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Demystifying the Lithium Clearance Challenge
Dr Vincent Millischer, MD, PhD, discussed key findings from his study "Improving Lithium Dose Prediction Using Population Pharmacokinetics and Pharmacogenomics: a Cohort Genome-Wide Association Study in Sweden," recently published in The Lancet.
Clinicians treating patients with bipolar disorder frequently encounter the challenge of lithium clearance. In this Q&A, Dr Millischer describes the surprising association between lithium clearance and serum lithium as well as the role that genetics may play in helping to determine the proper lithium dosage for each patient.
Psych Congress Network: What led you and your colleagues to investigate how clinical and genomic data could improve lithium-dose prediction?
Vincent Millischer, MD, PhD: We started this project based on the clinical observation that there is a huge variability on how much lithium patients have to take in order to reach therapeutic lithium levels. Although this problem is well known in the clinical world and clinical predictors have been studied for a long time, it can be quite striking for a young clinician when observing it the first time. In the discussions between the clinical and the basic scientist in our research group, we realized that the genetics involved had not been studied before. Having access both to cohorts and the scientific resources to answer this question, we decided to set up this study.
PCN: Please briefly describe the study method and participants. How did you work to expand your sample size to transcend the limitations imposed by smaller sample sizes in previous studies?
Dr Millischer: We studied lithium clearance, the rate at which the body eliminates lithium and determines how much lithium has to be taken to keep stable levels in the blood. We analyzed it in relationship to several clinical variables, like age, sex, kidney function and co-medication, to see if we could predict how much a certain patient would have to take. We also performed a “genome-wide association study” to find out if some mutations in the human genome had an influence on lithium clearance.
We were able to include participants from two cohorts in our study. One was the cohort of bipolar patients that has been followed by our research group over recent years and that had been well characterized. The other cohort was obtained in collaboration with the Swedish Quality Registry for Bipolar Disorder, a registry where all patients with bipolar disorder can be registered by their treating doctor; approximately 30% of all patients with bipolar disorder in Sweden are included. The only information that was not included was the amount of lithium these patients were taking.
Here, the amazing possibility of linking different registries in Sweden helped us: by analyzing data from the prescription registry in Sweden, where all sold prescribed drugs are registered, we were able to estimate how much lithium was taken daily and could therefore almost quadruple our sample size, compared to our initial cohort.
PCN: Please briefly describe the most significant finding(s). Were any outcomes different than you expected?
Dr Millischer: We were able to replicate known associations between lithium clearance and demographic/clinical variables. Building a model with all these variables explained a huge part of the variance, more than we would have assumed originally. What surprised us all, clinical psychiatrists and pharmacologists included, was the association between lithium clearance and serum lithium. Normally, it is assumed that a doubling of the daily lithium intake would lead to a doubling of serum lithium levels, meaning that the ratio between the two is constant. This goes a bit against the common understanding that lithium clearance should not be dependent on serum lithium, and we can only speculate why this is the case.
We also found an association between lithium clearance with one genetic marker, which is—to our knowledge—a first, and could also show that genetic information associated with BMI and kidney function could by itself explain parts of how much lithium is needed. Our results show that genetics play a role, something that we would have expected.
It is important to note that our study is quite small compared to other genetic studies and that larger samples are needed to confirm our genetic findings. However, one further important finding is that there does not seem to be mutations that are common and that hugely influence lithium clearance. Such mutations exist for other psychiatric drugs and are used in clinical routine; the fact that we did not find any in our study gives a first indication that single mutation analyses will probably not play an important role for lithium treatment. Rather, the genetic architecture is quite complex, likely with many mutations exerting an influence.
Reference
Vincent Millischer, MD, PhD, studied medicine in Vienna and Paris from 2008-2014. He continued on to complete his PhD in medical science at Karolinska Institutet in Stockholm Sweden in 2015. After defending in 2020, he returned to Vienna to do his residency in psychiatry. Dr. Millischer's main research interests include psychiatric genetics and inflammation.
