Disentangling fatigue from anhedonia: a scoping review

Fatigue and anhedonia are commonly reported, co-occurring clinical symptoms associated with chronic illnesses. Fatigue is a multidimensional construct that is defined as a distressing, persistent, subjective sense of physical, cognitive, or emotional tiredness that interferes with usual functioning. Anhedonia is a component of depressive disorders and other psychiatric conditions, such as schizophrenia, and is defined by the reduced ability to experience pleasure. Both symptoms greatly affect the health-related quality of life of patients with chronic illnesses. Although fatigue and anhedonia are commonly associated with each other, understanding the differences between the two constructs is necessary for diagnosis and clinical treatment. A scoping review was conducted based on published guidance, starting with a comprehensive search of existing literature to understand the similarities and differences between fatigue and anhedonia. An initial search of PubMed using fatigue and anhedonia as medical subject headings yielded a total of 5254 articles. A complete full-text review of the final 21 articles was conducted to find articles that treated both constructs similarly and articles that presented fatigue and anhedonia as distinct constructs. About 60% of the reviewed articles consider both constructs as distinct, but a considerable number of the reviewed articles found these constructs indistinguishable. Nomenclature and biology were two themes from the reviewed articles supporting the idea that anhedonia and fatigue are indistinguishable constructs. The information generated from this review is clinically relevant to optimize the management of fatigue related to anhedonia from other fatigue subtypes.


Introduction
Fatigue is a commonly reported and disabling symptom in neurological 1,2 , rheumatologic 3,4 , and oncologic conditions 5 . It is generally defined as a feeling of malaise, lack of energy, and complaints of tiredness and exhaustion 6 . Fatigue is often associated with depression and is described as a core symptom of major depressive episode (MDE) 7,8 . However, one study reported that fatigue independently decreased the quality of life of patients when controlling for depression and other symptoms 6 . Despite its prevalence, the etiology of fatigue is still poorly understood due to the multidimensionality of this construct 9 . Fatigue is proposed to comprise of physical, affective, and cognitive dimensions 10,11 . Currently, fatigue is measured by validated self-report instruments 12 .
Anhedonia is also present in a myriad of diseases; however, it is most commonly known as a major symptom of depression 13 and other psychiatric conditions, such as schizophrenia 7,14 . Anhedonia, which translates to "without pleasure" in Greek 15 , is defined as the inability or diminished ability to experience pleasure 16 . Like fatigue, anhedonia has been proposed to comprise of different categories of pleasure, such as physical, social, anticipatory, motivational, and consummatory pleasures. Individuals with anhedonia are still able to experience pain and negative emotions, but usually they no longer participate in previously pleasurable activities 17 . Like fatigue, measuring anhedonia is difficult as it relies on the subjective experience of pleasure and is generally measured by self-report.
Seminal articles have explored the relationships of fatigue and anhedonia in psychiatric conditions. For example, endogenomorphic depression equated low energy to fatigue and anhedonia without distinguishing one from the other 18 . In schizophrenia, although there was also no distinction of low energy as fatigue or anhedonia, the understanding of low energy was linked to a neurological dysfunction in this disorder 19 . According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), anhedonia and fatigue are features of psychiatric disorders, most notably, major depressive disorder (MDD) and schizophrenia 7 . While the two symptoms are commonly understood as co-occurring within these psychiatric conditions, current research elucidates the individual complexities and unique attributes of each symptom 20,21 . The recommended management of fatigue and anhedonia involves pharmacological stimulants and treatment of the associated chronic illness 22 . Despite these advances, there is still limited literature that clarifies the relationship between fatigue and anhedonia. This scoping review was conducted based on established methodological frameworks 23 in order to clarify the relationship between fatigue and anhedonia from the extant literature.

