Lithium for Alzheimer Prevention: What Are We Waiting for?

October 7, 2016
James Phelps, MD
Volume 33, Issue 10

Why is there so little clamor for a drug that prevents neurodegeneration, carries very low risk, and is unlikely to produce significant side effects?

RESEARCH UPDATE

Imagine a drug company working on a pill to prevent progression to Alzheimer dementia for patients at high risk. Imagine that their animal studies show benefit in preventing neurodegeneration, reducing 2 of the major changes known to lead to Alz­heimer disease: tau protein phosphorylation and amyloid plaque formation. Imagine that their new drug had been shown to inhibit these 2 changes in humans, in a preliminary trial; and that so far, there were no known risks of their new medication, and no side effects in over 90% of patients.

Wouldn’t some patients and their families be interested in getting hold of this drug, even as formal clinical trials were getting underway?

That would surely be the case if the drug was already known to carry very low risk and unlikely to produce significant side effects. Because what else is there to do, when a patient and his or her family are facing likely decline into a progressive series of losses and stress-with no hope of reversing the process?

When such a drug was shown to have the desired effect in even a small sample of patients who already exhibited very early signs of the illness-to a greater extent than placebo-well, that would begin the stampede, would it not? The company would be besieged with requests that would likely soon turn into demands for humanitarian release of their new product, based on the extremely large number of adults at very high risk for Alzheimer disease in the next decade.

There would be calls for prudence: “This is just one trial; we need a replication.” That call would be drowned out by objections: “What else do you think we are going to do? If there’s even a 1% chance this could work, we’re ready to take it. Even if there was significant risk, we’d be ready to take it: why not? Why just wait for an inevitable decline?”

As you’ve surely gathered, there is indeed a randomized trial that shows lithium prevented cognitive worsening in patients with minimal cognitive impairment (MCI).1 The dose was roughly 1.5 mg of lithium carbonate per day: microdose lithium.1 Yet when one of my patients with MCI, who has been taking 300 mg/d of lithium for more than 5 years, was evaluated by a university dementia research program (he was debating whether to enter one of their clinical trials), they pooh-poohed the lithium. His blood level was 0.1 mEq/L. Not enough data to support this approach, they said-and they’re not alone in their opinion.2 I cannot understand this logic: what else have we got to offer? But new data may further tilt the balance.

The same Brazilian research group who performed the human trial has recently shown, in mice genetically engineered to have an equivalent of early Alzheimer disease (early development of amyloid plaques with attendant cerebrovascular, cognitive, and neuroinflammatory pathologies), that microdose lithium in their water supply prevented progression to disease to a dramatic extent.3 In addition to demonstrating that lithium attenuated the deleterious brain changes in the genetically engineered animals, they also found that the treated animals’ behavior was no different from that of “wild type” mice (ie, those not genetically altered).

This may strike you as backward: why the human study first, then the animal study? Answer: the group is working on demonstrating the value of lithium as a preventive agent in patients at risk for Alzheimer disease. Their first study in humans used low-dose lithium (blood levels of 0.25 to 0.5 mEq/L).4 Their follow-up human study used the microdose referenced above. They had to go back and show, in mice, that microdoses produced the same brain benefits seen in earlier mouse studies with larger doses.5

If more people knew of this Alzheimer research, hesitation might decrease substantially.

Why is there so little clamor from patients at high risk for Alzheimer disease and their families for microdose lithium? Might it be because this is lithium, with all its historical baggage and the stigma of being associated with bipolar disorder?

Whatever the reason, these data further establish that “the magic ion”6 in even tiny doses is psychoactive. Perhaps such data will increase willingness to use lithium for patients with bipolar disorder, especially in low doses. And that, after all, is my point: lithium is underutilized in depression and bipolar disorders. If more people knew of this Alzheimer research, hesitation might decrease substantially.

 

MORE ABOUT James Phelps, MD

“When work is a pleasure, life is a joy! When work is a duty, life is slavery.”

-Maxim Gorky

True! But there’s play as well, right? I’ve been fortunate to have been able to mix rewarding work and intense play. I was a skiing and whitewater kayak/canoe instructor (including through medical school) and have spent hours in and on the water. When age suggested this might not last, I rekindled an old love of sailing and now spend hours fooling around in boats on lakes and bays. I’ve been able to ride my bike to work my entire life, if you can imagine. And got lucky with a great job that left room to be a closet academic.

Thus, I slowly discovered that I have as much fun crafting a lecture or an essay as I do surfing a river wave. So gradually I’ve traded the boats and skis for the computer but still have about a 50/50 mix going. You can imagine how fortunate I am to have married a woman who understands these passions.(She carried a whitewater canoe with me up 1000 vertical feet to complete a lovely river trip, as we laughed the whole way up.) She completed her pathology residency while giving birth to both our kids. Her work in the lab and at home created room for all my writing and playing. Lucky me, huh?

[[{"type":"media","view_mode":"media_crop","fid":"53711","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_8221717718005","media_crop_h":"337","media_crop_image_style":"-1","media_crop_instance":"6724","media_crop_rotate":"0","media_crop_scale_h":"171","media_crop_scale_w":"125","media_crop_w":"247","media_crop_x":"45","media_crop_y":"13","style":"float: right; width: 103px; height: 125px;","title":" ","typeof":"foaf:Image"}}]]The website I developed to explain bipolar II and non-manic bipolarity to patients (PsychEducation.org: now 250 pages, still free, no ads, no tracking) has turned into 3 books on bipolar disorders- 2 just out from Norton this year: one for professionals, one for patients/families. So I seem to have kept the work/play ratio in reasonable balance. Thanks, Anna-thanks all.

 

This article was originally posted on 8/11/2016 and has since been updated.

Disclosures:

Dr Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore. He is the Bipolar Disorder Section Editor for Psychiatric Times. Dr Phelps stopped accepting honoraria from pharmaceutical companies in 2008 but receives honoraria from McGraw-Hill and W.W. Norton & Co. for his books on bipolar disorders.

References:

1. Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res. 2013;10:104-107.
2. Morris G, Berk M. The putative use of lithium in Alzheimer's disease. Curr Alzheimer Res. 2016;13:853-861.
3. Nunes MA, Schöwe NM, Monteiro-Silva KC, et al. Chronic microdose lithium treatment prevented memory loss and neurohistopathological changes in a transgenic mouse model of Alzheimer's disease. PLoS One. 2015;10:e0142267.
4. Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198:351-356.
5. Noble W, Planel E, Zehr C, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA. 2005;102:6990-6995.
6. Young AH. More good news about the magic ion: lithium may prevent dementia. Br J Psychiatry. 2011;198:336-337.