The researchers, from the University of Cambridge, conducted a retrospective analysis of the health records of nearly 30,000 patients from Cambridgeshire and Peterborough NHS Foundation Trust. The patients were all over the age of 50 and accessed NHS mental health services between 2005 and 2019.
The analysis suggested that patients who received lithium were less likely to develop dementia than those who did not, although the overall number of patients who received lithium was small.
Their findings, reported in the journal PLoS Medicine, support the possibility that lithium could be a preventative treatment for dementia, and could be progressed to large randomized controlled trials.
Dementia is the leading cause of death in elderly Western populations, but no preventative treatments are currently available: more than 55 million people worldwide have dementia, with Alzheimer’s disease the most common form.
“The number of people with dementia continues to grow, which puts huge pressure on healthcare systems,” said Dr. Shanquan Chen from Cambridge’s Department of Psychiatry, the paper’s first author. “It’s been estimated that delaying the onset of dementia by just five years could reduce its prevalence and economic impact by as much as 40 percent.”
Previous studies have proposed lithium as a potential treatment for those who have already been diagnosed with dementia or early cognitive impairment, but it is unclear whether it can delay or even prevent the development of dementia altogether, as these studies have been limited in size.
Lithium is a mood stabilizer usually prescribed for conditions such as bipolar affective disorder and depression. “Bipolar disorder and depression are considered to put people at increased risk of dementia, so we had to make sure to account for this in our analysis,” said Chen.
Chen and his colleagues analyzed data from patients who accessed mental health services from Cambridgeshire and Peterborough NHS Foundation Trust between 2005 and 2019. Patients were all over 50 years of age, received at least a one-year follow-up appointment, and had not been previously diagnosed with either mild cognitive impairment or dementia.
Of the 29,618 patients in the study cohort, 548 patients had been treated with lithium and 29,070 had not. Their mean age was just under 74 years, and approximately 40% of patients were male.
For the group that had received lithium, 53, or 9.7%, were diagnosed with dementia. For the group that had not received lithium, 3,244, or 11.2%, were diagnosed with dementia.
After controlling for factors such as smoking, other medications, and other physical and mental illnesses, lithium use was associated with a lower risk of dementia, both for short and long-term users.
However, since the overall number of patients receiving lithium was small and this was an observational study, larger clinical trials would be needed to establish lithium as a potential treatment for dementia.
Another limitation of the study was the number of patients who had been diagnosed with bipolar disorder, which is normally associated with an increased risk of dementia. “We expected to find that patients with bipolar disorder were more likely to develop dementia, since that is the most common reason to be prescribed lithium, but our analysis suggested the opposite,” said Chen. “It’s far too early to say for sure, but it’s possible that lithium might reduce the risk of dementia in people with bipolar disorder.”
This paper supports others which have suggested lithium might be helpful in dementia. Further experimental medicine and clinical studies are now needed to see if lithium really is helpful in these conditions.
Lithium therapy is generally accepted as the first-line treatment for bipolar disorder. The standard therapeutic levels range from around 0.4 mEq/L to 1.0 mEq/L whereas such mood-stabilizing effects of lithium disappear less than 0.4 mEq/L in most patients with bipolar disorder. However, the effects of lithium on suicide prevention may be observed from trace to standard levels.
A meta-analysis demonstrated an inverse association between trace lithium levels in drinking water and the total and female suicide mortality rates in epidemiological studies . In clinical studies, for example, Kanehisa et al.  reported that mean lithium levels in the control group and those in the suicide-attempt group were higher than those in suicide attempters (0.00089 ± 0.00060 mEq/L, 0.00090 ± 0.00046 vs. 0.00068 ± 0.00045 mEq/L) with significant tendency.
Multivariate logistic regression analysis with adjustment for age and gender revealed that patients with suicide attempts had significantly lower log-transformed lithium levels than control patients (p = 0.032, odds ratio 0.228, 95% CI 0.059–0.883). Moreover, Kurosawa et al.  reconfirmed the findings by adjusting for relevant factors, including eicosapentanoic acid and docosahexanoic acid. That is, multivariate logistic regression analysis with adjustment for age, gender, EPA, DHA, arachidonic acid and log-transformed lithium levels revealed that the negative associations with EPA levels (adjusted OR 0.972, 95% CI 0.947–0.997, p = 0.031) and log-transformed lithium levels (adjusted OR 0.156, 95% CI 0.038–0.644, p = 0.01) and the positive association with DHA levels (adjusted OR 1.026, 95% CI 1.010–1.043, p = 0.002) were significant in patients with suicide attempts than in control patients. With regard to standard levels of lithium on suicide, Smith and Cipriani  showed evidence for lithium treatment on rates of suicide in patients with mood disorder. Therefore, trace to standard levels of lithium may be effective for suicide prevention.
Dementia is characterized by a deterioration in memory, thinking, behavior, and the quality of life. It develops because of a variety of diseases and injuries that directly and/or indirectly affect the brain. I
n particular, Alzheimer’s disease (AD) is the most common form of dementia, characterized by the accumulation of beta-amyloid outside neurons and hyper-phosphorylated tau inside neurons. Despite the current unavailability of essential anti-dementia drugs, lithium may decrease beta-amyloid and hyper-phosphorylated tau by inhibiting glycogen synthase kinase-3 (GSK-3) α and β [5,6].
In this review, we hypothesized that trace to standard levels of lithium (i.e., corresponding to the therapeutic levels for bipolar disorder) may be effective for AD prevention.
Original Research: Open access.
“Association between lithium use and the incidence of dementia and its subtypes: A retrospective cohort study” by Shanquan Chen et al. PLOS Medicine