Clozapine (Trade name: Clozaril) is a an antipsychotic in the atypical antipsychotic class used in the treatment of schizophrenia, especially in patients who are resistant to other antipsychotics. It is commonly referred to as a “last-line antipsychotic.” It is a low potency antipsychotic and highly anticholingeric, which gives it a very low incidence of extrapyramidal side effects. However, it carries a risk of neutropenia and agranulocytosis, which requires intensive blood work and monitoring. Other serious side effects include the risk of constipation and related GI-issues.
Absorption | Clozapine undergoes almost complete absorption. Oral bioavailability is 27-47% due to variable first pass metabolism, and peak concentration is around 2.5 hours following oral dosing.[1] |
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Distribution | 95% bound to plasma proteins[2] |
Metabolism | Norclozapine is the major metabolite of clozapine. |
Elimination | |
Half-life |
Substrate of (Metabolized by) | 1A2 |
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Induces | |
Inhibits |
Clozapine has the same incidence of extrapyramidal symptoms as placebo.[6] This makes it a particularly useful switch antipsychotic for patients who are experiencing significant EPS from other antipsychotics.
Clozapine is only one of two psychotropics (the other is lithium) that has been clinically shown to reduce the risk of suicide.[7]
Starting | 25-50 mg PO daily, can be titrated 25-50 mg per day up to 300 mg. |
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Once at 300 mg daily… | Titration should not exceed more than 25 mg each day |
Once at daily doses of 400 mg, 500 mg 600 mg, 700 mg, 800 mg, and 900 mg… | Maintain at each interval for at least 2 weeks before moving on |
Once past 500 mg daily… | Consider increasing the dose by 25-50 mg only every 2 weeks. |
Maximum | 900 mg |
Note that an adequate trial of clozapine is considered to be a minimum of 8
weeks, but preferably 12
weeks, reaching a minimum dose of 400 mg per day.[8]
Investigations | |
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Physical | • Height • Weight • Waist circumference • Blood pressure • Heart rate |
Labwork | • CBC • Glucose fasting • AST, ALT, ALP • Lipid Panel • HbA1C • CRP • High sensitivity troponin I • Baseline ECG |
ng/mL (µg/L) | nmol/L (nM/L)* | Notes | |
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Lower bound | <200 | <600 | May place patients at a higher risk of relapse |
Recommended level (divided dosing)[10] | ≥250 | ≥765 | Typical dose is ~400mg to achieve this level |
Recommended level (once daily dosing)[11] | ≥350 | ≥1100 | Typical dose is ~400mg to achieve this level |
Upper bound | >1000 | >3000 | Increased risk of seizures |
Maximum/Toxic Levels[12] | >2000 | >6000 | Risk of clozapine-related toxicity |
Hematological monitoring is required prior to starting and also during treatment to monitor for agranulocytosis-and-neutropenia (see Table below). Orthostatic vitals should also be monitored daily during any initiation or dose titration period, since hypotension can result.
Treatment Status | Bloodwork | Action |
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Baseline | • WBC ≥3.5 x 109/L • ANC ≥2.0 x 109/L | Begin clozapine treatment |
Green | • WBC ≥3.5 x 109/L • ANC ≥2.0 x 109/L | • Continue treatment • Monitor patient: – Weekly for the first 26 weeks – q2 weeks for the next 26 weeks – q4 weeks thereafter |
Flashing Yellow | Any of the following: • A single (or sum of) fall in WBC of 3.0 x 109/L over the last 4 weeks, reaching a value <4.0 x 109/L• A single (or sum of) fall in ANC of 1.5 x 109/L over the last 4 weeks, reaching a value <2.5 x 109/Lo | • Patient should be evaluated immediately • Check WBC count and ANC twice weekly • Continue treatment |
Yellow | Any of the following: • WBC 2.0-3.5 x 109/L • ANC 1.5-2.0 x 109/L | • Patient should be evaluated immediately • Check WBC count and ANC twice weekly • Continue treatment |
Red | Any of the following: • WBC <2.0 x 109/L • ANC <1.5 x 109/L | • Immediately stop treatment and confirm results within 24 hours • Patient must be closely monitored • Attention must be paid to any flu-like complaints or other symptoms which might suggest infection • Clozapine must NOT be resumed if results are confirmed and the patient should be assigned a non-rechallengeable status |
Critical | Any of the following: • WBC <1.0 x 109/L • ANC <0.5 x 109/L | • Place the patient in protective isolation with close observation • Physician must watch for signs of infection |
Cigarette smoking induces the CYP1A2 isoenzyme which can lead to lower levels of clozapine. It can reduce clozapine plasma levels by up to 50% and higher doses may be required in smokers than in nonsmokers. The polycyclic aromatic hydrocarbons in cigarettes induce CYP1A2 activity, which increases the metabolism of clozapine.[22] Nicotine replacement products (patches, lozenges, nasal spray, inhalers, and gum) on the other hand, do not induce CYP1A2. The impact of electronic cigarettes and vaping is less clear, and there may be a potential to induce CYP1A2 as well (though less than cigarettes).[23]
Sedation, hypotension and seizure activity are most commonly correlated with higher plasma levels of clozapine.[24]
Clozapine-induced fever is a benign but common side-effect that can occur in up to half of all patients on treatment.[25] Fevers typically last for up to 2-3 days, and occur in the first month of treatment. Other differential diagnoses to consider include neuroleptic malignant syndrome and clozapine-induced myocarditis.
