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

Am J Geriatr Psychiatry. 2022 Jan;30(1):32-42. doi: 10.1016/j.jagp.2021.04.014. Epub 2021 May 12.


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

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

Method: 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.

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT02129348.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / complications
  • Alzheimer Disease* / diagnosis
  • Alzheimer Disease* / drug therapy
  • Double-Blind Method
  • Humans
  • Lithium Compounds / adverse effects
  • Lithium* / therapeutic use
  • Psychomotor Agitation / drug therapy
  • Psychomotor Agitation / etiology
  • Psychomotor Agitation / psychology
  • Treatment Outcome


  • Lithium Compounds
  • Lithium

Associated data

  • ClinicalTrials.gov/NCT02129348