Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold?

Rationale: Clozapine levels are advocated in the monitoring of patients on this drug and have now been used for a number of years. A safety-related threshold has also been proposed, as well as therapeutic lower and upper thresholds. While there has been reasonable consensus regarding a lower therapeutic threshold, this is not the case for the upper thresholds.

Objectives: Our aim was to review available evidence related to upper thresholds.

Methods: We carried out an electronic search of different databases and a manual search of articles between 1960 and 2011, cross-referencing the following terms with clozapine-interactions, monitoring, pharmacokinetics, plasma levels, serum levels, and toxicity.

Results: Sixty-nine articles met our search criteria and these could be divided into reviews (11), studies (24), and case reports (35). Study quality was evaluated, and none met criteria for a prospective, randomized controlled trial specifically addressing higher plasma levels, e.g., >500 ng/ml. Case reports emphasize in particular the impact of interactions, e.g., antidepressants and smoking. There is clear evidence indicating a dose-related increased risk of seizures, at least to 500-600 mg/day, but a lack of data to suggest such a relationship between plasma levels, dose, and side effects linked to safety, e.g., seizures, myocarditis, and agranulocytosis. The very limited evidence addressing an upper threshold related to clinical response suggests a "ceiling effect" in the range of 600-838 ng/ml.

Conclusions: It appears that the current safety-related threshold is not supported by evidence. There may be an upper threshold for clinical response, beyond which chance of response falls off, although further studies are warranted.