The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index; 12 of the 49 sources its claims cite were checked for support.
An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice
Open accessAbstract
The antidepressant drug citalopram decreased CSF amyloid-β in healthy humans, and in an aged transgenic mouse model of Alzheimer’s disease, it decreased ISF amyloid-β in a dose-dependent manner.
Overview
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Written from the paper’s full text.
TL;DR
In aged APP/PS1 mice, citalopram dose-dependently lowered brain interstitial fluid Aβ, blocked growth of existing plaques, and reduced new plaque appearance by 78%. In healthy human volunteers, acute citalopram reduced CSF Aβ production by 37% and total CSF Aβ concentrations by 38% without changing clearance.
Key findings
- In 12-month-old plaque-bearing APP/PS1 mice, citalopram reduced ISF Aβ at 5 mg/kg (12.4%) and 10 mg/kg (24.5%) versus baseline; 20 mg/kg gave no additional effect (27.5% reduction), while 2.5 mg/kg was not significant.
- Chronic citalopram (10 mg/kg daily for 28 days) prevented plaque growth: vehicle plaques grew 111.4 μm² on average, whereas citalopram plaques did not grow (−22.4 μm², p=0.26); new plaques were reduced from 10 (3.9) to 2.2 (1.1), p=0.01, a 78% reduction.
- In healthy human volunteers, citalopram lowered mean CSF Aβ production rate to 1.33 pg/hr (0.15) versus 2.11 pg/hr (0.20) for placebo, a 37% reduction (p=0.005), and lowered average CSF Aβ concentration by 38% over 37 hours (p=0.001).
- Aβ clearance rate was unchanged (−0.61 versus −0.96 per hour; p=0.115), and tracer/tracee ratio did not differ significantly between groups.
Methods
- Mouse studies used APP/PS1+/− mice: in vivo hippocampal microdialysis to measure ISF Aβ after acute citalopram doses (2.5, 5, 10, 20 mg/kg) and longitudinal multiphoton microscopy with thinned-skull cranial windows to track individual plaque growth over 28 days of citalopram (10 mg/kg) or vehicle.
- Human study was a randomized, double-blind, placebo-controlled trial in healthy volunteers receiving 60 mg citalopram in divided oral doses; CSF and blood were sampled hourly during stable-isotope labeling kinetics (SILK) with 13C6-leucine, and labeled/unlabeled Aβ was measured by mass spectrometry.
- Analyses used repeated-measures ANOVA with treatment, time, and treatment-by-time effects, mixed models, post-hoc approximate t-tests, and non-proportional odds cumulative logit models for plaque outcomes.
Limitations
- The paper states that human data were not collected during the first 8 hours after drug/placebo administration, so the timing of when CSF concentration differences arose is unknown.
- The paper states that human studies were conducted in young individuals presumably before plaque formation, so it is unknown whether the same effect occurs in older individuals with plaque deposition.
- The paper notes that production and clearance were modeled as independent phenomena even though they occur simultaneously; evident additional constraints include the small human sample (23 analyzed), acute dosing rather than long-term prevention outcomes, and adverse events including post-lumbar puncture headaches and nausea/vomiting.
Model-written summary. Check it against the paper before relying on it.
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Verification
Claims the paper makes
12 of 49 cited sources checked · 6 supported · 3 flagged · accuracy not yet measured
- Premiseown data
Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer's disease (AD).
“Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD).”
Quote in the paperSubstantial claim4 of 5 sources checked- cites [10] 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 951 135 9 27 2002 12231467 source
- cites [11] Nitsch RM Deng M Growdon JH Wurtman RJ Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion J Biol Chem 271 4188 2 23 1996 8626761 source
The Discussion (page not provided) reports that serotonin increased non-amyloidogenic APP ectodomain secretion in cultured cells, which could reduce amyloidogenic products. But the authors say they could not measure Aβ in those experiments and that an effect on Aβ secretion remained to be investigated. The cited paper also does not report experiments in animal models of AD. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [12] Robert SJ Zugaza JL Fischmeister R Gardier AM Lezoualc’h F The human serotonin 5-HT4 receptor regulates secretion of non-amyloidogenic precursor protein J Biol Chem 276 44881 11 30 2001 11584021 source
In “Effect of 5-HT4 Receptor Activation on Aβ Production,” the authors report no effect of serotonin on Aβ production in CHO cells compared with untreated controls, contrary to the claimed in vitro suppression. The provided passages do not report Aβ suppression in animal models of AD. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [13] Cirrito JR Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans Proc Natl Acad Sci U S A 108 14968 9 6 2011 21873225 PMC3169155 source
- cites [14] Nelson RL Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice Exp Neurol 205 166 5 2007 17368447 PMC1979096 source
The Results (page not provided) show that paroxetine treatment lowered Aβ1−40 levels in 3xTgAD mice, but did not significantly affect Aβ1−42. The Discussion says serotonergic signaling might mediate this effect, while also allowing a mechanism independent of serotonin signaling. The paper does not establish that serotonin signaling suppresses Aβ generation, and it reports no in vitro experiment of its own. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Activation of serotonin receptors reduces Aβ production in vitro.
“Activation of serotonin receptors has been shown to reduce Aβ production in vitro; treatment with serotonin or receptor agonists activates intracellular signaling cascades and increases levels of the α-secretase product sAPP-α (10–12).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [10] 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 951 135 9 27 2002 12231467 source
- cites [11] Nitsch RM Deng M Growdon JH Wurtman RJ Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion J Biol Chem 271 4188 2 23 1996 8626761 source
The Discussion says the authors could not measure Aβ secretion in the serotonin-treated 3T3 cells and that whether serotonin receptor stimulation changes Aβ secretion remains to be investigated. The Results show increased APPs secretion, but not the claimed reduction in Aβ production. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [12] Robert SJ Zugaza JL Fischmeister R Gardier AM Lezoualc’h F The human serotonin 5-HT4 receptor regulates secretion of non-amyloidogenic precursor protein J Biol Chem 276 44881 11 30 2001 11584021 source
In “Effect of 5-HT4 Receptor Activation on Aβ Production” (page not supplied), the authors report no effect of serotonin on Aβ production in their CHO-cell experiment. The Discussion likewise says that receptor stimulation did not change secreted Aβ levels, although it increased sAPPα secretion. (LLM, conf=0.93)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
In animal models, a 12-25% reduction in Aβ concentrations was sufficient to dramatically decrease plaque formation.
