Cognitive behavioural therapy for anxiety disorders in Parkinson's disease: Design of a randomised controlled trial to assess clinical effectiveness and changes in cerebral connectivity.

BACKGROUND: Anxiety disorders occur in up to 35% of patients with Parkinson's disease (PD) and have a negative effect on motor symptoms and quality of life. To date, no clinical trials specifically targeting anxiety in PD patients have been published. OBJECTIVE: To describe the rationale and methodology of a randomised controlled trial (RCT) that aims to study the clinical effectiveness, alterations in brain circuitry, and cost-effectiveness of cognitive behavioural therapy (CBT) for anxiety in PD. METHODS: This study is a prospective, two-centre RCT in which sixty PD patients with anxiety will be randomised to CBT treatment and clinical monitoring (intervention group) or to clinical monitoring only (control group). The CBT module used in this study was specifically developed to address symptoms of anxiety in PD patients. Participants will undergo standardised clinical, cognitive and behavioural assessment at baseline and at 2 follow-up measurements, as well as resting-state fMRI and DTI scanning before and after the intervention. The primary outcome measure is changes in severity of anxiety symptoms. Secondary outcome measures involve long-term changes in anxiety symptoms, changes in functional and structural connectivity between limbic and frontal cortices, and cost-effectiveness of the treatment. The study is registered at the ClinicalTrials.gov database under registration number NCT02648737. CONCLUSION: This study is the first that evaluates both the clinical effectiveness, cost-effectiveness, as well as the biological impact of CBT for anxiety in PD patients that, if proven effective, will hopefully contribute to a better and evidence-based approach for these non-motor symptoms.

Clinical Markers of Anxiety Subtypes in Parkinson Disease.

OBJECTIVE: The aim of this work was to investigate marker profiles for proposed anxiety subtypes in Parkinson disease (PD). METHODS: We used the persistent anxiety, episodic anxiety, and avoidance behavior subscales of the Parkinson Anxiety Scale as dependent variables in multivariable linear regression analyses using a cross-sectional data set of 311 patients with PD. Independent variables consisted of a range of demographic, psychiatric, and disease-specific markers. RESULTS: In the most parsimonious model of persistent anxiety, higher Hamilton Depression Rating Scale scores, a history of anxiety, fewer years of education, lower Mini-Mental State Examination scores, lower Lawton Instrumental Activities of Daily Living scores, female sex, and complications of therapy (higher Unified Parkinson Disease Rating Scale part IV scores) were all associated with more severe persistent anxiety. Markers associated with more severe episodic anxiety included PD-specific disturbances of activities of daily living, complications of therapy, higher Hamilton Depression Rating Scale scores, female sex, and a history of anxiety. Finally, higher Hamilton Depression Rating Scale scores, a history of anxiety, complications of therapy, and longer disease duration were associated with avoidance behavior. After excluding clinically depressed patients with PD, disease severity and longer disease duration were significantly associated with episodic anxiety, but not with persistent anxiety. CONCLUSION: Persistent anxiety is mainly influenced by nonspecific markers, while episodic anxiety seems to be more PD-specific compared to persistent anxiety and may be more situational or contextual. These results provide support for possible distinct underlying constructs for anxiety subtypes in PD.

Functional connectivity disruptions correlate with cognitive phenotypes in Parkinson's disease.

