Neurol Sci DOI 10.1007/s10072-014-1874-6
BRIEF COMMUNICATION
A pilot psychometric study of aberrant salience state in patients with Parkinson’s disease and its association with dopamine replacement therapy Michele Poletti • Daniela Frosini • Cristina Pagni • Filippo Baldacci • Claudio Lucetti • Paolo Del Dotto Roberto Ceravolo • Ubaldo Bonuccelli
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Received: 15 April 2014 / Accepted: 27 June 2014 Ó Springer-Verlag Italia 2014
Abstract An overactive striatal dopaminergic neurotransmission is described in psychosis and may be associated with a state of aberrant salience attribution. This pilot psychometric study investigated if features suggestive of an aberrant salience state, a condition of psychosis proneness, are associated with dopamine replacement therapy in patients with early Parkinson’s disease (PD). 77 participants (50 medicated PD patients, 12 newly diagnosed drug-naive PD patients and 15 healthy controls) were enrolled and assessed with the Aberrant Salience Inventory (ASI). Differences between groups were found for ASI scores, and ASI scores correlated with the dopaminergic therapy, in particular levodopa. These findings preliminary suggested that the presence and the degree of an aberrant salience state may be associated with features of the dopaminergic therapy; further studies are needed to investigate which neuropsychiatric complications more common in PD patients may be characterized by an underlying aberrant salience state. Keywords Parkinson’s disease Aberrant salience Dopamine overdose Levodopa Dopamine agonists Psychosis M. Poletti (&) Department of Mental Health and Pathological Addiction, AUSL of Reggio Emilia, Reggio Emilia, Italy e-mail:
[email protected] D. Frosini C. Pagni F. Baldacci R. Ceravolo U. Bonuccelli Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy e-mail:
[email protected] C. Lucetti P. Del Dotto Neurology Unit, Versilia Hospital, USL12 Toscana, Viareggio, Italy
Introduction An overactive striatal dopaminergic neurotransmission, both at rest and in response to stimulation, is associated with psychosis [1]. Dopamine being involved in the conversion of the neural representations of environmental stimuli from a neutral bit of information into an attractive or aversive entity, this alteration may produce at a cognitive/affective level an alteration of reward processing and may induce a state of aberrant salience attribution [2], a process whereby events and thoughts come to grab attention, drive action and influence behaviour because of their association with reward or punishment. An overactive striatal dopaminergic transmission is also present in patients at early stages of Parkinson’s disease on dopamine replacement therapy [3]: dopaminergic drugs as levodopa and dopamine agonists restore dopaminergic levels in the early affected dorsal frontostriatal loop, but usually overdose the ventral frontostriatal loop, almost preserved in the early PD stages and involved in reward processing. This suggests that dopaminergic drugs could be associated with the development of symptoms related to a state of aberrant salience also in PD patients. This hypothesis received empirical confirmation in a behavioral study [4] with newly diagnosed drug-naı¨ve PD patients; 12 weeks of treatment with dopamine agonist rapidly induced aberrant associations between conditioned stimuli and rewards that were associated with unusual feelings and experiences, considered subclinical manifestations of psychotic-like symptoms. This study aimed at further confirming this hypothesis with a psychometric approach.
