. An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014 May 14;6(236):236re4. PubMed.

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  1. This study was well-conducted and is elegant because it shows consistent effects of the drug citalopram in transgenic mice and in humans. Regarding the potential use of citalopram in Alzheimer’s disease patients, Mark Mattson correctly points out that positive behavioral data are lacking for citalopram in transgenic mice, and Lon Schneider correctly notes that a recent study found that citalopram accelerated cognitive decline in AD patients (Porsteinsson et al., 2014).

    I would like to add that this is the third drug, after semagacestat (Doody et al., 2013) and avagacestat (Coric et al., 2012), for which a lowering effect on CSF Aβ production in humans is associated with detrimental cognitive effects in AD patients. The detrimental effect of citalopram on cognition in AD patients described in the JAMA paper is not trivial. In only nine weeks, the drug at 30 mg/day significantly (p = 0.03) lowered, compared with placebo, MMSE by 1.05 points (95 percent confidence interval 0.13-1.97 points). This effect size corresponds to at least six months of accelerated cognitive decline.

    It will be interesting to see in the future if other drugs that inhibit the production of Aβ in CSF in humans will also cause detrimental cognitive effects in AD patients.

    References:

    . Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014 Feb 19;311(7):682-91. PubMed.

    . A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50. PubMed.

    . Safety and Tolerability of the γ-Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease. Arch Neurol. 2012 Aug 13;:1-12. PubMed.

    View all comments by Bruno Pietro Imbimbo
  2. This elegant study is another contribution to the demonstration that activation of the serotonergic neurotransmission could have a beneficial effect in the context of AD. Such data should lead us to explore which serotonin receptor subtypes mediate such action. Among the 14 different receptors that respond to serotonin, all but 5-HT3 receptors are G protein-coupled receptors (GPCRs). More than 30 percent of the currently marketed drugs target GPCRs, and some already target serotonin receptors. We have recently demonstrated that chronic administration of a 5-HT4 receptor agonist is able to slow down amyloid pathology conjointly with cerebral inflammation and also to prevent cognitive deficits in 5XFAD mice (Giannoni et al., 2013).

    I would like to point out that activation of 5-HT4 receptors (and probably of other 5-HT receptors subtypes) is efficient in slowing down the progression of the pathology by activation of the non-amyloidogenic pathway and the release of the neuroprotective sAPPα fragment. Thus, chronic treatments using 5-HT4 agonists should be conducted in early stages of the disease, when the amyloid load is not too high. Then, they could delay amyloid accumulation. Translation in the clinic is far away, and we need safe drugs that will not increase the QT interval. That means back to the screening of molecules …

    References:

    . Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer's disease. Front Aging Neurosci. 2013 Dec 24;5:96. PubMed.

  3. If we believe both the Porsteinsson results regarding cognition and the new data on SSRIs lowering Aβ, this may—together with the results of the γ-secretase inhibitor trials—indicate that lowering Aβ production as such is not only useless but may even be harmful for people with cognitive impairment. In any case, I would strongly support Richard Wurtman's suggestion to use existing clinical data (the various large epidemiology data bases should provide sufficient material) before starting any new trials based on this hypothesis.

    View all comments by Albrecht Stöffler

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  1. Antidepressant Citalopram Shows Promise as Future Anti-Amyloid Agent