Contrary to promising results from a recent small pilot study that generated a high level of off-label use, lithium does not delay disease progression in patients with amyotrophic lateral sclerosis (ALS)*, also known as motor neuron disease or Lou Gehrig's disease, according to the first double-blind randomised trial of the drug. As such, lithium should not be used as a treatment in patients with ALS, concludes the Article published Online First and in the May edition of The Lancet Neurology.
Since the licensing of riluzole (which has been shown to extend the lives of patients with ALS by an average of 3 months) 15 years ago, no new drug has been approved for the treatment of ALS and there is currently no therapy that can cure ALS.
However, in 2008 a small pilot study reported that daily doses of the drug lithium, traditionally used in the treatment of bipolar affective disorder, might dramatically slow down progression of ALS. Results showed that after 15 months, there were no deaths in the 16 patients treated with lithium plus riluzole, but 30% of those taking riluzole alone died. Additionally, patients taking lithium had a slower decline in disease-related disability. To date, no other treatment has shown such a dramatic effect on ALS. However, the study involved a small number of patients and the participants were not blinded to treatment, so definite conclusions about the effectiveness of lithium could not be made.
To further investigate the potential of lithium as a possible treatment for ALS, a team of researchers from the Northeast and Canadian ALS Consortia led by Swati Aggarwal from Massachusetts General Hospital and Lorne Zinman from Sunnybrook Health Sciences Center designed a novel, double-blind, placebo-controlled, time-to-event trial. Initially, 84 patients with ALS from across the USA and Canada were randomly assigned to receive lithium plus riluzole (40) or placebo plus riluzole (44) in similar doses to the pilot study. Several reviews of the data were planned, the first after the 84th person was enrolled, when a decision was to be made on whether to expand the trial to include 250 patients.
The primary outcome measure was time to an event, defined as a decrease in ALS functional rating scale-revised (ALSFRS-R) score by at least six points or death. A log-rank statistical test was done at the initial interim analysis to compare the distributions of the time to an event between the lithium and placebo groups.
The trial was stopped after the first interim analysis as the evidence suggested that a large effect of lithium would not be seen as demonstrated in the earlier pilot study.
The authors say: "Although a modest benefit of lithium was not ruled out by the study…we found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone."
They conclude: "At this time, there remains no convincing evidence for the use of lithium as a treatment for patients with ALS."
In an accompanying Comment, Michael Swash from Barts and the London School of Medicine and Dentistry, London, UK, praises the unique trial design as an important advance for testing possible future treatments for ALS because of the potential for a rapid result and the option for patients to cross over from placebo to treatment.
Dr Swati Aggarwal, Massachusetts General Hospital, Massachusetts, USA. T) +1 617 726 5097 E) spaggarwal@partners.org
Dr Lorne Zinman, Sunnybrook Health Sciences Center, Toronto, Canada. T) +1 416 480 4213 E) Lorne.Zinman@sunnybrook.ca
Professor Michael Swash, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Royal London Hospital, London, UK. T) +44 (0)776 824 2335 (mobile) E) mswash@btinternet.com
For full Article and Comment, see: http://press.thelancet.com/tlnlithium.pdf
Notes to Editors:
*ALS is a degenerative disease of unknown cause that attacks motor neurons and leads to progressive loss of muscle control, paralysis, and ultimately death. It affects about 30,000 Americans a year, and most patients only live between 3 and 5 years after diagnosis.
Journal
The Lancet Neurology