Parkinson's disease (PD) is the second-most common neurodegenerative disorder, with a dramatic increase in prevalence predicted over the next 10 years.1 The cardinal signs of PD are bradykinesia, rigidity, and resting tremor;2 however, non-motor symptoms (NMS) are increasingly being recognized as drivers of PD-related disability.3 NMS include cognitive, sleep, mood, autonomic, and sensory disorders.4 Depression and anxiety, the most common mood disorders in PD, have been associated with higher mortality rates,5 worsening functional status, and impaired cognition.6 The diagnosis and management of mood disorders in this patient population remains challenging, as depression and anxiety can fluctuate with motor states and can be difficult to distinguish from medication-related mood effects.3 This review discusses the prevalence, clinical presentation, diagnosis, and treatment of mood disorders in patients with PD, with a focus on depression and anxiety.
It is estimated that approximately 35% of patients with PD suffer from clinically significant depression, although rates cited in studies vary, likely due to differences in patient populations studied.3 The spectrum of depressive disorders in PD includes major depression, minor depression, and dysthymia, with an estimated prevalence of 17%, 22%, and 13%, respectively.7 Diagnosing depression in patients with PD can be difficult, as it often presents with symptoms such as anhedonia and apathy.3 Additionally, patients frequently underreport symptoms or attribute their depressed mood as a consequence of their PD diagnosis. Despite these challenges, the diagnosis of PD-related depression should be made using the standard criterial found in the International Statistical Classification of Diseases and Related Health Problems, tenth revision (ICD-10)8 and the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)9 for patients without PD.10
The onset of PD-related depression may predate motor symptoms but can also occur in later stages of the disease, where it is often associated with cognitive decline.3,11 Screening for depression in PD is essential, and the screening tools recommended by the American Academy of Neurology are the Hamilton Depression Rating Scale (HAMD-17), Montgomery-Asberg Depression Rating Scale (MADRS), and the Beck Depression Inventory (BDI).12 The Geriatric Depression Scale (GDS), a quick and easy-to-use instrument, was also deemed appropriate for depression screening in patients with PD by the Movement Disorder Society Task Force in 2007.13 Although the HAMD-17 and MADRS scales need to be administered by a health care professional, the BDI and GDS are self-report instruments. Risk factors for depression in PD include presence of sleep disorders, anxiety, autonomic dysfunction, female gender, advanced disease, and cognitive impairment.14 It is important to note that some patients may experience significant worsening of depression after deep brain stimulation surgery, which can often be mitigated by adjusting stimulation parameters.15
Depression in PD has been associated with a number of factors, but no single etiology has been identified. Studies to date have implicated serotonergic, dopaminergic, and noradrenergic systems as playing a role in the pathogenesis of PD-related depression. Evidence supporting the dopaminergic system in the development of PD-related depression has been elucidated from binding assay studies correlating imaging with neuropathology in areas of the brain with higher levels of dopamine, namely the limbic and striatal regions.3 A study by Remy et al.16 compared the binding potential of a [11C]RTI-32 positron-emission tomography (PET) tracer to dopamine transporters (DaT) in different brain regions in patients with PD and found that patients suffering from PD-related depression exhibited decreased uptake in the locus coeruleus and regions of the limbic system when compared to non-depressed patients with PED. In addition, a study performed by Vriend et al.17 demonstrated reduced binding of a [123I]FP-CIT single-photon emission computed tomography (SPECT) tracer to DaT in the caudate nucleus correlated with higher depression severity scores in a sample of 100 patients with PD. On a structural basis, a study using voxel-based morphometry comparing patients with PD with and without depression found white matter tissue loss in dopaminergic areas within the corticolimbic network in patients with depression, demonstrating overlap with regions involved in major depressive disorder.18 In one of the largest studies to date examining risk factors for depression in PD, longer disease duration and higher doses of levodopa, which are markers of increased severity of disease, were shown to correlate with higher depression rates, thus suggesting that pathology of PD plays a role in PD-related depression.19
Research has shown mixed evidence regarding the association of serotonergic system dysfunction and PD-related depression.3 A study measuring the concentration of serotonin, dopamine, and norepinephrine metabolites in the cerebrospinal fluid (CSF) of patients with PD found that CSF levels of 5-HIAA were lowest in patients with PD and major depression.20 In contrast, research by Guttman et al.21 suggested that diffuse loss of serotonin may be a result of PD pathology and not specific for PD-related depression. In this study, patients with PD with depression had significantly reduced binding of a second-generation SERT ligand within the orbitofrontal cortex, caudate, putamen, and midbrain but only a mild, nonsignificant reduction within the dorsolateral prefrontal cortex, which is the area implicated in major depression.21 Furthermore, in a study by Frisina et al.,22 postmortem neuropathology of patients diagnosed with PD-related depression did not demonstrate significant neuropathology in brain areas known to have higher concentrations of serotonin; however, the study found a higher prevalence of neuropathology in catecholaminergic areas, specifically the locus coeruleus, dorsal vagus nerve, and substantia nigra pars compacta. The noradrenaline system has also been implicated in the study by Remy et al.16 that found reduced binding capacity of the [11C]RTI-32 PET tracer in the locus coeruleus in patients with PD-related depression, a region known to send noradrenergic projections to the frontal cortex, amygdala, and ventral striatum. Further research is needed to understand the interplay of factors implicated in PD-related depression and determine differences from endogenous depression.
