Neuroprotective effects of Li - it is elementary
T. Hajek 1,2, A. Young 3
1 Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
2 National Institute of Mental Health, Klecany, Czech Republic
3 Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Great Britain
Correspondence: Tomas Hajek, MD, PhD
Department of Psychiatry, Dalhousie University
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Lithium was formed within the first three minutes of the beginning of the universe and has been constantly present throughout the history of life on Earth. Since the re-introduction of Li to psychiatry’s therapeutic armamentarium in 1949 it has gained and maintained an important role in the treatment of mood disorders. Even after 66 years of clinical use and systematic study, we are still discovering new therapeutic and pharmacodynamic properties of this monovalent cation. Consistent pre-clinical evidence, for example, shows that Li can protect neurons from a wide range of neurotoxic effects. Among 28 psychiatric medications, including antipsychotics, anticonvulsants, antidepressants, Li shows the most replicated evidence for neuroprotection in the widest range of neurodegenerative disease models 1. Do these intriguing pharmacodynamic properties of Li translate into therapeutic neuroprotective effects in human subjects?
As reviewed in this thematic issue, there is converging evidence which when viewed overall suggests that this indeed might be the case. Pharmacoepidemiological studies show a lowering of risk for Alzheimer dementia (AD) with repeated prescriptions of Li. The positive effects of Li in AD are also supported by cohort studies 2. Even more importantly, three randomized controlled trials demonstrated beneficial effects of Li in amnestic mild cognitive impairment (aMCI; a recognised precursor to AD) or AD 3. Last, but not least, there is consistently replicated body of evidence from cross sectional as well as prospective studies that Li treatment is positively associated with brain gray matter volume 4. In the absence of disease modifying treatments for any neurodegenerative disorders, we cannot afford to ignore this robust and replicated evidence base. Yet, the Alzheimer Dementia Collaborative Study has decided to abandon future testing of Li, based on the concerns about safety of achieving sufficient Li levels 5. In addition, the registry of clinical trials shows only a single ongoing study of Li (specifically lithia water) in AD. This study is carried out by American Society Of Thermalism And Climatology (https://clinicaltrials.gov/ct2/show/NCT02204969?term=Lithia+water&rank=2).
However, investigating Li as a treatment for neurodegenerative disorders may not be the best strategy or the best use for the neuroprotective effects of this element. Firstly, treatment trials in neurodegenerative disorders are very expensive. Pharmaceutical companies are unlikely to invest into clinical studies of Li, which cannot be patented and has never made a large profit for anyone. Consequently, future research of neuroprotective effects of Li will remain in the hands of motivated academic researchers doing relatively small trials with limited funding. Secondly, trying to intervene at the stage when patients already show clinical signs of neurodegeneration may be too late.
Considering these two issues, perhaps it might be preferable to alter our strategy. One option would be to test Li treatment in subjects at increased risk for developing AD, for example carriers of ApoE4, severe affective disorders or those with aMCI. An even better option might be to investigate neuroprotective effects of pre-treatment with Li during clinical interventions, which carry a marked risk of neurotoxic adverse events, such as brain radiation or chemotherapy.
In parallel, we should also attempt to define the minimum levels of Li required to clinically engage the neuroprotective targets. Using the therapeutic window from studies in mood disorders is purely arbitrary and may not be optimal in subjects with dementia. Many of the side effects of Li are dose related and particularly problematic among elderly people with multiple medical comorbidities and polypharmacy. However, there is evidence that even very low levels of lithium may have clinical benefits. Several population studies have demonstrated a negative association between concentrations of Li in drinking water and suicide or crime rates 6;7. Interestingly, 2 recent trials have suggested that levels of Li lower than those used in acute and prophylactic treatment of mood disorders might suffice for treatment of aMCI or AD 8;9. One of these studies even used microdoses of Li (300 mcg/day), which are safe to use even among elderly patients 8. Therefore, it would be extremely interesting to test whether the Li concentration in drinking water is negatively associated with risk for dementia. Data necessary to perform such analyses are available in Denmark (R. Nielsen, personal communication). Such studies would greatly strengthen the case for long-term studies testing very low doses of Li in prevention of neurodegenerative disorders.
Lithium has always been a Cinderella among psychiatric medications. In absence of any positive advertisement or pharma support, it has survived due to the strength of evidence, proven efficacy and advocacy of clinicians and patients who have benfited from lithium treatment. History often seems to repeat itself. Despite the wide range of supporting evidence, the neuroprotective effects of Li are mostly neglected and little known outside of the mood disorders field. Currently, the clinicaltrials.org lists only 3 active trials looking into the neuroprotective effects of Li – one of these investigates a non medicinal preparation of Li (lithia water see above) and another one is just a feasibility trial. Thus, there is a real danger that future research of neuroprotective effects of Li will come to a halt. Considering the current paucity of treatments available we cannot let this happen. This thematic issue is an attempt to draw more attention to the effects of Li on neuronal survival and hopefully to stimulate more research. All we are saying is “give Li a chance!”.
Reference List
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