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 The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy.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. Funding: National Institute for Health Research Programme Grant for Applied Research. © 2012 Elsevier Ltd.
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