Management of Lithium’s Adverse Effects: Update on Weight Gain

BIPOLAR UPDATE

It has long been assumed that lithium causes patients to gain a lot of weight when used to manage bipolar disorder. However, since we last reviewed this topic in Psychiatric Times 6 years ago, investigators have conducted a new systematic review and meta-analysis of 20 controlled trials of lithium vs placebo and other medications.¹ Weight gain was not significant, with a mean increase of approximately 1 lb, which may surprise readers. Lithium also caused less weight gain than most competing mood stabilizing medications, including valproate, olanzapine, and quetiapine, as demonstrated in head-to-head comparison studies with these other options.^1-3

So why is there a clinical impression that lithium is associated with some, and sometimes a lot of, weight gain? A speculation would be that lithium is not very good for treating patients with bipolar depression, either acutely or for maintenance.⁴ Such depressions frequently meet criteria for the atypical features specifier in DSM-5-TR, a syndrome that includes increased appetite and weight gain when depressed, as compared with more typical nonbipolar depressions that frequently involve loss of appetite and weight loss. Unless you have additional treatment that successfully manages bipolar depressions (some of which, like quetiapine, definitely cause weight gain), your patient may gain weight on lithium due to these depressions.

Nevertheless, at least 4 other processes may lead to weight gain from lithium. All should be anticipated and may require specific management strategies. First, there is the increased thirst associated with ingesting this salty inorganic compound. The key here is to avoid caloric beverages, including sugary sodas and fruit juices (which have just as much sugar as the sodas). Sugar-free sodas, water, and sugar-free sports beverages with more solute load than water are preferred. Before a patient starts lithium, ask what they like to drink when thirsty. If their preferences are for problem beverages, they need to prepare to find alternatives.

Next, there is the water retention secondary to the salt retention. A few patients put on weight very quickly,¹ and this is the likely explanation; adipose-based weight would increase much more slowly. There may be increased urination, which eliminates some of the water, but there is a net retention of fluid in some patients. A diuretic may help with this common problem of lithium-induced nephrogenic diabetes insipidus–like syndrome, which includes thirst and increased urine volume. The preferred diuretic is the potassium-sparing amiloride, 5 mg to 20 mg daily, because it does not (in most cases) increase lithium levels.⁵ It does increase them occasionally, so you must do an extra check to see if the level changes. Thiazide diuretics such as hydrochlorothiazide (HCTZ) also treat these symptoms, but they also raise lithium levels, typically by 50% to 100%. HCTZ is not contraindicated, but close monitoring is required to prevent lithium toxicity, and it may make sense to cut the lithium dose in half initially when HCTZ is started. The nephrogenic diabetes–like symptoms can also improve by prescribing lithium to be taken at night using the immediate release (24-hour half-life) formulation.⁶

A third factor in weight gain is slowed metabolism, associated with the well-known lithium adverse effect of hypothyroidism. This weight gain develops very slowly. Regular monitoring of thyroid-stimulating hormone levels and thyroid function, at least every 6 months, should detect this problem, and treatment may be required with replacement thyroid.

Finally, some patients report craving carbohydrates while taking lithium, though they may have had the craving before starting treatment. Patients will have a craving for bread, candy bars, cookies, and other sugary baked goods. This problem is associated with many other psychiatric medications (eg, the famous “munchies” from quetiapine), but finding alternative ways to manage hunger is tough. Advanced warning about this is important so patients recognize it if it starts and have a management strategy ready to implement, rather than having the problem identified only after the patient has gained 50 lb.

I hope the information in this article will influence clinical decisions.

Dr Osser is an associate professor of psychiatry at Harvard Medical School, and the lead psychiatrist, VA National Bipolar Disorders Telehealth Program, at VA Boston Healthcare System in Brockton, Massachusetts.

References

1. Gomes-da-Costa S, Marx W, Corponi F, et al. Lithium therapy and weight change in people with bipolar disorder: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2022;134:104266.

2. Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry. 2005;66(1):111-121.

3. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex and lithium vs placebo in the treatment of mania. The Depakote Mania Study Group. JAMA. 1994;271(12):918-924.

4. 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.

5. Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med. 1985;312(7):408-414.

6. 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.