Lithium toxicity profile: a systematic review and meta-analysis

Background Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium. Methods We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity. Findings We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by -6.22 mL/min (95% CI -14.65 to 2.20, p=0.148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference -158.43 mOsm/kg, 95% CI -229.78 to -87.07, p<0.0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0.5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5.78, 95% CI 2.00-16.67; p=0.001), and thyroid stimulating hormone was increased on average by 4.00 iU/mL (95% CI 3.90-4.10, p<0.0001). Lithium treatment was associated with increased blood calcium (+0.09 mmol/L, 95% CI 0.02-0.17, p=0.009), and parathyroid hormone (+7.32 pg/mL, 3.42-11.23, p<0.0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1.89, 1.27-2.82, p=0.002), but not those receiving olanzapine (0.32, 0.21-0.49, p<0.0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders. Interpretation Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment.