Maximum Clozapine Dose
The maximum licensed dose of clozapine is 900 mg/day in most countries, though doses up to 1400 mg/day may be necessary in select patients—particularly young male heavy smokers—when therapeutic plasma levels cannot be achieved at standard dosing. 1
Standard Maximum Dosing
- The typical maximum recommended dose is 900 mg/day in the UK and most jurisdictions 1
- In the United States, daily doses of 300-600 mg/day are commonly recommended for average metabolism 2
- The median dose used in clinical practice is 300 mg/day, with patients experiencing adverse reactions typically on 250 mg/day 3
When Higher Doses May Be Required
Ultra-rapid metabolizers may require doses exceeding the standard maximum:
- Young male heavy smokers may need up to 1400 mg/day to achieve therapeutic plasma levels due to rapid clozapine clearance 1
- Doses greater than 900 mg/day are rarely justified in women 1
- Anyone receiving ≥600 mg/day requires regular monitoring for adverse events and changes in smoking habits 1
Therapeutic Target Levels Guide Dosing
Dose titration should target plasma levels of 350-550 ng/mL rather than focusing solely on mg/day dosing:
- The therapeutic threshold is ≥350 ng/mL for treatment-resistant schizophrenia 4, 5, 6
- The optimal therapeutic range is 350-550 ng/mL 5, 6
- If positive symptoms persist after 12 weeks at therapeutic levels, doses can be increased to achieve concentrations up to 550 ng/mL 5, 6
- Concentrations above 550 ng/mL show decreased efficacy (NNT=17) and significantly increased seizure risk 5, 6
Critical Safety Considerations at Higher Doses
Seizure risk increases substantially with higher plasma concentrations:
- Grand mal seizures occur in 0.183% of patients overall 3
- Risk increases particularly with rapid dose changes and plasma levels above 550 ng/mL 5
- Prophylactic lamotrigine should be considered when using concentrations above 550 ng/mL 5, 6
Other dose-related adverse effects:
- Delirium (0.180%), increased liver enzymes (0.120%), and agranulocytosis (0.107%) are the most frequent severe adverse reactions 3
- Paralytic ileus carries an 18.75% mortality rate when it occurs 3
- Pre-existing organ system damage is the main risk factor for adverse drug reactions 3
Ancestry-Based Dosing Adjustments
Maximum therapeutic doses vary significantly by ancestry and metabolic factors:
- Asian ancestry or indigenous peoples of the Americas with average metabolism: 175-300 mg/day 2
- European/Western Asian ancestry with average metabolism: 250-400 mg/day 2
- US patients (non-Asian ancestry) with average metabolism: 300-600 mg/day 2
- Obesity or valproate co-prescription reduces required doses by approximately 50% across all ancestry groups 2
Monitoring Requirements at Maximum Doses
- Measure trough clozapine levels on at least two occasions separated by one week at stable dosing 5
- Monitor for signs of toxicity including sedation, hypotension, tachycardia, seizures, myoclonus, and delirium 4
- Baseline and weekly C-reactive protein (CRP) monitoring for at least four weeks to identify inflammation 2
- Regular assessment for changes in smoking status, which dramatically affects clozapine metabolism 1