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Introduction
Parkinson's disease (PD) stands as the second most prevalent neurodegenerative disorder, affecting millions globally1. Characterized by distinct motor symptoms encompassing bradykinesia, rigidity, and/or resting tremor, PD is accompanied by a wide array of non-motor manifestations2. These encompass cognitive decline, psychiatric conditions, autonomic irregularities, and sleep disturbances, among others3. It is of notable significance that the appearance of psychosis and autonomic dysfunction represents a critical moment in the trajectory of PD, exerting a profound impact on the quality of life for patients and heightening the risks associated with hospitalization, morbidity, and mortality4-6.
Psychosis in PD is reported in approximately 40-60% of patients and may manifest early in the disease course7, with potential triggers including intrinsic disease pathophysiology, PD medications, or as part of non-motor fluctuations8. Various risk factors for psychosis in PD patients have been identified, encompassing prior medical history, both dopaminergic and non-dopaminergic medications, disease duration, genetic predispositions, prior psychiatric symptoms, vivid dreams, and cognitive decline9. Autonomic dysfunction occurs in the majority of PD patients at some stage, potentially compromising one or several organ systems including gastrointestinal, cardiovascular, urinary, sexual, thermoregulatory, and pupillomotor functions10. When present, such dysfunction is associated with a more aggressive disease course and an accelerated progression4,11.
It is worth noting that only a limited number of studies have reported a potential association between autonomic disturbances and psychosis in PD12. Despite the lack of consensus regarding the direct correlation between psychosis and autonomic dysfunction in PD, there is an accumulating body of evidence that may inform clinical understanding of their relationship. This observational study investigates the association between autonomic dysfunction and psychosis within a PD patient cohort, aiming to enrich the growing body of evidence on the subject.
Material and methods
We conducted a multicentric observational cross-sectional study to investigate the potential association between autonomic dysfunction and psychosis in PD patients. The study received approval from the appropriate institutional review board. A total of 306 participants were recruited through non-probabilistic convenience sampling from the Mexican Parkinson Study Group cohort, a national database comprising demographic and clinical data of PD patients from various neurological clinics across Mexico. Data collection took place between July 2017 and June 2018. The sample size was determined using convenience sampling, based on patients' attendance at their scheduled appointments during the designated sampling period. All 306 selected subjects were included in the final analysis. The documented demographic data were current age, age at diagnosis, gender, and years of education. The clinical characteristics documented were disease duration, side of initial symptoms, PD motor subtype (based on previously reported classification)13, PD and non-PD medications, and the movement disorders society-unified Parkinsons disease rating scale (MDS-UPDRS)14.
Outcome variables
To determine the presence of symptoms of psychosis as our dependent variable, we used item 1.2 from the MDS-UPDRS. Item 1.2 asks the patient if, over the past week, they have seen, heard, smelled, or felt things that were not really there. For this study, we registered the presence of symptoms if the score was from 1 (slight) to 4 (severe). If the score was 0 (normal), we registered symptoms as not present. To determine the presence of autonomic dysfunction as our independent variable, we used items 1.10 (urinary problems), 1.11 (constipation problems), and 1.12 (orthostatic hypotension) from the MDS-UPDRS. Item 1.10 asks the patient if, over the past week, they have had trouble with urine control; item 1.11 asks the patient if, over the past week, they have had constipation troubles that cause them difficulty moving their bowels; and item 1.12 asks the patient if, over the past week, they have felt faint, dizzy, or foggy when standing up after sitting or lying down. For this study, we registered the presence of symptoms if the score in either item was from 1 (slight) to 4 (severe). If the score was 0 (normal), we registered symptoms as not present.
