Bipolar disorder (BD) is a chronic condition associated with relapse and elevated suicide risk, for which lithium remains a key maintenance therapy to reduce recurrence, readmission, and self-harm.^1,2 However, concerns about its renal and thyroid effects persist.^2-4 Researchers from the Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine of the University of Hong Kong (HKUMed) conducted a population-based study to evaluate the association between lithium use and the risk of thyroid dysfunction and chronic kidney disease (CKD) in newly diagnosed BD patients, identify serum lithium thresholds linked to these complications, and to compare the adverse effects with nonlithium mood stabilizers.²

The long-term safety profile of lithium in the treatment of BD has raised ongoing concern, particularly related to thyroid and renal complications.² While previous studies have reported associations between lithium use and adverse renal and endocrine outcomes, the supporting evidence has been inconsistent and limited by methodological weaknesses.² Notably, no prior study has defined the serum lithium thresholds at which these risks become clinically significant.²

To address this gap, a population-based cohort study using data from the local Clinical Data Analysis and Reporting System (CDARS) was conducted.² The study included over 16,000 patients with newly-diagnosed BD (ICD-10: F30-F31) between 2002 and 2018.² Patients were stratified into lithium and nonlithium treatment groups, the latter comprising users of valproate, quetiapine, olanzapine, or risperidone.² The incidence of hypothyroidism (thyrotropin >5mIU/L), hyperthyroidism (thyrotropin <0.35mIU/L), and CKD stage 3 or higher (CKD3+; defined as two eGFR measurements <60mL/min/1.73m² at least three months apart, using the CKD-EPI equation was assessed.² Multivariable models adjusted for demographics, comorbidities, and concurrent use of psychotropic or nephrotoxic medications.²

Consistent with previous research, the study found that lithium use was associated with a modestly increased risk of hypothyroidism (adjusted hazard ratio [aHR]=2.00; 95% CI: 1.72-2.33) and a 35% increased risk of CKD3+ (aHR=1.35; 95% CI: 1.15-1.60) compared with nonlithium mood stabilizers such as valproate and commonly used second-generation antipsychotics (SGAs).² In contrast, the risks of hyperthyroidism, CKD stage 4, and end-stage kidney disease (ESKD) requiring replacement therapy did not differ significantly between the lithium and nonlithium groups.²

Importantly, the study was the first to define serum lithium thresholds associated with thyroid and renal complications in BD patients.² A mean lithium level >0.5028mEq/L was associated with an increased risk of hypothyroidism, while levels >0.5034mEq/L were linked to higher hyperthyroidism risk.² For CKD3+, a threshold of 0.5865mEq/L corresponded to increased renal risk.² Further analyses showed that higher serum lithium concentrations were significantly associated with increased risks of hypothyroidism (aHR=2.08; 95% CI: 1.67-2.59), hyperthyroidism (aHR=1.81; 95% CI: 1.31-2.50), and CKD3+ (aHR=2.11; 95% CI: 1.57-2.85).² Patients with more frequent episodes of lithium toxicity also had a higher risk of CKD3+, although no such association was observed for thyroid dysfunction.²

When compared to lithium, the use of other mood stabilizers was associated with significantly lower risks of adverse events.² Valproate (aHR=0.47; 95% CI: 0.39-0.56), quetiapine (aHR=0.47; 95% CI: 0.36-0.62), olanzapine (aHR=0.30; 95% CI: 0.19-0.48), and risperidone (aHR=0.51; 95% CI: 0.36-0.73) were all associated with reduced risks of hypothyroidism.² Valproate and olanzapine users were also linked to lower risks of hyperthyroidism (aHR=0.51; 95% CI: 0.40-0.66; and aHR=0.29; 95% CI: 0.14-0.58, respectively), while quetiapine was associated with a lower risk of CKD3+ (aHR=0.65; 95% CI: 0.49-0.86).2 However, no significant differences were observed between lithium and these comparators in the risk of ESKD.²

In summary, the study identified serum lithium levels linked to thyroid and kidney issues, offering evidence that can guide clinical recommendations for lithium treatment.² This approach aims to balance efficacy and safety, ultimately promoting personalized care and equitable treatment of BD in Asian populations.² These results underscore the need for future research to refine optimal lithium ranges and develop risk-predictive tools to support individualized care.² Clinicians should weigh lithium’s proven therapeutic efficacy against its potential safety risks, engaging patients in shared decision-making and ongoing monitoring.²