Dose Lithium Once a Day at Night: An Update

Use of multiple daily doses of lithium is still common. Practitioners may not be aware of the evidence, summarized in a systematic review, that a once-daily dosing schedule helps prevent lithium-induced nephrogenic diabetes insipidus and lithium nephropathy.¹ This was confirmed in a survey of outcomes of 4306 patients in a large New England health care system who were taking lithium. Investigators found there was an increased prevalence of renal insufficiency in patients who took lithium more than once daily.² Renal biopsy studies have found that multiple daily doses are associated with more pathological changes to the kidneys.³ No reduction in maintenance effectiveness has been noted in any of the trials of once-daily lithium, and adherence is better.³

To minimize renal adverse effects, lithium is best administered at night, and one should routinely use the regular-release (24-hour half-life) preparation.³ 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 are available in 150-mg doses, which is a convenient size for some patients taking 450 or 750 mg daily. Plasma levels during acute treatment should not exceed 1.0 mEq/L to reduce the risk of long-term kidney harm,⁴ and for maintenance, the least harm is associated with levels of 0.6 mEq/L or lower.² The optimal level for maintenance efficacy with lithium is 0.6 to 0.8 mEq/L, according to an analysis of the pertinent evidence.⁵ 

The regular-release formulation is preferred over sustained-release formulations because it provides superior pharmacokinetics, sparing the kidney from potential harm. After the patient reaches the 12-hour postdose level following their evening dose, their level continues to drop throughout 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 toxicity at the higher levels. When using a longer-acting preparation, levels remain relatively high during the second half of the day, so the opportunity for relief from toxicity does not occur.

Another possible advantage of giving the whole dose at bedtime is that the kidneys filter lithium more slowly at night. The net effect is that you only need approximately 80% of the daily divided doses when changing patients to a once-nightly regimen. For instance, if a patient 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 total exposure and the need to excrete lithium compared with divided doses. It is also possible that tremors will be less bothersome with the once-daily dose. The worst tremors will occur in the middle of the night, when the patient is (hopefully) asleep, and the lowest level of severity will be in late afternoon and evening.

Higher maintenance levels of lithium have been associated with more frequent depressive episodes.⁶ If patients experience breakthrough manias or hypomanias requiring treatment despite optimal maintenance levels of 0.6 to 0.8 mEq/L, and are also prone to significant depressive episodes, it is better to add another antimanic agent rather than increase the lithium dose. 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, cariprazine, or lumateperone.^7,8

Dr Osser is an associate professor of psychiatry at Harvard Medical School and lead psychiatrist of the US Department of Veterans Affairs' National Bipolar Disorders Telehealth Program in Brockton, Massachussetts. He has no conflicts of interest to disclose.

References

1. Schoot TS, Molmans THJ, Grootens KP, Kerckhoffs APM. Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy. Eur Neuropsychopharmacol. 2020:31:16-32.

2. Castro VM, Roberson AM, McCoy TH, et al. Stratifying risk for renal insufficiency among lithium-treated patients: an electronic health record study. Neuropsychopharmacology. 2016;41(4):1138-1143.

3. 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.

4. 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.

5. 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.

6. 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.

7. Osser DN. Update: bipolar depression algorithm. In: Psychopharmacology Algorithms. 2nd ed. Wolters Kluwer Health;2025:38-46.

8. Wang D, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on bipolar depression. Bipolar Disord. 2020;22(5):472-489.