27 Feb 2008

The drug lithium is usually prescribed to patients with bipolar disorder. But evidence is growing that it might help with some neurodegenerative diseases as well, particularly the rapid and devastating Lou Gehrig's disease, known as amyotrophic lateral sclerosis (ALS). ALS, which attacks motor neurons, usually leads to death within 4-6 years and is diagnosed in 5,600 Americans a year, according to the ALS Association. While physical therapy and the only FDA-approved drug, a form of riluzole, sometimes slow the progression of symptoms, a study published online on February 4 in the Proceedings of the National Academy of Science indicates that lithium may slow the disease. Despite its being a small pilot study, ALS patients have been abuzz about it on the Internet and some are deciding to take lithium without waiting for further studies.

Conducted by Francesco Fornai, Antonio Paparelli, and colleagues at the University of Pisa and at institutions in Pozzilli, Rome, and Novara, the study suggests that lithium carbonate may be neuroprotective. The Italian scientists first tested the drug on the G93A ALS mouse model and then on a small sample of patients. Lithium treatment prolonged the survival of these mice. It also correlated with neurological changes in treated versus untreated mice, including more mitochondria in their motor neurons, less reactive gliosis, and more neurons in lamina VII. Interneurons in this area become impaired and die early in ALS mouse models and in patients. The authors found that these neurons were more numerous in the lithium-treated mice (up to 131 percent) than in control mice. While prior research had shown that lithium can stimulate neurogenesis in the hippocampus, this is the first time the drug was reported to correlate with neural growth in the spinal cord. Lithium also decreased several markers of ALS progression, such as α-synuclein, ubiquitin, and SOD1 aggregation in motor neurons, as well as mitochondrial vacuolization (where neurons appear to be filling with vacuoles as mitochondria swell).

Lithium seems to have helped motor neurons survive by activating autophagy, a process by which cells dispose of damaged organelles, for example, mitochondria, and aggregates (see ARF related news story). Lithium treatment led to an increase in autophagic vacuoles. Following the hypothesis that autophagy deficiency causes neurodegeneration in ALS, the team treated spinal cord cultures with the autophagy inhibitor 3-MA and found that the inhibitor increased motor neuron death by 58 percent compared to controls and by 51 percent compared to the lithium-treated cultures. When the scientists administered the inhibitor and lithium together, lithium was no longer effective. This suggests that lithium neuroprotection happens in part through an autophagic route, probably by blocking activity of inositol-1,4,5-trisphosphate (IP3), the authors suggest.

“One of the major concerns in using drugs which promote autophagy is getting rid of too many mitochondria and leaving the cell without these important organelles,” says first author Fornai. “This is the first time a routine drug has been shown to promote the genesis of mitochondria while at the same time inducing autophagy.”

These results encouraged the researchers to study 44 patients with ALS, treating 16 with lithium at doses of 300-450 mg a day in addition to riluzole for 15 months, and 28 patients with riluzole only. They found that all patients in the lithium group survived for the 15 months while a third of the riluzole-only group died. The lithium-treated patients scored higher on lung capacity, reported a better quality of life, and had better muscle strength than the control group. After 15 months, patients with lithium treatment had a slower progression of the disease. “This is a pilot study,” cautioned Fornai. “We need to look at hundreds and hundreds of patients to have a final conclusion.” According to the paper, this was a single-blind trial, where one physician assigned patients to the treatment group and adjusted their dose based on blood levels, and blinded physicians carried out the assessments. Neurodegenerative diseases are known for producing strong placebo effects, and a larger double-blind trial with more extensive statistical analysis is needed to test these initial observations.

Continuing study of lithium's effects might guide scientists to other, more precise types of therapy, said Pierre Tariot, Director of the Memory Disorders Center at the Banner Alzheimer's Institute in Phoenix, Arizona. Tariot also works with the Alzheimer's Disease Cooperative Study, which aims to conduct a trial on about 70 Alzheimer's patients to pinpoint biological markers of pathways that lithium is thought to influence. “Lithium is like a shotgun blast; I'd rather have a single bullet,” Tariot said, adding, “Lithium is a potentially dangerous drug, so it has to be used carefully and monitored carefully. It is really too soon to say if lithium is going to have a meaningful role in neurodegenerative disorders.”

For ALS patients with no other alternatives, however, lithium may seem like a godsend despite its quick turn to toxicity and side effects, which can include nausea, dizziness, hypothyroidism, and increased white blood cell count. Forty-four-year-old David Saunders was diagnosed with ALS in March of 2007, 6 months after his first symptom. He tried riluzole briefly but reacted poorly to it. “Basically I was told I would die in 3 years. Every scientist said there was no cure and nothing to even remotely stop the progression,” says Saunders. When he heard about the Italian study in December (it first appeared in that language in November 2007), he started taking lithium carbonate a month later. “When I started taking the drug I was actually shocked because my hands started to move better,” Saunders said. “I had fewer muscle cramps and my body overall felt more lucid. I've been on it for 5 weeks now. I'm a fairly fast progressor, and I don't think I've progressed much at all.” He said that he has no lithium side effects at present.

Saunders has joined forums on several websites, including alslithium.atspace.com, als.net, and patientslikeme.com, where patients share and compare treatment and dosing information. On these forums, people raise reasons to be cautious about the Italian study, such as its small sample size, and the fact that the patients were all slow progressors, which is less typical for most people with ALS. For Saunders, websites like these are helpful not just as a source of information, but also for support and to facilitate research and education. “It's like our own trial,” he said.

At Patients Like Me, thousands of people with neurodegenerative disorders track and compare their treatments, symptoms, and progression. James Heywood, founder of the ALS Therapy development Institute and co-founder of Patients Like Me, said the group is organizing information of patients taking lithium. Currently, that number stands at 80, and Heywood expects it to be up to 200 by the end of March. “Our objective here is not to produce a publishable result, but to produce information with which patients and their clinicians can make better decisions,” Heywood said.—Kristina Grifantini

Kristina Grifantini is a freelance writer in Boston, Massachusetts.

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References

News Citations

1. Sirtuins Link Stress, Autophagy 22 Feb 2008

External Citations

1. Alzheimer's Disease Cooperative Study
2. alslithium.atspace.com
3. als.net
4. patientslikeme.com

Further Reading

Papers

1. Macdonald A, Briggs K, Poppe M, Higgins A, Velayudhan L, Lovestone S. A feasibility and tolerability study of lithium in Alzheimer's disease. Int J Geriatr Psychiatry. 2008 Jul;23(7):704-11. PubMed.
2. Avila J, Hernández F. GSK-3 inhibitors for Alzheimer's disease. Expert Rev Neurother. 2007 Nov;7(11):1527-33. PubMed.

News

1. Sirtuins Link Stress, Autophagy 22 Feb 2008
2. Lithium Takes Indirect Route to Inhibit GSK-3β 11 Jan 2008