Regular Research Article| Volume 30, ISSUE 1, P32-42, January 2022

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Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial


      • What is the primary question addressed by this study?
        The main goal was to evaluate the efficacy and side effects of low-dose lithium to treat agitation in Alzheimer's disease (AD).
      • What is the main finding of this study?
        In 77 patients with AD and agitation randomized to lithium or placebo in a four-site study, lithium was not significantly superior to placebo in treating agitation/aggression but demonstrated excellent safety. Compared to patients who received placebo, patients who received lithium showed greater improvement in Clinical Global Impression scores and greater improvement in patients with high Young Mania Rating Scale scores.
      • What is the meaning of the finding?
        Low-dose lithium was not efficacious in treating agitation in AD but was associated with global clinical improvement, reduction in behavioral symptoms that overlap with mania, and excellent safety.



      A case series suggested efficacy for lithium to treat agitation in dementia, but no placebo-controlled trials have been conducted.


      To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD).


      In a four-site trial, patients with AD and agitation/aggression score ≥4 on the Neuropsychiatric Inventory (NPI) were randomized, double-blind, to lithium carbonate 150–600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response (30% reduction in NPI score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved). Safety profile of lithium was assessed.


      Fifty-eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium was not significantly superior to placebo for agitation/aggression. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p = 0.26). Moderate or marked improvement (CGI) was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher's exact test p <0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p's<0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (β=5.06; 95%CI,1.18 to 8.94, p = 0.01). Oral dose and serum levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on safety outcomes.


      Low-dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted of likely lithium-responsive behavioral symptoms that overlap with mania.
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