REVIEW
Biba R Stanton,1 Alan Carson2
1
Department of Neurology, Royal
Free Hospital, London, UK
Departments of Clinical
Neurosciences and Rehabilitation
Medicine, NHS Lothian, and
Centre for Clinical Brain Studies,
University of Edinburgh,
Edinburgh, UK
2
Correspondence to
Dr Biba R Stanton, Department
of Neurology, Royal Free
Hospital, Pond St, London,
NW3 2QG, UK;
biba.stanton@nhs.net
Accepted 20 September 2015
Published Online First
27 October 2015
ABSTRACT
Apathy is an under-recognised and
underestimated problem for people with chronic
neurological disorders. Despite being common
and disabling, it is seldom volunteered as a
symptom by patients or even their caregivers.
Yet apathy undoubtedly has an important impact
on caregiver stress, functional disability and
quality of life. A detailed clinical assessment can
distinguish apathy from depression and allow
clinicians to make practical suggestions to reduce
the impact of symptoms on individual patients
and their families. Pharmacological approaches
to treatment include cholinesterase inhibitors,
dopamine agonists and stimulants.
CASE 1
To cite: Stanton BR,
Carson A. Pract Neurol
2016;16:42–47.
42
A 66-year-old man with progressive supranuclear palsy returned to clinic for review.
His wife was upset and finding it difficult
to cope. She described him as ‘completely
lazy’, as he just sat in his chair all day
watching television, even though he could
still do things for himself. She felt that he
could not be bothered to speak to her
anymore because he was ‘obsessed with
TV’. He did not seem to engage with the
visits to the grandchildren that she
arranged. He said that he felt fine apart
from the problems with his walking.
The neurologist was confident that the
patient was not depressed, and that the
wife’s concerns reflected the apathy that is
often very pronounced in progressive
supranuclear palsy. By explaining to the
man’s wife that these problems were due
to his disease, their relationship improved
and she felt more able to cope with caring
for him.
CASE 2
A 75-year-old man attended clinic with his
wife. She had worried about him for over a
year, as he had become increasingly withdrawn. He used to enjoy going to the local
pub but now stayed at home all day. He
seemed less concerned about his personal
appearance, about which he used to be
meticulous. More recently, she had noticed
that he had become forgetful. On examination, he had a mild episodic memory
deficit but no impairments in other
domains.
He was diagnosed with mild cognitive
impairment but the presence of apathy
suggested a high risk of him developing
Alzheimer’s disease. He did not improve
with a trial of antidepressant treatment but
had useful input from an occupational
therapist. His apathy improved after he
started a cholinesterase inhibitor a year
later, when his cognitive symptoms had
progressed.
INTRODUCTION
The term apathy derives from the Greek
‘pathos’, meaning passions. Apathy as
used by the stoic philosophers referred to
a desirable state of ascendancy of reason
over unwanted emotional influence
(figure 1). In common use today, apathy
means lack of interest, enthusiasm,
concern or emotion and can refer to an
aspect of normal experience. The clinical
syndrome of apathy refers to a disorder
of goal-directed behaviour, manifesting as
reduced motivation compared with a previous level of functioning.1
APATHY IS COMMON
The reported prevalence of apathy in different disorders inevitably depends on
Stanton BR, Carson A. Pract Neurol 2016;16:42–47. doi:10.1136/practneurol-2015-001232
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Apathy: a practical guide for
neurologists
REVIEW
Parkinson’s disease
Progressive supranuclear palsy
Stroke
Alzheimer’s disease
Mild cognitive impairment
Frontotemporal dementia
Traumatic brain injury
20–30%2
80%3
40%4
50%5
30%6
up to 90%7
50%8
Apathy generally becomes more common with
more severe disease9 but can also be a very early
symptom; apathy in the context of mild cognitive
impairment suggests an increased risk of developing
Alzheimer’s disease.6
THE IMPACT OF APATHY ON PATIENTS AND
CAREGIVERS
Patients themselves are rarely distressed by apathy: by
definition, apathy is associated with lack of insight
and lack of concern about symptoms. Despite this, it
has a major impact on quality of life.10 More importantly, perhaps, there is good evidence that caregivers
find apathy distressing. Carers of patients with traumatic brain injury rate lack of motivation as one of
the three most distressing problems.11 In dementia,
apathy significantly predicts carer burden, even after
controlling for functional disability and caregiver
depression.12 Apathy also increases patients’ functional disability because they fail to engage in activities
that they could otherwise perform and need prompting to structure their daily life.13 It also presents a
major barrier to engagement in rehabilitative activities. The negative impact of apathy on activities of
daily living is likely to result in increased healthcare
costs and need for care.14
DEFINING AND ASSESSING APATHY
Current psychiatric classifications do not define
apathy as an independent disorder but rather as a
symptom; The International Classification of Diseases
10th Revision (ICD-10) does not mention it at all.
