Long term toxicity of lithium treatment – a longitudinal population based study

Background

Lithium is an effective mood stabilizer and has been associated with reduced mortality, but long-term treatment is limited by concerns regarding nephrotoxicity. Because kidney function declines with age, distinguishing lithium-associated renal injury from expected age-related reduction in glomerular filtration rate can be challenging. The extent to which lithium-associated renal risk and potential survival benefit coexist within the same active-comparator population remains uncertain. Objective: To evaluate the association between lithium treatment and the risks of chronic kidney disease (CKD), chronic dialysis, and all-cause mortality compared with an active mood-stabilizer comparator, valproic acid, among patients with major psychiatric disorders treated for at least one year.

Methods

This population-based nested case–control study used electronic health records from Clalit Health Services, the largest health maintenance organization in Israel. Patients with schizophrenia, bipolar disorder, or depression who purchased prescriptions for lithium or valproic acid for at least one year were eligible. Separate matched nested case–control datasets were constructed for chronic kidney disease (CKD), dialysis, and mortality. Lithium exposure was evaluated as a binary exposure and further characterized by treatment intensity, defined as lithium purchases per year, and cumulative exposure, defined as the cumulative number of lithium purchases over follow-up. Associations were estimated using conditional logistic regression and reported as odds ratios (ORs) with 95% confidence intervals (CIs).

Results

The chronic kidney disease (CKD) analysis included 1,343 cases and 4,029 controls, the dialysis analysis included 158 cases and 790 controls, and the mortality analysis included 5,244 deceased patients matched to 5,244 controls. Following matching, baseline covariates were well balanced, with standardized mean differences below 0.1. Lithium use was more frequent among chronic kidney disease (CKD) cases than controls (49% vs 35%) and among dialysis cases than controls (51%vs 36%), whereas lithium use was less frequent among deceased patients than matched controls (30% vs 34%). Among patients treated for at least one year, lithium was associated with increased odds of chronic kidney disease (CKD) (OR 1.76, 95% CI 1.56–2.00) and dialysis (OR 1.89, 95% CI1.34–2.66), but lower odds of all-cause mortality (OR 0.84, 95% CI 0.78–0.92), compared with valproic acid. In cumulative exposure analyses, associations with chronic kidney disease (CKD), dialysis, and mortality were not consistently observed in patients treated with lithium for less than five years, whereas risk of renal dysfunction and increased risk of mortality became more evident in patients treated for five years or more.

Conclusions

Among patients with major psychiatric disorders treated with mood stabilizers for at least one year, lithium was associated with higher risks of CKD and dialysis but lower all-cause mortality compared with valproic acid. These findings suggest that the long-term benefit–risk profile of lithium should be evaluated over extended treatment durations, while considering both age-related renal decline and the need for renal monitoring after several years of cumulative exposure.

References

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