Clozapine Monitoring
Neutrophils
Risk of neutropenia peaks at two months. After two years, the risk is negligible, around 0.001%. In line with these figures, guidelines recommend tapering down from weekly to monthly neutrophil monitoring after 18 weeks and then to annual checks after two years.
The cut-offs for absolute neutrophil count (ANC) are different for the general population and patients with benign ethnic neutropenia (BEN), a condition of normal-low neutrophils more common in people of African, Caribbean, Middle Eastern, and West Indian descent.
During treatment, if the ANC falls below 1.0 ×10⁹/L (or 0.5 × 10⁹/L in BEN), stop clozapine immediately. If the ANC falls between 1.0-1.5 ×10⁹/L (or 0.5-1.0 × 10⁹/L in BEN), increase monitoring to twice a week.
If these abnormal levels occur after two years on clozapine, consider alternative causes before stopping it, such as infections or other medication toxicities. Part of the reason for checking the complete blood count after two years is to screen for blood cancers. These are slightly more common on clozapine (61 vs 41 cases per 100,000 person-years).
Cardiac
Just as lamotrigine can inflame the skin, clozapine can cause potentially fatal cardiac inflammation in the first two months of treatment, resulting in myocarditis, pericarditis, or cardiomyopathy. Monitoring for this reaction depends on the setting. Ideally, check the high-sensitivity troponin and C-reactive protein (CRP) along with the ANC labs every week for 4-8 weeks. At follow-up visits, check postural blood pressure (for hypotension), heart rate, temperature, and peripheral oxygen saturation for 4-8 weeks. Check an ECG at least once, between weeks 2-4, or twice if able to (at weeks 2 and 4).
Metabolic Monitoring
Clozapine is among the antipsychotics with the highest metabolic risks, and the recommendations for monitoring are similar for others in this class. Check fasting glucose, lipids, and hgba1c at 3 months, 6 months, then annually. Monitor weight and waist circumference
Serum Levels
After stabilizing the dose, check serum levels annually or as indicated by symptoms, a change in smoking status, or drug interactions. Aim for levels between 200-300 ng/ml2, and higher (350-450 ng/ml2) if insufficient response. Avoid levels above 600 ng/ml2, which can cause seizures, arrhythmias, and delirium.
Most laboratories return the levels of clozapine and its metabolite, norclozapine, which is produced through CYP1A2. Strong inducers of this enzyme will increase the ratio of the metabolite (eg, smoking, omeprazole, carbamazepine, St John’s wort), while strong inhibitors will raise clozapine levels and reduce the metabolite (eg, fluvoxamine). Besides altering the therapeutic response, higher levels of norclozapine are associated with more adverse effects on the antipsychotic.
Restarting
When patients stop clozapine for more than 30 days, whether due to nonadherence or other factors, the risks return. Titrate the medication with the original schedule and restart the monitoring at week zero. If they stop the medication for more than 2 days but less than 30 days, the decision to retitrate and restart the monitoring depends on their risk level, such as whether they had previous cardiac or ANC problems.