Addiction, Anhedonia, en Comorbid Mood Disorder. 'N Narratiewe oorsig (2019)

Voorpsigiatrie. 2019; 10: 311.

Gepubliseer aanlyn 2019 Mei 22. doi: 10.3389 / fpsyt.2019.00311

PMCID: PMC6538808

PMID: 31178763

Marianne Destoop, ^{1, 2} Manuel Morrens, ^{1, 3} Violette Coppens, ^{1, 3} en Geert Dom ^{1, 2, *}

Abstract

Inleiding

Disorders in the use of substances (DUS) as defined by the Diagnostic and Statistical Manual of Mental Disorder-5 (DSM-5) are a set of highly prevalent disorders with an enormous negative impact on individuals, their families, and society as a whole (1). From a neuroscientific perspective, DUS can be conceptualized as complex disorders, i.e., multiple symptom clusters and underlying neurobiological circuitries/systems play a role. In its core lay both a hypersensitivity to drug-related stimuli and an impairment in (executive) control over these impulses. On the other hand, and increasingly as the disorder progresses, a “darker” side has been suggested where an increase of brain-stress system, impaired stress tolerance, negative affect, and anhedonia take the upper hand (2).

From a clinical perspective, anhedonia, i.e., a markedly diminished interest or pleasure in activities that are naturally rewarding, is an essential characteristic for many addicted individuals. Anhedonia-like symptoms have been reported in the context of active chronic substance use, (protracted) withdrawal, and during sustained abstinence. Also, anhedonia may, for some individuals, act as a pre-existing vulnerability for substance initiation, regular use, and the subsequent development transition to addiction (3). The symptoms characterizing anhedonia may reflect underlying neurochemical changes, typically associated with the “dark side” of addiction, where negative reinforcement drives continuing substance use and the neurochemical picture is dominated by dysregulation of brain-stress systems (2). These may also include peripheric inflammation processes that have been reported in the context of chronic substance use and associated with depression and anhedonia (4). In line with this are the recent findings indicating that antidepressants, i.e., agomelatine, might affect anhedonia, possibly via decreasing C-reactive protein and increasing BDNF serum levels (5-7). Furthermore, anhedonia may have specific clinical importance, i.e., for outcome and treatment response. Indeed, anhedonia increases the likelihood of relapse and is associated with craving (3).

Characteristic of DUS is the high prevalence of comorbidity with other psychiatric disorders. This might be the result of the diagnostic vagueness inherent to the currently used diagnostic categorical systems such as DSM and ICD. Alternatively, common underlying factors may drive different behavioral–phenotypical presentations that when diagnosed “categorical” on a behavioral level results in statistical high levels of comorbidity (8). Disorders of mood (MD) are one of the psychiatric disorders that have been reported to co-occur frequently with DUS are mood disorders (MD). The co-occurrence of MD and DUS has been well established with an estimated two- to fivefold increase in odds of having an MD when the other condition is present (9). With respect to the pathogenesis of psychiatric disorders, anhedonia has been considered as a principal, transdiagnostic characteristic, within the phenotypic concept of different mental disorders, e.g., mood disorders, schizophrenia, and also DUS (10). Recent studies suggest that reward hyposensitivity within unipolar depression will be most strongly associated with a state of anhedonia characterized by motivational versus hedonic deficits (11, 12). From this perspective, it might be hypothesized that anhedonia as an underlying neurobiological construct acts as a driver explaining the high prevalence of the DUS–depression comorbidity. Alternatively, anhedonia might be a symptom within both disorders but of which its origin is based on different pathogenetic pathways, e.g., anhedonia as a result of down-regulation of reward pathways in a response of chronic substance (ab)use.

Anhedonia is by far not the only common construct underlying comorbidities between DUS and other psychiatric disorders. Indeed, using the Research Domain Criterion (RDoC) terminology, deficits in threat-related processes (Negative Valence Systems), executive control (Arousal/Regulatory Systems), and working memory (Cognitive Systems) are observed across many psychiatric disorders in both the “internalizing” spectrum (e.g., depression, anxiety) and the “externalizing” spectrum, i.e., DUS (8, 11). However, up to now, the role of anhedonia in both the pathogenesis of addiction and in the comorbidity with mood disorders has been mainly left understudied. This is an essential caveat since an increasing number of studies indicate that anhedonia, e.g., within the context of depression, is a factor that negatively impacts treatment outcome. Indeed, anhedonia is a predictor of poor longitudinal course of symptoms of major depression, suicidality, and suicidal ideation and poor response on pharmacological treatment (13-16).

