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Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study.
J Clin Psychiatry 2009; 70(6):922-31JC

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+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.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -