Can lithium improve longevity in the context of affective disorders? Original paper

In this cohort study, participants with an affective disorder taking lithium lived longer than participants taking another antipsychotic medication.

Whether taking lithium is associated with improved survival among people with an affective disorder, compared to taking other antipsychotic medications.

882 participants with an affective disorder (i.e., bipolar disorder, hypomania, depressive episode, or recurrent depressive disorder).

Using data from the UK Biobank cohort study, the investigators formed two groups of people with an affective disorder who were exclusively taking either lithium or another antipsychotic drug. The investigators used a technique called propensity score matching, resulting in two groups that were similar with respect to age (average ages of 57 and 58, respectively), sex, affective disorder diagnoses, and comorbidities (diabetes, cardiovascular disease, and cancer).

Mortality rates were then compared between the groups during 12 years of follow-up. This analysis excluded deaths resulting from accidents or suicide to determine whether lithium improves survival beyond what can be explained by effects on suicidality.

Compared to taking another antipsychotic medication, taking lithium was associated with a substantially lower likelihood of mortality (hazard ratio: 0.274).

Survival with lithium compared to other antipsychotic medications

This study found that taking lithium for an affective disorder is associated with a reduced mortality rates beyond what can be explained by a reduction in suicides alone. One 5-year study in people with bipolar disorder also found that use of lithium was associated with a lower risk of non-suicide mortality than use of other mood stabilizers.^[1] These studies were limited by their observational nature, but a few animal studies have also investigated whether lithium has pro-longevity effects, with the mineral extending the lifespan in yeast,^[2] roundworms,^[3][4][5] and fruit flies.^[6] However, one study in mice found that lithium did not increase lifespan, although it did improve measures of health span (e.g., physical function, glucose tolerance) in male mice, but not female mice.^[7] So although there is some evidence suggesting lithium has longevity-promoting properties, the evidence is not especially strong.

Lithium is also not without risks. To achieve a medicinal effect on mood disorders, blood levels of lithium typically need to be around 0.4–1.2 mmol/L. Lithium toxicity can occur once levels are near 1.4 mmol/L, meaning that the therapeutic window (the dose that provides a benefit without toxicity) of lithium is very narrow.^[8] Lithium toxicity can result in various adverse effects, including tremors, muscle weakness, nausea, impaired cognitive function, and hypothyroidism.^[9] Some studies have also reported an association between taking lithium and a higher risk of blood clotting events (e.g., pulmonary embolism),^[10][11] kidney disease,^[12][11] and Parkinson’s disease.^[11][13][14] Given the need to carefully monitor blood lithium levels to avoid toxicity, medical practitioners have become more reluctant to prescribe lithium in recent years.^[15]

Still, it’s theoretically possible that the level of lithium needed to extend lifespan might be low enough that such risks are mitigated. In fact, a number of researchers have speculated that “low-dose” or “microdose” lithium may indeed improve health and have antiaging effects in the general population.^[16][17] But is there actually compelling evidence to support this hypothesis?

Lithium is a mineral that is naturally present in the environment. As a result, tap water often contains some lithium, with variability depending on region.^[18] Even though the amount of lithium found in drinking water is at most a small fraction of the amount given in a medical context, some studies have examined whether this level might still affect health. One such study, conducted in Japan, found a correlation between higher lithium levels in tap water and lower mortality rates, even after adjusting for suicides.^[3] A separate study in Texas also found a correlation between higher tap water levels of lithium and lower rates of all-cause mortality, again, after adjusting for suicide rates.^[19] Unfortunately, these were both ecological studies, which are considered one of the weaker forms of observational evidence, so these studies are hardly definitive.

There is also some concern that the risks of even low doses of lithium are not fully understood, with one ecological study finding that greater exposure to lithium from tap water during pregnancy was associated with higher rates of autism in offspring.^[20]

When it comes to taking lithium for longevity, the evidence for taking higher doses may be outweighed by potential risks and the evidence for lower doses is currently too weak to inspire much confidence. That said, there are planned and ongoing clinical trials looking into the effects of low-dose or microdose lithium on conditions like dementia, long COVID, and bone fracture healing.

The study also compared the lifespan of participants with an affective disorder to that of a separate group of participants without an affective disorder and found that participants with an affective disorder had a higher likelihood of dying during follow-up. However, this does not appear to have been the primary focus of the study, and no adjustments for covariates or propensity matching were performed to minimize potential confounding between groups.