Schizophrenia in adults: Guidelines for prescribing clozapine

INTRODUCTION — 

Clozapine is an effective agent in the treatment of schizophrenia including in those who have been resistant to other antipsychotic agents and in those with persistent suicidal or self-injurious behavior. Clozapine’s unique side effect profile, which includes a low rate of life-threatening agranulocytosis, and metabolic dysregulation, gives rise to numerous considerations that must be addressed during treatment. (See 'Pretreatment evaluation' below and 'Monitoring for major adverse effects/toxicity' below.)

This topic describes treatment with clozapine including indications, administration, adverse effects and precautions, and monitoring. Other topics related to the use of clozapine including efficacy in the treatment of schizophrenia are found elsewhere. (See "Second-generation and other antipsychotic medications: Pharmacology, administration, and side effects" and "Treatment-resistant schizophrenia".)

INDICATIONS — 

The primary indication for the use of clozapine is schizophrenia or schizoaffective disorder, partially or fully resistant to treatment with other antipsychotic agents, or in those with persistent suicidal or self-injurious behaviors.

Other clinical indications in patients with schizophrenia include sensitivity to extrapyramidal symptoms, aggression in the setting of psychosis, and patients with tardive dyskinesia. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Side effect management' and "Treatment-resistant schizophrenia".)

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 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 [1].

Pharmacokinetics and potential drug interactions — 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 [2].

Clozapine is extensively metabolized by the cytochrome P450 system in the liver, and excreted in both the urine and feces. We avoid cytochrome-related problems by monitoring clozapine plasma levels while gradually increasing clozapine from a low starting dose. (See 'Starting dose and titration' below.)

Cytochrome P450 1A2 is primarily responsible for clozapine metabolism; cytochromes 2C19, 2C9, 2D6, and 3A4 play less important roles:

●Agents that induce cytochrome CYP1A2 (eg, tobacco cigarette smoke) will increase the metabolism of clozapine. Tobacco smokers may require twice the dose of nonsmokers to achieve similar blood levels.

●Agents that inhibit CYP1A2 (eg, ciprofloxacin, fluvoxamine) will decrease the metabolism of clozapine and may produce clinical toxicity at usual doses [3].

●Potent inducers of CYP3A4 (eg, phenytoin, phenobarbital, carbamazepine) will reduce serum concentrations of clozapine; additive bone marrow toxicity with carbamazepine has been described [4-8].

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 [9].

PRETREATMENT EVALUATION — 

We review the medication regimen using the drug interactions program in all patients that are being started on clozapine or having a dose adjustment.

Prior to beginning treatment with clozapine, we also review the following general health considerations. We use these as a baseline measurement for comparison during monitored treatment. In some cases, for example, in individuals with neutropenia, we do not start the medication until certain conditions are met. These are discussed below and elsewhere. (See 'Monitoring for major adverse effects/toxicity' below and 'Other adverse effects' below.)

●Vital signs and temperature. We do not begin clozapine in individuals with possible underlying infectious process or other signs of acute illness.

●Complete blood count that includes an absolute neutrophil count (ANC). An ANC of ≥1500/microL is recommended prior to initiating clozapine. (See 'Neutropenia' below.)

An exception is made for patients with Duffy-null associated neutrophil count (DANC), a cause of neutropenia that is not associated with recurrent infection. This is most often seen in individuals of African descent and individuals of Sephardic Jewish descent [10]. In these patients, treatment can be instituted and continued in patients with an ANC of at least 1000/microL. We collaborate with hematology to manage moderate or severe neutropenia in this patient group. (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL'.)

●Patient weight and height (body mass index), waist circumference, fasting blood sugar (or HbA1c), and fasting lipids.

Clozapine use can cause metabolic effects leading to increased cardiovascular risk, obesity, diabetes, dyslipidemias, and atherosclerotic cardiovascular disease. Thus, individuals with these disorders may require more aggressive treatment when treated with clozapine. (See 'Metabolic syndrome' below.)

●Electrocardiogram (ECG) – A baseline ECG is obtained regardless of cardiovascular risk. We avoid clozapine in patients with arrhythmia, ischemia, or other injury.

We also avoid clozapine in individuals with congenital long QT syndrome as clozapine causes dose-dependent prolongation of the QT interval. QT prolongation increases the risk of torsade de pointes and potentially lethal arrhythmias. Additionally, the labelling cautions against use in persistent corrected QT interval (QTc) >500 ms on ECG [11]. We are cautious in prescribing clozapine in individuals who are on other medications that may prolong QT interval (table 1). (See 'QT prolongation' below.)

