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

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ClinicalTrials.gov 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

Sponsor:

Information provided by:

University of Sao Paulo

Study Description

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

Study Design


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

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Alzheimer disease

MedlinePlus related topics: Alzheimer's Disease

Drug Information available for: Lithium carbonate Lithium citrate

Genetic and Rare Diseases Information Center resources: Familial Alzheimer Disease

U.S. FDA Resources

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Information from the National Library of Medicine

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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

Criteria

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;

Contacts and Locations

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 ClinicalTrials.gov identifier (NCT number): NCT01055392

Locations


Brazil
Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
Sao Paulo, SP, Brazil, 05403-010

Sponsors and Collaborators

University of Sao Paulo

Investigators


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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Aprahamian I, Santos FS, dos Santos B, Talib L, Diniz BS, Radanovic M, Gattaz WF, Forlenza OV. Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. J Clin Psychiatry. 2014 Jul;75(7):e672-8. doi: 10.4088/JCP.13m08741.

Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6. doi: 10.1192/bjp.bp.110.080044.


Responsible Party:	Orestes Vicente Forlenza, Department and Institute of psychiatry, Faculty of Medicine - University of Sao Paulo
ClinicalTrials.gov Identifier:	NCT01055392 History of Changes
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 Lithium	disease-modification cognition early Alzheimer`s disease

Additional relevant MeSH terms:


Alzheimer Disease Cognitive Dysfunction Dementia Brain Diseases Central Nervous System Diseases Nervous System Diseases Tauopathies 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

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