Lithium for Bipolar Disorder Linked to Higher Risk of Thyroid, Kidney Dysfunction

 

• Lithium was associated with a higher risk of thyroid and kidney dysfunction versus non-lithium treatments in bipolar disorder patients.
• Associations were dose-dependent and serum level cutoffs for increased risks fell within the recommended therapeutic range.
• Lithium was not tied to increased risks for stage 4 chronic kidney disease or end-stage kidney disease.

Lithium was associated with a slightly increased risk of thyroid and kidney dysfunction among patients with bipolar disorder compared with other drugs, a Chinese retrospective cohort study suggested.

Over a mean 8-9 years of follow-up, use of lithium was associated with an increased risk of hypothyroidism (adjusted HR 2.00, 95% CI 1.72-2.33) and chronic kidney disease (CKD) stage 3 or higher (aHR 1.35, 95% CI 1.15-1.60) compared with non-lithium treatments, reported Wing Chung Chang, MD, of the University of Hong Kong, and colleagues in JAMA Network Openopens in a new tab or window.

The link was dose-dependent, with higher serum lithium levels tied to higher risks for thyroid and kidney dysfunction:

• Hypothyroidism: aHR 2.08, 95% CI 1.67-2.59
• Hyperthyroidism: aHR 1.81, 95% CI 1.31-2.50
• CKD stage 3 or higher: aHR 2.11, 95% CI 1.57-2.85

Lithium was not tied to increased risks for stage 4 chronic kidney disease or end-stage kidney disease compared with the non-lithium treatments, which included valproate, olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal). Because this study only had an average lithium exposure of around 8.5 years, Chang said this was likely too short to see any associations with these outcomes.

While prior studiesopens in a new tab or window have linked lithium with thyroid and renal dysfunction, Chang told MedPage Today this was the first study to explore the cutoffs of lithium serum levels that were associated with such dysfunction, "which may in turn facilitate more personalized clinical decision making in lithium treatment in the future."

Using receiver operating characteristic analyses, they determined that mean lithium serum levels greater than 0.5028 mEq/L, greater than 0.5034 mEq/L, and greater than 0.5865 mEq/L represented thresholds associated with hypothyroidism, hyperthyroidism, and CKD stage 3 or higher, respectively.

However, these levels are lower than the therapeutic range of 0.60 to 0.80 mEq/L recommended by some clinical guidelines for lithium maintenance treatment and are comparatively lower than what the researchers were expecting, Chang said. "The precise therapeutic range for lithium maintenance treatment for bipolar disorder still requires further investigation, with some suggesting 0.4 mEq/L as the minimally effective level for maintenance treatment."

These findings "underscore the importance of adhering to the guideline recommendations for regular lithium, thyroid, and renal function monitoring to facilitate early detection and intervention for lithium-related thyroid and renal dysfunction," he noted.

"Given that lithium is the first-line mood stabilizer recommended by clinical guidelines with superior efficacy in prevention of mood-episode recurrence and anti-suicidality relative to other mood-stabilizers ... the potential lithium-related risk of thyroid and renal dysfunction should be weighed against the evidence-based benefit of continued lithium maintenance treatment in the clinical decision-making process on an individual basis," Chang suggested.

Clinicians should consider patients' past illness and treatment history, especially given that patients with bipolar disorder who discontinue lithium treatment may exhibit significantly higher risks of recurrence, rehospitalization, and suicide or self-harm, he advised.

For this study, Chang and co-authors used a medical record database of public healthcare services for Hong Kong residents ages 15 and older first diagnosed with bipolar disorder between 2002 and 2018. Of these patients, 4,752 were analyzed for hypothyroidism (mean age 39.5, 60.8% women), 4,500 for hyperthyroidism (mean age 39.7, 60.4% women), and 7,029 for CKD (mean age 37.9, 60.5% women).

Incidence rates per 1,000 person-years were 25.7 for hypothyroidism, 12.9 for hyperthyroidism, and 10.8 for CKD stage 3 or higher. Regardless of lithium cutoffs, a higher number of lithium toxicity episodes was associated with elevated risk of CKD but not thyroid dysfunction.

Longer cumulative exposure to lithium was associated with a lower risk of hypothyroidism (aHR 0.28, 95% CI 0.20-0.35), hyperthyroidism (aHR 0.66, 95% CI 0.48-0.90), and CKD stage 3 or higher (aHR 0.74, 95% CI 0.56-0.98). This suggests that dysfunction might occur early after initiation of lithium treatment, the researchers noted.

According to age- and sex-stratified analyses, lithium was linked with a higher hypothyroidism risk in both sexes and all age categories except for men ages 40-59 and 60 and older, as well as an increased risk of CKD stage 3 or higher in men and women ages 40-59.

The cohort focused on an Asian population, which may limit the generalizability of the findings. Also, data on lifestyle including body mass index, diet, smoking, and physical activity weren't adjusted for in the analyses.

Disclosures

Chang reported no disclosures.

Co-authors reported relationships with AbbVie, Angelini, Lundbeck, Otsuka, Boehringer Ingelheim, Janssen, Takeda, Alkermes, Allergan, Aristo Pharma, Bristol Myers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnytsia, Delpor, Denovo, Eli Lilly, Eumentis Therapeutics, Gedeon Richter, Hikma, Holmusk, Intra-Cellular Therapies, Jamjoom Pharma, Johnson & Johnson, Karuna, Küleon Bioscience, LB Pharma, MedinCell, MedLink, Merck, Mindpax, Mitsubishi Tanabe Pharma, MapLight, Mylan, Neumora Therapeutics, Neuraxpharm, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, PPD Biotech, Quantic, Recordati, Relmada, Reviva, Rovi, Saladax Biomedical, Sanofi, Seqirus, Servier, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Teva, Terran, Tolmar, Vertex, Viatris, Xenon Pharmaceuticals, and UpToDate.

Primary Source

JAMA Network Open

Source Reference: opens in a new tab or windowChan JKN, et al "Lithium for bipolar disorder and risk of thyroid dysfunction and chronic kidney disease" JAMA Netw Open 2025; DOI: 10.1001/jamanetworkopen.2024.58608.

https://www.medpagetoday.com/psychiatry/bipolardisorder/114165