Apathy is a common non-motor symptom in Parkinson’s disease (PD), but is often under-recognized. Apathy is defined as a lack of motivation characterized by reduced emotional expression and diminished goal-oriented behavior. The prevalence of apathy differs greatly between studies, most likely due to diverse population characteristics and the instruments used to assess apathy. Apathy has negative implications for the quality of life of patients and the long-term outcome. In addition, apathy contributes significantly to caregiver burden. Therefore, recognition and understanding of apathy is crucial for the treatment and care of patients with PD. In this blog, we invited Dr. Javier Pagonabarraga and Dr. Tanya Harlow to discuss key clinical aspects of the presentation and treatment of apathy in PD.
What is the relationship between apathy and depression in PD?
The extended limbic system including hippocampal and parahippocampal cortices, and the executive areas of the lateral prefrontal cortex help to store and manipulate perceived emotions, generating more complex feelings and mood states that influence new incoming stimuli and experiences. Through different regions of the anterior cingulate cortex (ACC), the constant flow of past and incoming information within the amygdala and ventral striatum (nucleus accumbens and anteromedial striatal territories) is transferred to the medial and lateral prefrontal cortex, and finally to motor preparatory areas (SMA, PMC). Considering all these intricate complex functional circuits, apathy, defined as a state of diminished goal-directed behaviors, can be the consequence of either executive dysfunction, depressive mood state or reward deficiency syndrome.
In patients with depression, the feelings of sadness, hopelessness, or the increased presence of negative ruminations, negative automatic thoughts, or recurrent negative emotions have been directly linked to increased activity of the subgenual ACC (sgACC) and decreased activity in lateral prefrontal regions. In these patients, the frequent concurrence of apathetic behaviors is more associated with decreased activity in medial prefrontal regions and decreased excitability of nucleus accumbens (NAcc) and other regions of the limbic system. This functional dissociation is much more evident in some neurodegenerative diseases such as Parkinson’s disease (PD), progressive supranuclear palsy (PSP), Huntington disease (HD) or frontotemporal dementia (FTD). When symptoms related to sadness and hopelessness are explored along with symptoms of decreased motivation or reward-induced experience, it is possible to diagnose patients with depression and associated apathetic symptoms, or patients with isolated apathy and no depressive feelings or thoughts.
Isolated apathy without depression is common in PD, and it is the most frequent mood disorder in PSP, HD and FTD patients. The clinical differentiation between these two nosological entities is crucial since potentials treatments differ. While serotonin and/or norepinephrine reuptake inhibitors improve depression, they are not efficacious in patients with isolated apathy, and selective serotonin reuptake inhibitors may even worsen it. Conversely, isolated apathy (or even apathetic symptoms in patients with depression) can improve with psychostimulants like methylphenidate or dopamine agonists, although formal studies are needed to measure the clinical impact of these drugs in patients with neurodegenerative diseases.
How to differentiate apathy from depression in PD?
Differentiation of apathy from depression is mainly based on a well-structured clinical interview. The diagnosis of depression is based on the presence of cognitive and emotional symptoms of depression, while the diagnosis of apathy (associated with or independent from depression) will be based on the presence of diminished activities, interests, and emotions. While the emotional symptoms of depression are characterized by the enhancement of negative thoughts, beliefs and emotions, apathy refers to a state of decreased self-generated activities as a consequence of decreased rewarding experiences, which is verbally explained as a spontaneous reduction of interests. It is noteworthy that while in depression patients are able to explain sadness as the source of their inactivity, apathetic patients are no longer able to understand which is the origin of that progressive development of decreased interest in the world around them.
Apathetic symptoms to consider in the clinical interview include reduced initiative, decreased participation in external activities (unless engaged by another person), loss of interest in social events or everyday activities, decreased interest in starting new activities, emotional indifference, diminished emotional reactivity, less affection than usual, or lack of concern for others’ feelings or interests. The emotional and cognitive symptoms of depression include an increase or enhancement of sadness, feelings of guilt, recurrent (and even involuntary intrusion of) negative thoughts and/or feelings, helplessness, hopelessness, pessimism, self-criticism, anxiety, and even suicidal ideation. If the patient manifests apathetic symptoms but depressive symptoms are absent, a diagnosis of isolated apathy (associated with reward deficiency syndrome) can be established.
A more practical approach is the use of validated scales for depression or apathy. In the field of neurodegenerative diseases, it has been useful to select scales in which the number of items assessing somatic symptoms is less important. The Starkstein Apathy Scale (SAS) and the Lille Apathy Rating Scale (LARS) are useful for both the screening and assessment of severity of apathy in neurological disorders. Depression can be accurately screened and measured by the Montgomery–Åsberg Depression Rating Scale, Geriatric Depression Scale, and the Hospital Anxiety and Depression scale, although other scales, such as the Hamilton Depression Scale and the Beck Depression Inventory have also been validated in different neurological disorders.
Pagonabarraga J, Kulisevsky J, Antonio P Strafella AP, Krack P. Apathy in Parkinson’s disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol 2015;14:518–31.
Starkstein SE, Brockman S. The neuroimaging basis of apathy: Empirical findings and conceptual challenges. Neuropsychologia. 2018;118:48-53.
Dujardin K, Sockeel P, Devos D, Delliaux M, Krystkowiak P, Destée A, Defebvre L. Characteristics of apathy in Parkinson's disease. Mov Disord. 2007;22(6):778-84.
Does apathy affect cognitive function in PD?
It is challenging to study the independent effect of apathy on cognitive function because apathy often coexist with cognitive dysfunction (such as dementia) and depression. Apathy is more prevalent in PD patients with depression or cognitive impairment. For the PD population in general, apathy is present in about 40% of patients. However, apathy is present only in approximately 22% of the patients who do not have coexisting depression or cognitive impairment. Apathy is associated with lower MMSE scores (den Brok et al., 2015).
