Clinical and Neuroscientific Perspectives from Neurology and Psychiatry
Edited by
André Aleman
Professor of Cognitive Neuropsychiatry, University Medical Center Groningen and University of Groningen
Krista L. Lanctôt
Senior Scientist, Hurvitz Brain Sciences Program, Sunnybrook Research Institute; Professor of Psychiatry and Pharmacology, Vice Chair of Basic and Clinical Science, Department of Psychiatry, University of Toronto
3
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Preface
Apathy, or a significant reduction of goal-directed activity, is a common and clinically relevant problem for many patients with a neurological or psychiatric condition. It is a prominent and severely debilitating aspect of many such disorders, including among others schizophrenia, depression, traumatic brain injury, stroke, and neurodegenerative diseases (e.g. Alzheimer’s disease and Parkinson’s disease). Patients with apathy show reduced initiative, indolence, and general passivity of thought and action. Apathy involves changes in affect, behaviour, and cognition. No wonder it impacts the lives of patients and their loved ones, especially affecting patients’ independence and quality of life.
In recent years, there has been an increasing interest in studying apathy in its own right, given the prognostic value of apathy and its impact on daily functioning. Indeed, apathy can manifest itself independently from other neurological and psychiatric conditions and therefore deserves focused investigation. The advent of reliable measures and investigations of underlying mechanisms will also aid the development of novel treatment strategies.
The purpose of this book is to bring together current knowledge regarding apathy, ranging from conceptual insights to measurement, neurobiology, and treatment. For example, conceptual topics include the definition of apathy and the classification of dimensions pertaining to behaviour, cognition, and emotion. In addition, clinical observations suggest that a distinction can be made between different types of apathy. Measurement includes questionnaire and interview approaches, involving information obtained from self-report, informant (relative or close other), or clinician. Different brain circuits may be involved, such as frontoparietal, frontolimbic, and frontostriatal circuits. The neural structures subserving motivation and reward are highly relevant. Treatment has focused on diverse pharmacological approaches, and also psychosocial approaches such as behavioural activation therapy. More recently, neurostimulation has been introduced as a way of increasing brain activation of relevant circuits. Leading experts in the field have been asked to contribute a chapter on a diversity of topics, comprehensively covering different areas of apathy research. Despite the widespread presence of apathy across neurological and psychiatric disorders, much of the research has been done in artificial silos dictated by diseases. It is our hope that bringing together knowledge from across these disciplines will expand progress through cross-fertilization.
The book will be of interest to a wide range of professionals, including clinicians (psychiatrists, neurologists, psychologists, and psychiatric nurses) and researchers in the fields of neurology, psychiatry, and clinical psychology. We also trust that it will
benefit students of psychiatry, neurology, clinical psychology, neuropsychology, and related disciplines.
We would like to take this opportunity to thank our colleagues for contributing to this book by accepting our invitation and for their scholarly, informative, and interesting chapters. We are very happy with the contribution of so many leading experts. We also want to thank Danielle Vieira (Sunnybrook Research Institute, Toronto) for her indispensable help in getting the chapters reviewed and sent to the publisher. Finally, we extend our gratitude to Oxford University Press and editor Lauren Tiley for their enthusiasm and help with this book.