Cognitive deficits in Parkinson's disease are thought to be related to altered functional brain connectivity. To date, cognitive-related changes in Parkinson's disease have never been explored with dense-EEG with the aim of establishing a relationship between the degree of cognitive impairment, on the one hand, and alterations in the functional connectivity of brain networks, on the other hand. This study was aimed at identifying altered brain networks associated with cognitive phenotypes in Parkinson's disease using dense-EEG data recorded during rest with eyes closed. Three groups of Parkinson's disease patients (N = 124) with different cognitive phenotypes coming from a data-driven cluster analysis, were studied: G1) cognitively intact patients (63), G2) patients with mild cognitive deficits (46) and G3) patients with severe cognitive deficits (15). Functional brain networks were identified using a dense-EEG source connectivity method. Pairwise functional connectivity was computed for 68 brain regions in different EEG frequency bands. Network statistics were assessed at both global (network topology) and local (inter-regional connections) level. Results revealed progressive disruptions in functional connectivity between the three patient groups, typically in the alpha band. Differences between G1 and G2 (p < 0.001, corrected using permutation test) were mainly frontotemporal alterations. A statistically significant correlation (ρ = 0.49, p < 0.001) was also obtained between a proposed network-based index and the patients' cognitive score. Global properties of network topology in patients were relatively intact. These findings indicate that functional connectivity decreases with the worsening of cognitive performance and loss of frontotemporal connectivity may be a promising neuromarker of cognitive impairment in Parkinson's disease.

Factor analysis of the Hamilton Depression Rating Scale in Parkinson's disease.

INTRODUCTION: Several studies have validated the Hamilton Depression Rating Scale (HAMD) in patients with Parkinson's disease (PD), and reported adequate reliability and construct validity. However, the factorial validity of the HAMD has not yet been investigated. The aim of our analysis was to explore the factor structure of the HAMD in a large sample of PD patients. METHODS: A principal component analysis of the 17-item HAMD was performed on data of 341 PD patients, available from a previous cross sectional study on anxiety. An eigenvalue ≥1 was used to determine the number of factors. Factor loadings ≥0.4 in combination with oblique rotations were used to identify which variables made up the factors. Kaiser-Meyer-Olkin measure (KMO), Cronbach's alpha, Bartlett's test, communality, percentage of non-redundant residuals and the component correlation matrix were computed to assess factor validity. RESULTS: KMO verified the sample's adequacy for factor analysis and Cronbach's alpha indicated a good internal consistency of the total scale. Six factors had eigenvalues ≥1 and together explained 59.19% of the variance. The number of items per factor varied from 1 to 6. Inter-item correlations within each component were low. There was a high percentage of non-redundant residuals and low communality. CONCLUSION: This analysis demonstrates that the factorial validity of the HAMD in PD is unsatisfactory. This implies that the scale is not appropriate for studying specific symptom domains of depression based on factorial structure in a PD population.

Severity of depression and anxiety are predictors of response to antidepressant treatment in Parkinson's disease.

BACKGROUND: Antidepressants have appeared to be more effective than placebo treatment in treating depressive syndromes in patients with Parkinson's disease (PD). OBJECTIVE: To identify factors that predict improvement in depressive symptoms during antidepressant treatment in depressed PD patients. METHODS: A secondary analysis was performed on the dataset of the Randomized Placebo-controlled Study of Antidepressants in PD (SAD-PD), in which 76 patients received active treatment with either paroxetine or venlafaxine extended release (XR), and 39 patients received placebo treatment. Backward stepwise regression analyses were conducted with change in 24-item Hamilton Depression Rating Scale (HAMD-24) score between assessments at baseline and week 12 as the main outcome measure, and sex, age, baseline HAMD-24 score, Unified Parkinson's Disease Rating Scale section III (UPDRS-III) score, Mini-Mental State Examination (MMSE), and the Clinical Anxiety Scale (CAS) as independent variables. RESULTS: In both the active treatment and placebo groups, higher baseline HAMD-24 score and lower UPDRS-III score were associated with greater reduction in HAMD-24 score. Higher anxiety scores predicted less response in the active treatment group. Higher MMSE scores predicted greater response only in the placebo-treated group. Sex and age were no predictors of response. CONCLUSIONS: Higher pre-treatment depression scores and lower pre-treatment anxiety scores are the two most important predictors for improvement during antidepressant treatment in depressed PD patients, which is in line with those found in treatment studies of depressed non-PD patients. Furthermore, our results indicate the requirement for different or more intensive treatment for depressed PD patients with more severe anxiety symptoms.