Lithium in Drinking Water for Dementia and Suicide

Bipolar disorder has been reported to be associated with increased risk of dementia [1,2] and the risk may increase with every new affective episodes [3] while lithium, which is the first-line agent for bipolar disorder, may reduce the risk of dementia because long-term lithium treatment significantly reduces tau phosphorylation and amyloid βproduction, increases synaptic plasticity and facilities long-term potentiation and cell firing, most of which are due to GSK-3 inhibition [4]. Epidemiological studies revealed that continued lithium treatment was associated with reduction of the rate of dementia to the same level as that for general population [5] and the effects were not found in anticonvulsants, antidepressants, or antipsychotics [6], suggesting a specific effect of lithium. In a clinical setting, 35 patients who were 60 years or older without initial diagnosis of dementia and had previously received lithium treatment and/or were currently prescribed lithium had significantly better Mini-mental State Examination (MMSE) scores than 20 control patients [7]. Moreover, Alzheimer's disease was diagnosed in 3 of 66 (5%) elderly euthymic patients with bipolar disorder who were on chronic lithium treatment and in 16 of 48 (33%) similar patients without recent lithium treatment [8], suggesting lithium effects on dementia. Although another study showed that patients who received lithium had a higher risk of dementia compared with those who did not [9], most of these findings suggest both possibilities that lithium may directly prevent dementia via its inhibition of GSK-3 and that lithium may indirectly prevent dementia via its prophylactic effects on mood episodes [10].

As shown in Table 1,3 placebo-controlled studies have been performed to investigate lithium effects on dementia or mild cognitive impairment. Two studies showed lithium effects on dementia [11] and mild cognitive impairment [12] whereas another study failed to show such effects [13]. It seems likely that lithium dose is not important because the successful 2 studies used completely deferent doses; routine doses (150-600 mg/day titrated to target serum levels of 0.25- 0.5 mmol/l) [12] and microdose (300 μg/day, serum levels were not measured) [11], respectively. Rather, administration period may be important because successful 2 studies administered lithium for 15 months [11] and 12 months [12], respectively whereas unsuccessful study gave lithium for only 10 weeks [13]. Therefore, further studies may be required to administer lithium for 12 months or longer to detect lithium effects on dementia or mild cognitive impairment. If administrative period is 12 months or longer, lithium doses can be much lower than usual because 300 μg/day of lithium bought about the effects [11]. This possibility may evoke an interesting idea that lithium in drinking water can prevent dementia.

  

    
Authors 
    
Subjects    and methods 
    
Results 
  
  

    
Nunes    et al (2013) [11] 
    
113 patients with Alzheimer's disease were    randomised to receive lithium (300 μg/day) (n=58) or placebo (n=55) in a    15-month, double-blind trial.
    
Lithium group showed no decreased performance in    the mini-mental state examination test, in opposition to the lower scores    observed for placebo group, with significant differences starting 3 months    after the beginning of the treatment, and increasing progressively.
  
  

    
Forlenza    et al (2011) [12] 
    
45 participants with a mild cognitive impairment    were randomised to receive lithium (0.25-0.5 mmol/l) (n=24) or placebo (n=21)    in a 12-month, double-blind trial.
    
Lithium treatment was associated with a    significant decrease in phosphorylated tau of cerebrospinal fluid and better    performance on the cognitive subscale of the Alzheimer's Disease Assessment    Scale (ADAS-Cog) and in attention tasks.
  
  

    
Hampel    et al (2009) [13] 
    
71 patients with mild Alzheimer's disease were    randomised to lithium treatment (0.5-0.8 mmol/l) (n=33) or placebo (n=38) in    a 10-week, single-blind trial.
    
No treatment effect on glycogen synthase kinase-3    activity or phosphorylated tau of cerebrospinal fluid was observed. Lithium    treatment did not lead to change in global cognitive performance as measured    by the ADAS-Cog subscale or in depressive symptoms.
  

Table 1: Placebo-controlled trials investigating lithium effects on dementia or mild cognitive impairment.