Saliva testing as a means to monitor therapeutic lithium levels in patients with psychiatric disorders: identification of clinical and environmental covariates, and their incorporation into a prediction model

Abstract

Abstract The narrow therapeutic window of lithium medications necessitates frequent serum monitoring, which can be expensive and inconvenient for the patient. The use of saliva as a biofluid may have advantages over blood, as it is non-invasive, easier to collect, requires less processing, and can be collected without the need for trained personnel. This study investigated the utility of saliva as a longitudinal means of monitoring lithium levels. We measured lithium levels using Inductively-Coupled Plasma Optical Emission Spectrometry (ICP-OES) in n=171 saliva samples collected via the passive drool method, from a multi-center cohort consisting of n=75 patients with bipolar disorder or other psychiatric conditions. We found that saliva and serum levels of lithium were highly correlated (unadjusted Spearman r=0.74, p<0.0001) and that consideration of daily lithium dose, dosing schedule, cotinine-confirmed smoking status and diabetes status could improve this relationship (adjusted Spearman r=0.77, p<0.0001). Using this adjusted intersubject equation to predict an individual’s serum lithium levels from their salivary lithium value, we observed a strong linear correlation between the predicted vs. actual serum lithium levels r=0.70; P<0.0001). Longitudinal samples were collected from patients for up to 18 months from the initial assessment. The saliva/serum ratios across these multiple visits were highly stable for most patients. Variability in the saliva/serum ratios across observations was found to be significantly associated with age. Using the intrasubject saliva/serum ratio from a single prior observation was not better than using the interpatient linear regression equation at predicting the serum lithium levels. However, the using the mean intrasubject ratio calculated from three prior observations could robustly predict serum levels with a predicted vs. actual serum correlation of r=0.90 (p<0.0001). These findings strongly suggest that saliva could be used for lithium monitoring and open the door for the development and implementation of a point-of-care salivary lithium device that could be used at home or in the clinic. We propose that the use of saliva will dramatically improve treatment opportunities for patients with mood disorders. Data availability statement Anonymized summary data will be shared by reasonable formal request from qualified researchers, subject to a data sharing agreement and in compliance with the requirements of the funding bodies and institutions.