The psychologists Robert Marin and Sergio Starkstein
have done much to raise awareness of apathy as a clinical problem and to define it more rigorously for the
purpose of research. Current criteria define apathy as
reduced motivation, with symptoms in at least two of
three domains of:
▸ reduced initiative (lack of effort, dependency on others
to structure activity);
▸ reduced interest (lack of interest in learning new things
or in new experiences, lack of concern about one’s personal problems);
▸ reduced emotional responsiveness (unchanging affect,
lack of emotional responsivity to positive or negative
events).15
Patients typically have poor insight into the symptoms, not recognising them at all or not perceiving
them as problematic. Despite the burden it causes,
caregivers may not volunteer apathy as a problem,
because they often perceive the patient’s behaviour as
laziness, or as an inevitable response to their illness,
rather than a core part of the disease. It is therefore
important to ask specific questions of carers to detect
apathy symptoms as part of the routine assessment in
any chronic neurological condition (box 1).
Box 1 Questions to ask of carers to detect apathy
Figure 1 Zeno of Citium (334–262 BC) was the founder of
the Stoic school of philosophy and taught that the ‘pathe’
(emotions and passions) should be extirpated.
Stanton BR, Carson A. Pract Neurol 2016;16:42–47. doi:10.1136/practneurol-2015-001232
▸ Does he seem more passive or withdrawn?
▸ Do you need to prompt or encourage her to get
started with things?
▸ Has he lost interest in things that he used to enjoy?
▸ Does she seem less emotional than she used to be?
43
Pract Neurol: first published as 10.1136/practneurol-2015-001232 on 26 October 2015. Downloaded from http://pn.bmj.com/ on 15 July 2018 by guest. Protected by copyright.
how it is defined and what population is assessed. The
summary of evidence from different studies suggests
the following rates of clinically important apathy
symptoms in neurology clinic patients:
REVIEW
THE RELATIONSHIP BETWEEN APATHY AND
DEPRESSION
The symptoms of depression, as defined in ICD-10,
include loss of interest and diminished activity in addition to low mood. However, the experience of anhedonia in depression (the inability to perceive pleasure)
is characterised, even among those who describe it as
an ‘emptiness’, as a highly negative affective experience. This contrasts with the neutral experience of
apathy, which is essentially an emotionally deficit
state. There is good evidence that while depression
and apathy sometimes occur together in neurological
disorders, they can also be present independently:
depression without apathy is common in Parkinson’s
disease, whereas apathy without depression is
common in progressive supranuclear palsy.19 Scores
on apathy and depression rating scales correlate modestly because of the overlap in symptoms included,20
but dysphoria and apathy do not correlate at all.21
This distinction is not always clear cut and perhaps
some older people who meet criteria for a depressive
illness might be better classified as apathetic (eg, due
to small vessel disease). Alexopoulos described a
group of older patients with ‘depression’ who have
prominent apathy, little agitation or guilt, marked
executive dysfunction, white matter disease on
imaging, and a poor response to antidepressant
treatment.22
In practical terms, it is crucial to consider underlying depression in any patient with apathy symptoms
because depression is more amenable to treatment. It
is essential to obtain a history from the caregiver as
well as from the patient. Table 1 suggests some useful
clues, from our clinical experience, to distinguish
between apathy and depression in a patient with lack
of interest or motivation.
44
Table 1 Clinical features suggesting apathy versus depression
Suggesting apathy
Suggesting depression
▸ Reduced experience of negative
as well as positive emotions
▸ Marked executive dysfunction
on cognitive testing
▸ ‘Frontal release’ signs, such as
grasp reflex or utilisation
behaviour
▸ Lack of concern about
symptoms
▸ Displaying an emotional
emptiness
▸ Feeling sad, tearful or guilty
▸ A sense of hopelessness about
the future
▸ Agitation
▸ Diurnal variation in mood
▸ Negative cognitive bias (seeing
the ‘bad or upsetting’ in
everything)
▸ Feeling an emotional emptiness
NOSOLOGY OF APATHY
The nosological position of apathy is complicated by
the use of other terms to describe similar clinical features. The concept of negative symptoms in schizophrenia overlaps with definitions of apathy in
neurological disorders. Negative symptoms include:
▸ avolition (equivalent to the behavioural domain of
apathy)
▸ alogia (poverty of speech, which may be another behavioural aspect of apathy)
▸ asociality (which overlaps with lack of interest as
described in apathy)
▸ affective flattening (similar to the emotional domain of
apathy)
▸ anhedonia (a more specific lack of pleasure, not part of
definitions of apathy)
The phenomenology of negative symptoms in
schizophrenia has not been directly compared with
that of apathy in neurological disorders, but the
general view is that they represent a degenerative cognitive component to the illness23 and it seems likely
that there will be considerable overlap in the neurobiological substrate. The term abulia has been used
interchangeably with the term apathy, or to describe
particularly severe impairment of initiation of purposeful behaviour in the context of organic brain
disease.