Within the scope of this review, we first present ideas on conceptualizing and assessing anhedonia. Next, we review the literature exploring the relationship between anhedonia and substance use disorders. In the discussion, we extend on how these findings match with current concepts on anhedonia and how this, potentially, reflect on treatment and future research.

Conceptualization of Anhedonia

Anhedonia refers to a decreased interest or pleasure in response to stimuli that are either by nature or previously perceived as rewarding. As such, anhedonia is inherently associated with reward processing. Reward processing involves multiple components that can be dissected experimentally in animal models but are likely intermingled in real life-situations: sensory detection of a stimulus, affective hedonic reaction, pleasure itself (liking), motivation to obtain the reward and work for it (wanting or incentive salience), and reward-related learning processes (17).

At least two broad dimensions underlying anhedonia have been identified through animal and human research: 1) reward hyposensitivity and 2) reduced approach motivation. Of importance, both aspects can be dissected regarding their underlying neurobiological pathways and neurochemical hallmarks (11).

Reward hyposensitivity has been suggested to be associated with the functionalities related to the “consummatory” part of reward processing, i.e., often reflected by the term “liking.” Pleasure experience is suggested to be mediated by the endogenous opioid and endocannabinoid receptor pathways in different brain areas (18). This component could be called the hedonic dimension of anhedonia, i.e., “hedonic anhedonia.”

Approach motivation is viewed as the driver that facilitates approach or goal-directed behavior to obtain rewards. Information encoded by dopaminergic transmission within the mesolimbic system is suggested to play a role in reward motivational value and motivational salience (17). The primary system is proposed to be dopaminergic frontostriatal circuitries. Reducing dopaminergic functioning has an adverse effect on the motivation to pursue and work for rewarding stimuli. This dimension could be called the motivational component of anhedonia, i.e., “motivational anhedonia.” Of interest, administration of a dopamine agonist (d-amfetamine) produces an increase in the willingness to work for rewards in animal models (11, 19).

Taken together, growing evidence from self-report, behavioral, and neurophysiological studies suggest that reward hyposensitivity and reduced approach motivation reflect anhedonia (11). From this perspective, two distinct neural circuits underlying motivational (anticipation, wanting; i.e., associated with dopamine signaling within the frontostriatal circuitry) versus hedonic (consumption, liking; i.e., associated with endogenous opioids signaling) reward-related states can be hypothesized (11). For this review, we conceptualize anhedonia to these two basic dimensions ( Figuur 1 ).

Review: Aim and Questions

Within the scope of this explorative–narrative review part of this manuscript, we aim to explore the following questions:

• What is the prevalence of anhedonia within human DUS individuals?

• What types of measurement instruments of anhedonia are used in human studies within DUS samples?

• Is there a differentiation according to hedonic versus motivation anhedonia?

• How does anhedonia relate to DUS–depression comorbidity?

• What is the role of anhedonia in DUS course and treatment response?

Metode

The most recent systematic review on the relation between substance use disorders (SUD) and anhedonia reviewed the literature up to 23 May 2013 (3). So, with this review, we aimed at expanding this body of work by reviewing the literature published after this date, i.e., last 5 years. A search was performed in PubMed using the same search terms as in this latter publication (3). We included pathological gambling and internet gaming in this search because they recently were included in the DUS chapter of the DSM-5 (and will be in the next ICD11) as addictive disorders.

In order to obtain original studies investigating the link between anhedonia and DUS, a PubMed search (May 2013–November 2018) for English language articles was conducted using the following search terms: (Anhedonia OR Reward Deficiency) AND ((Drug Dependence OR Abuse) OR Alcohol OR Nicotine OR Addiction OR Gambling OR (Internet Gaming)). The papers were filtered for human studies only. An overview of the inclusion process can be found in Figuur 2 . The PubMed search yielded 171 results; abstract screening led to the exclusion of 136 papers, leaving 35 papers. Of these, one full paper could not be retrieved, and two validation studies were excluded, so 32 articles were included in the review.

Results

The majority of studies (n = 13) focused on tobacco smoking compared to alcohol (n = 4), cannabis (n = 4), cocaine (n = 5), benzodiazepines (n = 1), and opioids (n = 4). Behavioral addictions remain poorly studied, i.e., one study on gambling and none on online gaming. See Tabel 1 for an overview of all studies.

Bespreking

In this exploratory–narrative review, we identified 32 original research papers exploring anhedonia and its relationship with substance use disorders. Results provide indications that 1) anhedonia is associated with substance use problems/disorders and their severity, 2) anhedonia is especially prominent in DUS with comorbid depression and early life stress experiences, 3) anhedonia may be both a trait and a state dimension in its relation to DUS, and 4) anhedonia tends to negatively impact DUS treatment outcome. Finally, most evidence points to motivational anhedonia as the most involved subdimension of anhedonia within its relationship with DUS.

