Lithium's Safety Examined

Findings Reaffirm Drug's Role as First-Line Therapy for Bipolar Disorder

Fran Lowry

January 20, 2012

January 19, 2012 — Lithium is linked to thyroid and parathyroid abnormalities, weight gain, and an increased risk for reduced urinary concentrating ability, but the jury is still out on whether it causes birth defects, new research suggests.

The systematic review and meta-analysis of 385 randomized, controlled trials and observational studies also found scant evidence that lithium produced a clinically significant reduction in renal function in most patients and that the risk of end-stage renal failure among users of the drug is low.

"Lithium is the most effective long-term therapy for bipolar disorder, protecting against both depression and mania and reducing the risk of suicide and short-term mortality," Professor John R. Geddes, MD, University of Oxford and Warneford Hospital, Oxford, United Kingdom, and colleagues write.

"Because lithium has always been an unpatented, cheap drug, it is not commercially promoted and the potential for adverse effects has been a substantial deterrent to use," they write.

There have been concerns about lithium’s effect on renal function and its purported teratogenicity. Despite these concerns, there has not been an "adequate synthesis of the evidence for adverse effects," the authors note.

With first author Rebecca F. McKnight, BMBCh, the study is published online January 20 in the Lancet.

Small Risk of Renal Failure

The investigators assessed 385 studies investigating the association between lithium and all major adverse effects that have been reported to obtain a "clinically informative" toxicity profile.

The analysis showed that lithium reduced glomerular filtration rate by an average of −6.22 mL/min (95% confidence interval [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).

The absolute risk of renal failure was small, the authors report. A few patients (18 of 3369, or 0.5%) receiving lithium also underwent renal replacement therapy.

There was an increase in the prevalence of clinical hypothyroidism in patients taking lithium compared with patients who did not (odds ratio [OR], 5.78; 95% CI, 2.00 to 16.67; P = 0.001).

Additionally, lithium increased thyroid stimulating hormone by an average of 4.00 iU/mL (95% CI 3.90 to 4.10, P < 0.0001).

Lithium was also linked to increased blood calcium (+0.09 mmol/L, 95% CI, 0.02 to 0.17; P = 0.009) and increased parathyroid hormone (+7.32 pg/mL, 95% CI, 3.42 to 11.23; P < 0.0001).

Weight gain was also associated with lithium use. Patients receiving lithium gained more weight compared with those not receiving lithium (OR, 1.89; 95% CI, 1.27 to 2.82; P = 0.002). However, weight gain was lower with lithium than with olanzapine (OR, 0.32; 95% CI, 0.21 to 0.49; P < 0.0001).

Evidence of Teratogenicity "Weak"

The researchers note that they were unable to find any significant increased risk for congenital abnormalities, hair loss, or skin disorders.

"The evidence that exposure to lithium is teratogenic is quite weak, and our findings accord with the notion that the risk has been overestimated," they write.

Currently, it is recommended that lithium be avoided during pregnancy, but the authors suggest that a "sounder approach" would be to explain the uncertainty about the risk to women of childbearing age.

They also recommend that calcium levels be checked before and during treatment with lithium because of the high prevalence of hyperparathyroidism.

They conclude that lithium has long been recommended as a first-line treatment for bipolar disorder, but its use has decreased, owing to concerns about its safety.

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

"This is a synthesis of data on harms, and as such is less of an exciting new result," Dr. Geddes told Medscape Medical News.

"There were not too many surprises in the results, although the need to monitor calcium is a change from some guidelines. Also, the risk of harm to the kidney and during pregnancy that we found is probably less than is often thought," he said.

"Hopefully, this analysis will help patients and clinicians make informed decisions about care," Dr. Geddes said.

Still Treatment of Choice

In an accompanying editorial, Australian researchers Gin S. Mahli, MD, from the University of Sydney, and Michael Berk, MD, from the University of Melbourne, write that correctly judging the treatment options for bipolar disorder "has never been more crucial."

They congratulate the investigators for their systematic quantification of lithium’s potential risks, but they also caution that there are caveats to be considered when interpreting the findings.

Among these are the heterogeneity of the studies in the meta-analysis and the absence of key information, such as the timing of the onset of side effects in relation to the start of lithium treatment.

Despite these limitations, "this study provides timely clarification of the toxicity associated with lithium therapy and, on balance, reaffirms its role as a treatment of choice for bipolar disorder," they conclude.

This study was funded by the National Institute for Health Research Programme Grant for Applied Research. Dr. McKnight reports no relevant financial relationships. Dr. Mahli reports financial relationships with AstraZeneca, Eli Lilly, Organon, Pfizer, Servier, Wyeth, Janssen-Cilag, Lundbeck, and Ranbaxy. Dr. Berk reports financial relationships with Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Organon, Novartis, Mayne Pharma, Servier, Janssen-Cilag, Lundbeck, Merck, Sanofi-Synthelabo, Solvay, and Wyeth. The editorialists have disclosed no relevant financial relationships.

Lancet. Published online January 20, 2012. Abstract, Editorial

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