Guidelines For Prescribing Clozapine in Schizophrenia

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Official reprint from UpToDate®

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Guidelines for prescribing clozapine in schizophrenia

Authors: Oliver Freudenreich, MD, Joseph McEvoy, MD
Section Editor: Stephen Marder, MD
Deputy Editor: Michael Friedman, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: Jan 04, 2023.
INTRODUCTION
Clozapine has been found to be an effective treatment in persons with schizophrenia resistant
to treatment with other antipsychotic drugs. In addition, clozapine is an effective treatment for
schizophrenia accompanied by persistent suicidal or self-injurious behavior. (See "Schizophrenia
in adults: Maintenance therapy and side effect management".)
Clozapine’s unique side effect profile, which includes a low rate of life-threatening
agranulocytosis, gives rise to numerous considerations in prescribing, monitoring, and side
effect management in the use of the drug.
This topic describes clozapine’s indications/contraindications, pharmacology, adverse effects,

and administration in schizophrenia or schizoaffective disorder. The efficacy of clozapine in
schizophrenia is discussed separately. Clozapine is compared with other antipsychotic drugs
separately. (See "Evaluation and management of treatment-resistant schizophrenia", section on
'Clozapine' and "Second-generation antipsychotic medications: Pharmacology, administration,
and side effects".)
INDICATIONS
Primary indications for clozapine in patients with schizophrenia or schizoaffective disorder are
schizophrenia symptoms partially or fully resistant to treatment with other antipsychotic drugs,
or accompanied by persistent suicidal or self-injurious behavior. Other clinical indications in
schizophrenia patients include sensitivity to extrapyramidal symptoms and patients with tardive
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dyskinesia. (See "Evaluation and management of treatment-resistant schizophrenia", section on

'Clozapine'.)
CONTRAINDICATIONS AND PRECAUTIONS
Neutropenia — Potentially life-threatening agranulocytosis led to restrictions on clozapine’s

use in many countries, but neutrophil monitoring has allowed for safer use of the medication.
The US Food and Drug Administration requires patients in the United States to have a minimum
absolute neutrophil count (ANC) greater than or equal to 1500/microL to initiate clozapine [1].
An exception is made for patients with Duffy-null associated neutrophil count (DANC) who are
subject to a lower ANC level. (See 'Duffy-null associated neutrophil count (DANC)' below.)
A history of clozapine-induced severe neutropenia or agranulocytosis (ANC below 500/microL) is

a relative contraindication for restarting clozapine. Because the adverse effects and benefits of
the drug vary widely among patients, the risks, benefits, and alternatives need to be weighed
for each patient, and clozapine can be restarted if the harm from not using clozapine greatly
outweighs the potential risks. Clozapine should be used with extreme caution when restarted.
Many patients will quickly develop agranulocytosis again, but they cannot be identified in
advance through testing. In a study of 53 patients who had experienced leukopenia or
neutropenia from clozapine, 20 patients developed another blood dyscrasia that was more
severe and occurred more rapidly upon rechallenge [2].
Continuing clozapine, as opposed to initiating, is subject to further restrictions in the United

States based on ANC monitoring, described below. (See 'Monitoring' below.)
Duffy-null associated neutrophil count (DANC) — Lower neutrophil thresholds were

established for starting and treating clozapine in patients with confirmed DANC, a cause of
neutropenia not associated with recurrent or severe infection that is most often seen in
individuals of African descent and Sephardic Jews [3]. Treatment can be instituted and
continued in patients with an ANC of at least 1000/microL. Collaboration with hematology is
recommended to manage moderate or severe neutropenia in this patient group. (See
"Approach to the adult with unexplained neutropenia", section on 'Normal variants
<1500/microL'.)
Cardiac disease — In patients with risk factors for cardiovascular disease, a more complete
baseline cardiovascular evaluation (including baseline echocardiogram) may be useful. The
prevalence of asymptomatic left ventricular dysfunction is approximately 3 to 5 percent in
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adults 50 to 70 years old, and is higher among men, older patients, and patients with coronary
disease.
Patients with a history of clozapine-induced myocarditis should only be rechallenged if the

harm from not using clozapine greatly outweighs the potential risks. Individuals with
preexisting heart disease are at greater risk of morbidity from clozapine-induced myocarditis or
the effects of orthostatic hypotension; they have less cardiac reserve should any, even
temporary, cardiac damage and malfunction occur during the initiation of clozapine. When a
rechallenge is considered after an episode of myocarditis due to clozapine or clozapine is used
in individuals with preexisting heart disease, clozapine should be initiated in the inpatient
setting with close monitoring of cardiac function. (See 'Cardiovascular' below and
'Myocarditis/cardiomyopathy' below.)
Seizures — Clozapine is relatively contraindicated in patients with a history of seizure, to be

used only if the harm from not using clozapine greatly outweighs the potential risks. Individuals
with a seizure disorder should have their seizures optimally controlled before clozapine is
started. Patients with an elevated seizure risk, including those with an alcohol use disorder or a
history of febrile seizures or epilepsy, should be considered for prophylactic treatment with an
anticonvulsant medication when clozapine is initiated. They should be observed carefully as
clozapine is initiated, using a conservative titration schedule and therapeutic drug monitoring
to avoid excessive clozapine blood levels. A follow-up electroencephalogram may be indicated
after clozapine treatment is established, and adjustment of anticonvulsant treatment may be
necessary. (See "Overview of the management of epilepsy in adults".)
Other conditions — The metabolic effects of clozapine should be taken into account when
weighing the risks and benefits from clozapine. Individuals with obesity, diabetes mellitus,
dyslipidemias, or atherosclerotic cardiovascular disease may have worsening of these
conditions when treated with clozapine, and more aggressive treatment of these disorders will
be required.
PHARMACOLOGY
The pharmacologic mechanisms underlying clozapine’s superiority for treatment-resistant

schizophrenia are not known.
Pharmacodynamics — Clozapine binds loosely and transiently to dopamine D2 receptors.

