APNA 34th Annual Conference Session 4022: Saturday, October 3
APNA 34th Annual Conference
Session 4022: Saturday, October 3
DISCLOSURES
? Over the past twelve months, Rob
Cotes has received research
funding from Alkermes, Lundbeck,
Otsuka, and Roche. He is a paid
consultant to Saladax Biomedical
and the American Psychiatric
Association. His research is also
supported by the Foundation for
Excellence in Mental Health Care,
the Jim and Billie Ellis Foundation,
the John and Polly Sparks
Foundation, and the Betty and
Davis Fitzgerald Foundation.
Demystifying Clozapine to Support Recovery of
Patients with Persistent Psychosis
Robert Cotes, MD
Donna Rolin, PhD, APRN, PMHCNS\BC, PMHNP\BC
Physician Expert, APA/SMI Adviser
Clinical Nurse Expert, APA / SMI Adviser
PMHNP Program Director, University of Texas at Austin School of Nursing
Associate Professor, Emory University School of Medicine
? Donna Rolin presents no
disclosures.
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? 2020 American Psychiatric Association. All rights reserved.
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LEARNING OUTCOMES
? Demonstrate best practices for implementing clozapine prescribing in
routine clinical care.
? Recall team\based models for treating persistent psychosis.
? Apply side\effect assessment and education to patients with psychosis.
PERSISTENT PSYCHOSIS
Prevalence
Definition
Effective treatments
Systematic Approach
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Treatment Resistant Schizophrenia (TRS)
Prevalence of TRS
? Causes considerable suffering, including
34 billion dollars in direct medical costs
to the US
? High rate of suicidal ideation (44%)
? High rates of smoking (56%) and
substance abuse (51%)
? Likely includes 20\30% of individuals
with schizophrenia
? 392 never\treated patients with schizophrenia
? Remission rates at 3 years during follow up treatment
?
?
?
?
Kennedy, J. L., Altar, C. A., Taylor, D. L., Degtiar, I., & Hornberger, J. C. (2014). The social and economic burden of
treatment\resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol, 29(2), 63\76.
Conley, R. R., & Kelly, D. L. (2001). Management of treatment resistance in schizophrenia. Biol Psychiatry, 50(11),
898\911.
? 2020 American Psychiatric Association. All rights reserved.
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60.3% symptoms
45.4% functioning
57.0% subjective wellbeing
14% never fulfilled any remission criteria
Lambert, M., Naber, D., Schacht, A., Wagner, T., Hundemer, H. P., Karow, A., . . . Schimmelmann, B. G. (2008). Rates and predictors of remission and recovery during 3 years in 392 never\treated patients with
schizophrenia. Acta Psychiatr Scand, 118(3), 220\229.
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Robert O. Cotes, M.D.
Donna Rolin, PhD, APRN, PMHCNS\BC, PMHNP\BC
? 2020 American Psychiatric Association. All rights reserved.
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APNA 34th Annual Conference
Session 4022: Saturday, October 3
Defining TRS
Treatment Resistant Schizophrenia (TRS)
? Highlights of TRIPP Guidelines (minimum requirement)
? Clozapine is the only medication approved by
the US FDA for TRS
? 4.8% of people with schizophrenia are
prescribed clozapine in the US
? Many clinicians do not have clinical
competencies necessary to prescribe
clozapine, and many organizations do not
have supports in place.
? Current symptoms are moderate in severity with at least moderate functional
impairment despite:
? 2 or more antipsychotic medication trials
? Antipsychotic dose equivalent to 600 mg chlorpromazine per day
? Antipsychotic trial 6 weeks at therapeutic dosage
? 80% of prescribed doses taken
Howes, O. D., McCutcheon, R., Agid, O., de Bartolomeis, A., van Beveren, N. J., Birnbaum, M. L., . . . Correll, C. U. (2017). Treatment\Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP)
Working Group Consensus Guidelines on Diagnosis and Terminology. Am J Psychiatry, 174(3), 216\229.
? 2020 American Psychiatric Association. All rights reserved.
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Olfson, M., Gerhard, T., Crystal, S., & Stroup, T. S. (2016). Clozapine for Schizophrenia: State Variation in Evidence\Based Practice. Psychiatr
Serv, 67(2), 152.
