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Apathy syndrome in a patient previously treated with selective serotonin reuptake inhibitors for depression

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Apathy syndrome in a patient previously treated with selective serotonin reuptake inhibitors for depression

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There is considerable overlap in the clinical presentations of apathy and depression. However, differential diagnosis between apathy and other psychiatric conditions, including depression and dementia, is important. In this report, we present the case of a 67-year-old woman with a history of receiving selective serotonin reuptake inhibitor (SSRI) treatment for depression. Differential diagnosis between treatment-resistant depression and SSRI-induced apathy syndrome was required. The symptoms of her apathy syndrome were relieved after the discontinuation of SSRIs and the addition of olanzapine, methylphenidate, and modafinil. Furthermore, we briefly review related literature in this article.
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There is considerable overlap in the clinical presentations of apathy and depression. However,
differentiating between apathy and other psychiatric conditions, including depression and de-
mentia, is important. In this report, we present the case of a 67-year-old female with a history
of receiving selective serotonin reuptake inhibitor (SSRI) treatment for depression. Differential
diagnosis between treatment-resistant depression and SSRI-induced apathy syndrome was re-
quired. The symptoms of her apathy syndrome were relieved after the discontinuation of SSRIs
and the addition of olanzapine, methylphenidate, and modafinil. Furthermore, we briefly re-
view related literature in this article.
Keywords: Apathy; Depression; Serotonin reuptake inhibitor
Apathy syndrome in a patient previously treated with
selective serotonin reuptake inhibitors for depression
Hye-Geum Kim, Bon-Hoon Koo, Seung Woo Lee, Eun-Jin Cheon
Department of Psychiatry, Yeungnam University College of Medicine, Daegu, Korea
Introduction
Apathy is a behavioral syndrome characterized by a decrease in
interest, motivation, or initiation of action. Apathy may present in
a similar manner as depression. However, Marin [1] emphasized
the importance of differentiating between apathy and other
psychiatric conditions, including depression, dementia, delirium,
abulia, akinesia, despair, and demoralization. He proposed
the following definition of apathy: a syndrome in which there
is a primary absence of motivation that is not attributable to
cognitive impairment, emotional distress, or diminished level of
consciousness [1]. Many patients with apathy syndrome reported
that “this feeling was unlike the lack of motivation they had
sometimes experienced during prior episodes of depression,” or
that “their feelings of apathy bore no relationship to depression.
One reason for the importance of differentiating apathy
syndrome from depression is that apathy syndrome has been
reported in a number of patients receiving selective serotonin
reuptake inhibitor (SSRI) treatment over the last decade [2].
Case report
eISSN 2384-0293
Yeungnam Univ J Med [Epub ahead of print]
https://doi.org/10.12701/yujm.2019.00150
Received: January 25, 2019
Revised: March 5, 2019
Accepted: March 6, 2019
Corresponding author:
Eun-Jin Cheon
Department of Psychiatry,
Yeungnam University College of
Medicine, 170, Hyeonchung-ro,
Nam-gu, Daegu 42415, Korea
Tel: +82-53-620-3340
Fax: +82-53-629-0256
E-mail: pyejc@ynu.ac.kr
Apathy also serves as a behavioral marker for rapidly progressing
dementia, with a greater decline in cognitive, functional, and
emotional impairment [3]. The presence of apathy is linked
to deficits in the performance of activities of daily living and
a functional decline [4]. Thus, the prompt recognition and
treatment of apathy are crucial [4].
Here, we report the case of a patient who experienced apathy
syndrome that was difficult to differentiate from depression and
dementia. Written informed consent for the publication of this
case report, approved by the institutional review board (YUMC
2017-12-022), was obtained from the patient.
Case
A 67-year-old woman with a remote history of depression
was referred to our clinic due to the presentation of resistant
depressive symptoms despite being treated with multiple
antidepressant drugs, including escitalopram, paroxetine,
duloxetine, and mirtazapine. She was admitted to the psychiatric
1
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clinic for approximately a month with depression diagnosed about
two years previously. Subsequently, her symptoms had improved.
About 3 months previously, she relapsed and was admitted to
the same clinic again, where she received medications including
duloxetine 60 mg, mirtazapine 30 mg, escitalopram 20 mg,
aripiprazole 1 mg, and quetiapine 75 mg for 2 months. However,
her symptoms did not improve with the medication, and she
was referred to our clinic. The depression symptoms included
diminished interest, loss of energy, psychomotor agitation,
weight loss, and insomnia. She reported that she was lethargic
and did not want to do anything but she was not particularly
depressed and had not experienced any increase in stress recently.
She was admitted to our department of psychiatry for accurate
assessment and treatment. The patient received a score of 26 on
the Hamilton Depression Rating Scale. In addition to depressive
symptoms, she had experienced cognitive impairment with
gradual onset. She had a score of 22/30 on the Korean-Mini
Mental State Examination, 1 on the Clinical Dementia Rating,
and 4 on the Global Deterioration Scale. Her cognitive functions,
including memory, executive function, and language function,
were particularly impaired. In a structural brain imaging study, no
degenerative changes other than a small aneurysm and internal
carotid artery stenosis that had already been diagnosed were
observed (Fig. 1). The results of the brain single-photon emission
computed tomography for the evaluation of brain function
indicated reduced perfusion in both anterior cingulate gyri (Fig. 2).
She had no other medical history.
During the evaluation, we prescribed antidepressants such
as fluoxetine 60 mg, venlafaxine 225 mg, mirtazapine 30 mg,
and aripiprazole 5 mg, because the patient’s symptoms for
depression required immediate treatment. She continued to
take the medications for more than a month, but the symptoms
did not improve, and she appeared to be deteriorating. In a
reassessment of the patient's medical history we focused on her
apathy symptoms instead of her depression symptoms. At that
point, the patient was evaluated and received a score of 72 on
the Apathy Evaluation Scale (AES). This 18-item scale assesses
apathy in behavioral, cognitive, and emotional domains over the
previous 4 weeks. Scores range from 18 to 72, with higher scores
indicating greater apathy. Subsequently, we first reduced and then
discontinued all antidepressants, including SSRIs. Olanzapine
and sleeping pills were continued to control her insomnia and
agitation. Subsequently, she became slightly more active but
this change was not sufficient. We prescribed methylphenidate
and gradually increased its dosage to 25 mg. We then added
modafinil 200 mg to her treatment regime. Following these
changes of medication, her score on the AES improved to 35,
and she continued performing her daily activities after discharge.
The drugs she was taking at discharge were: methylphenidate 25
mg, modafinil 200 mg, olanzapine 10 mg, donepezil 10 mg, and
aripiprazole 5 mg. As her activity levels increased a little, her daily
life function improved slightly but her subjective cognitive decline
continued. We will keep track of the changes in her cognitive
function in the future.
Discussion
Apathy is a common behavioral problem that often goes
undiagnosed and untreated [4]. There is considerable overlap in
the clinical presentations of apathy and depression. Furthermore,
apathy may be part of a cluster of negative symptoms in patients
with illnesses such as schizophrenia or Alzheimer’s disease [5].
However, apathy has been demonstrated to relate, independently
of these other psychiatric symptoms, to a variety of outcomes [5].
The presence of apathy is linked to deficits in the performance
of activities of daily living and functional decline and can be of
considerable clinical significance [4].
A common feature of many of the conditions in which apathy
is prominent is the presence of lesions or other abnormalities in
the frontal lobe-subcortical circuitry. Neuroimaging studies of
various clinical populations have reported correlations between
apathy and structural and functional changes within the frontal
Fig. 1. No degenerative changes on T2-flair image. RPF, right
posterior feet.
https://doi.org/10.12701/yujm.2019.00150
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Kim HG et al. Apathy syndrome in a patient previously treated with SSRIs
lobe, particularly the anterior cingulate gyrus and subregions of
the basal ganglia. Neuropsychological studies have reported a
relationship between apathy and poorer performance on tests of
executive functions [6]. Indeed, in the present case, the patient
displayed decreased function of the anterior cingulate gyri as well
as deterioration of executive functions.
A recent case-control study [7] reported that apathy appeared
to be greater in patients who were treated with SSRI than in
patients who were not. Currently, we do not have enough data
to understand how altering of serotonergic signaling might cause
apathy. It is biologically possible that frontal lobe dysfunction,
induced by SSRIs, may be responsible for the apathy [7].