Abbreviations
Contributors
1. Definition of Apathy and Differential Diagnosis 1
Philippe Robert and Valeria Manera
2. Measurement of Apathy 19
Moyra Mortby, Bria Mele, Zahinoor Ismail, and David Miller
3. Apathy in Alzheimer’s Disease
Danielle Vieira, Celina Liu, and Krista L. Lanctôt
4. Apathy in Movement Disorders (Parkinson’s Disease, Huntington’s Disease) 55
Eliyas Jeffay, Kyrsten M. Grimes, and Konstantine K. Zakzanis
9. Apathy: A Pathology of Goal-Directed Behaviour and Prefrontal Cortex–Basal Ganglia Circuits
Richard Levy
10. Neural Basis of Apathy: Structural Imaging Studies
Ingrid Agartz and Lynn Mørch-Johnsen
11. Brain Reward Systems and Apathy
Stefan Kaiser and Florian Schlagenhauf
12. Neural Basis of Apathy: Functional Imaging Studies
André Aleman
13. Pharmacology of Apathy 224
Lisa Nobis and Masud Husain
14. Psychosocial Approaches to the Treatment of Apathy 242
Marcel Riehle, Zuzana Kasanova, and Tania M. Lincoln
15. Brain Stimulation 259
André Aleman, Jozarni J. Dlabac-De Lange, and Prasad Padala
Index 273
Abbreviations
AA Alzheimer’s Association
AAD auto-activation deficit
ACC anterior cingulate cortex
ACT acceptance and commitment therapy
AD Alzheimer’s disease
AES Apathy Evaluation Scale
AES-C Apathy Evaluation Scale Clinician reported
AES-I Apathy Evaluation Scale Informant reported
AES-S Apathy Evaluation Scale Self-reported
AI Apathy Inventory
aMCI amnestic mild cognitive impairment
APADEM-NH Apathy in Dementia, Nursing Home
AS Apathy Scale
BOLD blood oxygen level-dependent
BPRS Brief Psychiatric Rating Scale
CAINS Clinical Assessment Interview for Negative Symptoms
CBSST Cognitive Behavioral Social Skills Training
CBT cognitive behavioural therapy
CI confidence interval
CNS central nervous system
CT computed tomography
DAIR Dementia Apathy Interview and Rating
DAS Dimensional Apathy Scale
DFC dynamic functional connectivity
DLPFC dorsolateral prefrontal cortex
DSM-5 Diagnostic and Statistical Manual of Mental Disorders, fifth edition
DSM-IV Diagnostic and Statistical Manual of Mental Disorders, fourth edition
DTI diffusion tensor imaging
DWI diffusion-weighted imaging
FA fractional anisotropy
FDG fluorodeoxyglucose
FrSBe Frontal Systems Behaviour Scale
GABA gamma-aminobutyric acid
GCS Glasgow Coma Scale
GDB goal-directed behaviour
HD Huntington’s disease
ICD-10 International Classification of Diseases, tenth revision
ISTAART International Society to Advance Alzheimer Research and Treatment
LARS Lille Apathy Rating Scale
LARS-i Lille Apathy Rating Scale Informant
x Abbreviations
MBI mild behavioural impairment
MBI-C Mild Behavioural Impairment Checklist
MCI mild cognitive impairment
MDD major depressive disorder
MID monetary incentive delay
MND motor neuron disease
MOVE Motivation and Enhancement
MR magnetic resonance
MRI magnetic resonance imaging
mTBI mild traumatic brain injury
NAc nucleus accumbens
naMCI non-amnestic mild cognitive impairment
NCI no cognitive impairment
NIMH National Institute of Mental Health
NOSIE Nurses’ Observation Scale for Inpatient Evaluation
NPI Neuropsychiatric Inventory
NPI-C Neuropsychiatric Inventory Clinician
NPI-NH Neuropsychiatric Inventory Nursing Home
NPI-Q Neuropsychiatric Inventory Questionnaire
NPS neuropsychiatric symptom(s)
OFC orbitofrontal cortex
OR odds ratio
PANSS Positive and Negative Symptoms Scale
PAT Positive Affect Treatment
PD Parkinson’s disease
PEPS Positive Emotions Program for Schizophrenia
PET positron emission tomography
PFC prefrontal cortex
PRIME personalized real-time intervention for motivational enhancement
PST problem-solving therapy
PTA post-traumatic amnesia
RDoC Research Domain Criteria
RL reinforcement learning
ROI region of interest
RS-FC resting-state functional connectivity
rTMS repetitive transcranial magnetic stimulation
SANS Scale for the Assessment of Negative Symptoms
SCIA Structured Clinical Interview for Apathy
SMA supplementary motor area
sMRI structural magnetic resonance imaging
SNc substantia nigra compacta
SNS Self-evaluation of Negative Symptoms
SSRI selective serotonin reuptake inhibitor
SST social skills training
SVD small vessel disease
TAU treatment as usual
Abbreviations
TBI traumatic brain injury
tDCS transcranial direct current stimulation
TEPS Temporal Experiences of Pleasure Scale
UPDRS Unified Parkinson’s Disease Rating Scale VS ventral striatum
VTA ventral tegmental area
Contributors
Ingrid Agartz
Division of Mental Health and Addiction, University of Oslo and Diakonjemmet Hospital, Oslo, Norway
André Aleman
Department of Neuroscience, University of Groningen, Groningen, The Netherlands
