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Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial
D P Devanand1, Elizabeth Crocco1, Brent P Forester1
1Division of Geriatric Psychiatry (DPD, LSP, EDH, DAD, GHP), New York State Psychiatric Institute, NY; Department of Psychiatry (DPD, SL, HA, EDH, BAD, GHP), Columbia University Medical Center, NY; Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, (DPD, EDH), Columbia University Medical Center, NY; Center for Cognitive Neuroscience and Aging, Department of Psychiatry and Behavioral Sciences (EC, LL), University of Miami Miller School of Medicine Miami, FL; Division of Geriatric Psychiatry (BPF, IVV), McLean Hospital, Harvard Medical School, MA; Departments of Psychiatry and Neurology (MMH, NI), University of Texas Southwestern Medical Center, TX; Mental Health Data Science, Department of Psychiatry (SL, HA), Columbia University Medical Center and New York State Psychiatric Institute, NY.
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.