Clozapine does not induce catalepsy or inhibit apomorphine-induced stereotypy in animal
models as is seen with conventional antipsychotic medications; this may explain its reduced
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potential for producing movement abnormalities relative to tightly binding dopamine D2

antagonists such as haloperidol. Clozapine also binds to D1, D3, and D5 receptors, and has a
high affinity for the D4 receptor, but the implications of these binding activities are unclear.
Clozapine also interacts at histamine H1, acetylcholine muscarinic M1 and serotonin 5-HT2A, 5-
HT2C, 5-HT6, and 5-HT7 receptors, and at alpha-1-adrenoceptors. Postural dizziness, sedation,
and increased appetite may reflect actions of clozapine at alpha-1, H1, and 5-HT2c receptors,
respectively. Actions at the 5-HT2A and M1 receptors may reduce movement side effects [4].
Pharmacokinetics — Clozapine is well absorbed. First-pass metabolism reduces its

bioavailability to 60 to 70 percent of the administered dose; food has little effect on the
bioavailability of clozapine. The elimination half-life of clozapine averages approximately 14
hours under steady state conditions, but there is substantial variability across individuals [5].
Clozapine is extensively metabolized by the cytochrome P450 system in the liver, and excreted
in both the urine and feces. Cytochrome P450 1A2 is primarily responsible for clozapine
metabolism; cytochromes 2C19, 2C9, 2D6, and 3A4 play less important roles. Agents that induce
cytochrome CYP1A2, such as tobacco cigarette smoke, will increase the metabolism of
clozapine. Tobacco smokers may require twice the dose of nonsmokers to achieve similar blood
levels. Strong inducers of CYP3A4 (eg, phenobarbital, carbamazepine) will also reduce serum
concentrations of clozapine; additive bone marrow toxicity with carbamazepine has been
described [6-10]. Agents that inhibit CYP1A2 (eg, ciprofloxacin, fluvoxamine) will decrease the
metabolism of clozapine and may produce clinical toxicity at usual doses [11]. Cytochrome-
related problems can be avoided by monitoring clozapine plasma levels while gradually
increasing clozapine from a low starting dose. (See 'Dose titration and plasma levels' below.)
In addition, patients prescribed clozapine should have their medication regimen analyzed for
drug interactions when initiating and adjusting therapy; this may be done by use of the
Lexicomp drug interactions program.
The major metabolite of clozapine, norclozapine (desmethylclozapine), has failed to

demonstrate any therapeutic activity in clinical trials. Clozapine and norclozapine plasma levels
are both reported by clinical labs, but only the clozapine level is useful for dose optimization
[12].
ADMINISTRATION
Pretreatment assessment — Assessment prior to treatment with clozapine should include

evaluation of the patient’s general and cardiovascular health status. Other components of an
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evaluation include documentation and testing of:
● Complete blood count that includes an absolute neutrophil count (ANC). The minimum
ANC required to initiate clozapine is described above [3]. (See 'Neutropenia' above.)
● Weight and height (body mass index), waist circumference, fasting blood sugar (or HbA1c),
and fasting lipids. (See 'Weight gain' below and 'Insulin resistance and diabetes mellitus'
below.)
● Drug levels for patients on anticonvulsant medications (need to be in the therapeutic

range). (See 'Seizures' below.)
● Vital signs.
● Electrocardiogram.
● An Abnormal Involuntary Movement Scale documenting absence or presence of abnormal

motor movements ( form 1).
● Pregnancy test in women of childbearing age.
In addition, consider obtaining measures of inflammation (eg, C-reactive protein) and cardiac
muscle damage (eg, troponin levels). (See 'Cardiovascular' below.)
Dose titration and plasma levels
● Starting dose and titration – For patients initially starting clozapine in nonurgent
situations, we prefer a slow titration. As an example, we suggest 12.5 to 25 mg once daily
at bedtime for three to four days, then 25 to 50 mg once daily at bedtime for three to four
days. We then increase further by 25 mg twice weekly. An initial test dose of 12.5 mg is
recommended to confirm tolerability in patients who have never received clozapine.
In urgent situations (active aggression/violence or self-injury/suicide) we double the

titration rate above. For example, we suggest 50 mg once daily for three or four days, then
100 mg once daily for three to four days followed by increases of 50 mg twice weekly.
Sleepiness is the primary clinical ceiling side effect, so as clozapine dose is increasing, we
simultaneously taper off other sedating agents. We monitor for seizure risk by asking
patients or their families to report myoclonic jerking movements.
We adjust dosing for individuals of Asian descent as they require less clozapine to reach
therapeutic blood levels.
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● Initial target dose – The initial target dose for healthy, young adults is 300 mg/day. Older
adult patients and patients with cardiac disease may need a lower target dose and a
slower titration, particularly if they experience sedation or orthostatic hypotension to
avoid falls or worsening cardiac function.
● Target plasma levels – Plasma levels can be checked after the initial target dose is
reached or earlier (eg, after reaching 100 mg). A clozapine plasma level in the range of 250
to 350 ng/mL is a reasonable target for a patient with schizophrenia. However, patients
show great variation in both their symptomatic response and side effects and the target
plasma level should be individualized based on these outcomes. Once the therapeutic
plasma level is reached, the patient’s clinical response should be monitored for two weeks
before considering any further dose increase. For those who have refractory symptoms, it
is reasonable to target levels higher than 350 ng/mL, despite there being limited evidence
to suggest greater efficacy. In our experience, some patients can benefit from higher
levels, and this approach is consistent with recommendations from the Treatment
Resistance in Psychosis Working Group [13]. Side effects such as sleepiness and
electroencephalogram slowing increase as clozapine blood levels increase [14].
Plasma levels should be checked in the morning, ideally 8 to 10 hours following the
previous evening dose. Given the pharmacokinetics of clozapine, differences of a few
hours in the time of evening dosing or morning plasma sampling will lead to large
differences in reported plasma levels.
Maintenance dosing — A maintenance dose of 300 to 600 mg/day is usually required for
efficacy. The average final daily dose in patients with treatment-resistant psychosis is
approximately 400 mg daily. Doses higher than 900 mg/day are not recommended.
Due to great interindividual variability in clozapine metabolism, in rare instances, levels can
reach toxic range with lower doses (eg, 100 mg/day) or fail to achieve therapeutic levels at
higher doses (eg, 600 to 900 mg/day). Checking plasma levels is thus important during the
titration phase; however, once a target dose is achieved, ongoing plasma level monitoring is not
routinely necessary. Regular therapeutic drug monitoring can help detect unsuspected
adherence problems early enough to take counter measures. (See 'Dose titration and plasma
levels' above.)
Once the patient is stabilized on an effective maintenance dose, all or most of the daily dose
may be given at bedtime. This will aid patients in getting to sleep and avoiding daytime
sedation. Adherence can be improved by taking the medication at the time of routine,
consistent behaviors, such as breakfast or bedtime preparations, and by prescribing once or
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twice daily rather than more frequently. However, some patients require split doses to avoid
bed wetting or morning grogginess.
Re-initiation after interruption — If clozapine treatment is interrupted for two or more days,
we start clozapine at 12.5 mg once or twice daily in order to assess tolerability and decrease the
risk of severe cardiovascular effects including orthostatic hypotension, syncope, and cardiac
arrest [15]. If well tolerated, however, the previous dose can be achieved more quickly
compared with patients who are initially started on clozapine.
MONITORING
Neutrophil count — For all patients taking clozapine in the United States, the US Food and
Drug Administration (FDA) requires regular monitoring and registry reporting of neutrophil
counts [1]. This process has been successful in allowing safe use of clozapine while avoiding
deaths due to clozapine-induced agranulocytosis [16]. Revisions to United States regulations in
2015 lowered certain absolute neutrophil count (ANC) thresholds, expanding the number of
patients eligible to receive the medication, and permitted clinicians to override ANC-based
treatment recommendations to continue or restart clozapine in patients for whom the benefits
of clozapine clearly exceed the risk of agranulocytosis [1]. Six separate registries administered
by clozapine manufacturers were replaced with a single registry (the Clozapine Risk Evaluation
and Mitigation Strategy [REMS] Program, available at their website).
As part of REMS, clinicians need to be registered and demonstrate that they are competent to
prescribe clozapine (ie, review clozapine-related materials from the Clozapine REMS Program
website and pass a knowledge test). Pharmacies also need to be certified if they dispense
clozapine. In order to receive clozapine, a patient must be entered into this registry and
undergo regular monitoring of ANC that continues as long as a patient receives clozapine (“No
blood, no drug”). Routine neutrophil monitoring is performed at the following intervals:
● Weekly during the first six months of clozapine administration
● Every other week for the second six months
● Every four weeks after one year, for the duration of treatment
If neutropenia develops during treatment, clozapine would either need to be monitored more
frequently, stopped temporarily, or discontinued, based on the severity of neutropenia [1]:
● Mild neutropenia (ANC: 1000 to 1499/microL) – Continue treatment but increase

monitoring frequency to three times per week.
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● Moderate neutropenia (ANC: 500 to 999/microL) – Interrupt clozapine treatment, increase

monitoring to daily until ANC is 1000/microL at which point clozapine can be reinstituted.
● Severe neutropenia/agranulocytosis (ANC: <500/microL) – Discontinue clozapine.

Rechallenge should only occur if the benefits outweigh the risks, in consultation with
hematology.
ANC-based guidelines for continuing clozapine differ in patients with Duffy-null associated
neutrophil count (DANC) in the United States. (See 'Duffy-null associated neutrophil count
(DANC)' above.)
Hospice patients receiving clozapine only require ANC monitoring at six-month intervals.
All initial reports of an ANC under 1500/microL should be confirmed with a repeat ANC within
24 hours.
Clinicians can override the registry rules for treatment interruption due to neutropenia and
continue clozapine treatment despite moderate or severe neutropenia if continuing clozapine is
clinically justified (ie, the psychiatric benefit outweighs the medical risk). Clinicians can similarly
decide to rechallenge a patient who developed severe neutropenia. (See 'Contraindications and
precautions' above.)
If agranulocytosis occurs, filgrastim hastens the return to ANC counts [17,18], although it is not
clear this alters infection rates or mortality.
Required bloodwork and COVID-19 — Monitoring ANC is required for prescribing and
dispensing clozapine. However, the coronavirus 2019 (COVID-19) public health emergency has
necessitated social isolation and staying at home, which poses problems for patients treated
with this medication. Patients and clinicians need to decide whether the risks of infection
outweigh the benefits of obtaining blood work according to the monitoring schedule mandated
by the FDA.
On March 22, 2020, the FDA offered guidance regarding the COVID-19 public health emergency
and access to medications that are subject to REMS-required testing [19]. The guidelines allow
patients to receive clozapine in the absence of laboratory testing of ANC if there are compelling
reasons not to complete the testing. Based upon the existing evidence with respect to clozapine
and neutropenia, the FDA guidance, and an expert consensus statement [20], we suggest the
following approach to using clozapine and monitoring ANC:
● For patients treated with clozapine, one may reasonably decide that obtaining mandated
clozapine blood work (ANC monitoring) during the COVID-19 pandemic is impossible or
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entails unacceptably high risks for patients or others. As an example, patients may be in
isolation or in quarantine, or at high risk for mortality if they get infected with COVID-19
while traveling to a clinic or laboratory for blood work.
● One factor that determines whether it is acceptable to waive ANC testing is duration of
clozapine treatment. As an example, it is reasonable to temporarily forego testing in
patients who have received the drug for at least one year and have never had an ANC
<2000/microL (or <1500/microL if there is a history of DANC). The rationale is that the risk
of severe neutropenia after 12 months of clozapine treatment is very low. In a meta-
analysis of seven studies that included more than 31,000 patients who were treated with
clozapine and followed for up to two years, the cumulative incidence of severe
neutropenia after 12 months of treatment declined to an almost negligible level of 0.3 to
0.4 cases per 100 person-years of exposure [21]. The peak incidence of severe neutropenia
occurred at one month of exposure.
● Clinicians should decide whether to continue clozapine treatment in the absence of

scheduled ANC monitoring in collaboration with patients and family members (or legal
guardian), explaining the risks and benefits of proceeding without ANC monitoring and
the rational for of this approach.
● For patients without a current ANC, clozapine prescriptions should specify the appropriate
number of pills. For many patients on long-term clozapine treatment, this may simply be
an additional 30-day supply of clozapine, if an ANC can be obtained the next month.
However, a 60- or 90-day supply may be prudent if patients remain at high risk due to the
pandemic. For patients newly started on clozapine, we suggest dispensing only a one- or
two-week supply during the first six months of treatment, in conjunction with weekly ANC
monitoring.
● Patients who develop flu-like symptoms such as fever, cough, and sore throat during a
period without ANC monitoring should obtain an ANC and an urgent assessment for
clozapine-associated neutropenia, either in-person or by telehealth, depending upon local
protocols. Symptoms should not simply be attributed to possible COVID-19.
● Patients with flu-like symptoms may develop clozapine toxicity (eg, sedation, myoclonus,
or seizures) that requires reducing the dose by up to one-half. The reason is that some
acute systemic infections are associated with increased serum clozapine concentrations.
In addition, patients with respiratory illnesses may cease smoking, which is also
associated with increased serum concentrations.
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The reduced dose should continue until the fever has abated for three days, after which
the dose is then increased stepwise back to the dose used prior to onset of flu-like
symptoms. Serum clozapine concentrations can help with the dose adjustments.
Cardiovascular
Myocarditis — In rare cases, clozapine-induced myocarditis can progress rapidly into

cardiomyopathy and congestive heart failure. (See 'Myocarditis/cardiomyopathy' below.)
All patients should be monitored closely for at least the initial four weeks of treatment. This
should include assessment of symptoms concerning for myocarditis (eg, malaise, chest pain,
shortness of breath), vital signs each visit, electrocardiogram (ECG) at baseline, and then weekly
laboratory tests including:
● Sedimentation rate or C-reactive protein

● Troponins
A significant increase in C-reactive protein (over 100 mg/L) and troponin elevation (greater than
twice the upper limit of normal) have been reported to be 100 percent sensitive in detecting
clozapine-induced myocarditis in symptomatic patients [22]. The eosinophil count often rises as
well but less reliably and delayed.
In patients with suspected myocarditis or cardiomyopathy, echocardiography is a key imaging

test to assess ventricular function and valve function. (See "Clinical manifestations and
diagnosis of myocarditis in adults" and "Determining the etiology and severity of heart failure
or cardiomyopathy".)
QTc prolongation — Due to its propensity to cause a dose-dependent QTc prolongation, we

try to obtain an ECG prior to starting clozapine for all patients, regardless of cardiovascular risk.
A repeat ECG may be desirable once steady state is obtained.
The formula that most ECG machines use to calculate the corrected QT interval (Bazett formula)
may overestimate it in patients with tachycardia. We typically seek consultation with a
cardiologist in patients who develop tachycardia and a QTc >500 msec while on clozapine. Some
of these patients may have a lower QTc and be able to safely continue the medication.
Metabolic — In order to detect treatment-emergent hyperglycemia and prevent diabetic

ketoacidosis, fasting plasma glucose monitoring should be considered monthly at the
beginning of treatment. Obtaining fasting glucose, however, can be difficult in outpatient
settings; rising triglycerides may be a better indicator of developing insulin resistance. (See
'Insulin resistance and diabetes mellitus' below.)
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Gastrointestinal — Gastrointestinal hypomotility, which can result in an adynamic ileus,

requires close clinical attention [23]. In patients who cannot reliably identify bowel problems, a
preventive laxative (stool softener) is often prescribed when starting clozapine. (See
'Gastrointestinal hypomotility' below.)
ADVERSE EFFECTS
Neutropenia/agranulocytosis — Clozapine-induced agranulocytosis was estimated to occur at

a rate of approximately 0.8 percent in a study of 12,760 patients receiving the medication;
leukopenia occurred in almost 3 percent of cases [24]. The peak risks for both occurred early in
treatment, between 6 to 18 weeks from initiation. Advancing age was a risk factor for
agranulocytosis in this cohort. Regular blood monitoring over a five-year period has been
estimated to reduce the risk of agranulocytosis from approximately 1 to 2 percent to 0.38
percent [25]. Neutrophil-monitoring during clozapine treatment is discussed above. (See
'Monitoring' above.)
Myocarditis/cardiomyopathy — Studies have estimated the risk of clozapine-induced

myocarditis to be 1 in 500 to 1 in 10,000 [26]. The true risk is likely closer to the 1 in 500 rate, as
often only a minority of adverse medication-related events are diagnosed and reported. Early
myocarditis is more common than later development of cardiomyopathy; cardiomyopathy may
be accompanied by mitral regurgitation [27].
Most cases of myocarditis occur early in the course of clozapine treatment. The condition was
detected within 16 days (median) of initiating clozapine in a study of 116 cases [26].
Approximately 80 percent of cases of clozapine-induced myocarditis occur within four weeks of
drug initiation, and 90 percent occur within eight weeks.
Postmortem examination has most commonly revealed damaged myocytes and eosinophilic
infiltration suggesting a type I Ig E-mediated acute hypersensitivity reaction. The time of onset
of clozapine-induced myocarditis and the pathological findings support this hypothesis. Other
contributing mechanisms may include cytokine release and high levels of catecholamines.
A typical pattern of nonspecific clinical symptoms (fever, tachycardia) and laboratory findings
(elevated eosinophil count, sedimentation rate or c-reactive protein, troponins, creatine
phospho-kinase, and brain natriuretic peptide), combined with a high index of suspicion for
myocarditis (nonspecific symptoms, including malaise, as well as more alarming symptoms like
chest pain or shortness of breath) in a patient started on clozapine within the past four to eight
weeks is needed to diagnose myocarditis in a clozapine patient. Some patients will have a mild
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and temporary increases in inflammatory markers and eosinophils at the beginning of

treatment without progression to myocarditis.
In patients with suspected myocarditis or cardiomyopathy, echocardiography is a key imaging

test to assess ventricular function and valve function. (See "Clinical manifestations and
diagnosis of myocarditis in adults" and "Determining the etiology and severity of heart failure
or cardiomyopathy".)
A diagnosis of myocarditis should be followed by prompt discontinuation of clozapine and

medical follow-up with the patient’s primary care clinician for supportive treatment. This course
will usually lead to spontaneous resolution. Subsequent use of clozapine in cases with clear
clozapine-induced myocarditis leads to recurrence of myocarditis in most cases when the drug
is restarted.
Use of clozapine in patients with preexisting heart disease and monitoring of patients at the
initiation of clozapine treatment are discussed above. (See 'Cardiac disease' above and
'Cardiovascular' above.)
QTc interval prolongation — Clozapine causes dose-dependent prolongation of the QT

interval on electrocardiogram (ECG) similar in magnitude to olanzapine and quetiapine [28-31].
QT prolongation increases the risk of torsade de pointes and potentially lethal arrhythmias.
Clozapine should be avoided in patients with congenital long QT syndrome; labeling cautions
against use in persistent corrected QT interval (QTc) >500 ms on ECG [32]. Higher risk clinical
scenarios such as patients with known heart disease, treatment-emergent increase of QTc
interval >60 ms from baseline, or co-administration of high-risk medications, may warrant
cardiology consultation ( table 1). (See 'QTc prolongation' above and "Acquired long QT
syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for drug-induced
long QT syndrome'.)
Pulmonary embolism — Clozapine has been associated with an increased risk of venous
thromboembolic events including pulmonary embolism leading to death [33-39]. Of the
published cases with a known outcome, the mortality rate of a clotting complication while on
clozapine was 44 percent [40].
Risk factors for thromboembolic disease in the general population include:
● Genetic factors (mainly the factor V Leiden mutation or a high concentration of factor VIII)
● Recent immobilization
● Recent surgery
● Pregnancy or the postpartum state
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● Obesity
Clinicians starting patients on clozapine should advise recipients to remain physically active.
Although prophylactic use to prevent clozapine-associated venous thrombosis of aspirin and

statins has not been studied in patients receiving clozapine, aspirin has been shown to reduce
the risk of venous thromboembolism in patients undergoing orthopedic surgery [41], and
statins have been shown to reduce venous thromboembolism among individuals receiving
chemotherapy for cancer [42]. The routine use of these agents among individuals without
contraindications may reduce risk of venous thromboembolism. (See "Statins: Actions, side
effects, and administration" and "Aspirin in the primary prevention of cardiovascular disease
and cancer".)
Weight gain — Clozapine can cause significant weight gain [43-47]. The average weight gain in
a 10-year cohort study of clozapine was 30 pounds [43]. While most weight gain occurs during
the first 6 to 12 months, some patients continue to gain weight without reaching a plateau [45].
Weight should be routinely monitored and behavioral interventions recommended if patients
gain weight on clozapine. Metformin has been used to blunt antipsychotic-induced weight gain
and improve insulin sensitivity [48]. The benefits of added metformin, however, are lost when it
is discontinued [49]. (See "Schizophrenia in adults: Maintenance therapy and side effect
management", section on 'Metabolic dysregulation' and "Schizophrenia in adults: Maintenance
therapy and side effect management", section on 'Endocrinologic and metabolic side effects'.)
Insulin resistance and diabetes mellitus — Of 96 patients with chronic schizophrenia treated
with clozapine and followed for up to 10 years, 34 percent developed diabetes mellitus [43]. The
progressive increases in obesity, diabetes, elevated triglycerides, and hypertension in their
population resulted in substantially increased cardiovascular risk. The insulin resistance from
clozapine treatment is at least in part independent from clozapine-induced weight gain [50].
Screening for diabetes at six-month intervals or more frequently (ie, fasting blood sugar or
HbA1c) should be done. (See "Screening for type 2 diabetes mellitus".)
Seizures — Clozapine is associated with a dose-dependent seizure risk at a rate higher than
that seen with most other antipsychotic drugs [51,52]. In a review of 1418 patients treated with
clozapine, the cumulative seizure risk was estimated to be 10 percent after 3.8 years of
treatment [53]. Higher doses of clozapine were associated with a greater rate of seizures:
● 600 mg/day or more – 4.4 percent

● 300 to 600 mg/day – 2.7 percent
● 300 mg/day or less – 1.0 percent
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In a review of 101 patients experiencing a seizure while receiving clozapine, the most frequently
described type of seizure was tonic-clonic; myoclonic/atonic seizures comprise approximately
one-quarter of reported seizures [54]. The mean clozapine dose in the cohort was less than 600
mg per day. (See 'Seizures' above.)
Excessive salivation — Clozapine-induced hypersalivation is a common side effect that can be

treatment-limiting as patients are unable to tolerate incessant drooling that is stigmatizing
during the day and hinders sleeping at night. It often occurs at low doses [55] and can worsen
during sleep. Its mechanism is thought to be due to a disturbance of deglutition and not merely
an increase in salivary flow rate [56]. Hypersalivation may be a risk factor for aspiration
pneumonia, which has been observed in clozapine-treated patients [57].
A reduction in clozapine dose can be tried to limit salivation, but this step alone is often
inadequate. Among treatment options, glycopyrrolate at a dose of 2 to 4 mg given at night is a
good initial choice. A randomized trial compared glycopyrrolate with biperiden [58]. While both
were associated with a reduced rate of drooling, a larger decrease was seen in the group taking
glycopyrrolate. Glycopyrrolate does not penetrate the blood-brain barrier, thus avoiding central
anticholinergic effects such as impairment of memory. However, it adds to clozapine’s already
significant intrinsic peripheral anticholinergic burden. (See 'Gastrointestinal hypomotility'
below.)
Other treatment approaches, based on case reports or case series, include the use of sugarless
chewing gum to increase the rate of swallowing, anticholinergic agents (eg, 5 to 15 mg/day of
trihexyphenidyl), topical agents (eg, sublingual atropine or ipratropium spray) or alpha-2
agonists (eg, clonidine). In refractory cases, botulinum toxin injections into the salivary glands
can be effective if this treatment can be arranged.
Urinary incontinence — Treatment with clozapine appears to be associated with an increased

incidence of urinary incontinence. The potent anti-alpha-adrenergic effects of clozapine, which
relax the bladder-neck sphincter, are hypothesized to contribute to the incontinence. An open
trial of 16 patients suggested that ephedrine, an alpha-adrenergic agonist, may be highly
effective in treating clozapine induced urinary incontinence, supporting the hypothesis [59]. A
dose of 25 mg ephedrine at night or 25 mg twice daily is often sufficient to treat urinary
incontinence. Ephedrine may be difficult to obtain due to concerns about diversion to the
synthesis of methamphetamines; pseudoephedrine may be a reasonable substitute at doses of
30 to 60 mg twice daily.
Gastrointestinal hypomotility — Gastrointestinal hypomotility likely due to the anticholinergic

properties of the medication [60] may lead to constipation. Constipation has been reported in
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approximately 14 percent of patients treated with clozapine [61]. Delayed diagnosis and
treatment may result in fecal impaction, megacolon, intestinal obstruction, perforation,
ulceration, or necrosis [62].
Severe constipation, culminating in adynamic ileus, can be fatal. In a report of 102 cases of life-
threatening gastrointestinal hypomotility suspected to be caused by clozapine, considerable
morbidity was seen (largely due to bowel resection) along with a mortality rate of 27.5 percent
[63]. Probable risk factors included:
● Recent initiation of clozapine

● High clozapine doses or serum levels
● Use of other drugs with anticholinergic activity
● Comorbid medical illness
In a retrospective analysis of diagnostic and pharmacy data on 26,720 inpatients with

schizophrenia over an 11-year period, 123 cases of ileus were observed [64]. Female sex and
clozapine treatment were associated with an increased risk of ileus. Nine of the ileus cases (7.3
percent) had a fatal course, with clozapine treatment and anticholinergic use associated with
lethality. The onset of ileus occurred on average more than three years after the first
prescription of the offending drug. In a comparative effectiveness study of 3123 patients who
initiated clozapine, intestinal obstruction emerged as a clinically significant adverse effect, seen
in a greater proportion of clozapine patients compared with patients on a standard
antipsychotic (0.9 versus 0.3 percent; hazard ratio 2.50, 95% CI 0.97-6.44) [65].
Patients receiving psychotropics associated with significant anticholinergic properties should

undergo proper clinical monitoring and interventions in order to minimize the burden of
constipation and the risk of ileus. Patients can be encouraged to eat a diet high in fiber, drink
plenty of fluids, and exercise. (See "Management of chronic constipation in adults".)
Sedation — Clozapine can cause significant sedation, particularly during the initiation of
treatment. Tolerability of the sedating effect can be enhanced by gradually titrating to a
therapeutic dose. Some clinicians add stimulants or stimulant-like drugs if patients continue to
experience sedation. However, two small randomized trials in patients with clozapine-induced
sedation found no benefit from modafinil (200 to 300 mg/day) on measures of fatigue or
wakefulness [66,67].
Teratogenic and neonatal risks — Although no definitive association has been found between
use of antipsychotic medications during pregnancy and an increased risk of congenital anomaly
or other adverse outcomes, there is a paucity of information, with a lack of large, well-designed,
prospective studies. Second-generation antipsychotics cross the placenta [68]. Case reports
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have demonstrated concentrations of clozapine in breast milk [69]. The American College of
Obstetricians and Gynecologists does not recommend the routine use of second-generation
antipsychotics during pregnancy; however, assessment of risk-benefit may indicate that such
use is appropriate [70]. The American Academy of Pediatrics has classified clozapine as a drug
whose effect on the nursing infant is unknown but may be of concern [71]. (See "Teratogenicity,
pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and
electroconvulsive therapy", section on 'Second-generation'.)
Mortality risk — The US Food and Drug Administration has reported that the use of first- and
second-generation antipsychotic medications for the treatment of behavioral symptoms in
older adult patients with dementia is associated with increased mortality [72,73]. (See
"Management of neuropsychiatric symptoms of dementia", section on 'Mortality risk'.)
Movement disorders — Compared with other antipsychotics, clozapine has a reduced risk of
causing tardive dyskinesia or extrapyramidal movement disorders including akathisia. However,
patients can still develop these movement disorders and need to be monitored for their
development (eg, standardized motor exam with the Abnormal Involuntary Movement Scale
every six months) ( form 1). Despite clozapine’s weak affinity for the dopamine receptor, the
neuroleptic malignant syndrome can develop [74]. (See "Tardive dyskinesia: Prevention,
treatment, and prognosis" and "Neuroleptic malignant syndrome".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Psychotic disorders".)
SUMMARY AND RECOMMENDATIONS
● Indications – Primary indications for clozapine include schizophrenia or schizoaffective

