Evaluation of Lithium as a Glycogen-Synthase-Kinase-3 (GSK-3) Inhibitor in Mild Cognitive Impairment

August 5, 2021 updated by: University of Dundee

The project is designed to generate critical information to design and justify a robust trial on lithium prevention of the onset of Alzheimer's disease (AD). Lithium exerts and inhibitory effect on Glycogen synthase kinase 3 (GSK-3) a brain biomarker of neuroprotection. The study consists of 3 phases:

  1. Phase 1 investigates rats to establish a reliable method to measure brain biomarker activity levels from blood biomarker activity.
  2. Phase 2 will determine whether the GSK3 enzyme activity is significantly different in subjects with MCI compared to normal individuals.
  3. Phase 3 investigates patients with MCI taking lithium to establish the minimum lithium dose required to inhibit the activity of GSK-3.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Lithium has been used for decades to treat Bipolar Affective Disorder. Some of its therapeutic benefits are through the inhibition of the enzyme Glycogen Synthase Kinase-3 (GSK-3). GSK3 activity is associated with the development of several aspects of AD and thus lithium can regulate an enzyme linked to AD development. As an important step towards designing a clinical trial to investigate the potential of lithium for AD prevention the investigators propose to establish the minimum dose of lithium needed to block GSK3 in people with Mild Cognitive Impairment (MCI), a high-risk condition for progression to AD. The study will establish whether GSK3 activity is altered in MCI and monitor lithium regulation of GSK3 biomarkers in this population. At the same time the study will investigate how GSK3 measured in blood relates to GSK3 activity in the brain in a small animal study. In further preparation for a future large scale trial, this pilot study will generate technical data to develop the technique of using Magnetic Resonance Spectroscopy (MRS) as a biomarker to detect the earliest brain changes of AD.

Recruitment will be shared between the two sites for this study, Dundee and Oxford. The study will involve 12 patients with MCI and 12 controls, who will be asked for two sets of blood tests, and 20 patients with MCI who consent to take Lithium who will be asked for blood tests at regular intervals. For all participants the study period is 12 weeks.

Study Type

Interventional

Enrollment (Actual)

11

Phase

  • Not Applicable

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

53 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • diagnosis of Mild Cognitive Impairment (MCI).

Exclusion Criteria:

  • Previous hypersensitivity to Lithium or other contraindication to Lithium carbonate Priadel (see most recent SmPC), Dementia Diabetes BMI <18 or >30 Rheumatoid Arthritis and Autoimmune Inflammatory disorders Currently taking NSAIDS Moderate renal failure (defined in BNF by gGFR <60 mL/minute/1.73m2) or severe Renal failure (defined in BNF by eGFR <29 mL/minute/1.73m2 Addison's disease, Brugada syndrome (or family history of Brugada syndrome), cardiac insufficiency, congestive cardiac failure, epilepsy, suicidality incapacity to consent currently prescribed lithium participation in another clinical trial of an Investigational Medicinal Product (IMP) in the last 28 days.

Uncontrolled serious concomitant physical illness

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: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Phase 3
Administration of Lithium to 11 individuals with MCI (non-randomised) for 9 weeks. Lithium dose escalates from 100mg to 200mg to 400mg, then a 3 week wash out period, total study duration 12 weeks. Blood samples taken at regular intervals throughout trial and analysed for GSK-3 enzyme activity in blood.
Drug: Lithium Carbonate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
GSK-3 activity in PBMC isolates
Time Frame: 12 weeks
Measures are six robust measures are of upstream/downstream signalling and GSK3 function and will be validated by other work by the investigators. GSK-3 function will be described according to plasma Lithium concentration.
12 weeks

Collaborators and Investigators

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

Sponsor

University of Dundee

Collaborators

University of Oxford

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

August 1, 2016

Primary Completion (Actual)

June 1, 2017

Study Completion (Actual)

June 1, 2017

Study Registration Dates

First Submitted

November 2, 2015

First Submitted That Met QC Criteria

November 6, 2015

First Posted (Estimate)

November 10, 2015

Study Record Updates

Last Update Posted (Actual)

August 9, 2021

Last Update Submitted That Met QC Criteria

August 5, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2014MH08

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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