The clinical utility of therapeutic drug monitoring for clozapine

To the Editor

Therapeutic drug monitoring (TDM) has been well established in psychiatric practice for many years, most notably for tricyclic antidepressants, lithium and sodium valproate for acute mania (Lopez and Kane, 2013). The Royal Australian and New Zealand College of Psychiatrists (RANZCP) guidelines for schizophrenia (Galletly et al., 2016) mentions the role of clozapine serum-level monitoring, mainly in the context of changes in smoking behavior, as clozapine levels can increase markedly following abrupt smoking cessation, leading to dose-dependent side effects. In this correspondence, we would like to add some additional clinical points in relation to the potential value of clozapine TDM. Clozapine levels should generally be measured at least a week after a stable clozapine dose has been reached, as a trough level. It is important to specifically note that there are significant differences between individuals with respect to clozapine absorption and metabolism, which will then impact on clozapine serum levels. There are also ethnic differences, which will affect clozapine metabolism and clozapine dose. There is evidence that above clozapine serum levels of 600 µg/mL, seizures are more likely (Lopez and Kane, 2013), with some consideration for prophylactic antiepileptic use, to prevent seizures. There is evidence that Clozapine levels above 600 μg/mL can increase risk of seizures (Lopez and Kane, 2013), and in such cases prophylactic antiepileptics should be considered. It is also known that certain serotonin-specific reuptake inhibitor (SSRI) medication like fluvoxamine can increase clozapine levels, through inhibition of cytochrome P450 (CYP) 1A2.

Clozapine serum-level monitoring can also be useful to assess clinical efficacy, in addition to monitoring for side effects and toxicity (Lopez and Kane, 2013). Spina et al. (2000) identified that plasma clozapine levels between 350 and 400 µg/mL were significantly associated with improved clinical response rates for patients with schizophrenia, but these blood levels also significantly increased side-effect burden. Therefore, when psychiatrists are faced with clozapine non-responsive patients with schizophrenia, the first suggested step would be to measure clozapine serum levels, aiming for between 350 and 400 µg/mL (Spina et al., 2000), if clozapine side effects can be tolerated. This would be a recommended strategy before adding a second antipsychotic medication. TDM is particularly important in differentiating between psychotic symptoms due to either break-through psychosis or non-compliance with clozapine. Break-through psychosis due to non-response at maintenance clozapine doses will possibly require an increased dose of clozapine, while non-compliance to clozapine will generally require re-initiation of the usual maintenance clozapine dose.

At this stage, beyond clozapine, there is only limited evidence for regular TDM for other second-generation antipsychotic medication (Lopez and Kane, 2013).