Methods Seventy-seven participants were enrolled and gave written informed consent: 50 medicated PD patients, 12 newly
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Neurol Sci Table 1 Demographic and clinical characteristics and ASI scores of PD patients and healthy controls
Age
Healthy controls (N = 15)
Newly diagnosed drug-naive PD patients (N = 12)
Medicated PD patients (N = 50)
Medicated PD patients Dopamine agonist (N = 13)
Levodopa (N = 11)
Dopamine agonist?Levodopa (N = 26)
61.00 (13.05)
63.36 (8.66)
67.38 (6.84)
66.09 (6.83)
66.77 (7.47)
68.23 (6.69)
Education
12.67 (0.57)
10.71 (4.42)
10.00 (3.93)
12.33 (1.15)
9.18 (3.92)
10.63 (4.40)
Gender M/F
9/6
9/3
37/13
10/3
8/3
19/7
MMSE
30 (0.00)
29.55 (1.03)
28.57 (1.39)
28.62 (1.93)
28.45 (1.29)
28.65 (1.16)
HY
/
1.20 (0.25)
1.91 (0.56)
1.61 (0.54)
2.00 (0.50)
2.01 (0.57)
Disease duration
/
1.00 (0.30)
6.82 (4.37)
4.08 (2.06)
7.09 (3.50)
8.08 (4.49
LEDD for DA
/
/
/
218. 46 (82.52)
/
236.58 (100.33)
LD dose
/
/
/
/
752.27 (196.35)
445.19 (273.22)
Total LEDD
/
/
576.82 (304.47)
218. 46 (82.52)
752.27 (196.35)
681.77 (266.88)
ASI total score
7.23 (4.12)
6.45 (4.10)
10.32 (5.49)
9.23 (7.79)
12.09 (3.93)
10.12 (4.66)
ASI-F1
3.00 (1.73)
2.55 (1.75)
3.62 (1.89)
3.15 (2.03)
4.09 (1.37)
3.65 (2.01)
ASI-F2 ASI-F3
0.85 (0.80) 1.38 (0.76)
1.27 (1.10) 0.64 (0.67)
1.70 (1.31) 1.79 (1.19)
1.54 (1.76) 1.77 (1.53)
2.00 (1.26) 1.73 (0.90)
1.65 (1.09) 1.65 (1.16)
ASI-F4
1.46 (1.66()
1.27 (1.19)
2.08 (1.74)
1.62 (2.06)
2.09 (1.92)
2.31 (1.51)
ASI-F5
0.54 (0.66)
0.73 (0.78)
1.22 (1.11)
1.15 (1.40)
2.18 (0.98)
0.85 (0.73)
Values are mean (SD) ASI Aberrant Salience Inventory, DA Dopamine Agonists, HY Hoehn & Yahr Staging Score, LEDD Levodopa Equivalent Daily Dose, LD Levodopa, MMSE MiniMental State Examination, SD Standard Deviation
diagnosed drug-naı¨ve (de novo) PD patients and 15 healthy controls. All patients fulfilled research diagnostic criteria for idiopathic PD and were not demented, according to cognitive screening with the Mini Mental State Examination (MMSE) [5] and neurocognitive testing; in all patients we recorded demographic and clinical characteristics (disease duration, disease stage according to the Hoehn & Yahr staging [6] ) and parkinsonian therapies, calculating the levodopa equivalent daily dose (LEDD) (Table 1): 13 patients were ‘‘on’’ dopamine agonists (6 pramipexole: mean LEDD 179.33 ± 82.06 mg; 5 ropinirole, mean LEDD 256.0 ± 87.63 mg; 2 rotigotine, 8 mg), 11 patients were ‘‘on’’ levodopa (mean LEDD 752.27 ± 196.35 mg), 26 patients were ‘‘on’’ levodopa (mean LEDD 445.19 ± 273.22 mg) plus dopamine agonists (mean LEDD 236.58 ± 100.33 mg; 15 pramipexole, mean LEDD 212.47 ± 82.85 mg; 9 ropinirole, mean LEDD 275.56 ± 113.92 mg; 1 rotigotine 4 mg?1 rotigotine 12 mg). Aberrant salience was evaluated in all subjects with the Aberrant Salience Inventory (ASI), a 29-item questionnaire to measure psychosis proneness providing a total score and
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5 sub-scores [7] (F1: Increased Significance; F2: Senses Sharpening; F3: Impending Understanding; F4: Heightened Emotionality; F5: Heightened Cognition).
Results A Kruskal–Wallis test revealed that subgroups of medicated PD patients presented differences in HY and disease duration, respectively v2 (2, n = 50) = 6.964 p = .031 and v2 (2, n = 50) = 7.440 p = .024; Bonferroni-corrected post hoc analyses with Mann–Whitney U test revealed that both patients on levodopa and patients on levodopa?dopamine agonists had higher HY and disease duration that patients on dopamine agonists. The ASI total score did not correlate with any demographic and clinical characteristic in the whole PD sample but correlated with the levodopa daily dose in the subgroup of 37 patients ‘‘on’’ levodopa (r = .420, p = .010). ASI-F1 correlated with LEDD (r = .284, p = .046), ASI-F4 with levodopa dose (r = .367, p = .025) and LEDD (r = .369,
Neurol Sci
p = .008) and ASI-F5 with levodopa dose (r = .420, p = .010); the score at the MMSE negatively correlated with ASI-F5 in the subgroup of medicated patients (r = -.349, p = .016). Differences between subgroups (medicated PD patients, de novo PD patients, healthy controls) were present for ASI total score v2 (2, n = 77) = 7.592, p = .022 and ASI-F3 v2 (2, n = 77) = 8.907, p = .012; Bonferroni-corrected post hoc analyses with Mann–Whitney U test revealed that medicated PD patients had higher mean score in the ASIF3 in comparison to de novo PD patients (p = .014). Differences between subgroups (patients ‘‘on’’ dopamine agonists, patients ‘‘on’’ levodopa, patients ‘‘on’’ levodopa?dopamine agonist, de novo PD patients, healthy controls) were present for ASI total score v2 (2, n = 77) = 11.113 p = .025 and ASI-F5 v2 (2, n = 77) = 17.591 p = .001); the subgroup of patients ‘‘on’’ levodopa reported the highest ASI-F5 mean score (2.18 ± 0.982) that was significantly higher than those of patients on levodopa?dopamine agonists (p = .001), de novo PD patients (p = .004) and healthy controls (p \ .001).