Methods and study selection
An initial literature query was conducted using the PubMed database with the assistance of a medical librarian at the National Institutes of Health. We used "fatigue" and "anhedonia" as MeSH terms and included the corresponding synonyms, such as "lassitude" and "tiredness." This initial search yielded 5254 articles.
Fatigue and tiredness are used interchangeably. For example, in some measures like the Fibromyalgia Impact Questionnaire (FIQ), its main descriptor is fatigue, and then one of its subscale is morning tiredness 65 . In this case, fatigue and tiredness are loosely differentiated. This non-differentiation is also observed in the way fatigue is described in many medical conditions where it states, "the tiredness or lack of energy in fatigue is associated with exhaustion" 66 . For this review, the authors focused solely on fatigue as the construct of interest and its association with anhedonia. After removing "lassitude" and "tiredness" as search terms, 117 articles remained.
Our second filtering criteria aimed to remove articles that were not written in English, did not enroll human participants, or were published before 2008. Letters, commentaries, meeting abstracts, editorials, and dissertations were also excluded. This second screen narrowed our initial yield total to 61 articles for full-text review.
To establish the relationship between the two constructs, articles that did not measure both fatigue and anhedonia were excluded. Further, articles that did not define at least one of the constructs or help elucidate the relationship between the two constructs were also excluded. A final 21 articles were included in this scoping review (Fig. 1). These 21 articles are summarized in Tables 1 and 2.
A common patient population studied was those with heart conditions (19%), including depression in acute coronary syndrome patients 41 , heart failure 28 , coronary heart disease 31 , and impaired cardiac function in community-dwelling elders 29 . About 14% of the studies enrolled patients with Parkinson's disease (PD) 37,45,47 . Other patient populations included patients with chronic hepatitis C virus (HCV) 24 , cancer 40 , anxiety and mood disorders 27 , MDD or depression 30,33 , dysphoric episodes 38 , and non-psychiatric conditions who were hospitalized 36 . Healthy volunteers 25,32,46 and primary care patients 42 were also assessed, as were communitydwelling elder adults 35 and tobacco smokers 44 .
Two studies collected data via online assessments 32,38 , and four studies either retrospectively analyzed data or utilized previously collected datasets 29,31,39,47 . Two studies utilized healthy controls 30,45 , and six studies used the control groups or placebo groups for comparison [24][25][26]33,46,47 . The Snaith-Hamilton Pleasure Scale was the commonly used questionnaire to assess anhedonia 24,32,45 and has been validated to measure anhedonia 48 . Other questionnaires that were used to assess anhedonia included the Visual Analog Scale for anhedonia, the Quick Inventory of Depressive Symptomology-Self Report, Mood and Anxiety Symptom Questionnaire-Anhedonic Depression Symptom, item 8 of the MADRS-Anhedonia, and the mood/apathy domain of the NMSS.

Definition of fatigue
There was no consensus on the definition of fatigue. By far, the most common definition of fatigue described it as a loss of energy or a lack of energy 29,33,36,42 . Similarly, Fig. 1 Screening flow process. Figure describes the procedures and the eligibility criteria used to select articles to be included in the review, based on the methods required for scoping reviews 67 . fatigue was also described as a physical feeling of lassitude 46 , feeling tired 35 , the feeling of exhaustion or vital exhaustion 32,41 , worn out as described by POMS 44 , and decreased energy or increased fatigability 36 . Some articles classified fatigue as a non-motor symptom of PD 26,37 , while other articles classified it as a somatic or physical symptom of depression 28,31,35,38,39 . Capuron et al. 24 tested different subscales of fatigue, including general fatigue, physical fatigue, and mental fatigue. Bennett et al. 40 described both physical and mental fatigue, where physical fatigue in chronic fatigue syndrome was defined as "difficulty achieving motor tasks" and mental fatigue was defined as "difficulty achieving cognitive tasks."   "Fatigue (e.g., "worn out," "fatigued")"

POMS-Fatigue
Anhedonia, a specific factor for depression indicative of reduced interest/motivation, pleasure, and positive affect, and is putatively distinct from anxiety MASQ-AD; (e.g., "felt like there wasn't anything interesting or fun to do," "felt like nothing was very enjoyable")

CES-D; DSM-V criteria
Depression is not a unitary phenomenon. Fatigue and other physical symptoms were not predicted by any of the early maladaptive schemas (EMSs). The occurrence of anhedonia was predicted by the EMS Failure, that is, the belief that one is inadequate compared with others Lists the articles that presented fatigue and anhedonia as distinct constructs.

