonstrate clozapine better than other atypical antipsychotics for treatment resistant (TR) schizophrenia [

13 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 psychosis.““  [ [

14 What is the Evidence to support clozapine’s claim to be the gold standard?  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 S 1, 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. Leucht SCipriani ASpineli LMavridis DOrey DRichter FSamara MBarbui CEngel RR Geddes JRKissling WStapf MPLässig BSalanti GDavis JM

15 CATIE Phase 2E: Time to Discontinuation Overall p-value= 0.028* McEvoy et al, AJP 2006

16 Symptoms Leucht et al. Lancet 2013

17 Balancing the Risks and Benefits of clozapine  Risks  Agranulocytosis...<1.0 % 1 st 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

18 Clozapine Agranulocytosis Risk  Overall Risk of agranulocytosis or granulocytopenia is 0.7-1.0%.  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 agranulocytosis. 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

19 Weight gain Leucht et al. Lancet 2013

20 Sedation Leucht et al. Lancet 2013

21 Extrapyramidal symptoms Leucht et al. Lancet 2013

22 How to mange the side effects of clozapine?

23 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 treatment.  Date of clozapine initiation __________________  Today’s Date __________________  Heart Rate __________________  Blood Pressure __________________  Temperature __________________  Complaints of:  Chest pain/pressure  Dyspnea/orthopnea  Peripheral edema  Persistent palpitations  Fatigue or decreased exercise capacity  Fever or flu-like symptoms  Nausea/vomiting  Diaphoresis  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.

24 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 psychosis.  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

25 Psychiatric Services, November 2012 Data specifically from New York State is very similar Is there other data to support the Stroup article?

26 Antipsychotic starts for Schizophrenia in NYS Medicaid 2009 (N=7035)

27 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: 321 (2.2%)  Total number of patients on clozapine plus at  least one other antipsychotic: 541 (3.7%)  All patients on clozapine (alone or in combination): 862 (5.8%)   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): 73 (5.0%)  Ohio new clozapine starts: Stroup, et al, 2001-2005 of all antipsychotic starts (1-8-2.6%)  *Schizophrenia spectrum disorder (schizophrenia, schizoaffective, schizophreniform, delusional disorder, psychosis NOS)  October 10 th, 2014: Data courtesy of NEOMED Dept. of Psychiatry : Mark Munetz, Chris Ritter, Sara Dugan and OHMAS Carol Karstens

28 New York OMH Clozapine Utilization  denominator: patients with 295.x diagnosis receiving antipsychotic  numerator: 295.x patient receiving clozapine  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 Q4 2011Q4 2013 INPATIENT27.3%30.0% OUTPATIE NT 16.8%17.3%

29 Clozapine: perspectives so far in the 21 st 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 initiative  Clozapine would likely reduce hospital readmissions for persons with TR Schizophrenia....ACA payment reform looks at hospital readmission rates  Families and persons with a lived experience are not advocating as in past  Awareness of the benefits and risks of clozapine is essential for increasing the use of this lifesaving agent (Meltzer) 

30 What are the Special Benefits of Clozapine? (NY)

31 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 perspectives.  “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

32 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?"‘authorTED Lloyd Sederer,MD, Huffington Post, [ [

33 “Keep your eye upon the star” “Do the right thing” "Start With Why” 33  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 administration?

34 Clozapine: The why is clear...but some barriers 25 years later… a challenge for the mental health system FDA Indicated for treatment refractory psychosis, suicide Other: violence/aggression, co-morbid substance Remains the most effective antipsychotic for TR psychosis: 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 Vastly underutilized for a number of reasons: Delay in trial of 5-10 years, if given at all Should be considered after 2 failed antipsychotic trials The quintessential science to service gap in behavioral health?

35 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, ADAMH  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”

36 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. Administration (Regulation, Payment, Systems, Business Approach, etc.) Persons & Family Clinical Care

37 WHAT: 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”

38 Reasons for current interest in clozapine  Newer antipsychotic medications have not matched clozapine’s effectiveness for people with refractory symptoms  Continued lack of evidence for alternative strategies, including antipsychotic polypharmacy

39 “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!

40 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 thoughts. Don Wood

41 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 Clozapine  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 time  A joint effort benefitting both Departments of Psychiatry

42 “Find a Parade and Get in Front of it”  State of Ohio Optimizing Pharmacotherapy For Schizophrenia Polypharmacy & cost Low dose antipsychotics for FEP clozapine use ?fund an initiative “When the problem seems impossible to resolve try reframing it”

43 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 non- adherence 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% SMART AIM Communication Cost Training Public Relations/Outreach KEY DRIVER DIAGRAM Project Name: Revisiting Pharmacotherapy in Schizophrenia KEY DRIVERSINTERVENTIONS Resource and supportive materials Education Increase the number of patients with schizophrenia that take antipsychotics who achieve functional recovery. GLOBAL AIM Obstacles/resistance Evaluation Education Identification/Collaboration with Partner institutions

44 . 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 ) 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

45 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 Development  NCMHS  State of Ohio, Office of Health Transformation, Ohio Medicaid, OHMAS, State Hospitals  NEOMED...develop the implementation approach further  NY OMH...Scott Stroup, Feb. 25 th, 2015  Grand Rounds and Consultation  ADAMH  Ohio Hospitals...e.g., OHA  NAMI, MHA  OHIO EMPOWERMENT COALITION and Consumer Operated Services  Persons with a Lived Experience  OPPA  Other Universities, Disciplines, training programs  Others

46 "Considering Clozapine“ if we have time 

47 Thanks for listening Please share your thoughts and ideas

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