“In animal models, a 12–25% reduction in Aβ concentrations was sufficient to dramatically decrease plaque formation (32).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [32] Yan P Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice J Neurosci 29 10706 8 26 2009 19710322 PMC2756291 source
The Results report that Compound E dramatically attenuated new plaque appearance in APP/PS1 mice, while a separate Results passage reports 24-hour reductions of 22% and 25% in interstitial-fluid Aβ. Our copy does not report a 12% reduction, and the Discussion describes the reduction in Aβ as associated with—not definitively sufficient to cause—the reduction in plaque formation. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Chronic SSRI treatment over four months reduced Aβ plaque load by 50% in mice.
“Chronic SSRI treatment over the course of four months reduced Aβ plaque load by 50% in mice (13).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Cirrito JR Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans Proc Natl Acad Sci U S A 108 14968 9 6 2011 21873225 PMC3169155 source
- Premisecitation
In humans, CSF Aβ concentrations begin changing before tau levels.
“In humans, CSF Aβ concentrations begin changing before tau levels; amyloid deposition occurs in the brain decades before the onset of clinical symptoms (3–5).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [3] Price JL Morris JC Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease Ann Neurol 45 358 3 1999 10072051 source
- cites [4] Hardy J Selkoe DJ The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics Science 297 353 7 19 2002 12130773 source
- cites [5] Bateman RJ Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease N Engl J Med 7 11 2012 PMC3474597 22784036 source
- Premisecitation
Stimulation of serotonin receptors activates the ERK signaling cascade in as little as 5 minutes.
“Stimulation of serotonin receptors activates the ERK signaling cascade in as little as 5 minutes (27–29).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [27] Lione A Errico M Lin S Cowen D Activation of extracellular signal-regulated kinase (ERK) and Akt by human serotonin 5-HT1B receptors in transfected BE(2)-C neuroblastoma cells is inhibited by RGS4 J Neurochem 2000 9 75 3 934 8 10936173 source
- cites [28] Johnson-Farley N Kertesy S Dubyak G Cowen D Enhanced activation of Akt and extracellular-regulated kinase pathways by simultaneous occupancy of Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT7A receptors in PC12 cells J Neurochem 2005 1 92 1 72 82 15606897 source
- cites [29] Norum J Hart K Levy F Ras-dependent ERK activation by the human Gs-coupled serotonin receptors 5-HT4(b) and 5-HT7(a) J Biol Chem 2003 1 31 278 5 3098 104 12446729 source
- Premisecitation
In those studies, serotonin signaling did not alter the rate of Aβ clearance.
“In those studies, serotonin signaling did not alter the rate of Aβ clearance, suggesting that reduced Aβ production was responsible for lower Aβ concentrations.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] Cirrito JR Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans Proc Natl Acad Sci U S A 108 14968 9 6 2011 21873225 PMC3169155 source
- Premisecitation
Aggregation of the Aβ peptide into plaques appears concentration dependent.
“Given that aggregation of the Aβ peptide into plaques appears to be concentration dependent (6,7), methods for reducing Aβ concentrations are important targets for therapy.”
- Also stated in: § Discussion · plain
“Conversion of Aβ from its normal soluble form into these toxic conformations is concentration-dependent; high concentrations of Aβ are much more prone to aggregate than lower concentrations of Aβ (7).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [6] Bero AW Neuronal activity regulates the regional vulnerability to amyloid-beta deposition Nat Neurosci 14 750 6 2011 21532579 PMC3102784 source
- cites [7] Lomakin A Teplow DB Kirschner DA Benedek GB Kinetic theory of fibrillogenesis of amyloid beta-protein Proc Natl Acad Sci U S A 94 7942 7 22 1997 9223292 PMC21534 source
- Also stated in: § Discussion · plain
- Findingown data
In 6-month-old APP/PS1 mice, plaques in citalopram-treated mice did not grow over 28 days (−22.4 μm2, not significantly different from 0).
“During this 28-day interval, plaques in mice treated with vehicle grew on average 111.4 μm2, a growth rate significantly different from 0 (p = 0.0003), whereas plaques in citalopram-treated mice did not grow (−22.4 μm2, a growth rate not significantly different from 0, p = 0.26) (Fig 2A,B).”
Quote in the paperSubstantial claim - Findingown data
Citalopram treatment reduced the number of newly appearing plaques in APP/PS1 mice (2.2 vs 10, p=0.01).
“Furthermore, citalopram treatment reduced the number of newly appearing plaques [2.2 (1.1) vs. 10 (3.9), p= 0.01], but had no effect on the number of disappearing plaques [3.7 (1.1) vs. 3.6 (1.5), p = 0.93] (Fig 2D).”
Quote in the paperSubstantial claim - Findingown data
In 12-month-old plaque-bearing APP/PS1 mice, citalopram at 10 mg/kg reduced ISF Aβ concentrations by 24.5% at 24 hours compared to baseline.
“At 24 hours after administration, however, there was a significant dose-dependent reduction in ISF Aβ at both 5 and 10 mg/kg citalopram (mean reduction of 12.4% and 24.5%, respectively, compared to baseline concentrations).”
Quote in the paperSubstantial claim - Findingown data
Citalopram arrested the growth of pre-existing amyloid plaques in plaque-bearing APP/PS1 mice.
“Citalopram arrested the growth of pre-existing plaques and reduced the appearance of new plaques by 78%.”
- Also stated in: § Chronic citalopram treatment blocks plaque-growth in APP/PS1 mice · plain
“During this 28-day interval, plaques in mice treated with vehicle grew on average 111.4 μm2, a growth rate significantly different from 0 (p = 0.0003), whereas plaques in citalopram-treated mice did not grow (−22.4 μm2, a growth rate not significantly different from 0, p = 0.26) (Fig 2A,B).”
