[1] 12w Dopamine Agonists and Delusional Jealousy in Parkinson's Disease: A Cross-Sectional Prevalence Study

[1] 157w Background: Delusional jealousy (DJ) has been described in patients with Parkinson's disease (PD) on dopaminergic therapy, but a role for dopaminergic therapy in DJ has not been established. Methods: The current cross-sectional study on DJ investigated its association with dopaminergic therapies compared with their associations with hallucinations and its prevalence in PD patients. Eight hundred five consecutive patients with PD were enrolled between January 2009 and June 2010. Results: DJ was identified in 20 patients (2.48%) and hallucinations in 193 patients (23.98%). In the multivariate logistic regression analyses, dopamine agonists were significantly associated with DJ (odds ratio, 18.1; 95% CI, 3.0-infinity; P 5 .0002) but not with hallucinations (odds ratio, 0.73; 95% CI, 0.49-1.10; P 5 .133). Conclusions: These findings suggest that dopamine agonist treatment represents a risk factor for DJ in PD independent of the presence of a dementing disorder, and the presence of this additional nonmotor side effect should be investigated in this clinical population.

[1] 65w In all, 805 consecutive PD patients were screened and enrolled in the study (Table 1). DJ was identified in 20 patients (2.48%) and VHs in 193 patients (23.98%). There were 593 cognitively preserved patients (73.7%) and 212 demented patients (26.3%). Of the cognitively preserved patients, 15 had DJ (2.53%) and 91 VHs (14.87%). Of the demented patients, 5 had DJ (2.36%) and 102 VHs (48.11%).

[2] 96w In the whole PD sample, DJ was associated with age (P < .0001), age at PD diagnosis (P ¼ .0002), HY score (P ¼ .020), and dopamine agonist treatment (P < .0001); see Table 1. Patients with versus those without DJ were younger at the time of DJ diagnosis (63.7 6 7.6 vs 72.7 6 9.4 years) and at the time of PD diagnosis (53.5 6 9.0 vs 62.8 6 10.9 years) and had a lower HY score (2.1 6 0.8 vs 2.5 6 0.8) and a higher prevalence of dopamine agonist treatment (100% vs 48.5%).

[3] 53w VHs were associated with age (P < .0001), HY (P < .0001), PD duration (P < .0001), dementia (P < .0001), levodopa treatment (P < .0001), dopamine agonist treatment (P < .0001), and rasagiline treatment (P ¼ .016). Patients with versus those without VHs were older at the time of VH diagnosis (75.

[4] 439w 3 6 Table 1. Demographic and clinical characteristics of the whole PD sample and of PD subgroups on the basis of delusional jealousy and hallucinations Variable PD sample (n ¼ 805) Delusional jealousy Hallucinations Yes (n ¼ 20) No (n ¼ 785) P Yes (n ¼ 193) No (n ¼ 612) P Sex (M), n (%) 481 (59.8) 14 (70.0) 467 (59.5) .489 121 (62.7) 360 (58.8) .355 Age, mean 6 SD 72.5 6 9.5 63.7 6 7.6 72.7 6 9.4 < .0001 75.3 6 9.0 71.6 6 9.5 < .0001 Age at PD diagnosis, mean 6 SD 62.6 6 10.9 53.5 6 9.0 62.8 6 10.9 < .0001 63.6 6 10.3 62.3 6 11.1 .148 Dopamine agonists, n (%) 401 (49.8) 20 (100) 381 (48.5) < .0001 69 (35.7) 332 (54.2) < .0001 Levodopa, n (%) 689 (85.6) 15 (75.0) 674 (85.8) .190 175 (90.7) 514 (84.0) .025 Amantadine, n (%) 155 (19.3) 4 (20.0) 151 (19.2) 1.00 42 (21.8) 113 (18.5) .346 Benzodiazepine, n (%) 114 (14.2) 4 (20) 110 (14.0) .510 30 (15.5) 84 (13.7) .554 SSRI, n (%) 185 (23.0) 4 (20.0) 181 (23.1) 1.00 47 (24.3) 138 (22.5) .624 Rasagiline, n (%) 176 (21.9) 4 (20.0) 172 (21.9) 1.00 30 (15.5) 146 (23.9) .016 Hoehn and Yahr, mean 6 SD 2.5 (0.8) 2.1 6 0.8 2.5 6 0.8 .020 2.8 6 0.8 2.4 6 0.8 < .0001 Dementia, n (%) 212 (26.3) 5 (25.0) 207 (26.4) 1.00 102 (52.8) 110 (18.0) < .0001 PD duration, mean 6 SD 9.9 6 7.2 10.2 6 5.6 9.9 6 7.1 .582 11.7 6 6.9 9.3 6 7.0 < .0001 Hallucinations, n (%) 193 (23.9) 2 (10.0) 191 (24.3) .186 ---DJ, n (%) 20 (2.5) ---2 (1.0) 18 (2.9) .186 DJ, delusional jealousy; PD, Parkinson's disease; SD, standard deviation; SSRI, selective serotonin reuptake inhibitors. P O L E T T I E T A L . 9.0 vs 71.6 6 9.5 years), had a longer PD duration (11.7 6 6.9 vs 9.3 6 7.0 years), a higher HY score (2.8 6 0.8 vs 2.4 6 0.8), higher prevalence of dementia (52.8% vs 18.0%) and levodopa treatment (90.7% vs 84.0%), and a lower prevalence of dopamine agonist treatment (35.7% vs 54.2%) and rasagiline treatment (15.5% vs 23.9%). No associations were found between psychotic disorders and other pharmacological treatments (see Table 1); anticholinergics were not included in the analysis because no patients with DJ and just a few patients with VHs were treated with these drugs. No patients with DJ were in treatment with atypical neuroleptics; among patients with VHs, 113 of 193 (58.5%) were treated with quetiapine or clozapine.