WHAT CAUSES APATHY?
Although apathy can occur across a wide range of
neurological disorders, the common factor in all of
these is damage either to the frontal lobes or to the
subcortical structures. Focal brain lesions in the
frontal lobes, thalamus or basal ganglia can be sufficient to cause apathy, consistent with the role of these
brain regions in normal goal-directed behaviour and
emotional processing. Studies using structural brain
imaging in clinical groups to explore the neuroanatomical correlates of apathy report an association with
volume loss in regions including the frontal pole, orbitofrontal cortex, insula, anterior cingulate cortex, and
dorsolateral prefrontal cortex (figure 2).24 Different
apathy symptoms (reduced initiative and emotional
blunting) may be associated with distinct patterns of
Stanton BR, Carson A. Pract Neurol 2016;16:42–47. doi:10.1136/practneurol-2015-001232
Pract Neurol: first published as 10.1136/practneurol-2015-001232 on 26 October 2015. Downloaded from http://pn.bmj.com/ on 15 July 2018 by guest. Protected by copyright.
To some extent, apathy can be the understandable
result of physical or cognitive limitations: patients
with neurological disorders may lose interest or
pleasure in things they used to enjoy because of difficulties in walking, speech, memory or concentration.
Yet there is a psychopathological aspect to the
absence of emotion in apathy that separates it from
this mournful withdrawal as part of an illness
response. There is good evidence that patients with
neurological disorders have much more prominent
apathy than equally disabled patients with nonneurological conditions.16
Apathy can be more formally assessed and quantified using several different rating scales. It is included
in broader assessments of behavioural symptoms, such
as the Neuropsychiatric Inventory,17 and can be
assessed in more detail with instruments such as the
Apathy Evaluation Scale.18 Clinician-rated or carerrated scales are usually more reliable than self-report
questionnaires, because apathy is usually accompanied
by a lack of insight.
REVIEW
Figure 2 Differences in regional grey matter volume between
patients with and without apathy in Alzheimer’s disease and
progressive supranuclear palsy. Red clusters show reduced grey
matter volume in the cingulate gyrus and insula in apathetic
patients (adapted from Stanton et al25).
frontal atrophy.25 Many studies have used Single
Photon Emission Computed Tomography (SPECT) or
Positron Emission Tomography (PET) to examine the
relationship between apathy and regional brain blood
flow/metabolism. In Alzheimer’s disease, the anterior
cingulate cortex and orbitofrontal cortex appear most
consistently associated with apathy (figure 3).26
The brain regions implicated by these studies map
well on to the ‘salience network’, a group of functionally linked brain regions thought to be crucial in motivation and readiness to act.27 Functional connectivity in
the salience network, studied with resting state functional MRI, is reduced in elderly depressed patients
with high apathy, compared with those without.28
MANAGEMENT OF APATHY
The first step in managing apathy is to recognise it.
‘Has he become more passive or withdrawn?’ is a
useful single screening question to ask a carer. If
the answer is yes, then it is helpful to explore
symptoms in more detail with the following questions
in mind:
If there is any suspicion of depression, a trial of an
antidepressant is indicated but medication should be
stopped if it is ineffective. There is some evidence that
selective serotonin-reuptake inhibitors, which can
cause extrapyramidal side effects, may actually worsen
apathy symptoms.29 In theory, there might be a rationale for selecting a more ‘activating’ antidepressant
(such as reboxetine or venlafaxine) but there is no evidence base for this.
It is important to address any other reversible problems that could aggravate apathy symptoms, including visual or hearing impairment, motor or cognitive
symptoms and medications. In particular, antidopaminergic drugs can certainly worsen apathy and should
be stopped where possible.
