Clozapine administered once versus twice daily: does it make a difference?

Clozapine, generally considered to be the most effective antipsychotic, is the gold standard for treatment-resistant schizophrenia. With a relatively short half-life of 12h and a very quick dissociation rate from the dopamine D2 receptor, pharmacokinetic and pharmacodynamics principles would dictate that clozapine be administered twice daily. However, due to clozapine's side effects (e.g., sedation), it is often prescribe once daily at bedtime. Even if the patient develops tolerance to the side effects, it is still often prescribed once daily to simplify medication regimens in hopes of increasing adherence. Unfortunately, good intentions and convenience do not always make for optimal pharmacotherapy. Based upon clozapine's pharmacokinetic and pharmacodynamic profiles, we hypothesize that optimal treatment with clozapine requires it be given twice daily rather than once daily. We present here some pharmacokinetic simulations and published data to support our hypothesis.