Quote in the paperSubstantial claim - Also stated in: § Chronic citalopram treatment blocks plaque-growth in APP/PS1 mice · plain
- Findingreasoning
Here, a decrease of 25% in Aβ concentration produced a 78% reduction in new plaque formation.
“Here, a decrease of 25% in Aβ concentration produced a 78% reduction in new plaque formation.”
Quote in the paperSubstantial claim - Findingown data
Plaque load within the hippocampus did not differ between citalopram and vehicle groups at 24 hours after dosing in 12-month-old APP/PS1 mice.
“Plaque-load within the hippocampus was assessed histologically in all mice at the 24 hour time point and did not differ between groups (Fig. S1).”
Quote in the paperNot a substantial claim - Findingown data
Citalopram did not increase the likelihood of plaque regression in APP/PS1 mice (OR 2.1, 95% CI 0.96-4.7, p=0.063).
“Citalopram reduced the likelihood of plaque growth [Odds Ratio, OR (95% CI)], 0.298 (0.148, 0.600), p=0.0008; but did not increase the likelihood of plaque regression, 2.1 (0.96, 4.7), p= 0.063 (Fig 2C).”
Quote in the paperNot a substantial claim - Findingown data
The tracer/tracee ratio (labeled Aβ/unlabeled Aβ) over the 37 hours of CSF sampling was overlapping for both groups.
“Interestingly, the tracer/tracee ratio (labeled Aβ/unlabeled Aβ) (TTR) over the 37 hours of CSF sampling was overlapping for both groups (Fig. S2 suggesting that the fractional turnover of Aβ was unchanged at the time of the SILK study and that Aβ metabolism had reached a new steady state.”
Quote in the paperSubstantial claim - Findingown data
In 12-month-old plaque-bearing APP/PS1 mice, citalopram at 20 mg/kg produced no additional reduction in ISF Aβ beyond 10 mg/kg (27.5% reduction).
“The maximum reduction in ISF Aβ occurred at 10 mg/kg, as a higher dose of 20 mg/kg citalopram had no additional effect (27.5% reduction).”
Quote in the paperNot a substantial claim - Findingown data
Citalopram had no effect on the number of disappearing plaques in APP/PS1 mice (3.7 vs 3.6, p=0.93).
“Furthermore, citalopram treatment reduced the number of newly appearing plaques [2.2 (1.1) vs. 10 (3.9), p= 0.01], but had no effect on the number of disappearing plaques [3.7 (1.1) vs. 3.6 (1.5), p = 0.93] (Fig 2D).”
Quote in the paperNot a substantial claim - Findingown data
The longitudinal change in concentrations of newly-produced Aβ, as assessed by plasma 13C6-Leucine normalized labeled Aβ, differed significantly between citalopram-treated subjects and placebo (time by treatment group p=0.0004; main effect p=0.008).
“The longitudinal change in concentrations of newly-produced Aβ, as assessed by plasma 13C6-Leucine normalized labeled Aβ, also differed significantly between citalopram-treated subjects relative to placebo (time by treatment group, p = 0.0004), along with a significant main effect of treatment group (p=0.008) (Fig. 3C).”
Quote in the paperSubstantial claim - Findingown data
Citalopram treatment was associated with a similar effect on amyloid angiopathy progression in APP/PS1 mice (1.2 vs 2.9, p=0.03) over 28 days.
“A similar effect on amyloid angiopathy progression was observed (1.2 (0.2) versus 2.9 (0.8) p= 0.03) during 28 days of treatment (Fig 2E).”
Quote in the paperSubstantial claim - Findingown data
The rate of plaque growth in vehicle-treated APP/PS1 mice was significantly higher than in citalopram-treated mice over 28 days.
“The rate of plaque growth in the vehicle group was significantly higher relative to the citalopram group (p=0.0003).”
Quote in the paperSubstantial claim - Findingown data
Citalopram-treated subjects had significantly different changes in Aβ concentrations over time compared to placebo (time by treatment group p=0.002; main effect p=0.001).
“Citalopram-treated subjects had significantly different changes in Aβ concentrations over time compared to placebo (repeated measures ANOVA: time by treatment group p = 0.002), along with a significant main effect of the treatment group (p=0.001) (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
In 12-month-old plaque-bearing APP/PS1 mice, citalopram decreased brain interstitial fluid (ISF) Aβ in a dose-dependent manner.
“We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), decreased Aβ in brain interstitial fluid (ISF) in a dose-dependent manner.”
- Also stated in: § Citalopram dose-response in aged APP/PS1 mice · plain
“At 24 hours after administration, however, there was a significant dose-dependent reduction in ISF Aβ at both 5 and 10 mg/kg citalopram (mean reduction of 12.4% and 24.5%, respectively, compared to baseline concentrations).”
Quote in the paperSubstantial claim - Also stated in: § Citalopram dose-response in aged APP/PS1 mice · plain
- Findingown data
Citalopram reduced the likelihood of plaque growth in APP/PS1 mice (OR 0.298, 95% CI 0.148-0.600, p=0.0008).
“Citalopram reduced the likelihood of plaque growth [Odds Ratio, OR (95% CI)], 0.298 (0.148, 0.600), p=0.0008; but did not increase the likelihood of plaque regression, 2.1 (0.96, 4.7), p= 0.063 (Fig 2C).”
Quote in the paperSubstantial claim - Findingown data
The longitudinal course of TTR was not significantly different between the two groups (time by treatment group p=0.99, main effect p=0.91).
“The longitudinal course of TTR was not significantly different between the two groups (time by treatment group p = 0.99, main effect of treatment group p=0.91).”
Quote in the paperNot a substantial claim - Findingown data
In 12-month-old plaque-bearing APP/PS1 mice, citalopram at 5 mg/kg reduced ISF Aβ concentrations by 12.4% at 24 hours compared to baseline.
“At 24 hours after administration, however, there was a significant dose-dependent reduction in ISF Aβ at both 5 and 10 mg/kg citalopram (mean reduction of 12.4% and 24.5%, respectively, compared to baseline concentrations).”
Quote in the paperSubstantial claim - Findingown data
In healthy human volunteers, acute citalopram dosing slowed CSF Aβ production by 37% compared to placebo.
“Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo.”
- Also stated in: § Citalopram reduces CSF Aβ production and concentrations in humans · plain
“The mean production rate of Aβ within CSF calculated over hours 13–22 was significantly lower in citalopram-treated individuals (mean, SE) [1.33 pg/hr (0.15)] versus placebo [2.11 pg/hr (0.20] (p=0.005), a reduction of 37%.”
Quote in the paperSubstantial claim - Also stated in: § Citalopram reduces CSF Aβ production and concentrations in humans · plain
- Findingown data
Post-hoc approximate t-tests revealed significant differences between treatment and placebo in change in mean Aβ concentrations from baseline at hours 10, 13-16, 19, 22-27, 29, 32-41, 44-45.
“Post-hoc approximate t-tests revealed significant differences (p < 0.05) between the treatment and placebo groups in terms of change in the mean Aβ concentrations from baseline, at hours 10, 13–16, 19, 22–27, 29, 32–41, 44–45 from treatment.”
Quote in the paperSubstantial claim - Findingown data
In 12-month-old plaque-bearing APP/PS1 mice, citalopram at 2.5 mg/kg had no significant change in ISF Aβ concentrations compared to vehicle at 24 hours after dosing.
“Mice administered citalopram at 2.5 mg/kg had no significant change in ISF Aβ concentrations compared to vehicle-treated mice at 24 hours after dosing (Fig. 1B).”
Quote in the paperNot a substantial claim - Findingown data
Citalopram reduced the appearance of new plaques by 78% in plaque-bearing APP/PS1 mice.
“Citalopram arrested the growth of pre-existing plaques and reduced the appearance of new plaques by 78%.”
- Also stated in: § Chronic citalopram treatment blocks plaque-growth in APP/PS1 mice · plain
“Furthermore, citalopram treatment reduced the number of newly appearing plaques [2.2 (1.1) vs. 10 (3.9), p= 0.01], but had no effect on the number of disappearing plaques [3.7 (1.1) vs. 3.6 (1.5), p = 0.93] (Fig 2D).”
Quote in the paperSubstantial claim - Also stated in: § Chronic citalopram treatment blocks plaque-growth in APP/PS1 mice · plain
- Findingown data
In 6-month-old APP/PS1 mice, plaques in vehicle-treated mice grew on average 111.4 μm2 over 28 days, a growth rate significantly different from 0.
“During this 28-day interval, plaques in mice treated with vehicle grew on average 111.4 μm2, a growth rate significantly different from 0 (p = 0.0003), whereas plaques in citalopram-treated mice did not grow (−22.4 μm2, a growth rate not significantly different from 0, p = 0.26) (Fig 2A,B).”
Quote in the paperSubstantial claim - Findingown data
The clearance rate of Aβ was unchanged in citalopram-treated individuals compared to placebo (−0.61 vs −0.96 per hour; p=0.115).
“However the clearance rate of Aβ was unchanged (−0.61 (0.14) versus −0.96 (0.16) per hour mean & 95% CI; p=0.115).”
Quote in the paperSubstantial claim - Findingown data
In healthy human volunteers, acute citalopram dosing was associated with a 38% decrease in total CSF Aβ concentrations compared to placebo.
“This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group.”
- Also stated in: § Citalopram reduces CSF Aβ production and concentrations in humans · plain
“Citalopram treatment was associated with a 38% lower average Aβ concentration over the 37 hour sampling period compared to placebo (p=0.001) (Fig. 3B).”
Quote in the paperSubstantial claim - Also stated in: § Citalopram reduces CSF Aβ production and concentrations in humans · plain
- Premisecitation
Single-dose treatment of SSRIs in young APP/PS1 mice reduced Aβ levels in brain ISF by 25%.
“Modulating serotonin levels in vivo shows consistent effects: single-dose treatment of SSRIs in young APP/PS1 mice reduced Aβ levels in the brain interstitial fluid (ISF) by 25% (13).”
- Also stated in: § Citalopram dose-response in aged APP/PS1 mice · boosted
“Previous studies demonstrated in 3 month old APP/PS1+/− mice, an age prior to Aβ pathology, that 10mg/kg citalopram reduces brain ISF Aβ concentrations by 25% (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Cirrito JR Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans Proc Natl Acad Sci U S A 108 14968 9 6 2011 21873225 PMC3169155 source
- Also stated in: § Citalopram dose-response in aged APP/PS1 mice · boosted
- Study design and conductown data
Placebo and citalopram treated volunteers included in the analysis did not differ in demographic characteristics, including age, gender or race.
“The placebo versus citalopram treated volunteers included in the analysis did not differ in demographic characteristics, including age, gender or race.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Maintaining low Aβ concentrations with any agent, including secretase inhibitors or SSRIs, should limit the rate at which toxic species of Aβ are formed.
“Maintaining low Aβ concentrations with any agent, including secretase inhibitors or SSRIs, should limit the rate at which toxic species of Aβ are formed.”
Quote in the paperSubstantial claim - Interpretationreasoning
Small changes in CSF Aβ concentration have dramatic effects on Aβ accumulation as plaques.
“Small changes in CSF Aβ concentration have dramatic effects on Aβ accumulation as plaques.”
Quote in the paperSubstantial claim - Premisecitation
In studies using BACE knock-out mice, a 12% decrease in Aβ concentrations, assessed in total brain tissue, resulted in a marked blocking of plaque formation.
“In studies using BACE knock-out mice, a 12% decrease in Aβ concentrations, assessed in total brain tissue, resulted in a marked blocking of plaque formation (33).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] McConlogue L Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice J Biol Chem 282 26326 9 7 2007 17616527 source
- Premisecitation
The γ-secretase subunit nicastrin is an ERK substrate.
“Adding activated ERK to an in vitro γ-secretase cleavage assay reduced activity in a dose-dependent manner, and the γ-secretase subunit nicastrin is an ERK substrate (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Kim SK Park HJ Hong HS Baik EJ Jung MW Mook-Jung I ERK1/2 is an endogenous negative regulator of the gamma-secretase activity FASEB J 2006 1 20 1 157 9 16293708 source
- Interpretationreasoning
Citalopram likely had a sustained effect on Aβ throughout CSF sampling despite the single administration at the beginning of the study.