Jozarni J. Dlabac-De Lange
University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Ann Faerden
Clinic of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
Zahra Goodarzi
Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, AB, Canada
Kyrsten M. Grimes
Department of Psychology, University of Toronto Scarborough, Toronto, ON, Canada
Bradleigh Hayhow
School of Medicine, University of Notre Dame Australia, Fremantle, WA, Australia
Jayna Holroyd-Leduc
Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, AB, Canada
Masud Husain
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
Zahinoor Ismail
Departments of Psychiatry and Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
Eliyas Jeffay
KITE, Toronto Rehabilitation Institute, University Health Network, Toronto, ON, Canada
Stefan Kaiser
Adult Psychiatry Division, Department of Mental Health and Psychiatry, Geneva University Hospitals, Geneva, Switzerland
Zuzana Kasanova
Katholieke Universiteit Leuven, Belgium
Krista L. Lanctôt
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
Richard Levy
University Hospitals Pitié Salpêtrière, Paris, France
Tania M. Lincoln
Department of Clinical Psychology and Psychotherapy, University of Hamburg, Hamburg, Germany
Celina Liu
Neuropsychopharmacology Research Group, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada
Valeria Manera
University of Nice Sophia Antipolis, Nice, France
Bria Mele
Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada
David Miller
Signant Health, Blue Bell, PA, USA
Lynn Mørch-Johnsen
NORMENT, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatry and Department of Clinical Research, Ostfold Hospital, Graalum, Norway
Moyra Mortby
Neuroscience Research Australia, Randwick, Sydney, NSW, Australia
Lisa Nobis
Oxford Centre for Human Brain Activity, Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Oxford, UK
Prasad Padala
University of Arkansas for Medical Sciences, Little Rock, AR, USA
Marcel Riehle
Department of Clinical Psychology and Psychotherapy, University of Hamburg, Hamburg, Germany
Philippe Robert Institut Claude Pompidou, Nice, France
Gabriella Santangelo Department of Psychology, University of Campania ‘Luigi Vanvitelli’, Caserta, Italy
Division of Psychiatry, University of Western Australia, Perth, WA, Australia
Danielle Vieira
Neuropsychopharmacology Research Group, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada
Konstantine K. Zakzanis
Department of Psychology, University of Toronto Scarborough, Toronto, ON, Canada
1 Definition of Apathy and Differential Diagnosis
Philippe Robert and Valeria Manera
Introduction
Apathy is prevalent across many neurodegenerative, neurological, and psychiatric disorders. It represents the most common behavioural and psychological symptom in people with Alzheimer’s disease (AD), and is often observed in Parkinson’s disease (PD), vascular dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis/ motor neurone disease (MND), frontotemporal dementia, progressive supranuclear palsy, major depression, and schizophrenia (1). The definition and the diagnostic criteria for apathy have evolved over time, and the terminology employed to refer to apathy can vary in the context of different pathological conditions. In addition, the term apathy is employed to describe both a symptom and a syndrome (2).
Apathy Definition and Concept
The word apathy stems from the Greek apatheia, derived from apathes: ‘a’ (without) ‘pathos’ (feeling). In Stoic philosophy, the term described the state of a soul that has voluntarily become alien to the sensitive affections, which are also called ‘passions’ in the vocabulary of the Stoics. The term has undergone changes in meaning over the ages. The Oxford English Dictionary defines apathy as a lack of interest or enthusiasm, an approach emphasizing a ‘cognitive’ dimension (interest) and a ‘feeling’ or ‘emotional’ dimension (enthusiasm). The French Larousse dictionary defines apathy as indolence or indifference, slowness to act or react, passivity, inertia of a group, and of the economy.
Modern medicine conceptualizations of apathy reflect efforts to reconcile these various aspects of apathy. Despite differences, such as, for example, disagreements as to whether disturbances of motivation (3) or of initiative and self-generated voluntary and purposeful behaviour (4) are central features, most conceptualizations of apathy acknowledge that it is a multidimensional syndrome in which all these dimensions are prominent (Table 1.1).
