Lower lithium therapeutic ranges for older adults with bipolar disorder

Lithium is prescribed as a first-line mood stabilizer for the management of bipolar disorder. It is effective during both the depression and mania/hypomania phases of this condition and may offer neuroprotection in addition to reducing the risk of suicide. However, due to its narrow therapeutic index, lithium toxicity is a concern, particularly in older adults who are ≥60 years of age. A recent study by Fung, et al. (EJIFCC 2023; 34:153–166) reported their experience implementing clinically appropriate, age-stratified lithium therapeutic ranges in the hopes of raising awareness and promoting the safe and effective use of lithium in older adults globally.

What is an appropriate lithium therapeutic range in older adults?

A:The International Society for Bipolar Disorder (ISBD) established an Older Adults Task Force aiming to provide specific directions for lithium therapy in older adults with bipolar disorder (OABD). In 2019, this group published recommendations for lithium therapeutic ranges in OABD, which are in the range of 0.4-0.8 mmol/L for ages 60-79 and in the range of 0.4-0.7 mmol/L for ages 80 and above (Bipolar Disord 2019; doi: 10.1111/bdi.12714).

In 2017, a Delphi consensus survey conducted by the ISBD Older Adults Task Force and a pattern-of-practice survey administered by the Institute for Quality Management in Healthcare (IQMH) in Toronto both found that the most common therapeutic range for lithium reported by laboratories was in the range of 0.6-1.2 mmol/L without age-dependent stratification. Thus, requests were made to the clinical laboratory community to update and provide lower and narrower therapeutic ranges for lithium in older adults to improve the safety of lithium therapy in this vulnerable population.

Why are lower and narrower lithium therapeutic ranges important in older adults?

In older adults, the risk of lithium toxicity is increased due to decreased renal function, co-morbidities, and polypharmacy-associated drug-drug interactions with commonly used drugs, such as diuretics, angiotensin-converting enzyme inhibitors, and nonsteroidal anti-inflammatory medications. Moreover, lithium toxicity is often unrecognized and misdiagnosed as other conditions, resulting in inappropriate additional prescriptions. The commonly reported lithium therapeutic ranges (0.6-1.2 mmol/L) are too high for older adults and may lead to missed lithium toxicity because some potentially toxic levels can be misinterpreted as “within the therapeutic range.” Providing lower and narrower therapeutic ranges for older patients would help to prevent adverse side effects, particularly neurotoxicity.

Is it feasible to adopt standardized therapeutic ranges for lithium therapeutic drug monitoring?

Review of proficiency testing survey reports between September 2020 and September 2022 from IQMH and the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP) in St. Leonards, Australia, demonstrated acceptable agreement between commonly used lithium measurement methods with minimal variations. Specifically, the all-methods’ standard deviation showed a range of 0.04-0.06 mmol/L for concentrations ≤1.5 mmol/L and <0.12 mmol/L for concentrations >1.5 mmol/L amongst eight different instrument groups of lithium colorimetric assays from five major manufacturers and reported data from 311 RCPAQAP and 86 IQMH clinical laboratory participants.

However, proficiency testing survey reports from the College of American Pathologists showed that some rarer methods, such as direct ion selective electrode, can have a bias of up to +0.3 mmol/L when compared to the all-methods’ means, even though most of the common methods are generally agreeable. Thus, a review of site-specific laboratory and clinical data is still needed prior to the implementation of the recommended ISBD OABD therapeutic ranges.

In summary, it is feasible to use standardized lower lithium therapeutic ranges in older adults and they may improve the safety of lithium therapy for this patient population.

Acknowledgement: The author is grateful for the critical review of and edits from Kenneth Shulman, MD, and Angela Fung, PhD.

Lei Fu, PhD, DABCC (CC, TC, MD), FADLM, FCACB, is a clinical biochemist at Sunnybrook Health Sciences Centre in Toronto and at the University of Toronto. +Email: [email protected]