Definition of anhedonia
There was not a clear consensus on the definition of anhedonia. By far, the most common definition of anhedonia was a loss of interest or pleasure in activities 29,31,33,36 . Similarly, anhedonia was also defined as a decreased/lack of interest 42 , dysphoria or a markedly diminished interest/pleasure in most daily activities 34 , and reduced interest/motivation, pleasure, and positive affect and is putatively distinct from anxiety 44 . Anhedonia was also defined as an impaired ability to experience pleasure or difficulty experiencing pleasure 24,30,47 . The construct of anhedonia was categorized as a behavioral, non-somatic symptom of depression 28 or classified as a non-motor, affective symptom in PD 37 or an affective symptom in community-dwelling older adults 35 . Anhedonia was also commonly classified as a mood disturbance or motivational symptom 32,40,45 . Anhedonia was also defined by its dimensions, such as social anhedonia, which was assessed by a one-item VAS, "I want to be alone" on one end and "I want to be with others" on the other end 46 . Trincas et al. 38 noted that anhedonia was predicted by the Failure schema in the Young Schema Questionnaire, which is the belief that one is inadequate compared with others in the context of depressive symptoms following dysphoric episodes.

Relationship of fatigue and anhedonia
Eight studies presented fatigue and anhedonia as associated or overlapping constructs. For example, four articles presented fatigue and anhedonia both as symptoms of depression 24,33,39,46 . These articles showed the two constructs as related within the context of depression. Three articles presented potentially common mechanisms or pathways to explain how the symptoms of fatigue and anhedonia are associated 24,46,47 . Capuron et al. 24 presented a potential mechanism by which inflammatory cytokines affect fatigue and anhedonia, thereby implicating dopamine function as a common mechanism shared by the two constructs in the HCV patient population. Hannestad et al. 46 implicated citalopram, a serotonin reuptake inhibitor, as having a preventative effect on endotoxin-induced increases in fatigue and motivation (anhedonia). Chaudhari et al. 68 found that the rotigotine transdermal system (a non-ergoline dopamine receptor agonist) may have a positive effect on fatigue and mood disturbances (anhedonia) in patients with PD. Fatigue and anhedonia when amalgamated into a symptom cluster called "sickness behavior," were also shown to be associated with inflammation and directly affected by impaired cardiac function in patients with cardiac failure 29 . Finally, two articles presented fatigue and anhedonia as one of the prodromal symptoms of a condition, such as early-stage PD 26,37 .
However, 12 articles presented fatigue and anhedonia as separate constructs, each with its own unique implications. Four articles presented anhedonia as a unique and distinguishable symptom of depression in that fatigue alone is not enough to diagnose major depression 31,36,40,42 . These four articles described the importance of anhedonia, more so than fatigue, as a diagnostic screening tool for depression, because it was found that anhedonia is an essential and distinguishing feature of a depression diagnosis. Two articles implicated separate pathophysiological mechanisms for fatigue and anhedonia 30,45 . Drijgers et al. 45 found that acute stimulation of methylphenidate (norepinephrine-dopamine reuptake inhibitor) improved anhedonia and vigor in PD patients, implying that dopamine plays a role in anhedonia (mood) but not fatigue (cognition). Lapidus et al. 30 found that anhedonia, but not fatigue, is negatively correlated with brain glutathione levels in patients with MDD. Three other articles found that either fatigue or anhedonia had unique implications on specific patient populations 28,41,44 . Doyle et al. 41 found that anhedonia could potentially be less cardiotoxic than fatigue and sadness in hospitalized patients with acute coronary syndrome. Hawkins et al. 28 found that interventions targeting patients' somatic symptoms, such as fatigue, may not yield maximum cognitive benefit in comparison to comprehensive treatment targeting non-somatic symptoms, such as anhedonia in patients with heart failure. Leventhal et al. 44 implicated anhedonia, but not fatigue, as being predictive of greater smoking relapse risk in the tobacco-smoking population.
Anhedonia was found to be predicted by an early maladaptive schema of failure when analyzing symptoms of depression that emerged after dysphoric episodes and its potential to be predicted by stable personality characteristics like early maladaptive schemas 38 . In aging populations (age >65 years), fatigue but not anhedonia was found to be most related to other symptoms and most commonly reported by the elderly population 35 . Finally, fatigue and anhedonia were also shown to be associated with different subtypes of apathy in healthy people 32 .

Discussion
This review explored the association between fatigue and anhedonia. About 60% of the reviewed articles considered both constructs as distinct, but still, a considerable number of the reviewed articles found these constructs indistinguishable. This finding has several clinical and research implications: (1) the lack of agreement in the association of both constructs poses more questions on current diagnostic criteria that clumps both constructs together, (2) the initial evidence of distinct biologic underpinnings for each construct provides opportunities to develop targeted therapies, and (3) the lack of consensus in a standard approach to measuring these constructs provides challenges to appropriately apply the diagnostic criteria and evaluate distinct etiologies for these constructs.

