title: Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil.
abstract: Apathy is one of the most common symptoms encountered in Parkinson's disease, and is defined as a lack of motivation accompanied by reduced goal-directed cognition, behaviour and emotional involvement. In a previous study we have described a delayed withdrawal syndrome after successful motor improvement related to subthalamic stimulation allowing for a major decrease in dopaminergic treatment. This withdrawal syndrome correlated with a diffuse mesolimbic dopaminergic denervation. To confirm our hypothesis of parkinsonian apathy being related to mesolimbic dopaminergic denervation, we performed a randomized controlled study using piribedil, a relatively selective D2/D3 dopamine agonist to treat parkinsonian apathy, using the model of postoperative apathy. A 12-week prospective, placebo-controlled, randomized, double-blinded trial was conducted in 37 patients with Parkinson's disease presenting with apathy (Starkstein Apathy Scale score > 14) following subthalamic nucleus stimulation. Patients received either piribedil up to 300 mg per day (n = 19) or placebo (n = 18) for 12 weeks. The primary end point was the improvement of apathy under treatment, as assessed by the reduction of the Starkstein Apathy Scale score in both treatment groups. Secondary end points included alleviation in depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), improvement of quality of life (PDQ39) and anhedonia (Snaith-Hamilton Pleasure Scale). Exploratory endpoints consisted in changes of the Robert Inventory score and Hamilton depression scales. An intention to treat analysis of covariance analysis was performed to compare treatment effects (P < 0.05). The number of premature study dropouts was seven in the placebo and five in the piribedil groups, mostly related to intolerance to hypodopaminergic symptoms. At follow-up evaluation, the apathy score was reduced by 34.6% on piribedil versus 3.2% on placebo (P = 0.015). With piribedil, modifications in the Beck depression and anxiety scores were -19.8% and -22.8%, respectively versus +1.4% and -8.3% with placebo, without reaching significance level. Piribedil led to a trend towards improvement in quality of life (-16.2% versus +6.7% on placebo; P = 0.08) and anhedonia (-49% versus -5.6% on the placebo; P = 0.08). Apathy, assessed by the Robert Inventory score, improved by 46.6% on piribedil and worsened by 2.3% on placebo (P = 0.005). Depression, measured by the Hamilton score, improved in the piribedil group (P = 0.05). No significant side effects were observed. The present study provides a class II evidence of the efficacy of the dopamine agonist piribedil in the treatment of apathy in Parkinson's disease.
authors.affiliation: Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Neurologie C 59 Bd Pinel, 69677 Bron, France. stephane.thobois@chu-lyon.fr
authors.forename: Stéphane
authors.initials: S
authors.lastname: Thobois
authors.forename: Eugénie
authors.initials: E
authors.lastname: Lhommée
authors.forename: Hélène
authors.initials: H
authors.lastname: Klinger
authors.forename: Claire
authors.initials: C
authors.lastname: Ardouin
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Schmitt
authors.forename: Amélie
authors.initials: A
authors.lastname: Bichon
authors.forename: Andrea
authors.initials: A
authors.lastname: Kistner
authors.forename: Anna
authors.initials: A
authors.lastname: Castrioto
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.forename: Valerie
authors.initials: V
authors.lastname: Fraix
authors.forename: Pierre
authors.initials: P
authors.lastname: Pelissier
authors.forename: Stephan
authors.initials: S
authors.lastname: Chabardes
authors.forename: Patrick
authors.initials: P
authors.lastname: Mertens
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Quesada
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Bosson
authors.forename: Pierre
authors.initials: P
authors.lastname: Pollak
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Broussolle
authors.forename: Paul
authors.initials: P
authors.lastname: Krack
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D057565:Apathy / Q000187:drug effects* / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy* / Q000523:psychology; D010891:Piribedil / Q000494:pharmacology / Q000627:therapeutic use*; D011446:Prospective Studies; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000502:physiology; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D010891:Piribedil