“Citalopram has a long half-life, meaning there was likely a sustained effect on Aβ throughout CSF sampling despite the single administration at the beginning of the study.”
Quote in the paperSubstantial claim- Rests on an assumption: Citalopram has a long half-life.
- Premisecitation
Previously depressed patients who had undergone SSRI treatment in the five years preceding enrollment in a PET study had less evidence of Aβ deposits than those who had not been exposed to SSRI treatment.
“Previously depressed patients who had undergone SSRI treatment in the five years preceding their enrollment in a positron emission tomography (PET) study to quantify amyloid binding, had less evidence of Aβ deposits than those who had not been exposed to SSRI treatment (13).”
- Also stated in: § Discussion · plain
“Further, we previously showed in retrospective studies in humans that SSRI exposure within the 5 years prior to amyloid PET scan was associated with lower amyloid binding as determined by PIB-PET imaging (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Cirrito JR Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans Proc Natl Acad Sci U S A 108 14968 9 6 2011 21873225 PMC3169155 source
- Also stated in: § Discussion · plain
- Premisecitation
ERK activity can reduce γ-secretase activity, which would lower Aβ levels.
“ERK activity can also reduce γ-secretase activity, which would lower Aβ levels.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Kim SK Park HJ Hong HS Baik EJ Jung MW Mook-Jung I ERK1/2 is an endogenous negative regulator of the gamma-secretase activity FASEB J 2006 1 20 1 157 9 16293708 source
- Premisenone given
SSRI drugs have a proven safety record.
“Because asymptomatic participants in a large prospective prevention trial might be exposed to an experimental compound for many years, the compound should have a proven safety record, as is the case for selective serotonin reuptake inhibitor (SSRI) drugs.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Cipriani A Furukawa T Salanti G Geddes J Higgins J Churchill R Watanabe N Nakagawa A Omori I McGuire H Tansella M Barbui C Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis Lancet 373 746 758 2009 19185342 source
- Interpretationreasoning
The mechanisms by which SSRIs mediate depression treatment and Aβ reduction are likely very different.
“The mechanisms by which SSRIs mediate these two effects are likely to be very different.”
Quote in the paperNot a substantial claim - Premisecitation
In prior SILK studies, plasma 13C6-leucine enrichment was found to adequately represent 13C6 labeling in the precursor pool for Aβ synthesis.
“In prior SILK studies (19), plasma 13C6-leucine enrichment was found to adequately represent 13C6 labeling in the precursor pool for Aβ synthesis.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Bateman RJ Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo Nat Med 12 856 7 2006 16799555 PMC2983090 source
- Premisecitation
A 10 mg/kg dose of citalopram in mice is approximately comparable to 50 mg/day in humans.
“Importantly, a calculation to determine roughly equivalent doses of citalopram between mice and humans estimated that a 10 mg/kg dose for a mouse is comparable to 50 mg/day in humans (16), a common though high dose of citalopram prescribed to treat depression (17).”
- Also stated in: § Discussion · plain
“Importantly, the maximal effective dose of citalopram that lowered brain Aβ concentrations and plaques in mice (10 mg/kg) is approximately comparable to a dose of citalopram (50 mg/day) that has been administered to humans as an antidepressant, and similar to the dose we used in this study, 60 mg.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Reagan-Shaw S Nihal M Ahmad N Dose translation from animal to human studies revisited FASEB J 22 659 3 2008 17942826 source
- Also stated in: § Discussion · plain
- Premisecitation
The APP/PS1+/− mouse model at 12 months of age contains ample Aβ deposits throughout the hippocampus and cortex.
“then used the APP/PS1+/− offspring for experiments at 12 months of age, when this model contains ample Aβ deposits throughout the hippocampus and cortex.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Savonenko A Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities Neurobiol Dis 18 602 4 2005 15755686 source
- Premisecitation
Adding activated ERK to an in vitro γ-secretase cleavage assay reduced activity in a dose-dependent manner.
“Adding activated ERK to an in vitro γ-secretase cleavage assay reduced activity in a dose-dependent manner, and the γ-secretase subunit nicastrin is an ERK substrate (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Kim SK Park HJ Hong HS Baik EJ Jung MW Mook-Jung I ERK1/2 is an endogenous negative regulator of the gamma-secretase activity FASEB J 2006 1 20 1 157 9 16293708 source
- Interpretationreasoning
The current dose-response studies and prospective plaque visualization studies in older mice (with plaques) suggest that the Aβ lowering effects of citalopram likely will be effective in older amyloid-plaque positive humans.
“However, the current dose-response studies and prospective plaque visualization studies in older mice (with plaques) suggest that the Aβ lowering effects of citalopram likely will be effective in older amyloid-plaque positive humans.”
Quote in the paperSubstantial claim - Premisecitation
ERK activation was required for serotonin-dependent suppression of Aβ.
“Our previous studies demonstrated that ERK activation was required for serotonin-dependent suppression of Aβ (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Cirrito JR Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans Proc Natl Acad Sci U S A 108 14968 9 6 2011 21873225 PMC3169155 source
- Premisecitation
SSRI treatment in the 3xTg AD mouse model showed similar reductions in Aβ.
“SSRI treatment in the 3xTg AD mouse model showed similar reductions in Aβ (14).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Nelson RL Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice Exp Neurol 205 166 5 2007 17368447 PMC1979096 source
- Interpretationreasoning
The effects of citalopram on plaques are consistent with citalopram's inhibition of Aβ production without enhancing Aβ clearance mechanisms.
“These effects are consistent with citalopram’s inhibition of Aβ production without enhancing Aβ clearance mechanisms.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 21
- It may state two separate claims as one. 11
Probably not a substantial claim. The paper may give no reason why it holds.
Interpretationnone givenThe efficacy of the current proposed prevention strategy depends critically on the validity of the amyloid hypothesis of Alzheimer's disease.
“Nonetheless, the efficacy of the current proposed prevention strategy depends critically on the validity of the amyloid hypothesis of Alzheimer’s disease.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCitalopram has among the most favorable side effect profiles compared with other antidepressants.