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When to Use Clozapine
A Systematic Approach to TRS
? Recommends clozapine after minimal or no response to two trials of
antipsychotic medication
? Recommends that patients with schizophrenia be treated with clozapine if
the risk for suicide attempts or suicide remains substantial despite other
treatments.
? Suggests that patients with schizophrenia be treated with clozapine if the
risk for aggressive behavior remains substantial despite other treatments
? 5 Cs
American Psychiatric Association. (2019). The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia (Draft Guideline). from
\practice\guidelines
Roerig, J. L. (2019). Clozapine augmentation strategies. Ment Health Clin, 9(6), 336\348.
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Correct Diagnosis
Comorbidities
Compliance
Concentration of Antipsychotics
Continuous psychosocial stressors
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Care and Staffing Models for Use of Clozapine
CARE & STAFFING MODEL
STRUCTURE
? Complexity of Implementation
? Patient Selection Process
? Indications
? Treatment team identification
? Patient discussions
Successful Use of Clozapine
REMS Registry & Monitoring/Reporting
? Leadership of clozapine systems
? Psychiatrists
? Psychiatric Mental Health Nurses are well suited to lead clozapine systems
? 2020 American Psychiatric Association. All rights reserved.
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Robert O. Cotes, M.D.
Donna Rolin, PhD, APRN, PMHCNS\BC, PMHNP\BC
? 2020 American Psychiatric Association. All rights reserved.
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APNA 34th Annual Conference
Session 4022: Saturday, October 3
Successful Care and Staffing Models
Clozapine Survey (SMIA)
? Multidisciplinary clinic
? Psychiatrist or PMHNP, nurse, pharmacist, case manager, rehabilitation
? One prescriber or multiple prescribers, usually with a psychiatrist medical director
? One\stop shopping: Vital signs, education, lab test, prescriber when needed,
dispense, REMS
? Lab or point of care ANC testing
? Virtual team
? Psychiatrist or PMHNP prescriber, pharmacist, laboratory
? Clozapine management organization: labs, dispensing, REMS, manage side\effects,
travel and logistical issues
N=81
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Clozapine Survey
Easing Burden of Clozapine
N=81
? Laboratories
? Most labs accept standing orders, or can place standing order in EMR
? Request results to be faxed to the pharmacy
? Consider point of care testing with automated REMS reporting and dispensing
? Pharmacies
?
?
?
?
?
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Ese pharmacy with clozapine experience
Many will accept refills on clozapine prescriptions
Many will dispense after they check the ANC themselves
Most will report the ANC to the REMS in place of clinician reporting
Some pharmacies and states allow collaborative arrangements to increase role of
pharmacist
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Easing Burden of Clozapine
Easing Burden of Clozapine
Prescriber
? Patients
?
?
?
?
?
Weekly or monthly visits are not always necessary
Can often check in by phone or video telehealth
Need to evaluate for side\effects, manage titration, and handle barriers
Engage families or other supports
Communicate confidence and usual course of clozapine titration and response
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Robert O. Cotes, M.D.
Donna Rolin, PhD, APRN, PMHCNS\BC, PMHNP\BC
Patient
? 2020 American Psychiatric Association. All rights reserved.
