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Managing depression in Parkinson’s patients: risk factors and clinical pearls
Rachel Biemiller1 & Irene Hegeman Richard*,1 Practice points
Depression & Parkinson’s disease ●●
Depressed mood is a stronger indicator than anhedonia for depression.
Apathy may be a core feature of Parkinson’s disease (PD) and does not necessarily indicate depression.
Negative emotions are more likely to indicate depression than apathy.
PD symptoms and depression symptoms can be similar.
Mood symptoms can fluctuate with motor symptoms.
Depression and anxiety frequently overlap.
Use an inclusive approach.
Evaluate in the ‘on’ state.
Get input from care partner.
Use depressed mood as a core symptom.
Use a rating scale to screen for depression or to rate severity of depressive symptoms.
Pramipexole – use if mood fluctuates with motor symptoms.
Tricyclic antidepressants – effective but poorly tolerated due to side effects.
Selective serotonin/noreinephrine reuptake inhibitors – currently first line therapy.
Use cognitive behavioral therapy alone or in addition to pharmacotherapy.
Future research needs ●●
A better understanding of the role of anxiety in depression in PD is needed.
More research into treatment options for refractory depression and anxiety.
The role of surgical and other non-pharmacologic interventions should be further investigated.
University of Rochester, Rochester, NY, USA *Author for correspondence: Tel.: +1 585 341 7500; Fax: +1 585 276 1870; [email protected]
10.2217/NMT.14.31 © 2014 Future Medicine Ltd
Neurodegen. Dis. Manage. (2014) 4(4), 329–336
Review Biemiller & Richard Practice points (cont.)
Conclusion & future perspective ●●
dPD can be difficult to recognize and diagnose and the use of screening tools and diagnostic guidelines is suggested.
We now have some evidence on which to base treatment decisions in dPD but additional treatment studies are needed.
Our understanding of anxiety in PD and its role in the recognition and treatment of dPD is evolving but requires more study.
Further research involving DBS may help us understand the pathophysiology of and inform adaptations for its use as a treatment for dPD.
SUMMARY Parkinson’s disease (PD) is a neurodegenerative condition that is on the rise as the world’s population ages. As our understanding of the disease increases, depression has emerged as a common syndrome in this population that significantly reduces quality of life, making its understanding, recognition and treatment an important area of focus for clinicians and researchers alike. It is hypothesized that depression is a consequence of the disease process itself, sometimes developing prior to the onset of motor symptoms. Many of the diagnostic tools and treatments for depression have not been fully evaluated in the PD population. However, several traditional diagnostic interviews and depression rating scales have been used in recent clinical trials. These study results suggest that some of the currently available antidepressant medications may be effective and well tolerated in this population. This paper reviews our understanding of depression in PD as well as the current recommendations for its diagnosis and treatment. KEYWORDS
• antidepressants • depression • diagnosis • Parkinson’s disease • treatment
Parkinson’s disease (PD) is a neurodegenerative process, which typically affects older adults. Over the next few decades, this population is expected to increase. A study by Dorsey estimates that the prevalence of PD in the top 15 most populated nations will reach 8.7–9.3 million by 2030. This number is more than double the prevalence in 2005, which was 4.1–4.6 million  . Researchers and clinicians continue efforts to better understand the risk factors, biological underpinnings and manifestations of PD while simultaneously attempting to develop markers of disease progression, novel approaches to potential disease modification and refinement of existing symptomatic therapies. One area of increased focus that merits further attention is the diagnosis and treatment of depression. Depression has been associated with a decrease in quality of life and poorer outcomes in the PD population  and has even been associated with worsening motor symptoms, including gait dysfunction  . This review addresses depression in PD and includes a discussion of risk factors, diagnosis and treatment strategies. Depression & PD Depression in PD (dPD) affects roughly 52% of patients with PD. The majority of individuals
Neurodegen. Dis. Manage. (2014) 4(4)
suffer from minor depression (22%) with major depression (17%) and dysthymia (13%) composing the remainder of the depressed population  . Dysfunction of dopamine, norepinephrine and serotonin have all been implicated as etiologic factors causing or contributing to depression in PD. Immunological and neurotrophic hypotheses have also been suggested  . However, not all patients with PD develop depression. One study from Leentjens  evaluated risk factors for depression in PD patients by examining nonspecific and PD-specific risk factors for depression. The most important nonspecific risk factors identified were age, gender, a personal history of depression and the presence of comorbid illnesses These depression risk factors are well established in the general population [6,7] . PD-specific risk factors for depression include the need for levodopa, increasing disease duration and higher Unified Parkinson’s Disease Rating Scale motor scores. Though the PD specific risk factors had a significant role in causing depression in the individual, the non-specific risk factors had a much larger overall effect. Despite the prevalence of dPD, it remains difficult to diagnose. Distinguishing between symptoms of depression and symptoms of PD is the first challenge and has likely contributed to