Statistical analysis
Descriptive statistics were used to report central tendency measures, frequencies, and percentages as required. A KolmogorovSmirnov test was used to verify the assumptions of the distribution of continuous variables. A Chi-square test was used to determine associations between independent categorical variables and dependent categorical variables. We employed a MannWhitney U test to assess associations between independent continuous variables and dependent categorical variables. A multiple logistic regression model was constructed to identify variables that independently explained the presence of the items exploring psychosis in our cohort. The significantly associated variables (p ≤ 0.05) from the univariate analysis were included in the model. The model with less deviance was selected. The IBM Statistical Package for the Social Sciences version 25 was used in the analysis.
Results
Table 1 provides an overview of the sociodemographic and clinical characteristics of our study cohort. In relation to symptoms of psychosis, among the 306 patients analyzed, 55 (18%) reported experiencing symptoms. Within this group, 32 (58.2%) reported slight symptoms, 13 (23.6%) reported mild symptoms, 8 (15.0%) reported moderate symptoms, and 2 (0.04%) reported severe symptoms. Concerning dysautonomic symptoms, a significant number of 229 (74.8%) patients reported experiencing one or a combination of these symptoms, which included orthostatic hypotension, urinary issues, and constipation problems.
Table 1 Sociodemographic and clinical characteristics of our PD cohort
| Study variables | Total | Presence of symptoms of psychosis (n = 55) | Absence of symptoms of psychosis (n = 251) | p-value |
|---|---|---|---|---|
| Male, n (%) | 171 (55.9) | 29 (52.7) | 142 (56.6) | 0.603 |
| Age, years. mean (SD) | 65.29 (11.7) | 67.73 (11.3) | 64.76 (11.8) | 0.110 |
| Education, years. mean (SD) | 10.55 (5.3) | 10.31 (5.0) | 10.61 (5.4) | 0.719 |
| Disease duration, years. mean (SD) | 6.69 (4.8) | 9.31 (5.0) | 6.12 (4.6) | < 0.001 |
| PIGD motor subtype, n (%) | 160 (52.3) | 37 (67.3) | 123 (49.0) | 0.048 |
| Cognitive impairment, n (%) | 134 (43.8) | 37 (67.3) | 97 (38.6) | < 0.001 |
| Depression, n (%) | 177 (57.8) | 39 (70.9) | 138 (55.0) | 0.030 |
| Anxiety, n (%) | 123 (40.2) | 32 (58.2) | 91 (36.3) | 0.003 |
| Apathy, n (%) | 53 (17.3) | 21 (38.2) | 32 (12.7) | < 0.001 |
| Sleep problems, n (%) | 166 (54.2) | 33 (60.0) | 133 (53.0) | 0.344 |
| Daytime sleepiness, n (%) | 150 (49.0) | 31 (56.4) | 119 (47.4) | 0.229 |
| Pain, n (%) | 151 (49.3) | 30 (54.5) | 121 (48.2) | 0.394 |
| Urinary problems, n (%) | 173 (56.5) | 37 (67.3) | 136 (54.2) | 0.076 |
| Constipation, n (%) | 161 (52.6) | 32 (19.9) | 129 (51.4) | 0.361 |
| Orthostatic symptoms, n (%) | 78 (25.5) | 24 (43.6) | 54 (21.5) | 0.001 |
| Fatigue, n (%) | 178 (58.2) | 30 (54.5) | 148 (59.0) | 0.547 |
| Freezing of gait, n (%) | 55 (18.0) | 17 (30.9) | 38 (15.1) | 0.006 |
| MDS-UPDRS part I, mean (SD) | 8.13 (6.2) | 13.65 (8.3) | 6.92 (4.9) | < 0.001 |
| MDS-UPDRS part II, mean (SD) | 5.32 (5.7) | 6.78 (7.6) | 5.0 (5.2) | 0.037 |
| MDS-UPDRS part III, mean (SD) | 35.92 (15.7) | 41.64 (19.8) | 34.67 (14.4) | 0.003 |
| MDS-UPDRS part VI, mean (SD) | 2.74 (4.0) | 4.25 (4.7) | 2.4 (3.8) | 0.002 |
| Hoehn and Yahr stage I-II, n (%) | 281 (91.8) | 44 (80.0) | 237 (94.4) | < 0.001 |
| LEED, mean (SD) | 741.45 (479.9) | 809.25 (484.8) | 726.59 (478.6) | 0.216 |
PIGD: postural instability with gait difficulty; MDS-UPDRS: movement disorders society-unified Parkinson's disease rating scale; LEED: levodopa equivalent daily dosage.
