Improving response inhibition systems in frontotemporal dementia with citalopram

Hughes, Laura E.; Rittman, Timothy; Regenthal, Ralf; Robbins, Trevor W.; Rowe, James B.

doi:10.1093/brain/awv133

Cited by 76 publications

(77 citation statements)

References 108 publications

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“…The mean plasma drug concentrations were 401.9 ng/mL after atomoxetine (range 31.7-889.0 ng/mL), 40.2 ng/mL after citalopram (6.6-70.3 ng/mL), and 0 ng/mL after placebo. The current range of plasma drug concentration was comparable to that in previous human studies using similar oral dose of atomoxetine [Chamberlain et al, 2009;Kehagia et al, 2014] and citalopram [Hughes et al, 2015]. The control subjects were tested without drug or placebo, to provide normative data on the task and imaging.…”

Section: Experimental Designmentioning

confidence: 73%

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Zheng

Rae

Nombela

et al. 2016

Human Brain Mapping

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Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double‐blind randomized three‐way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion‐weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave‐one‐out cross‐validation (LOOCV) to predict patients’ responses in terms of improved stopping efficiency. We identified two optimal models: (1) a “clinical” model that predicted the response of an individual patient with 77–79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion‐weighted imaging scan; and (2) a “mechanistic” model that explained the behavioral response with 85% accuracy for each drug, using drug‐induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026–1037, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Experimental Designmentioning

confidence: 73%

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Zheng

Rae

Nombela

et al. 2016

Human Brain Mapping

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“…We found increased serotonin levels in FLTD (FC 10.71, p < 0.001). Central nervous serotonergic pathways are abnormal in FTLD [18] and serotonin reuptake inhibitors have been used as a symptomatic treatment in FTLD [19]. However, there is usually a limited exchange of serotonin across the blood brain barrier, and the significance of this peripheral serotonin result is unclear for the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic changes associated with frontotemporal lobar degeneration syndromes

et al. 2020

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Objective Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study we looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration. Methods Plasma metabolomic profiles were measured from 134 patients with a syndrome associated with frontotemporal lobar degeneration (behavioural variant frontotemporal dementia n = 30, non fluent variant primary progressive aphasia n = 26, progressive supranuclear palsy n = 45, corticobasal syndrome n = 33) and 32 healthy controls. Results Forty-nine of 842 metabolites were significantly altered in frontotemporal lobar degeneration syndromes (after false-discovery rate correction for multiple comparisons). These were distributed across a wide range of metabolic pathways including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide pathways. The metabolomic profile supported classification between frontotemporal lobar degeneration syndromes and controls with high accuracy (88.1-96.6%) while classification accuracy was lower between the frontotemporal lobar degeneration syndromes (72.1-83.3%). One metabolic profile, comprising a range of different pathways, was consistently identified as a feature of each disease versus controls: the degree to which a patient expressed this metabolomic profile was associated with their subsequent survival (hazard ratio 0.74 [0.59-0.93], p = 0.0018). Conclusions The metabolic changes in FTLD are promising diagnostic and prognostic biomarkers. Further work is required to replicate these findings, examine longitudinal change, and test their utility in differentiating between FTLD syndromes that are pathologically distinct but phenotypically similar.

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“…There is limited support for this approach from trials of selective serotonin reuptake inhibitors (SSRIs) in FTD where a systematic review and meta-analysis found that antidepressant treatment results in a 15.4 point reduction on the Neuropsychiatric Inventory with the strongest evidence for SSRIs, although acknowledging that the evidence was derived from small trials [53]. Furthermore, enhancing serotonergic transmission with citalopram may have an effect on response inhibition systems in FTD [54]. Trazadone is also well tolerated in people with neurodegenerative diseases [55,56] while Mirtazepine can promote sleep and the maintenance of weight which may be of benefit in PSP.…”

Section: Medicationmentioning

confidence: 99%

Managing Cognition in Progressive Supranuclear Palsy

Rittman

Coyle‐Gilchrist

Rowe

2016

Neurodegener. Dis. Manag.

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Cognitive impairment is integral to the syndrome of progressive supranuclear palsy. It is most commonly described as a frontal dysexecutive syndrome but other impairments include apathy, impulsivity, visuospatial and memory functions. Cognitive dysfunction may be exacerbated by mood disturbance, medication and communication problems. In this review we advocate an individualized approach to managing cognitive impairment in progressive supranuclear palsy with the education of caregivers as a central component. Specific cognitive and behavioral treatments are complemented by treatment of mood disturbances, rationalizing medications and a patient-centered approach to communication. This aims to improve patients’ quality of life, reduce carer burden and assist people with progressive supranuclear palsy in decisions about their life and health, including discussions of feeding and end-of-life issues.

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Improving response inhibition systems in frontotemporal dementia with citalopram

Cited by 76 publications

References 108 publications

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures

Metabolomic changes associated with frontotemporal lobar degeneration syndromes

Managing Cognition in Progressive Supranuclear Palsy

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