Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients

Abstract

These findings indicate a possible link between CYP activity and response to clozapine that is not mediated through differences in serum concentrations. No clinically meaningful pattern in serum parameters could be identified that differentiates responders from non-responders. Thus, clozapine TDM seems ineffective for predicting clinical response. Smoking behavior is a major determinant of clozapine clearance while CYP2D6 genotype does not impact clozapine disposition.

Clozapine-induced Agranulocytosis and Hereditary Polymorphisms of Clozapine Metabolizing Enzymes: No Association with Myeloperoxidase and Cytochrome P4502D6

“…Moreover, one could argue that the hypothesized link between CYP2D6 activity by altering physiological clozapine metabolism and CA may be only weak, as in vitro and in vivo studies have revealed that CYP1A2 and CYP3A4 appear to be the principal enzymes involved in clozapine metabolism. Indeed, we found no associations between CYP2D6 genotype, clozapine and clozapine metabolite serum concentrations in a clozapine-TDM study of clozapine treated patients without CA [8]. However, this does not rule out a minor involvement of 2D6 in the development of idiosyncratic drug reactions.…”

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

“…In a recent study by Weiner et al (2004) showed that higher NDMC/clozapine ratios predicted greater improvement in subscales of quality of life measures, multiple measures of cognition as well as in some subscales of negative symptomatology and also predicted improvement in delusions, but not hallucinations. However, not everyone finds a positive impact of higher NDMC/ clozapineFeven this measure has met with conflicting findings in terms of clinical response to clozapine treatment ranging from no correlation (Dettling et al, 2000;Mauri et al, 2004) to a positive one (Hasegawa et al, 1993;Spina et al, 2000;Frazier et al, 2003;Mauri et al, 2003;Weiner et al, 2004). Thus, while one can only draw indirect inferences from mixed NDMC/clozapine studies, there are some hints that NDMC may be contributing additional anti 'psychotic' or pro-cognitive efficacy via its muscarinic effects.…”

“…At the muscarinic receptors, NDMC differs from clozapine by being a more potent partial agonist at M 1 receptors and also shows increased agonist efficacy at M 4 and M 5 receptors (Weiner et al, 2004). The interest in a therapeutic role for NDMC has been highlighted by recent findings that high NDMC/clozapine ratios predict improvement in cognitive functioning and quality of life better than plasma levels of either compound alone (Weiner et al, 2004) though, not all previous studies have found positive benefits of a high NDMC/clozapine ratio (Dettling et al, 2000;Mauri et al, 2004). Also the recent identification of NDMC as a partial agonist at the D 2 receptor has raised considerable interest in its possible role as an antipsychotic (Burstein et al, 2005) as aripiprazole, a recently introduced partial-agonist D 2 antipsychotic, has been found to be effective, safe, and well tolerated for positive and negative symptoms in schizophrenia and schizoaffective disorder (Potkin et al, 2003).…”

Pharmacogenetics for the Individualization of Psychiatric Treatment

“…[53] However, several studies have failed to find clear association between drug metabolism and therapeutic response. [54][55][56] More importantly, CYP2D6 variants have been related to abnormal movements observed during neuroleptic treatment, [57] and CYP2D6 and CYP1A2 alleles have been associated with drug induced tardive dyskinesia in schizophrenic patients. [58,59] In view of the adverse reactions caused by deficient drug metabolism, previous knowledge of a patient's metabolic status and drug pharmacokinetics are vital to avoid such responses.…”