Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial

Devos, David; Moreau, Caroline; Maltête, David; Lefaucheur, Romain; Kreisler, Alexandre; Eusebio, Alexandre; Defer, Gilles; Ouk, Thavarak; Azulay, Jean‐Philippe; Krystkowiak, Pierre; Witjas, Tatiana; Delliaux, Marie; Destée, Alain; Duhamel, Alain; Bordet, Régis; Defebvre, Luc; Dujardin, Kathy

doi:10.1136/jnnp-2013-306439

Cited by 167 publications

(134 citation statements)

References 30 publications

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“…Some neuroimaging studies have, for instance, reported the involvement of norepinephrine in the pathogenesis of several non-motor signs, such as depression or anxiety (Remy et al, 2005). Similarly, the role of the cholinergic system dysfunction as a possible pathophysiological mechanism in apathy has been suggested, notably by some pharmacological studies having demonstrated an improvement of apathy following anticholinesterasic drug intake (Devos et al, 2014). Moreover, and not surprisingly, several anatomical, biochemical and electrophysiological studies also point toward interactions between different neurotransmitters in the behavioural control (Flik et al, 2015;De Deurwaerdère and Giovanni, 2016).…”

Section: Dopamine Serotonin and Non-motor Manifestations In Early Pamentioning

confidence: 99%

The prominent role of serotonergic degeneration in apathy, anxiety and depression inde novoParkinson’s disease

Maillet

Krack

Lhommée

et al. 2016

Brain

214

198

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) for a scientific commentary on this article.Apathy, which can occur separately or in combination with depression and anxiety, is one of the most frequently encountered neuropsychiatric symptoms in Parkinson's disease. Pathophysiological evidence suggests that parkinsonian apathy is primarily due to a mesolimbic dopaminergic denervation, but the role of the serotonergic alteration has never been examined, despite its well-known involvement in the pathogenesis of depression and anxiety. To fill this gap, we address here the pure model of de novo Parkinson's disease, without the confounding effects of antiparkinsonian treatment. Fifteen apathetic (Lille Apathy Rating Scale scores 5 À21) and 15 non-apathetic (À36 4 Lille Apathy Rating Scale scores 4 À22) drug-naïve de novo parkinsonian patients were enrolled in the present study and underwent detailed clinical assessment and positron emission tomography imaging, using both dopaminergic [ 11 C-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane (PE2I)] (n = 29) and serotonergic [ 11 C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine (DASB)] (n = 27) presynaptic transporter radioligands. Apathetic parkinsonian patients presented higher depression (P = 0.0004) and anxiety (P = 0.004) scores -as assessed using the Beck Depression Inventory and the part B of the State-Trait Anxiety Inventory, respectively -compared to the non-apathetic ones -who were not different from the age-matched healthy subjects (n = 15). Relative to the controls, the non-apathetic parkinsonian patients mainly showed dopaminergic denervation (n = 14) within the right caudate nucleus, bilateral putamen, thalamus and pallidum, while serotonergic innervation (n = 15) was fairly preserved. Apathetic parkinsonian patients exhibited, compared to controls, combined and widespread dopaminergic (n = 15) and serotonergic (n = 12) degeneration within the bilateral caudate nuclei, putamen, ventral striatum, pallidum and thalamus, but also a specific bilateral dopaminergic disruption within the substantia nigra-ventral tegmental area complex, as well as a specific serotonergic alteration within the insula, the orbitofrontal and the subgenual anterior cingulate cortices. When comparing the two parkinsonian groups, the apathetic patients mainly displayed greater serotonergic alteration in the ventral striatum, the dorsal and the subgenual parts of the anterior cingulate cortices, bilaterally, as well as in the right-sided caudate nucleus and the right-sided orbitofrontal cortex. Regression analyses also revealed that the severity of apathy was moreover mainly related to specific serotonergic lesions within the right-sided anterior caudate nucleus and the orbitofrontal cortex, while the degree of both depression and anxiety was primarily linked to serotonergic disruption within the bilateral subgenual parts and/or the right dorsal part of the anterior cingulate cortex, without prominent role of the dopaminergic degeneration in the pathogenesis of these three non-motor signs. Alto...