disorder partially or fully resistant to treatment with other antipsychotic drugs, or
schizophrenia/schizoaffective accompanied by persistent suicidal or self-injurious
behavior. (See 'Indications' above.)
● Pretreatment assessment – Prior to beginning clozapine, we do the following baseline

evaluation (see 'Pretreatment assessment' above):
• General and cardiovascular health status, vital signs, weight, height, body mass index
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• Complete blood count (absolute neutrophil count [ANC] must be ≥1500/microL to

initiate clozapine)
• Check for therapeutic drug levels of anticonvulsant medications
• Fasting blood sugar or HbA1c, fasting lipids (non-high-density lipoprotein cholesterol if
nonfasting)
• Electrocardiogram (ECG)
• Baseline Abnormal Involuntary Movement Scale test
• Pregnancy test in women of childbearing age
● Administration – For patients initially starting clozapine in nonurgent situations, we

prefer a slow titration. As an example, we suggest 12.5 to 25 mg once daily at bedtime for
three to four days, then 25 to 50 mg once daily at bedtime for three to four days. We
increase by 25 mg twice weekly. In urgent situations (active aggression/violence or self-
injury/suicide) we double the titration rate above.
The initial target dose for healthy, young adults is 300 mg/day. A maintenance dose of 300
to 600 mg/day is usually required for efficacy. Doses higher than 900 mg/day are not
recommended. We are cautious with older adults (>65 years) and in individuals with
comorbid medical or cardiac disease. Typical maintenance dose may be as low as 100 to
150 mg/day. We titrate slowly in these individuals to avoid adverse effects. We check
plasma levels once target dose is reached or earlier (after 100 mg are reached). (See
'Administration' above.)
● Monitoring – For all patients taking clozapine in the United States, the US Food and Drug
Administration requires regular monitoring and registry reporting of neutrophil counts.
Patients taking clozapine should receive routine weekly-to-monthly monitoring and
maintain an ANC ≥1500/microL (≥1000/microL for individuals with Duffy-null associated
neutrophil count. Lower ANC levels require more frequent monitoring, and possible
interruption of clozapine and/or reevaluation of its use. Monitoring frequency is as follows
(see 'Monitoring' above):
• Weekly during the first six months of clozapine administration

• Every other week for the second six months
• Every four weeks after one year, for the duration of treatment
If neutropenia develops during treatment, clozapine we either monitored more frequently,

stopped the medication temporarily, or discontinued the medication, based on the
severity of neutropenia.
● Adverse effects (see 'Adverse effects' above)

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• Neutropenia/agranulocytosis – Clozapine-induced agranulocytosis occurs at a rate of

approximately 0.8 percent. Leukopenia occurs in approximately 3 percent of cases. The
peak risks for both occurred early in treatment, between 6 to 18 weeks from initiation.
(See 'Neutropenia/agranulocytosis' above.)
• Cardiovascular effects – Clozaril is associated with early myocarditis that can lead to
the development of cardiomyopathy. Additionally, it can cause a dose dependent QTc
prolongation. We obtain an ECG prior to starting clozapine; we repeat the ECG once
steady state is obtained. (See 'Myocarditis/cardiomyopathy' above.)
• Insulin resistance, weight gain, metabolic dysregulation – Clozapine can cause

insulin resistance, metabolic dysregulation and weight gain. While most weight gain
occurs during the first 6 to 12 months, some patients continue to gain weight without
reaching a plateau. We monitor metabolic parameters at regular intervals. (See 'Insulin
resistance and diabetes mellitus' above.)
• Seizures – Clozapine is associated with a dose-dependent seizure risk at a rate higher

than that seen with most other antipsychotic drugs (See 'Seizures' above.)
• Other effects – Treatment with clozapine can cause constipation, sedation, sialorrhea,
incontinence, pulmonary embolism. Treatment with antipsychotics including clozapine
is associated with increased mortality in individuals with dementia. (See 'Adverse
effects' above.)
Use of UpToDate is subject to the Terms of Use.
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33. Walker AM, Lanza LL, Arellano F, Rothman KJ. Mortality in current and former users of
clozapine. Epidemiology 1997; 8:671.
34. Hägg S, Spigset O, Söderström TG. Association of venous thromboembolism and clozapine.
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35. Kortepeter C, Chen M, Knudsen JF, et al. Clozapine and venous thromboembolism. Am J
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36. Ihde-Scholl T, Rolli ML, Jefferson JW. Clozapine and pulmonary embolus. Am J Psychiatry
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37. Farah RE, Makhoul NM, Farah RE, Shai MD. Fatal venous thromboembolism associated with
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38. Yang TY, Chung KJ, Huang TL, Kung CT. Massive pulmonary embolism in a young patient on
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39. Liperoti R, Pedone C, Lapane KL, et al. Venous thromboembolism among elderly patients
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40. Paciullo CA. Evaluating the association between clozapine and venous thromboembolism.
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41. Marsland D, Mears SC, Kates SL. Venous thromboembolic prophylaxis for hip fractures.
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42. Khemasuwan D, Divietro ML, Tangdhanakanond K, et al. Statins decrease the occurrence of
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43. Henderson DC, Nguyen DD, Copeland PM, et al. Clozapine, diabetes mellitus,
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44. Lamberti JS, Bellnier T, Schwarzkopf SB. Weight gain among schizophrenic patients treated
with clozapine. Am J Psychiatry 1992; 149:689.
45. Umbricht DS, Pollack S, Kane JM. Clozapine and weight gain. J Clin Psychiatry 1994; 55
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46. Bai YM, Lin CC, Chen JY, et al. Association of initial antipsychotic response to clozapine and
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47. Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical
antipsychotics dose dependent? A literature review. J Clin Psychiatry 2009; 70:1041.
48. Carrizo E, Fernández V, Connell L, et al. Extended release metformin for metabolic control
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49. Chen CH, Huang MC, Kao CF, et al. Effects of adjunctive metformin on metabolic traits in
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51. Pacia SV, Devinsky O. Clozapine-related seizures: experience with 5,629 patients. Neurology
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52. Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical
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58. Liang CS, Ho PS, Shen LJ, et al. Comparison of the efficacy and impact on cognition of
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59. Fuller MA, Borovicka MC, Jaskiw GE, et al. Clozapine-induced urinary incontinence:
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69:1157.
Topic 14772 Version 32.0
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GRAPHICS
Abnormal involuntary movement scale
Graphic 51103 Version 4.0
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Some reported causes and potentiators of the long QT syndrome*
Congenital
Jervell and Lange-Nielsen syndrome (including "channelopathies")

