Hostname: page-component-745bb68f8f-cphqk Total loading time: 0 Render date: 2025-02-11T09:48:01.607Z Has data issue: false hasContentIssue false
  • English
  • Français

The dark side of dopaminergic therapies in Parkinson’s disease: shedding light on aberrant salience

Published online by Cambridge University Press:  07 March 2017

Michele Poletti
Michele Poletti*
Affiliation:
Department of Mental Health and Pathological Addiction, Azienda Unità Sanitaria Locale Reggio Emilia, Reggio nell’Emilia, Italy
*
*Address for correspondence: Michele Poletti, Department of Mental Health and Pathological Addiction, AUSL of Reggio Emilia, Via Amendola 2, 52100, Reggio Emilia, Italy. (Email: michele.poletti2@ausl.re.it)
Rights & Permissions [Opens in a new window]

Abstract

Psychotic subjects and patients with Parkinson’s disease (PD) “on” dopaminergic drugs, especially on dopamine agonists, present a hyperdopaminergic state that interferes with learning processing. These clinical populations present with distinct alterations of learning that share an increased potential motivational significance of stimuli: psychotic subjects may attribute salience to neutral stimuli, while medicated PD patients may overvalue rewards. Herein is discussed the speculative hypothesis that the hyperdopaminergic state induced by dopaminergic treatments, especially with dopamine agonists, may also facilitate the attribution of salience to neutral stimuli in PD patients, altering the physiological attribution of salience. Preliminary empirical evidence is in agreement with this speculative hypothesis, which needs further empirical investigation. The clinical implications of this hypothesis are discussed in relation to behavioral addictions, psychosis proneness, and enhanced creativity in medicated PD patients.

Keywords

Dopamine agonistsaberrant salienceimpulse control disorderspsychosiscreativity
Type
Opinions
Information
CNS Spectrums , Volume 23 , Special Issue 6: Theme: Neuropsychiatry , December 2018 , pp. 347 - 351
Copyright
© Cambridge University Press 2017 

Introduction

Striatal dopaminergic neurotransmission is overactive in drug-naïve psychotic subjects, both at rest and in response to stimulation, with no compensatory modulation.Reference Winton-Brown, Fusar-Poli, Ungless and Howes 1 The overactive dopaminergic neurotransmission may interfere with the attribution of salience, altering the potential motivational significance of stimuli: salience represents the ability of a stimulus to grab attention and drive behavior.Reference Kapur 2 , Reference Heinz and Schlagenhauf 3 Salience attribution is altered because the mesolimbic hyperdopaminergic state interferes with the basic mechanism of reward prediction error encoding,Reference Glimcher 4 , Reference Boehme, Deserno and Gleich 5 as experimentally demonstrated in studies reporting impaired learning in schizophrenic subjects.Reference Murray, Corlett and Clark 6 – Reference Roiser, Howes, Chaddock, Joyce and McGuire 8 In the present account, the unexpected “aberrant” assignment of salience to internal and external stimuli may initially induce a perplexing state marked by exaggerated importance of some percepts and thoughts and increased inner awareness. Such psychotic symptoms as delusions may arise from seemingly plausible top–down cognitive explanations that individuals come up with to understand the persistence of these experiences of internal and external stimuli with unexpected and aberrant salience.Reference Kapur 2 , Reference Howes and Nour 9

Striatal dopaminergic neurotransmission is also overactive in patients at the early stages of Parkinson’s disease “on” medication with levodopa or dopamine agonists.Reference Poewe, Antonini, Zijlmans, Burkhard and Vingerhoets 10 , Reference Bonuccelli, Del Dotto and Rascol 11 These drugs restore dopaminergic levels in the early-affected dorsolateral frontostriatal loop (linking the dorsal striatum and dorsolateral prefrontal cortex), but they may overdose the preserved orbital frontostriatal loop (linking the ventral striatum with the medial prefrontal cortex).Reference Kish, Shannak and Hornykiewicz 12 , Reference Gotham, Brown and Marsden 13 The overdosing effect of dopaminergic drugs may be more severe in patients with younger PD onset, considering that dopaminergic function physiologically declines with aging.Reference Shingai, Tateno and Arakawa 14

Dopaminergic drugs interfere with phasic processing of rewards provided by ventral striatum dopamine neurons, strengthening dopaminergic peaks (associated with unexpected rewards), and preventing dopaminergic dips (associated with failures of expected rewards), as confirmed by impairments in reward learning induced by dopaminergic therapy in the early stages of PD;Reference MacDonald, Monchi, Seergobin, Ganjavi, Tamjeedi and MacDonald 15 , Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler 16 this effect is stronger for the tonic stimulation provided by dopamine agonists in comparison with the phasic stimulation provided by levodopa.Reference Grace 17 , Reference Poletti and Bonuccelli 18

The alteration of reward learning (strengthened dopaminergic peaks associated with rewards, prevented dopaminergic dips associated with failures of expected rewards) induced especially by dopamine agonists represents the pathophysiological basisReference Shiner, Symmonds, Guitart-Masip, Fleming, Friston and Dolan 19 , Reference Voon, Mehta and Hallett 20 of behavioral addictions in PD patients.Reference Ceravolo, Frosini, Rossi and Bonuccelli 21 These include dopamine dysregulation syndrome (DDS),Reference Giovannoni, O’Sullivan, Turner, Manson and Lees 22 which is an addictive pattern of medication intake, particularly of large doses of dopaminergic drugs in excess of that required to control motor symptoms, and such impulse control disorders (ICDs)Reference Dagher and Robbins 23 as pathological gambling, hypersexuality, compulsive eating, punding, hoarding, and compulsive shopping.

Hypothesis

Psychotic subjects and patients in the early stages of PD “on” dopaminergic drugs present with a hyperdopaminergic state that alters reward processing. The alterations described in these clinical populations are not overlapping but share an increased potential motivational significance of stimuli: psychotic subjects attribute salience to neutral stimuli, while medicated PD patients overvalue rewards (and “neglect” punishments).

On the basis of this shared feature in reward processing, it could be hypothesized that the hyperdopaminergic state induced by dopaminergic drugs in PD patients may also facilitate the attribution of salience to neutral stimuli. This hypothesis could be tested investigating salience attribution and clinical features related to its alteration (such as psychosis and psychosis-proneness) in PD patients in comparison with healthy controls.

PD patients with such behavioral addictions as ICDs and DDS present with more overactive striatal dopaminergic activityReference Voon, Rizos and Chakravarty 24 and more altered reward processingReference Piray, Zeighami, Bahrami, Eissa, Hewedi and Moustafa 25 in comparison with PD patients who do not present these neuropsychiatric manifestations; therefore, the prevalence and severity of salience features could be higher in PD patients with behavioral addictions compared to PD patients without them. These speculative hypotheses should not be primarily investigated in the advanced stages of PD, in which such psychotic features as delusions and hallucinationsReference Fénelon 26 are mainly due to the widespread cortical diffusion of Lewy-body neuropathology.Reference Braak, Del Tredici and Rub 27 , Reference Stahl 28

Saliency and related features in Parkinson’s disease

Two studies directly assessed salience features in PD patients. A behavioral studyReference Nagy, Levy-Gigi, Somlaiu, Takáts, Bereczki and Kéri 29 assessed newly diagnosed drug-naïve PD patients before and after 12 weeks of dopamine agonist treatment, with a speeded-up reaction time task and with the probe stimulus preceded by conditioned stimuli signaling monetary reward by color or shape. Dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. Unusual feelings and experiences, considered subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus–reward associations (aberrant salience). The authors concluded that dopamine agonists may rapidly increase psychotic-like experiences in PD patients, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward.

Another studyReference Poletti, Frosini and Pagni 30 psychometrically investigated 50 medicated PD patients, 12 newly diagnosed drug-naïve PD patients, and 15 healthy controls with the Aberrant Salience Inventory.Reference Cicero, Kerns and McCarthy 31 Dopaminergic medication doses significantly correlated with some features of aberrant salience (increased significance, heightened emotionality, and heightened cognition), and some features of salience (impending understanding) were higher in comparison with drug-naïve PD patients.

One paradigm related to salience attribution is latent inhibition,Reference Schmidt and Roiser 32 a process that occurs when an organism is exposed to a stimulus that is not followed by a significant consequence: the stimulus subsequently becomes less effective, as compared to a novel stimulus, in the acquisition of a new association.Reference Lubow 33 Latent inhibition has been shown to be dysfunctional in psychotic patients,Reference Lubow 34 who allocate more attention to irrelevant stimuli in comparison with healthy controls. Dopaminergic drugs may decrease latent inhibition in de-novo PD patients,Reference Polner, Moustafa, Nagy, Takáts, Győrfi and Kéri 35 , Reference Gyorfi, Nagy, Bokor, Kelemen and Kéri 36 enhancing at the same time perceptual psychotic-like experiences (changes in subjective feelings in thinking, time perception, and mental “highness”). Psychosis proneness has also been reported in cognitively preserved PD patients, especially in the subgroup with ICDs.Reference Housden, O’Sullivan, Joyce, Lees and Roiser 37

Increased frequency of psychotic symptoms has been reported in PD patients with ICDsReference Pettorusso, Fasano and De Risio 38 – Reference Poletti, Logi and Lucetti 40 and DDSReference Cilia, Siri and Canesi 41 in comparison to PD patients without them, and one studyReference Poletti, Lucetti, Baldacci, Del Dotto and Bonuccelli 42 directly reported a case series of nondemented patients developing concomitantly both delusional jealousy and hypersexuality. Moreover, several studies reported isolated psychosis in cognitively preserved PD patients when exposed to dopamine agonists.Reference Cannas, Solla, Floris, Tacconi, Marrosu and Marrosu 43 – Reference Stefanis, Bozi and Christodoulou 46

Discussion

The empirical findings presented herein are preliminarily in agreement with the speculative hypothesis that dopaminergic treatments adopted to restore motor functions may interfere with the physiological process of salience attribution in patients in the early stages of PD, especially in those with younger disease onset. Moreover, they are also in agreement with the related speculative hypothesis that this interference effect is stronger in PD patients who present such behavioral addictions as ICDs and DDS. The tonic dopaminergic stimulation of dopamine agonists, rather than the phasic stimulation of levodopa, may cause an attribution of salience to neutral stimuli. The altered increased motivational significance of stimuli at the basis of behavioral addictions in medicated PD patients probably could include features related not only to overvalue of rewards but also related to aberrant salience attribution. Therefore, behavioral addictions may be considered a nonmotor side effect of dopamine agonists that may emerge in a subclinical “atmosphere” of altered salience, representing a condition of psychosis proneness and a risk factor for the development of comorbid psychotic features. The decreased latent inhibition induced by dopaminergic drugs may also contribute to alteration of this subclinical atmosphere, in which irrelevant stimuli continue to activate the attention of subjects.

This could explain why PD patients with such behavioral addictions as ICDs and DDS may present increased psychotic features compared to PD patients without behavioral addictions and why in some cases dopaminergic treatments, especially dopamine agonists, may induce the concomitant development of ICDs and psychosis.

This subclinical atmosphere of altered salience/psychosis proneness may represent the “dark” side of dopaminergic treatments in early-stage PD patients, especially those with younger onset. In this subgroup, the overdosing effect of dopamine agonists is stronger considering that dopaminergic function physiologically declines with aging.Reference Shingai, Tateno and Arakawa 14 Behavioral addictions, being associated with more overactive striatal dopaminergic activityReference Voon, Rizos and Chakravarty 24 and more altered reward processing,Reference Piray, Zeighami, Bahrami, Eissa, Hewedi and Moustafa 25 are probably also associated with more altered salience attribution, that is, psychosis proneness. From this perspective, disease-related characteristicsReference Stahl 28 and such individual characteristics as cognitive functioning, premorbid impulsivity, and previous history of addiction, as well as other psychiatric features, may play the role of moderating factors in the clinical expression of an increased motivational significance of stimuli.

Furthermore, the attribution of salience to neutral stimuli, increasing their motivational significance and inducing an atmosphere of altered salience, could be involved in the physiological bases of enhanced creativity detected in early PD patients on dopamine agonistsReference Faust-Socher, Kenett, Cohen, Hassin-Baer and Inzelberg 47 that is not simply due to an increase of impulsivity nor to behavioral addictions,Reference Canesi, Rusconi, Isaias and Pezzoli 48 and is associated with such signs of increased psychosis proneness as schizotypal traits.Reference Polner, Nagy, Takáts and Keri 49 This speculative hypothesis needs empirical investigation.

Conclusions

Reviewed empirical findings only preliminarily support the speculative hypothesis discussed in the present opinion piece. This hypothesis deserves further empirical investigation. Once supported by empirical data, the clinical implication could be that such behavioral addictions as ICDs and DDS should be considered a clinical indicator of a hyperdopaminergic state associated not only with overvalue of rewards (sustaining addictions) but also with altered salience attribution, increasing the risk of psychotic phenomena. Therefore, an accurate neuropsychiatric assessment covering both risks for addiction and psychosis proneness is needed before beginning any dopaminergic treatment, especially for young-onset PD patients.

