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Don’t Go Breaking My Heart: Re-Initiation Following Clozapine-Induced Myocarditis

Raeschell “Shelly” Williams, PharmD, MPH PGY1 Pharmacy Resident

South Texas Veterans Health Care System The University of Austin College of Pharmacy

Pharmacotherapy Grand Rounds February 9, 2018

Learning Objectives 1. Review the definition, pathophysiology, and treatments of schizophrenia, as well as how it can

lead to treatment-resistant schizophrenia (TRS)

2. Describe the role of clozapine in the management of TRS

3. Recognize the pathophysiology and common clinical markers of clozapine-induced myocarditis

4. Formulate an opinion regarding re-initiation of clozapine therapy following clozapine-induced

myocarditis

2 | W i l l i a m s

Introduction to Schizophrenia I. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of

schizophrenia1

a. Thought disorder involving a complex mix of symptoms

b. Diagnostic criteria

i. Two (or more) of the following, each present for a significant portion of time

during a one-month period (or less if successfully treated); with one of the

symptoms including delusions, hallucinations, or disorganized speech

1. Delusions

2. Hallucinations

3. Disorganized speech

4. Grossly disorganized or catatonic behavior

5. Negative symptoms

Table 1: Categories of Schizophrenia-Associated Symptoms2

Positive Negative Cognitive

Hallucinations

Delusions

Paranoia or suspiciousness

Conceptual disorganization

Hostility

Grandiosity

Excitement

Loose associations

Thought broadcasting

Thought insertion

Blunted or flat affect

Social withdrawal (passive-

apathetic)

Lack of personal hygiene

Prolonged time to respond

Poor rapport

Poor abstract thinking

Poverty of speech

Emotional withdrawal

Alogia

Ambivalence; prevents decision

making

Autism (internally directed)

Amotivation (avolition)

Anhedonia

Poor executive function

Impaired attention

Impaired memory

ii. Level of functioning is markedly below the level achieved prior to the onset of

symptoms

iii. Continuous signs of the disturbance persist for at least six months, including one

month of active symptoms

iv. Minimal or lack of mood symptoms

v. The disturbances are not attributable to the physiological effects of a substance

or another medical condition

II. Epidemiology3-7

a. Incidence

i. Affects 21 million people worldwide

ii. Occurs in 1% of the general population

iii. Most common age of onset:

3 | W i l l i a m s

1. Men – early to mid-20s

2. Women – late 20s

Figure 1. Natural Course of Illness in Schizophrenia

b. Risk factors

i. Genetic

1. Family history

a. Heritable component accounts for nearly 70% of schizophrenia

cases

b. People which schizophrenia tend to have higher rates of rare

genetic mutations

i. Hundreds of different genes may be disrupted

ii. Mutations may impact brain development

2. Older age of the father

ii. Environmental

1. Early life

a. Obstetric complications, including infections

b. Season of birth

c. Maternal malnutrition or stress

2. Childhood

a. Child abuse

b. Head injury

3. Late life

a. Drug abuse

b. Urbanization

c. Immigration

d. Social adversity

iii. Autoimmune

III. Pathophysiology7-12

a. Neurotransmitter involvement (Figure 2)

i. The Dopamine Hypothesis

1. Schizophrenia is caused by dysregulation of dopamine

a. Increased dopamine levels

4 | W i l l i a m s

i. Occurs in the mesolimbic tract

ii. Excess dopamine is hypothesized to cause the positive

symptoms of schizophrenia

b. Decreased dopamine levels

i. Occurs in the nigrostriatal and mesocortical pathways

ii. Contributes to extrapyramidal symptoms (EPS),

negative symptoms, and cognitive defects

2. Flaws in this theory

a. Blockade of dopaminergic neurotransmission does not fully

alleviate symptoms

b. Role of dopamine is very complex

ii. Glutamate

1. Major central nervous system (CNS) excitatory neurotransmitter

2. Hypofunction of the NMDA glutamate receptor has been hypothesized

to contribute to cognitive symptoms of schizophrenia

iii. Gamma-aminobutyric acid (GABA)

1. Major CNS inhibitory neurotransmitter

2. GABAergic interneurons are important for regulation of prefrontal

cortical function, through their modulation of glutamatergic pyramidal

cells

3. Interneuron dysfunction in schizophrenia

a. Decrease in their overall number

b. Diminished expression of the enzymes that synthesize GABA

c. Diminished expression of neuropeptides that are released

during neurotransmission

Table 2. Summary of Neurotransmitter Changes in Schizophrenia12

Neurotransmitter Brain pathway Effect in patients without

schizophrenia

Change Effect in patients

with schizophrenia

Dopamine Mesolimbic tract

(ventral

tegmental area)

Motivation

Pleasure

Reward

↑ Positive symptoms

Substantia nigra

and mesocortical

areas

Substantia nigra – motor

movements

Mesocortical tract – cognition,

executive function, emotion,

affect

↓ Extrapyramidal,

negative, and

cognitive

symptoms

Glutamate Prefrontal cortex Decision making capabilities NMDA

receptor

hypofunction

Cognitive

symptoms; may

cause positive

symptoms via

interaction with

dopamine neurons

GABA Prefrontal cortex Decision making capabilities Alterations

in GABA

interneurons

Positive symptoms

via interaction with

glutamate and

dopamine

5 | W i l l i a m s

Figure 2. Neuronal Circuits Possibly Involved in Schizophrenia and its Treatment8

b. Multiple brain regions dysfunction

i. Enlarged ventricles

ii. Less gray matter

iii. Decreased number of neurons in various brain regions

IV. Treatment

a. Antipsychotics are the mainstay of treatment for schizophrenia (Appendix A)

b. Selection based on efficacy, side effects, and available formulations

6 | W i l l i a m s

Treatment-Resistant Schizophrenia I. Based on meta-analyses, 10% to 30% of patients with schizophrenia do not respond adequately

to treatment13

II. Definition14-18

a. Various psychiatric guidelines and algorithms have developed differing definitions of

treatment-resistant schizophrenia (TRS)

b. Overall, no consensus exists for how to appropriately define TRS, but commonalities

between guidelines suggest the following:

i. A history of failure of at least 2 antipsychotic trials (one of them with an atypical

antipsychotic) with adequate doses, with 4 to 6 weeks’ duration, and without

satisfactory response, particularly in terms of persistence of psychotic

symptoms

ii. High levels of psychopathology, particularly the presence of psychotic

symptoms that have an impact on the patient’s conduct and functionality

iii. Presence of suicidality, violence, and substance abuse

III. Evaluation and management19-23

a. “Pseudoresistance”

i. Re-evaluate primary diagnosis

ii. Co-occurring conditions

iii. Side effects

iv. Nonadherence

b. Non-pharmacologic modalities

i. Cognitive-behavioral therapy for persistent delusions or hallucinations

ii. Family psychoeducational interventions for those with significant family

involvement

iii. Social skills training to improve independent skills for daily functioning

iv. Assertive community treatment for those with repetitive hospitalizations or

homelessness

v. Crisis intervention for patients whose symptoms are exacerbated by emotional

crises or other psychosocial stressors

c. Optimizing current therapies

IV. Treatments2, 24-38

a. Antipsychotic augmentation

i. Electroconvulsive therapy (ECT)

ii. Transcranial magnetic stimulation

iii. Antidepressants

iv. N-acetylcysteine

v. Topiramate

b. Clozapine

i. Background

1. Initially developed in the 1958 and withdrawn from the market due to

fatal agranulocytosis

2. Re-introduced in 1990 as a third-line agent for patients with TRS

3. Considered the “gold standard” in TRS

7 | W i l l i a m s

4. Tricyclic dibenzodiazepine derivative

Figure 3. Clozapine chemical structure37

5. Receptor activity

a. Broad-spectrum antagonistic properties at the following

receptors:

