Question

Caitlyn Morris is 35-year-old, single African American female who has been hospitalized for the fourth time in two months after another psychotic episode including paranoid delusions and both auditory and visual hallucinations. Caitlyn lives in a group home and attends a partial hospital program at a local community mental health center. She was diagnosed with paranoid schizophrenia (ICD 10 F20.0) in her early twenties.

Caitlyn has been on multiple second-generation antipsychotics and several first-generation antipsychotics; none has been shown to be effective. During a team meeting at the hospital to discuss Caitlyn’s care, it was determined that she will be started on clozapine (Clozaril).

Questions

From your perspective as a psychiatric nurse practitioner, answer the following questions in a paper no longer than two double-spaced pages (not including the reference page) and in APA format. Include at least three peer-reviewed, evidence-based references.

1. Articulate why clozapine (Clozaril) would be an effective choice for Caitlyn. Under what circumstances should be clozapine (Clozaril) generally be considered?
2. What baseline laboratory tests, diagnostic tests, and monitoring should you complete when treating Caitlyn? Please provide a rationale.
3. Articulate the dosing for clozapine (Clozaril).
4. What is the prescriber site (URL and title) required for those who prescribe clozapine (Clozaril). Why are prescribers required to register?
5. Describe the ongoing monitoring that is required for a patient taking clozapine (Clozaril) and identify the rationale for this monitoring.
6. Articulate the side effects that you should monitor fo

Answer 1

1. Clozapine is an atypical antipsychotic which works by-

block D2 receptors in the
mesolimbic and mesofrontal systems (concerned
with emotional reactions).Sedation is caused by
alpha-adrenergic blockade. Anti dopaminergic
actions on basal ganglia are responsible for
causing EPS (Extra Pyramidal Symptoms).
Atypical antipsychotics have antiserotonergic
(5-hydroxytryptamine or 5-HT) antiadrenergic effects. This is recommended for Caitlyn because she has been suffering from paranoid schizophrenia and having symptoms of delusions and hallucinations. As there is a chance of suicidal ideation so clozapine is best suited to prevent suicidal ideation and side effects are less than other antipsychotics.

CLOZAPINE IS CONSIDERED FOR-

Primary indications for clozapineinclude 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.

2.

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Guidelines for prescribing clozapine in schizophrenia

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of UpToDate content is governed by the UpToDate Terms of Use. ©2019 UpToDate, Inc. All rights reserved.

Authors:

Oliver Freudenreich, MD

Joseph McEvoy, MD

Section Editor:

Stephen Marder, MD

Deputy Editor:

Richard Hermann, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2019. | This topic last updated: Jun 25, 2018.

INTRODUCTIONClozapine 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 "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment".)

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".)

INDICATIONSPrimary 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 side effects and patients with tardive dyskinesia. (See "Evaluation and management of treatment-resistant schizophrenia", section on 'Clozapine'.)

CONTRAINDICATIONS

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 benign ethnic neutropenia, who are subject to a lower ANC level. (See 'Benign ethnic neutropenia' 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.)

Benign ethnic neutropenia — Lower neutrophil thresholds were established for starting clozapine in patients with confirmed benign ethnic neutropenia, a cause of neutropenia often seen in patients of African descent [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 'Benign ethnic neutropenia (BEN)'.)

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 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 drug 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.

PHARMACOLOGYThe 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 [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 2C, 2D6, and 3A3/4 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. Agents that inhibit CYP1A2 (eg, theophylline, ciprofloxacin, fluvoxamine) will decrease the metabolism of clozapine and may produce clinical toxicity at usual doses [6]. Cytochrome-related problems can be avoided by monitoring clozapine plasma levels while gradually increasing clozapine from a low starting dose. (See 'Dosing'below.)

The major metabolite of clozapine, norclozapine (desmethyl-clozapine), 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 [7].

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 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 drugs (need to be in the therapeutic range). (See 'Seizures'below.)

●Vital signs.

●ECG.

●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.)

