Background
Amyotrophic lateral sclerosis (ALS; motor neuron disease, MND) is a rapidly progressive neurodegenerative disorder characterised by loss of corticospinal tract motor neurons and spinal anterior horn motor neurons leading to severe weakness and death from respiratory failure usually within 3-5 years [
1]. In about 5% of cases there is a family history of ALS, and in about a quarter of such cases, mutation in the SOD1, TARDBP, FUS or OPTN genes is responsible. ALS is the first neurodegenerative disease to provide hope that neuroprotective strategies may be feasible. Riluzole prolongs survival in ALS with a reduction in mortality of ~7% at 18 months for 100 mg daily riluzole versus placebo and a relative risk reduction of ~35% [
2‐
4]. Riluzole has been licensed by the MHRA and approved by NICE
http://www.nice.org.uk. Nonetheless there remains a pressing need for effective treatments that further slow disease progression, while maintaining quality of life.
Any drug that can be shown to slow the course of ALS in a clinically significant way and to be safe and well tolerated will be an important advance for patients with this disease. A published report has suggested a dramatic effect of lithium carbonate on survival, albeit in a very small group of patients [
5]. 44 patients were studied, with 16 randomly selected to take LiCO3 and riluzole and 28 allocated to take riluzole alone. In the group treated with lithium, no patients had died (i.e., 100% survival) at the end of the study (15 months from entry), compared to 71% surviving in the riluzole-only group. The difference in survival was significant at 12 and 15 months. There were also significant differences in the rate of functional deterioration measured by MRC Manual Muscle Testing scores (MMT; 18% decline in LiCO
3 + riluzole group versus 35% in the riluzole only group), the Norris scale (11% versus 46%), ALSFRS-R (14% versus 40%), and forced vital capacity (FVC; 14% versus 33%).
Unfortunately, the trial design can be criticised on several counts. First, the patients were not well matched for age, the LiCO3 group being approximately three years younger at age of onset than the control (riluzole only) group, which is known to be a prognostic factor. Secondly, and crucially, the groups were not truly randomised, but 'randomly selected'- no details of how this was done were provided, although the authors stated that patients were selected on the basis of matched forced vital capacity and pattern of clinical presentation. The study was single-blind, with the physicians carrying out the functional assessments being blinded. Adjustments of plasma lithium levels were carried out by an unblinded observer, and the patients were not blinded. The dose of lithium carbonate ranged from 300 mg to 450 mg daily, with plasma lithium levels targeted to reach 0.4-0.8 mmol/l.
ALS is a heterogeneous disease, and each group of patients entering a trial will differ, to a greater or lesser extent, in the average rate of progression measured by death or by measures of function such as the ALSFRS-R. The smaller the sample, the greater is the chance that there will be major differences in average rates of progression between treatment groups. While large samples and true randomisation will usually balance differences in prognostic factors such as the anticipated rate of disease progression between patients taking the active drug or placebo, this is not always the case [
6,
7]. Even in large randomised trials in which patients are recruited using standardized entry criteria, there are patients with slow disease progression as well as patients with a high risk of dying before the end of the study [
3,
4,
6]. It is therefore possible, by chance, to select a small group of patients with unusually good prospects for survival. On the other hand, despite the weaknesses of trial design, the size of the observed difference between the lithium and control groups (i.e., the assumed drug effect) is difficult to explain on the basis of imbalance of major prognostic factors alone.
The same study [
5] also included a series of experiments in mice transgenic for the G93A Superoxide Dismutase 1 (SOD1) mutation, known to cause ALS in humans. There was a prolonged mean survival time (p < 0.001) and increased disease duration (p = 0.05) with lithium treatment compared to saline treatment, starting at 75 days of age. The mean survival time in the lithium group was 148 ± 4.3 days (n = 20), compared to 110.8 ± 5 days (n = 20) in vehicle treated mice, representing ~36% increase in lifespan. Disease duration was increased from a mean of 9 days to more than 38 days (i.e., > 300%) in lithium compared to vehicle treated mice.
The authors comment that even when lithium treatment was started at the onset of motor symptoms there was still a comparable increase in disease duration, but these data were not shown. In addition, lithium delayed the onset of paralysis and limb adduction and also improved function on tests such as rotarod, grip strength and stride length. The authors found that lithium treatment increased the number of surviving α motor neurons in the G93A mice and had a number of other effects on pathological changes including increasing the numbers of Renshaw-like neurons in the spinal cord. They hypothesised that this was mediated through an effect on neurogenesis, since lithium has been reported to produce neurogenesis in physiological conditions in the hippocampus, albeit not in the spinal cord. They also reported that lithium rescues spinal cord mitochondria and facilitates the clearance of α-synuclein, ubiquitin and SOD1, and that it increases the number of autophagic vacuoles in the spinal cord.