i. Dopamine

1. Antagonist at the D1, D2, D3, and D5 receptors

2. High affinity for the D4 receptor

3. Relatively weak D2-receptor affinity

ii. Serotonin – 5HT2, 5HT3, 5HT6, and 5HT7 subtypes

iii. Norepinephrine

iv. Histamine

v. Acetylcholine – muscarinic A1 and A2 receptors

b. Significant effects on GABAergic and glutamatergic systems

Figure 4. Clozapine receptor activity12

ii. Efficacy

1. In 1988, clozapine was initially compared to chlorpromazine in a double-

blind comparison lasting 6 weeks

a. Up to 900 mg/day of clozapine vs up to 1800 mg/day of

chlorpromazine

b. 30% of clozapine-treated patients were categorized as

responders compared to 4% of chlorpromazine-treated patients

8 | W i l l i a m s

c. Clozapine produced significantly greater improvement in the

BPRS, CGI, and NOSIE scales; with improvements in both

positive and negative symptoms

2. More recently, in 2013, clozapine was shown to be more effective in

TRS than olanzapine

a. Systematic review comparing clozapine with olanzapine in

patients with TRS

i. Seven RCTs were included in the analysis

ii. Over 600 patients involved

b. Clozapine was superior to olanzapine for PANSS positive and

negative subscales

3. Along with symptom improvement, clozapine has been associated with

decreased rates of mortality, suicide, and aggression

iii. Prescribing

1. Supplied as a 25 mg or 100 mg tablet

2. Dosing

a. Initial:

i. 12.5 mg orally 1 to 2 times daily and continue with daily

increases in increments of 25 to 50 mg/day, as tolerated

ii. Target dose of 300 to 450 mg/day (in 2 to 3 divided

doses) by the end of 2 weeks

b. Maintenance:

i. Dosage adjustments should be made no more than 1 to

2 times per week in increments not to exceed 100 mg

ii. Max daily maintenance dose of 900 mg

3. REMS Program

a. Established due to the severe neutropenia associated with

clozapine (ANC < 500/µL)

b. Required by the FDA for clozapine to ensure that the benefits of

the drug outweigh the risk of severe neutropenia

c. Required of clozapine prescribers, dispensing pharmacies, and

patients

d. Available at: https://www.clozapinerems.com

iv. Monitoring

1. Boxed warnings

a. Agranulocytosis

b. Seizures

c. Myocarditis and cardiomyopathy

d. Other adverse effects

i. Orthostatic hypotension

ii. Bradycardia

iii. Syncope

iv. Cardiac arrest

e. Increased mortality in elderly patients with dementia-related

psychosis

9 | W i l l i a m s

2. Additional adverse effects

a. Weight gain

b. Sedation

c. Hypersalivation

d. Rapid heart rate

e. Fever

Clozapine-Induced Myocarditis I. Myocarditis39

a. Defined as an inflammatory disease of the myocardium

b. Clinical presentation

i. Variable presentation

ii. May include the following:

1. Fatigue or exercise intolerance

2. Chest pain

3. Heart failure

4. Cardiogenic shock

5. Arrhythmias

6. Respiratory distress/tachypnea

c. Etiology

i. Infections – viral, bacterial, spirochetal, mycotic, protozoal, helminthic,

rickettsial

ii. Cardiotoxins

iii. Hypersensitivity reaction

iv. Systemic disorders

d. Diagnostic and laboratory changes (Table 3)

Table 3. Diagnostic and Laboratory Abnormalities in Myocarditis39

Diagnostic or Laboratory Test Observations in Myocarditis

EKG May be normal

ST changes similar to an acute MI

Atrial or ventricular ectopic beats

Ventricular arrhythmias

Cardiac biomarkers Serum cardiac troponins

BNP or NT-proBNP

Chest radiograph Enlarged heart

May or may not involve pleural effusions

Cardiovascular magnetic resonance Edema

Myocyte necrosis and scar tissue

Changes in ventricular size and geometry

Pericardial effusion

e. Diagnosis

i. Endomyocardial biopsy (EMB) is required for a definitive diagnosis of

myocarditis

10 | W i l l i a m s

ii. Diagnosis is supported with histology, immunohistochemcial staining, and

detection of viral genomes by polymerase chain reaction (PCR)