●Echocardiogram in individuals with risk factors for cardiovascular disease – 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.

●Seizure history – Clozapine may increase seizure risk. Clozapine is relatively contraindicated in patients with a history of seizure. For patients who are treated with antiseizure medications, we check that drug levels are within the therapeutic range and the seizures are optimally controlled prior to starting clozapine. We typically adjust the starting dose and titration schedule of clozapine to avoid excessive sedation. (See 'Starting dose and titration' below and 'Seizures' below.)

In patients with an elevated seizure risk (including those with an alcohol use disorder, or a history of febrile seizures), we prefer prophylactic treatment with an antiseizure medication when clozapine is being initiated. (See 'Administration of clozapine' below and 'Seizures' below.)

●High-sensitivity cardiac troponin assay (hs-cTn), C-reactive protein to detect inflammation or other evidence of myocardial injury. These are followed on treatment and thus require baseline assessment. (See 'Myocarditis' below.)

●Abnormal Involuntary Movement Scale (AIMS) documenting absence or presence of abnormal motor movements (form 1). This provides a baseline for monitoring for extrapyramidal side effects. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Side effect management'.)

●Pregnancy test in women of childbearing age – 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 in selected patients [12]. The American Academy of Pediatrics has classified clozapine as a drug whose effect on the nursing infant is unknown but may be of concern [13]. (See 'Other adverse effects' below.)

ADMINISTRATION OF CLOZAPINE

Starting dose and titration — To maximize tolerability and reduce the risk of adverse effects, we prefer to begin clozapine at a low dose and titrate slowly. However, in urgent situations (active aggression or violence, suicidality), we use a more rapid titration and monitor closely with a more rapid titration.

●Nonurgent situations – In nonurgent situations in patients who have never been treated with clozapine, we confirm tolerability with an initial test dose of 12.5 mg. We look for adverse effects such as dizziness (eg, hypotension) or sedation. If tolerated, we begin clozapine at 12.5 to 25 mg once daily at bedtime for three to four days. We increase to 25 to 50 mg once daily at bedtime (or in two divided doses) for three to four days. We increase further by 25 mg twice weekly if tolerated, to the initial target dose.

●Urgent situations – In urgent situations (eg, active aggression/violence or self-injury/suicide), if the benefits of a more rapid titration outweigh the risks (eg, otherwise healthy patient, closely monitored for adverse effects such as seizures, orthostatic changes, sedation), we skip the test dose and double the titration rate. For example, we start at 50 mg once daily or in two divided doses for three or four days, then 100 mg once daily or in divided dose, for three to four days followed by increases of 50 mg twice weekly. We monitor closely for side effects such as sedation or orthostasis. Sleepiness is the primary clinical ceiling side effect, so we simultaneously taper off other sedating agents as clozapine dose is increasing.

●Specific populations – In the following populations, we begin with a lower initial dose and titrate more slowly. For example, in these populations we might start with 12.5 mg for three or four days then titrate by 12.5 mg to 25 mg every three or four days to a reduced initial target dose. (See 'Initial target dose' below.)

•Individuals of Asian descent may be poor metabolizers of clozapine and may require less clozapine to reach therapeutic blood levels [14-16].

•Adults >65 years or in those with cardiac disease. If clozapine is used in individuals with preexisting heart disease, clozapine should be initiated in the inpatient setting with close monitoring of cardiac function.

•Individuals with a history of a seizure disorder, febrile seizures, or those at increased risk for seizures (eg, active alcohol use disorder). (See 'Seizures' below.)

Initial target dose — The initial target dose for healthy, young adults is 300 mg/day. For some specific populations we lower the initial target dose to 100 to 150 mg/day. (See 'Starting dose and titration' above.)

Check plasma levels — We check plasma levels after the initial target dose is reached. (See 'Starting dose and titration' above and 'Initial target dose' above.)

We check plasma levels 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.

A clozapine plasma level in the range of 250 to 350 ng/mL is a reasonable target for a patient with schizophrenia. 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 Response and Resistance in Psychosis Working Group [17]. (See "Treatment-resistant schizophrenia", section on 'Prescribing clozapine'.)

