Lithium, the cornerstone treatment for bipolar disorder, is associated with a decline in renal function, hypothyroidism, and hypercalcemia, new research suggests.

“Lithium is a widely used and highly effective treatment for mood disorders, but causes poorly characterized adverse effects in kidney and endocrine systems,” write investigators, led by Brian Shine, MD, from John Radcliffe Hospital, Oxford, United Kingdom. “We aimed to analyze laboratory information system data to determine the incidence of renal, thyroid, and parathyroid dysfunction associated with lithium use.”

The findings were published online May 20 in the Lancet.

For the study, the investigators extracted routinely collected data from the laboratory information system of the Clinical Biochemistry Department, Oxford University Hospitals National Health Service Trust.

The laboratory performs routine tests for primary and secondary care for about 650,000 people in Oxfordshire, United Kingdom, and surrounding counties and has been in continuous operation since 1985.

The study cohort included all patients aged 18 years or older who had had at least two creatinine, thyrotropin, calcium, glycated hemoglobin, or lithium measurements taken between October 1, 1985, and March 31, 2014.

The main exposure was lithium therapy, defined as more than two serum measurements in which lithium was detected. A total of 4678 patients had serum lithium concentrations measured once, and 60% of these (2795) had more than one measurement.

The remaining 689,228 patients in the cohort were matched for sex and age and served as nonexposed control participants.
The analysis showed that the presence of lithium in serum was strongly associated with a decline in renal function (estimated glomerular filtration rate <60 mL/min per 1.73 m2), hypothyroidism, and increased total serum calcium concentration, but not with hyperthyroidism or increased adjusted calcium concentration.

Table. Effects of Lithium on Renal and Endocrine Function

Function Hazard Ratio 95% Confidence Interval P-value
Stage 3 chronic kidney disease 1.93 1.76 – 2.12 < 0.0001
Hypothyroidism 2.31 2.05 – 2.60 < 0.0001
Increased total serum calcium concentration 1.43 1.21 – 1.69 < 0.0001
Hyperthyroidism 1.22 0.96 – 1.55 0.1
Increased adjusted calcium concentration 1.08 0.88 – 1.34 0.46

Rapid Effect

Young women had higher hazard ratios than other groups, which suggests they have the greatest risk for kidney disease and hypothyroidism.

The results also showed that the adverse effects occurred early in treatment and lessened with length of treatment (HR <1 for length of treatment with lithium). Higher than median lithium concentrations were associated with increased risk for all adverse outcomes.

The finding that length of lithium treatment has a negative association suggests that the onset of effects is rapid once patients start taking lithium, the authors write.

“All patients taking lithium therapy should have regular monitoring of renal function. The low risk of serious renal dysfunction should be balanced against the risks of the mood disorder and those of other mood stabilizers,” they add.

Because data for lithium dosing and renal risk are scarce, a “sensible” approach would be to minimize the dose of lithium used in general.

Patients receiving lithium should also undergo regular thyroid testing and have calcium levels measured at baseline and once a year thereafter, the authors advise.

They note that the strengths of their study are the large number of individuals and the length of follow-up, which, in many cases, was longer than 20 years.

The main limitations are the heterogeneity of the study population, the limited information on patients’ clinical features, not knowing why the specimens were taken, not knowing what proportion of patients taking lithium had bipolar vs unipolar disorder, and the lack of any information about the doses of lithium that were taken.

Balancing Act

In an accompanying editorial, Gin S. Malhi, MD, from the University of Sydney, in Australia, writes that lithium is “without doubt the best treatment for many patients with bipolar disorder because it confers long-term mood stability and prophylaxi…reduces the risk of suicide and is possibly neuroprotective.”

Dr Malhi agrees with Dr Shine and colleagues that patients receiving lithium therapy should have their renal and thyroid function and blood calcium levels checked at the start of therapy and monitored closely thereafter.

“Maintenance of lithium concentrations at the lower end of the therapeutic range (ie, 0.6 mmol/L) can reduce the adverse outcomes associated with lithium treatment,” Dr Malhi writes.

However, acheiving blood concentrations of lithium high enough to be efficacious but low enough to avoid toxicity is a “delicate balance,” he writes.

“The dilemma of lithium therapy arises because, if poorly managed, lithium can compromise renal function, sometimes irreversibly, and severely disrupt endocrine homoeostasis — ultimately limiting its usefulness. Therefore, lithium therapy remains a challenge that will benefit from a better understanding of its therapeutic properties,” Dr Malhi writes.