From the Editor
Since the extraordinary work of John Cade some seven decades ago, lithium has been used as a medication to help people with bipolar. But the history of lithium use is longer – for many years, people have understood that it has medicinal value, and bottled water containing lithium was popular at the turn of the twentieth century (long before Dr. Cade started medical school).
We know that lithium affects the brain in many ways (for example, it slows apoptosis, or programmed cell death); we also that know that dementia can work on those same pathways, but in a negative way (it may sped up apoptosis). In this week’s selection, the authors wonder if lithium can prevent dementia. It’s a big question – and the authors tap a big national database. They find a non-linear correlation between lithium in drinking water and dementia.
Tap water: A potential prevention for dementia if it has lithium in it?
So – does this paper represent something of a breakthrough? We look at the paper and an editorial to answer that question.
Lithium and Prevention
“Association of Lithium in Drinking Water With the Incidence of Dementia”
Lars Vedel Kessing, Thomas Alexander Gerds, Nikoline Nygård Knudsen, Lisbeth Flindt Jørgensen, Søren Munch Kristiansen, Denitza Voutchkova, Vibeke Ernstsen, Jörg Schullehner, Birgitte Hansen, Per Kragh Andersen, Annette Kjær Ersbøll
JAMA Psychiatry, 23 August 2017 Online First
Dementia is the leading cause of dependence and disability in the elderly population worldwide. As the mean life expectancy increases, the prevalence of dementia and associated monetary costs are expected to increase exponentially. The pathogenesis of Alzheimer disease is highly complex and likely to be multifactorial, including deregulated amyloid-β, phosphorylated τ, and glycogen synthase kinase 3, as well as inflammation, mitochondrial dysfunction, and calcium dyshomeostasis, suggesting that combination therapy or multitarget drugs might be effective. Lithium is a multitarget drug that seems to possess neuroprotective abilities by modulating a large array of intracellular cascades and pathways involved in oxidative stress, inflammation, mitochondrial dysfunction, membrane homeostasis, and inhibitory effects on glycogen synthase kinase 3. Animal studies have found that long-term lithium treatment improves learning and memory, and human observational studies suggest that continued treatment with lithium may reduce the risk of dementia among patients with bipolar disorder. In bipolar disorder, treatment with lithium in usual therapeutic daily doses (600-2400 mg) for mood stabilization increases the risk of chronic kidney disease in the elderly population. In accordance with this finding, lower doses have been used in trials investigating the effects of lithium on cognition among older individuals. A placebo-controlled, randomized 2-year trial suggested that long-term treatment with daily low-milligram doses of lithium (150-600 mg) may decrease the rate of developing Alzheimer disease and cerebrospinal fluid concentrations of phosphorylated τ among individuals with mild cognitive impairment. Furthermore, in a 15-month, placebo-controlled randomized clinical trial, a microdose of 300 µg/d of lithium stabilized cognitive impairment in patients with Alzheimer disease. We investigated whether the incidence of dementia in the general population covaries with long-term exposure to microlevels of lithium in drinking water, hypothesizing that higher long-term lithium exposure may be associated with a lower incidence of dementia.
Lars Vedel Kessing
So begins a paper written by Kessing et al. that considers lithium and dementia.
Here’s what they did:
- The data was drawn from Danish databases, including the Danish National Patient Register, which cover the 5.6 million people living in Denmark, and includes data from all psychiatric and non-psychiatric hospitalizations.
- For the study period of January 1, 1995, through December 31, 2013, all people with a dementia diagnosis (inpatients and/or outpatients) were identified.
- The authors used a “nested case-control study design” – for every person with dementia, ten people were randomly selected as controls (excluding any with dementia).
- To determine lithium exposure, water samples were drawn from 151 waterworks (supplying 42% of all water to the population) with the results extrapolated to the full country. Exposure was determined by people’s home addresses (allowing for people who move to have their lithium exposure calculations adjusted).
