Lithium Shows Promise, But Not Definitive, in Mild Cognitive Impairment Trial

A pilot study published in JAMA Neurology suggests a trial of low-dose lithium carbonate may be feasible for individuals with mild cognitive impairment (MCI), though definitive conclusions about its effectiveness require larger, more robust research. The two-year randomized, double-blind, placebo-controlled trial, led by researchers at the University of Pittsburgh, aimed to assess both the safety and potential impact of lithium on cognitive performance and brain structure in older adults experiencing early cognitive decline. While the study didn’t demonstrate statistically significant improvements, it provides encouraging data regarding retention and safety, paving the way for future investigations into lithium’s potential role in neurodegenerative disease.

Understanding Mild Cognitive Impairment

Mild cognitive impairment represents a transitional stage between normal age-related cognitive changes and more serious conditions like Alzheimer’s disease. Individuals with MCI may experience noticeable problems with memory, language, or thinking skills, but these deficits don’t yet interfere significantly with daily life. The Alzheimer’s Association estimates that up to 16 million Americans may be living with MCI, and a significant proportion will eventually develop dementia.

Lithium’s Potential Neuroprotective Effects

Lithium, a well-established mood stabilizer primarily used in the treatment of bipolar disorder, has garnered increasing attention for its potential neuroprotective properties. Previous research suggests lithium may promote brain health by increasing levels of brain-derived neurotrophic factor (BDNF), a protein crucial for neuronal survival and growth, and by modulating other pathways involved in neuroplasticity. These findings prompted researchers to explore whether low-dose lithium could slow cognitive decline in individuals with MCI.

Study Design and Key Findings

The University of Pittsburgh study enrolled 80 participants aged 60 and older diagnosed with MCI. Participants were randomly assigned to receive either daily low-dose lithium carbonate (mean dose of 195 mg) or a placebo for two years. Researchers assessed cognitive performance using several measures, including the California Verbal Learning Test-II (CVLT-II), Brief Visuospatial Memory Test-Revised, and a preclinical Alzheimer cognitive composite. They also monitored changes in hippocampal volume, cortical gray matter volume, and BDNF levels using MRI scans.

Retention rates were high, with over 80% of participants completing the study’s outcome assessments. Pill compliance among those who finished the trial was also excellent, at 98% in both the lithium and placebo groups. While there were no statistically significant differences between the groups on most cognitive measures, the lithium group exhibited a nominally significant, though not pre-specified, slower rate of decline in verbal memory scores as measured by the CVLT-II (P = .05). Hippocampal volume also showed a similar trend, decreasing less in the lithium-treated group, but this difference wasn’t statistically significant.

Safety Profile and Adverse Events

The study found that lithium was generally well-tolerated at the low dose used. A slightly higher proportion of patients in the lithium group (29%) experienced a serious adverse event compared to the placebo group (23%), but researchers determined that none of these events were “definitely related to study medication.” One patient in the placebo group died during the study. Common adverse events included increased creatinine levels (more frequent in the placebo group) and diarrhea and tiredness (more frequent in the lithium group). Tremor was also reported more often in the lithium group (24%) than in the placebo group (15%).

Interpreting the Results: Caution and Context

Ariel G. Gildengers, MD, professor of psychiatry at the University of Pittsburgh School of Medicine and geriatric psychiatrist at UPMC, emphasized the need for caution in interpreting these findings. “Lithium is not recommended to treat mild cognitive impairment or dementia, either on-label or off-label,” she stated. “While the results were encouraging, they were not definitive, and larger, well-designed clinical trials are still needed.”

The study’s limitations include its relatively small sample size and the lack of biological markers to identify participants most likely to benefit from lithium treatment. The nominally significant finding regarding verbal memory requires confirmation in larger studies with a more stringent statistical threshold.

What’s Next for Lithium and Cognitive Impairment Research?

Researchers are planning future studies to address these limitations. These trials will likely involve larger sample sizes and incorporate biomarkers of Alzheimer’s disease to identify individuals at higher risk of progression. There’s also growing interest in exploring whether lithium could be used in combination with other therapies to enhance cognitive function and slow disease progression. March 11th also marks National Dream Day, a fitting reminder of the ongoing pursuit of treatments for cognitive decline.

Ariel G. Gildengers, MD can be reached at [email protected].