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 [18]. 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).

Once the therapeutic plasma level is reached, we monitor the patient’s clinical response for two weeks before considering any further dose increase.

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.

Once a target dose is achieved, ongoing plasma level monitoring in not routinely necessary. However, regular therapeutic drug monitoring can help detect unsuspected adherence problems early enough to take counter measures.

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 twice daily rather than more frequently. However, some patients require split doses to avoid bed wetting or morning grogginess.

MONITORING FOR MAJOR ADVERSE EFFECTS/TOXICITY — 

We monitor and document the following at regular intervals as described below.

Neutropenia — Historically, prescribers, pharmacies, and patients in the United States were required to participate in the Risk Evaluation and Mitigation Strategy (REMS) program to prescribe, dispense, and receive clozapine, respectively, with mandated absolute neutrophil count (ANC) for the duration of clozapine treatment [19,20]. While the US Food and Drug Administration (FDA) has voted to abolish this program, the recommended schedule for monitoring remains on the package insert; we follow this conservative approach in our patients:

●Routine monitoring - We perform routine neutrophil monitoring 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

Potentially life-threatening agranulocytosis is the most concerning adverse effect associated with clozapine. In a registry study including 12,760 participants treated with clozapine, clozapine-induced agranulocytosis was estimated to occur at a rate of approximately 0.8 percent; leukopenia occurred in almost 3 percent of cases [21]. The peak risks for both occurred early in treatment, between 6 to 18 weeks from initiation. Advancing age was a risk factor for agranulocytosis. 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 [22].

Alternative monitoring approaches may be appropriate for some patients. As experience with clozapine has grown, it has become clear that the risk of clozapine-associated agranulocytosis is highest at the beginning of treatment, with unclear benefit from regular blood monitoring after the first 6 to 12 months of clozapine treatment [23,24]. Thus, less stringent monitoring may be sufficient after six to nine months. Guidelines regarding agranulocytosis monitoring vary widely between countries. For example, the European Clozapine Task Force recommends weekly monitoring for the first 18 weeks; then monthly monitoring for the next 34 weeks. If there is no history of leukopenia or neutropenia during the first year, monitor every 12 weeks for the second year, then once yearly after two years [25].

Any deviation from the FDA-recommended ANC monitoring should be documented in the patient’s clinical chart, following a risk-benefit discussion with patients and their families. The discussion should include education about signs and symptoms of agranulocytosis and the need to immediately inform their provider if they develop any of these (eg, fever, sore throat, infection).

●If neutropenia develops during treatment – If ANC drops below 1500/microL, clozapine needs to be monitored more frequently, stopped temporarily, or discontinued, based on the severity of neutropenia [19]:

•Mild neutropenia (ANC 1000 to 1499/microL) – Continue treatment but increase monitoring frequency to three times per week.

•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. (See 'Rechallenge after adverse effects' below.)

We do not routinely use granulocyte colony-stimulating factor (G-CSF) to manage clozapine-associated neutropenia. G-CSF hastens the increase in absolute neutrophil counts, although it is not clear this alters infection rates or mortality [26,27].

QT prolongation — In addition to obtaining an electrocardiogram (ECG) prior to starting clozapine, we repeat the ECG once the patient is on maintenance dosing [28-31].

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 [32].

In patients with treatment-emergent increase of QTc interval of >60 ms from baseline or for the addition of high-risk medications (table 1), we seek cardiology consultation. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for drug-induced long QT syndrome'.)

Myocarditis — Individuals with preexisting heart disease are at greater risk of morbidity from clozapine-induced myocarditis. We monitor all patients weekly for at least the initial eight weeks of treatment for symptoms of myocarditis (eg, malaise, chest pain, shortness of breath). If clozapine is used in individuals with preexisting heart disease, it should be initiated in the inpatient setting with close monitoring of cardiac function.

Most cases of myocarditis occur early in the course of clozapine treatment. 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.

●Presentation – 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. Some patients will have a mild and temporary increases in inflammatory markers and eosinophils at the beginning of treatment without progression to myocarditis.

In rare cases, clozapine-induced myocarditis can progress rapidly into cardiomyopathy and congestive heart failure.