Overall, the findings in this review, focusing on articles over the last 5 years, are in line with the earlier review of Garfield et al. (3). Across the different substances of abuse, findings in this review provide indications that anhedonia—as a broad concept—is associated with DUS and DUS severity. However, these findings need to be looked upon prudently. Indeed, the number of studies using a control group remains very limited. Also, the severity measures used throughout the different studies are very variable, leaving consistent interpretation difficult. Altogether, the number of studies remains very limited especially when compared to the number of studies published on impulse/executive control in SUD. This is remarkable. Indeed, in a recent consensus paper, RDoC Positive Valence System (Reward Valuation, Expectancy, Action Selection, Reward Learning, Habit) was put forward as an essential domain with respect to the pathogenesis of addictive disorders, implicated in vulnerabilities for initiation, continuation, and chronicity of the disorder (8). Anhedonia can be positioned on the bridge of both negative and positive Valence Systems, but associates close to Reward Valuation, Reward Expectancy, and Reward Learning. This theoretical ground and the findings of our review indicate that anhedonia deserves more attention.

Moreover, anhedonia is looked upon as an important “transdiagnostic” concept underlying many different psychiatric disorders, e.g., depression, bipolar disorder, and schizophrenia (11). All these disorders relate, in different ways, to altered reward processing. Finally, anhedonia might have relevance bridging with a growing literature on the role of inflammation in the pathogenesis of psychiatric disorders such as mood disorders or addictive disorders (56). From this perspective, it can be hypothesized that a neurobiological vulnerability to inflammatory stimuli may drive the link between chronic substance use (early life stress) and anhedonia.

A sizable number of (large) studies in this review focused on comorbidity and provided indications that DUS patients with a comorbid mood disorder had higher levels of anhedonia as compared to single diagnosis groups. These findings give some ground for the hypothesis that anhedonia might be a common factor underlying both types of disorder or at least a subtype of each. Subtypes in depression with anhedonia being the prominent feature have recently been suggested. Specifically, an “inflammatory” subtype has been proposed with a neurobiological vulnerability to inflammatory stimuli that drive the link between stress and anhedonic symptoms (56). Of interest, early childhood adversity may be one of the most critical factors modulating this neurobiological vulnerability. It is remarkable that two studies in this review showed a clear association between anhedonia and substance use severity, specifically in a population of individuals exposed to trauma (21, 23). Given the high prevalence of early childhood adversity within individuals with DUS, future studies need to explore whether this subgroup is associated with anhedonia.

Research on anhedonia in other psychiatric disorders, e.g., depression, can also help to provide more insight into how research on anhedonia in SUD needs to be done. As mentioned above, self-reports are the most used instrument, while they are mostly unable to distinguish the different aspects of reward processing and reward learning. In depression literature, however, various aspects of reward in relation to anhedonia could be disentangled based on numerous studies combining behavioral tasks and neurobiological measures, mainly event related potential (ERP) studies. Neuroimaging studies could be useful as well, taking into account the idea that fMRI paradigms are mostly unable to dissect into anticipatory, consummatory, and learning components of reward processing (23). A multimodal approach using the same paradigms in future research projects is recommended.

Data from this review show mixed results as to the trait versus state characteristic of anhedonia within the context of substance use. Some studies give support to the hypothesis that anhedonia might be a trait that underlies a vulnerability for early substance use initiation and early escalation. This is in line with the self-medication theory whereby substances are used to mediate mood disorders or innate reward deficiencies (9). Also, adolescents with high stress and amygdala reactivity are more likely to consume a full standard alcoholic drink, are more likely to experience early intoxication, and are at a heightened risk for the onset of an alcohol use disorder (57). In line with this, anhedonia can be hypothesized as a vulnerability trait for early substance use trajectories and subsequent increase of DUS risk. A hypothesis is also in line with the reward deficiency hypothesis (58). Inversely, different studies in this review indicate that anhedonia is associated with ongoing substance use and withdrawal while improving over time in abstinence. This is in line with earlier studies showing improvement in reward responsiveness during treatment and abstinence (59). These findings are indicative of a state characteristic. However, longitudinal studies remain very scarce, i.e., in this review, only one study followed the course of anhedonia over a 6-month abstinence period showing improvement over time (45). So, any conclusion concerning trait or state is at best preliminary.