[5] 79w Dopamine agonist treatment was significantly associated with lower frequency of treatment in men (P ¼ .008), younger age (P < .0001), younger age at the time of PD diagnosis (P < .0001), lower HY (P < .0001), lower prevalence of dementia (P < .0001), lower prevalence of VH (P < .0001), levodopa treatment (P < .0001), and a higher prevalence of DJ (P < .0001), amantadine treatment (P < .0001), and rasagiline treatment (P < .0001); see Table 2.

[6] 83w In the multivariate logistic regression analysis, also adjusting for covariates significantly associated with dopamine agonist therapy and with DJ (age and HY), dopamine agonist therapy was significantly associated with DJ (odds ratio [OR], 18.1; 95% CI, 3.0-infinity; P ¼ .0002). In the multivariate logistic regression analysis, also adjusting for covariates associated with dopamine agonist therapy and with VH (age, HY, dementia, PD duration, levodopa, and rasagiline), dopamine agonist therapy was not significantly associated with VH (OR, 0.73; 95% CI, 0.49-1.10; P ¼ .133).

[1] 247w Several case reports have been published on DJ in PD, [5][6][7]11,12,14 and 2 retrospective database surveys identified 6 DJ cases in 116 PD patients (5.2%) 8 and 6 DJ cases in 563 nondemented PD patients (1.1%). 13 The present study is the first large crosssectional survey investigating DJ in PD patients. DJ and VH resulted in distinct psychotic phenomena in PD: DJ was associated with younger age, lower HY, and dopamine agonist therapy, and its low prevalence (2.48% in the whole PD sample, 5.0% in patients treated with dopamine agonists) suggests that probably only subjects with predisposing individual factors develop DJ when treated with dopamine agonists; VHs had a higher prevalence (23.98%), as previously reported, 31 and were associated with clinical features of PD progression (higher HY and disease duration, dementia, levodopa treatment), confirming that disease-related factors play an important role in the genesis of PD-associated VH. 17 DJ appeared independent of VH, given that only 2 of 20 patients with DJ presented also VH; however, this lack of relationship could be because, at the time of screening, patients with VHs but not patients with DJ were more frequently taking atypical neuroleptics and dopamine agonists had been reduced in dose or withdrawn. Pramipexole and ropinirole were similarly represented in our database of 805 PD patients and in patients with DJ (11 pramipexole, 8 ropinirole), suggesting these dopamine agonists are associated with a similar risk of psychosis induction. No other nondopaminergic drugs were associated with DJ and VH.

[2] 88w Strengths of this study are the cross-sectional methodology, differing from the retrospective methodology of previous studies, 8,13 and the large sample of PD patients. This study has several limitations. First, the clinical setting (tertiary neurological unit) may not have been representative of the whole PD population. Second, there was an absence of investigation of other delusions. And, finally, as patients may not have revealed their concerns about their partners' sexual unfaithfulness, this assessment procedure could have produced underdetection of DJ in cognitively preserved patients who were interviewed directly.