Disclosures

Michele Poletti hereby declares that he does not have any conflicts of interest to disclose.

References

1. Winton-Brown, TT, Fusar-Poli, P, Ungless, MA, Howes, OD. Dopaminergic basis of salience dysregulation in psychosis. Trends Neurosci. 2014; 37(2): 85–94. Epub ahead of print Jan 2.Google Scholar
2. Kapur, S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003; 160(1): 13–23. Available at: http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.160.1.13.Google Scholar
3. Heinz, A, Schlagenhauf, F. Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr Bull. 2010; 36(3): 472–485. Epub ahead of print May 7. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879696/.Google Scholar
4. Glimcher, PW. Understanding dopamine and reinforcement learning: the dopamine reward prediction error. Proc Natl Acad Sci U S A. 2011; 108(Suppl 3): 15647–15654. Epub ahead of print Mar 9. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176615/.Google Scholar
5. Boehme, R, Deserno, L, Gleich, T, et al. Aberrant salience is related to reduced reinforcement learning signals and elevated dopamine synthesis capacity in healthy adults. J Neurosci. 35(28): 10103–10111. Available at: http://www.jneurosci.org/content/35/28/10103.Google Scholar
6. Murray, GK, Corlett, PR, Clark, L, et al. Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry. 2008; 13(239): 267–276. Epub ahead of print Aug 7, 2007. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564111/.Google Scholar
7. Roiser, JP, Stephan, KE, den Ouden, HE, Barnes, TR, Friston, KJ, Joyce, EM. Do patients with schizophrenia exhibit aberrant salience? Psychol Med. 2009; 39(2): 199–209. Epub ahead of print Jun 30, 2008. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635536/.Google Scholar
8. Roiser, JP, Howes, OD, Chaddock, CA, Joyce, EM, McGuire, P. Neural and behavioral correlates of aberrant salience in individuals at risk for schizophrenia. Schizophr Bull. 2013; 39(6): 1328–1336. Epub ahead of print Dec 12, 2012. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796080/.Google Scholar
9. Howes, OD, Nour, MN. Dopamine and the aberrant salience hypothesis of schizophrenia. World Psychiatry. 2016; 15(1): 3–4. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780291/.Google Scholar
10. Poewe, W, Antonini, A, Zijlmans, JC, Burkhard, PR, Vingerhoets, F. Levodopa in the treatment of Parkinson’s disease: an old drug still going strong. Clin Interv Aging. 2010; 7(5): 229–238. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938030/.Google Scholar
11. Bonuccelli, U, Del Dotto, P, Rascol, O. Role of dopamine receptor agonists in the treatment of early Parkinson’s disease. Parkinsonism Relat Disord. 2009; 15(Suppl 4): S44–S53.Google Scholar
12. Kish, SJ, Shannak, K, Hornykiewicz, O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. N Engl J Med. 1988; 318(14): 876–880.Google Scholar
13. Gotham, A, Brown, R, Marsden, C. Levodopa treatment may benefit or impair frontal function in Parkinson’s disease. Lancet. 1986; 2(8513): 970–971.Google Scholar
14. Shingai, Y, Tateno, A, Arakawa, R, et al. Age-related decline in dopamine transporter in human brain using PET with a new radioligand [18F]FE–PE2I. Ann Nucl Med. 2014; 28(3): 220–226. Epub ahead of print Jan 3.Google Scholar
15. MacDonald, AA, Monchi, O, Seergobin, KN, Ganjavi, H, Tamjeedi, R, MacDonald, PA. Parkinson’s disease duration determines effects of dopaminergic therapy on ventral striatum function. Mov Disord. 2013; 28(2): 153–160. Epub ahead of print Nov 19, 2012.Google Scholar
16. Vaillancourt, DE, Schonfeld, D, Kwak, Y, Bohnen, NI, Seidler, R. Dopamine overdose hypothesis: evidence and clinical implications. Mov Disord. 2013; 28(14): 1920–1929. Epub ahead of print Oct 9. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859825/.Google Scholar