The bivariate analysis revealed that the presence of urinary and constipation problems was not significantly associated with the presence of symptoms of psychosis (p = 0.076 and p = 0.361, respectively). The presence of orthostatic hypotension on standing was significantly associated with the presence of symptoms of psychosis (p = 0.001, OR 2.82, 95% CI 1.53-5.21). These results suggest that symptoms of orthostatic hypotension on standing but not urinary or constipation problems may affect the presence of symptoms of psychosis.
Other variables in the bivariate analysis found to be significantly associated with the presence of symptoms of psychosis were postural instability and gait difficulty motor subtype (p = 0.048, OR = 2.14, 95% CI 1.15-3.96), Hoehn and Yahr (HY) IV-V stage (p < 0.001, OR = 4.23, 95% CI 1.80-9.92), presence of symptoms of cognitive impairment (p < 0.001, OR 3.26, 95% CI 1.76-6.05), depression (p = 0.030, OR 1.99, 95% CI 1.06-3.76), anxiety (p = 0.003, OR 2.45, 95% CI 1.35-4.43), apathy (p < 0.001, OR 4.23, 95% CI 2.19-8.17), freezing of gait (p = 0.006, OR 2.51, 95% CI 1.29-4.89), disease duration (p < 0.001, d = 0.67), MDS-UPDRS part I (p < 0.001, d = 0.99), part II (p = 0.037, d = 0.27), part III (p = 0.003, d = 0.40), part IV (p = 0.002, d = 0.43), and the total score (p < 0.001, d = 0.70). These results suggest that other non-motor symptoms, such as cognitive impairment, depression, anxiety, and apathy, as well as PD motor subtype, HY stage, disease duration, and motor severity, may affect the presence of symptoms of psychosis.
A regression model was constructed to identify variables that independently predict the presence of symptoms of psychosis. Those patients with the presence of apathy (p = 0.003, ß 2.99), cognitive impairment (p = 0.012, ß 2.33), and longer disease duration (p = 0.001, ß 1.10) were more likely to present symptoms of psychosis, as shown in table 2. The presence of orthostatic hypotension was not a significant independent predictor of symptoms of psychosis in our regression model (p = 0.052, ß 1.95). The results of the model suggest that non-motor symptoms of cognitive impairment and apathy, and disease duration best predicted the presence of symptoms of psychosis in our cohort.
Table 2 Logistic regression model identifying predictors of symptoms of psychosis
| Parameters | ß | SE | Wald | p | Exp (ß) | 95% CI |
|---|---|---|---|---|---|---|
| Constant | −3.17 | 0.37 | - | - | - | - |
| Presence of apathy | 1.09 | 0.37 | 8.78 | 0.003 | 2.99 | 1.45-6.16 |
| Presence of cognitive impairment | 0.85 | 0.34 | 6.36 | 0.012 | 2.33 | 1.21-4.51 |
| Disease duration | 0.10 | 0.03 | 10.38 | 0.001 | 1.10 | 1.04-1.17 |
| Presence of orthostatic hypotension | 0.67 | 0.34 | 3.78 | 0.052 | 1.95 | 1.00-3.83 |
Discussion
We conducted an observational cross-sectional study with the aim of investigating the association between autonomic dysfunction and the presence of symptoms of psychosis among a multicenter cohort of Mexican PD patients. The key findings of this study were as follows: (1) the reported frequency of dysautonomias (74.8%) was higher than that of symptoms of psychosis (18%); (2) patients who reported symptoms of orthostatic hypotension upon standing were 2.82 times more likely to exhibit symptoms of psychosis; and (3) patients presenting symptoms of apathy, cognitive impairment, and longer disease duration were more likely to manifest symptoms of psychosis.
