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

• ClinicalTrials.gov Identifier: NCT01055392
• Recruitment Status: Unknown
• First Posted: January 25, 2010
• Last Update Posted: January 25, 2010
• Sponsor: University of Sao Paulo
• 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

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.

Outcome Measures

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 ]

Eligibility Criteria

• 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

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):

Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry. 2019 Nov;215(5):668-674. doi: 10.1192/bjp.2019.76.

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
• Other Study ID Numbers: OVForlenza-Lithium; 554535/2005-0 ( Other Grant/Funding Number: Conselho Nacional de Pesquisa Científica )
• First Posted: January 25, 2010
• 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