17. Grace, AA. The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving. Addiction. 2000; 95(Suppl 2): S119–S128.Google Scholar
18. Poletti, M, Bonuccelli, U. Acute and chronic cognitive effects of levodopa and dopamine agonists in patients with Parkinson’s disease: a review. Ther Adv Psychopharmacol. 2013; 3(2): 101–113. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805397/.Google Scholar
19. Shiner, T, Symmonds, M, Guitart-Masip, M, Fleming, SM, Friston, KJ, Dolan, RJ. Dopamine, salience and response set shifting in prefrontal cortex. Cereb Cortex. 2015; 25(10): 3629–3639. Epub ahead of print Sep 21, 2014. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585507/.Google Scholar
20. Voon, V, Mehta, AR, Hallett, M. Impulse control disorders in Parkinson’s disease: recent advances. Curr Opin Neurol. 2011; 24(4): 324–330. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154756/.Google Scholar
21. Ceravolo, R, Frosini, D, Rossi, C, Bonuccelli, U. Spectrum of addictions in Parkinson’s disease: from dopamine dysregulation syndrome to impulse control disorders. J Neurol. 2010; 257(Suppl 2): S276–S283.Google Scholar
22. Giovannoni, G, O’Sullivan, JD, Turner, K, Manson, AJ, Lees, AJ. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry. 2000; 68(4): 423–428. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1736875/.Google Scholar
23. Dagher, A, Robbins, TW. Personality, addiction, dopamine: insights from Parkinson’s disease. Neuron. 2009; 61(4): 502–510. Available at: http://www.cell.com/neuron/fulltext/S0896-6273(09)00124-X.Google Scholar
24. Voon, V, Rizos, A, Chakravarty, R, et al. Impulse control disorders in Parkinson’s disease: decreased striatal transporter levels. J Neurol Neurosurg Psychiatry. 2014; 85(2): 148–152. Epub ahead of print Jul 30, 2013. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031642/.Google Scholar
25. Piray, P, Zeighami, Y, Bahrami, F, Eissa, AM, Hewedi, DH, Moustafa, AA. Impulse control disorders in Parkinson’s disease are associated with dysfunction in stimulus valuation but not action valuation. J Neurosci. 2014; 34(23): 7814–7824. Available at: http://www.jneurosci.org/content/34/23/7814.long.Google Scholar
26. Fénelon, G. Psychosis in Parkinson’s disease: phenomenology, frequency, risk factors, and current understanding of pathophysiologic mechanisms. CNS Spectr. 2008; 13(Suppl 4): 18–25.Google Scholar
27. Braak, H, Del Tredici, K, Rub, U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003; 24(2): 197–211.Google Scholar
28. Stahl, SM. Parkinson’s disease psychosis as a serotonin–dopamine imbalance syndrome. CNS Spectr. 2016; 21(5): 355–359.Google Scholar
29. Nagy, H, Levy-Gigi, E, Somlaiu, Z, Takáts, A, Bereczki, D, Kéri, S. The effect of dopamine agonists on adaptive and aberrant salience in Parkinson’s disease. Neuropsychopharmacology. 2012; 37(4): 950–958. Epub ahead of print Nov 16, 2011. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280658/.Google Scholar
30. Poletti, M, Frosini, D, Pagni, C, et al. A pilot psychometric study of aberrant salience state in patients with Parkinson’s disease and its association with dopamine replacement therapy. Neurol Sci. 2014; 35(10): 1603–1605. Epub ahead of print Jul 11.Google Scholar
31. Cicero, DC, Kerns, JG, McCarthy, DM. The Aberrant Salience Inventory: a new measure of psychosis proneness. Psychol Assess. 2010; 22(3): 688–701.Google Scholar
32. Schmidt, K, Roiser, JP. Assessing the construct validity of aberrant salience. Front Behav Neurosci. 2009; 3(58): 1–9. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802547/pdf/fnbeh-03-058.pdf.Google Scholar
33. Lubow, RE. Latent inhibition. Psychol Bull. 1973; 79: 398–407.Google Scholar
34. Lubow, RE. Construct validity of the animal latent inhibition model of selective attention deficits in schizophrenia. Schizophr Bull. 2005; 31(1): 139–155. Epub ahead of print Feb 16. Available at: https://academic.oup.com/schizophreniabulletin/article-lookup/doi/10.1093/schbul/sbi005.Google Scholar
