Research Brief: Lithium for ALS—Another Nail in the Coffin?

Yet again, lithium has failed to live up to its promise in the treatment of amyotrophic lateral sclerosis. In a Neurology article posted online August 11, researchers of the LITALS Study Group report on a multicenter trial in Italy, which was deemed futile and stopped early in November 2009.

Adriano Chiò, of the Università degli Studi di Torino in Italy, led this latest effort to follow up on a 2008 report that lithium extended survival in a small cohort (see ARF related news story on Fornai et al., 2008). Another lithium trial was also halted early due to futility in September 2009 (see ARF related news story on Aggarwal et al., 2010).

The Italian group recruited 171 people with ALS and divided them into two treatment arms. One group received the same lithium dose as used in the 2008 trial. The others received half that dose, a level not known to have efficacy in any of lithium’s uses, as a pseudo-placebo. Because many people in the ALS community have pursued lithium prescriptions on their own, it is difficult to recruit subjects for a study including a regular placebo.

By last fall, when more than 85 percent of participants had completed 15 months of therapy or dropped out, the researchers evaluated the results. Between the two treatment groups, there was no difference in people’s ability to breathe on their own or perform daily functions. Compared to historic controls, the authors write, people on lithium may have actually done a bit worse.

People on both doses reported adverse side effects, including neurologic problems, tremors, and thyroid problems. More than one-third of the participants dropped out, either because they experienced unpleasant side effects or perceived no benefit from the therapy.

Is this the last of lithium for ALS? Not quite, according to an editorial penned by Carmel Armon of the Baystate Medical Center in Springfield, Massachusetts. He notes that with no placebo in the study, it is difficult to definitively interpret the results. In addition, two lithium trials are still running: LiCALS and LITRA. Previous trials were designed to find large effects, but these two are aiming for more subtle benefit. “These studies are expected to produce a definitive answer regarding the efficacy of lithium in ALS, or lack thereof,” Armon writes.—Amber Dance

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References

News Citations

  1. Study Looks to Lithium for Treating ALS—Patients Follow Suit
  2. Paper Alert: Lithium for ALS Deemed Futile, Study Stops Early

Paper Citations

  1. Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelli A. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2052-7. PubMed.
  2. Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, Kaufman P, Conwit RA, Schoenfeld D, Shefner J, Cudkowicz M, . Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 May;9(5):481-8. PubMed.

External Citations

  1. LiCALS
  2. LITRA

Further Reading

Papers

  1. Siciliano G, Carlesi C, Pasquali L, Piazza S, Pietracupa S, Fornai F, Ruggieri S, Murri L. Clinical trials for neuroprotection in ALS. CNS Neurol Disord Drug Targets. 2010 Jul;9(3):305-13. PubMed.
  2. Swash M. Lithium time-to-event trial in amyotrophic lateral sclerosis stops early for futility. Lancet Neurol. 2010 May;9(5):449-51. PubMed.
  3. Gill A, Kidd J, Vieira F, Thompson K, Perrin S. No benefit from chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using a standard mouse model of familial ALS. PLoS One. 2009 Aug 3;4(8):e6489. PubMed.
  4. Ferrucci M, Spalloni A, Bartalucci A, Cantafora E, Fulceri F, Nutini M, Longone P, Paparelli A, Fornai F. A systematic study of brainstem motor nuclei in a mouse model of ALS, the effects of lithium. Neurobiol Dis. 2010 Feb;37(2):370-83. PubMed.
  5. Pasquali L, Longone P, Isidoro C, Ruggieri S, Paparelli A, Fornai F. Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve. 2009 Aug;40(2):173-94. PubMed.
  6. Young W. Review of lithium effects on brain and blood. Cell Transplant. 2009;18(9):951-75. PubMed.
  7. Zhong J, Lee WH. Lithium: a novel treatment for Alzheimer's disease?. Expert Opin Drug Saf. 2007 Jul;6(4):375-83. PubMed.
  8. Shin JH, Cho SI, Lim HR, Lee JK, Lee YA, Noh JS, Joo IS, Kim KW, Gwag BJ. Concurrent administration of Neu2000 and lithium produces marked improvement of motor neuron survival, motor function, and mortality in a mouse model of amyotrophic lateral sclerosis. Mol Pharmacol. 2007 Apr;71(4):965-75. PubMed.

Primary Papers

  1. Armon C. Is the lithium-for-ALS genie back in the bottle?: Not quite. Neurology. 2010 Aug 17;75(7):586-7. PubMed.
  2. Chiò A, Borghero G, Calvo A, Capasso M, Caponnetto C, Corbo M, Giannini F, Logroscino G, Mandrioli J, Marcello N, Mazzini L, Moglia C, Monsurrò MR, Mora G, Patti F, Perini M, Pietrini V, Pisano F, Pupillo E, Sabatelli M, Salvi F, Silani V, Simone IL, Sorarù G, Tola MR, Volanti P, Beghi E, . Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology. 2010 Aug 17;75(7):619-25. PubMed.

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