●ECG and laboratory testing – In addition to ECG at baseline and upon reaching maintenance dose, we send weekly laboratory testing including high-sensitivity troponin assay (hs-cTn), and C-reactive protein. Significant increases in C-reactive protein (over 100 mg/L) and troponin elevation (greater than twice the upper limit of normal) has been reported to be 100 percent sensitive in detecting clozapine-induced myocarditis in symptomatic patients [33]. Longitudinal measurement of troponin levels is the most sensitive and specific laboratory marker that is easily available in most settings to detect clozapine-induced myocarditis [34]. The eosinophil count often rises as well but less reliably and is delayed.

In a review of 116 cases of clozapine-associated myocarditis, the condition developed within 16 days (median) of initiating clozapine [35]. Approximately 80 percent of cases of clozapine-induced myocarditis occur within four weeks of drug initiation, and 90 percent occur within eight weeks. Studies have estimated the risk of clozapine-induced myocarditis to be 1 in 500 to 1 in 10,000 [35]. 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 [36].

Rechallenge with clozapine after clozapine induced myocarditis is discussed below. (See 'Rechallenge after adverse effects' below.)

Metabolic syndrome — We monitor metabolic effects of antipsychotic medications by checking weight, waist circumference, blood pressure, HgBA1c, and fasting lipid profile at regular intervals. Our preferences for monitoring parameters and frequency are found on the table (table 2).

●Weight gain – Clozapine can cause significant weight gain [37-41]. The average weight gain in a 10-year cohort study of clozapine was 30 pounds [37]. While most weight gain occurs during the first 6 to 12 months, some patients continue to gain weight without reaching a plateau [39]. Addressing weight gain in individuals with antipsychotic-associated obesity is found elsewhere. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Metabolic dysregulation' and "Cardiovascular risk in patients with serious mental illness: Managing antipsychotic-associated obesity".)

●Diabetes mellitus – The insulin resistance from clozapine treatment is at least in part independent from clozapine-induced weight gain [37,42]. Screening for type 2 diabetes and prediabetes are found elsewhere. (See "Screening for type 2 diabetes mellitus and prediabetes".)

Movement disorders — We monitor for the development of movement disorders such as tardive dyskinesia or other extrapyramidal symptoms using the Abnormal Involuntary Movement Scale (AIMS) every six months (form 1). 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. Additionally, despite clozapine’s weak affinity for the dopamine receptor, the neuroleptic malignant syndrome can develop [43]. (See "Tardive dyskinesia: Prevention, treatment, and prognosis" and "Neuroleptic malignant syndrome" and "Schizophrenia in adults: Maintenance therapy and side effect management".)

OTHER ADVERSE EFFECTS

Seizures — Clozapine is associated with a dose-dependent seizure risk at a rate higher than that seen with most other antipsychotic drugs [44,45].

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 [46]. 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

In a separate review of 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 [47].

We coordinate treatment with a neurologist in all individuals with a seizure history, or in individuals who have a seizure while on clozapine. (See 'Administration of clozapine' above.)

Gastrointestinal hypomotility — Due to its anticholinergic and serotonergic properties, clozapine induces gastrointestinal hypomotility (“slow gut”) in the majority of patients. Delayed diagnosis and treatment may result in fecal impaction, megacolon, intestinal obstruction, perforation, ulceration, or necrosis. Severe constipation, culminating in adynamic ileus, can be fatal [48-50].

●Risk factors – 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 [51]. Probable risk factors included:

•Recent initiation of clozapine

•High clozapine doses or serum levels

•Use of other drugs with anticholinergic activity

•Comorbid medical illness

●Prevention and management – We monitor individuals receiving clozapine for the presence of hypomotility at every visit (constipation, abdominal pain). We encourage all individuals taking clozapine to eat a diet high in fiber, drink plenty of fluids, and exercise (see "Management of chronic constipation in adults", section on 'Optimizing fiber and fluid intake'). However, these measures alone are often insufficient in clozapine-treated patients. In many cases, self-report of constipation due to clozapine is not sensitive and prospective constipation management with a prophylactic laxative bowel using the Porirua protocol (standing docusate plus senna, augmented by an as-needed osmotic laxative [polyethylene glycol]) has been shown to reduce clozapine-associated hypomotility and its potential complications [52,53].

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 [54]. 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. While recent initiation of clozapine is a risk factor for gastrointestinal hypomotility, in these cases, 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) [55].

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, and case reports have demonstrated concentrations of clozapine in breast milk [56,57].

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 in selected patients [12]. The American Academy of Pediatrics has classified clozapine as a drug whose effect on the nursing infant is unknown but may be of concern [13]. (See "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and neuromodulation", section on 'Teratogenicity'.)

Mortality risk in patients with dementia — The US Food and Drug Administration (FDA) 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 [58,59]. (See "Management of neuropsychiatric symptoms of dementia", section on 'Mortality risk'.)

Other systemic effects

●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. Side effects such as sleepiness increase as clozapine blood levels increase [60].

While some clinicians add stimulants or stimulant-like drugs if patients continue to experience sedation, 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 [61,62].

●Excessive salivation – Clozapine-induced hypersalivation (sialorrhea) is a common side effect that may occur in 30 percent or more of patients treated with clozapine [11]. Sialorrhea 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 [63] and can worsen during sleep. Its mechanism is thought to be due to a disturbance of swallowing and not merely an increase in salivary flow rate [64]. Hypersalivation may be a risk factor for aspiration pneumonia, which has been observed in clozapine-treated patients [65].

A reduction in clozapine dose can be tried to limit salivation, but this step alone is often inadequate.

Topical agents (eg, sublingual atropine or ipratropium spray) are preferred first-line treatments. If this is insufficient, glycopyrrolate at a dose of 1 to 2 mg given at night may be effective. A randomized trial compared glycopyrrolate with biperiden [66]. 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' above.)

Other treatment approaches, based on case reports or case series, include the use of sugarless chewing gum to increase the rate of swallowing 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.

These and other treatments for sialorrhea are discussed separately. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Sialorrhea'.)

●Hematologic malignancies – While the absolute risk for hematologic malignancies associated with clozapine use is small, any clinical concerns for hematologic malignancy including sustained abnormalities in white blood cell counts should prompt an evaluation by hematology [67-69]. (See 'Neutropenia' above.)

A pharmacovigilance study of the World Health Organization’s pharmacovigilance database (VigiBase) of 140,226 clozapine-associated reports found that treatment with clozapine is associated with reports of malignant lymphoma (adjusted odds ratio 9.14, 95% CI 7.75-10.77) and leukemia (adjusted odds ratio 3.54, 95% CI 2.97-4.22) [67]. A nationwide case-control and cohort study from Finland found an increased risk for hematologic malignancies in a dose-response manner in patients treated with clozapine (adjusted odds ratio 3.35, 95% CI 2.22-5.05) [68]. The majority of cases were lymphomas, and the effect was specific for hematologic malignancies but not for other cancers.

●Pulmonary Embolism – A number of cases have reported fatal venous thromboembolism (VTE) in patients taking clozapine [70-78]. In one review of 42 published cases of VTE-associated with clozapine use, the mortality rate was 32.5 percent [77]. However, whether clozapine is associated with an increased risk of VTE and the nature of that potential association is uncertain.

Risk factors for thromboembolic disease in the general population include (among others):

•Genetic factors (mainly the factor V Leiden mutation or a high concentration of factor VIII)

•Recent immobilization

•Recent surgery

•Pregnancy or the postpartum state

•Obesity

We advise all patients starting on clozapine to remain physically active to lower the risk of pulmonary embolism.

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 [79], and statins have been shown to reduce venous thromboembolism among individuals receiving chemotherapy for cancer [80].

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".)

●Urinary incontinence – Treatment with clozapine appears to be associated with an increased incidence of urinary incontinence [11,81]. The potent anti-alpha-adrenergic effects of clozapine, which relax the bladder-neck sphincter, are hypothesized to contribute to the incontinence.

We refer patients with incontinence to a urologist for consultation. Clozapine associated incontinence has been reported to respond to ephedrine among other interventions. A dose of 25 mg ephedrine at night or 25 mg twice daily is often sufficient to treat patients with urinary incontinence [81-83]. 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.

RE-INITIATION AFTER INTERRUPTION

For missed doses — If clozapine treatment is briefly interrupted, we restart clozapine at a reduced dose to minimize side effects such as orthostasis, syncope, or cardiac arrest [84]. The re-initiation is guided by anticipated patient tolerability taking into account previous tolerability, patient age, and medical comorbidities.

●If one day of clozapine is missed, we resume clozapine treatment at 40 to 50 percent of the previous total daily dose

●If two days of clozapine are missed, we resume clozapine at 25 percent of the previous total daily dose

●If dosing is interrupted for more than two days, we resume clozapine at 12.5 mg once or twice daily

In patients who tolerate this dose, we increase to the previous daily dose more rapidly than initial titration, modifying our approach according to the patient’s symptoms. (See 'Starting dose and titration' above.)

