A Chinese medicine called Danggui Longhui may be a new clinically relevant clozapine inducer: Two case reports identified by therapeutic drug monitoring.

BACKGROUND: Danggui Longhui is a traditional Chinese medicine made from the dried root of Angelica sinensis. It is used in psychiatric patients in China to reduce associated constipation. In a population pharmacokinetic model in olanzapine patients from Beijing Anding Hospital, we demonstrate that dangguilonghui tablets doubled olanzapine clearance, indicating the induction of olanzapine metabolism. Olanzapine metabolism is similar to clozapine metabolism. METHODS: Two cases of possible clozapine induction using dangguilonghui tablets 4 g/day were identified in Beijing Anding Hospital. Dividing the minimum therapeutic concentration of 350 ng/mL by the concentration-to-dose (C/D) ratio provides the minimum therapeutic dose. RESULTS: Case 1 was a female smoker on clozapine for 415 days. The mean of 6 clozapine C/D ratios associated with smoking provided a minimum therapeutic dose of 267 mg/day. There were 6 steady-state concentrations on the combination of valproic acid and dangguilonghui tablets, which provided a much higher minimum therapeutic dose of 833 mg/day. Four steady-state clozapine C/D ratios based on smoking and valproate after 4 months of carbamazepine 200 mg/day provided a minimum therapeutic dose of 603 mg/day. Case 2 was a female non-smoker on clozapine for 58 days. She had 3 clozapine C/D ratios on dangguilonghui tablets with a mean of 0.30 ng/mL providing a minimum therapeutic dose of 1167 mg/day. CONCLUSION: Future clinical studies with repeated measures need to replicate the possibility that dangguilonghui tablets are a moderate-to-strong inducer of clozapine metabolism as suggested by these two limited cases.

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.

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). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).

Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs.

A brief history of clozapine in China with a look forward.

Clozapine was first manufactured in China in 1976. Clozapine is currently used not only for treatment-refractory schizophrenia (TRS), but also continues to be used in the treatment of patients with non-TRS and other mental disorders; moreover, low-dose clozapine is also used in sedative-hypnotic therapy and in combination with other drugs. There is need for studies in China using various titrations and assessing their risk for myocarditis and aspiration pneumonia. The Chinese clozapine package insert will also greatly benefit from these changes.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Clozapine-induced myocarditis in children and adolescents: a pharmacovigilance study using VigiBase and a systematic literature review.

INTRODUCTION: Clozapine-induced myocarditis in children (age ≤18 yo) was studied from a PubMed search (18 July 2022) (9 cases) and from the World Health Organization's pharmacovigilance database, called Vigibase, of adverse drug reaction (ADR) reports (72 non-duplicated cases). VigiBase uses a logarithmic measure of disproportionality called the information component (IC). A logistic regression model of presence/absence (40/32) of seriousness in VigiBase was developed. AREAS COVERED: VigiBase provided a significant myocarditis IC = 4.2 with an IC025 = 3.8; only 4 clozapine-induced myocarditis cases were expected, while 72 were observed. The PubMed search identified 9 cases, while VigiBase identified 72 cases (of which 67 did not overlap with published cases). These 76 combined cases included 35 doubtful (most with missing information on the day of diagnosis), 19 possible and 22 probable, according to the ADR scale. After adjusting for confounders, quetiapine increased the risk of seriousness with an odds ratio (OR) of 17.6 (95% confidence interval CI, 1.56 to 198.6), while Australian origin decreased it with an OR = 0.13 (CI, 0.04 to 0.47). EXPERT OPINION: These 41 cases of at least possible clozapine-induced myocarditis indicated that this ADR can definitively occur in children, particularly in the first 30 days of up-titration. Children's and adult cases appeared similar.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries.