Dosing — Treatment with clozapine usually commences at a low dose (12.5 to 25 mg/day). During the initial titration in inpatient settings, twice or three times daily dosing is typically employed to reduce autonomic side effects, like orthostatic hypotension, and to take advantage of clozapine’s sedating effects. If well tolerated, the dose can be increased gradually, typically by 12.5 to 25 mg every one to two days, with the target dose and frequency determined by the plasma clozapine level and adverse effects. A clozapine plasma level can be checked after an initial target dose is reached, generally after two weeks in the inpatient setting. Given the pharmacokinetics of clozapine, differences of a few hours in the time of evening dosing and/or morning plasma sampling will lead to large differences in reported plasma levels. Orthostatic blood pressure should be monitored daily when feasible (ie, in inpatient setting).

A clozapine plasma level in the range of 250 to 350 ng/mL is a reasonable target for a patient with schizophrenia, but patients show great variation in both their symptomatic response and side effects. Once the target dose is reached, the patient’s clinical response should be monitored for two weeks before a further increase. There is little evidence to suggest greater efficacy at blood levels greater than 350 ng/mL, but outliers may exist. Side effects such as sleepiness and electroencephalogram slowing increase as clozapine blood levels increase [8].

A maintenance dose of 300 to 600 mg/day is usually required for efficacy. Doses higher than 900 mg/day are not recommended. In the older adult and medically ill population, the titration may need to be slower, and maintenance doses are typically in the 100 to 150 mg/day range. However, due to great interindividual variability in clozapinemetabolism, rare patients can reach toxic levels with low doses like 100 mg/day, and some patients fail to achieve therapeutic levels with 900 mg/day.

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. Compliance 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.

If clozapine treatment is interrupted for more than two days, clozapine needs to be restarted carefully, with 12.5 mg once or twice daily. 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 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 [9]. 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, https://www.clozapinerems.com/).

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.

●Moderate neutropenia (ANC: 500 to 999/microL) – Interrupt clozapinetreatment, 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 benign ethnic neutropenia in the United States. (See 'Benign ethnic neutropenia' 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' above.)

If agranulocytosis occurs, filgrastim hastens the return to ANC counts [10,11], although it is not clear this alters infection rates or mortality.

Cardiovascular — 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 at baseline, and then weekly laboratory tests including:

●Eosinophil count

●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 [12]. 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".)

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.)

Gastrointestinal — Gastrohypomotility, which can result in an adynamic ileus, requires close clinical attention. In patients who cannot reliably identify bowel problems, a preventive laxative (stool softener) is often prescribed when starting clozapine. (See 'Constipation' 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 [13]. 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 [14]. Neutrophil-monitoring during clozapinetreatment 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 [15]. 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 [16].

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 [15]. 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 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.)

Pulmonary embolism — Clozapine has been associated with an increased risk of venous thromboembolic events including pulmonary embolism leading to death [17-23]. Of the published cases with a known outcome, the mortality rate of a clotting complication while on clozapine was 44 percent [24].

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

●Obesity

Clinicians starting patients on clozapineshould 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 [25], and statins have been shown to reduce venous thromboembolism among individuals receiving chemotherapy for cancer [26]. 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 [27-31]. The average weight gain in a 10-year cohort study of clozapine was 30 pounds [27]. While most weight gain occurs during the first 6 to 12 months, some patients continue to gain weight without reaching a plateau [29]. 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 [32]. The benefits of added metformin, however, are lost when it is discontinued [33]. (See "Pharmacotherapy for schizophrenia: Side effect management", section on 'Clinical management'.)

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 [27]. 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 [34]. 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 [35,36]. 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 [37]. 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 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 [38]. 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 [39] 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 [40]. Hypersalivation may be a risk factor for aspiration pneumonia, which has been observed in clozapine-treated patients [41].

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 [42]. 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 'Constipation' 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), or alpha-2 agonists (eg, clonidine).

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 [43]. 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.

Constipation — Constipation has been reported to occur in approximately 14 percent of patients treated with clozapine, and can be severe [44]. This is most likely due to the drug’s anticholinergic properties [45]; other medications with anticholinergic properties may exacerbate it.

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 [46]. 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 [47]. 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) [48].

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 [49,50].

Teratogenic and neonatal risks — Although no definitive association has been found between use of antipsychotic medications during pregnancy and an increased risk of birth defects 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 [51]. Clozapine is labeled a pregnancy category B medication by the US Food and Drug Administration. (Animal studies have failed to demonstrate a risk to fetus; no adequate human studies.) (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 [52,53]. (See "Management of neuropsychiatric symptoms of dementia", section on 'Excess mortality'.)

