Clozapine (Clozaril)

SGA • Last reviewed 2025-09-23

General information

Clozapine is an atypical second-generation antipsychotic approved in the United States for treatment-resistant schizophrenia and for reducing recurrent suicidal behavior in adults with schizophrenia or schizoaffective disorder (FDA 1989; REMS-managed access since 2015). It is not available as a long-acting injectable and must be administered orally; however, it is frequently used when other antipsychotics fail to control persistent positive symptoms, suicidality, or hostility. Comparative trials and meta-analyses suggest clozapine provides modest advantages for negative symptoms and functional outcomes relative to other SGAs.

The drug is available as scored tablets (12.5 mg, 25 mg, 100 mg, 200 mg), orally disintegrating tablets (ODT) 12.5–200 mg, and a 50 mg/mL oral suspension. Standard initiation begins with 12.5 mg once or twice daily to limit orthostatic hypotension, with 25–50 mg daily increases to reach 300–450 mg/day by the end of week two. Typical maintenance ranges from 300–600 mg/day divided twice daily, with some patients requiring up to 900 mg/day; doses beyond 600 mg/day increase seizure risk and require prophylaxis consideration. Clozapine may be taken with or without food, but patients should use a consistent routine to avoid variability in absorption. Therapeutic drug monitoring (TDM) is recommended, targeting a trough plasma concentration of 350 ng/mL (200–450 ng/mL minimum effective window) and noting that levels above ~600 ng/mL confer greater adverse effect burden without clear efficacy gains.

Clozapine’s efficacy is attributed to a unique receptor-binding profile: high affinity antagonism of dopamine D4 receptors, low transient occupancy of striatal D2 receptors (<60%), potent antagonism at serotonin 5-HT2A/5-HT2C, 5-HT6, 5-HT7, muscarinic M1–M5, histamine H1, and alpha-adrenergic receptors, and partial agonism at 5-HT1A. This balance is thought to drive robust antipsychotic effects while limiting extrapyramidal symptoms, yet it underlies characteristic adverse effects (e.g., metabolic changes, sialorrhea, orthostasis, constipation).

Clozapine is extensively metabolized in the liver, producing pharmacologically active norclozapine (N-desmethylclozapine) and inactive clozapine N-oxide. Norclozapine has partial agonist activity at muscarinic and 5-HT1A receptors and contributes to clinical response. With repeated dosing, clozapine reaches steady state in 7–10 days, whereas norclozapine may require 2–3 weeks because of its longer half-life. Peak plasma concentrations occur 2.5–3 hours post-dose, the apparent elimination half-life averages 12 hours after a single dose and extends to ~14–18 hours at steady state, while norclozapine’s half-life is ~30 hours.

Dosing & administration

Start 12.5 mg once or twice daily; increase by 25–50 mg/day as tolerated to 300–450 mg/day during weeks 1–2 (slower titration if orthostasis or sedation prominent).

Maintenance 300–600 mg/day divided twice daily; some patients require evening-heavy dosing to manage sedation. Doses above 600 mg/day raise seizure risk—consider valproate prophylaxis when >600 mg/day or plasma level >600 ng/mL.

Re-titration is required if dosing is interrupted for ≥48 hours to mitigate cardiovascular collapse.

Dose targets by clinical scenario

Treatment-resistant schizophrenia: Titrate to 300–600 mg/day; assess plasma level ≥350 ng/mL before declaring non-response.
Suicidality in schizophrenia/schizoaffective disorder: Use therapeutic-range dosing (≥350 ng/mL) with frequent monitoring during first 6 months.
Augmentation in schizoaffective or bipolar disorder (off-label): 300–500 mg/day; monitor mood destabilization and anticholinergic load.
Renal/hepatic impairment: Use slower titration and lower targets; monitor plasma levels closely.

Mechanism of action

Clozapine exerts antipsychotic effects through broad receptor antagonism. High serotonergic (5-HT2A/2C) and dopaminergic D4 affinity facilitate mesolimbic modulation with minimal nigrostriatal D2 blockade, explaining low EPS liability. Muscarinic M1 agonist/antagonist activity and alpha-adrenergic blockade underlie cholinergic rebound and orthostasis, while histamine H1 antagonism contributes to weight gain and sedation.

Norclozapine’s partial agonism at M1 and 5-HT1A receptors may enhance cognition and mood but also drives sialorrhea and constipation. The drug’s weak partial agonism at D2/5-HT1A adds to its atypical profile.

D4 antagonism (Ki ~10 nM) and transient D2 occupancy (<60%).
Potent 5-HT2A/5-HT2C antagonism supporting negative-symptom benefits.
M1–M5 muscarinic binding → anticholinergic spectrum (constipation, tachycardia) and cholinergic rebound if abruptly stopped.
H1 antagonism → sedation and weight gain.
Alpha1 and alpha2 blockade → orthostatic hypotension, tachycardia.

Metabolism & pharmacokinetics

Clozapine displays 27–60% bioavailability due to first-pass metabolism; food has minimal impact but consistent administration is advised. It is ~95% protein bound, with a mean volume of distribution ~1.6 L/kg. Metabolism is hepatic via CYP1A2 (primary), CYP3A4, and CYP2D6 to norclozapine and clozapine N-oxide; minor pathways include flavin monooxygenase and UGTs. Norclozapine is 70% protein bound and has ~30-hour half-life.

Steady state is typically achieved after 5–7 half-lives (~7–10 days for clozapine, 2–3 weeks for norclozapine). Smoking status markedly influences clearance: polycyclic aromatic hydrocarbons from tobacco induce CYP1A2, lowering plasma concentrations by 30–50%. Conversely, abrupt smoking cessation, strong CYP1A2 inhibitors (e.g., fluvoxamine), or systemic inflammation can double levels within days.