Conditions that can induce frontal lobe dysfunctions are often
caused by imbalances of neurotransmitters in the brain. Prolonged
and excessive serotonin in the synapse may lead to a decrease in
the transmission of dopamine in the frontal lobe. High serotonin
levels may also cause a decrease in acetylcholine which can
induce an increase in dopamine function. A relationship between
serotonin and noradrenaline is another possible mechanism [8].
If SSRI-induced apathy is detected, reduction of SSRI dose or
discontinuation of SSRIs is required. When discontinuation of the
SSRI is not successful, augmentation or switching to a different
class of medications is helpful [2]. Apathy has been emerging as a
target for pharmacotherapeutic interventions, and new trials have
recently been completed [9]. Methylphenidate for the treatment
of apathy has been investigated in double-blind, placebo-
controlled randomized trials (RCTs), and an effect on apathy was
reported [10]. The findings of these studies were consistent with
other findings supporting dopaminergic dysfunction in apathy.
Other catecholamine agonists that can treat the symptoms of
Fig. 2. Mild reduction of perfusion in anterior cingulate gyrus on brain single-photon emission computed tomography.
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https://doi.org/10.12701/yujm.2019.00150
Yeungnam Univ J Med [Epub ahead of print]
apathy include amantadine [11], bromocriptine [12], levodopa
[13], selegiline [14], and bupropion [15]. RCTs have provided
evidence of the efficacy of cholinesterase inhibitors [16] and
memantine [17] in the treatment of apathy in Alzheimer’s
disease. Modafinil is a multimodal stimulant that increases the
activity of histamine, norepinephrine, serotonin, dopamine, and
orexin systems in the brain [18]. Two recent case reports [4,19]
suggested its effectiveness in the treatment of apathy. Additionally,
several studies have investigated the effects of olanzapine on
negative symptoms, including apathy. Apathetic patients with
major depressive disorder may benefit from treatment with
olanzapine. In an open-label study [20] with nonpsychotic, major
depressive disorder patients who were treated with SSRIs and
displayed significant apathy, the addition of olanzapine in the
treatment regime yielded a significant decrease on the AES.
In the present case, the apathy symptoms improved slightly
but the patient continued to experience cognitive impairment.
Apathy is the most common behavioral problem associated
with Alzheimer’s dementia, affecting 70–90% of patients, and
the presence of apathy is linked to deficits in the performance
of activities of daily living and functional decline [4]. In one
study, minor cognitive impairment (MCI) patients with apathy
symptoms, not depressive symptoms, were diagnosed with
Alzheimer’s dementia almost seven times more frequently
than MCI patients without apathy symptoms. Patients with
apathy should keep track of their cognitive function, taking into
consideration the risk of dementia.
The growing body of empirical investigations on the
neurobiology of apathy will likely prove helpful in providing a
sound theoretical basis for the application of currently available
treatments, as well as for the development of novel therapeutic
interventions [5].
Conflicts of interest
No potential conflicts of interest relevant to this article was
reported.
ORCID
Hye-Guem Kim, https://orcid.org/0000-0002-9677-7011
Bon-Hoon Koo, https://orcid.org/0000-0001-9633-3835
Seung Woo Lee, https://orcid.org/0000-0002-3730-066X
Eun-Jin Cheon, https://orcid.org/0000-0002-6986-0768
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... With characteristically being described as a neuropsychiatric syndrome with loss of motivation and emotions that are not associated with acute distress, intellectual impairment, or diminished level of consciousness, our review found that a few authors have used the term emotional blunting and emotional apathy syndrome interchangeably (Kim et al., 2019;Lee and Keltner, 2005;Marangell et al., 2002;Padala et al., 2012;Sato et al., 2020). These studies have described a similar kind of symptomatology of emotional impairment as the studies using the term emotional blunting previously. ...
... Furthermore, cross tapering with bupropion has also improved SSRI-induced emotional blunting (Padala et al., 2012). In another case of a 67-year-old woman, adding methylphenidate and modafinil after discontinuing the SSRI agent proved effective in treating SSRI-induced apathy syndrome (Kim et al., 2019). Similarly, the addition of buspirone to the SSRI agent also showed a role in ameliorating emotional blunting in one of the case reports (Holguín-Lew and Bell, 2013). ...
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