There is a substantial rationale from other laboratory studies that lithium is worth investigating therapeutically in ALS. One previous study also identified a modest protective effect of lithium in the ALS transgenic mouse [
8]. Lithium has been shown to have neuroprotective effects in several models of neurodegeneration through a variety of mechanisms [
9,
10]. The kinesin light chain, a key component of the cellular motor mediating fast anterograde axonal transport, is a substrate for glycogen synthase kinase 3 Beta (GSK3β) [
11‐
13] and lithium reverses deficits in axonal transport in a microtubule-associated protein tau (MAPT) over-expression model in drosophila [
14]. Fast axonal transport of mitochondria is impaired by SOD1 mutations, resulting in a maldistribution of mitochondria in the neuron [
11] so lithium might counteract this.
The neuroprotective effects of lithium are thought to be mediated to some degree and in some models through GSK3β inhibition [
9,
10,
15,
16] but also by modification of NMDA-subtype glutamate receptor function through inhibition of NR2B tyrosine phosphorylation [
17], activation of cell survival factors such as the PI 3- kinase/Akt signalling pathway, [
1] the induction of neurotrophic proteins, including brain-derived neurotrophic factors (BDNF) [
9,
18,
19] and up-regulation of heat-shock protein and Bcl-2 [
9,
20‐
23]. Lithium enhances neurogenesis in various experimental systems [
5,
24]. In addition, lithium may promote autophagy through the inhibition of inositol-monophosphatase-15, and thus through the neuroprotective effects of autophagy in neurodegeneration [
25‐
28]. However, the effects of lithium on autophagy are complex, as lithium may reduce autophagy by inhibiting GSK3β, but stimulate it by inducing the mammalian target of rapamycin (mTOR)-dependent autophagy [
26]. Thus combinations of lithium with agents that inhibit mTOR may prove more useful in neuroprotection than lithium alone. We have no data on possible interactions between lithium and riluzole.
Thus, despite reservations regarding the strength of the clinical trial data, there is a strong argument to carry out a phase II/III study of LiCO
3 in ALS. We take the view that such a study should be powered to detect a large effect, i.e., close to that observed in the original human study [
5].
There are various systematic reviews of neuroprotective strategies in ALS, as well as Cochrane systematic reviews of riluzole and failed treatments [
29]. In essence, apart from Riluzole, none of the many agents tested have had any positive effect on survival or function in ALS, and there remains a pressing need for disease-modifying therapy, the aim being to slow disease progression while maintaining reasonable quality of life, in conjunction with symptomatic treatments and palliative care.
It is hoped that results from our study will be used to inform decisions of whether lithium should be added to riluzole in the routine management of patients with ALS, to improve their survival, motor function and quality of life without significant adverse effects.
The protocol includes dose titration and monitoring to achieve therapeutic plasma levels of > = 0.4- < = 0.8 mmol/L.
Lithium has been prescribed in long term use over many decades for other patient groups [
30]. Because the effective dose is fairly close to the toxic dose, it is necessary to conduct careful dose titration [
30‐
32]. We have taken advice on initiation and monitoring of therapy from senior psychiatrists with extensive expertise in the pharmacology and clinical use of lithium therapy and will follow the NICE guidelines (
http://www.nice.org.uk, Guideline No 38, 2006). The protocol will also involve un-blinded "safety monitoring" physicians who will be responsible for monitoring lithium levels and assessing patients for all aspects of safety and possible toxicity.
UKMND-LiCALS members
Ambily Sathish, Research Nurse, Manchester
Amina Chaouch, Blinded Physician, Preston
Ammar Al-Chalabi, Chief Investigator, King's College Hospital, London
Amy Palmer, Trial Administrator, Plymouth
Andrea Stutt, Research Nurse, Newcastle
Andrew Dougherty, Research Nurse, King's College Hospital, London
Ann Cochrane, Clinical Research Officer, NHNN, London
Annette Taylor, Research Nurse, Sheffield
Biruk Asfaw, Research Nurse, Birmingham
C Oliver Hanemann, Principal Investigator, Plymouth
Carlos Guevara, Unblinded Physician, King's College Hospital, London
Carolyn Young, Principal Investigator, Liverpool
Catherine Whatley, Unblinded Research Nurse, Oxford