Rechallenge after adverse effects

●After neutropenia or agranulocytosis – A history of clozapine-induced severe neutropenia or agranulocytosis (absolute neutrophil count [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. (See 'Neutropenia' above.)

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 [85].

●After clozapine-induced myocarditis – Patients with a history of clozapine-induced myocarditis should only be rechallenged if the harm from not using clozapine greatly outweighs the potential risks. When a rechallenge is considered after an episode of myocarditis due to clozapine or if clozapine is used in individuals with preexisting heart disease, clozapine should be initiated in the inpatient setting with close monitoring of cardiac function.

Subsequent use of clozapine in cases with clear clozapine-induced myocarditis leads to recurrence of myocarditis in most cases when the drug is restarted. (See 'Myocarditis' above.)

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 – The primary indication for the use of clozapine is schizophrenia or schizoaffective disorder, partially or fully resistant to treatment with other antipsychotic agents, or in those with persistent suicidal or self-injurious behaviors. Other clinical indications in schizophrenia patients include sensitivity to extrapyramidal symptoms, aggression in the setting of psychosis, and patients with tardive dyskinesia. (See 'Indications' above and "Treatment-resistant schizophrenia", section on 'Clozapine as first-line treatment'.)

●Pretreatment considerations – Prior to beginning treatment with clozapine we review the following (table 2) (see 'Pretreatment evaluation' above):

•Patient is afebrile, stable vital signs

•Complete blood count that includes an absolute neutrophil count (ANC) ≥1500/microL

•Weight and height (body mass index), waist circumference, fasting blood sugar (or HbA1c), and fasting lipids

•Electrocardiogram (table 1)

•Drug levels in the therapeutic range for antiseizure medications

•High-sensitivity cardiac troponin assay (hs-cTn), C-reactive protein

•Echocardiogram in individuals with risk factors for cardiovascular disease

•Baseline Abnormal Involuntary Movement Scale (AIMS) test

•Pregnancy test in women of childbearing age

●Administration – To maximize tolerability and reduce the risk of adverse effects, we begin clozapine at a low dose and titrate slowly. (See 'Starting dose and titration' above.)

•In nonurgent situations, we confirm tolerability with an initial test dose of 12.5 mg. If tolerated, we begin clozapine at 12.5 to 25 mg once daily at bedtime for three to four days. We increase to 25 to 50 mg once daily at bedtime (or in two divided doses) for three to four days. We then increase further by 25 mg twice weekly if tolerated, to the initial target dose.

•In urgent situations (active aggression, self-injurious behavior), we typically double the titration rate.

•In some populations, such as those of Asian descent, older adults, and in those with a seizure disorder or at increased risk for seizure, we titrate more slowly. (See 'Starting dose and titration' above.)

We check clozapine plasma levels once the initial target dose (usually 300 mg/day) is reached. (See 'Initial target dose' above.)

●Monitoring for major adverse effects – We monitor and document the following:

•Neutropenia – Routine neutrophil monitoring at the following intervals (see 'Neutropenia' 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

•Cardiac effects – We monitor for arrhythmia or myocarditis with a repeat electrocardiogram (ECG) when steady state is reached and with weekly hs-cTn and C-reactive protein. (See 'QT prolongation' above and 'Myocarditis' above.)

•Metabolic syndrome – We monitor for metabolic effects by measuring weight, waist circumference, blood pressure, HgBA1c, and fasting lipid profile at regular intervals (table 2). (See 'Metabolic syndrome' above.)

•Movement disorders – We monitor for the development of movement disorders every six months with the AIMS (form 1). (See 'Movement disorders' above.)

●Other adverse effects – Other adverse effects of clozapine may include an increased risk of seizures, gastrointestinal hypomotility, and sedation. The use of clozapine for the treatment of behavioral symptoms in older adults with dementia is associated with increased mortality. (See 'Other adverse effects' above.)

●Rechallenge after adverse effects – Severe neutropenia and myocarditis are likely to recur in patients who are rechallenged when the drug is held for these adverse effects. The risks, benefits, and alternatives need to be weighed for each patient. (See 'Re-initiation after interruption' above and 'Rechallenge after adverse effects' above.)