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Antidepressant Decreases Amyloid-Beta in AD Mice, Healthy People

Talan, Jamie

doi: 10.1097/01.NT.0000451830.73217.d1
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In two novel experiments — one in animals and the other in healthy people — researchers reported that the selective serotonin reuptake inhibitor antidepressant, citalopram, had a potent effect on reducing amyloid-beta levels.

Selective serotonin reuptake inhibitors (SSRIs) have long been thought to induce neurogenesis, at least in animal models. Now, a team of scientists at Washington University School of Medicine in St. Louis and the University of Pennsylvania has evidence that this same class of antidepressants can reduce the burden of amyloid-beta (Abeta) in key brain regions in animals and lowers levels in the cerebrospinal fluid (CSF) in healthy people.

The findings suggest that it may be possible to use these drugs to protect against, if not treat, Alzheimer's disease (AD).

The paper, published in Science Translational Medicine on May 14, outlines two novel experiments — one in animals and the other in healthy people — suggesting that the SSRI antidepressant citalopram has a potent effect on reducing Abeta levels.

They chose citalopram because it is the most selective SSRI for increasing serotonin, the neurotransmitter signaling required to lower Abeta. It also has a good side effect profile, the investigators said.

In the mouse model, citalopram appeared to stop the growth of pre-existing plaques and reduced the appearance of new plaques by 78 percent, according to first author Yvette Sheline, MD, a professor of psychiatry, radiology and neurology, and director of the Center for Neuromodulation in Depression and Stress at the University of Pennsylvania Perelman School of Medicine.

In the clinical study, one dose of citalopram administered to 23 cognitively healthy people between 18 and 50 years old was enough to reduce newly produced Abeta in the CSF by 37 percent over a single day.

“The ability to safely decrease Abeta concentrations is potentially important as a prevention strategy for AD,” Dr. Sheline said.

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The investigators first looked at year-old transgenic animals with two genes associated with AD: amyloid precursor protein and presenilin. They implanted probes into the hippocampus of the mice and sampled the brain interstitial fluid every 90 minutes for 32 hours while the animals were awake. They started at 2.5 mg/kg and went up to 20 mg/kg.

After 24 hours they measured a significant dose-dependent reduction in Abeta. They found that the highest clearance came with the 10 mg/kg dose (25 percent), but higher doses did not produce greater reductions. Then they tested younger animals, around six months, for 28 days. Plaques did not grow in the citalopram-treated group.

Dr. Sheline said these effects were consistent with the antidepressant's inhibition of Abeta production, but the drug did not seem to clear the aggregated protein away. They repeated the dosing trial in year-old animals and showed similar benefits. There was no greater benefit after the 10 mg/kg dose.

In human subjects, they tested the effects of an antidepressant dose (10 mg/kg) that lowered Abeta concentrations in the AD animal models. They used the stable isotope labeling kinetics method to quantify the amount of newly generated Abeta, as well as the rate of production and clearance, in the CSF of 23 healthy people.

Thirteen of the volunteers had CSF sampling hourly for almost two days. They tested a marker for newly generated Abeta, 13C-labeled leucine. Even the single dose of citalopram was enough to reduce levels by 37 percent.

While daily doses of SSRIs generally take a few weeks to reduce depression symptoms, the scientists found that the antidepressants work within eight hours of the first dose to reduce amyloid concentrations. They suspect it works on different signaling pathways, possibly through alpha secretase, an enzyme related to the production of amyloid.

“The effect we saw in our paper is a completely different chemical effect than the one seen in depressed patients. One drug can have more than one chemical effect and act through a whole different set of pathways,” said Dr. Sheline.

“Maintaining low amyloid-beta concentrations with any agent, including secretase inhibitors or SSRIs, should limit the rate at which toxic species of amyloid beta are formed,” the researchers wrote. Based on these studies, it would not clear the pathology that has already built up.

“Right now, there are no implications for clinical care,” Dr. Sheline noted. “But it does provide hope that these medications could be a powerful strategy for future prevention of Alzheimer's disease. We are hoping that this is a sustained effect.”

