Age-Specific Therapeutic Ranges for Serum/Plasma Lithium Testing in Older Adults with Bipolar Disorder

The therapeutic range recommendations for serum/plasma lithium testing for patients with bipolar disorder are:

Background

• Bipolar disorder (BD) affects approximately 2.4% of the world population. Older adults with bipolar disorder (OABD, ages ≥60) comprise about 25% of all BD cases.
• Lithium remains the preferred choice for maintenance monotherapy in OABD. It is effective in both depression and mania/hypomania phases and may have benefits in neuroprotection and in reducing the risk of suicide.
• Due to its narrow therapeutic index, therapeutic drug monitoring (TDM) of serum lithium, typically measured 12 hours after the last dose, is used for optimizing lithium dosage, ensuring treatment adherence, and preventing adverse effects, such as toxicity.
• In older adults, the risk of lithium toxicity increases due to decreased renal function, co-morbidities, and polypharmacy-associated drug-drug interactions such as with diuretics, ACE inhibitors, and non-steroidal anti-inflammatory medications.
• Clinical experience suggests that lithium toxicity can be missed in older adults, and instead, can lead to the “prescribing cascade” that mistakes lithium side effects and signs of toxicity for another disorder such as parkinsonism, dementia, or gastrointestinal disorder.

Rationale

• In 2017, a Delphi consensus survey conducted by the International Society for Bipolar Disorder (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 serum lithium reported by clinical laboratories is in the range of 0.6–1.2 mmol/L without age-dependent stratification.
  • The ISBD taskforce summarized that this range is too high for OABD and can lead to false sense of “safe practice,” especially for clinicians with limited experience in the use of lithium in OABD.
• In 2019, the ISBD Older Adults Task Force published recommendations for serum lithium therapeutic ranges in OABD which are 0.4–0.8 mmol/L for ages 60–79 and 0.4–0.7 mmol/L for ages 80 and above.
• A 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), demonstrated acceptable agreement between commonly used serum/plasma lithium measurement methods with minimal variations. This data supports feasibility to use standardized serum lithium therapeutic ranges.
• Additionally, a recent study carried out a direct comparison between six commonly used commercial methods for lithium and showed that sufficient precision and method agreement exist around the recommended lithium therapeutic ranges for older adults.
• Age-stratified therapeutic ranges for serum lithium for OABD have been implemented in Alberta, province wide, and in individual clinical laboratories in British Columbia, Quebec, and Ontario.

Impact on organizations and clinical stakeholders

• Operational impact to key stakeholders, including clinical laboratories, health care providers (primary care and hospitals/specialists), and pharmacists should be minimal.
• Result flagging rates may change as laboratories update their therapeutic ranges for serum/plasma lithium testing in older adults with bipolar disorder. An increased number of flagged results is possible following the change.

Potential Implementation Risks and Mitigations

• Prior to implementing the change, clinical laboratories should utilize existing organization-specific communication channels to alert clinical stakeholders of the change and have a forum to discuss feedback. This document can serve as a reference.
• It is recommended that laboratory reports include a temporary comment highlighting the change, date of implementation, and reminding health care providers to interpret results in context of the new therapeutic range.

Additional Considerations

• Although the 2017 Delphi consensus survey conducted by the International Society for Bipolar Disorder (ISBD) did not make a recommendation for an alert for imminent toxicity, based on clinical experience, it is suggested that a level of 1.5 mmol/L can be considered in OABD.
• For adults <60 years old, the Canadian Network for Mood and Anxiety Treatments (CANMAT) 2018 ISBD Guidelines recommend that the target range for serum lithium in acute treatment is 0.8–1.2 mmol/L, while in maintenance treatment, levels of 0.6–1.0 mmol/L may be sufficient. Similarly, the ISBD Task Force in 2019 recommended the standard lithium serum level in maintenance treatment should be 0.60–0.80 mmol/L.
• Renal failure is not a contraindication to lithium use but it is a concern. Consultation with a nephrologist would be recommended if maintenance lithium therapy is being considered. The recommended age-stratified therapeutic ranges are still an appropriate guideline, but case-specific precautions should be taken for these patients.

Stakeholder Consultation

• The following clinical recommendation was subject to a provincial consultation period where stakeholder feedback was collected and incorporated into this final recommendation.
• Consultation included a detailed webinar outlining the proposal with an open question and answer period, as well as an online clinical recommendation feedback form where all stakeholders could provide direct feedback related to the clinical recommendation and rationale.
• For more information, please contact the Ontario Laboratory Medicine Program.