Table
1.1
Concepts and definitions of apathy
Author Concept/definition
Marin et al., 1990 (5)
Cummings et al., 1994 (6)
Stuss et al., 2000 (7)
Robert et al., 2002 (8)
Sockeel et al., 2006 (9)
Levy and Dubois, 2006 (4)
Starkstein and Leentjens, 2008 (10)
Ang et al., 2017 (11)
Husain and Roiser, 2018 (1)
Diminished motivation (not attributable to diminished level of consciousness, cognitive impairment, or emotional distress)
Disorder of interest or motivation; it includes lack of emotion, lack of initiation, lack of enthusiasm
Disorder of initiative, manifested as a lack of self-initiated action, which may be affective, behavioural, or cognitive; it includes ‘social apathy’—a disorder of sense of self and of social awareness
Disorder of motivation including emotional blunting, lack of initiative, and lack of interest
Disorder of intellectual curiosity, action initiation, emotion, and self-awareness
Disorder of voluntary and goal-directed behaviours; with three subtypes of disrupted ‘signal’ processing—emotionalaffective, cognitive, and auto-activation
Disorder of motivation with diminished goal-directed behaviour and cognition
Disorder of motivation characterized by reduced behavioural initiation, emotional sensitivity, and social motivation, that is also apparent to varying degrees in healthy people
Multicomponent entity; it is essential to understand the functional and brain mechanisms underlying the ‘surface manifestations’ of apathy
Robert et al., 2018 (12) A quantitative reduction of goal-directed activity either in behavioural/cognitive, emotional, or social dimensions
Among the key figures that made it possible to move towards a better definition of apathy, we must first mention Robert Marin, who in 1990 defined apathy as a disorder of motivation (5). It is on this basis that Sergio Starkstein and colleagues provided a first assessment of the frequency of apathy in AD and other neuropsychiatric diseases (13). Finally, we should acknowledge that the interest in apathy increased in parallel with the renewed interest of neurologists and psychiatrists in dementia. Jeffrey Cummings’ introduction of a specific area devoted to apathy into the Neuropsychiatric Inventory (6)—which has become the gold standard for assessing neuropsychiatric disorders—played a fundamental role in its recognition and the proliferation of scientific research.
Apathy Diagnostic Criteria
Starting from Marin’s definition of apathy (3), Starkstein (14) and, in a second step, Starkstein and Leentjens (10) proposed a standardized set of diagnostic criteria for apathy. Based on these criteria, a patient is diagnosed with apathy if they present with a lack of motivation compared to the previous level of functioning or the standards of their age and culture (criterion A). Symptoms should be present for at least 4 weeks for most of the day, in at least one domain (goal-directed behaviour, cognition, and/ or emotions; criterion B). These symptoms should cause significant impairment in important areas of functioning (criterion C). Finally, these symptoms should not be explained by a diminished level of consciousness or the direct effects of substances (criterion D). This represented the first attempt to structure the apathy criteria in four parts: A, the definition; B, the description of domains where the apathy symptoms can appear; C, the consequence of the symptoms in term of functioning; and D, the exclusion criteria. In this work, the authors strongly stressed the importance of reaching a consensus on such criteria to facilitate future research.
Another important reason for formulating formal consensus criteria regarding apathy in dementia and neuropsychiatry was the recognition of its growing importance to neuropsychiatric research and practice. Under the auspices of the Association Française de Psychiatrie Biologique and the European Psychiatric Association, a task force was set up in 2008 to revise Starkstein’s original criteria and to develop criteria for apathy that could be widely employed, have clear operational steps, and could be easily applied in clinical practice and in research settings (15). There is wide acknowledgement that apathy is an important behavioural syndrome in AD and in various neuropsychiatric disorders. In light of recent research and the renewed interest in the correlates and impacts of apathy, and in its treatments, it is important to develop criteria for apathy that will be widely accepted, have clear operational steps, and will be easily applied in practice and research settings. Meeting these needs is the focus of the task force work reported here. The task force includes members of the Association Française de Psychiatrie Biologique, the European Psychiatric Association, the European Alzheimer’s Disease Consortium, and experts from Europe, Australia, and North America. An advanced draft was discussed at the consensus meeting (during the European Psychiatric Association conference on 7 April 2008) and a final agreement reached concerning operational definitions and hierarchy of the criteria (published in 2009). Apathy is defined as a disorder of motivation that persists over time and should meet the following requirements. Firstly, the core feature of apathy, diminished motivation, must be present for at least 4 weeks; secondly, two of the three dimensions of apathy (loss of, or diminished, goal-directed behaviour, goal-directed cognitive activity, or emotions) must also be present; thirdly, there should be identifiable functional impairments attributable to the apathy. Finally, exclusion criteria are specified to exclude symptoms and states that mimic apathy (15). One of the principal characteristics of these criteria (presented in Box 1.1) was that change in motivation
Box 1.1 The 2009 apathy diagnostic criteria
For a diagnosis of apathy, the patient should fulfil the criteria A, B, C, and D.
A Loss of or diminished motivation in comparison to the patient’s previous level of functioning and which is not consistent with his age or culture. These changes in motivation may be reported by the patient himself or by the observations of others.
B Presence of at least one symptom in at least two of the three following domains for a period of at least 4 weeks and present most of the time:
Domain B1. Loss of, or diminished, goal-directed behaviour as evidenced by at least one of the following:
• Loss of self-initiated behaviour (e.g. starting conversation, doing basic tasks of day-to-day living, seeking social activities, communicating choices).
• Loss of environment-stimulated behaviour (e.g. responding to conversation, participating in social activities).
Domain B2. Loss of, or diminished, goal-directed cognitive activity as evidenced by at least one of the following:
• Loss of spontaneous ideas and curiosity for routine and new events (i.e. challenging tasks, recent news, social opportunities, personal/family and social affairs).
• Loss of environment-stimulated ideas and curiosity for routine and new events (i.e. in the person’s residence, neighbourhood, or community).
Domain B3. Loss of, or diminished, emotion as evidenced by at least one of the following:
• Loss of spontaneous emotion, observed or self-reported (e.g. subjective feeling of weak or absent emotions, or observation by others of a blunted affect).
• Loss of emotional responsiveness to positive or negative stimuli or events (e.g. observer reports of unchanging affect, or of little emotional reaction to exciting events, personal loss, serious illness, emotional-laden news).
C These symptoms (A–B) cause clinically significant impairment in personal, social, occupational, or other important areas of functioning.
D The symptoms (A–B) are not exclusively explained or due to physical disabilities (e.g. blindness and loss of hearing), to motor disabilities, to diminished level of consciousness, or to the direct physiological effects of a substance (e.g. drug of abuse, a medication).
Reproduced from Eur Psychiatry, 24(2), Robert P, Onyike CU, Leentjens AFG, et al., Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders, pp. 98–104, Copyright (2009), with permission from Elsevier Masson SAS.
could be observed (and measured) by examining a patient’s responsiveness to internal or external stimuli. In this way, each of the three domains within criterion B (behaviour, cognition, and emotion) includes two types of symptoms. The first symptom pertains to self-initiated or ‘internal’ actions, cognitions, or emotions, and the second symptom to the patient’s responsiveness to ‘external’ stimuli.
Several prevalence studies employed the Robert et al. criteria (15). In a crosssectional, multicentre, observational study (16), the frequency of apathy was 55% in AD, 70% in mixed dementia, 43% in mild cognitive impairment, 53% in schizophrenia, and 94% in major depressive episodes. In another study focusing on PD (17), 17.2% of patients were diagnosed with apathy according to the criteria. Interestingly, the prevalence observed with the 2009 apathy diagnosis criteria is close to the overall pooled prevalence of apathy (49%) in AD observed across 25 studies reporting on 7671 persons (18).
The 2009 criteria were widely used in clinical and research practice (19) but research in the last decade has provided considerable advances in understanding the domain of apathy in brain disorders, including the biological and neural bases (20), which led a group of experts to propose a revision of the criteria. Several reasons emerged to update the diagnostic criteria of apathy. First, the definition of apathy as a disorder of ‘motivation’ has been extensively criticized, as ‘motivation’ (criterion A) is a psychological interpretation of behavioural internal states, which may be difficult to measure objectively (4). At the same time, the construct of goal-directed behaviour/ activity—construed as a set of related processes by which an internal state is translated, through observable action, into the attainment of a goal—is increasingly used in the domain of neuroscience (2), and it has been proposed to be a useful way to operationalize apathy, particularly in clinical context. Second, the different apathy domains (criterion B) have been the subject of discussion, particularly the importance of adding ‘social interaction’ as a domain of apathy (11).
Using a Delphi panel methodology, a group of experts reached a consensus on the 2018 apathy diagnostic criteria (reported in Box 1.2) (12). The main modifications compared to the criteria published in 2009 included (i) replacing the term ‘motivation’ with goal-directed behaviour. This was a pragmatic choice, because ‘goal-directed behaviours’ are easier to observe and describe compared to motivation, which is an internal state that can only be inferred; and (ii) the modification of the dimensions in which symptoms can be observed (criterion B), to cognition/behaviour, emotion, and social interaction.
