clozapine

General Information

Clozapine (brand Clozaril, owned by Novartis/Sandoz) is a second-generation antipsychotic (SGA). Clozaril refers to the oral tablet; two additional branded formulations—FazaClo (an orally disintegrating tablet, or ODT) and Versacloz (an oral suspension)—support patients who cannot swallow standard tablets.

ODTs dissolve on the tongue without water, which aids adherence when swallowing is difficult. Oral suspensions are liquid formulations measured with an oral syringe so clinicians can titrate doses with finer precision.

In 1989 the FDA approved clozapine for treatment-resistant schizophrenia (TRS) or for intolerable motor side effects with other antipsychotics. TRS typically means two adequate antipsychotic trials have not delivered meaningful symptom reduction, and clozapine remains the only antipsychotic specifically approved for this population.

Early agranulocytosis reports—most notably eight Finnish deaths in 1975—delayed U.S. adoption and led to mandatory blood monitoring when clozapine launched. Effective June 2025 the FDA discontinued the U.S. clozapine REMS program, so ANC monitoring is now clinician-guided rather than tied to a dispensing registry, though vigilance for neutropenia is still prudent.

Clozapine gained a 2002 indication to reduce recurrent suicidal behavior in schizophrenia or schizoaffective disorder and is recommended in APA guidelines when persistent aggression or suicidality endures despite other antipsychotics.

A 2025 Finland/Sweden register study found clozapine use was associated with lower psychiatric hospitalization versus other oral antipsychotics across schizophrenia-spectrum disorders and several affective disorders (including bipolar disorder and psychotic depression), without evidence of increased mortality; borderline personality disorder did not show benefit.

The clozapine compare view, the clozapine evidence feed, and the clozapine print page can support care discussions; the schizophrenia hub and bipolar disorder hub include related longitudinal pathways when suicidality or aggression persists.

Multiple manufacturers (Teva, Hikma, Sun, Aurobindo, Accord, Apotex, Mylan/Viatris, among others) supply generic tablets and ODTs; Versacloz 50 mg/mL oral suspension remains brand-only in the United States.

Tablets ship in 12.5, 25, 50, 100, and 200 mg strengths; FazaClo ODTs are 12.5, 25, 100, 150, and 200 mg; Versacloz provides 50 mg/mL in 120 mL bottles. No long-acting injectable formulation exists—patients needing depot support must transition to an LAI antipsychotic.

Despite unmatched efficacy for treatment-resistant schizophrenia and suicidality, clozapine use remains modest—roughly 5–6% of U.S. outpatient antipsychotic prescriptions in 2023—because of historical REMS logistics, close follow-up requirements, and side effects such as sialorrhea. Utilization is higher in specialty early-psychosis and clozapine clinics, and many experts advocate considering clozapine earlier rather than waiting for two failed antipsychotic trials.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Clozapine displays broad receptor activity that stabilizes dopamine and serotonin signalling while moderating histaminergic, adrenergic, and muscarinic pathways.

Low-to-moderate D2 antagonism with higher D4 affinity and rapid dissociation reduces extrapyramidal symptoms; potent 5-HT2A/5-HT2C antagonism and 5-HT1A partial agonism modulate dopamine release and mood, while α1 and H1 antagonism explain orthostasis and sedation and muscarinic blockade drives anticholinergic effects.

• Strong antagonist at serotonin 5-HT2A/5-HT2C/5-HT6 and dopamine D4 receptors with relatively fast-off D2 binding.
• Partial agonist at serotonin 5-HT1A receptors, supporting mood and anxiety benefits.
• Antagonist at adrenergic α1 and histamine H1 receptors, contributing to orthostasis and sedation.
• Broad muscarinic (M1–M5) antagonism leading to anticholinergic effects.

Metabolism and Pharmacokinetics

• Oral bioavailability is roughly 27–60%; high-fat meals may delay the ~2.5 hour Tmax without materially altering exposure.
• Highly distributed (≈95% protein bound; apparent volume of distribution 1.6–7 L/kg).
• Metabolized hepatically via CYP1A2 (major) with CYP3A4 and CYP2D6 contributions; norclozapine is the principal active metabolite.
• Smoking induces CYP1A2 and lowers exposure; abrupt smoking cessation or acute infection can rapidly increase serum concentrations.
• Parent half-life ≈12 hours at steady state (range 8–16 hours); norclozapine half-life ≈14 hours.
• Eliminated predominantly in urine and feces as metabolites; consider norclozapine when interpreting therapeutic drug monitoring results.

Dosing and Administration

• Initiate 12.5 mg once or twice on day 1; increase by 25–50 mg/day in divided doses as tolerated.
• Typical maintenance is 300–450 mg/day in divided doses; some patients require up to 600 mg/day. The labeled maximum is 900 mg/day.
• Therapeutic drug monitoring: trough clozapine + norclozapine ≥350 ng/mL often correlates with response, whereas >600 ng/mL increases seizure risk.
• If therapy is interrupted for ≥48 hours, restart with a slow titration; counsel patients that smoking changes or intercurrent infections may necessitate urgent serum level checks.

Monitoring & Labs

• ANC monitoring: Weekly for first 6 months, every 2 weeks for months 6–12, then monthly thereafter per label.
• Metabolic: Track weight/BMI and fasting lipids/glucose at baseline, 3 months, then periodically.
• Clinical: Monitor for infection; inflammation or smoking changes can alter serum levels.
• Early myocarditis vigilance: Follow local guidance (some protocols include troponin/CRP during initial weeks).

Sources: FDA/DailyMed labeling; consensus monitoring schedules.

Adverse Effects

Interactions

• CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) markedly raise levels—dose reduction and monitoring (clinical response or serum concentrations) are typically needed.
• CYP1A2 inducers (smoking, carbamazepine, omeprazole, rifampin) lower exposure—co-use is generally avoided when possible; if unavoidable, dose adjustments with monitoring are common.
• CYP3A4/CYP2D6 modulators (ketoconazole, paroxetine) alter clozapine and norclozapine concentrations; adjust doses as needed.
• Concomitant CNS depressants (benzodiazepines, opioids, alcohol) increase sedation and respiratory risk—slower initiation and closer monitoring are typical.
• QTc-prolonging agents warrant ECG monitoring, especially in patients with additional cardiac risk factors.
• Strong anticholinergics or opioids heighten gastrointestinal hypomotility risk; bowel function monitoring is emphasized.
• Bone marrow suppressants compound neutropenia risk—avoid combinations when feasible.

Other Useful Information

• Lifestyle changes such as smoking cessation, sudden illness (particularly respiratory infections), or major caffeine shifts can markedly alter serum levels—patients are often counseled to report changes promptly.
• Bowel and sialorrhea strategies are often started proactively to improve adherence and prevent serious gastrointestinal complications.
• Monitor weight, waist circumference, fasting lipids, glucose, and HbA1c regularly; baseline cardiac assessment is often obtained during the initial months of therapy.
• Counseling often covers seizure warning signs, infection symptoms, and when to seek urgent evaluation.

References

1. CLOZARIL (clozapine) label — DailyMed (2025)
2. FDA removes Clozapine REMS — FDA (2025)
3. Transdiagnostic Effectiveness AND Safety OF Clozapine IN Individuals With Psychotic, Affective, AND Personality Disorders: Nationwide AND Meta Analytic Comparisons With Other Antipsychotics — Lancet Psychiatry (2025)
4. Nssc Clozapine First 2021
5. Everypalmer2017 Cigh
6. Cohen2017 Clozapine GIH
7. Himmerich2021 Clozapine Guidance