The reported frequency of symptoms of psychosis and dysautonomic symptoms in our study population is consistent with the literature, where the prevalence of psychosis varies from 16% to 75%8, and that of dysautonomia varies from 27% to 87%15, depending on the specific manifestations studied and the criteria or scales utilized. In our study, we employed Part I of the MDS-UPDRS scale, which assesses the presence of certain non-motor symptoms over the past week, potentially influencing the reported frequency.
We observed that PD patients reporting symptoms of orthostatic hypotension on standing were more likely to manifest symptoms of psychosis. This observation is consistent with findings from both a longitudinal study, which noted an increased risk of developing psychosis in the presence of orthostatic hypotension16, and a cross-sectional study that reported a higher risk of psychosis associated with a greater burden of autonomic symptoms17. The association between dysautonomia and psychosis in PD may be explained by the higher density of Lewy bodies found in the brainstem nuclei, such as the dorsal vagal nucleus, of patients with PD who experience visual hallucinations18. Furthermore, the correlation between symptoms of psychosis and autonomic symptoms in PD may not merely be based on their presence but rather on the overall disease burden.
Our study population demonstrated that the symptoms most strongly associated with the presence of symptoms of psychosis were apathy, cognitive impairment, and a longer disease duration. These findings are consistent with prior literature reports. A cross-sectional study found that patients with lower scores on the Frontal Assessment Battery were more likely to develop psychosis at an earlier stage of the disease19. In addition, it has been documented that cognitive impairment or dementia are significant factors related to the presence of psychosis symptoms20. Apathetic symptoms, along with other affective neuropsychiatric disorders, are commonly reported in PD patients with psychosis21. Moreover, patients displaying symptoms of apathy have been linked to lower cognitive levels22. Apathy in PD is associated with not only executive dysfunction but also a decline in overall cognitive function, particularly in tasks related to the temporal lobes, which may contribute to its role as an early indicator of dementia in the disease23. It has also been previously reported that the duration of the disease is associated with the presence of visual hallucinations, typically occurring in the later stages of the disease20. These findings indicate that although there is an association between orthostatic hypotension and psychosis in PD, other non-motor symptoms such as cognitive impairment and apathy, along with disease duration, significantly contribute to the presence of symptoms of psychosis in the cohort. Furthermore, it is important to consider unexplored factors in our study, such as pharmacological treatments, disease severity, and genetics, among others.
Our study has several limitations that should be taken into consideration when interpreting our results. First, it was conducted within a specific cohort of Mexican PD patients, which prompts consideration of the generalizability of our findings to broader populations. Second, certain influential factors, such as pharmacological treatments, and lack of objective evaluation of other non-motor aspects such as sleep, disease severity, and genetic influences, were not included in our study, limiting the comprehensiveness of our results. We should also take into account that some patients may have an alternative cause of synucleinopathy. In addition, our reliance on Part I of the MDS-UPDRS scale, which assesses symptoms over the past week, might have influenced the reported frequency of certain symptoms and could be a limitation. We would like to emphasize the constraints posed by available resources and study design in utilizing more objective measures to assess dysautonomic symptoms, while also highlighting the potential for future investigations to explore the incorporation of specific scales for psychotic symptoms to further enhance the comprehensiveness of our findings. The cross-sectional design of our study restricts our ability to establish causal relationships between variables. There may also be unmeasured confounding factors not accounted for in our analysis. Finally, the use of a specific language and cultural context in our study may introduce biases or limitations related to linguistic and cultural variations in symptom reporting.
Conclusion
Our findings suggest that while orthostatic hypotension is associated with symptoms of psychosis, other non-motor symptoms such as cognitive impairment and apathy, along with disease duration, significantly contribute to the presence of symptoms of psychosis in the cohort. These findings contribute to the body of literature on the complex interplay between non-motor symptoms and psychosis in PD.
