Many researchers believe that slowing the buildup of amyloid in the brain holds the key to delaying or preventing Alzheimer’s disease. Scientists previously reported that selective serotonin reuptake inhibitors (SSRIs)—a class of commonly used antidepressants—suppressed Aβ and lowered amyloid plaque load in mice. Now, a follow-up report claims that the drugs inhibit Aβ production in people, as well. Yvette Sheline, formerly at Washington University in St. Louis and now at the University of Pennsylvania, Philadelphia, and John Cirrito at WashU, published the human data in the May 14 Science Translational Medicine.
A single dose of the SSRI citalopram, marketed under the brand name Celexa, cut Aβ production by a third in the cerebrospinal fluid (CSF) of healthy volunteers. Future studies may reveal whether chronic dosing produces the same effect, and if this would lessen amyloid buildup in the brain, Sheline said. If there is a sustained benefit, then SSRIs may join immunotherapy and BACE inhibitors as another possible route to curb amyloid pathology. Many SSRIs have been approved by the FDA and they have acceptable safety profiles.
Other researchers called the findings promising, while noting that the road to a potential therapy remains long. “It seems clear that citalopram decreases Aβ production and aggregation in both mice and humans. The big question is, can that translate into a clinical preventative or therapeutic effect?” asked William Klunk at the University of Pittsburgh.
SSRIs block the reuptake of serotonin by neurons, making this neurotransmitter more available in the synaptic cleft and pumping up its signaling. Several groups have shown that serotonin dampens Aβ production in vitro, and also lightens plaque load and preserves cognition in 3xTg AD model mice (see Robert et al., 2001; Arjona et al., 2002; Nelson et al., 2007). In previous studies, Sheline and colleagues found that a single dose of any of several SSRIs cut Aβ levels in the interstitial fluid (ISF) of young APP/PS1 mice by a quarter, and four months of treatment halved plaque load.
The authors wondered if people taking SSRIs might be similarly protected from amyloid buildup. To investigate this, the researchers recruited 186 cognitively normal volunteers with an average age of 69. Amyloid PET scanning revealed that participants who had used any antidepressants in the last five years had significantly less amyloid in their brains than those who had not taken the drugs (see Cirrito et al., 2011). This retrospective study could not establish if SSRI use suppressed amyloid production, however.
To explore a direct connection, Sheline and colleagues used stable isotope labeling kinetics (SILK), a technique developed by Randall Bateman at WashU to measure production of new proteins in the brain. Researchers intravenously administer 13C-labeled leucine to track newly generated Aβ, then collect CSF samples at regular intervals (see Apr 2009 news story). This allows them to determine rates of Aβ production and clearance. Sheline recruited 23 healthy adult volunteers below the age of 50. SILK revealed that two 30 mg doses of citalopram two hours apart suppressed Aβ production by 37 percent over the next 45 hours, without affecting clearance. The authors arrived at the dosage based on dose-response studies in mice. This amount is on the high end of what people take for depression, the authors note.
What might citalopram do long term? For this question, human data is not available, but Sheline and colleagues looked at the effects of chronic citalopram administration in 6-month-old APP/PS1 mice, which actively deposit amyloid. The authors followed the fate of individual plaques in live animals using high-power, two-photon microscopy. Four weeks of citalopram arrested the growth of existing plaques and prevented new ones from forming. It did not clear deposits.
Stopping Plaque in Its Tracks: In mice treated with placebo, amyloid plaques grow and new deposits appear (top panels). In mice taking citalopram, plaques stay static (bottom panels).
[Image courtesy of Science Translational Medicine/AAAS.]
Commentators praised the methodology of the study, but cautioned that many questions about the therapeutic potential of SSRIs remain. Mark Mattson at the National Institute on Aging, Bethesda, Maryland, noted that the current study lacks behavioral data in mice, leaving open the question of clinical efficacy. Richard Wurtman at the Massachusetts Institute of Technology in Cambridge suggested that before advancing to large-scale human trials, it would be worth mining large epidemiological datasets to see if antidepressant use correlates with a lower risk of AD. Paul Aisen at the University of California, San Diego, wrote to Alzforum, “There is not yet strong evidence that citalopram reduces brain amyloid in humans; the effect on CSF Aβ42 is intriguing, but the relationship between CSF amyloid peptides and brain amyloid is complex.”
Nonetheless, researchers agreed that the data merit further human studies. “I think trials in people with mild cognitive impairment or who have biomarker evidence of AD should be seriously considered,” Constantine Lyketsos at Johns Hopkins University, Baltimore, told Alzforum. Citalopram may not be the best SSRI to use, however. A recent trial for agitation in AD found that the drug causes some adverse effects, including accelerated cognitive decline and abnormal heart rhythms, said Lon Schneider at the University of Southern California, Los Angeles (see Feb 2014 news story). The Food and Drug Administration now recommends that people take no more than 40 mg/day of citalopram. It further specifies that people over 60 should take no more than 20 mg/day, because the drug builds up in the blood of older adults and can increase the risk for heart arrhythmias.
For this reason, Sheline plans to use a different SSRI in future studies. All drugs in this class have similar effects on Aβ in mice, she told Alzforum. She will investigate the effect of chronic dosing by treating cognitively normal volunteers between the ages of 65 and 85 with an SSRI for two weeks, comparing baseline and final levels of Aβ in spinal fluid. If Aβ stays low, the next step would be a larger study using PET amyloid imaging to look for any changes in brain amyloid load. These studies might eventually pave the way for a longer clinical trial in cognitively healthy older adults at risk for AD, Sheline said.—Madolyn Bowman Rogers.
Research Models Citations
- Studies Reveal New Hope, Old Problems With AD Biomarkers
- Citalopram Calms Agitation in Alzheimer’s, but Carries Risks
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- Arjona AA, Pooler AM, Lee RK, Wurtman RJ. Effect of a 5-HT(2C) serotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs. Brain Res. 2002 Sep 27;951(1):135-40. PubMed.
- Nelson RL, Guo Z, Halagappa VM, Pearson M, Gray AJ, Matsuoka Y, Brown M, Martin B, Iyun T, Maudsley S, Clark RF, Mattson MP. Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Exp Neurol. 2007 May;205(1):166-76. PubMed.
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- Sheline YI, West T, Yarasheski K, Swarm R, Jasielec MS, Fisher JR, Ficker WD, Yan P, Xiong C, Frederiksen C, Grzelak MV, Chott R, Bateman RJ, Morris JC, Mintun MA, Lee JM, Cirrito JR. An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014 May 14;6(236):236re4. PubMed.