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Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial

  • Orestes V. Forlenza (a1), Márcia Radanovic (a1), Leda L. Talib (a1) and Wagner F. Gattaz (a1)

Experimental studies indicate that lithium may facilitate neurotrophic/protective responses in the brain. Epidemiological and imaging studies in bipolar disorder, in addition to a few trials in Alzheimer's disease support the clinical translation of these findings. Nonetheless, there is limited controlled data about potential use of lithium to treat or prevent dementia.


To determine the benefits of lithium treatment in patients with amnestic mild cognitive impairment (MCI), a clinical condition associated with high risk for Alzheimer's disease.


A total of 61 community-dwelling, physically healthy, older adults with MCI were randomised to receive lithium or placebo (1:1) for 2 years (double-blind phase), and followed-up for an additional 24 months (single-blinded phase) (trial registration at NCT01055392). Lithium carbonate was prescribed to yield subtherapeutic concentrations (0.25–0.5 mEq/L). Primary outcome variables were the cognitive (Alzheimer's Disease Assessment Scale – cognitive subscale) and functional (Clinical Dementia Rating – Sum of Boxes) parameters obtained at baseline and after 12 and 24 months. Secondary outcomes were neuropsychological test scores; cerebrospinal fluid (CSF) concentrations of Alzheimer's disease-related biomarkers determined at 0, 12 and 36 months; conversion rate from MCI to dementia (0–48 months).


Participants in the placebo group displayed cognitive and functional decline, whereas lithium-treated patients remained stable over 2 years. Lithium treatment was associated with better performance on memory and attention tests after 24 months, and with a significant increase in CSF amyloid-beta peptide (Aβ1−42) after 36 months.


Long-term lithium attenuates cognitive and functional decline in amnestic MCI, and modifies Alzheimer's disease-related CSF biomarkers. The present data reinforces the disease-modifying properties of lithium in the MCI–Alzheimer's disease continuum.

Declaration of interest


Corresponding author
Correspondence: Orestes V. Forlenza, Laboratorio de Neurociencias (LIM-27), Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina daUniversidade de São Paulo, São Paulo, SP, BR. Rua Dr. Ovídio Pires de Campos 785, São Paulo, SP 05403-010, Brazil. Email:
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Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial

  • Orestes V. Forlenza (a1), Márcia Radanovic (a1), Leda L. Talib (a1) and Wagner F. Gattaz (a1)
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