“Citalopram is one of the most selective SSRIs for serotonin re-uptake and has among the most favorable side effect profiles compared with other antidepressants (17).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Cipriani A Furukawa T Salanti G Geddes J Higgins J Churchill R Watanabe N Nakagawa A Omori I McGuire H Tansella M Barbui C Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis Lancet 373 746 758 2009 19185342
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationCurrent theories for SSRI-mediated treatment of depression include increased production of BDNF, increased hippocampal neurogenesis, and reduced expression of serotonin autoreceptors.
“Current theories for SSRI- mediated treatment of depression include increased production of BDNF (22), increased hippocampal neurogenesis (23–25) and reduced expression of serotonin autoreceptors (26).”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [22] Sen S Duman R Sanacora G Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications Biol Psychiatry 2008 9 15 64 6 527 32 18571629 PMC2597158
- cites [23] Malberg J Eisch A Nestler E Duman R Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus J Neurosci 2000 12 15 20 24 9104 10 11124987 PMC6773038
- cites [24] Kempermann G Kronenberg G Depressed new neurons--adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression Biol Psychiatry 2003 9 1 54 5 499 503 12946878
- cites [25] Eisch AJ Petrik D Depression and hippocampal neurogenesis: a road to remission? Science 2012 10 5 338 72 5 23042885 PMC3756889
- cites [26] Hamon M Blier P Monoamine neurocircuitry in depression and strategies for new treatments Prog Neuropsychopharmacol Biol Psychiatry 2013 8 1 45 54 63 23602950
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataFor newly generated Aβ, the power of the main effect of treatment was 66.18%.
“For newly generated Aβ, the power of time by treatment group interaction was also > 99.99% while the power of the main effect of treatment was 66.18%.”
- Also stated in: § Study Design · plain
“For newly generated Aβ, the power of time by treatment group interaction was also > 99.99% while the power of the main effect of treatment was 66.18%.”
Quote in the paperNot a substantial claim- Also stated in: § Study Design · plain
Probably not a substantial claim.
Study design and conductreasoningThe statistical models incorporated a random intercept at the subject level and, for plaque growth, also a random intercept at the plaque level to account for within-subject dependencies.
“In order to account for the within-subject dependencies in the outcome variables, these models incorporated a random intercept at the subject level and, for plaque growth, also a random intercept at the plaque level.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Study design and conductown dataThe concentrations over the time course were such that steady-state kinetics applied reasonably well after the first 12 hours and the rate of change of concentration appeared similar in both groups.
“The concentrations over the time course were such that steady-state kinetics applied reasonably well after the first 12 hours and the rate of change of concentration appeared similar in both groups.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataFor Aβ concentration, the power of the time by treatment group interaction was >99.99%.
“Based on the power analysis of the data, for Aβ concentration with alpha=0.05, the power of the time by treatment group interaction was > 99.99% and the power of the main effect of treatment was 95.03%.”
- Also stated in: § Study Design · plain
“Based on a repeated measures ANOVA, with a compound symmetry covariance structure and alpha=0.05, for Aβ concentration the power of the time by treatment group interaction was > 99.99% and the power of the main effect of treatment was 95.03%.”
Quote in the paperNot a substantial claim- Also stated in: § Study Design · plain
It may state two separate claims as one.
Interpretationown dataThe fractional turnover of Aβ was unchanged at the time of the SILK study and Aβ metabolism had reached a new steady state.
“Interestingly, the tracer/tracee ratio (labeled Aβ/unlabeled Aβ) (TTR) over the 37 hours of CSF sampling was overlapping for both groups (Fig. S2 suggesting that the fractional turnover of Aβ was unchanged at the time of the SILK study and that Aβ metabolism had reached a new steady state.”
- Also stated in: § Discussion · hedged
“Tracer kinetics established that the fractional turnover rate in the two groups was very similar suggesting that Aβ metabolism had reached a new steady state at the time when the SILK study was carried out.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · hedged
Probably not a substantial claim.
PremisecitationAmyloid deposition occurs in the brain decades before the onset of clinical symptoms.
“In humans, CSF Aβ concentrations begin changing before tau levels; amyloid deposition occurs in the brain decades before the onset of clinical symptoms (3–5).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [3] Price JL Morris JC Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease Ann Neurol 45 358 3 1999 10072051
- cites [4] Hardy J Selkoe DJ The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics Science 297 353 7 19 2002 12130773
- cites [5] Bateman RJ Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease N Engl J Med 7 11 2012 PMC3474597 22784036
Probably not a substantial claim. It may state two separate claims as one.
Study design and conductown dataThe human study was randomized, double-blind, and placebo-controlled.
“A randomized double-blind placebo controlled study was performed to determine the central nervous system effect of 60 mg of the SSRI antidepressant citalopram, given in divided oral doses (2 doses of 30 mg each).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataCitalopram reduced CSF Aβ concentrations by suppressing Aβ production while having a negligible effect on Aβ clearance mechanisms.
“These data suggest that citalopram reduced CSF Aβ concentrations by suppressing Aβ production while having a negligible effect on Aβ clearance mechanisms.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataFor newly generated Aβ, the power of the time by treatment group interaction was >99.99%.
“For newly generated Aβ, the power of time by treatment group interaction was also > 99.99% while the power of the main effect of treatment was 66.18%.”
- Also stated in: § Study Design · plain
“For newly generated Aβ, the power of time by treatment group interaction was also > 99.99% while the power of the main effect of treatment was 66.18%.”
Quote in the paperNot a substantial claim- Also stated in: § Study Design · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
InterpretationreasoningPhosphorylation of secretase enzymes by activated ERK could occur within minutes of SSRI treatment, thus accounting for the rapid changes in Aβ levels.
“Phosphorylation of either of these secretase enzymes by activated ERK could occur within minutes of SSRI treatment, thus accounting for the rapid changes in Aβ levels.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataCitalopram reduces plaque appearance and growth, but has no effect on plaque regression in APP/PS1 mice.
