Taking the patient perspective has led to increasing recognition of the importance of depression and other non-motor features in Parkinson’s disease

Twenty years ago, we published a paper examining which of the clinical features of Parkinson’s disease (PD) were most closely associated with patients’ self-reported health-related quality of life (HR-QoL).1 In the early 1990s, the focus of clinical management and treatment trials in PD had been the development of better management options for the motor features and complications of therapy, such as motor fluctuations and dyskinesias. The key target in clinical trials was improvement on the primary outcome measure, the Unified Parkinson’s Disease Rating Scale (UPDRS).2 However, clinical assessment, and in particular clinical trials, almost entirely relied on clinicians’ judgement of severity of disease and its complications. This was a reflection of lack of availability of robust measures to capture patients’ own view, and probably also a different attitude in medicine and society in general, which placed greater emphasis on clinician judgement than on patients’ evaluation. However, in the late 1990s, this had started changing and the development of standardised scales to assess how patients evaluate their own health problems, so-called HR-QoL measures, had recently enabled standardised quantitative assessment of patients’ views. HR-QoL scales made it possible to assess impact on patients’ lives, independent from clinicians' assessments, and to incorporate other aspects of HR-QoL, such as the emotional and social impact of the disease. A HR-QoL specifically for patients with PD had been developed through careful analysis of interviews and validation in patients with PD.3 This allowed assessment of the impact of PD on patients from more than a physical, objective point of view; it also provided the opportunity to assess which aspects of the features of PD have the greatest impact from patients’ perspective. However, no such studies had been published to answer this question.

In the planning of a community-based prevalence study of parkinsonism in UK, which included an in-depth characterisation of patients’ clinical features,4 we therefore took the opportunity to quantitatively assess patients’ own experiences using the newly developed PD-specific HR-QoL scale. In particular, we were interested in how this reflects the importance of individual features of PD, whether motor, non-motor or medication induced, from the patients’ point of view. The study was conducted in a community-based, unselected sample of patients recruited through primary care practices in and around London, many of whom were seen at home. Assessing a large number of individuals, and choosing a representative sample in the community rather than a specialist centre population, allowed us to draw conclusions applicable to the overall population of PD. We studied, for the first time, the areas of greatest impairment of HR-QoL in PD and which of the manifestations of PD impacted the most on their life from the patients’ own point of view. The expectation was that the key determinant of HR-QoL would be the severity of motor function, captured in the UPDRS motor part. However, despite disease severity ranging from mild to severe, motor severity, as assessed on the UPDRS motor part, was not the main contributor to the HR-QoL as evaluated by patients.

The importance of depression

While overall disability was an important factor, the key and overwhelmingly determining feature associated with poorer HR-QoL was the severity of depressive features, as assessed on the Beck Depression Inventory. Depression had been recognised as associated with PD, but was often considered a consequence5 although it had also been suggested as a manifestation of brain dysfunction.6 We now know that, at least in part, it is an integral feature of the disease, and is significantly more common many years before the diagnosis7 8 in people with a later diagnosis of PD than in controls. However, at the time few research studies had been conducted into recognising, treating or understanding depressive features of PD, and relatively little attention was paid to it in clinical practice. The result of our study,1 which demonstrated that depression is closely linked with how patients evaluate their own HR-QoL, over and above their physical impairment, has since been replicated multiple times in other PD populations, spanning different countries, disease stages and research methodologies. This included another study with the same aim, across different countries, published soon after our study9 and a recent study pooling data from 25 centres in 3206 patients.10 Clearly, the presence of other clinical features of PD, particularly when severe, can also be associated with reduced HR-QoL, as examined in studies in different populations (eg, tertiary care, younger age groups or later disease stage), or examining specific aspects such as fatigue, apathy or pain in more detail.10 11 Their improvement, for example, of dyskinesia, can lead to an improvement of HR-QoL.12 However, depression, when measured, has uniformly been shown to be the most robust predictor of HR-QOL scores in virtually all studies when included in the assessment. It may be argued that those with depression are likely to rate their health worse than those who are not but, like in subsequent studies in other conditions such as multiple sclerosis where similarly strong associations between depression and HR-QoL were found 13, this does not negate the importance of alleviating this symptom of PD in order to improve HR-QoL. When the ultimate aim of treatment is improvement of patients’ judgement of quality life, the mechanism of this relationship matters considerably less than it does in studies assessing a ‘hard’ outcome such as a biomarker or clinician-rated outcome.

Subsequent research

Research on depression in PD has proliferated since then, leading to a much greater understanding of its pathophysiology and treatment, and we now recognise this as an integral part of the symptomatology of PD, contributed to by the early pathological changes of PD as well as psychosocial factors. Imaging studies have explored MRI and PET markers of depression in PD,14 the clinical phenomenology of depression in PD has been assessed15 16 and a number of treatment trials for depression in PD have been completed.17 Depression in PD has also been suggested as a predictor of poorer outcome,18 and PD associated with depression has been considered a possible subtype of PD.19 20 Most importantly, especially as depression may not be volunteered spontaneously, we need to recognise its importance in the management of individual patients in clinical practice, as its treatment can improve HR-QoL beyond the treatment of motor features.

Other factors

There is no doubt that other features of PD also contribute to reduced HR-QoL. In keeping with our a priori hypothesis, the other key determining factors in our study were the degree of disability, and the presence of postural impairment, which also emerged as strong predictor of HR-QoL scores. This reflects the well-described morbidity, including risk of injuries, consequent fear of falling and social consequence of falls.21 Furthermore, cognitive impairment, as assessed on the Mini Mental State Examination, was also a key determining factor for reduced HR-QoL. There had been no previous studies on the relationship of cognitive impairment with HR-QoL in PD, and the importance of this relationship was not clear at the time, but has been replicated in several studies since then.22 Our study and subsequent ones in different populations have helped bring into more focus the importance of cognitive impairment, even in those who do not have dementia. Perhaps most importantly, the recognition that non-motor features, such as depression and cognitive impairment, may be more important to patients’ evaluation of the impact of their disease than pure motor impairment began to shift the focus in both research and clinical practice from the improvement of motor scores towards a broader view of motor and non-motor symptoms. The assessment and treatment of unmet non-motor symptoms has become a key target in PD research,23 including in many treatment trials.

There remained a proportion of unexplained variation of HR-QoL scores. This was to be expected, given the heterogeneity of the disease and its context between individuals, the multifaceted aspects of an individual’s life that contribute to their evaluation of HR-QoL, and the fact that not all features of PD could be assessed in our study. For example, impulse control disorders associated with dopamine agonists were not yet recognised and we did not specifically assess other aspects of PD such as some autonomic features in detail. Other studies later assessed a range of specific features, for example, impulse control disorders, autonomic features, fatigue or hallucinations and found them also to be associated with reduced quality of life. Although we did not assess psychosocial or healthcare-related factors, nevertheless personal factors, such as level of optimism and experiences of healthcare or how the diagnosis was communicated, have been recognised to be important additional factors.9