[3] 111w In conclusion, the current study suggests that dopamine agonists play an important role in DJ development in PD; therefore, DJ probably represents another behavioral nonmotor side effect of dopamine agonists. Nondemented patients and their partners are often ashamed of DJ and consider it unrelated to antiparkinsonian therapy, resulting in difficult and late diagnoses; therefore, although our results showed low DJ prevalence in PD, patients and their families probably should be warned about this uncommon but significant potential medication complication, as for impulse control disorders, and the management of medicated PD patients should include the evaluation of clinical characteristics potentially relevant to the prevention or early recognition of DJ or other delusions.

[1] 102w We enrolled 805 consecutive patients who attended our movement disorder outpatient clinic between January 2009 and June 2010 and fulfilled the research diagnostic criteria for idiopathic PD. 22 We did not include newly diagnosed drug-naive PD patients or patients with clinical signs and neuroimaging findings suggestive of either secondary parkinsonism or primary atypical parkinsonism, such as Lewy body dementia, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Twenty patients declined participation. Informed written consent was obtained in compliance with research standards for human research for all participating institutions and in accordance with the Helsinki Declaration. This study received ethics committee approval.

[2] 151w PD was staged according to Hoehn and Yahr (HY) 23,24 and the Unified Parkinson's Disease Rating Scale (UPDRS). 25 Dementia was established according to DSM-IV-TR criteria. 26 Assessment of DJ and VH was undertaken in 2 ways 27 : in cognitively preserved patients, DJ and VH were investigated using the specific sections of the Parkinson Psychosis Questionnaire 28 ; in demented patients, DJ and VH were investigated by interviewing spouses or caregivers (without the patient nearby) using the specific sections of the Neuropsychiatry Inventory. 29 When DJ was suspected, each patient underwent neurological and psychiatric assessment, and DJ was diagnosed according to DSM-IV-TR criteria. 26 In the whole sample, in addition to dopaminergic therapies, therapies with rasagiline, amantadine, anticholinergics, SSRIs, and benzodiazepines were recorded. Among patients with DJ and/or VH, therapy with atypical neuroleptics was also recorded. Blood chemistry tests and EEGs were carried out to exclude other causes of psychosis.

[3] 131w At baseline, differences in demographic and clinical features between subgroups (with and without DJ, with and without VH, with and without dopamineagonist treatment) were evaluated using Fisher's exact test for categorical variables and the nonparametric unpaired Wilcoxon test for continuous variables. A multivariate analysis by multiple logistic regression was performed to compare psychotic disorders (DJ and VH) in the 2 treatment subgroups (with and without dopamine-agonist treatment) adjusting for covariates. Covariates related to both the variable of interest (DJ or VH) and dopaminergic treatment were included in the model. For DJ, exact logistic regression 30 was used. Significance was assessed by the likelihood ratio test, and 95% profile likelihood confidence intervals (CIs) were computed. A 2-sided P value < .05 was considered statistically significant. Statistical analyses were performed using SAS software.

[1] 191w Delusional jealousy (DJ), also defined as Othello's syndrome, is a content-specific delusion characterized by a range of irrational thoughts and emotions, together with associated unacceptable or extreme behavior, in which the dominant theme is a preoccupation with a partner's sexual unfaithfulness based on unfounded evidence. 1,2 DJ has been described in neurological patients, especially those with right hemispheric stroke 3 and those with neurodegenerative disorders, including Alzheimer's disease, 4,5 frontotemporal dementia, 5 Lewy body dementia, 5 and Parkinson's disease (PD). [5][6][7][8][9][10][11][12][13][14] In patients with PD, psychotic disorders may be present from the early stages, 15,16 with an estimated cumulative lifetime prevalence of 40%-60%. 17,18 Hallucinations are the most common of these [16][17][18] ; delusions are uncommon in cognitively preserved PD patients 19,20 and are present in about 4%-5% of demented patients, often representing a deterioration of hallucinations. 17,18,21 Although DJ has been described in PD patients on dopaminergic therapy, 8,10,13,14 the role of dopaminergic therapy on DJ has not been fully established. We performed a cross-sectional study on DJ in PD to investigate its association with dopaminergic therapies compared with another psychotic disorder such as visual hallucinations (VHs) and its prevalence.