Commentary

Since the 1950s, lithium has been the drug of choice for treating bipolar affective disorder. Its optimal steady state concentration for maintenance therapy is generally considered to be 0.6–1.2 mEq/l, but the therapeutic index is rather narrow because toxicity occurs at levels >1.5 mEq/l and could even be present at lower concentrations. Lithium is excreted by glomerular filtration, and close monitoring of serum concentrations is mandatory in patients with altered renal function or who are receiving ACE inhibitors or NSAIDs.¹ Older patients with decreased glomerular filtration rate (GFR) are at risk of renal insufficiency after diuretic induced volume contraction, and it is likely that patients treated with long term lithium are at higher risk of toxicity because of tubular damage and impaired sodium reabsorption.^2,3 This could also partly explain why the risk of lithium intoxication is so high in patients newly treated with ACE inhibitors.

The observation of Juurlink et al, that patients newly treated with loop diuretics also have increased risk much higher than that associated with recent thiazide treatment, deserves other explanations. 60% of filtered lithium is reabsorbed in the proximal tubule, in a way similar to that of sodium, and 20% more is reabsorbed between the loop of Henle and the collecting duct. As for sodium, furosemide increases lithium clearance by blocking loop reabsorption, and thiazides do the same by blocking distal reabsorption. However, 3 pharmacological differences could explain the distinctive effects of these drugs on the risk of lithium intoxication. Firstly, a decrease in loop reabsorption increases the amount of lithium arriving in the distal tubule and induces a compensatory distal reabsorption that limits net excretion changes. Secondly, furosemide is a potent stimulator of the renin-angiotensin system, which could increase proximal lithium reabsorption. Thirdly, the shorter effect of furosemide is followed by large “sodium avid” periods, during which lithium balance could become positive enough to result in lithium intoxication.