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 [54]. (See "Tardive dyskinesia: Prevention, prognosis, and treatment" and "Neuroleptic malignant syndrome".)

SOCIETY GUIDELINE LINKSLinks 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

●Primary indications for clozapineinclude 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 and "Evaluation and management of treatment-resistant schizophrenia", section on 'Clozapine'.)

●Prior to regular neutrophil monitoring, clozapine-induced agranulocytosis was estimated to occur at a rate of approximately 0.8 percent. Subsequent clozapine use in the United States and other countries has been subject to required, regular monitoring and registry reporting of absolute neutrophil counts (ANC) [1], a process that has succeeded in avoiding deaths due to this adverse effect. Revisions to United States regulations in 2015 permitted clinicians to override ANC-based treatment recommendations to continue or restart clozapine in patients where the benefits of clozapine clearly exceed the risk of agranulocytosis. (See 'Neutropenia' above and 'Monitoring'above.)

●Assessment of patients prior to starting clozapine include baseline evaluation of (see 'Pretreatment assessment' above):

•General and cardiovascular health status

•Complete blood count with an ANC ≥1500/microL (see 'Neutropenia'above)

•Drug levels for anticonvulsant drugs, need to be in therapeutic range

•Weight, height, body mass index, and waist circumference

•Fasting blood sugar or HbA1c

•Fasting lipids (non-HDL cholesterol if non-fasting)

•Vital signs

•ECG

•Absence or presence of abnormal motor movements on Abnormal Involuntary Movement Scale test

•Pregnancy test in women of childbearing age

●Patients taking clozapine should receive routine weekly-to-monthly monitoring and maintain an ANC ≥1500/microL (≥1000/microL for benign ethnic neutropenia). Lower ANC levels require more frequent monitoring, and possible interruption of clozapine and/or reevaluation of its use.

3.

4.ONGOING MONITORING-

• A patient receiving clozapine is at risk for
developing agranulocytosis. Monitor TC,DC
essentially in the first few weeks oftreatment.
Stop the drug if the WBCcount drops to less
than 3000/mm3 of blood. The patient should
also be told to report if sore throat or fever
develop, which might indicate infection
Instruct the patient to take sips of water fre-
quently to relieve dryness ofmouth. Frequent
mouth washes, use of chewing gum, applying
glycerine on the lips are also helpful.
• A high-fiber diet, increased fluid intake and
laxatives if needed, help to reduce consti-
pation.
• Advise the patient to get up from the bed or
chair very slowly. Patient should sit on the
edge of the bed for one full minute dangling
his feet, before standing up. Check BPbefore
and after medication is given. This is an
important measure to prevent falls and other
complications resulting from orthostatic
hypotension.
• Differentiate between akathisia and agitation
and inform the physician. A change of drug

may be necessary if side-effects are severe.
Administer antiparkinsonian drugs as pres-
cribed.
• Observe the patient regularly for abnormal
movements.
• Take all seizure precautions.
• Patient should be warned about driving a car
or operating machinery when firsttreated with
antipsychotics. Giving the entire dose at
bedtime usually eliminates any problem from
sedation.
• Advise the patient to use sunscreen measures
(use of full sleeves, dark glasses etc) for
photosensitive reactions.
• Teach the importance of drug compliance,
side-effectsofdrugs and reporting iftoo severe,
regular follow-ups. Give reassurance and
reduce unfounded fears and anxieties.

: • Seizure precautions should also be taken as
clozapine reduces seizure threshold. The dose
should be regulated carefully and the patient
may also be put on anticonvulsants such as
eptoin.

5.

honetsiag; if na dietary advice ; liaise agraneclo oses . Flide effects of clozapine - ② weight gain pespouse Dret, exereise adrice, moneto (2) Hyperlipe dernia bietares advice, monitoriage persisteoll add hy anti-keypertensives. ③ Emergent or Monitoring, dietary advice worseling diabetes ng diabetes. ¿ endociend Logist ēf* persists. 4 Neutropenia . + Hematology; reveiw, t for persistent méld neubopencov, .consider lithelem augmentation, ☺ constipation * High dåber diet, eusese adequate excerdősé'd non caffeinat edo fluced intake. 0 Li alorrhea Towel over pillow at night ... ② Sédation * Take af bedtime; avoid driving after intake ® Some episodes of extrapysanédal F Cs Symptomen foccasional) CamScanner