Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study.

Abstract

OBJECTIVE:

Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer's disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer's disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer's disease.

METHOD:

A total of 71 patients with mild Alzheimer's disease (Mini-Mental State Examination score > or = 21 and < or = 26) were successfully randomly assigned to placebo (N = 38) or lithium treatment (N = 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5-0.8 mmol/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and beta-amyloid(1-42) (Abeta(1-42)), plasma levels of Abeta(1-42), Alzheimer's Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005.

RESULTS:

No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P > .05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P = .11) or in depressive symptoms.

CONCLUSIONS:

The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer's disease target population.

TRIAL REGISTRATION:

(Controlled-Trials.com) Identifier: ISRCTN72046462.

• Authors: Harald Hampel, Michael Ewers, Katharina Bürger, Peter Annas, Anette Mörtberg, Anna Bogstedt, Lutz Frölich, Johannes Schröder, Peter Schönknecht, Matthias W Riepe, Inga Kraft, Thomas Gasser, Thomas Leyhe, Hans-Jürgen Möller, Alexander Kurz, Hans Basun
• Journal: The Journal of clinical psychiatry (J Clin Psychiatry) Vol. 70 Issue 6 Pg. 922-31 (Jun 2009) ISSN: 1555-2101 [Electronic] United States
• PMID: 19573486 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Physicians Postgraduate Press, Inc.

Chemical References

• Amyloid beta-Peptides
• Enzyme Inhibitors
• MAPT protein, human
• Peptide Fragments
• amyloid beta-protein (1-42)
• tau Proteins
• Lithium Carbonate
• Glycogen Synthase Kinase 3

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (diagnosis, drug therapy, psychology)
• Amyloid beta-Peptides (metabolism)
• Enzyme Inhibitors (adverse effects, therapeutic use)
• Female
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Humans
• Lithium Carbonate (adverse effects, therapeutic use)
• Male
• Mental Status Schedule (statistics & numerical data)
• Middle Aged
• Neuropsychological Tests (statistics & numerical data)
• Peptide Fragments (metabolism)
• Phosphorylation
• Psychometrics
• Single-Blind Method
• tau Proteins (metabolism)