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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.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Trinity Center for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Tallaght, Dublin 24, Ireland. harald.hampel@med.uni-muenchen.de

    , , , , , , , , , , , , , ,

    Source

    The Journal of clinical psychiatry 70:6 2009 Jun pg 922-31

    MeSH

    Aged
    Aged, 80 and over
    Alzheimer Disease
    Amyloid beta-Peptides
    Enzyme Inhibitors
    Female
    Glycogen Synthase Kinase 3
    Humans
    Lithium Carbonate
    Male
    Mental Status Schedule
    Middle Aged
    Neuropsychological Tests
    Peptide Fragments
    Phosphorylation
    Psychometrics
    Single-Blind Method
    tau Proteins

    Pub Type(s)

    Journal Article
    Multicenter Study
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19573486

    Citation

    Hampel, Harald, et al. "Lithium Trial in Alzheimer's Disease: a Randomized, Single-blind, Placebo-controlled, Multicenter 10-week Study." The Journal of Clinical Psychiatry, vol. 70, no. 6, 2009, pp. 922-31.
    Hampel H, Ewers M, Bürger K, et al. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009;70(6):922-31.
    Hampel, H., Ewers, M., Bürger, K., Annas, P., Mörtberg, A., Bogstedt, A., ... Basun, H. (2009). Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. The Journal of Clinical Psychiatry, 70(6), pp. 922-31.
    Hampel H, et al. Lithium Trial in Alzheimer's Disease: a Randomized, Single-blind, Placebo-controlled, Multicenter 10-week Study. J Clin Psychiatry. 2009;70(6):922-31. PubMed PMID: 19573486.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. AU - Hampel,Harald, AU - Ewers,Michael, AU - Bürger,Katharina, AU - Annas,Peter, AU - Mörtberg,Anette, AU - Bogstedt,Anna, AU - Frölich,Lutz, AU - Schröder,Johannes, AU - Schönknecht,Peter, AU - Riepe,Matthias W, AU - Kraft,Inga, AU - Gasser,Thomas, AU - Leyhe,Thomas, AU - Möller,Hans-Jürgen, AU - Kurz,Alexander, AU - Basun,Hans, PY - 2008/08/08/received PY - 2008/11/13/accepted PY - 2009/7/4/entrez PY - 2009/7/4/pubmed PY - 2009/7/21/medline SP - 922 EP - 31 JF - The Journal of clinical psychiatry JO - J Clin Psychiatry VL - 70 IS - 6 N2 - 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. SN - 1555-2101 UR - https://www.unboundmedicine.com/medline/citation/19573486/Lithium_trial_in_Alzheimer's_disease:_a_randomized_single_blind_placebo_controlled_multicenter_10_week_study_ L2 - http://www.psychiatrist.com/jcp/article/pages/2009/v70n06/v70n0619.aspx DB - PRIME DP - Unbound Medicine ER -