This trial is active, not recruiting.

Conditions cognitive impairment, alzheimer disease
Treatments lithium carbonate, placebo
Phase phase 2
Sponsor University of Sao Paulo
Start date March 2007
End date March 2009
Trial size 80 participants
Trial identifier NCT01055392, 554535/2005-0, OVForlenza-Lithium


Lithium salts have been used for the treatment of psychiatric disorders for over five decades, mostly as a mood-stabilizing drug. Recent evidence points to the inhibition of the enzyme glycogen synthase kinase-3beta (GSK3) as one of its mechanisms of action. The overactivity of this enzyme has been implicated in the pathogenesis of Alzheimer's disease (AD), given its involvement in mechanisms related to the hyperphosphorylation of Tau protein and the production of beta-amyloid peptide. These are key events leading respectively to the formation of neurofibrillary tangles and senile plaques, which are the neuropathological hallmarks of the disease. Several in vitro and animal studies have shown that the inhibition of GSK3 by lithium and other agents attenuates these pathological processes, reinforcing the notion that GSK3 is a likely target for future disease-modifying therapies for AD. Indeed, a recent study published by our group showed that chronic lithium use is associated with a decrement in the expected prevalence of dementia, in a sample of elderly individuals with bipolar disorder. To investigate this putative neuroprotective effect in a prospective way, the investigators started 24-month randomized, double-blinded controlled trial of lithium for the prevention of dementia in a sample of elderly individuals with amnestic mild cognitive impairment (MCI), a condition associated with increased risk for the development of AD. The clinical and biological outcomes of this trial include the attenuation of cognitive deficits, and the modification of certain biological markers of the disease (as measured in the cerebrospinal fluid, leukocytes and platelets). The objective of the present application is to enable the extension of this ongoing trial to an additional 2-year follow-up. A longer follow-up (48 months) will increase the statistical power to ascertain the primary outcome variables of this study, particularly the con-version from MCI to Alzheimer's disease. This will warrant a more consistent conclusion about the potential of lithium treatment in the prevention of dementia, in addition to a better evaluation of safety and tolerability profiles of the long-term use of lithium in older individuals.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose prevention
Patients received low doses of lithium salts (from 150 mg to 450 mg of lithium salts daily) to achieve sub-therapeutic lithium levels (target serum lithium level of 0,25 - 0,5 mEq/L). Lithium doses were administered twice a day. Lithium doses were titrated to achieve the target serum lithium levels within the first two weeks after study recruitment. After achieving the target serum lithium level, lithium salts doses remained stable until the end of the study.
lithium carbonate
lithium carbonate tablets, 150 mg to 450 mg (target serum lithium level 0.25 mEq/L - 0.5 mEq/L), divided in two doses, two years.
(Placebo Comparator)
Identical placebo tablets were administered twice-a-day for two years.
Identical placebo tablets were administered twice-a-day for two years.

Primary Outcomes

effect of lithium to delay progression of cognitive deficits in patients with amnestic MCI
time frame: two year

Secondary Outcomes

effect of lithium on CSF levels of Total Tau, Phosphorylated Tau and Amyloid-beta42
time frame: one year
the effect of lithium on the activity of GSK3β in platelets and leukocytes drawn from peripheral blood.
time frame: one year

Eligibility Criteria

Male or female participants from 60 years up to 80 years old.

Inclusion Criteria: - patients with amnestic mild cognitive impairment; - age: 60 to 80 years-old; Exclusion Criteria: - sensory deficiencies that might preclude the administration of cognitive tests; - active major psychiatry disorder; - unstable clinical conditions such as cardiac insufficiency, uncontrolled diabetes mellitus, renal failure; - previous use of lithium salts; - concurrent participation in other clinical trial or intervention studies;

Additional Information

Official title Disease-modifying Properties of Lithium in the Neurobiology of Alzheimer's Disease: a Double-blind, Placebo-controlled Prevention Study in Elderly Patients With Mild Cognitive Impairment
Principal investigator Orestes V Forlenza, Ph.D.
Trial information was received from ClinicalTrials.gov and was last updated in January 2010.
Information provided to ClinicalTrials.gov by University of Sao Paulo.