“Taken together, these results suggest that citalopram reduces plaque appearance and growth, but has no effect on plaque regression.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe covariance structures used for model errors in basal ISF Aβ, newly-generated Aβ, and CSF concentrations of total Aβ and TTR provided the best measures on Akaike's information criterion.
“The models also incorporated a Toeplitz covariance structure for the model errors in basal ISF Aβ, first-order autoregressive process heterogeneous variance covariance structure for the model errors in newly-generated Aβ and the same covariance structure but with homogeneous variance for CSF concentrations of total Aβ and TTR, as these provided the best measures on Akaike’s information criterion (”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Akaike H A new look at the statistical model identification IEEE Transactions on Automatic Control 19 716 1974
It may state two separate claims as one.
PremisecitationAfter citalopram treatment in mice, increased α-secretase activity was found, which appears to be downstream of ERK signaling.
“After citalopram treatment in mice, we also found increased α-secretase activity, which appears to be downstream of ERK signaling (30).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Cisse M Duplan E Guillot-Sestier MV Rumigny J Bauer C Pages G Orzechowski HD Slack B Checler F Vincent B The extracellular regulated kinase-1 (ERK1) controls regulated alpha-secretase-mediated processing, promoter transactivation, and mRNA levels of the cellular prion protein J Biol Chem 2011 8 19 286 33 29192 206 21586567 PMC3190726
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe human studies were conducted in young individuals, presumably prior to plaque formation.
“Another limitation is that our human studies were conducted in young individuals, presumably prior to plaque formation.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCitalopram is one of the most selective SSRIs for serotonin re-uptake.
“Citalopram is one of the most selective SSRIs for serotonin re-uptake and has among the most favorable side effect profiles compared with other antidepressants (17).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Cipriani A Furukawa T Salanti G Geddes J Higgins J Churchill R Watanabe N Nakagawa A Omori I McGuire H Tansella M Barbui C Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis Lancet 373 746 758 2009 19185342
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSerotonin receptor levels are reduced in human AD brains.
“Serotonin receptor levels are reduced in human AD brains (8,9).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [8] Arai H Kosaka K Iizuka R Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimer-type dementia J Neurochem 43 388 8 1984 6204013
- cites [9] Reynolds GP 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases British journal of pharmacology 114 993 3 1995 7780656 PMC1510307
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe model is limited by presuming that production and clearance rates are independent phenomena in the analysis, while practically production and clearance occur simultaneously.
“Admittedly, this model is limited by presuming that production and clearance rates are independent phenomena in the analysis, while practically production and clearance occur simultaneously.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: The model presumes that production and clearance rates are independent phenomena in the analysis.
Probably not a substantial claim.
PremisecitationAccumulation of Aβ peptide in the brain and its aggregation into amyloid plaques is currently considered the pathological trigger for AD.
“The accumulation of amyloid-β (Aβ) peptide in the brain and its aggregation into amyloid plaques is currently considered the pathological trigger for AD (2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Holtzman DM Morris JC Goate AM Alzheimer’s disease: the challenge of the second century Science translational medicine 3 77sr1 4 6 2011 21471435 PMC3130546
Probably not a substantial claim. It may state two separate claims as one.
Study design and conductown dataPlacebo and citalopram treated volunteers were matched on gender and as closely as possible in age, always within 5 years.
“Placebo and citalopram treated volunteers were first matched on gender and then as closely as possible in age, always within 5 years.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataThe effect of citalopram on Aβ was seen in the production phase with no significant group differences initially, but with subsequent differences that remained throughout the production phase and with no effect on clearance.
“Importantly, this effect was seen in the production phase of Aβ with no significant group differences initially, but with subsequent differences that remained throughout the production phase and with no effect on clearance.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAt study mid-point, groups were checked by an unblinded research assistant to ensure they were balanced in racial composition.
“In addition, since the groups were not explicitly matched on race, at study mid-point the groups were checked by an unblinded research assistant to ensure that they were balanced in racial composition.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataFor Aβ concentration, the power of the main effect of treatment was 95.03%.
“Based on the power analysis of the data, for Aβ concentration with alpha=0.05, the power of the time by treatment group interaction was > 99.99% and the power of the main effect of treatment was 95.03%.”
- Also stated in: § Study Design · plain
“Based on a repeated measures ANOVA, with a compound symmetry covariance structure and alpha=0.05, for Aβ concentration the power of the time by treatment group interaction was > 99.99% and the power of the main effect of treatment was 95.03%.”
Quote in the paperNot a substantial claim- Also stated in: § Study Design · plain
Probably not a substantial claim.
Interpretationnone givenThese trials were conducted after the onset of clinical symptoms and thus may have been too late to prevent further disease progression.
“However, these trials were conducted after the onset of clinical symptoms and thus may have been too late to prevent further disease progression.”
Quote in the paperSubstantial claim- Rests on an assumption: There have been many clinical trials using Aβ lowering drugs in AD and MCI that were unsuccessful.
It may state two separate claims as one.
PremisecitationTreatment with serotonin or receptor agonists activates intracellular signaling cascades and increases levels of the α-secretase product sAPP-α.
“Activation of serotonin receptors has been shown to reduce Aβ production in vitro; treatment with serotonin or receptor agonists activates intracellular signaling cascades and increases levels of the α-secretase product sAPP-α (10–12).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [10] 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 951 135 9 27 2002 12231467
- cites [11] Nitsch RM Deng M Growdon JH Wurtman RJ Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion J Biol Chem 271 4188 2 23 1996 8626761
- cites [12] Robert SJ Zugaza JL Fischmeister R Gardier AM Lezoualc’h F The human serotonin 5-HT4 receptor regulates secretion of non-amyloidogenic precursor protein J Biol Chem 276 44881 11 30 2001 11584021
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenData were not collected during the eight hours following drug/placebo administration.
“A limitation of the study is that data were not collected during the eight hours following drug/placebo administration.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
To date, there have not been drugs with both an established safety profile and a mechanism-based rationale that have been tested in primary or secondary prevention trials of AD.
“To date, there have not been drugs with both an established safety profile and a mechanism-based rationale that have been tested in primary or secondary prevention trials of AD.”
The paper relies on this without support.