Discussion This pilot psychometric study provided preliminary evidence on the presence of features related to an aberrant salience state in medicated PD patients. Differences in ASI scores emerged between subgroups suggesting that differences in dopaminergic stimulation (increased in the ventral frontostriatal loop in medicated PD patients, decreased in untreated PD patients) could influence the presence and the degree of aberrant salience. In disagreement with behavioral evidence [4], we found an association between ASI scores and levodopa but not with dopamine agonists. Although dopaminergic drugs may induce an aberrant salience state that is behaviorally detectable after only 12 weeks of treatment [4], its subjective effects may probably become conscious and therefore detectable with self-report measures after longer duration of treatment: this could explain why an association was found with levodopa, more used in mild and in advanced PD patients, but not with dopamine agonists, more used in early PD patients. Interestingly, global cognitive functioning, as assessed with the MMSE, was inversely correlated with salience-related heightened cognition, suggesting that not only features of the dopaminergic therapy may play a role in the development of aberrant salience states.
Findings of this pilot study need further empirical confirmation in larger samples of PD patients and further studies are needed to investigate which neuropsychiatric complications more common in medicated PD patients may be characterized by an underlying aberrant salience state, as preliminary suggested for isolated delusions [8] and Impulse Control Disorders [9]. Conflict of interest Full financial disclosures of all authors for the past 3 years: Consultancies: none. Advisory Boards: Bonuccelli: GSK, Lundbeck, Novartis, UCB. Partnerships: none. Honoraria: Bonuccelli for speeches at meeting by Boeringehr, GSK, Novartis. Grants: Bonuccelli: Regione Toscana Health Authority. Expert Testimony: none. Employment: University of Pisa (DF, CP, FB, RC UB) USL12 Toscana (CL, PDD, AN, PB, GC), AUSL RE (MP). Contracts: none. Royalties: none. Other: none.
References 1. Winton-Brown TT, Fusar-Poli P, Ungless MA, Howed OD (2014) Dopaminergic basis of salience dysregulation in psychosis. Trends Neurosci 37:85–94 2. Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology and pharmacology in schizophrenia. Am J Psychiatry 160:13–23 3. Poletti M, Bonuccelli U (2013) Acute and chronic cognitive effects of levodopa and dopamine agonists in patients with Parkinson’s disease: a review. Ther Adv Psychopharmacol 3:101–113 4. Nagy H, Levy-Gigi E, Somlaiu Z, Takats A, Bereczki D, Keri S (2012) The effect of dopamine agonists on adaptive and aberrant salience in Parkinson’s disease. Neuropsychopharmacology 37:950–958 5. Folstein MF, Folstein SE, McHugh PR (1975) Mini Mental State. A practical method for grading the cognitive state of patients for the clinician. J Psychiatry Res 12:189–198 6. Goetz CG, Poewe W, Rascol O et al (2004) Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 19:1020–1028 7. Cicero DC, Kerns JG, McCarthy DM (2010) The Aberrant Salience Inventory: a new measure of psychosis proneness. Psychol Assess 22:688–701 8. Poletti M, Bonuccelli U (2013) From aberrant salience to jumping to conclusions: dopaminergic pathways to delusions in Parkinson’s disease. J Clin Psychopharmacol 33:148–151 9. Housden CR, O’Sullivan SS, Joyce EM, Lees AJ, Roiser JP (2010) Intact reward learning but elevated delay discounting in Parkinson’s disease patients with impulsive-compulsive spectrum behaviors. Neuropsychopharmacology 35:2155–2164
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