In terms of treatment interventions, there is a paucity of randomized controlled studies to guide evidence-based pharmacologic management of PD-related depression. In a meta-analysis by Bomasong-Lanyo et al.,23 selective serotonin reuptake inhibitors (SSRIs) were found to have significant efficacy in treating PD-related depression. A prior study by Menza et al.24 comparing paroxetine, nortriptyline, and placebo for 8 weeks in patients with PD with depression found significantly more responders to nortiptyline compared to paroxetine and placebo for primary and secondary outcomes. At this time, not enough data are available to conclusively recommend SSRIs versus tricyclic antidepressants (TCAs) as the first-line medication option for PD-related depression. Studies have also highlighted the effect of dopaminergic agents on PD-related depression. The dopamine agonists pramipexole and transdermal rotigotine demonstrated efficacy in treating depressive symptoms when compared to placebo,25,26 and pramipexole was concluded to be beneficial as a result of a systematic literature review.27
Similar to patients with endogenous depression, patients with PD with depression should be offered adjunctive nonpharmacologic therapy interventions. Early introduction to PD support groups to raise awareness of PD-related depression, identification and treatment of sleep disturbances, regular aerobic exercise, and psychotherapy are important measures to consider in this patient population.28 Studies have shown that physical activity in the form of aerobic training 2 to 3 times per week improves depression, likely mitigated through an increase in the release of beta endorphins and in the availability of serotonin, dopamine, and noradrenaline.29 Cognitive-behavioral therapy (CBT) has also shown significant efficacy in multiple studies, including a meta-analysis that showed a larger effect size of CBT compared to antidepressant therapy in the management of PD-related depression.30 A recent study on bright light therapy in patients with PD-related depression failed to demonstrate greater effectiveness in reducing depressive symptoms, but did find improved subjective sleep quality in the intervention compared to the control group.31
Anxiety is common in PD, with prevalence ranging from 25% to 52% in the literature.10,32 Studies have shown that clinically significant anxiety is more prevalent in patients diagnosed with PD at a young age, those suffering from advanced disease, and in female patients.20 Anxiety in PD patients is often, but not always, associated with concomitant depression. The most common anxiety disorders in PD are generalized anxiety disorder, social phobia, and anxiety disorder not otherwise specified.32
The pathophysiology of PD-related anxiety disorders is likely multifactorial in nature. Several studies have implicated an imbalance in dopaminergic, noradrenergic, and serotonin systems as having a role in anxiety development. One study in an animal model of PD demonstrated that lesioning of the nigrostriatal pathway subsequently caused reductions in dopamine, serotonin, and noradrenaline levels and increased anxiety in rats.33 Furthermore, delivering of alpha-synuclein into the substantia nigra via a viral vector also caused anxiety-like behavior in rats.34 Interestingly, anxiety has also been shown to be present before the onset of motor symptoms of PD, which implies a possible alternative underlying pathology unrelated to the nigrostriatal pathway.3 Additionally, anxiety may occur continuously or episodically with notable worsening during off periods, freezing, and motor fluctuations.28 The worsening of anxiety with motor fluctuations suggests that the pathophysiology involves the neurodegeneration of dopaminergic pathways.32
PD-related anxiety can have variable manifestations, with patients presenting with a wide spectrum of symptoms ranging from generalized anxiety with panic attacks to the development of social phobias.3 Screening for PD-related anxiety is essential for early detection and treatment. Appropriate screening tools include the HAMD-17, the Beck Anxiety Inventory, and the Hospital Anxiety and Depression Scale.28 The Parkinson Anxiety Scale was shown to have higher specificity and sensitivity for detection of PD-related anxiety and may, therefore, be the preferred screening tool in this population.35
