Leentjens AF, Koester J, Fruh B, Shephard DT, Barone P, Houben JJ. The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-controlled studies. Clin Ther 31: 89-98

Department of Psychiatry, Maastricht University Hospital, Maastricht, The Netherlands.
Clinical Therapeutics (Impact Factor: 2.73). 01/2009; 31(1):89-98. DOI: 10.1016/j.clinthera.2009.01.012
Source: PubMed


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.

34 Reads
  • Source
    • "S1), a potent non-ergoline dopamine receptor agonist, is being widely used in the treatment of both early-and advancestage PD [2] [3] [4]. PPX is also clinically valuable in the treatment of depressive and apathetic syndromes [5]. In addition, it is one of two medications with a FDA-approved indication for the treatment of restless legs syndrome [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Intranasal delivery is emerging as a promising alternative for oral or intravenous administration of central nervous system (CNS) drugs, such as pramipexole which is widely used for the treatment of Parkinson's disease. To evaluate the effectiveness of intranasal delivery of pramipexole, preclinical pharmacokinetic and tissue distribution studies following intranasal administration need to be investigated. In this paper, we developed and validated a robust and sensitive LC-MS/MS assay without matrix effect for accurate measurements of pramipexole in mouse plasma and tissue samples. Pramipexole and its stable isotope labeled internal standard (d3-pramipexole) were extracted from biological samples by protein precipitation (PPT) coupled with solid phase extraction (SPE) using weak cation exchange SPE cartridges. Matrix effects were studied using post-column infusion and post-extraction addition experiments by direct monitoring of typical phospholipids including glycerophosphocholines (GPChos) and lysoglycerophosphocholines (Lyso-GPChos). Chromatographic separation was achieved on a Welch Ultimate(®) XB-CN column using isocratic elution with a run time of 3.0min. The assay was linear in the concentration range of 0.05-100ng/mL and the intra- and inter-day precision and accuracy met the acceptance criteria. Compared with previous reported assays, the current sample preparation approach exhibited significant reduction of matrix effects due to the dramatically decreased levels of residual matrix components such as GPChos and Lyso-GPChos. This method has been successfully applied to pharmacokinetic and tissue distribution studies of pramipexole in mice following a single intravenous or intranasal dose of 50μg/kg. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 04/2015; 988. DOI:10.1016/j.jchromb.2015.02.032 · 2.73 Impact Factor
  • Source
    • "The lack of efficacy of L-DOPA prompted the analysis of alternative dopaminergic treatments. In particular, we focused on pramipexole, a D2R/D3R agonist, previously shown to reduce mood-related symptoms in parkinsonian patients (Leentjens et al., 2009; Barone et al., 2010). We found that treatment with pramipexole effectively reverted the increase in immobility time displayed by lesioned mice in the forced swim test, as well as the anxiogenic-like effect produced by 6-OHDA in the elevated plus maze test. "
    [Show abstract] [Hide abstract]
    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. DOI:10.3389/fnbeh.2014.00290 · 3.27 Impact Factor
  • Source
    • "Another pharmacological evidence supporting the antidepressant effect of D3R activation is given by pramipexole, a D3R preferring D2R/D3R agonist. Randomized trials performed in PD patients have shown that treatment with this drug significantly improves depressive symptoms with an efficacy comparable to other antidepressants, such as sertraline [18] [64]. Moreover, pramipexole also exerts antidepressant effects in animal models for depression and apathy [21] [65] [66] and has synergic action with available antidepressants [65] [67]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the last decade accumulating evidence suggests that brain dopamine (DA) has a role in depression, particularly given the high comorbidity of depression with Parkinson's Disease (PD) and the antidepressant effects of the DA receptor subtype 3 (D3R) agonist pramipexole. The present study assesses the role of D3R in depression. Here we hypothesized that D3R mediates the antidepressant effects of DA. Thus, genetic deficiency of D3R in D3R knockout (D3RKO) mice would yield animals with chronic depressive symptoms. Whereas D3R deficient mice did not show significant alterations in locomotion when tested in the openfield, these animals showed anxiety-like symptoms measured as a significant increase in thigmotaxis at the openfield and a significantly lower time spent in the lit compartment at the light/dark exploration test. D3RKO animals also showed depressive-like symptoms as measured by increased immobility time in the Porsolt forced swim test and the tail suspension test, as well as anhedonia measured in the non-motor dependent sucrose test. In conclusion, D3R deficiency results in anxiety-like and depressive-like symptoms that cannot be attributed to motor dysfunction. Words: 181.
    Behavioural Brain Research 08/2014; 274. DOI:10.1016/j.bbr.2014.07.055 · 3.03 Impact Factor
Show more