Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults

Sheline, Yvette I.; Snider, B. Joy; Beer, Jacob; Seok, Darsol; Suckow, Raymond F.; J, Lee; Waligórska, Teresa; Korecka, Magdalena; Aselcioglu, Irem; Morris, John C.; Shaw, Leslie M.; Cirrito, John R.

doi:10.1212/wnl.0000000000010725

Cited by 29 publications

(19 citation statements)

References 28 publications

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“…While mouse studies have suggested that the treatment with antidepressants may modulate Aβ levels or even reduce Aβ plaques, evidence in human studies is just starting to arise. In this regard, a recent prospective study has shown an overall 9.4% reduction in CSF Aβ 42 levels in cognitively normal older adults treated with shortterm longitudinal doses of escitalopram compared to those receiving placebo [75]. In addition, a study using ADNI data found that MCI subjects with a remote history of depression had a 3-year delay of progression to AD if they had been treated with selective serotonin reuptake inhibitors for more than four years [76].…”

Section: Discussionmentioning

confidence: 99%

Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer’s disease and cognitively unimpaired individuals

Chiew

Rosa‐Neto

et al. 2021

Transl Neurodegener

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The development of in vivo biomarkers of Alzheimer’s disease (AD) has advanced the diagnosis of AD from a clinical syndrome to a biological construct. The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals. While neuropsychiatric symptoms (NPS) are non-cognitive symptoms that are increasingly recognized as early manifestations of AD, the associations of NPS with AD pathophysiology in preclinical AD remain unclear. Here, we review the associations between NPS and AD biomarkers amyloid-β (Aβ), tau and neurodegeneration in preclinical AD and cognitively-unimpaired individuals in 19 eligible English-language publications (8 cross-sectional studies, 10 longitudinal, 1 both cross-sectional and longitudinal). The cross-sectional studies have consistently shown that NPS, particularly depressive and anxiety symptoms, are associated with higher Aβ. The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time. However, most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology. For the association of NPS and neurodegeneration, two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD, respectively. However, evidence for the association between atrophy and NPS in preclinical AD is less consistent. Therefore, future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N) biomarkers, NPS and cognitive decline, but also to elucidate the contribution of comorbid pathology to preclinical AD.

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Section: Discussionmentioning

confidence: 99%

Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer’s disease and cognitively unimpaired individuals

Chiew

Rosa‐Neto

et al. 2021

Transl Neurodegener

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“…Studies in APP/PS1 transgenic mice showed that the SSRI citalopram caused a 50% reduction in brain amyloid plaque load, and escitalopram, citalopram's S-isomer, reduced interstitial fluid Aβ by 25% 81,82 . A controlled clinical trial of cognitively normal adults showed that escitalopram could decrease CSF Aβ42 levels in humans, with a difference of 11.1% between the control and treatment groups 83 . Our results corroborate the association of low serotonin with AD, and suggest that this effect, and potentially the benefit of serotonin modulation via SSRIs, spans all three genetic groups.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer disease brains

Novotny

Fernandez

Bahena³

et al. 2021

Preprint

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The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence to support that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain, including information on treatment targets. In this study, we interrogate the metabolomic and lipidomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ε4 and TREM2 risk variant carriers, and non-carrier sporadic AD (sAD). We generated metabolomic and lipidomic data from parietal cortical tissue from 366 participants with AD pathology and 26 cognitively unimpaired controls using the Metabolon global metabolomics platform. We identified 133 metabolites associated with disease status (FDR q-value<0.05). In sAD brains these include tryptophan betaine (b=-0.57) and N-acetylputrescine (b=-0.14). Metabolites associated with sAD and ADAD include ergothioneine (b=-0.21 and -0.26 respectively) and serotonin (b=-0.34 and -0.58, respectively). TREM2 and ADAD showed association with α-tocopherol (b=-0.12 and -0.12) and CDP-ethanolamine (b=-0.13 and -0.10). β-citrylglutamate levels are associated with sAD, ADAD, and TREM2 compared to controls (b=-0.15; -0.22; and -0.29, respectively). Additionally, we identified a signature of 16 metabolites that is significantly altered between genetic groups (sAD vs. control p = 1.05×10-7, ADAD vs. sAD p = 3.21×10-5) and is associated with Braak tau stage and disease duration. These data are available to the scientific community through a public web browser (http://ngi.pub/Metabolomics). Our findings were replicated in an independent cohort of 327 individuals.

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“…There are numerous reports that antidepressants from the SSRI group exhibit neuroprotective effects with a diverse mechanism of action. Preclinical and clinical studies indicate beneficial effects on cognitive function [ 14 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ]. Furthermore, literature data indicate that SSRIs “ increase neurotrophic factors including brain-derived neurotrophic factor, promote neurogenesis in the hippocampus, and reduce levels of toxic Aβ ” [ 124 ].…”

Section: Selective Serotonin Reuptake Inhibitors (Ssri)mentioning

confidence: 99%

“…Sheline et al [ 120 ] recently published the results of a double-blind placebo-controlled clinical trial on escitalopram. The study was conducted in healthy older volunteers who were then allocated to the following groups: placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks.…”

Section: Selective Serotonin Reuptake Inhibitors (Ssri)mentioning

confidence: 99%

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Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

Miziak

Błaszczyk²,

Czuczwar

2021

Pharmaceuticals

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Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements—curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon.

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Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults

Cited by 29 publications

References 28 publications

Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer’s disease and cognitively unimpaired individuals

Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer’s disease and cognitively unimpaired individuals

Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer disease brains

Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

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