Effects of dopamine agonist dose and gender on the prognosis of impulse control disorders in Parkinson's disease
Introduction
Cross-sectional studies have revealed clear associations between impulse control disorders (ICDs) and antiparkinsonian medications. In particular, these associations have been seen with dopamine agonists, also in the context of non-Parkinsonian disorders, such as the restless legs syndrome [1], [2]. There are additional anecdotal reports of resolved ICDs after discontinuation of dopamine agonists in Parkinson’ disease (PD) patients [3], [4], [5], [6], [7]. However, ICDs also occur in the absence of dopamine agonists, and they have been linked to other dopaminergic medication types apart from dopamine agonists [8], [9]. There is mixed evidence concerning the possible dose-dependent effects of these medications on ICDs [10]. In the largest cross-sectional epidemiological study so far [9], although an association of dopamine agonists and ICDs was seen, there was no clear evidence of a dose-dependent effect. Also in our previous cross-sectional study with 575 PD patients, no significant relationship between dopamine agonist dose and ICD prevalence was seen [11]. However, cross-sectional studies lack the power to detect possible delayed and dose-dependent effects due to considerable inter-individual variation in both the optimal agonist dose for treating motor symptoms of PD, and in the severity and characteristics of ICDs. The excess variation can be partially controlled for in within-subject longitudinal studies. To date, only a few prospective follow-up studies with small numbers of PD patients with ICDs have been published. For a clinical practitioner, the knowledge of possible dose-related effects of dopamine agonists on ICDs would be useful since the complete discontinuation of dopamine agonists due to an ICD can be difficult because of worsening motor symptoms and the possibility of dopamine agonist withdrawal syndrome [12].
In this study, we investigated the stability and prognostic factors of ICDs in PD patients at baseline and after a follow-up of approximately 15 months. Our aim was to explore dose-dependence of medications and other factors that could be useful for clinicians treating PD. There were two focuses in the study: 1) factors that could predict the resolving of an ICD (ICD at baseline, but no ICD at follow-up) and 2) factors that could predict the appearance of an ICD (no ICD at baseline, but ICD at follow-up). In addition, special attention was addressed to temporal relationships between depression and ICDs in PD.
Section snippets
Participants
The first survey was sent to 1000 patients and 575 responders were included in the published cross-sectional study as described previously [11]. The second survey was sent to all 376 subjects who had indicated in the first study that they were willing to participate. Two hundred ninety-six patients out of 376 (78.7%) participated, six subjects were excluded because of inadequate data, and thus the final data set consisted of 290 patients investigated at baseline and follow-up. However, only 270
Patients and surveys
Of the 290 patients, 62.4% (n = 181) were males. The median (IQR) follow-up time was 449 (440–456) days. In the follow-up examination, mean (95% CI) levodopa dose (and subsequently total LEDD) had significantly increased by 46.4 mg (15.5–77.4) and there were more patients using levodopa (n = 220 at baseline, n = 236 at follow-up, P < 0.001) reflecting treatment interventions for PD symptom progression. There were no differences in the doses or in the number of patients using dopamine agonists,
Discussion
This is the first large-scale prospective study with two time-points investigating ICDs in PD. The results suggest a dose-dependent effect of dopamine agonists on ICDs. The results also suggest that the male sex is associated with more persistent ICDs, and indicate that depression is associated with the development of ICDs.
The first focus of the present study was to detect factors associated with resolving ICDs. Two independent factors were found: low dopamine agonist dose at baseline and the
Conclusions
In summary, the results of this study suggest that dopamine agonist dose and gender are associated with the outcome of ICDs in patients with Parkinson's disease. Depressive symptoms increase in parallel with the development of new ICDs.
Funding
This work was supported by the Finnish Alcohol Research Foundation, the Finnish Medical Foundation, the Turku University Hospital (EVO-funds), the Turku University Foundation, the Paulo Foundation, and the Finnish Parkinson Foundation.
Conflict of interest
Juho Joutsa has received lecturer honoraria from Boehringer-Ingelheim. Kirsti Martikainen has received lecture and/or consultant fees from Boehringer-Ingelheim, GlaxoSmithKline, UCB Pharma, and Orion Pharma. Tero Vahlberg discloses no financial interests. Valtteri Kaasinen has received speaker honoraria and/or travel grants from Boehringer-Ingelheim, Orion-Pharma, Abbott, UCB Pharma and Lundbeck; and serves as a member of the advisory board of UCB Pharma and as a consultant for Orion-Pharma and
Acknowledgments
The authors thank Hannele Hyppönen from the Finnish Parkinson Foundation for her skillfull assistance during the study.
References (22)
- et al.
Long term follow-up of Parkinson's disease patients with impulse control disorders
Parkinsonism Relat Disord
(2010) - et al.
Risk factors for pathologic gambling and other compulsions among Parkinson's disease patients taking dopamine agonists
J Clin Neurosci
(2007) Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease
Physiol Behav
(2011)- et al.
Impulse control disorders and depression in Finnish patients with Parkinson's disease
Parkinsonism Relat Disord
(2012) - et al.
Parkinsonism Relat Disord
(2011) - et al.
Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy
Parkinsonism Relat Disord
(2005) - et al.
Impulse control disorders in patients with Parkinson's disease receiving dopamine replacement therapy: evidence and implications for the addictions field
Addiction
(2011) - et al.
Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome
BMC Neurol
(2011) - et al.
Long-term follow-up of impulse control disorders in Parkinson's disease
Mov Disord
(2008) - et al.
Clinical follow up of pathological gambling in Parkinson's disease in the West Scotland study
Mov Disord
(2009)
Outcomes of patients with Parkinson disease and pathological gambling
Can J Neurol Sci
Cited by (41)
Editorial: Inclusion, equity, diversity and social justice in movement disorders research
2021, Parkinsonism and Related DisordersImpulse control disorders in Parkinson's disease: A systematic review on risk factors and pathophysiology
2019, Journal of the Neurological SciencesHyperdopaminergic behavioral spectrum in Parkinson's disease: A review
2018, Revue NeurologiqueCitation Excerpt :Thus, selective D3-receptor stimulation by DAs within the mesocorticolimbic system appears to play a crucial role in the emergence of behavioral addictions [12,36]. However, although there is wide interindividual variability of tolerance to behavioral DA side-effects, in any given patient, these effects are highly dose-dependent and the threshold for behavioral side-effects seems to remain relatively stable [40]. The pulsatility of dopaminergic treatment is another important risk factor for developing symptoms within the spectrum of hyperdopaminergic behavior [7,36,41].
Risk factors for non-motor symptoms in Parkinson's disease
2018, The Lancet NeurologyThe high prevalence of impulse control behaviors in patients with early-onset Parkinson's disease: A cross-sectional multicenter study
2016, Journal of the Neurological SciencesCitation Excerpt :The results would have probably changed if we had included a more number of patients. Concerning the dose of dopamine agonists it remains unclear whether higher doses of DA increase the risk of developing ICDs [11,21,32,33]. Our patients with ICBs appeared to be receiving a higher DA LEDD dose than those that did not, and perhaps the small number of patients studied was responsible for this difference not reaching statistical significance, particularly since these data are in accordance with the results of other studies [21,32,33].