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Disease-modifying Properties of Lithium in the Neurobiology of Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01055392
Recruitment Status : Unknown
Verified December 2009 by University of Sao Paulo.
Recruitment status was:  Active, not recruiting
First Posted : January 25, 2010
Last Update Posted : January 25, 2010
Information provided by:
University of Sao Paulo

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Cognitive Impairment Alzheimer Disease Drug: Lithium Carbonate Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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
Study Start Date : March 2007
Actual Primary Completion Date : March 2009

Arm Intervention/treatment
Experimental: Lithium
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.
Drug: 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: Placebo
Identical placebo tablets were administered twice-a-day for two years.
Drug: Placebo
Identical placebo tablets were administered twice-a-day for two years.

Primary Outcome Measures :
  1. effect of lithium to delay progression of cognitive deficits in patients with amnestic MCI [ Time Frame: two year ]

Secondary Outcome Measures :
  1. effect of lithium on CSF levels of Total Tau, Phosphorylated Tau and Amyloid-beta42 [ Time Frame: one year ]
  2. the effect of lithium on the activity of GSK3β in platelets and leukocytes drawn from peripheral blood. [ Time Frame: one year ]

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Ages Eligible for Study:   60 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01055392

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Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
Sao Paulo, SP, Brazil, 05403-010
Sponsors and Collaborators
University of Sao Paulo
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Principal Investigator: Orestes V Forlenza, Ph.D. Department and Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
Study Director: Wagner F Gattaz, Ph.D. Department and Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Orestes Vicente Forlenza, Department and Institute of psychiatry, Faculty of Medicine - University of Sao Paulo Identifier: NCT01055392    
Other Study ID Numbers: OVForlenza-Lithium
554535/2005-0 ( Other Grant/Funding Number: Conselho Nacional de Pesquisa Científica )
First Posted: January 25, 2010    Key Record Dates
Last Update Posted: January 25, 2010
Last Verified: December 2009
Keywords provided by University of Sao Paulo:
mild cognitive impairment
Alzheimer's disease
early Alzheimer's disease
Additional relevant MeSH terms:
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Alzheimer Disease
Cognitive Dysfunction
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Lithium Carbonate
Antidepressive Agents
Psychotropic Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs