Higher lithium levels are associated with a greater risk of long-term kidney harm and more frequent depressive episodes. This bipolar update reviews ways to minimize renal side effects.
To minimize renal side effects, lithium is best administered once daily at night, and one should routinely use the regular-release (24-hour half-life) preparation.1 It comes in tablets or capsules. Capsules are sometimes better tolerated because they do not have the salty taste that can contribute to nausea. They also are available in 150-mg doses, which is a convenient size for some patients on doses like 450 or 750 mg daily. Plasma levels during acute treatment should not be allowed to go higher than 1.0 mEq/L for a lower risk of long-term kidney harm.2
The regular-release formulation is preferred over the sustained release version (Lithobid; now available as a generic) because it provides superior pharmacokinetics for sparing the kidney of potential harm. Studies have shown that once-a-day lithium at night, compared with multiple daily doses, lowers urine volume and other symptoms of the lithium-induced diabetes insipidus-like syndrome.3 After the patient reaches the 12-hour postdose level following their evening dose (eg, 0.7 mEq/L), the patient’s level continues to drop during the day, reaching a low point just before the next once-daily dose. This low level is thought to give the kidneys an opportunity to have relatively little lithium coursing through them, which aids recovery from dysfunction, such as increased urine volume. When using a longer-acting preparation, further lowering the level during the second half of the day is minimal and, hence, the protective effect should be lower.
Trials examining renal biopsy results also found that multiple daily doses were associated with more pathological changes to the kidneys.1 Why doesn’t the higher peak lithium level associated with a large once-daily dose harm the kidneys? We can only say, based on the studies, that this effect must be less harmful than the absence of the daily low trough level. No reduction in effectiveness has been noted in any of the trials of once-daily lithium.1
Another possible advantage of giving the whole dose at night is that the kidneys filter lithium more slowly at night. The net effect is that you only need 80% of the daily divided doses when changing patients to a once-nightly regimen. For instance, if someone was on 1500 mg daily in divided doses, they would usually need 1200 mg at night to get the same 12-hour postdose level. The once-daily dose at night reduces the total exposure and need to excrete lithium as compared with the divided doses. It is also possible that tremors will be less bothersome with the once-daily dose: the worst of the tremors will occur in the middle of the night when the patient is (hopefully) sleeping, and the lowest level of severity will be in late afternoon and evening.
The optimal level for maintenance treatment with lithium is 0.6 mEq/L to 0.8 mEq/L, according to a recent analysis of the pertinent evidence.4 Higher maintenance levels are associated with a greater risk of long-term kidney harm and (surprisingly) more frequent depressive episodes.5 If patients are having breakthrough manias or hypomanias despite optimal maintenance levels of lithium and are also prone to serious depressions, it is better to add another antimanic agent instead of increasing lithium. Most patients with bipolar disorder experience more time in depressive states than manic states, so this will be a very common situation. If there are breakthrough depressions, consider adding lamotrigine, lurasidone, quetiapine, or cariprazine.6
Dr Osser is associate professor of psychiatry at Harvard Medical School and colead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.
1. Carter L, Zolezzi M, Lewczyk A. An updated review of the optimal lithium dosage regimen for renal protection. Can J Psychiatry. 2013;58(10):595-600.
2. Kirkham E, Skinner J, Anderson T, et al. One lithium level >1.0 mmol/L causes an acute decline in eGFR: findings from a retrospective analysis of a monitoring database. BMJ Open. 2014;4(11):e2006020.
3. Bowen R, Grof P, Grof E. Less frequent lithium administration and lower urine volume. Am J Psychiatry. 1991;148(2):189-192.
4. Nolen WA, Licht RW, Young AH, et al. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord. 2019;21(5):394-409.
5. Severus WE, Kleindienst N, Seemüller F, et al. What is the optimal serum level in the long-term treatment of bipolar disorder? A review. Bipolar Disord. 2008;10(2):231-237.
6. Wang D, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on bipolar depression. Bipolar Disord. 2020;22:472-489.❒