Your 65-year-old patient Mr. Hoffman recently saw his father through a devastating course of Alzheimer’s disease. Mr. Hoffman had his own risk assessed with ApoE genotyping, and the result—E4/E4—indicates a high risk. He comes to your office after reading an online article about low-dose lithium for dementia prevention and asks if you can prescribe it.

Dementia is a disaster for patients and their families. Current treatments can only temporarily slow the decline, but new evidence suggests that tiny doses of lithium can significantly delay the onset of dementia. Is it enough evidence to support prescribing 150 mg of lithium for patients like Mr. Hoffman?

Evidence for low-dose lithium

Several studies have found that patients with mood disorders who took lithium had a lower incidence of dementia than similar patients who were not prescribed lithium. This finding held up in three of four epidemiologic studies and five of six clinical studies (Ishii N et al, Int J Environ Res Public Health 2021;18(15):7756).

Another line of evidence is more indirect. Multiple studies have found an inverse relationship between lithium concentrations in drinking water and suicide rates. Those findings prompted studies of trace lithium exposure and incidence of dementia. Of these three epidemiologic studies, two found a correlation in support of lithium’s preventive effects. In the one negative study, average lithium exposures were unusually low.

Lacking industry support, randomized trials of lithium for the prevention of dementia are few and small. Of six studies reviewed in 2014 by Mauer et al, one was negative, one was positive, one used trace lithium (300 mcg/day) but was positive for preservation of cognitive function, and the rest examined only indirect outcome measures (Mauer S et al, Aust N Z J Psychiatry 2014;48(9):809–818).

Then came a 2019 continuation of the positive low-dose study by Forlenza and colleagues. All patients began the trial with mild cognitive impairment. The average serum lithium level was 0.4 mEq/L. At two- to three-year follow-up, cognition had declined in the placebo group but not in the lithium group (p=0.05). Unfortunately, nearly half the sample was lost to attrition (illness, medical complications, withdrawal from the study—not lithium-related problems) for a final N of only 34 participants, making it difficult to generalize these results (Forlenza OV et al, Br J Psychiatry 2019;215(5):668–674).

To sum up, the existing empirical evidence is suggestive of an antidementia effect with low-dose lithium, but we need more studies before drawing definitive conclusions. A larger randomized trial using full-dose lithium (serum levels of 0.6–0.8 mEq/L) is scheduled for completion in 2023 (the LATTICE trial).

Risks of low-dose lithium

What are the potential risks of low-dose lithium? Renal impairment is rare and is mainly a risk in patients on relatively high lifelong cumulative doses, especially when there are spikes above 0.8 mEq/L (Clos S et al, Lancet Psychiatry 2015;2(12):1075–1083). Lithium at low serum levels presents no significant renal risk if creatinine is monitored, as suggested by a two-year controlled trial that found no changes in renal function with low-dose lithium in the elderly (Aprahamian I et al, J Clin Psychiatry 2014 Jul;75(7):e672–678).

On the other hand, thyroid suppression by therapeutic doses of lithium is very common, affecting roughly 10% of patients who start standard doses of lithium (Kirov G et al, J Affect Disord 2005;87(2-3):313–317). Two sources of data suggest that even tiny doses of lithium can lower thyroid hormone. First, in the high Andes, some villages have as much as 1000 mcg/L of lithium in their water supply. In this region, urinary lithium concentrations are inversely correlated with free T4 (p=0.007). Second, in a small primary care study, 12% of patients given low-dose lithium (average level 0.43 mEq/L) had a TSH increase >4.2 mIU/L during follow-up. Thus it appears that low lithium doses, perhaps even less than 1 mg/day, may suppress thyroid function.

What about lithium orotate?

Lithium orotate is a salt of lithium and orotic acid. It is available in health food stores and via the internet, in doses closer to the lithium concentrations found in drinking water in some regions. For example, the common 5 mg pill contains 220 mcg of elemental lithium. However, low doses might not translate to low tissue levels. A 1978 study in rats found that brain lithium concentrations were three times higher with lithium orotate than regular lithium. Unfortunately, further research on lithium orotate was abandoned in 1979 when another rat study found greater renal toxicity with lithium orotate than with lithium carbonate.

Should you prescribe low-dose lithium?

The LATTICE study will substantially advance our understanding of lithium’s putative benefit for the prevention of dementia, but while awaiting those results in the next two to three years, are there some patients for whom lithium should be considered now?

Current evidence does not support widespread recommendation of low-dose lithium, but we can help patients who inquire about it. Lithium may be considered if a patient is seriously concerned about their risk of dementia for a variety of reasons: a strong family history, positive ApoE testing, mild cognitive impairment, or simply an acute awareness of the disastrous personal and family consequences of the illness. Cardiovascular disease, diabetes, obesity, sleep apnea, a history of substance abuse, recurrent depression, or schizophrenia also raise the risk.

Of course, first steps include behavioral risk reduction: regular physical activity, cognitive and social engagement, and a lipid-lowering, heart-healthy diet (van den Brink AC et al, Adv Nutr 2019;10(6):1040–1065). (Editor’s note: Both the Mediterranean and DASH diets have epidemiologic evidence to prevent dementia, and these approaches are very similar to the diet we presented for depression in the May 2019 and Nov/Dec 2021 issues of The Carlat Psychiatry Report.)

When those steps are in place, a highly motivated patient with no relative contraindications to lithium (eg, cardiac arrhythmias, psoriasis, renal impairment) could be offered low-dose lithium. Until further data are available to establish the safety of lithium orotate, the simplest practical dose to prescribe is 150 mg of lithium carbonate. Titration to higher doses could be considered for patients who already have minimal cognitive impairment, if fully tolerable (as treatment may go on for years), up to a serum level of 0.6–0.8 as per the LATTICE study.

CARLAT VERDICT

Accumulating evidence supports low-dose lithium to delay the onset of dementia. Until further data arrive, low-dose lithium could be considered for patients at high risk of dementia with monitoring of creatinine and TSH.