Lithium’s Medical Risks Reconsidered

Only one medical risk was greater after a decade of lithium use: Hypothyroidism

Hugh study questions lithium’s medical risks

STUDY: Kessing LV et al, European Neuropsychopharmacology 2024;84:48–56

STUDY TYPE: Population-based cohort study emulating a target trial

FUNDING: Independent Research Fund Denmark

Background

Lithium is a paradox. On the one hand, people with bipolar disorder live longer on lithium than on any other medication. On the other hand, it is linked to serious medical risks like kidney disease, thyroid dysfunction, heart arrhythmias, hyperparathyroidism, and toxicity. This study adds clarity with real-world data.

The Study

Using linked Danish national registers covering all 5.9 million inhabitants, researchers identified two cohorts: 12,607 patients with bipolar disorder starting lithium, lamotrigine, or valproate, and a broader group of 156,678 first-time users of any of the three drugs regardless of diagnosis. Sustained exposure over 10 years was compared across a wide range of physical outcomes including stroke, heart disease, diabetes, dementia, kidney disease, Parkinson’s disease, and cancer.

Lithium showed no increased risk compared to lamotrigine or valproate for any physical disorder — stroke, heart disease, diabetes, dementia, kidney disease, Parkinson’s, cancer — with one exception: hypothyroidism (myxedema), where lithium raised absolute risk by 7–10% compared to the anticonvulsants.

The findings are in line with another large trial that found no difference in kidney risks between lithium and valproate, and several that find no renal problems if the lithium levels are kept low, such as between 0.6-0.8. Most of the kidney problems on lithium appear related to toxic events when the levels surge beyond that, and bipolar itself is linked to high rates of renal disease.

Earlier hopes that lithium might protect against dementia were not confirmed here. The data did show some protective effects against osteoporosis (bone thinning), though not statistically significant, other studies suggest this is a real benefit.

Practice Implications

• This study brings big-data reassurance, but doesn’t refute earlier findings of kidney problems on lithium.
• You can reduce those renal risks by keeping the levels lower (0.6-0.8), dosing entirely at night (either instant or controlled release), and possibly with N-acetylcysteine (NAC). This antioxidant protects against other kidney toxins in human studies and against lithium toxicity in an animal model. It may also protect the heart on lithium.
• Some diabetes medications may also protect the kidneys on lithium.
• Consult nephrology if eGFR ≤ 60 or creatinine ≥ 1.5.
• Learn more ways to reduce lithium’s side effects in Difficult to Treat Depression.