Effect of Lithium and Divalproex in Alzheimer's Disease

March 3, 2008 updated by: National Institute of Neurological Disorders and Stroke (NINDS)

Glycogen Synthetase Kinase 3 (GSK-3) Inhibition in Alzheimer's Disease

This study will examine the effect of the drugs lithium and divalproex (Depakote) on tau proteins, a type of protein in the brain and spinal fluid that are altered in patients with Alzheimer's disease. Both drugs are approved by the Food and Drug Administration to treat mood disorders, and both have been shown in animal studies to decrease the amount of altered tau protein. This study will determine whether lithium alone or in combination with divalproex reduces the altered tau protein in the spinal fluid of patients with Alzheimer's disease.

Patients with Alzheimer's disease who are between 40 and 90 years of age may be eligible for this study. Candidates are screened with a medical history and physical examination, neurologic and neuropsychological evaluation, blood and urine tests, electrocardiogram (EKG), and, if needed, a magnetic resonance imaging (MRI) scan of the brain.

Participants undergo the following tests and procedures:

  • Drug treatment: Patients take study drugs for 6 weeks.
  • Weekly clinic visits: Patients come to the clinic once a week for a physical examination, blood and urine tests, a review of drug side effects, and to receive the next week's supply of medications.
  • Lumbar puncture (spinal tap): Patients have a lumbar puncture at study weeks 2, 4, and 6 to measure various brain chemicals and tau proteins in the cerebrospinal fluid (CSF), which bathes the brain and spinal cord. For this test, a local anesthetic is given and a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle.
  • Follow-up visit: Two weeks after completing the study medication, patients return to the clinic for a final evaluation, including a physical examination and blood and urine tests.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The overall objective of this study is to examine the acute effects of lithium alone and/or in combination with divalproex on surrogate measures of neuroprotective activity in patients with Alzheimer's disease. It is hypothesized that at safe and tolerable doses these drugs will inhibit glycogen synthase kinase-3 activity and reduce the phosphorylated tau epitopes threonine-181 and threonine-231 implicated in the pathogenesis of this disorder. In this proof-of-principle study, efficacy on reducing tau phosphorylated epitopes will be assessed through cerebrospinal fluid (CSF) measurements. Safety will be monitored by means of frequent clinical evaluations and laboratory tests.

Study Type

Interventional

Enrollment

35

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institute of Neurological Disorders and Stroke (NINDS)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

INCLUSION CRITERIA:

Patient is between the ages of 40 and 90 (inclusive).

Patient will have a diagnosis of AD; the study will be confined to patients who are able to provide consent (pass a capacity assessment).

The modified Hachinski Ischemia Score must be less than 4.

Brain MRI performed within 15 months of enrollment must be compatible with the diagnosis of AD.

Patient and/or caregiver are willing to adhere to protocol requirements as evidenced by written, informed consent.

EXCLUSION CRITERIA:

Patients meeting any of the following exclusion criteria during screening or during the study will not be enrolled or will be immediately excluded from the study, as appropriate:

Patient has a history of any medical condition that can reasonably be expected to subject the patient to unwarranted risk.

Patient has clinically significant laboratory abnormalities that would preclude administration of lithium and divalproex.

Patient is taking a prohibited concomitant medication. The following medications are forbidden for at least one month prior to the treatment phase (unless otherwise noted) and during the course of the study:

Any investigational drugs;

Anti-depressants (eligibility will be considered as long as dosage remains stable throughout the study);

Anticonvulsants and other mood stabilizing drugs;

Treatment that may provoke lithium toxicity due to reduced renal clearance, including metronidazole, spectinomycin, tetracycline;

Treatment that may substantially increase steady-state plasma lithium levels resulting in lithium toxicity, including angiotensin-converting enzyme inhibitors, NSAIDS, diuretics;

Treatment that may increase the risk of neurotoxicity, including calcium channel blocking agents;

Drugs that may increase urinary lithium excretion resulting in lower serum lithium concentrations, such as acetazolamide, urea, xanthine preparations, alkalinizing agents such as sodium bicarbonate, theophylline;

Drugs that interact with lithium, including methyldopa;

Neuroleptics (eligibility will be considered as long as dosage remains stable throughout the study). If patient is on existing atypical neuroleptic drugs, these will be continued at the same dose. Patients will not start a new prescription for atypical antipsychotics during the study;

Drugs that may prolong the effects of lithium, including neuromuscular blocking agents;

Digoxin, warfarin.

Patient has not been using an adequate contraceptive method for the last 30 days or unwilling to continue contraception throughout the study, or is not at least one year post-menopausal (if female).

Patient is pregnant or breastfeeding.

Patient has participated in a clinical study with an investigational drug within the last 30 days.

Patient has a condition (such as active drug or alcohol abuse) that, in the opinion of the investigators, would interfere with compliance or safety.

Patient has known hypersensitivity to lithium or divalproex.

Patient's inability to swallow tablets or to comply with medication schedule.

Patient has no adequate caregiver.

Patient and/or caregiver are unwilling to sign an informed consent or to comply with protocol requirements.

Patient is unwilling to have lumbar puncture.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2004

Study Completion

March 1, 2005

Study Registration Dates

First Submitted

July 23, 2004

First Submitted That Met QC Criteria

July 23, 2004

First Posted (ESTIMATE)

July 26, 2004

Study Record Updates

Last Update Posted (ESTIMATE)

March 4, 2008

Last Update Submitted That Met QC Criteria

March 3, 2008

Last Verified

March 1, 2005

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 040243
  • 04-N-0243

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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