II. Epidemiology24, 40-47

a. Incidence

i. Approximately 1.2% of patients on clozapine have been reported to develop

myocarditis

1. Incidence varies in the literature

2. Could be under-reported due to nonspecific initial symptoms

ii. Most cases occur early in treatment

1. More than 85% of cases occur in the first 2 months

2. Up to 75% of cases are reported within 3-4 weeks of starting clozapine

therapy

3. Average time to onset approximates 15 days (± 7 days)

b. Prognosis

i. Mortality rate has been reported to approach 50%

ii. Death from clozapine-induced myocarditis may be independent of coronary

artery disease (CAD), except in cases where CAD is severe

c. Risk factors

i. Thought to be related to rapid dose titration

ii. Medication interactions

1. Antibacterials – sulfonamides and beta-lactams

2. Thyroxine – levothyroxine sodium

3. Ranitidine

4. Cyclophosphamide

5. Lithium

6. Phenothiazines

7. Certain antidepressants – sertraline and TCAs (amitriptyline,

imipramine, desipramine)

III. Pathophysiology35, 48-51

a. Inflammation

i. Clozapine increases the release of inflammatory cytokines

ii. Primarily focused around elevations in TNF-α

b. Allergy

i. IgE-mediated hypersensitivity reaction

ii. Hypereosinophilic syndrome

1. Eosinophils block cholinergic M2 receptors

a. Leads directly to cardiotoxicity

b. Infiltrates in myocardial and perivascular areas

2. Evidence of peripheral eosinophilia on autopsy

3. Dose-independent

c. Hypothesized mechanisms

i. Elevation in norepinephrine

1. Elevated plasma norepinephrine levels in clozapine-treated patients

compared to those treated with other antipsychotics

2. Increased noradrenergic tone may lead to myocarditis in select patients


ii. Clozapine accumulation

1. Possibly due to cytochrome P450 1A2/1A3 deficiency

2. Decreased metabolism leads to toxicity

IV. Clinical Presentation24

a. Presentation may be highly variable (Table 4)

b. Initial symptoms may mimic common side effects seen when initiating clozapine

titration, including mild fever, tachycardia, and fatigue

c. Prodromal syndrome may present preceding the onset of myocarditis by several days to

a few weeks

i. Fever

ii. Rash

iii. Myalgias and arthralgias

iv. Fatigue

v. Respiratory or gastrointestinal symptoms

d. Myocarditis may also present without accompanying symptoms

Table 4. Signs and Symptoms that may be Associated with Clozapine-Related Myocarditis24

More Common Signs and Symptoms Less Common Signs and

Symptoms

Flu-like symptoms, such as fever, myalgias, dizziness or faintness,

arthralgias, nasal congestion, sensations of “scratchy throat”

Fatigue or decreased exercise tolerance

Respiratory symptoms such as dyspnea, cough, subjective sensations of

chest discomfort, orthopnea

Cardiovascular symptoms such as persistent resting tachycardia, increased

heart rate, palpitations, chest pain, syncope, arrhythmias, hypotension

Gastrointestinal symptoms such as diarrhea, vomiting, abdominal pain

Acute mental status change and delirium

Dysuria

Left-shoulder pain on

inspiration

Rash

Cyanosis

Seizures

Dysarthria

Peripheral edema

Paroxysmal nocturnal

dyspnea

V. Monitoring and diagnosis24, 38, 49

a. Monitoring

i. No established guidelines surrounding monitoring of clozapine-induced

myocarditis

ii. According to the package insert, patients should be monitored for other signs of

myocarditis if they develop tachycardia within the first month of starting

clozapine therapy

iii. Monitoring protocols have been proposed for patients starting on clozapine

(Appendix B)

b. Diagnosis

i. No consensus of diagnostic criteria

ii. May consider myocarditis in patients who present with unexplained fatigue,

dyspnea, tachypnea, fever, chest pain, palpitations, other signs of symptoms of

heart failure, or electrocardiographic abnormalities (Table 5)

iii. Hypereosinophilia may be present in clozapine-induced myocarditis, but is not a

predictive marker of the condition


Table 5. Laboratory and Instrumental Data that may Assist in the Diagnosis of Clozapine-Related

Myocarditis24

Lab Techniques Diagnosis of Clozapine-Related Myocarditis

Blood count Hypereosinophilia, leukocytosis, neutrophilia

Cardiac biomarkers ↑ troponin I or T

↑ CK or CK-MB levels

↑ BNP levels

Inflammatory biomarkers ↑ CRP levels

↑ ESR

Transthoracic Echocardiography Left ventricular systolic dysfunction

Global systolic dysfunction

Right ventricular systolic dysfunction

Reduced ejection fraction

Abnormal diastolic filling patterns

Pericardial effusion

Electrocardiogram Sinus tachycardia

Nonspecific T-wave abnormalities

ST-segment elevation or depression

PR depression

Pathologic Q waves

Supraventricular or ventricular arrhythmias

Chest radiograph changes Cardiomegaly; pericardial effusion; pulmonary venous congestion

Cardiovascular magnetic resonance Subepicardial enhancement; myocardial inflammation and edema;

pericardial effusion

Myocardial biopsy Extensive inflammatory infiltrates, mainly represented by eosinophils

and lymphocytes

VI. Treatment24, 38, 49, 52

a. Discontinue clozapine treatment immediately

i. Cardiac abnormalities may be reversible

ii. Cardiac function may improve over time once clozapine therapy is ceased

b. Supportive care based on symptoms, including standard heart failure therapies, until

clinically stable

i. Diuretics

ii. ACEIs or ARBs

iii. Beta-blockers

VII. Some clinicians may choose to continue clozapine in mild cases of myocarditis

Clinical Question

Should clozapine be reinitiated in patients with TRS who have experienced clozapine-induced

myocarditis?


Literature Review Jayathilake I, Singh AK: Clozapine rechallenge after myocarditis. Australas Psychiatr 2009; 17(5):421-422.53

Year published 2009

Patient characteristics 42 year old male

Paranoid schizophrenic

Poor response to antipsychotic therapy for 25 years

No previous history of cardiac disease

Risk factor of smoking

Clozapine dosing upon discontinuation 175 mg daily

Time until onset of symptoms 15 days

Myocarditis symptoms Subjective

Chest pain lasting 15 minutes in duration

Heart palpitations

Objective

HR 120 BPM

BP 120/90 mmHg

Troponin 0.06 μg/L

EKG showed inferolateral T wave inversions

Time to resolution of symptoms 2 days

Time until rechallenge Unclear, ~2 weeks

Monitoring parameters Daily – physical exam Every other day - troponin levels, CRP, and CBC Weekly – EKG

Titration 12.5mg initially, followed by 12.5mg dose increases every 3rd day

Clozapine dose following rechallenge 50 mg daily

Additional comments No eosinophilia, normal CXR noted

Outcome On Day 12 of clozapine re-initiation, patient experienced chest pain with palpitations, elevated troponin (0.05 μg/L), elevated HR (112 BPM), and abnormal EKG; clozapine discontinued

Hassan I, Brennan A, Carroll A, Dolan M. Monitoring in clozapine rechallenge after myocarditis. Positive

rechallenge of one patient. Australia in Psychiatry 2011; 19:370-371.54

Year published 2011

Patient characteristics Male in his early 30s

Paranoid schizophrenic; would carry weapons on his person when experiencing paranoid delusions

Poor response to antipsychotic therapy for 5 years

No previous history of cardiac disease

Clozapine dosing upon discontinuation 225 mg



Intermittent chest pain

Objective

Troponin I was 1.7 μg/L

Time to resolution of symptoms Unclear

Time until rechallenge 25 months


Monitoring parameters Baseline EKG Daily – nursing physical observations Twice weekly – full blood examination, serum troponin, CK, CRP, EKG Routine EKG on day six following initiation, and approximately every month for the first six months Urgent EKG in the setting of troponin elevation or other suspicious cardiac anomalies

Titration 6.25 mg daily initially, with an increase of 12.5 mg every two days

Clozapine dose following rechallenge 400 mg

Additional comments Troponin peaked again at 0.17 μg/L with mild CRP elevation of 16.2 mg/L when clozapine dose reached 137.5 mg daily on day 26 of post-rechallenge; no changes to therapy documented

Outcome Patient discharged to a less restrictive setting. EKG monitoring every six months along with annual outpatient cardiology review.