Cathy Ellis, Unblinded Physician, King's College Hospital, London
Ceryl Harwood, Unblinded Physician, Sheffield
Channa Hewamadduma, Blinded Sub-investigator, Sheffield
Chinea Eziefula, Clinical Officer, NHNN, London
Chris Murphy, Unblinded Physician, Manchester
Christine Cosby, Clinical Trial Unit Manager, Plymouth
Christopher McDermott, Unblinded Physician, Sheffield
Claire McHugh, Blinded Physician, Preston
Claire Merritt, Research Nurse, Oxford
Clare Williams, Unblinded Research Nurse, Oxford
David Paling, Blinded Physician, Preston
Dave Watling, Clinical Trial Unit Manager, Liverpool
David Burn, Unblinded Physician, Institute for Ageing and Health, Newcastle
David Rog, Unblinded Physician, Manchester
Dominic Sexton, Research Nurse, Manchester
Douglas Mitchell, Principal Investigator, Preston
Elizabeth Johnson, Research Nurse, Manchester
Emma Oughton, Research Nurse, Manchester
Erica Waines, Trial Administrator, Sheffield
Faye OKeeffe, Trial Administrator, Manchester
Fiona Evans, Unblinded Physician, Liverpool
Gemma Woods, Unblinded Research Nurse, Manchester
Gill Mill, Research Nurse, Sheffield
Gill Siuda, Research Nurse, Oxford
Hannah Hollinger, Research Nurse, Sheffield
Hisham HM Hamdalla, Blinded Co-investigator, Manchester
Helen Beaumont-Kellner, Research Nurse, Manchester
Helen Vanek, Unblinded Research Nurse, Manchester
Hugh Rickards, Unblinded Physician, Birmingham
Ibrahim Imam, Unblinded Physician, Plymouth
Iracema Leroi, Unblinded Physician, Manchester/Preston
Jan Clarke, Research Nurse, NHNN, London
Jane Houghton, Research Nurse, Newcastle
Janice Birt, Unblinded Research Nurse, Preston
Janiki Panicker, Unblinded Physician, Liverpool
Jennifer Smith, Trial Administrator, Manchester
Joanna Glennon, Unblinded Research Nurse, Oxford
Joanne Brown, Research Nurse, Newcastle
John Ealing, Principal Investigator, Manchester
Jonathan Anderson, Research Nurse, NHNN, London
Jonathan Williams, Blinded Sub-investigator, Oxford
Justine Adams, Trial Administrator, Oxford
Karen Morrison, Principal Investigator, Birmingham
Kate O'Hanlon, Unblinded Research Nurse, Liverpool
Katie Sidle, Unblinded Physician, NHNN, London
Kevin Talbot, Principal Investigator, Oxford
Leanne Walker, Clinical Officer, Plymouth
Lindsey Copeland, Trial Administrator, Manchester
Lokesh Wijesekera, Unblinded Physician, King's College Hospital, London
Louise Pate, Research Nurse, Liverpool
Lucy Partington-Jones, Unblinded Research Nurse, Manchester
Lynne Savage, Research Nurse, Birmingham
Lynne Wyatt, Research Nurse, Liverpool
Marianne Hare, Unblinded Research Nurse, Preston
Martin R Turner, Unblinded Physician, Oxford
Mary Jo Trimmer, Research Nurse, Plymouth
Meneka Sidhu, Blinded Physician, Preston
Michael Grieves, Trial Administrator, Newcastle
Muhammad Rafiq, Blinded Sub-investigator, Sheffield
Nazir Sharaf, Unblinded Physician, Preston
Nichola Ritchie, Unblinded Research Nurse, Manchester/Preston
Nick Davies, Unblinded Physician, Birmingham
Nicola Maycock, Clinical Research Officer, NHNN, London
Nigel Leigh, Previous Chief Investigator, King's College Hospital, London
Nikolay Dimitrov, Blinded Physician, King's College Hospital, London
Pamela Shaw, Principal Investigator, Sheffield
Partha Ray, Unblinded Physician, Liverpool
Paula Nuttall, Unblinded Research Nurse, Preston
Phil Paterson, Research Nurse, Manchester
Rachael Hibberd, Research Nurse, Sheffield
Rachel Hornabrook, Research Nurse, Birmingham
Rehiana Ali, Blinded Sub-investigator, Liverpool
Reshma Shah, Clinical Officer, NHNN, London
Reza Sadjadi, Unblinded Physician, King's College Hospital, London
Richard Orrell, Principal Investigator, NHNN, London
Richard Sylvester, Unblinded Physician, NHNN, London
Robert Addison-Jones, Research Nurse, Preston
Robin Howard, Unblinded Physician, NHNN, London
Roisin Turner, Research Nurse, Preston
Rupert Mcshane, Unblinded Physician, Oxford
Saiffuddin Shaik, Unblinded Physician, Preston
Samirah Anane, Blinded Physician, Preston
Sarah Dhariwal, Research Nurse, Birmingham
Steven Dodds, Unblinded Research Nurse, Newcastle
Sue Palmer, Research Nurse, Birmingham
Susie Crawford, Research Nurse, Sheffield
Syed Zaidi, Blinded Physician, Preston
Tahir Majeed, Principal Investigator, Preston
Theresa McCarthy, Research Nurse, Birmingham
Theresa Walsh, Research Nurse, Sheffield
Tien Khoo, Unblinded Physician, Institute for Ageing and Health, Newcastle
Tim Williams, Principal Investigator, Newcastle
Val Russell, Research Nurse, Oxford
Wendy Barrett, Research Nurse, Oxford
NHNN is the National Hospital for Neurology and Neurosurgery