Romano-Ward syndrome
Idiopathic
Acquired
Metabolic disorders
Hypokalemia
Hypomagnesemia
Hypocalcemia
Starvation
Anorexia nervosa
Liquid protein diets
Hypothyroidism
Bradyarrhythmias
Sinus node dysfunction
AV block: Second or third degree
Analgesic, anesthetic, and sedative drugs

Anesthetic/sedative:
Moderate risk: Propofol
Low risk: Dexmedetomidine ¶
Opioids:
High risk: Methadone
Low risk: Buprenorphine Δ
Androgen deprivation therapy (GnRH agonist/antagonist therapy or bilateral surgical orchiectomy)
Antianginal drugs
Low risk: Ranolazine (due to bradycardia)
Antiarrhythmic drugs
High risk: Amiodarone ◊ , disopyramide, dofetilide, dronedarone, ibutilide, procainamide,
quinidine, sotalol, vernakalant §
Moderate risk: Flecainide, pilsicainide § , propafenone
Anticholinergic drugs (antimuscarinics)

Low risk: Solifenacin
Antihistamines
High risk: Astemizole ¥ , terfenadine ¥
3/30/23, 2:11 PM 14772
Lower risk: Bilastine § , hydroxyzine
Antimicrobials
Antimalarial:
High risk: Delamanid § , quinidine, quinine
Moderate risk: Chloroquine, halofantrine, piperaquine
Lower risk: Artemether-lumefantrine, hydroxychloroquine (rare reports, noted in labeling)
Antiparasitic and antiprotozoal:
Moderate risk: Fexinidazole, meglumine antimoniate
Antituberculous:
High risk: Bedaquiline
Azole antifungals:
Moderate risk: Fluconazole, voriconazole
Low to moderate risk: Itraconazole, ketoconazole (systemic)
Clofazimine (moderate risk)
Fluoroquinolones (systemic):
Moderate risk: Gemifloxacin § , levofloxacin, moxifloxacin, sparfloxacin §
Low to moderate risk: Ciprofloxacin, norfloxacin, ofloxacin
Foscarnet (low to moderate risk)
HIV antiretrovirals:
Moderate risk: Saquinavir
Low to moderate risk: Efavirenz, fostemsavir, lopinavir-ritonavir, rilpivirine
Macrolide antibiotics:
Moderate risk: Azithromycin, clarithromycin, erythromycin
Low to moderate risk: Roxithromycin, telithromycin
Metronidazole (low to moderate risk)
Pentamidine (IV) (moderate risk)
Telavancin (low to moderate risk)
Triclabendazole (low to moderate risk)
Antineoplastic drugs
High risk: Adagrasib, arsenic trioxide, ivosidenib, lenvatinib, mobocertinib, selpercatinib,
vandetanib
Moderate risk: Capecitabine, ceritinib, crizotinib, dabrafenib, dasatinib, encorafenib, floxuridine,
fluorouracil (systemic), gilteritinib, inotuzumab ozogamicin, midostaurin, nilotinib, osimertinib,
pazopanib, ribociclib, sunitinib, toremifene, vemurafenib
Lower risk: Bosutinib, eribulin, glasdegib, lapatinib, oxaliplatin, pacritinib, panobinostat,
romidepsin, sorafenib, tamoxifen, vorinostat
Bronchodilators (beta-2 agonists)

Moderate risk: Terbutaline
Lower risk: Albuterol, arformoterol, formoterol, indacaterol, levalbuterol, olodaterol, salmeterol,
vilanterol
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Diuretics
Via electrolyte changes (especially hypokalemia or hypomagnesemia)
Gastrointestinal drugs
Antidiarrheal: Loperamide ‡ in overdose (lower risk)
Antiemetics:
Moderate risk: Droperidol, ondansetron (risk with IV use greater than oral)
Low to moderate risk: Amisulpride (IV antiemetic dose), dolasetron, granisetron,
hydroxyzine, tropisetron §
Promotility:
High risk: Cisapride (restricted availability)
Moderate risk: Domperidone §
Low to moderate risk (rare reports): Metoclopramide
Proton pump inhibitors: ‡ Chronic use leading to hypomagnesemia (rare)
Neurologic drugs
Low to moderate risk: Apomorphine, deutetrabenazine, donepezil, ezogabine, fingolimod,
ozanimod † , pimavanserin, ponesimod, tetrabenazine
Oxytocic drugs
Moderate risk: Carbetocin § , oxytocin
Psychotropic drugs
Antidepressants:
Selective serotonin reuptake inhibitors (SSRIs), serotonin modulators, and atypical agents:
Moderate risk: Citalopram, escitalopram
Low to moderate risk: Fluoxetine, sertraline, trazodone
Low risk: Mirtazapine
Tricyclic and tetracyclic antidepressants (TCAs):**
Moderate risk: Clomipramine, doxepin, and imipramine
Antipsychotics:
High risk: Chlorpromazine, IV haloperidol, sertindole § , ziprasidone
Moderate risk: Amisulpride (oral) § , clozapine, flupentixol § , haloperidol (oral), olanzapine,
pimozide, quetiapine, risperidone, thioridazine
Low to moderate risk: Asenapine, iloperidone, paliperidone, periciazine § , pimavanserin
Others:
Low to moderate risk: Atomoxetine
Low risk: Dexmedetomidine sublingual film ¶
Vasodilator drugs
High risk: Bepridil ¥
Other drugs
High risk: Levoketoconazole, papaverine (intracoronary)
Moderate risk: Etelcalcetide, gadobenate dimeglumine, lofexidine, probucol ¥
3/30/23, 2:11 PM 14772
Low to moderate risk: Alfuzosin, anagrelide, cocaine (topical), eliglustat, mifepristone,

pasireotide, voclosporin
Herbs: Cinchona (contains quinine), licorice extract (glycyrrhizin) in overuse leading to electrolyte
abnormalities
Other factors
Myocardial ischemia or infarction, especially with prominent T-wave inversions
Intracranial disease
HIV infection
Hypothermia
Toxic exposure: Organophosphate insecticides
This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include
drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be
safe in most patients but may need to be avoided in patients with congenital long QT syndrome
depending upon clinical circumstances. A more complete list of such drugs is available at the
CredibleMeds website. For clinical use and precautions related to medications and drug interactions,
refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the
Lexicomp drug interactions tool.
AV: atrioventricular; IV: intravenous.
* Classifications provided by Lexicomp according to US Food & Drug Administration guidance:

Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-
Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and Drug
Administration, June 2017 (revision 2) available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M073161.pdf with additional data from CredibleMeds QT drugs list [1,2] . The use of other
classification criteria may lead to some agents being classified differently by other sources.
¶ The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against
use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual
formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated
in TdP.
Δ Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use
disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc
prolongation. Refer to UpToDate clinical topic reviews.
◊ In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with
torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT
syndrome.
§ Not available in the United States.
¥ Withdrawn from market in most countries due to adverse cardiovascular effects.
‡ Over-the-counter; available without a prescription.
3/30/23, 2:11 PM 14772
† Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical
topic for potential adverse cardiovascular (CV) effects in patients with CV disease.
** Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on
cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic
antidepressant poisoning.
Data from:
1. Lexicomp Online. Copyright ©1978-2023 Lexicomp, Inc. All Rights Reserved.
2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at
http://crediblemeds.org/.
Graphic 57431 Version 140.0
3/30/23, 2:11 PM 14772
Contributor Disclosures
Oliver Freudenreich, MD Grant/Research/Clinical Trial Support: Alkermes [Schizophrenia]; Janssen
[Schizophrenia]; Otsuka [Schizophrenia]. Consultant/Advisory Boards: Alkermes [Schizophrenia drug
development]; Integral [Drug delivery development]; Janssen [Schizophrenia drug development];
Neurocrine [Tardive dyskinesia drug development]. Other Financial Interest: American Psychiatric
Association [Medical content]; Elsevier [Medical editing]; Medscape [CME talk]. All of the relevant financial
relationships listed have been mitigated. Joseph McEvoy, MD Grant/Research/Clinical Trial Support:
Alkermes [Schizophrenia];Biogen [Schizophrenia];Boehringer Ingelheim
[Schizophrenia];Otsuka[Schizophrenia];Takeda [Schizophrenia]. Consultant/Advisory Boards: Sunovion
[Schizophrenia]. All of the relevant financial relationships listed have been mitigated. Stephen Marder,
MD Grant/Research/Clinical Trial Support: Boeringer-Ingleheim [Psychosis/schizophrenia].
Consultant/Advisory Boards: Bioexcel [Psychosis/schizophrenia]; Biogen [Psychosis/schizophrenia];
Boeringer-Ingleheim [Psychosis/schizophrenia]; Merck [Psychosis]; Otsuka [Psychosis/schizophrenia];
Sunovion [Psychosis/schizophrenia]. All of the relevant financial relationships listed have been
mitigated. Michael Friedman, MD No relevant financial relationship(s) with ineligible companies to
disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Guidelines For Prescribing Clozapine in Schizophrenia

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Guidelines For Prescribing Clozapine in Schizophrenia

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Official reprint from UpToDate®

Guidelines for prescribing clozapine in schizophrenia

This topic describes clozapine’s indications/contraindications, pharmacology, adverse effects,

dyskinesia. (See "Evaluation and management of treatment-resistant schizophrenia", section on

CONTRAINDICATIONS AND PRECAUTIONS

Neutropenia — Potentially life-threatening agranulocytosis led to restrictions on clozapine’s

A history of clozapine-induced severe neutropenia or agranulocytosis (ANC below 500/microL) is

Continuing clozapine, as opposed to initiating, is subject to further restrictions in the United

Duffy-null associated neutrophil count (DANC) — Lower neutrophil thresholds were

Patients with a history of clozapine-induced myocarditis should only be rechallenged if the

Seizures — Clozapine is relatively contraindicated in patients with a history of seizure, to be

The pharmacologic mechanisms underlying clozapine’s superiority for treatment-resistant

Pharmacodynamics — Clozapine binds loosely and transiently to dopamine D2 receptors.

potential for producing movement abnormalities relative to tightly binding dopamine D2

Pharmacokinetics — Clozapine is well absorbed. First-pass metabolism reduces its

The major metabolite of clozapine, norclozapine (desmethylclozapine), has failed to

Pretreatment assessment — Assessment prior to treatment with clozapine should include

evaluation include documentation and testing of:

● Drug levels for patients on anticonvulsant medications (need to be in the therapeutic

● An Abnormal Involuntary Movement Scale documenting absence or presence of abnormal

● Pregnancy test in women of childbearing age.

Dose titration and plasma levels

In urgent situations (active aggression/violence or self-injury/suicide) we double the

● Weekly during the first six months of clozapine administration

● Every other week for the second six months

● Mild neutropenia (ANC: 1000 to 1499/microL) – Continue treatment but increase

● Moderate neutropenia (ANC: 500 to 999/microL) – Interrupt clozapine treatment, increase

● Severe neutropenia/agranulocytosis (ANC: <500/microL) – Discontinue clozapine.

● Clinicians should decide whether to continue clozapine treatment in the absence of

Myocarditis — In rare cases, clozapine-induced myocarditis can progress rapidly into

● Sedimentation rate or C-reactive protein

In patients with suspected myocarditis or cardiomyopathy, echocardiography is a key imaging

QTc prolongation — Due to its propensity to cause a dose-dependent QTc prolongation, we

Metabolic — In order to detect treatment-emergent hyperglycemia and prevent diabetic

Gastrointestinal — Gastrointestinal hypomotility, which can result in an adynamic ileus,

Neutropenia/agranulocytosis — Clozapine-induced agranulocytosis was estimated to occur at

Myocarditis/cardiomyopathy — Studies have estimated the risk of clozapine-induced

and temporary increases in inflammatory markers and eosinophils at the beginning of

In patients with suspected myocarditis or cardiomyopathy, echocardiography is a key imaging

A diagnosis of myocarditis should be followed by prompt discontinuation of clozapine and

QTc interval prolongation — Clozapine causes dose-dependent prolongation of the QT

Risk factors for thromboembolic disease in the general population include:

Although prophylactic use to prevent clozapine-associated venous thrombosis of aspirin and

● 600 mg/day or more – 4.4 percent

Excessive salivation — Clozapine-induced hypersalivation is a common side effect that can be

Urinary incontinence — Treatment with clozapine appears to be associated with an increased

Gastrointestinal hypomotility — Gastrointestinal hypomotility likely due to the anticholinergic

● Recent initiation of clozapine

In a retrospective analysis of diagnostic and pharmacy data on 26,720 inpatients with

Patients receiving psychotropics associated with significant anticholinergic properties should

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Indications – Primary indications for clozapine include schizophrenia or schizoaffective

● Pretreatment assessment – Prior to beginning clozapine, we do the following baseline

• Complete blood count (absolute neutrophil count [ANC] must be ≥1500/microL to

● Administration – For patients initially starting clozapine in nonurgent situations, we

• Weekly during the first six months of clozapine administration

If neutropenia develops during treatment, clozapine we either monitored more frequently,

● Adverse effects (see 'Adverse effects' above)

• Neutropenia/agranulocytosis – Clozapine-induced agranulocytosis occurs at a rate of

• Insulin resistance, weight gain, metabolic dysregulation – Clozapine can cause

• Seizures – Clozapine is associated with a dose-dependent seizure risk at a rate higher