Bray A, Reid R: Successful clozapine rechallenge after acute myocarditis. Aust N Z J Psychiatry 2011;

45(1):90.55

Year published 2011

Patient characteristics 43 year old male

Resistant to non-clozapine antipsychotics, alone or in combination, over 20 year history of schizophrenia

No previous history of cardiac disease, family history, or cardiac risk factors

Clozapine dosing upon discontinuation Not published



Fainting

Objective

Troponin 0.89 μg/L

Sinus tachycardia noted on EKG

Time to resolution of symptoms 3 days

Time until rechallenge Not published

Monitoring parameters Serum troponin three times weekly for the first six weeks, then weekly for four months, then monthly EKG at months 1, 3, 6 and 12

Titration 12.5 mg daily and increased daily

Clozapine dose following rechallenge Not published

Additional comments When clozapine was discontinued, patient decompensated and experienced catatonia requiring ECT three times weekly

Outcome Successful rechallenge – patient able to return home 8 weeks following clozapine re-initiation, free of delusions and no longer catatonic


Summary

Authors Monitoring Slow

Titration

Comments Successful? Limitations

Cardiac Psych

Jayathilake

and Singh

(2009)

CBC

monitored

X

X

Unknown EKG results

Hassan et al.

(2011) Approached

max dose

CK measured

Weapon

carrying

/X

No discussion about decision

to continue therapy following

cardiac abnormalities

Markedly elevated troponins

compared to Case #1

Bray and Reid

(2011) Troponin and

EKG

Catatonia ? No comments on final

clozapine dose. Lack of

follow-up cardiac exams.

Minimal monitoring

parameters.

Recommendations

I. Re-initiation of clozapine may be beneficial in patients with treatment-resistant schizophrenia,

in light of suspected myocarditis

a. Depends on the severity of myocarditis

b. Clozapine may allow for improved functioning and quality of life in patients

II. Clinicians must weigh potential risks vs. benefits for individual patients when considering

whether to re-initiate clozapine

III. Monitoring

a. Daily for the first two months, then weekly for two months, then biweekly indefinitely

i. Blood pressure

ii. Heart and respiratory rates

iii. Temperature

iv. Subjective assessment – chest pain, flu-like symptoms, palpitations

b. Weekly for the first month, then every other week for one month, then once monthly

for the first year, and as needed clinically

i. CRP

ii. Troponins

iii. EKG iv. CBC

IV. Re-initiation should occur under strict medical supervision and close follow-up

Future Considerations I. Greater published literature of rechallenging attempts, irrespective of outcome, to allow for

more informed risk-benefit analyses

II. Screening protocol for patients initiated on clozapine and those deemed to be at risk for

developing clozapine-induced myocarditis

III. Defined monitoring parameters for clozapine-induced myocarditis need to be established for

consistency among clinicians


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Appendix A. TMAP Antipsychotic Algorithm14


Appendix B. Proposed monitoring protocol for clozapine-induced myocarditis in clozapine naïve

patients52


Appendix C. Abbreviations used

Abbreviation Full name

ACEI Angiotensin-converting enzyme inhibitor

ANC Absolute neutrophil count

ARB Aldosterone receptor blocker

BNP/NT-proBNP Brain-type natriuretic peptide

BP Blood pressure

BPM Beats per minute

BPRS Brief Psychiatric Rating Scale

CAD Coronary artery disease

CBC Complete blood count

CGI Clinical Global Impression Scale

CK/CK-MB Creatine kinase

CNS Central nervous system

CRP C-reactive protein

CXR Chest X-ray

DSM Diagnostic and Statistical Manual of Mental Disorders

ECG Electrocardiogram

ECT Electroconvulsive therapy

EMB Endomyocardial biopsy

EPS Extrapyramidal symptoms

ESR Erythrocyte sedimentation rate

FDA Food and Drug Administration

FGA First-generation antipsychotic

GABA Gamma-aminobutyric acid

HR Heart rate

IgE Immunoglobulin E

MI Myocardial infarction

NMDA N-methyl-D-aspartate

NOSIE Nurses’ Observation Scale for Inpatient Evaluation

PANSS Positive and Negative Syndrome Scale

PCR Polymerase chain reaction

RCT Randomized control trial

REMS Risk Evaluation and Mitigation Strategy

SGA Second-generation antipsychotic

TCA Tricyclic antidepressant

TMAP Texas Medication Algorithm Project

TNF-α Tissue necrosis factor-alpha

TRS Treatment-resistant schizophrenia

don’t go breaking my heart: re-initiation following ... · b. decreased dopamine levels i. occurs...

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