The present study assessed the impact of anxiety disorder subtypes on HS in PD. We report a novel and selective association between fluctuation-associated anxiety, a non-DSM `PD-specific' anxiety subtype, and HS. Other anxiety subtypes were not independently associated with HS after multivariate adjustment. Diagnosis of depression, younger age, ADL disability, bradykinesia and dyskinesia were also associated with poorer HS.
Anxiety presenting as a feature of non-motor fluctuations is recognized as a specific clinical problem, but its management remains ambiguous. Up to 66% of patients with PD and motor fluctuations experience anxiety.[18
] While temporal correlates of anxiety, motor fluctuations, and dosing of dopaminergic medications have been examined,[26
] fluctuation-associated anxiety as a discrete psychiatric disturbance that warrants specific treatment has been overlooked. One reason may be that non-motor fluctuations are regarded as a primary function of dopaminergic therapy, and therefore fall under the purview of neurological management. Another reason, however, may be that the current DSM nosological system fails to capture PD-specific psychiatric disturbances. This is clinically significant because long-term levodopa treatment almost inevitably leads to motor and non-motor fluctuations. In our sample, for example, anxiety disorders were associated with a longer duration of PD, and the group with fluctuation-associated anxiety had the longest duration of PD. Although subjects with fluctuation-associated anxiety were on significantly higher doses of l-dopa, total daily l-dopa equivalent dose[19
] did not contribute to group differences in the final regression model. Failure to find this group effect was unexpected given the central role of l-dopa on fluctuations. While anxiety and mood fluctuations are related to measured l-dopa plasma levels, these effects may depend more on the rate of increase in l-dopa than the total dose; the experience of anxiety fluctuations may follow a different temporal pattern unrelated to l-dopa plasma levels.[27
The basis for a selective relationship between fluctuation-associated anxiety and HS, as measured by the PDQ-8, is unclear. While the combined group of anxiety disorders in our series was associated with worse HS relative to subjects without anxiety diagnoses, the small number of patients in individual anxiety subgroups may have prevented detection of HS differences. Compared to non-anxious PD subjects, we found that the group with fluctuation-associated anxiety had a higher proportion of women, a younger age onset and longer duration of PD, a higher daily l-dopa dose, and greater dopaminergic complications of therapy. The PDQ-8 asks subjects to rate how often in the last month they have experienced certain problems “due to having Parkinson's disease.” While the small sample size precludes conduction of an item analysis of the PDQ-8, the close association between motor symptoms and problems listed on the PDQ-8, e.g., muscle spasms, difficulties communicating, or social embarrassment, may contribute to higher scores in patients with motor fluctuations. For episodic anxiety disorders, in which anxiety symptoms are not directly linked to PD symptoms, correspondence to a PD-specific HS scale may be less likely. The presence of the fluctuation-associated anxiety subtype and its impact on HS in PD may also reflect a contribution of motor fluctuation severity that is not captured by the current version of UPDRS Part-IV.
Similar to other studies, we found that a depressive diagnosis, bradykinesia, dyskinesia, and disability correlated with poorer HS in PD.[1
] At the time of the interview, 47% of the total sample had a depressive diagnosis, which was independently correlated with worse HS. Although co-morbid anxiety and depression were common in our sample (55%), the interaction between these disorders was not associated with lower HS in the multivariate model. Other psychiatric disorders including psychosis were also unassociated with HS in the model. The association between younger age and poorer HS is consistent with previous studies.[28
] Younger patients tend to report worse HS, even after accounting for disease severity, suggesting that the impact of PD on HS is moderated in part by independent psychosocial factors.[28
The selective relationship between fluctuation associated-anxiety and HS raises an important consideration for clinical trials. In clinical trials that assess HS as an outcome, particularly those evaluating motor therapies for patients with advanced PD, anxiety and depressive disorders are likely to contribute independently to the HS measure, in addition to the effects of the primary motor intervention, e.g., deep brain stimulation. In clinical settings, recognizing effects of anxiety fluctuations on emotional, social, and physical functioning may encourage multidisciplinary approaches to management of these disabling phenomena, as opposed to a limited focus on medication manipulations to reduce motor fluctuations. Cognitive-behavioral therapy, for example, effectively reduces anxiety and depressive symptoms, and may be an important adjunctive treatment to consider when patients present with motor and non-motor fluctuations.[29
] However, it is also important to recognize that other anxiety subtypes, including other subgroups of the Anxiety Disorder NOS classification, are not less important because of an absence of a discrete relationship with HS. By definition, diagnosis of a psychiatric disorder requires the presence of clinically significant distress or disability as a result of symptoms.
Our data suggest that the PDQ-8 is a useful outcome measure for HS in studies that include patients with non-motor anxiety fluctuations. Although the term HS has been used synonymously with “quality of life”, HS can be distinguished by its focus on the perceived impact of PD on functioning rather than an assessment of the subject's internal experiences and level of life satisfaction despite the burdens of the disease.[1
] Whether the selective association with HS would be limited to fluctuation-associated anxiety using other HS or quality of life scales has not been examined. A number of PD-specific and generic HS and quality of life measures are available, and the choice of instruments should be based on the goals of the study.[30
] The measurement of anxiety and depressive symptoms within the PDQ-8 and other HS instruments introduces a confound in any analysis that investigates the relationship between affective disturbances and HS.[4
] In the case of the PDQ-8, two of eight items overlap directly with DSM-IV-TR criteria for Major Depression: “Felt depressed” and “Had problems with your concentration.”[31
] It is therefore not surprising that the PDQ-8 and the diagnosis of DSM-IVTR depression are highly correlated because the same clinical symptoms are assessed. The high rate of co-morbidity between anxiety, depression, and other PD-related symptoms may account for the bivariate associations between panic disorder and social phobia with lower HS in .
Another limitation to this study is the absence of validated criteria for defining non-DSM `PD-specific' anxiety disorders. This may make replication of our findings difficult. To account for this and improve diagnostic accuracy, we used previously reported descriptions of fluctuation-associated anxiety and `panic-like' anxiety to improve generalizability[17
] and best-estimate diagnostic procedures that included an expert panel to determine all clinically significant psychiatric disturbances. In addition, previous work on the prevalence of neuropsychiatric symptoms using cluster analysis with the Neuropsychiatric Inventory in non-demented PD patients identified a subgroup of patients with medium-high scores on anxiety and medium-low scores on depression with low scores on most other symptoms.[32
] This “anxiety“ cluster identified by Kulisevsky et al appears to share many of the same characteristics found in the anxiety subgroups identified in this study, supporting the assertion that this may be a valid clinical entity.
In summary, fluctuation-associated anxiety in PD is a significant predictor of lower HS, as measured by the PDQ-8. The heterogeneity of anxiety disorders and their high co-morbidity with depressive diagnoses must be accounted for when interpreting HS data from subjects with PD. The selective association of fluctuation-associated anxiety with HS suggests that it is a distinct clinical subtype of anxiety disorders that is specific to PD and warrants future research on its etiology, treatment, and contribution to HS outcomes when motor aspects of PD are the main focus of therapeutic interventions.