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Managing depression in Parkinson’s patients: risk factors & clinical pearls an under diagnosis of dPD. Slowness, difficulty concentrating, fatigue and sleep disturbances are common symptoms of depression but they are also frequently seen in PD patients without depression  . While further exploring the nature of the symptom can sometimes provide insights, it often remains difficult to determine if it can be attributed to depression. For example, REM sleep behavior disorder is common in PD and unlikely to be due to depression  . However, frequent awakening could be due to depression. Nocturia, restless leg syndrome, difficulty turning over in bed or a combination of these and other factors can contribute to poor sleep in PD as well [10–12] . While impaired sexual function may be related to depression, PD-associated autonomic impairment may cause erectile dysfunction  . Therefore, the presence or absence of these symptoms in and of themselves cannot be used to make a diagnosis of depression in a patient with PD. Generally, a diagnosis of depression requires either the presence of depressed mood or loss of interest or pleasure (anhedonia). In dPD, the presence of depressed mood is the most reliable indicator of a depressive disorder  . This is because apathy (loss of interest and decreased motivation), while sometimes seen in the context of depression, may also occur as a core feature of PD  . Furthermore, some research suggests that anhedonia (the loss of pleasure derived from activities previously enjoyed) may be less common in dPD  . Another challenge to diagnosing dPD is the frequent presence of motor and non-motor fluctuations in patients with advancing PD who have been treated with dopaminergic medications. Many patients experience fluctuations in their motor state related to plasma (and therefore brain) levels of dopamine. When their medication is working well, their PD symptoms are effectively treated. This is referred to as the ‘on’ state. However, as the disease progresses, the mobility they derive from the levodopa may be associated with dyskinesia (excessive, involuntary movements). This state is referred to as ‘on with dyskinesias’. As the levodopa levels decrease, patients may experience a gradual reemergence of their PD symptoms, referred to as ‘wearing off’, and when patients have virtually no effect from their medications, they are considered to be in the ‘off’ state, during which they may even be rendered immobile. In addition to these motor fluctuations, patients may also experience non-motor fluctuations, which can include autonomic and sensory symptoms as well
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as changes in mood, frequently characterized by dysphoria and anxiety. One study found that two-thirds of subjects had depressed mood only in their ‘off’ state  . Those with a very high Beck Depression Inventory (BDI) score were more likely to have depression in both the ‘on’ and ‘off’ states but the severity of the depressed mood was worse during the ‘off’ period  . Another facet of depression in PD is the role of anxiety. A review of the literature reveals that anxiety and depression can occur together 67–76% of the time  . This poses a challenge since patients with depression and anxiety may be less likely to respond to treatment than those with depression alone  . Therefore, recognition of anxiety is important as more aggressive treatment may be required. Anxiety disorders in PD may be different than those outlined in the DSM-IV. One study examined symptoms of anxiety and depression in patients with PD and found four groups. They have been described as: 1) neither anxious nor depressed, 2) episodic anxiety only, 3) persistent anxiety and depression and 4) persistent plus episodic anxiety with depression. Episodic anxiety was described as occurrence of panic attacks and increased rates of specific phobias. The most common phobias were social and agoraphobia. Persistent anxiety was found to be similar to a generalized anxiety disorder, which tended to have a higher correlation with depression  . Investigations are underway to improve diagnosis of anxiety in this population but this has been difficult. Not only has the DSM-IV criteria been found to be unreliable for the diagnosis of anxiety disorders in PD but it also appears that the most commonly used anxiety rating scales (Beck Anxiety Inventory, Hamilton Anxiety Rating Scale and the Hospital Anxiety and Depression Scale – Anxiety subscale) may not adequately assess anxiety in PD  . Anxiety in PD is clearly an area which merits further research and has direct relevance to the understanding of dPD. Diagnosis It appears as though depression in PD has been under recognized. In one study, movement disorder neurologists with more than 10 years of experience were asked to diagnose depression in patients with new onset PD, without using screening instruments or rating scales. Though their diagnosis based on clinical judgment had a high level of specificity, sensitivity was only 33%  , further emphasizing how difficult it is for
