Is lithium used in the treatment of dementia?

Lithium for Dementia Treatment

Lithium is not currently recommended in established clinical practice guidelines for the treatment of dementia, though emerging research evidence suggests potential protective effects that warrant consideration in specific clinical contexts.

Current Guideline Recommendations

The major dementia treatment guidelines do not include lithium as a standard therapeutic option:

• Standard pharmacological treatments for dementia include cholinesterase inhibitors (donepezil, galantamine, rivastigmine) for mild to moderate Alzheimer's disease and memantine for moderate to severe dementia 1, 2.

• No mention of lithium appears in the American Academy of Neurology's dementia guidelines 1 or the American College of Physicians/American Academy of Family Physicians joint guideline 1 for dementia treatment.

• The only guideline reference to lithium for any cognitive disorder is for Kleine-Levin syndrome (a hypersomnolence disorder, not dementia), where the American Academy of Sleep Medicine suggests lithium use 1.

Emerging Research Evidence

Despite the absence of guideline support, recent research provides increasingly compelling evidence for lithium's potential role:

Prevention of Dementia

The most recent and highest quality evidence comes from a 2022 retrospective cohort study of 29,618 patients that found lithium use was associated with significantly lower risk of:

• Overall dementia (HR 0.56,95% CI 0.40-0.78) 3
• Alzheimer's disease (HR 0.55,95% CI 0.37-0.82) 3
• Vascular dementia (HR 0.36,95% CI 0.19-0.69) 3

This protective effect appeared in both short-term (≤1 year) and long-term (>5 years) users, with evidence suggesting additional benefit with longer exposure 3.

Meta-Analysis Findings

A 2024 meta-analysis of seven studies confirmed that lithium therapy:

• Reduced AD risk (RR 0.59,95% CI: 0.44-0.78) 4
• Reduced overall dementia risk (RR 0.66,95% CI: 0.56-0.77) 4
• Showed duration-dependent effects on dementia incidence (RR 0.70,95% CI: 0.55-0.88) 4

Treatment of Behavioral Symptoms

For treating existing dementia with behavioral complications, the evidence is less supportive:

• A 2022 randomized controlled trial (the Lit-AD trial) found that low-dose lithium (150-600 mg daily) did not significantly reduce agitation/aggression in Alzheimer's disease patients compared to placebo 5.

• However, lithium was associated with greater global clinical improvement (36.8% vs 0% showing moderate/marked improvement on CGI, p<0.001) and showed excellent safety 5.

• Exploratory analyses suggested benefit for delusions and irritability/lability, particularly in patients with high mania scores 5.

Mechanistic Rationale

Lithium's theoretical benefits stem from:

• Inhibition of glycogen synthase kinase-3 (GSK-3) 6
• Reduction of beta-amyloid and hyperphosphorylated tau 6
• Neuroprotective effects even at trace or low doses 7

Clinical Considerations and Caveats

Critical Limitations

• No large-scale randomized controlled trials have been conducted specifically for dementia prevention or treatment 6, 7.
• Most evidence comes from observational studies with inherent confounding risks 3.
• The bipolar disorder indication for lithium creates confounding, as bipolar disorder itself is a dementia risk factor 3.
• Small sample sizes in clinical trials limit generalizability 5.

Safety Concerns

• Lithium toxicity is closely related to serum concentrations and can occur at doses close to therapeutic levels 1.
• Regular monitoring of serum lithium concentrations is mandatory 1.
• Potential fetal harm based on animal and human studies 1.
• Common adverse effects include tremor, polyuria-polydipsia, diarrhea, and subclinical hypothyroidism 1.

Practical Clinical Approach

Given the current evidence landscape:

For dementia prevention in patients already on lithium for bipolar disorder:

• Continue lithium therapy with appropriate monitoring, as emerging evidence suggests potential protective benefits 4, 3.

For treating behavioral symptoms in established dementia:

• Prioritize non-pharmacological approaches first 2.
• Use standard antipsychotics when environmental manipulation fails 1.
• Consider lithium only in research settings or exceptional circumstances where standard treatments have failed and the patient has prominent manic-like symptoms 5.

For primary prevention in patients without bipolar disorder:

• Do not initiate lithium solely for dementia prevention outside of clinical trials, as this remains investigational 6, 7.

The evidence suggests lithium may have disease-modifying potential for dementia, but larger randomized controlled trials are urgently needed before lithium can be recommended as standard dementia treatment 1, 6, 3.