Clozapine (Clozaril)

Second generation antipsychotic (dopamine, serotonin, norepinephrine receptor antagonist (dopamine D2, serotonin 5-HT2, norepinephrine alpha-2))

Dosing

25mg 1 hs x7, 2 hs x7, 3 hs x7, then 100mg x7, then 200 mg hs if tolerating. Can raise faster if urgent (though risk of hypotension). Target based on symptoms, though ideal blood level > 350.

INTERACTIONS: Metabolized by 1A2. Fluvoxamine raises it 3x, but you can use this as a strategy to improve tolerability (because it blocks the formation of the metabolite responsible for side effects, norclozapine). After stabilizing the clozapine dose, check level. Then lower clozapine (divide dose by 3) and add fluvoxamine 50 mg/d. Recheck clozapine serum levels 2 weeks later. Do not use this strategy if manic risk.

Management

Use after 2 failed antipsychotic trials. Chance of responding is 80% if started in first 3 years of illness, but 30% if started later. Useful for problematic aggression, suicidality, and tardive dyskinesia. Can use in treatment resistant bipolar if patient has frequent manic/psychosis. Clozapine leads to fuller recoveries and longer lives (by 10 years) compared to other antipsychotics.

Monitor CBC: Weekly for 6 mth, Every 2 weeks for 6 mth, then monthly (if no interruptions). Stop clozapine for WBC<3 or ANC<1.5; increase monitoring frequency if WBC<3.5, ANC<2. Raise by 2x if using with carbamazepine.

To improve efficacy and tolerability, can add fluvoxamine 50 mg/d (see above).

TOLERABILITY: Weight gain, sedation, anticholinergic, drooling (use rubber pillow). Monitor and treat constipation on it aggressively, starting with peri-colace.

RISKS: Neutropenia (1:100 risk if not monitored), metabolic, orthostasis (falls), cardiotoxicity, QTc prolongation, seizures, severe constipation (potentially fatal).

No risk of TD. Little-to-no risk of prolactinemia, akathisia, EPS.

EMR Text