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Section: Dopamine Serotonin and Non-motor Manifestations In Early Pamentioning

confidence: 99%

The prominent role of serotonergic degeneration in apathy, anxiety and depression inde novoParkinson’s disease

Maillet

Krack

Lhommée

et al. 2016

Brain

214

198

View full text Add to dashboard Cite

show abstract

“…When depressive and cognitive symptoms are absent, a diagnosis of apathy associated with reward defi ciency syndrome could be established (panel 3). 130 of 31 patients with Parkinson's disease with moderate to severe apathy without dementia and depression, a signifi cant improvement in the LARS was reported after 6 months of treatment with rivastigmine at 9·5 mg/day (adjusted eff ect size -0·9; p=0·031) (Level B, one Class I study according to evidence based medicine assessment).…”

Section: Review Diagnosis Of Apathy In Parkinson's Diseasementioning

confidence: 99%

“…Two double-blind, placebo-controlled studies 109,130 have shown promising results with drugs that either enhance acetylcholine (rivastigmine) or stimulate dopamine D2 or D3 receptors (piribedil) for the treatment of apathy in patients with Parkinson's disease without dementia and depression. Preliminary results suggest that methylphenidate (which reinforces mesocorticolimbic stimulation by selective inhibition of mesocorticolimbic dopamine reuptake) might be a useful drug to reduce apathy in Parkinson's disease and Alzheimer's disease.…”

Section: Search Strategy and Selection Criteriamentioning

confidence: 99%

Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment

Pagonabarraga

Kulisevsky

Strafella

et al. 2015

The Lancet Neurology

431

394

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Normal maintenance of human motivation depends on the integrity of subcortical structures that link the prefrontal cortex with the limbic system. Structural and functional disruption of diff erent networks within these circuits alters the maintenance of spontaneous mental activity and the capacity of aff ected individuals to associate emotions with complex stimuli. The clinical manifestations of these changes include a continuum of abnormalities in goal-oriented behaviours known as apathy. Apathy is highly prevalent in Parkinson's disease (and across many neurodegenerative disorders) and can severely aff ect the quality of life of both patients and caregivers. Diff erentiation of apathy from depression, and discrimination of its cognitive, emotional, and auto-activation components could guide an individualised approach to the treatment of symptoms. The opportunity to manipulate dopaminergic treatment in Parkinson's disease allows researchers to study a continuous range of motivational states, from apathy to impulse control disorders. Parkinson's disease can thus be viewed as a model that provides insight into the neural substrates of apathy.

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“…It has been used in specific patient groups, for example those with frontotemporal dementia, 9 and as an outcome measure, for example in a trial of rivastigmine for apathy in Parkinson's disease. 10 The aims of this study were to: • measure caregiver burden using different ZBI versions at the initial assessment of patients referred to a dedicated cognitive disorders clinic with cognitive complaints • examine correlations between ZBI scores and patient age and scores on patient performancebased cognitive screening instruments • compare ZBI scores between different patient diagnostic groups to assess what utility the instrument might have as an informant-based cognitive screening instrument.…”

mentioning

confidence: 99%

Zarit Burden Interview: pragmatic study in a dedicated cognitive function clinic

Stagg¹,

Larner²

2015

Prog. Neurol. Psychiatry

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Increased caregiver burden impacts adversely not only on caregivers, in terms of physical and psychological morbidity, but also on people with dementia, since it is associated with an increased likelihood of patient institutionalisation. Here, the authors examine effectiveness and ease of administration of the Zarit Burden Interview (ZBI) tool in day‐to‐day clinical practice for identifying caregiver burden.

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Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial

Abstract: Clinicaltrials.gov reference: NCT00767091.

Cited by 167 publications

References 30 publications

The prominent role of serotonergic degeneration in apathy, anxiety and depression inde novoParkinson’s disease

The prominent role of serotonergic degeneration in apathy, anxiety and depression inde novoParkinson’s disease

Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment

Zarit Burden Interview: pragmatic study in a dedicated cognitive function clinic

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