Laboratory
Pharmacy
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REMS
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APNA 34th Annual Conference
Session 4022: Saturday, October 3
CLOZAPINE REMS\The
Single Shared
SystemFrequency
for Clozapine
Recommended
Monitoring
and Clinical Decisions by ANC Level
FAMILY PERSPECTIVE & ROLE IN CARE
Recommended Monitoring Frequency and
Clinical Decisions by ANC Level
ANC Level
Engaging the patients family/support system can be a tremendous benefit
? Ask the person who they consider to be a source of support for them
? Secure releases of information
? Invite them into sessions to explain
o Whats involved in Clozapine therapy C benefits and challenges
o What they can expect and look for
o How they can be supportive of their loved one
Treatment Recommendation
Normal range for a new patient \ Initiate treatment
\ If treatment interrupted
\ General population
\ ? 30 days, con nue monitoring as
\ (ANC 1500/?L)
before
\ ? 30 days, monitor as if new
BEN POPULATION
patient
\ BEN Population
\ (ANC 1000/?L)
\ Obtain at least two baseline \ Discontinuation for reasons other than
ANC levels before initiating
neutropenia (other conditions or side
treatment
effects)
? Including the patient and the family in the treatment process can yield the
best outcomes
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ANC Monitoring
\ Weekly from initiation to 6 months
\ Every 2 weeks from 6 to 12 months
\ Monthly after 12 months
\ See section Discontinuation of
Treatment of the full Prescribing
Information
\
zapineUI/prescribingInformation.s#
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Moderate Neutropenia
(500 to 999/?L)*
GENERAL POPULATION
\ Recommend hematology consultation
\ Interrupt treatment for suspected
clozapine induced neutropenia
\ Resume treatment once ANC
normalizes to 1000/?L
GENERAL POPULATION
\ Daily until ANC 1000/?L, then
\ Three times weekly until ANC 1500/?L
\ Once ANC 1500/?L, check ANC weekly
for 4 weeks, then return to patients last
Normal Range ANC monitoring
interval**
BEN POPULATION
\ Recommend hematology consultation
\ Continue treatment
BEN POPULATION
\ Three times weekly until ANC 1000/?L or
patients known baseline.
\ Once ANC 1000/?L or patients known
baseline, then check ANC weekly for 4
weeks, then return to patients last
Normal Range ANC monitoring
interval**
Planning for Continuation of Clozapine During Emergencies
(such as coronavirus COVID\19 pandemic)
? Emergencies/Disasters/Pandemics \ prevent patients from coming to a
clinic or laboratory for necessary assessments or blood monitoring
? First is to consider whether the patient is appropriate for the creation of
an extra clozapine supply
? Access to point\of\care (POC) ANC testing
? Plan for remote follow\up
? For more stable patients, a phone call may be sufficient.
? Also, the U.S. FDA has the authority to change guidance during major
crises.
* Confirm all initial reports of ANC less than 1500/?L (ANC 1000/?L for BEN patients) with a repeat ANC measurement within 24 hours
** If clinically appropriate
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Update from the FDA regarding COVID\19,
Clozapine REMS, and blood monitoring
Point of Care (POC) Technology
? A new portable device (Athelas One) provides WBC and ANC monitoring results within
6 minutes by capillary draw
? Per communication with FDA and Clozapine REMS, prescribers and pharmacies have discretion
to order and dispense clozapine without an absolute neutrophil count reported within the
specified time frames. [This information is current as released on 1/23/2020; obtained on
3/22/2020.]
? Drop of blood goes into test strip to create peripheral blood smear
? Device images and automatically analyzes the cells morphologically with machine
learning and pathologist oversight, and then generates + clears the final count report
? Uses computer vision and our remote pathology lab on the backend using CLIA lab
? Clinicians receive results on computer or app
? Connects via WIFI or Ethernet
? Can integrate automatically with ClozapineREMS
? Potential for reimbursement with testing
? The following is posted on the Clozapine REMS website (click to view full guidance):
? ***Important Program Update (as of 01/23/2020; updated 4/20/2020)***
? ANC Current Lab Requirements Absolute Neutrophil Count not current (i.e., within 7, 15, or 31
days of the lab draw date) based on the patients monitoring frequency (MF) will not prevent a
patient from receiving clozapine from the pharmacy. Although ANC not current will not
prevent a patient from receiving clozapine from the pharmacy, pharmacies are encouraged to
submit the ANC to the Clozapine REMS Program when the pharmacist is made aware of a more
current ANC than the most recent lab value reported in the PDA response.
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Robert O. Cotes, M.D.
Donna Rolin, PhD, APRN, PMHCNS\BC, PMHNP\BC
? 2020 American Psychiatric Association. All rights reserved.
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APNA 34th Annual Conference
Session 4022: Saturday, October 3
Validation of ANC
? Has been rigorously clinical validated across 800
patients, and especially in patients exhibiting
drug\induced neutropenia at the Dale Lab in
University of Washington
OUTCOMES
? More than 30,000 ANC tests have been run on
the Athelas One device platform to\date
Monitoring effectiveness
Side effect monitoring & management
? Recently granted Class II FDA device clearance
in US
? First in class in US for this type of technology
r=0.94
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Monitoring for Side Effects: Myocarditis
Monitoring Effectiveness
? Myocarditis is a rare, but potentially serious side effect of clozapine. It can be fatal.