Hypersialorrhea (hypersalivation) is the excessive production of saliva. Clozapine-induced hypersalivation/sialorrhea (CIH, or CIS) is a common side effect related to clozapine use (but can also occur in other antipsychotics).[26] Sialorrhea can range from being mildly uncomfortable drooling and excessive saliva, to potentially life-threatening conditions, such as parotitis, choking, and aspiration. Sialorrhea is not dose-related and can occur at any point during treatment. Although clozapine has many anticholinergic properties, the cause of CIS is thought to be due to clozapine agonism at the muscarinic (M4) receptors and blockade of a-2 adrenergic receptors, which increases salivary production and flow.[27]
CIS can be treated with an muscarinic receptor antagonist (i.e. - an antimuscarinic/anticholinergic) such as atropine or ipratropium, which can administered sublingually at night time.[28][29] Common treatment regimens include:
Constipation is very common and can affect up to 50% of patients.[31] It is critical for every patient on clozapine to have bowel monitoring for constipation. Clozapine has the potential to decrease GI motility, and is associated with risk of paralytic ileus, bowel obstruction, fecal impaction, bowel perforation, and in rare cases, death.[32] If other anticholingerics are also being used, then the prescribing clinician needs to be even more vigilant about bowel monitoring, since anticholingeric effects are additive. In addition, the risk of medication-related constipation also increases with age. Other conditions like diabetes mellitus can also further worsen constipation due to autonomic neuropathy.
1st line | Osmostic agents: • Polyethylene glycol (PEG): start 17 grams daily, and increase to 17 grams BID as needed (this is beyond manufacturers’ recommended dose). • Lactulose: start 15-30 mL daily, and increase to 30 mL BID Note: Combining lactulose and PEG 3350 combined is not a rational pharmacotherapy due to overlapping mechanisms. |
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2nd line | Stimulant laxatives: • Sennosides • Bisacodyl |
3rd line | Fibre and bulk-forming products may be helpful, but can also worsen constipation in underlying dehydration and should be used cautiously. |
Adjunctive | Dietary and exercise interventions should be considered as adjunct to laxative therapy as they are not likely to improve clozapine-induced constipation alone. |
Not recommended | There is no evidence for the use of surfactant agents (“stool softeners”) like docusate sodium for chronic constipation. These agents only lower the surface tension of stool, but are not effective at preventing and treating medication-induced constipation.[34] |
Myocarditis and cardiomyopathy are the two serious cardiac-related adverse events to monitor for, both during initiation of treatment and throughout the course of treatment.[37]
Onset | % of patients | Signs and Symptoms | Pathophysiology | Bloodwork | Investigations and Treatment | |
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Myocarditis | Generally occurs within first few weeks (14-21 days) of clozapine initiation. Mortality rates as high as 50% have been reported, when undetected. | 0.2% | Myocarditis has non-specific symptoms, including fever, tachycardia and chest pain. There may be signs of heart failure such as dyspnea (especially while supine) or dry cough. Other symptoms include diarrhoea, vomiting, dysuria or rashes. | The pathophysiology of clozapine-associated myocarditis not well understood but is not dose-dependent. | • CBC (↑ WBC, ↑ eosinophils) • CRP (↑)* • Troponin, BNP, CK, ESR | Echocardiogram, CXR. Treatment includes stopping clozapine, and usual treatment for myocarditis. Diagnosis is not straightforward, and suspected cases should be referred urgently for a cardiology opinion. |
Cardiomyopathy | Usually occurs later in clozapine treatment compared to myocarditis. Clinicians need to maintain a high index of suspicion for cardiomyopathy throughout clozapine treatment, regardless of how long a patient has been on clozapine. | 0.02–0.1%[38] | Signs of heart failure, flu-like symptoms, cough, fever, sinus tachycardia/ palpitations, fatigue, hypotension and chest discomfort.[39] | Poorly understood, may be secondary to untreated, acute clozapine-induced myocarditis.[40] | • CBC (↑ WBC, ↑ eosinophils) • CRP (↑)* • Troponin, BNP, CK, ESR | Echocardiogram (reduced ejection fraction), ECG. Treatment includes stopping clozapine and usual treatment for heart failure. |
Seizure risk increases in a dose-dependent manner with clozapine, and is most frequent in patients with serum levels above 1000 μg/L, or at doses more than 500 mg per day. Clozapine-induced seizures can be managed and prevented with either valproate or lamotrigine. Valproate has the most data to support its use and it is widely regarded as the drug of choice. Adjunctive antiepileptic treatment is recommended as prophylaxis against seizures and myoclonus when plasma levels are above 600 μg/L. There is also a relationship between clozapine dose, plasma level, and the likelihood of an abnormal EEG.[43]
Multiple factors can affect the true plasma level of clozapine. Plasma levels are generally lower in smokers, younger ages, and males. Conversely, plasma levels are generally higher in Asian patients, and they may have a higher risk of seizures even at low doses of clozapine.[44]
We reviewed the common side effects of clozapine: elevated heart rate, ECG abnormalities, orthostatic hypotension, hyperlipidemia, hyperglycemia, drowsiness, dizziness, falls, insomnia, akathisia, excess saliva production, dry mouth, weight gain, constipation, nausea, vomiting, abdominal discomfort and heartburn, enuresis, EPS. Potentially rare, but more serious risks: agranulocytosis, tardive dyskinesia, neuroleptic malignant syndrome (muscle stiffness, fever, sudden rise in blood pressure, agitation and confusion), myocarditis, pericarditis, cardiomyopathy, stroke, blood clots, lowered blood cells (such as platelets and eosinophils), aspiration pneumonia, dysregulation of body temperature, arrhythmias, suicidal thinking, bowel obstruction and seizures. We also reiterated that sudden cardiac death is possible with patients who are prone to arrhythmias and QTc prolongation. Reviewed that patients with dementia have a known risk for death and stroke like events with use of neuroleptics.