The new criteria were employed in a recent survey conducted in specialized memory settings (21), which showed that the frequency of apathy ranged from 25% in patients with mild neurocognitive disorders, to 57% in patients with affective disorders (depression, anxiety, and bipolar disorders), and to 77% in patients with major neurocognitive disorders. All subjects with apathy fulfilled the criteria for the behaviour/cognition dimension, 73.1% fulfilled the criteria for the emotion dimension, and 97.4% fulfilled the criteria for the social interaction dimension. Behaviour/cognition showed the highest sensitivity, and the co-presence of emotion and social interaction
Box 1.2 The 2018 apathy diagnostic criteria
For a diagnosis of apathy, the patient should fulfil the criteria A, B, C, and D.
Criterion A A quantitative reduction of goal-directed activity either in behavioural, cognitive, emotional, or social dimensions in comparison to the patient’s previous level of functioning in these areas. These changes may be reported by the patient himself/herself or by observation of others.
Criterion B The presence of at least two of the three following dimensions for a period of at least 4 weeks and present most of the time:
B1. Behaviour and cognition. Loss of, or diminished, goal-directed behaviour or cognitive activity as evidenced by at least one of the following:
• General level of activity: the patient has a reduced level of activity either at home or work, makes less effort to initiate or accomplish tasks spontaneously, or needs to be prompted to perform them.
• Persistence of activity: he/she is less persistent in maintaining an activity or conversation, finding solutions to problems, or thinking of alternative ways to accomplish them if they become difficult.
• Making choices: he/she has less interest or takes longer to make choices when different alternatives exist (e.g. selecting TV programmes, preparing meals, choosing from a menu, etc.).
• Interest in external issue: he/she has less interest in or reacts less to news, either good or bad, or has less interest in doing new things.
• Personal well-being: he/she is less interested in his/her own health and well-being or personal image (general appearance, grooming, clothes, etc.).
B2. Emotion. Loss of, or diminished, emotion as evidenced by at least one of the following:
• Spontaneous emotions: the patient shows less spontaneous (selfgenerated) emotions regarding their own affairs, or appears less interested in events that should matter to him/her or to people that he/she knows well.
• Emotional reactions to environment: he/she expresses less emotional reaction in response to positive or negative events in his/ her environment that affect him/her or people he/she knows well (e.g. when things go well or bad, responding to jokes, or events on a TV programme or a movie, or when disturbed or prompted to do things he/she would prefer not to do).
• Impact on others: he/she is less concerned about the impact of his/her actions or feelings on the people around him/her.
• Empathy: he/she shows less empathy to the emotions or feelings of others (e.g. becoming happy or sad when someone is happy or sad, or being moved when others need help).
• Verbal or physical expressions: he/she shows less verbal or physical reactions that reveal his/her emotional states.
B3. Social interaction. Loss of, or diminished engagement in social interaction as evidenced by at least one of the following:
• Spontaneous social initiative: the patient takes less initiative in spontaneously proposing social or leisure activities to family or others.
• Environmentally stimulated social interaction: he/she participates less, or is less comfortable or more indifferent to social or leisure activities suggested by people around him/her.
• Relationship with family members: he/she shows less interest in family members (e.g. to know what is happening to them, to meet them, or make arrangements to contact them).
• Verbal interaction: he/she is less likely to initiate a conversation, or he/she withdraws soon from it.
• Homebound: he/she prefer to stays at home more frequently or longer than usual and shows less interest in getting out to meet people.
Criterion C These symptoms (A–B) cause clinically significant impairment in personal, social, occupational, or other important areas of functioning.
Criterion D The symptoms (A–B) are not exclusively explained or due to physical disabilities (e.g. blindness and loss of hearing), to motor disabilities, to a diminished level of consciousness, to the direct physiological effects of a substance (e.g. drug of abuse, medication), or to major changes in the patient’s environment.
Reproduced from Eur Psychiatry, 54, Robert P, Lanctôt KL, Agüera-Ortiz L, et al., Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group, pp. 71–76, Copyright (2018), with permission from Elsevier Masson SAS.
the highest specificity. The concordance between the 2009 and the 2018 criteria indicated an almost perfect agreement (more information concerning the criteria are available at http://www.innovation-alzheimer.fr/assessment/).