Anhedonia and fatigue as indistinguishable constructs
In the reviewed articles, nomenclature and biology were two themes supporting the idea that anhedonia and fatigue are indistinguishable constructs. Some conditions, such as depression, historically consider fatigue and anhedonia as inter-related and interchangeable constructs, except when motor systems are affected. Depressive symptoms are often categorized into somatic and non-somatic symptoms 39 . Anhedonia is clustered together with concentration difficulties and psychomotor agitation/retardation; while fatigue, together with sleep difficulties, and appetite changes are often classified under the somatic category of depressive symptoms.
Anhedonia was first featured in the DSM and the International Classification of Diseases in 1992, while fatigue was featured in DSM-III in 1980 49 . In the early versions of the DSM, fatigue was suggested to mean physical energy 50 and described as "flu-like symptoms" in depressive disorders of DSM-III 51 . There were no diagnostic criteria for fatigue as a stand-alone somatoform disorder in DSM-III 51 . Hence, fatigue, like insomnia, was less frequently diagnosed as a separate condition because the established criteria prohibited the classification of either of these symptoms as a stand-alone somatoform disorder 52 .
As the historical usage of fatigue suggests a loss of physical energy, fatigue has been considered as synonymous with a loss in pleasure experience 16 . Researchers argue that loss of energy or loss of pleasure can be traced to neural systems that block reward reinforcement from the source of pleasurable stimuli 18 . When the DSM was revised, the term anhedonia expanded from the "loss of pleasure" to also include the loss of interest and/or capacity for pleasure with the inclusion of melancholia features, which is the inability to respond to all pleasurable stimuli 53 . It was from this distinction in DSM-IV that fatigue meshed with the melancholia construct 53 .
Another concept that clumps these two constructs together is sickness behavior. Sickness behavior refers to the coordinated set of behavioral changes that develop in individuals during the course of an infection. These changes are due to the effects of pro-inflammatory cytokines that influence the nervous system and behavior 54 . In depression, a network of cytokines are believed to regulate mood and influence motivation 54 . It is believed that, during acute infection, pro-inflammatory cytokines like interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha are released peripherally via a fast transmission pathway, which influences the activities of the primary afferent nerves. The interactions between the pro-inflammatory cytokines and the primary afferent nerves activate the hypothalamic-pituitary-adrenal axis producing a constellation of behavioral symptoms referred to as sickness behavior, which include fatigue and anhedonia 54,55 . What is lacking in this hypothesis is that these specific symptoms exist under a wider cluster of comorbid conditions so that these sickness behaviors may not exclusively include fatigue and anhedonia behaviors. Longterm administration of inflammatory cytokines was also observed to decrease activation in the ventral striatum, which significantly correlated with greater symptoms of anhedonia, depression, and fatigue 24 . Administration of these inflammatory cytokines was associated with decreased presynaptic striatal dopamine, and these changes correlated with behavioral alterations in fatigue and anhedonia 47 . Application of a non-ergoline dopamine receptor agonist (rotigotine transdermal patches) improved both fatigue and anhedonia in patients with PD. These findings support the idea that the interplay of peripheral and central mechanisms triggered by inflammation blur distinct pathways that can distinguish fatigue from anhedonia.

Anhedonia and fatigue as distinct constructs
Clinical reports of persistent fatigue after remission of depression helped pave the notion that perhaps anhedonia and fatigue are distinct constructs 32 . The reviewed articles proposed that distinct biology distinguishes these constructs. The roles of dopamine 47 , serotonin 25 , and oxidative stress/inflammation 30 were specifically mentioned as pathways that can distinguish fatigue and anhedonia.
Methylphenidate (dopamine reuptake inhibitor) was used to improve anhedonia but not fatigue in patients with PD in comparison to controls 45 . Pramipexole (a dopamine D2 receptor agonist), on the other hand, had negative effects on mood and fatigue but had an insignificant effect on anhedonia 46 . Pretreatment of bupropion (a dopamine and norepinephrine reuptake inhibitor) had no significant effect on lipopolysaccharide-induced anhedonia and fatigue, while pretreatment with citalopram (a serotonin reuptake inhibitor) significantly improved endotoxin-induced fatigue but had no effect in anhedonia 46 ). These findings serve to implicate the distinct roles of dopamine and serotonin receptors in distinguishing anhedonia from fatigue.

