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Lithium Trial in Alzheimer's Disease: A Randomized, Single-Blind, Placebo-Controlled, Multicenter 10-Week Study

Harald Hampel, MD, MsC; Michael Ewers, PhD; Katharina Bürger, MD; Peter Annas, PhD; Anette Mörtberg, MD; Anna Bogstedt, PhD; Lutz Frölich, MD, PhD; Johannes Schröder, MD; Peter Schönknecht, MD; Matthias W. Riepe, MD; Inga Kraft, PhD; Thomas Gasser, MD; Thomas Leyhe, MD; Hans-Jürgen Möller, MD; Alexander Kurz, MD; and Hans Basun, MD, PhD


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 ≥ 21 and ≤ 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-amyloid1–42 (Abeta1–42), plasma levels of Abeta1–42, 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.

Conclusion: 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

 

(J Clin Psychiatry 2009;70(6):922-931. doi:10.4088/JCP.08m04606)


Received August 8, 2008; accepted November 13, 2008. From the Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Laboratory of Neuroimaging & Biomarker Research, Trinity College, University of Dublin, and Trinity Centre for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital, Dublin, Ireland (Drs Hampel and Ewers); Dementia and Neuroimaging Research Section, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Munich, Germany (Drs Hampel, Ewers, Bürger, and Möller); AstraZeneca, Research & Development, Sodertaelje, Sweden (Drs Annas, Mörtberg, Bogstedt, Kraft, and Basun); the Central Institute of Mental Health, Mannheim, Germany (Dr Frölich); Section of Geriatric Psychiatry, University of Heidelberg, Germany (Drs Schröder and Schönknecht); the Division of Mental Health & Old Age Psychiatry, Ulm University, Germany (Dr Riepe); Department of Neurodegenerative Diseases, Hertie Institute of Clinical Brain Research, Eberhards-Karls University of Tübingen, Germany (Dr Gasser); the Department of Psychiatry and Psychotherapy, Geriatric Center at the University Hospital of Tübingen, Germany (Dr Leyhe); and Department of Psychiatry, Technical University of Munich, Germany (Dr Kurz).

The current study was funded by Astra Zeneca, Sodertaelje, Sweden, and by academic and research support of the Adelaide and Meath Hospital, Dublin Incorporating the National Children's Hospital; the Health Service Executive; and Trinity College; Dublin, Ireland (to Dr Hampel).

Acknowledgments are listed at the end of the article.

Drs Hampel and Ewers contributed equally to the study.

Financial disclosure is listed at the end of the article.

Corresponding author and reprints: Harald Hampel, MD, Trinity Center for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Tallaght, Dublin 24, Ireland (e-mail: harald.hampel@med.uni-muenchen.de).