- Different statistical analyses were done, including regression analyses.
Here’s what they found:
- Excluding those with inadequate data, there were 73,731 with dementia, and 733,653 controls.
- Demographically: the median age was 80.3, and people were female more than male (60.7% female).
- The mean (SD) lithium level in drinking water was 11.6 (6.8) µg/L – but there was a range, from 0.6 µg/L (western Denmark) to 30.7 µg/L (eastern Denmark).
- Lithium exposure was significantly different for people with dementia and controls (median, 11.5 µg/L vs. median, 12.2 µg/L). Using regression models, a non-linear relationship was found: “the IRR of dementia was decreased among individuals exposed to 10.1 µg/L of lithium or more compared with exposure to 2.0 to 5.0 µg/L, reaching statistical significance only among individuals exposed to more than 15.0 µg/L of lithium compared with 2.0 to 5.0 µg/L. However, exposure to 5.1 to 10.0 µg/L of lithium was associated with an increased IRR of dementia compared with 2.0 to 5.0 µg/L…” See the figure below. Different calculations were done, but the non-linear relationship was consistent.
Overall, we confirmed the hypothesis that higher long-term lithium exposure from drinking water may be associated with a lower incidence of dementia, although the association was nonlinear. This is the first study, to our knowledge, to investigate the association between lithium in drinking water and the incidence of dementia.
The paper runs with an editorial: “Could Lithium in Drinking Water Reduce the Incidence of Dementia?” written by John J. McGrath and Michael Berk.
Now more than ever, the research community should be concentrating on finding ways to reduce the incidence of dementia. The population is aging, and the number of individuals affected by dementia remains a major public health challenge. The reality is that we have no effective treatments for dementia. In the absence of treatments to cure the disorder (or even reduce the associated burden by delaying onset or reducing disability), the prevention of dementia must be a priority research topic.
John J. McGrath
They make several observations about the Kessing et al. paper:
- “The hypothesis is surprising but is mechanistically plausible.”
- “The hypothesis builds on preliminary evidence from clinical trials that suggest that lithium supplementation may improve cognitive outcomes in groups with mild cognitive impairmentand Alzheimer disease.”
- “Lithium affects many biological pathways linked to neuroprogressive and neurodegenerative disorders. For example, lithium affects diverse homeostatic mechanisms that include intracellular calcium, microglial activation, glutamate excitotoxicity, apoptosis and autophagy, inflammation, oxidative stress, and mitochondrial dysfunction…”
The editorial concludes with a call for us to tap our inner-alchemist (after more studies):
In the spirit of alchemy, could we convert lithium, a simple metal used as a mood stabilizer, into a golden public health intervention that could prevent dementia? This will depend on what the next generation of epidemiologic studies and clinical trials reveal.
A few thoughts:
- This is a clever paper.
- As McGrath and Berk argue, the Kessing et al. paper makes sense. Dementia is connected with various brain problems – think inflammation, cell apoptosis, etc. – and lithium could reverse those effects.
- And it’s difficult not to admire the incredible work that went into this paper: they tapped national databases, and the water sampling was from scores of sites. The number of people with dementia in the study is over 73,000.
- But is this paper too clever? There are clear limitations with the work here. The paper doesn’t consider other factors, such as access to health care (which, like lithium in drinking water, varies place to place, and especially urban vs. rural).
- The authors show a clear pattern with the results – but not a linear one. Is this evidence of an unexpected finding – or a data problem? The inverted U curve (much lower and higher lithium levels in the water were more associated with lower dementia rates than mid-level lithium) is – to quote University of Toronto Department of Psychiatry Chair Benoit Mulsant – “puzzling.” Dr. Mulsant does note, though, that there are other examples of inverted U curves, including the association between dementia and alcohol use. Still, the results are puzzling and, with that in mind, McGrath and Berk seem prudent in their tempered enthusiasm.
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.