Fatigue and anhedonia in the context of psychiatric conditions
Fatigue and anhedonia have been explored not only in depression but also in other psychiatric conditions such as schizophrenia, where one in every three patients has anhedonia 14,[56][57][58] . In depression, the seminal work of Klein 18 pointed out the construct of low energy in depression, specifically in individuals with the depressiveneurotic type of personality. This personality type has low self-esteem and depends on external environmental cues to experience pleasure 18 . In schizophrenia, anhedonia is a core negative symptom and is associated with functional impairment 59 . It is captured as the "diminished ability to experience pleasure" 19 .
Instruments used to assess depression used similar and distinguishing terms to capture fatigue and anhedonia. For example, MDD, as described in DSM-V, treats fatigue as "low energy" and anhedonia as a "lack of pleasurable interests." In the 17-item Hamilton Depression Scale, the construct of fatigue is captured in items that used the following terms: "somatic symptoms," "loss of energy," and "fatigability," while anhedonia is captured using the following terms: "loss of interest in hobbies, decreased social activities, decreased in productivity, and inability to work" 60 .

State versus trait anhedonia
In differentiating fatigue from anhedonia, the understanding of state versus trait anhedonia may be helpful. Anhedonia is a complex and nuanced symptom related to a number of health conditions. It occurs independently of one's ability to experience general stimulation and negative emotions 61 . In addition, it can occur with or without feelings of sadness 62 . The pathological symptom of anhedonia presents itself in various psychological and physical conditions and likely involves dysregulation of a number of neurochemical pathways in the brain 63 . When other mental or physical symptoms are present, anhedonia can be conceptualized as a pathologic symptom (state) of the primary condition, such as in depression or schizophrenia. Nevertheless, the literature is silent on whether state or trait anhedonia is associated with fatigue. However, hedonic inability, whether as a symptom or a trait, is frequently correlated with the presence of psychomotor delay even if confused with affective flattening in schizophrenia or even if it represents as a psychopathologic characteristic that is specific for depression 64 .

Gaps in the study
Three gaps were observed in this review: (1) lack in consensus in the definitions of fatigue and anhedonia, (2) lack of agreement in standard measures to assess fatigue and anhedonia, and (3) no validated shared and/or distinct pathways that can explain the association of both constructs. The lack of consensus stems from how the fatigue construct was understood within depression in DSM-III and the way fatigue has evolved to its current stand-alone construct in DSM-V to include its dimensions, such as physical, cognitive, and behavioral components 7 .
Anhedonia continues to be a diagnostic criterion in MDE diagnosis in DSM-V separate from fatigue. Its description overlapped and became more pronounced in the diagnostic criteria of unspecified depressive disorder with melancholic features 7 . However, since the anhedonia construct has evolved to include dimensions of perception (cognitive), action/sensorial/motor (physical), and pleasure (affective), it began to overlap with the construct of apathy (lack of emotion). These fatigue and anhedonia usages were first treated as co-existing constructs in depression. The comorbid status of depression with other medical conditions impacts the understanding of the fatigue-anhedonia relationship. One example of this is reflected in PD with comorbid depression. The lack of condition-specific definitions of constructs are observed in the current measures that assess anhedonia and fatigue. Further, the lack of clarity in the relationship of fatigue and anhedonia has slowed our understanding of the neural pathways that influence these behaviors, including the role of presynaptic striatal dopamine, the serotonergic regulation, oxidative stress pathways, and the role of inflammation.

Recommendations
There is a need to establish condition-specific definitions to understand further the dynamic relationships of fatigue and anhedonia. In the future revision of the DSM criteria, the dimensional construct of fatigue should be considered to classify its severity, duration, and frequency. Similarly, the melancholic features of depressive disorders require a dimensional understanding of anhedonia as a construct. Future research designs must capture the dimensional understanding of fatigue and anhedonia in relation to specific medical conditions of interest.

Conclusion
The purpose of this review was to clarify the relationship of fatigue and anhedonia. Historically, diagnostic nomenclature of fatigue and anhedonia had overlaps in its usage (DSM-III, DSM-IV). Through time, anhedonia had its own descriptive criteria in the melancholia features of MDDs. In DSM-V, fatigue severity is recognized as a unique entity. The future of discriminating the relationships between the two constructs must take into account the health condition being studied and its comorbidities.