Currently, there is limited evidence to guide the pharmacologic management of PD-related anxiety. With a lack of randomized clinical trials looking at anxiety as the primary outcome, initial interventions should include assessment of dopaminergic therapy to reduce off periods and explore additional pharmacologic therapies as a second step.28 SSRIs appear to be well tolerated and may be used as first step for anxiolytic therapy. TCAs are also shown to improve anxiety when compared with placebo, but adverse events are more prevalent than with SSRIs and should be taken into consideration.28 In a 12-week randomized controlled study evaluating the effect of buspirone on PD motor symptoms, buspirone at doses of 10 to 40 mg/day was associated with a slight beneficial effect on the secondary outcome of anxiety. As a caveat, higher daily doses can lead to worsening anxiety and parkinsonism presumably mitigated through stimulation of the central noradrenergic system.36 Of note, benzodiazepines should be used with caution in this population due to an increased risk for falls and confusion.28
Similar to depression, treatment of anxiety in PD should also include nonpharmacologic interventions and address associated factors including sleep disturbances. The gold standard for nonpharmacological treatment of anxiety is CBT. Two randomized controlled studies revealed that CBT was associated with improvement in anxiety symptoms and depression scores in patients with PD when compared to a control group with no intervention.28 Another nonpharmacological intervention holding promise for treatment of anxiety and depression in PD is mindfulness yoga. A randomized controlled trial with 138 patients practicing mindfulness yoga over 8 weeks demonstrated improvements in both motor symptoms as well as a reduction in depression and anxiety compared to stretching and resistance-training exercise.37
Another NMS manifested as a mood disorder is apathy, which is highly prevalent in people with PD (60%).3 Apathy can occur independently from other NMS but is frequently associated with dementia and depression. Several rating scales for apathy in PD have been developed and can be accessed through the International Parkinson and Movement Disorder Society website ( https://www.movementdisorders.org/MDS/MDS-Rating-Scales/MDS-Recommended-Rating-Scales.htm). Both dopaminergic and cholinergic dysfunction have been implicated in the pathophysiology of apathy in PD. Only a limited number of treatment studies for apathy have been conducted. A randomized clinical trial using a dopamine agonist currently not available in the United States (piribedil) at a dose of 300 mg/day led to a reduction in apathy scores at 12 weeks.38 Another study showed a significant improvement in apathy scores with use of rivastigmine.3 The use of stimulants such as methylphenidate has not been sufficiently studied to date to recommend its use for apathy in PD.
Other Mood Disorders
Recent studies have identified a possible association between PD and bipolar disorder (BD). A systematic review and meta-analysis found an increased likelihood of PD in patients with prior diagnosis of BD.39 Although the pathophysiologic mechanism remains unclear, the dopamine dysregulation theory provides a possible connecting link, with upregulation and downregulation of dopamine receptor sensitivity in the manic and depressive phases of BP, respectively, thought to cause an eventual loss of dopaminergic activity. This association implies that patients with BD with parkinsonian features should be carefully assessed for PD rather than presumed to have drug-induced secondary parkinsonism. Most importantly, these studies highlight the need for further research in mood disorders and PD.
Mood disorders are among the most disabling NMS in PD. Screening for depression and anxiety at all stages of PD is crucial for early detection and treatment to improve quality of life for patients and caregivers. Although there are not many randomized, controlled studies to guide treatment for mood disorders in PD, patients can benefit from pharmacologic and nonpharmacologic interventions as used for non–PD-related mood disorders. TCAs and SSRIs are the first-line pharmacologic treatment options for depression in PD, and CBT remains the most studied and effective nonpharmacological therapy in both depression and anxiety. Future research needs to be directed at further identifying the neurobiological substrates of PD-related mood disorders and developing more targeted and effective treatment interventions.
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