Review Biemiller & Richard clinicians to distinguish dPD from the general PD population. The National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke recognized these difficulties and published four basic recommendations to use when diagnosing dPD. First, it is best to interview and examine the patient while he is in the ‘on’ state. This limits the effects of motor and mood fluctuations related to levodopa levels, which could affect both the patient-reported history and the exam. Second, one should count all symptoms when scoring depression regardless whether they are thought to be due to the depression or the underlying PD (referred to as the ‘inclusive approach’). This prevents confusion in scoring and reliance on assumptions, leading to a more consistent approach. The third recommendation is to use depressed mood rather than loss of interest or pleasure as a ‘core’ symptom of a depressive disorder. As mentioned before, apathy and anhedonia (markedly decreased interest or pleasure in activities) are not reliable indicators of depression in PD. Fourth, to ascertain the cognitive abilities of patients, it is important to ask the opinion of another individual who knows the patient well. This becomes more important as patients begin to develop cognitive decline and may not accurately report their symptoms  . These guidelines should be used in conjunction with a depression rating scale for improved accuracy. Selecting a rating scale for depression in PD can be a daunting task as there are multiple scales from which to choose. Both the American Academy of Neurology and the Movement Disorders Society (MDS) commissioned task forces to examine depression rating scales in PD. Both agreed that the BDI and the Hamilton Depression Rating Scale (HAM-D) had the most evidence for diagnosing dPD. Many scales had varying degrees of utility and others could
not be recommended due to lack of data [23,24] . More recently Neurology published an article comparing nine commonly used scales, as shown in Table 1. This study revealed that, while all of the above scales, except the Unified Parkinson’s Disease Rating Scale Part 1, had some diagnostic utility, the 30-Item Geriatric Depression Scale (GDS-30) was the most useful in the clinical setting. Though the BDI was very similar to the GDS-30 in regard to accuracy, the GDS-30 was shorter and has no copyright  . Treatment The challenge does not end after recognition and diagnosis of depression as there are several approaches toward its treatment. If patients experience depressed mood solely related to the ‘wearing off’ phenomenon, adjusting PD medications to smooth fluctuations may suffice. This may include addition of a dopamine agonist  . There is evidence to support the notion that dopamine agonists, in particular pramipexole, may have antidepressant efficacy above and beyond their ability to improve fluctuations  . This led the MDS to recommend its use in their 2011 task force review  . An antidepressant is indicated for the treatment of a depressive disorder (characterized by pervasive depressed mood and other associated symptoms). Several studies of antidepressant medications have had inconclusive results or demonstrated marginal successes, but most have had small sample sizes. In 2012, Richard et al.  published results from the SAD-PD trial using paroxetine, a selective serotonin reuptake inhibitor (SSRI), and venlafaxine extended release, a serotonin norepinephrine reuptake inhibitor (SNRI), for dPD management. This was a multi-center, double-blind, randomized and placebo-controlled study. Prior studies had
Table 1. Depression rating scales commonly used in Parkinson’s disease. Self-administered
BDI CESD-R GDS-30 IDS-SR PHQ-9 UPDRS-I
HAM-D IDS-C MADRS
BDI: Beck Depression Inventory; CESD-R: Center for Epidemiologic Studies Depression Rating Scale-Revised; GDS-30: 30-Item Geriatric Depression Scale; HAM-D: 17 Item Hamilton Depression Rating Scale; IDS-C: Inventory of Depressive Symptoms-Clinician; IDS-SR: Inventory of Depressive Symptoms-Patient; MADRS: Montgomery-Asberg Depression Rating Scale; PHQ-9: Patient Health Questionnaire 9; UPDRS-I: Unified Parkinson’s Disease Rating Scale Part 1. Data taken from .
Neurodegen. Dis. Manage. (2014) 4(4)
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Managing depression in Parkinson’s patients: risk factors & clinical pearls suggested that tricyclic antidepressants (TCAs) were effective, perhaps more so than the SSRIs [30,31] . There had been no large-scale studies of the newer SNRI antidepressants. There had also been concerns that SSRIs may worsen parkinsonian motor function. The SAD-PD trial demonstrated that paroxetine and venflaxine were each more effective than placebo when comparing change in mean HAM-D scores after 12 weeks of treatment. However, when comparing the percentage of responders (subjects achieving at least 50% reduction in HAM-D score) and remitters (subjects achieving a final HAM-D score