Chapter 2 of this book is dedicated to the apathy assessment tools (scales, interviews) that can contribute to the diagnosis of apathy. Here we only want to recall the main clinical principles to follow in order to fulfil the diagnostic criteria for apathy. As with any evaluation in current practice, it is important to use the maximum number of available elements regarding the behaviour and emotions of the patient. Several sources of information may be available. Ideally, relying on all these sources should allow the most accurate apathy diagnosis. The assessment of whether a patient meets apathy diagnostic criteria should be done when the maximum of information has been collected.
Here are some rules:
• Always rely on the symptoms observed during the interview: answers to questions, spontaneous expressions, attitude and involvement in the clinical relationship, the patient’s subjective point of view, and scores on behavioural evaluation scales. These elements, in the absence of other information, should constitute the basis to complete the diagnostic criteria for apathy.
• Always take into account the story of the subject and their usual social relations, usual personality, and information given by the accompanying person (when present).
• When a family or professional caregiver is present, information on daily life or behavioural disorders can be collected either spontaneously or using an interview such as the Neuropsychiatric Inventory (6) or Mild Behavioural Impairment Checklist (22), both of which represent good complements.
• When a cognitive/behavioural assessment is performed, it is also important to observe or have information about the patient’s involvement during the tests.
• Observations of the patient in other situations (use of serious games, individual or group stimulation sessions) or information obtained through new technologies can also be useful. There is evidence that apart from the currently used assessment methods for apathy, information and communication technology approaches could provide clinicians with valuable additional information for apathy detection, and therefore a more accurate diagnosis of apathy. Actigraphy and methods used to monitor motor activity and rest–activity rhythms have already been demonstrated to be accurate and related to apathy (23, 24). Other information and communication technology-based methodologies are already employed, but only in research settings at the moment. These include, for instance, voice analysis (25), video analysis (26), and the use of serious games and applications (an example of the Motivation Application (MotAp) is available at http://www.innovation-alzheimer.fr/motivation-application-2/). Motionbased technologies must be used and interpreted with caution in patients with movement disorders (e.g. PD, Huntington’s disease, or progressive supranuclear palsy). These patients often have a reduction in total activity, related to their motor symptoms. In addition, they speak slowly, with a hypophonic voice, and have a low speech rate due to speech and respiratory disorders. They also have a hypomimic face which can give the incorrect impression that they do not react to emotion. Hence, the proposed measures need to be used with reservations.
It is important to have apathy diagnostic criteria for two main reasons: to promote research and to improve clinical practice.
In the research domain, having a better definition of apathy will contribute to a better understanding of the underlying biological mechanisms. In the context of clinical trials testing new pharmacological treatments, it is important to provide the scientific rational (biological basis) for targeting specific dimensions, and, if possible, to make the relation with the product intended for development explicit. These characteristics are difficult to reach if the pathological framework is not defined. In order
to unify the definition, the 2018 diagnostic criteria for apathy have the advantage of addressing all brain diseases, including neurodegenerative, neurological, and psychiatric conditions. However, there is also a need to understand the peculiarities of apathy in each diagnostic category. This goal was achieved by a consensus group in 2021 (27), which defined diagnostic criteria for apathy focused only on neurocognitive disorders as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (28) (see Chapter 3).
Clinical practice is also a crucial target of the diagnostic criteria, particularly in order to select the best non-pharmacological or ecopsychosocial approach (29). In fact, as indicated by Starkstein and Hayhow in a recent editorial (30), ‘It is likely that a generic approach to activities may fail to produce positive changes in many patients. What is therefore required is a “tailor-made” approach, designing specific activities depending on individuals’ interests and capacities’.
Differential Diagnosis
Apathy is frequently comorbid with other syndromes which may have symptoms of reduced interests/motivation/goal-directed behaviour, such as depression, anhedonia, and fatigue (1, 18, 31). Furthermore, terms such as avolition, abulia, and negative symptoms are sometimes used to describe apathy symptomatology (2). This raises the question of the extent to which apathy can be meaningfully distinguished from these other conditions. Overlaps also occur in terms of brain circuits: atrophy or functional disruption of the dorsal anterior cingulate cortex, ventromedial prefrontal cortex, orbitofrontal cortex, ventral striatum, and ventral tegmental area, as well as brain regions connected to these areas, can be found in apathy, anhedonia, fatigue, and depression, as well as in abulia and negative symptoms (1, 32, 33). Similarly, all these symptoms are mediated, among others, by dysfunctions of the dopaminergic system (see (1), and Chapters 11 and 12 in this book for more details). Table 1.2 provides examples of disorders/syndromes/symptoms that can partially overlap with apathy, focusing on their definitions and examples of disorders in which they have been more frequently investigated.
