Blood Test for Therapeutic Plasma Levels of Clozapine
The blood test for measuring therapeutic clozapine levels is a trough plasma or serum clozapine concentration, drawn immediately before the next scheduled dose (typically 12 hours after the last dose for twice-daily dosing). 1
Specimen Type and Collection
- Either serum or plasma can be used interchangeably for clozapine therapeutic drug monitoring, as both matrices provide clinically equivalent results with high correlation (r = 0.996) 2
- Plasma samples can be collected using either K3EDTA or lithium heparin anticoagulant tubes, with no practical differences in drug stability or measurement precision 2
- The difference between serum and plasma concentrations is minimal (approximately 7% higher in serum, reduced to 3% when corrected for hematocrit), making results transferable between specimen types 2
Timing of Sample Collection
- Trough levels must be obtained immediately before the next dose to provide the most consistent and reliable measurement of clozapine concentration 1
- For establishing therapeutic adequacy, measure trough levels on at least two separate occasions separated by at least one week while the patient is on a stable dose 1
- Trough sampling is critical because it helps establish both medication adherence and therapeutic efficacy, as non-trough samples may falsely elevate results 1, 3
Therapeutic Target Range
- The therapeutic threshold is ≥350 ng/mL (or 350-420 ng/mL range), with this level associated with significantly higher response rates in treatment-resistant schizophrenia 1, 4, 5
- The optimal therapeutic range is 350-550 ng/mL, balancing efficacy with safety 1, 6
- Levels above 550 ng/mL show diminishing returns (number needed to treat = 17) and substantially increased seizure risk 1, 6
- Approximately 40% absolute risk reduction in non-response occurs when levels exceed 350 ng/mL compared to lower concentrations 4
Clinical Interpretation Considerations
- Wide interpatient variability exists: at prescribed doses of 850 mg/day or higher, 23.3% of patients still have levels below 350 ng/mL, while 1.2% of patients on doses ≤150 mg/day have levels >1.0 mg/L 3
- Clozapine was undetectable (<0.01 mg/L) in 1.5% of samples across all dose ranges, indicating non-adherence 3
- The clozapine:norclozapine ratio provides additional information—a ratio >2 suggests either a non-trough sample or saturation of N-demethylation at higher concentrations 3
- Young male smokers often require doses exceeding 900 mg/day to achieve therapeutic levels due to enhanced metabolism 4
Common Pitfalls to Avoid
- Not obtaining true trough samples—blood drawn at incorrect times will overestimate steady-state levels and lead to inappropriate dose adjustments 1
- Failing to account for adherence—trough measurements help identify covert non-adherence, and unannounced blood tests may be more representative in suspected cases 1
- Single measurement decisions—at least two measurements one week apart are needed to confirm stable therapeutic levels 1
- Ignoring smoking status—smoking significantly affects clozapine metabolism, and changes in smoking habit require dose adjustment and repeat level monitoring 3