Several studies in this review showed a negative influence of anhedonia on DUS course and treatment effect, i.e., shorter posttreatment abstinence and higher relapse rates. This is confirmation of findings presented in the earlier review on this topic showing that anhedonia increases the likelihood of relapse and is associated with craving (3). In the depression research, anhedonia negatively influences disease course. This has also been documented within the context of treating depression (13-16). It can be hypothesized that anhedonia as a transdiagnostic characteristic modulates disease course and outcome.

Within the context of depression treatment, existing psychological and pharmacological treatments have proved to be rather ineffective for treating anhedonia. Some of the more commonly used antidepressants, e.g., fluoxetine, may even worsen anhedonic symptoms (60-62). Of importance, newer treatments such as ketamine are shown to have improvement of anhedonia, even in treatment-resistant depression (63, 64). This is of interest, also from the perspective of indication that ketamine can be used within the context of treatment of DUS (65). Although, at this point, no study has been published exploring the effectiveness of ketamine as a treatment for patients with DUS and depression/anhedonia comorbidity, this is an exciting idea. Of interest in this review is the finding that substitution treatment (i.e., nicotine patch) might be beneficial specifically for smokers scoring high on anhedonia. Powers et al. (30) showed an increased likelihood of short-term abstinence using a 21-mg/day nicotine patch therapy. Cook et al. (34) observed that administering nicotine replacement therapy suppressed abstinence-induced anhedonia and alleviated nicotine withdrawal symptoms during short-term abstinence. Moreover, depressed non-smokers show significant declines in depressive symptoms during nicotine patch treatment, suggesting that NRT (and nicotine patch in particular) may have antidepressant-like effects (66). It has been hypothesized that nicotine exposure ameliorates the hypoactivation in crucial structures of the reward pathway (including caudate, nucleus accumbens, putamen) among depressed smokers, with data showing increased activation after nicotine administration in the dorsal striatum during anticipatory reward responding and in the medial prefrontal cortex associated with sensitivity to reward (67). It has to be noted that the sample of anhedonic participants in the study of Powers et al. (30) was small, and the lack of a placebo condition made it difficult to draw inferences about the impact of nicotine patch therapy on pretreatment anhedonia or depression more generally. Finally, there is preliminary evidence that aripiprazole might promote alcohol abstinence and reduce anhedonia, possibly via dopaminergic and serotonergic modulations at the fronto-subcortical circuitries (68). However, this needs future replication.

Taken together, although anhedonia is notably challenging to treat and can negatively impact disease course, these preliminary studies hold promises for developing future—pharmacological—treatments.

Findings in this review need be looked upon critically. Several limitations need to be taken into account. First, the vast majority of studies focus on tobacco smoking. Other substances of abuse remain largely understudied, and regarding behavioral addictions, the information is zero. Next and most importantly, throughout the studies, a variety of anhedonia measures has been used. For none of these measures it is known what exact anhedonia dimension they measure, neither is enough information available on how these measures relate. This makes a comparison between studies impossible and may be responsible for sometimes contradictory findings. Third, different study designs and samples are used, which makes it difficult to draw general conclusions about the temporal and causal relationships between anhedonia and DUS. Finally, ours is an explorative, narrative review highlighting the broad field of the anhedonia–DUS relationship. Future hypothesis-driven studies are needed both on the clinical consequences and on elucidating the exact underlying mechanisms and neurocognitive dimensions.

Gevolgtrekkings

Findings from this review provide indications that anhedonia might be of relevance for a better understanding of the pathogenesis of addictive disorders and their comorbidities. Anhedonia might prove to be an unimportant transdiagnostic dimension underlying many disorders in their relationship with different reward processing impairments. Within the National Institute of Mental Health’s (NIH) Research Domain Criteria (RDoC), anhedonia is conceptualized as an RDoC Element (behavior) within the following Domains and Constructs: 1) Domain: Negative Valence Systems; 2) Construct: Loss and Construct. However, anhedonia might also be linked to other domains, i.e., Positive Valence Systems (11), so anhedonia might be important in bridging these systems and/or reflect different subgroups/mechanisms.

However, in contrast to the field of impulsivity, the study of anhedonia in the relationship with DUS is only nascent. Reflective of this is not only the relatively small number of studies but also the variability of measures and concepts used in the different studies. There is a great need of consensus in defining the neurocognitive dimensions and best measurement instruments/paradigms to help the field move on more quickly. Within this context, the recent international consensus paper identifying the most critical cognitive domains within neuroscience of addictions is a vital initiative (8). Let us see how and when anhedonia finds a place in this model.

Skrywer Bydraes

All authors contributed to the manuscript conception design and writing.

Konflik van belangstelling

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