Anhedonia
In psychiatry, anhedonia is defined as an inability to experience pleasure (34). Recently, anhedonia has also been associated with a loss of interest or pleasure in doing previously rewarding activities (35). Similar to apathy, anhedonia might exist for different dimensions, with dissociable axes of loss of interest or pleasure in social activities, sensory experiences, and hobbies (36). Anhedonia is one of the core symptoms of major depressive disorder (MDD). According to the DSM-5 (28), patients meet criteria for MDD if they have five or more symptoms, one of which must
Table 1.2 Medical conditions overlapping with apathy
Condition Definition
Apathy A quantitative reduction of goal-directed activity either in behavioural/cognitive, emotional, or social dimensions
Anhedonia Consistently and markedly diminished interest or pleasure in almost all daily activities
Negative symptoms Thoughts, feelings, or behaviours normally present that are absent or diminished
Aboulia Reduced spontaneous verbal, motor, cognitive, and emotional behaviours
Fatigue Feeling of exhaustion caused by the exertion of effort, which is unrelated to actual exertion of energy by muscles
Depression Mood disorder that causes a persistent feeling of sadness and loss of interest
be either depressed mood or anhedonia. However, anhedonia can occur outside of MDD. For example, it is included in the ‘negative symptoms’ of schizophrenia, and is also found in post-traumatic stress disorder, eating disorders, and substance use disorder (1). The overlap of apathy and anhedonia is evident in several conditions, such as PD and schizophrenia. This is also due to the fact that both apathy and anhedonia are assessed through clinical scales and questionnaires, and items used in the assessment of both syndromes are often overlapping (37). However, self-reports of apathy and anhedonia in the general population are not perfectly correlated, suggesting that there are also unique aspects of anhedonia not related to apathy, and vice versa (11).
Negative Symptoms
In the context of schizophrenia and other psychiatric disorders, negative symptoms include apathy, alogia (poverty of speech, increased latency of response), anhedonia,
asociality (e.g. decreased ability to feel intimacy and closeness to other people), physical anergia, affective blunting, and attentional impairment (2). Apathy is thus included in the spectrum of negative symptoms. Clinical descriptions and empirical studies on the negative syndrome of schizophrenia suggest that apathy may be a key criterion of this syndrome (37). However, the negative syndrome of schizophrenia has more clinical complexity than apathy, both in terms of its phenomenology and putative mechanisms.
Abulia/Avolition
People with avolition or abulia encounter difficulty in initiating behaviours but can perform the same actions when verbally prompted to do so. Avolition can be a prominent negative symptom of schizophrenia. An extreme form of avolition is akinetic mutism, which is characterized by little or no self-generated movement or speech (38). In psychiatry, abulia is considered by some to be a severe form of apathy (10). Indeed, psychiatrists and neurologists responding to a survey considered aboulia to be a state characterized by difficulty in initiating and sustaining spontaneous movements, and reductions in emotional responsiveness, spontaneous speech, and social interaction (39), and acknowledged that the terms apathy and abulia were often used interchangeably in clinical practice. However, apathy as defined in the 2009 and the 2018 diagnostic criteria for apathy includes symptoms related to both self-generated behaviour and/or environment-stimulated behaviour. The definition of apathy thus encompasses a wider range of symptoms.
Fatigue
Fatigue is a common symptom, with up to half of the general population reporting fatigue. It is also reported by at least 20% of patients seeking medical care. Typically, fatigue is transient, self-limiting, and explained by prevailing circumstances. However, a minority of people experience persistent and debilitating fatigue. When the fatigue cannot be explained by a medical condition such as anaemia or hypothyroidism, it may represent chronic fatigue syndrome or myalgic encephalomyelitis (40). Despite the fact that there is still no clear consensus on its definition (41), myalgic encephalomyelitis/chronic fatigue syndrome is usually described as a disorder of more than 6 months’ duration comprised of unexplained fatigue, post-exertional malaise, unrefreshing sleep, and either cognitive dysfunction or orthostatic intolerance. The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome requires the presence of a substantial reduction/impairment in the ability to engage in pre-illness activities (41). The definition of fatigue in terms of reduction in the ability to engage in pre-illness levels of activities constitutes the basis for the overlap with apathy, as well as with depression. Fatigue in terms of symptoms can be associated with apathy in