INTRODUCTION: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. METHODS: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. RESULTS: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005-IC995=5.9-6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. CONCLUSIONS: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries / Miocarditis asociada a la clozapina en la base de datos de farmacovigilancia de la Organización Mundial de la Salud: atención a los reportes de los diferentes países

Introduction: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. Methods: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. Results: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005–IC995=5.9–6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. Conclusions: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies. (AU)

Introducción: La incidencia de la miocarditis asociada a clozapina varía en cada país, y esta variación se exploró en VigiBase™, la base de datos de la Organización Mundial de la Salud con más de 25 millones de reportes de reacciones adversas a medicamentos de 145 agencias nacionales de medicamentos. Métodos: El 15 de enero del 2021, se llevó a cabo una búsqueda en VigiBase™ de las miocarditis y clozapina. El componente de información (CI) que es una medida logarítmica de desproporción se usó para estudiar los 3.752 reportes. Con modelos de regresión logística se estudió 3.274 pacientes diferentes después de eliminar los duplicados. Resultados: El primer caso fue publicado en 1980, pero desde 1993 el CI ha sido significativo; ahora es muy alto (CI=6,0; CI005-CI995=5,9-6,1), y estadísticamente significativo de otros antipsicóticos. En los 3.274 pacientes: el 43,4% de los casos fueron no graves, el 51,4% fueron casos graves, pero no letales y el 4,8% fueron casos letales. Australia contribuyó a más de la mitad de los casos (1.621/3.274): con un 69,2% de casos no graves, un 27,7% de casos graves, pero no letales y un 3,1% de casos letales. Cuarenta y un casos fueron de países de Asia. Conclusiones: Los factores de confusión pueden explicar asociaciones estadísticas pero el tamaño y la consistencia de estos resultados son compatibles con que la miocarditis está definitivamente asociada con el tratamiento inicial de la clozapina (el 84% [1.309/1.560] fueron durante el primer mes y otro 5% [82/1.560] durante el segundo). Australia está excesivamente representada, mientras que los países de Asia parecen reportar pocos casos a sus agencias de medicamentos. (AU)

An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine.

White blood cell (WBC) monitoring has reduced clozapine-treated patient deaths associated with agranulocytosis to a rarity. However, clozapine protocols and package inserts worldwide provide no instructions for preventing myocarditis or pneumonia during clozapine titrations. Prescribers worldwide are largely unaware of that. Meanwhile, as they worry about agranulocytosis, their clozapine-treated patients are at risk of dying from pneumonia or myocarditis. Consequently, an international guideline with 104 authors from 50 countries/regions was recently published to provide personalised clozapine titration schedules for adult inpatients. This forum article reviews pneumonia and myocarditis occurring during clozapine titration, as well as the three most innovative aspects of this new guideline: (1) personalised titration, (2) C reactive protein (CRP) measures, and (3) dose predictions based on blood levels. Clozapine metabolism is influenced by 3 levels of complexity: (1) ancestry groups, (2) sex-smoking subgroups, and (3) presence/absence of poor metabolizer status. These 3 groups of variables should determine the maintenance dose and speed of clozapine titration; they are summarised in a table in the full-text. The international clozapine titration guideline recommends measuring CRP levels simultaneously with WBC, at baseline and weekly at least for the first 4 weeks of titration, the highest risk period for clozapine-induced myocarditis.

Published population pharmacokinetic models of valproic acid in adult patients: a systematic review and external validation in a Chinese sample of inpatients with bipolar disorder.

BACKGROUND: This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to determine predictive performance. METHODS: Thirteen published PPK models (labeled with letters A to M) not restricted to children were identified in PubMed, Embase, and Web of Science databases. They were evaluated in a sample totaling 411 serum concentrations from 146 adult inpatients diagnosed with bipolar disorder in a Chinese hospital. Serum concentrations of VPA were analyzed by validated ultra-performance liquid chromatography-tandem mass spectrometry. Performance was assessed by four tests (prediction-based diagnostics, visual predictive checks, normalized prediction distribution error, and Bayesian forecasting). RESULTS: Models K and L, developed in large samples of Chinese and Thai patients, showed good performance in our Chinese dataset. Models H and J demonstrated good performance in 2 and 3 of the 4 tests, respectively. Another seven models exhibited intermediate performance. The models with the worst performance, F and M, could not be improved by Bayesian forecasting. CONCLUSION: In our validation study, the most important factors contributing to good performance were absence of children, Asian ethnicity, one-compartment models, and inclusion of body weight and VPA dose in previously published models.