Should patients with apathy be encouraged to
greater levels of activity, or should caregivers allow
patients to withdraw if they choose? This question can
only be answered for an individual, with an understanding of their particular psychosocial context.
In some families, the main problem is the caregiver’s
frustration with a patient’s behaviour. In this situation,
explaining that apathy is a symptom of their illness and
caused by a problem in the brain is a surprisingly useful
intervention.30 Caregivers may find it upsetting to see
their loved one more passive or withdrawn, but actually find apathetic behaviour easy to manage. Open discussion and reassurance from the patients themselves
that they are not distressed may be all that is required
in this situation. For others, the need for continuous
prompting and their increasingly limited activities may
have a hugely negative impact on daily life. Box 2 suggests some simple strategies that a couple or family
might use to minimise the impact of apathy symptoms.
For patients with dementia in nursing homes, there
is some evidence for interventions designed to
‘increase the reward potential of the environment’.
A randomised controlled trial of ‘activity therapy’ for
Figure 3 Reduced metabolism in the anterior cingulate and medial orbitofrontal cortex in apathetic patients compared with
non-apathetic patients with Alzheimer’s disease (adapted from Marshall et al26).
Stanton BR, Carson A. Pract Neurol 2016;16:42–47. doi:10.1136/practneurol-2015-001232
45
Pract Neurol: first published as 10.1136/practneurol-2015-001232 on 26 October 2015. Downloaded from http://pn.bmj.com/ on 15 July 2018 by guest. Protected by copyright.
▸ Are the symptoms out of proportion to what might be
expected in someone with these physical symptoms or
disability?
▸ Does the patient have awareness of the symptoms?
▸ Could there be significant depression?
▸ What specific problems are causing distress for that individual or family?
REVIEW
▸ Create a regular daily routine with more varied activities but fewer choices for the patient to make
▸ Use frequent prompts to remind the patient start
activities: these could be set as alarms on a mobile
phone rather than always having to come verbally
from a carer
▸ Get out of the house every day, even if only to the
local shops
▸ If motor or cognitive symptoms limit participation in
previous interests, think carefully about how these
could be adapted with advice from an occupational
therapist
▸ Encourage caregivers to take up regular respite care
without guilt
Key points
apathy showed improvements in apathy with activity
therapy and with the control intervention (one-to-one
meetings with a therapist to give the same time and
attention).31 A small controlled study of ‘validation
therapy’ (designed to improve communication with
patients with dementia) showed that this could
improve apathy.32 Specialised cognitive rehabilitative
approaches, for instance to enhance attention or performance speed, may help some people although
there is no evidence for this approach.
There are many pharmacological strategies suggested for managing apathy.
In dementia, a meta-analysis suggested that cholinesterase inhibitors modestly benefited neuropsychiatric
symptoms (as a secondary end point33). In a randomised study of 30 patients with Parkinson’s disease
who were apathetic but free of depression and dementia, rivastigmine significantly improved apathy.34.
Small open-label studies of cholinesterase inhibitors
for apathy following traumatic brain injury have also
suggested some benefits.35
Dopamine is the other neurotransmitter often implicated in apathy symptoms. Apathy can occur early in
Parkinson’s disease, and can worsen with antidopaminergic drugs.36 Patients with idiopathic Parkinson’s disease
and motor fluctuations may be more apathetic in their
‘off ’ state. Patients with Parkinson’s disease may become
apathetic following deep brain stimulation surgery when
their levodopa dose is reduced, and this may improve
with dopamine agonist treatment.37 Pramipexole may be
particularly useful because of its selective affinity for D3
dopamine receptors.38 There are two case reports of
success in using dopamine agonists for apathy following
stroke.39 40 There are also case reports of amantadine
(with effects on dopamine and glutamate41), buproprion
(a norepinephrine and dopamine reuptake inhibitor42)
and selegiline (a monoamine oxidase inhibitor43) for
apathy symptoms.
46
▸ Apathy is very common in patients with stroke, brain
injury and neurodegenerative disorders and has a
huge impact on caregiver distress.
▸ A useful screening question to ask caregivers is
whether the patient seems more passive or
withdrawn.
▸ Always assess whether the patient may be depressed,
as this may be more amenable to treatment.
▸ Education about apathy and suggestions of practical
strategies to reduce its impact on daily life can
greatly help patients and families.
Correction notice This paper has been corrected since it was
published Online First. Figure 2 has been corrected.
Contributors BRS drafted the article. AC provided comments
and helped to make revisions.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer
reviewed. This paper was reviewed by Masud Husain, Oxford,
UK.
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