? Usually occurs within 2\3 weeks of starting clozapine
? Inflammation of the heart muscle
? Symptom relief
? positive symptoms decreased: disorganization, hallucinations, delusions
? Clozapine blood levels
?
?
?
?
? symptoms are non\specific: fever, fatigue, flu\like symptoms, chest pain, tachycardia,
palpitations, hypotension, dyspnea, signs of heart failure, electrocardiographic changes
there is no therapeutic level or window: symptoms and side\effects guide dosage
levels useful for adherence, more side\effects, less efficacy, drug\drug interactions
steady state: more than 3 days after a patient is stable on a dose
trough: 12 hours after the last dose
? Management: discontinue clozapine and obtain cardiac evaluation upon suspicion
of myocarditis
? diagnostic evaluation include EKG, C\reactive protein (CRP) and troponin (I and T subtypes),
and cardiac MRI
? Clozapine levels and efficacy
? efficacy usually starts at levels above 250 ng/ml
? greatest efficacy at levels above 350 ng/ml
? risk of seizures increases at levels above 1000 ng/L
? If a patient has had myocarditis on clozapine, the decision regarding whether to
restart clozapine is made on a case\by\case basis.
? If the benefit of outweighs the risks, the clinician may consider restarting clozapine in
consultation with a cardiologist, after a complete cardiac evaluation, and with close monitoring
? Norclozapine levels
Schulte P (2003) What is an adequate trial with clozapine? Therapeutic drug monitoring and time to response in treatment\refractory schizophrenia. Clinical Pharmacokinetics 42: 607C618
Williams, A. M., & Park, S. H. (2015). Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs, 29(2), 101\111.
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Ronaldson, K. J., Fitzgerald, P. B., Taylor, A. J., Topliss, D. J., & McNeil, J. J. (2011). A new monitoring protocol for clozapine\induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N
Z J Psychiatry, 45(6), 458\465.
Cook, S. C., Ferguson, B. A., Cotes, R. O., Heinrich, T. W., & Schwartz, A. C. (2015). Clozapine\Induced Myocarditis: Prevention and Considerations in Rechallenge. Psychosomatics, 56(6), 685\690.
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Monitoring for Side Effects: Seizures
Monitoring for Side Effects: Weight Gain
? Significant weight gain occurs in one third of patients who take clozapine
? Weight and BMI should be measured monthly for 6 months then quarterly
? Seizures are an uncommon, but a potentially serious side effect of
clozapine.
? patients should weigh themselves weekly at home
? between 2% and 4% of patients taking clozapine have a seizure during
treatment
? the risk for seizure may be dose related
? patients should not drive while clozapine is titrated
? Obesity is associated with hyperlipidemia, hyperglycemia, hypertension
? it is easier to prevent weight gain than to lose weight
? 5\10 lb. weight gain should lead to intervention
? a substantial proportion of patients who take clozapine improve, and are able to
engage better with psychoeducational weight loss interventions
? Management: seizures can usually be controlled with dosage
reduction or adding an antiepileptic medication such as valproate
? Management
? taper or discontinue other medications that cause weight gain
? metformin can reduce body weight and reverse metabolic problems
? others: orlistat, topiramate, naltrexone\bupropion,
liraglutide
Pacia, S. V., & Devinsky, O. (1994). Clozapine\related seizures: experience with 5,629 patients. Neurology, 44(12), 2247\2249.
Williams, A. M., & Park, S. H. (2015). Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs, 29(2), 101\111.
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Robert O. Cotes, M.D.
Donna Rolin, PhD, APRN, PMHCNS\BC, PMHNP\BC
Nemani, K. L., Greene, M. C., Ulloa, M., Vincenzi, B., Copeland, P. M., Al\Khadari, S., & Henderson, D. C. (2019). Clozapine, Diabetes Mellitus, Cardiovascular Risk and Mortality: Results of a 21\Year
Naturalistic Study in Patients with Schizophrenia and Schizoaffective Disorder. Clin Schizophr Relat Psychoses, 12(4), 168\176.
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