The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-controlled studies.
ABSTRACT Mood and motivational symptoms have been reported in up to 35% and 51%, respectively, of patients with Parkinson's disease (PD). Preliminary evidence indicates that pramipexole may have a positive effect on these symptoms.
This analysis was conducted to evaluate the effects of pramipexole on mood and motivational symptoms in patients with PD.
Data for the meta-analysis were extracted from all randomized, double-blind, placebo-controlled trials of pramipexole in the manufacturer's database that included part I of the Unified Parkinson's Disease Rating Scale (UPDRS) as an outcome measure. Only patients with baseline scores >0 (range, 0-4) on item 3 (mood) and item 4 (motivation) were included. Separate analyses were performed for mood and motivational symptoms. The outcome of interest was improvement in scores, with no improvement including both unchanged and increased scores. Odds ratios (ORs), 95% CIs, and Cochran-Mantel-Haenszel tests were calculated to compare rates of improvement and no improvement, stratified by trial.
Fourteen randomized, double-blind, placebo-controlled trials of pramipexole were identified, all employing the severity of motor symptoms of PD as a primary outcome. Seven of these trials (N = 1296) employed part I of the UPDRS as a secondary outcome measure and were included in the meta-analysis; no other measure of mood or motivational symptoms was used in any of the 14 studies. Six of the 7 studies included patients with motor fluctuations due to levodo-pa treatment, and the remaining study included patients who did not yet require levodopa. Six studies were published in peer-reviewed journals, and all 7 were included in the New Drug Application for pramipexole. The published study reports were usually limited to motor symptoms; only 1 reported on mood and motivation. However, for the purpose of this meta-analysis, the authors had access to data that were not reported in the original publications. In the pooled data set, 480 patients (59.8% male; mean age, 63.3 years) had a baseline score >0 on item 3 (mood). These mood symptoms improved in 64.7% of patients treated with pramipexole and 43.4% of those receiving placebo (OR weighted by trial = 2.41; P < 0.001). Five hundred seventy patients (64.9% male; mean age, 64.1 years) had a baseline score >0 on item 4 (motivation). These motivational symptoms improved in 63.2% of patients treated with pramipexole and 45.0% of those receiving placebo (OR weighted by trial = 2.06; P < 0.001).
This meta-analysis of 7 randomized controlled trials suggests that pramipexole had a beneficial effect on mood and motivational symptoms in PD patients who did not have major depressive disorder. The clinical value of pramipexole in the treatment of depressive and apathetic syndromes requires further investigation.
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ABSTRACT: Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease (PD). These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA) in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to revert the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual noradrenergic terminals.Frontiers in Behavioral Neuroscience 08/2014; 8:290. · 4.16 Impact Factor
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ABSTRACT: Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D2/3 receptor (D2/3R) binding has not been investigated in TRD subjects. We used [123I]IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p<0.001) but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.PLoS ONE 11/2014; 9(11):e113612. · 3.53 Impact Factor