35. Polner, B, Moustafa, AA, Nagy, H, Takáts, A, Győrfi, O, Kéri, S. Dopamine improves exploration after expectancy violations and induces psychotic-like experiences in patients with Parkinson’s disease. Neurosci Lett. 2016; 616: 132–137. Epub ahead of print Jan 26.Google Scholar
36. Gyorfi, O, Nagy, H, Bokor, M, Kelemen, O, Kéri, S. A single dose of L-DOPA changes perceptual experiences and decreases latent inhibition in Parkinson’s disease. J Neural Transm (Vienna). 2016; 124(1): 113–119. Epub ahead of print Oct 7.Google Scholar
37. Housden, CR, O’Sullivan, SS, Joyce, EM, Lees, AJ, Roiser, JP. Intact reward learning but elevated delay discounting in Parkinson’s disease patients with impulsive-compulsive spectrum behaviors. Neuropsychopharmacology. 2010; 35(11): 2155–2164. Epub ahead of print Jul 14. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055316/.Google Scholar
38. Pettorusso, M, Fasano, A, De Risio, L, et al. Punding in non-demented Parkinson’s disease patients: relationship with psychiatric and addiction spectrum comorbidity. J Neurol Sci. 2016; 15(362): 344–347. Epub ahead of print Feb 8.Google Scholar
39. Pontieri, FE, Assogna, F, Pellicano, C, et al. Sociodemographic, neuropsychiatric and cognitive characteristics of pathological gambling and impulse control disorders NOS in Parkinson’s disease. Eur Neuropsychopharmacol. 2015; 25(1): 69–76. Epub ahead of print Nov 18, 2014.Google Scholar
40. Poletti, M, Logi, C, Lucetti, C, et al. A single-centre, cross-sectional, prevalence study of impulse control disorders in Parkinson’s disease: association with dopaminergic drugs. J Clin Psychopharmacol. 2013; 33(5): 691–694.Google Scholar
41. Cilia, R, Siri, C, Canesi, M, et al. Dopamine dysregulation syndrome in Parkinson’s disease: from clinical and neuropsychological characterization to management and long-term outcome. J Neurol Neurosurg Psychiatry. 2014; 85(3): 311–318. Epub ahead of print Apr 16, 2013. Available at: http://jnnp.bmj.com/content/85/3/311.long.Google Scholar
42. Poletti, M, Lucetti, C, Baldacci, F, Del Dotto, P, Bonuccelli, U. Concomitant development of hypersexuality and delusional jealousy in patients with Parkinson’s disease: a case series. Parkinsonism Relat Disord. 2014; 20(11): 1290–1292. Epub ahead of print Sep 18.Google Scholar
43. Cannas, A, Solla, P, Floris, G, Tacconi, P, Marrosu, F, Marrosu, MG. Othello syndrome in Parkinson disease patients without dementia. Neurologist. 2009; 15(1): 34–36.Google Scholar
44. Kiziltan, G, Ozekmekci, S, Ertan, S, Ertan, T, Erginöz, E. Relationship between age and subtypes of psychotic symptoms in Parkinson’s disease. J Neurol . 2007; 254(4): 448–452. Epub ahead of print Mar 31.Google Scholar
45. Poletti, M, Perugi, G, Logi, C, et al. Dopamine agonists and delusional jealousy in Parkinson’s disease: a cross-sectional prevalence study. Mov Disord. 2012; 27(13): 1679–1682. Epub ahead of print Nov 13.Google Scholar
46. Stefanis, N, Bozi, M, Christodoulou, C, et al. Isolated delusional syndrome in Parkinson’s disease. Parkinsonism Relat Disord. 2010; 16(8): 550–552.Google Scholar
47. Faust-Socher, A, Kenett, YN, Cohen, OS, Hassin-Baer, S, Inzelberg, R. Enhanced creativity thinking under dopaminergic therapy in Parkinson disease. Ann Neurol. 2014; 75(6): 935–942. Epub ahead of print Jun 10.Google Scholar
48. Canesi, M, Rusconi, ML, Isaias, IU, Pezzoli, G. Artistic productivity and creative thinking in Parkinson’s disease. Eur J Neurol. 2012; 19(3): 468–472. Epub ahead of print Oct 10, 2011.Google Scholar
49. Polner, B, Nagy, H, Takáts, A, Keri, S. Kiss of the muse for the chosen ones: de novo schizotypal traits and lifetime creative achievement are related to changes in divergent thinking during dopaminergic therapy in Parkinson’s disease. Psychol Aesthet Creat Arts. 2015; 9(3): 328–339.Google Scholar