“A lot more research is necessary before anyone can recommend antidepressants to slow the course of AD,” said another study author, John Cirrito, PhD, an assistant professor of neurology at Washington University, with whom Dr. Sheline has collaborated on earlier related research. [See “Earlier Research on SSRIs and Abeta.”]

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“This study shows us that antidepressants have multiple effects on the brain,” said Dean Hartley, PhD, director of science initiatives at the Alzheimer's Association, who was not involved with the study. “Citalopram reduced amyloid-beta levels within hours compared with weeks when used to treat depression. The mechanism is different than what happens when it works as an antidepressant.”

“It is important that the researchers were able to look at the effects of citalopram in lowering amyloid-beta in humans,” he added. “The investigators had the ability to sample CSF over a couple of days and they could see the rate of formation and degradation of the protein. The big question is what will happen over a longer period of time in older people. The good news is that we know that these drugs have a good safety profile.”

He added that medicines used to reduce Abeta levels may be akin to cholesterol-lowering medications. “This is definitely something that needs further study,” he said. “These scientists have definitely opened up the door to think about other ways to target amyloid-beta.” He said that it may have a place in any number of prevention trials now underway to reduce the risk of AD.

Samuel E. Gandy, MD, PhD, associate director of the Mount Sinai Alzheimer's Disease Research Center, agreed, adding: “This is a very well executed study. One might get a hint as to whether this has any clinical importance by looking at the age at onset of AD in patients who were taking the drug chronically during their 50s.”

“This would be something of a ‘poor man's prevention trial,’” added Dr. Gandy, who is also professor of neurology and psychiatry and Mount Sinai Chair in Alzheimer's Disease Research and director of the Center for Cognitive Health and NFL Neurological Care.

“If the drug has any impact on AD, then one might see delayed onset in those taking it,” said Dr. Gandy. “While simple amyloid-reducing approaches such as this have received most of the attention over the past 30 years, the accumulated evidence suggests that strategies based solely on amyloid-reducing, if begun after symptoms are established, are unlikely to be effective enough to merit Food and Drug Administration approval.”

Dr. Gandy added: “More and more, AD is being viewed as a disease of network pathology that might only be treatable with drugs that correct the dysfunction of entire networks. Even if amyloid deposition is the first step, that will almost certainly induce dozens or hundreds of downstream events,” explained Dr. Gandy. “By the time we intervene, these dozens or hundreds of downstream effects have been present for decades. At that point, simple amyloid-reducing seems highly unlikely to be adequate.”

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In earlier research, Yvette Sheline, MD, while at Washington University, had enrolled people in a study that involved undergoing a positron emission tomography (PET) scan to assess amyloid burden. When looking at the scans and comparing histories, she saw that those with a recent history of depression who had used of SSRIs (within a five-year period of the study) had fewer amyloid deposits in their brain. Dr. Sheline began searching for explanations. And that led her to the SSRIs and to collaboration with John Cirrito, PhD, an assistant professor of neurology at Washington University.

Studies have shown that serotonin receptors levels are reduced in the brains of AD patients. Dr. Cirrito and his colleagues showed that activation of serotonin receptors reduced Abeta production in mice. Treatment with serotonin activates intracellular signaling pathways and increases the product of alpha-secretase.

In their 2011 paper in Proceedings of the National Academy of Sciences, they treated young transgenic AD animals with one dose of an SSRI and found concentrations of amyloid beta were 25 percent lower in the interstitial fluid. They went on to administer the SSRI to mice chronically for four months, starting before they had signs of AD and observed a 50 percent reduced beta-amyloid plaque load.

“A lot more research is necessary before anyone can recommend antidepressants to slow the course of AD,” Dr. Cirrito said.

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•. Sheline YI, Yarasheshki K, Swarm, et al. An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Sci Transl Med 2014; 6(236):236re4.
    •. Cirrito JR, Disabato BM, Restivo JL, et al. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A 2011;108(36):14968–14973.
      © 2014 American Academy of Neurology