Lithium for Alzheimer disease
Some studies have explored lithium’s effects on mild cognitive impairment (MCI) (mild neurocognitive disorder) and Alzheimer disease; the results have been mixed. For instance, Hampel and associates5 tested the effects of short-term (10 weeks) lithium treatment in patients with mild Alzheimer disease. The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau and GSK-3 activity in lymphocytes. No treatment effect on GSK-3 activity or CSF-based biomarker concentrations was observed.
In a small, open-label study to investigate the feasibility and tolerability of lithium for Alzheimer disease, Macdonald and colleagues6 gave low-dose lithium to 22 patients with Alzheimer disease for up to a year. Discontinuation rates were high, but reports of adverse effects on the primary outcome scale did not differ between those who discontinued therapy and those who remained in the study. There were no differences in deaths, dropouts, or changes in the Mini Mental State Examination (MMSE) between patients who received lithium and the comparison group.
Conversely, in a single-center, randomized, double-blind, placebo-controlled study, Forlenza and colleagues7 sought to assess the potential neuroprotective effects of longterm low-dose lithium treatment in patients with amnestic MCI. Participants with amnestic MCI were randomized to receive lithium (0.25 to 0.5 mmol/L) (n = 24) or placebo(n = 21) in a 12-month trial. Lithium treatment was associated with a significant decrease in CSF concentrations of phosphorylated tau and better performance on the cognitive subscale of the Alzheimer Disease Assessment Scale and on attention tasks.
“The number of patients who progressed from amnestic MCI to Alzheimer disease was higher in the placebo group, which is suggestive evidence that lithium may be helpful against Alzheimer disease,” Gildengers said.
A more recent clinical trial conducted by Nunes and colleagues8 explored the use of microdose (300 µg/d) lithium administered to patients with Alzheimer disease for 15 months. In the evaluation phase, the treated group showed no decreased performance on the MMSE, yet the control group showed lower MMSE scores. Significant differences between the lithium-treated and control groups were observed starting at 3 months after treatment initiation. Their findings suggest that microdose lithium treatment is efficacious in preventing cognitive loss, which reinforces its therapeutic potential to treat Alzheimer disease.
In a recent review of lithium and the evidence regarding its neuroprotective properties and possible use in neurodegenerative diseases, Diniz and colleagues9 concluded that “current evidence points to a potential role of lithium as a drug with disease modifying properties in Alzheimer disease.” But they warned “it is very important to emphasize that the risk-benefit ratio of using lithium for neuroprotection is still very unclear and lithium should not yet be used for neuroprotection in older adults.” Additional clinical trials are necessary to establish efficacy, optimal dose regimen, and duration of drug use to attain optimal clinical benefit.
Carl Salzman, MD, Professor of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center and Massachusetts Mental Health Center in Boston and a discussant in the Advances in Geriatric Psychopharmacology session, also urged caution. “Lithium had been slipping into American obscurity in the past 10 years, but it is making a welldeserved comeback as a therapeutic substance that may have numerous uses. Not only is it the best mood stabilizer, but . . . it may have protective effects on the central nervous system. These effects could be clinically relevant and could provide the foundation for new research into molecular changes occurring in late life that may be associated with cognitive and other dysfunction.” Lithium may increase mitochondrial activity; may decrease oxidative stress; may suppress GSK-3; may increase levels of BDNF, which is food for neurons; and may even increase cortical gray matter.
“That’s all terrific. But in real life, lithium is hard to use in the elderly. It is highly toxic. Blood levels, in general, need to be quite low for therapeutic effect,” he warned. Lithium is difficult to use in older adults because of drug interactions and lithium’s effects on the kidney and thyroid. Also, the toxicity of lithium in older adults is mostly neurocognitive, which “may interfere with our diagnostic assessment of whether the patient is getting worse neurocognitively or whether the patient is experiencing a lithium side effect.” Moreover, compliance is very difficult in older adults, which makes most clinicians reluctant to use lithium as a mood stabilizer for that age-group.
Summing up, Gildengers told Psychiatric Times that while the growing evidence base for the positive effects of lithium on brain health is compelling, the evidence remains preliminary. “More carefully controlled, prospective clinical trials are needed before we can definitely say that lithium can protect or mitigate against the effects of neurodegenerative illnesses, such as Alzheimer disease.”
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