Should we routinely add CRP to clozapine titrations? - Learning from three cases.

Objectives: An international guideline recently provided certain personalized schedules for titrating clozapine in adult inpatients by considering: 1) DNA ancestry group, 2) sexsmoking subgroup, and 3) presence/absence of clozapine poor metabolizer (PM) status. Measuring CRP levels at baseline and during the first 4 weeks is recommended. Titrations too fast for the metabolism of specific patients can lead to clozapine-induced inflammations and CRP elevations. Methods: Three published cases are reinterpreted. Better outcomes might have been obtained by using the guideline. Results: Case 1 was a Chinese male non-smoker, a clozapine PM due to an underlying inflammation. Case 2 was a Turkish female non-smoker who developed clozapine-induced myocarditis in the context of 4 risk factors (undiagnosed infl ammation, obesity, valproate and olanzapine co-prescription). Case 3 was a United States patient of European ancestry with no known risk factors who developed myocarditis after a routine titration and had an unsuccessful rechallenge with 12.5 mg/day. Application of the international clozapine titration guideline may have prevented: 1) Case 1 by recommending against clozapine titration for a patient with an abnormal CRP level, 2) Case 2 by considering 4 risk factors and using a slow titration for clozapine PMs, and 3) Case 3 by using CRP elevations for early identification of a possible genetic PM. Conclusions: When baseline or prior CRPs are normal and then become abnormal during a clozapine titration, this indicates: 1) clozapine-induced inflammation associated with too-rapid titration for that specific patient, and/or 2) co-occurrence of an infection. Prospective studies need to verify this hypothesis.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Population pharmacokinetics of valproic acid in adult Chinese patients with bipolar disorder.

PURPOSE: To develop and validate a population pharmacokinetic (PPK) model of valproic acid (VPA) in adult Chinese patients with bipolar disorder, and provide guidance for individualized therapy in this population. METHODS: A total of 1104 serum concentrations from 272 patients were collected in this study. The data analysis was performed using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, biological characteristics, and concomitant medications. Bootstrap validation (1000 runs), normalized prediction distribution error (NPDE), and external validation of 50 patients were employed to evaluate the final model. RESULTS: A one-compartment model with first-order absorption and elimination was developed for VPA extended-release tablets. VPA clearance was significantly influenced by three variables: sex (12% higher in male patients), daily dose (increasing with the 0.13 exponent), and body weight (increasing with the 0.56 exponent). Typical values for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) for a female patient weighing 70 kg administered VPA 1000 mg/day were 0.18 h-1, 0.46 L/h, and 12.84 L, respectively. The results of model evaluation indicated a good stable and precise performance of the final model. CONCLUSIONS: A qualified PPK model of VPA was developed in Chinese patients with bipolar disorder. This model could be used as a suitable tool for the personalization of VPA dosing for bipolar patients.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries.

INTRODUCTION: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. METHODS: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. RESULTS: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005-IC995=5.9-6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. CONCLUSIONS: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.

The Impact of Smoking, Sex, Infection, and Comedication Administration on Oral Olanzapine: A Population Pharmacokinetic Model in Chinese Psychiatric Patients.

BACKGROUND AND OBJECTIVE: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting. METHODS: A total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate. RESULTS: Typical estimates for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h-1, 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model's performance was good, stable, and precise. CONCLUSION: This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.

This study included a total of 1546 serum olanzapine concentrations from 354 Chinese adult psychiatric patients that were analyzed by a complex mathematical model. The goal was to explore how oral olanzapine is eliminated from the body in Chinese psychiatric patients and how to personalize its dosing. Prior studies using similar complex mathematical models only studied the effects of sex and smoking on olanzapine elimination. This study also investigated the influence of co-occurrence of infection and comedications, including dangguilonghui tablets. This is a Chinese herbal medicine used to treat constipation, including constipation secondary to olanzapine treatment. Olanzapine elimination was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine elimination was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. This study contributes to the improvement of oral olanzapine dosing personalization, but further studies are needed to verify the effects of infection and comedications, including valproate and dangguilonghui.