Early in disease pathogenesis, soluble Aβ monomers aggregate into soluble Aβ oligomers and insoluble Aβ plaques, both of which can alter synaptic transmission and be toxic to neurons under certain conditions.
“Early in disease pathogenesis, soluble Aβ monomers aggregate into soluble Aβ oligomers and insoluble Aβ plaques, both of which can alter synaptic transmission and be toxic to neurons under certain conditions.”
The paper relies on this without support.
Individuals with autosomal dominant AD or Down’s syndrome have only 20–50% higher CSF Aβ42 concentrations than normal but manifest disease 20–30 years before AD patients with the sporadic form of the disease.
“Individuals with autosomal dominant AD or Down’s syndrome have only 20–50% higher CSF Aβ42 concentrations than normal but manifest disease 20–30 years before AD patients with the sporadic form of the disease.”
The paper relies on this without support.
There have been many clinical trials using Aβ lowering drugs in AD and MCI that were unsuccessful.
“A caveat is that there have been many clinical trials using Aβ lowering drugs in AD and MCI that were unsuccessful.”
The paper relies on this without support.
Citalopram has a long half-life.
“Citalopram has a long half-life, meaning there was likely a sustained effect on Aβ throughout CSF sampling despite the single administration at the beginning of the study.”
The authors state this as an assumption.
The model presumes that production and clearance rates are independent phenomena in the analysis.
“Admittedly, this model is limited by presuming that production and clearance rates are independent phenomena in the analysis, while practically production and clearance occur simultaneously.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Sheline et al. proposed that Citalopram, an SSRI, decreased cerebrospinal fluid (CSF) amyloid beta protein production in a dose-dependent manner in both animal and human studies.
“Sheline et al. proposed that Citalopram, an SSRI, decreased cerebrospinal fluid (CSF) amyloid beta protein production in a dose-dependent manner in both animal and human studies”
From Risk analysis of use of different classes of antidepressants on subsequent dementia: A nationwide cohort study in Taiwan (2017) · cites this paper as [56]
The Study Design and human Results report that citalopram reduced CSF Aβ production in healthy volunteers, while the Introduction and Discussion describe a dose-response effect on brain Aβ concentrations in mice. The claim extends dose dependence to the human findings, which used a single citalopram dose, and describes the mouse measurement as CSF production rather than brain interstitial-fluid Aβ concentrations. (LLM, conf=0.91)
Experimental — accuracy not yet measuredThis ability may be a potential preventive strategy for AD.
“and this ability may be a potential preventive strategy for AD [56].”
From Risk analysis of use of different classes of antidepressants on subsequent dementia: A nationwide cohort study in Taiwan (2017) · cites this paper as [56]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Human enrollment age range differs between sections
MinorThe Results describe enrolled subjects as aged 18-50, whereas the Methods describe enrollment of volunteers aged 21-50. The stated lower age limit differs by three years.
“Healthy subjects age 18–50, without medical disease, electrocardiogram (ECG) or laboratory abnormalities and with no prior history of antidepressant treatment, were enrolled in a double-blind study.”
“Healthy 21–50 year old male and female volunteers were invited to participate, screened, and enrolled.”
Microdialysis probe cutoff is reported as both 38 and 30 kilodaltons
MinorThe microdialysis method says the probe membrane admits molecules smaller than 38 kilodaltons, but later specifies a 30-kilodalton molecular-weight cutoff for the probes used.
“This technique samples soluble molecules within the extracellular fluid that are smaller than 38-kilodaltons, the molecular-weight cut off of the probe membrane.”
“Two millimeter microdialysis probes were inserted through the guides so the membrane was contained entirely within the hippocampus (BR-2, 30-kilodalton MWCO membrane, Bioanalytical Systems).”
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“We have previously shown in mice that SSRI antidepressants lower the production of Ab by 25% in the brain ISF, as demonstrated by in vivo microdialysis studies (13).”
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Metadata
- Authors
- Sheline, Y. I., West, T., Yarasheski, K., Swarm, R., Jasielec, M. S., Fisher, J. R., Ficker, W. D., Yan, P., Xiong, C., Frederiksen, C., Grzelak, M. V., Chott, R., Bateman, R. J., Morris, J. C., Mintun, M. A., Lee, J.-M., & Cirrito, J. R.
- Affiliations
- University of Pennsylvania (US)
- C2N Diagnostics (United States) (US)
- Washington University in St. Louis (US)
- Avid Radiopharmaceuticals (United States) (US)
- Corresponding author
- Sheline, Yvette I.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2014-05-14
- Volume
- 6
- Issue
- 236
- Pages
- 236re4-236re4
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4269372
- OpenAlex
- W2163894029
- Semantic Scholar
- 60d1eff17ddf2e7b53b76651fafa944ed8ffb4f3
- Cited by
- 223
- References
- 43
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 19 · 2023: 11 · 2022: 19 · 2021: 17 · 2020: 21 · 2019: 14 · 2018: 24 · 2017: 17 · 2016: 18 · 2015: 24 · 2014: 12
- FWCI
- 8.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p60dk020579-35)
- National Institute on Aging (R01AG042513, R01AG041502, R21AG039690)
- National Institute of Mental Health (K24MH079510)
- National Institute of General Medical Sciences (R24GM136766, P41GM103422)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK-020579, P30DK056341, P30DK020579)
- National Institute of Neurological Disorders and Stroke (R21NS082529, R01NS067905)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- citalopram, serotonin signaling, amyloid-beta, Alzheimer's disease, cerebrospinal fluid, amyloid plaques, APP/PS1 mice, selective serotonin reuptake inhibitors, amyloid-beta production, drug-target engagement, Alzheimer's disease prevention
- MeSH terms
- Adult, Alzheimer Disease, Animals, Antidepressive Agents, Brain, Dose-Response Relationship, Drug, Double-Blind Method, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Mice, Inbred C3H, Mice, Transgenic, Middle Aged, Prospective Studies, Serotonin, Citalopram, Signal Transduction, Amyloid beta-Protein Precursor, Selective Serotonin Reuptake Inhibitors, Microdialysis, Mice, Young Adult, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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