{Reference Type}: Journal Article {Title}: Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies. {Author}: Ruan CJ;Olmos I;Ricciardi C;Schoretsanitis G;Vincent PD;Anıl Yağcıoğlu AE;Eap CB;Baptista T;Clark SR;Fernandez-Egea E;Kim SH;Lane HY;Leung J;Maroñas Amigo O;Motuca M;Every-Palmer S;Procyshyn RM;Rohde C;Suhas S;Schulte PFJ;Spina E;Takeuchi H;Verdoux H;Correll CU;Molden E;De Las Cuevas C;de Leon J; {Journal}: Schizophr Res {Volume}: 268 {Issue}: 0 {Year}: 2024 Jun {Factor}: 4.662 {DOI}: 10.1016/j.schres.2023.07.002 {Abstract}: BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable.
METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study.
RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11).
CONCLUSIONS: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).