Lithium is associated with an increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain, but, despite widespread belief to the contrary, it may not be associated with congenital malformations, alopecia, skin disorders, or clinically significant reductions in renal function, according to findings from a systematic review and meta-analysis of data from 385 studies.

The review was undertaken in part because new evidence confirming the efficacy of lithium in bipolar disorder has led to suggestions that it be used more widely. Although it is considered an effective long-term therapy for bipolar disorder, its use has declined in recent years as new, more commercially promoted – but not always equally or more effective – drugs have become available. Concerns about potential teratogenic and other adverse effects, particularly on renal function, and have also contributed to declining use, Dr. Rebecca F. McKnight of the University of Oxford (England) and her colleagues reported online in the Jan. 20 issue of the Lancet.

To provide clinicians and patients with accurate evidence of lithium’s harms and benefits, the investigators set out to provide "a clinically informative systematic toxicity profile for lithium" they said (Lancet 2012 Jan. 20 [doi: 10.1016/S0140-6736(11)61516-X]).

Based on a hierarchy of evidence from the 22 randomized controlled trials, 197 cohort studies and case-control studies, and 166 case reports included in the review and meta-analysis, the investigators found that overall, glomerular filtration was reduced by –6.22 mL/min and urinary concentrating ability was reduced by 15% of normal maximum in patients receiving lithium, compared with controls.

"Data for the most clinically important outcome, renal failure, were scarce," the investigators said, noting that the only substantial cohort study showed that only 0.5% of patients receiving lithium were treated with renal replacement therapy.

As for clinical hypothyroidism, those taking lithium were significantly more likely than those on a placebo to develop the condition (odds ratio, 5.78), and based on a meta-analysis of the case-control studies, thyroid-stimulating hormone (TSH) concentrations were also significantly greater in those taking lithium (weighted mean difference, 4.00 IU/mL). Also, based on findings from 60 studies, blood calcium and parathyroid hormone levels were increased by about 10% over normal values in those taking lithium.

Clinically significant weight gain was also more frequent among those taking lithium than in controls (OR, 1.89), the investigators noted.

The evidence indicated, however, that lithium has little effect on hair or skin, with no significant difference seen in the incidence of alopecia in 24 publications reporting on the condition, and with no significant difference found in the prevalence of skin disorders between those taking lithium and controls in a meta-analysis of 77 publications.

Of note, six case-control studies that measured the association between Ebstein’s anomaly and lithium exposure found no link between the two. Although those estimates are unstable because of the low number of events, a case-control study of nearly 10,700 infants with a major congenital abnormality and more than 21,500 healthy controls also showed no significant association between lithium and congenital abnormalities.

Though limited by the quality and quantity of the primary evidence used in this study, which involved the screening of nearly 6,000 abstracts, the findings represent a "reasonable amount of evidence that allows cautious conclusions to be drawn about the safety of lithium," according to the investigators.

"This review provides a comprehensive synthesis of the evidence of harm that should inform clinical decision and draw attention to key questions in urgent need of further clarification," they said.

Based on their findings, the investigators developed the following recommendations for monitoring of lithium in clinical practice:

Before the start of lithium therapy, the risk of major adverse events should be discussed with the patient, a serum calcium level should be added to baseline blood tests, and uncertainty about the risk of congenital malformations to women of childbearing age should be explained. The latter two of these recommendations mark a change from current U.K. guidelines, the authors noted.

Also, during lithium therapy, renal, parathyroid, and thyroid function (at least glomerular filtration rate, TSH, and calcium) should be repeated at least every 12 months – and more frequently if an abnormal result is found or if the patient has a family history of endocrine disease; blood tests should all be repeated immediately in the event of a change in mood state; the occurrence of adverse effects should be routinely recorded; and women who would like to conceive or who have become pregnant during therapy should be advised that the increased risk of congenital malformation is uncertain, and the balance of risks between harm to the baby and maternal mood instability should be discussed before making a decision to discontinue lithium. All but the recommendation regarding repeat blood tests in the setting of mood state changes mark a change from current U.K. guidelines.

This study was funded by the National Institute for Health Research Programme Grant for Applied Research. The authors had no disclosures to report.

Meta-Analysis Outlines Lithium Toxicity Profile