Clozapine Dosing: Split Dosing is Preferred
For patients with treatment-resistant schizophrenia, clozapine should be administered in split (divided) doses rather than as a single nightly dose to minimize the risk of orthostatic hypotension, bradycardia, syncope, and seizures.
Rationale for Split Dosing
Safety Considerations from FDA Labeling
- The FDA explicitly recommends divided dosing to minimize cardiovascular risks, particularly orthostatic hypotension, bradycardia, and syncope, which are highest during initial titration and with rapid dose escalation 1
- Seizure risk is dose-related and can be reduced through divided dosing, as the risk increases with peak plasma concentrations 1
- The FDA mandates starting at 12.5 mg once or twice daily, with gradual titration using divided doses throughout treatment 1
Pharmacokinetic Rationale
- Split dosing reduces peak plasma concentrations, which directly correlates with reduced seizure risk—a critical safety concern as seizure risk increases significantly above plasma levels of 550 ng/mL 2, 3
- Divided dosing helps maintain more stable plasma levels throughout the day, avoiding the high peaks associated with single daily dosing that can trigger adverse cardiovascular events 1
Practical Dosing Algorithm
Initial Titration Phase
- Start at 12.5 mg once or twice daily 1
- Increase by 25-50 mg per day in divided doses if well-tolerated 1
- Target 300-450 mg per day (in divided doses) by end of 2 weeks 1
Maintenance Phase
- Continue divided dosing even at maintenance doses to sustain the cardiovascular and seizure safety benefits 1
- The typical therapeutic range of 300-450 mg/day should be split into 2-3 doses throughout the day 1
High-Dose Scenarios
- For doses ≥600 mg/day, divided dosing becomes even more critical due to enhanced seizure risk 2
- Consider prophylactic lamotrigine if plasma levels exceed 550 ng/mL, which is more likely with single daily dosing 2, 3
Common Pitfall to Avoid
- Do not switch to single nightly dosing once the patient is stable—the cardiovascular and seizure risks persist throughout treatment, not just during titration 1
- Even patients on low maintenance doses (e.g., 12.5 mg twice daily) benefit from split dosing, as orthostatic hypotension and syncope can occur with doses as low as 12.5 mg per day 4, 1
Special Populations
- Patients with cardiovascular disease, cerebrovascular disease, or conditions predisposing to hypotension (dehydration, concurrent antihypertensive use) require particular caution and should definitely receive divided dosing 1
- Patients with seizure history or risk factors (CNS pathology, medications lowering seizure threshold, alcohol abuse) must use divided dosing 1