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 4 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 5 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 À19.8% and À 22.8%, respectively versus + 1.4% and À 8.3% with placebo, without reaching significance level. Piribedil led to a trend towards improvement in quality of life ( À 16.2% versus + 6.7% on placebo; P = 0.08) and anhedonia (À 49% versus À 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.

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

“…In this 12 week prospective, placebocontrolled, randomised, double-blinded trial, 109 the SAS score was reduced by 34·6% in the piribedil group (n=19) compared with 3·2% in the placebo group (n=18; p=0·015) (Level B, one Class I study). In an open-label study, 108 the dopamine D2 and D3 receptor agonist ropinirole proved to be effi cacious in eight patients with apathy after STN-DBS, as shown by substantial decreases in SAS scores after 6 months of treatment.…”

“…92,[104][105][106] However, with regard to the on-period motivational aspects of the antiparkinsonian drugs, a slowly progressive desensitisation of the psychotropic eff ects of dopaminergic treatment after drug decrease 107 explains why the hypodopaminergic withdrawal syndrome in patients on chronic STN-DBS typically occurs with a substantial delay of several months after surgery 83,92 (unlike the much more acute withdrawal syndrome after cessation of dopamine agonists in patients not receiving chronic STN-DBS). 93 The potential to reverse postoperative apathy after D2 or D3 receptor stimulation with oral dopamine receptor agonists 108,109 clearly suggests a Parkinson's disease-related symptom that has been unmasked by a decrease in drug treatment. That is, postoperative apathy is not induced by current diff usion to non-motor territories of the subthalamic nucleus, as had been postulated in the absence of an association between reduction in drug treatment and occurrence of apathy.…”

“…An exploratory study 109 showed that the dopamine D2 and D3 receptor agonist piribedil signifi cantly improved apathy as assessed using the SAS score (>14) in 37 patients with Parkinson's disease presenting apathy after STN-DBS. In this 12 week prospective, placebocontrolled, randomised, double-blinded trial, 109 the SAS score was reduced by 34·6% in the piribedil group (n=19) compared with 3·2% in the placebo group (n=18; p=0·015) (Level B, one Class I study).…”

“…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.…”

Psychiatric considerations in deep brain stimulation for Parkinson’s disease

“…Patients and family members should be on the lookout for suicidal ideation or postoperative depression, and active enquiries made during postoperative assessments. Patients may be experiencing DAWS with associated behavioral symptoms, necessitating an increase in the dopamine agonist dose (Nirenberg, 2010;Lhommée et al, 2012;Pondal et al, 2013;Thobois, 2013). …”