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Bayesian Reanalysis of a Pilot Randomized Clinical Trial of Low-Dose Lithium in Mild Cognitive Impairment: A
Anderson M P da Silva1, Diogo Haddad-Santos2, Daniel Vicente de Siqueira Lima3
1Division of Neurology (AMPDS), MemoryHub, Cognitive and Neurodegenerative Disorders Research Group, São Paulo, São Paulo, Brazil.
Objective:
The LATTICE pilot randomized clinical trial found no statistically significant effect of low-dose lithium on 6 coprimary outcomes in mild cognitive impairment (MCI). We aimed to re-express these results in Bayesian terms and estimate the probability of benefit, negligible difference, or harm across cognitive, neuroimaging, biomarker, and safety outcomes.
Methods:
We conducted a Bayesian reanalysis of published aggregate data from LATTICE, a single-site, randomized, double-blind, placebo-controlled 2-year trial of low-dose lithium carbonate versus placebo. The trial randomized 83 older adults with MCI, of whom 80 initiated treatment. Outcomes included verbal and visuospatial delayed recall, Preclinical Alzheimer Cognitive Composite, hippocampal and cortical volume measures, brain-derived neurotrophic factor, and serious adverse events. Posterior means, 95% credible intervals (CrI), and posterior probabilities were estimated using weakly informative priors.
Results:
Lithium was associated with a posterior mean standardized effect of 0.38 SD for CVLT-II delayed recall (95% CrI, -0.03 to 0.80), corresponding to a 96.5% probability of benefit and an 80.6% probability of exceeding 0.20 SD. The raw between-group difference was 1.47 points (95% CrI, 0.18-2.75). Bayesian re-expression of the intention-to-treat model showed an annualized CVLT-II treatment-by-time effect of 0.69 points per year (95% CrI, 0.02-1.35). BVMT-R remained near null. Hippocampal outcomes were directionally favorable but imprecise. Other cognitive, biomarker, imaging, and safety outcomes showed no robust signal.
Conclusions:
This Bayesian reanalysis supports an inconclusive interpretation of LATTICE, while identifying a probabilistic signal for verbal delayed recall-not seen in the other outcomes-that warrants testing in adequately powered trials.
Insights
This Bayesian reanalysis of the LATTICE trial suggests low-dose lithium may benefit verbal memory in mild cognitive impairment (MCI). However, results for other outcomes were inconclusive, requiring further investigation in larger studies.
Area of Science:
- Neuroscience
- Gerontology
- Clinical Trials
Background:
- The LATTICE trial investigated low-dose lithium for mild cognitive impairment (MCI).
- Initial findings showed no statistically significant effect on primary outcomes.
- A Bayesian reanalysis was performed to explore probabilistic interpretations.
Purpose of the Study:
- To re-express LATTICE trial results using Bayesian methods.
- To estimate the probability of benefit, negligible difference, or harm for various outcomes.
- To assess low-dose lithium's potential in mild cognitive impairment (MCI).
Main Methods:
- Bayesian reanalysis of aggregate data from the LATTICE randomized clinical trial.
- Utilized weakly informative priors to estimate posterior means and credible intervals.
- Included cognitive, neuroimaging, biomarker, and safety outcomes.
Main Results:
- A probabilistic signal for benefit in verbal delayed recall (CVLT-II) was observed (96.5% probability of benefit).
- Other cognitive, neuroimaging, biomarker, and safety outcomes showed no robust signals.
- Hippocampal outcomes were directionally favorable but lacked precision.
Conclusions:
- The Bayesian reanalysis supports an inconclusive interpretation of the LATTICE trial.
- A probabilistic signal for verbal delayed recall benefit warrants further testing.
- Larger, adequately powered trials are needed to confirm these findings.