A meta-analytical study (D’Iorio et al, 2018) demonstrated that there was a strong association between “pure apathy” (PD patients with apathy but without depression or dementia) and cognitive dysfunctions, particularly deficits of memory and executive functions. To minimize the confounding effects of depression or dementia on cognitive status, this meta-analysis only used eight studies that excluded PD patients with depression or dementia. The study explored the cognitive correlates of pure apathy, which included the following outcomes: global cognitive function, memory, executive functions, processing speed/attention/working memory, visuospatial abilities and language. Results demonstrated a strong association between “pure apathy” and cognitive dysfunction, particularly regarding deficit of memory and executive function, which are related to altered prefronto-subcortical circuits. Unfortunately, the authors did not address if PD patients with mild cognitive impairment (MCI) were included in those eight studies used in the meta-analysis.
Apathy by itself, without the presence of MCI, does not affect cognitive performance. Costa et al. (2018) showed that in a PD group without MCI, the severity of apathy did not impact cognitive performance. By contrast, in a PD group with MCI, the AES (Apathy Evaluation Scale) scores correlated with the scores of executive tests, especially in relation to planning and abstract reasoning. These findings suggest that there is a specific association between apathy severity and reduced efficiency of the executive function in individuals with PD and MCI. The authors did not address if the study subjects had coexisting depression.
D’Iorio A, Maggi G, Vitale C, Trojano L, Santangelo G. “Pure apathy” and cognitive dysfunctions in Parkinson’s disease: A meta-analytic study. Neurosci Biobehav Rev. 2018;94:1-10.
den Brok MG, van Dalen JW, van Gool WA, Moll van Charante EP, de Bie RM, Richard E. Apathy in Parkinson's disease: A systematic review and meta-analysis. Mov Disord. 2015;30(6):759-69.
Costa A, Peppe A, Zabberoni S et al. Apathy in individuals with Parkinson's disease associated with mild cognitive impairment. A neuropsychological investigation. Neuropsychologia 2018; 118: 4–11.
How can we treat apathy?
Currently, there are no approved treatments for apathy. Apathy has traditionally been very difficult to treat in patients with Parkinson’s disease (PD). However, apathy was one of the four most important determinants of health-related quality of life in a recent study by Skorvanek et al. It has also been found to cause greater impairment in the patient’s ability to perform activities of daily living, and greater caregiver burden (see Leiknes et al., 2010, and Leroi et al.,2012). This indicates that treatment for apathy may result in improvement of quality of life for both the patient and caregiver.
Randomized clinical trials (RCTs) demonstrate that dopaminergic agents and cholinesterase inhibitors may improve apathy in PD. In several RCTs, the dopamine agonist rotigotine improved apathy, Piribedil, a D2 and D3 receptor agonist, improved the apathy developed after deep brain stimulation, and methylphenidate, a dopamine and norepinephrine reuptake inhibitor, improved apathy as well. Rivastigmine, an acetylcholinesterase inhibitor, tested also in RCTs improved apathy in PD (Liu et al.,2019).
Treating patients with apathy and coexisting depression requires special consideration. Apathy can be associated with depression, and treatment of the associated condition can sometimes help to improve apathy. There is some evidence to suggest that patients may have more apathy when depression is treated with selective serotonin reuptake inhibitors (SSRIs) (Zahondne et al.,2012), possibly indicating that treatment with a more activating antidepressant such as venlafaxine or bupropion may provide more benefit.
There has also been some consideration that treatment may vary depending on the subtypes of apathy. Three subtypes of apathy have been proposed: emotional-affective (motivation), cognitive (planning), and auto-activation (initiation) (see Levy and Dubois). For patients with both the emotional-affective and the auto-activation subtypes, treatment with dopaminergic agents may provide more benefit. For the cognitive subtype, acetylcholinesterase inhibitors may provide more benefit (Pagonabarraga et al.,2015).
A better design of clinical trials using a common, validated scale of apathy is necessary to assess apathy treatments in the future. One of the main problems in previous RCTs was that different scales were used to measure apathy (Liu et al.,2019). While further studies are needed, one could certainly consider treating apathy in PD with a dopaminergic agent or an acetylcholinesterase inhibitor in appropriate clinical settings. In patients with depression on SSRIs, a switch to a different class of antidepressants may be warranted.
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Leiknes I, Tysnes OB, Aarsland D, Larsen JP. Caregiver distress associated with neuropsychiatric problems in patients with early Parkinson’s disease: the Norwegian ParkWest study, Acta Neurol. Scan. 2010; 122 (6): 418-424
I. Leroi, V. Harbishettar, M. Andrews, K. McDonald, E.J. Byrne, A. Burns, Carer burden in apathy and impulse control disorders in Parkinson’s disease, Int. J. Geriatr. Psychiatr. 2012;27(2):160-166
J. Liu, C.A. Cooper, D. Weintraub, N. Dahodwala, Pharmacologic treatment of apathy in Lewy body disorders: A systematic review, Park. Relat. Disord. 2019;60 (March):14-24
L.B. Zahondne, O. Bernal-Pacheco, D. Bowers, H. Ward, G. Oyama, N. Limotai, et. All, Are selective serotonin reuptake inhibitors associated with greater apathy in Parkinson’s disease? J. Neuropsychiatry Clin. Neurosci. 2012;24 (3):326-330
R. Levy, B. Dubois, Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits, Cerebr. Cortex 2006;16 (7): 916-928
J. Pagonabarraga, J. Kulisevsky, A.P. Strafella, P. Krack, Apathy in Parkinson’s disease: clinical features, neural substrates, diagnosis, and treatment, Lancet Neurol. 2015;14 (5) :518-531