Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review
7 affiliations
- 1Queen’s University Faculty of Health Sciences, Canada
- 2Brain and Cognition Discovery Foundation, Canada
- 3Department of Human Biology, University of Toronto, Canada
- 4University of Toronto Institute of Medical Science, Canada
- 5Poul Hansen Family Centre for Depression, University Health Network, Canada
- 6Department of Pharmacology, University of Toronto, Canada
- 7Department of Psychiatry, University of Toronto, Canada
Abstract
Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium’s effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium’s role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.
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BibTeX
@article{deng2026lithium,
title = {{Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review}},
author = {Rosalyn Deng and Alisa Shargorodsky and Kayla Teopiz and Christine E. Dri and Sabrina Wong and Gia Han Le and Yang Jing Zheng and Roger S. McIntyre},
journal = {CNS Spectrums},
year = {2026},
month = jun,
doi = {10.1017/s1092852926100996},
url = {https://doi.org/10.1017/s1092852926100996},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review
AU - Rosalyn Deng
AU - Alisa Shargorodsky
AU - Kayla Teopiz
AU - Christine E. Dri
AU - Sabrina Wong
AU - Gia Han Le
AU - Yang Jing Zheng
AU - Roger S. McIntyre
PY - 2026
DA - 2026/06/09
JO - CNS Spectrums
DO - 10.1017/s1092852926100996
UR - https://doi.org/10.1017/s1092852926100996
AB - Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium’s effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium’s role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.
SN - 1092-8529
SN - 2165-6509
ER -