Aims: Olanzapine, a second-generation antipsychotic, can cause dose-adverse drug reactions. Its steady-state concentration can vary due to several factors. This study explores how physiological factors, smoking, inflammation, concomitant medications, and metabolic enzyme single nucleotide polymorphisms (SNPs) influence its metabolic levels, aiming to guide personalized dosing. Methods: This study analyzed data from 310 olanzapine-treated patients at Beijing Anding Hospital. Liquid chromatography-mass spectrometry (LC-MS/MS) quantified 1002 serum concentrations. Eleven SNPs from CYP1A2, CYP3A5, UGT1A4, and FMO1/3 were identified through real-time fluorescence quantitative polymerase chain reaction (q-PCR). A Bayesian network was applied to elucidate causal relationships between variables, followed by g-computation to quantify the effect of individual factors on the dose-adjusted concentration (C/D ratio) of olanzapine. The Wilcoxon signed-rank test assessed the intra-individual variations in the steady-state C/D ratio. Results: The Bayesian network suggested causality between smoking, sex, sertraline, Danggui-Longhui, valproic acid, and the olanzapine C/D ratio. None of the SNPs reached significance levels. The Wilcoxon signed-rank test confirmed that both polypharmacy and inflammation increased the C/D ratio within individuals. G-computation showed that the log ratio of olanzapine C/D decreased by 0.392 ± 0.037 in males and 0.004 ± 0.001 with smoking. Danggui-Longhui, sertraline, and valproic acid reduced the ratio by 0.652 ± 0.131, 0.398 ± 0.127, and 0.328 ± 0.039, respectively. Conclusion: Our study confirms that sex, age, smoking, inflammation, and co-prescription with sertraline, Danggui-Longhui, and valproic acid contributed to variability in olanzapine’s steady-state concentration. Considering these factors in clinical practice may help to personalize olanzapine treatment in Asian patients.

Aim We aimed to review cases of Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) characterized by neurological sequelae following acute lithium toxicity and to explore whether cerebellar sequelae are more frequent in cases presenting with fever and/or infection. Methods Case reports were identified from: (i) 6 reviews published up to 2005; (ii) MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search. Results We identified 123 SILENT cases published from 1965 to 2019, in which cerebellar sequelae were observed in an overwhelming proportion (79%). Nearly two out of three cases (63%) had maximal lithium plasma level <2.5 mEq/l (low/mild toxicity). Fever and/or infection were reported in nearly half of the patients (48%). The likelihood of presenting with cerebellar vs. other neurological sequelae was independently increased by elevated plasma lithium level ( 2.5 mEq/l) (OR=4.36, 95%CI 1.31-14.52, p = 0.02) and by a history of fever and/or infection (OR=6.48, 95%CI 2.0-21.0, p = 0.002). Conclusions During the SARS-CoV-2 pandemic, prescribers have to be aware of the risks of cerebral sequelae associated with infection and fever in lithium users, and should warn them of the need to consult in case of fever to adjust their lithium dosage. As the occurrence of SILENT is exceptional, there is no need to modify lithium treatment preventively because of the pandemic as the benefit/risk balance of this drug remains largely positive.