Optimal range of lithium serum levels for safer use in bipolar disorder

Researchers from the University of Hong Kong (HKU) have identified lithium level thresholds associated with risks of hypothyroidism, hyperthyroidism, and stage ≥3 chronic kidney disease (CKD). This provides empirical evidence that can facilitate the development of clinical guidelines for lithium treatment in bipolar disorder.

In an expert consensus based on a Delphi study, 90 percent of experts ranked lithium as first-line treatment for bipolar disorder. However, lithium has been underutilized, which is partly attributable to its low therapeutic window and adverse events (AEs) on the thyroid and kidneys. [Int J Bipolar Disord 2025;13:21]

“Existing data are heterogeneous, and lithium serum level thresholds associated with thyroid and kidney abnormalities remain unknown,” wrote the researchers.

In a population-based retrospective cohort study, the researchers used an electronic health record database developed by the Hospital Authority and identified 4,752 patients (mean age, 39.5 years; female, 60.8 percent) in Hong Kong who were first diagnosed with bipolar disorder over a 17-year observation period (from 1 January 2002 to 31 December 2018). Exposures included lithium (n=1,725) and nonlithium (n=3,027) treatment. [JAMA Network Open 2025;8:e2458608]

Compared with nonlithium treatments, lithium was associated with increased risks of hypothyroidism (adjusted hazard ratio [aHR], 2.00; 95 percent confidence interval [CI], 1.72–2.33) and stage ≥3 CKD (aHR, 1.35; 95 percent CI, 1.15–1.60), but not stage ≥4 CKD or end-stage kidney disease.

“Although the primary analysis showed that lithium was not associated with an increased risk of hyperthyroidism, the association became significant in sensitivity analyses restricted to lithium users with high lithium serum levels [aHR, 1.38; 95 percent CI, 1.09–1.74] and those prescribed lithium as the first-ever mood stabilizer [aHR, 1.38; 95 percent CI, 1.03–1.85],” reported the researchers. “Our findings indicated that hyperthyroidism is a lithium-related AE despite its comparatively low prevalence rate.”

Higher lithium serum levels were associated with elevated risks of hypothyroidism (aHR, 2.08; 95 percent CI, 1.67–2.59), hyperthyroidism (aHR, 1.81; 95 percent CI, 1.31–2.50), and stage ≥3 CKD (aHR, 2.11; 95 percent CI, 1.57–2.85) vs nonlithium treatment.

“To our knowledge, this is the first study to specifically determine the cut-offs of lithium levels associated with thyroid and kidney dysfunction in bipolar disorder,” noted the researchers.

The mean serum lithium level threshold was >0.5028 mEq/L for hypothyroidism, >0.5034 mEq/L for hyperthyroidism, and >0.5865 mEq/L for stage ≥3 CKD. The thresholds were lower than the therapeutic range of 0.60–0.80 mEq/L recommended by some clinical guidelines for lithium maintenance treatment. [JAMA Network Open 2025;8:e2458608; Bipolar Disord 2018;20:97-170; NICE clinical guideline, Bipolar disorder: Assessment and management, CG185]

“Evidence has consistently shown that patients with bipolar disorder who discontinue lithium exhibit a significantly higher risk of mood-episode recurrence than those who continue lithium,” suggested the researchers. “The identified lithium level thresholds may facilitate the development of evidence-based guidelines on lithium treatment, particularly in Asian populations, and the promotion of personalized care and risk-benefit balancing in the treatment for bipolar disorder.”