Renal elimination accounts for <5% unchanged drug; hepatic impairment increases exposure. Because of long metabolite persistence, therapeutic effects and adverse events may lag behind dose changes by 1–3 weeks.

Time to peak concentration (Tmax): 2.5–3 hours (tablets); ~1.5 hours (oral suspension)
Elimination half-life: Single dose ~12 h; steady state 14–18 h; norclozapine ~30 h
Steady state: Clozapine 7–10 days; norclozapine 14–21 days
Therapeutic trough range: Target ≥350 ng/mL (response probability rises to 500 ng/mL; adverse events >600 ng/mL)

Drug interactions

CYP1A2 is the dominant metabolic pathway: strong inhibitors (fluvoxamine, ciprofloxacin) can raise clozapine levels 2–3 fold, necessitating 30–50% dose reductions and urgent TDM. Smoking (CYP1A2 induction) halves plasma concentrations; advise level checks when patients start or stop tobacco or cannabis vaping.

CYP3A4 and CYP2D6 provide secondary metabolism; inducers (carbamazepine, phenytoin, rifampin) lower clozapine exposure and are generally contraindicated due to additive hematologic toxicity. Co-administration with other myelosuppressive or pro-arrhythmic agents (e.g., carbamazepine, ziprasidone) increases risk and should be avoided.

Clozapine is a substrate and weak inhibitor of P-glycoprotein; clinically significant P-gp interactions are uncommon, but caution is advised with narrow-therapeutic-index substrates (digoxin, dabigatran).

Mechanism	Agents / factors	Management
Strong CYP1A2 inhibition	Fluvoxamine, ciprofloxacin, enoxacin	Reduce clozapine dose by 30–50%, obtain trough within 3–5 days, monitor for seizures/myocarditis.
CYP1A2 induction	Tobacco smoke, carbamazepine, omeprazole (mild)	Expect lower levels; avoid carbamazepine (agranulocytosis risk); increase dose only with TDM guidance.
CYP3A4 induction	Rifampin, phenytoin, modafinil	Avoid when possible; if necessary, monitor levels twice weekly and titrate cautiously.
Additive myelosuppression	Carbamazepine, chloramphenicol, methotrexate	Contraindicated—select alternatives.
QTc prolongation	Ziprasidone, haloperidol IV, methadone	Baseline and follow-up ECG when combinations unavoidable; correct electrolytes.

Monitoring & safety checks

ANC (Absolute Neutrophil Count)
Baseline; weekly ×6 months → every 2 weeks ×6 months → monthly thereafter • Detect agranulocytosis early per FDA REMS requirements.
Metabolic panel (weight/BMI, waist, fasting lipids, glucose/A1c)
Baseline, 3 months, 6 months, then annually • High risk of weight gain, dyslipidemia, insulin resistance.
Blood pressure & heart rate
Each visit during titration, then quarterly • Monitor orthostatic hypotension and tachycardia.
Troponin & CRP
Baseline and weekly for first 4 weeks if clinically indicated • Early detection of myocarditis/cardiomyopathy.
TDM (trough plasma level)
At steady state, then as needed for efficacy/adverse effects • Verify ≥350 ng/mL exposure and adjust for smoking or interacting drugs.
Bowel function assessment
Every visit • Prevent fatal gastrointestinal hypomotility.
Seizure risk review
Baseline and when dose >600 mg/day or level >600 ng/mL • Dose-dependent seizure risk.

Enroll every patient in the Clozapine REMS program; dispensing without REMS compliance is prohibited.

Educate patients about myocarditis warning signs (fever, chest pain, dyspnea) during the first month.

Discontinuation guidance

Avoid abrupt cessation unless severe neutropenia, myocarditis, or other life-threatening adverse events occur. Taper over at least 1–2 weeks to limit cholinergic rebound, catatonia, and rapid psychotic relapse.

If urgent discontinuation is required, initiate cholinergic mitigation (e.g., short-term anticholinergics or low-dose benzodiazepines) and monitor closely for decompensation; plasma levels decline by ~50% within 1 week, but clinical deterioration may lag.

Special populations

Pregnancy: limited data suggest no major teratogenicity, but neonatal adaptation syndrome and floppy infant syndrome have been reported; weigh maternal benefit vs. fetal risk and monitor for gestational diabetes.

Older adults: start 6.25 mg once daily, titrate slowly, and monitor for falls, anticholinergic burden, and myocarditis/myocardial infarction.

Hepatic impairment: baseline LFTs and slower titration; discontinue if hepatitis or significant transaminase elevation occurs.

Renal impairment: active metabolites accumulate; consider lower targets and closer TDM.

Key adverse effects

Very common: sialorrhea, sedation, weight gain, constipation, tachycardia.

Serious risks: agranulocytosis (~0.4% lifetime risk under REMS), myocarditis/pericarditis (highest during first month), cardiomyopathy, seizures (dose related), severe gastrointestinal hypomotility, diabetic ketoacidosis.

Mitigation strategies include aggressive bowel regimens, metabolic monitoring, seizure prophylaxis when plasma levels exceed 600 ng/mL, and rapid evaluation of infectious symptoms or chest pain.

References

Clozapine Tablets USP – Prescribing Information — FDA/Teva Pharmaceuticals (2023)
Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018) DOI: 10.1007/s00213-017-4813-7
Clozapine Concentration–Response Relationships — CNS Drugs (2018) DOI: 10.1007/s40263-018-0538-6
Clozapine for treatment-resistant schizophrenia: systematic review and meta-analysis — CNS Drugs (2016) DOI: 10.1007/s40263-016-0382-1

Educational use only — verify details in the Clozapine REMS materials, current prescribing information and authoritative clinical guidelines before making prescribing decisions.