Low-Dose Lithium Shows Mixed Benefits for Alzheimer, Fails to Improve Behavioral Complications

Despite not being significantly superior to placebo on agitation and aggression, lithium showed a greater reduction in those with high Young Mania Rating Scale scores.

Results from Lit-AD (NCT02129348), a multisite randomized controlled trial, found no evidence that treatment with low-dose daily lithium improves agitation in patients with Alzheimer disease (AD), but was associated with global clinical improvement and excellent safety. The findings, presented at the 14th Clinical Trials on Alzheimer’s Disease Conference (CTAD), November 9-12, were deemed likely unsuccessful due to the study’s limited statistical power, according to the study authors.

In total, 77 patients with agitation/aggression scores of at least 4 on the Neuropsychiatric Inventory (NPI) and Folstein Mini-Mental State Examination (MMSE) scores ranging 5-26, were randomized 1:1 to either low-dose lithium carbonate 150-600 mg daily (n = 38) or placebo (n = 39) for 12 weeks, with within-site stratification by psychosis status. In total, 58 of the 77 patients (75.3%) completed the trial.

Led by Davangere P. Devanand, MD, director, Geriatric Psychiatry, and professor of psychiatry and neurology, Columbia University Medical Center, mixed effects models showed that lithium (NPI change, 3.2 [95% CI, 1.7-4.6]) was not significantly superior to placebo (NPI change, 2.5 [95% CI, 1.1-4.0]) for agitation/aggression. The proportion of responders, a secondary outcome, was 31.6% (n = 12) for those on lithium and 17.9% (n = 7) for those on placebo (X2(1) = 1.26; P = .26).

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Investigators observed that Clinical Global Impression (GCI) behavior change on lithium (31.6%; n = 12) was not greater than on placebo (20.5% [n = 8]; X2(1) = 0.72; P = .40); however, there was a greater GCI global change in the lithium group (36.8%; n = 10) compared with placebo (0% [n = 0]; Fisher’s exact test; P <.001).

Devanand et al wrote, "these pilot findings suggest the need for a larger clinical trial with precision pharmacological targeting of likely lithium-responsive behavioral symptoms that may overlap with symptoms of mania."

Secondary analysis showed that lithium (change, 14.1 [95% CI, 6.1-22.1]) was not greater than placebo (change, 8.8 [95% CI, 0.8-16.7]) on improving NPI total score. Patients on low-dose lithium did however show more improvements on NPI delusions (P = .04) and irritability/lability (P <.05). Lithium was superior to placebo in patients with high Young Mania Rating Scale (YMRS) scores defined by a median split (B = 5.06 [95% CI, 1.18-8.94]; t(62) = 2.61; P = .01), but not in patients with low YMRS scores (B = –0.91 [95% CI, –4.78 to 2.96]; t(63) = –0.47; P = .641).

The time by treatment group by YMRS group interaction was significant (P = .03). Even after including age, sex, baseline MMSE, baseline Cumulative Illness Rating Scale-Geriatric score, apolipoprotein E4 genotype, and antidepressant or antipsychotic use, the results of all efficacy analyses remained true. Investigators observed no significant treatment group effect for change in semantic adverse effects, serum creatinine, thyroid function test, cognition or function.

"Lithium can be difficult to use in older adults, but the favorable side effect profile observed with low doses and low blood levels suggests potential clinical applicability if efficacy is established in a larger clinical trial,” Devanand et al concluded.

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REFERENCE
Devanand DP, Crocco E, Forester BP, et al. Low dose lithium treatment of behavioral complications in Alzheimer disease: Lit-AD randomized clinical trial. Presented at CTAD 2021; November 9-12; Boston, MA, and virtual. Poster P4.