ReviewReconsidering anhedonia in depression: Lessons from translational neuroscience
Research highlights
▶ Anhedonia includes motivational and consummatory aspects of reward processing. ▶ Current research often fails to discriminate between these two aspects. ▶ Preclinical data suggest that these two aspects are neurobiologically dissociable. ▶ Consequently, we propose motivational and consummatory anhedonia. ▶ We also introduce “decisional anhedonia” to address anhedonic effects on decisions.
Introduction
With a lifetime prevalence of approximately 16% (Kessler et al., 2003), major depressive disorder (MDD) is predicted to become the second leading cause of death and disability in the United States by the year 2020 (Murray and Lopez, 1997). Dating back to the original Feighner criteria published in 1972, anhedonia has long been presumed as a core feature of MDD (Feighner et al., 1972). The DSM-IV-TR (American Psychiatric Association, 2000) defines anhedonia as diminished interest or pleasure in response to stimuli that were previously perceived as rewarding during a pre-morbid state (DSM-IV-TR). Along with depressed mood, anhedonia is one of two required symptoms for a diagnosis of MDD (American Psychiatric Association, 2000, World Health Organization, 1992). Recent reports estimate that approximately 37% of individuals diagnosed with MDD experience clinically significant anhedonia (Pelizza and Ferrari, 2009). Anhedonia is a particularly difficult symptom to treat, as accruing evidence suggests that current first-line pharmacotherapies (e.g., SSRIs) do not adequately address motivational and reward-processing deficits in depression (APA, 2000, Dunlop and Nemeroff, 2007, McCabe et al., 2009a, McCabe et al., 2009b, Nutt et al., 2007, Price et al., 2009, Shelton and Tomarken, 2001), and the presence of anhedonic symptoms is a predictor of poor treatment response generally (Spijker et al., 2001).
In an effort to find more effective treatments for psychiatric symptoms, the National Institute of Mental Health has emphasized translational research approaches to identify neurobiological mechanisms underlying psychiatric symptoms and disorders (Insel, 2009), such as the development of the newly proposed Research Domain Criteria (RDoC) (Insel and Cuthbert, 2009, Miller, 2010). Reward-related symptoms represent an excellent opportunity for translational neuroscience, given the vast basic science literature from which to draw upon (Berridge and Robinson, 2003, Gold et al., 2008). However, application of this important preclinical work to human conditions is hampered by the enormous heterogeneity in psychiatric disorders, and the limited phenotypic characterization of clinical samples in most group studies. This is true not only for the presence or absence of specific symptoms within a disorder (diagnostic heterogeneity), but also for the presence or absence of co-morbid conditions (heterogeneity of co-morbidity), etiological pathways involved in disorders (etiological heterogeneity), and even for definitions of symptoms (symptom heterogeneity).
Attention to these multiple forms of heterogeneity is critical for elucidating the neurobiological pathways involved. For example, under the DSM-IV definition of Major Depressive Episode, which requires the presence of 5 out of 9 possible symptoms, it is possible for two individuals to both be diagnosed with major depression while only sharing a single symptom of the disorder. Such heterogeneity in how an individual meets criteria may be both practical and theoretically appropriate, but it may also mask important associations that are related to specific symptoms, rather than the whole diagnostic category. Similarly, co-morbidity may obscure disorder specific, or symptom specific associations. For instance, while multiple studies have shown that individuals with depression exhibit increased amygdala activation in response to negatively valenced stimuli (Fu et al., 2004, Siegle et al., 2002, Siegle et al., 2006, Siegle et al., 2007), newer evidence suggests that this amygdala activity may occur primarily in individuals with MDD and co-morbid anxiety symptoms (Beesdo et al., 2009). Heterogeneity in etiological factors may also be important. In testing the role of the hypothalamic-pituitary-adrenal (HPA) axis in MDD, it has been demonstrated that individuals with both depression and early-life trauma exhibit structural reductions in regions involved in HPA axis regulation, while individuals with depression alone do not (Treadway et al., 2009b, Vythilingam et al., 2002). Group designs in MDD research that ignore this type of etiological heterogeneity may conceal important neurobiological differences (Heim et al., 2004).
A less commonly addressed form of heterogeneity—symptom heterogeneity—can arise from the presence of compound diagnostic criteria, or criteria that may be met in multiple ways. In the case of anhedonia, the DSM-IV-TR states that individuals meeting criteria “may report feeling less interest in hobbies, ‘not caring anymore,’ or not feeling any enjoyment in activities that were previously considered pleasurable” (American Psychiatric Association, 2000, p. 349). In other words, clinical diagnosis of anhedonia does not discriminate between a decrease in motivation and a reduction in experienced pleasure. The failure to draw such a distinction may reflect the long-held assumption that people are motivated to pursue the things they find pleasurable, and vice versa.
In the present review, we suggest that heterogeneity at the level of symptom definition is at least as problematic as the more commonly acknowledged issues of co-morbidity or etiological variability in group samples. In making this argument, we use anhedonia in MDD as a case study, and suggest that the distinction between the motivational and hedonic aspects of anhedonia is critical, especially when attempting to elucidate neurobiological pathways underlying the expression of this symptom. Indeed, overly broad definitions may sometimes point towards spurious relationships between symptom and substrate. When Roy Wise first presented the highly influential dopamine deficiency hypothesis of anhedonia, he argued that dopamine (DA) critically mediated an organism's experience of pleasure, or “yumminess”, in response to rewarding stimuli (Wise, 1980). Consequently, it was posited that anhedonia in mood disorders could be explained by a reduction in DA transmission (Willner, 1983a, Willner, 1983b, Willner, 1983c). In the intervening quarter-century however, only half of this original hypothesis has found empirical support. Namely (and as described below), subsequent research using neuroimaging, pharmacological and genetic methods in both humans and animals has provided some support for the claim that DA function is impaired in at least a sub-population of individuals with MDD (Dunlop and Nemeroff, 2007, Yadid and Friedman, 2008). However, contrary to the original anhedonia hypothesis, the conceptualization of DA as being primarily related to pleasure has been largely abandoned (Berridge and Robinson, 2003, Salamone et al., 2007).
These two developments raise a potential problem: if alterations in DA are a significant component in the pathogenesis of MDD but are unrelated to deficits in experience of pleasure, what is their functional and clinical consequence? In the present review, we suggest that this problem may be resolved through a refined definition of anhedonia, which attends more closely to the distinction between deficits in the hedonic response to rewards (“consummatory anhedonia”) and a diminished motivation to pursue them (“motivational anhedonia”). These facets of anhedonia are intended to roughly correspond to the reward-processing components of ‘liking’ and ‘wanting’ proposed in the preclinical literature (Berridge and Robinson, 1998, Berridge and Robinson, 2003). In addition, we suggest that bridging the gap between preclinical and clinical models of anhedonia may require moving away from the conceptualization of anhedonia as a steady-state, mood-like phenomena, and towards a more behavioral model that emphasizes the influence of anhedonic symptoms on decision-making. To address this issue, we present the concept of “decisional anhedonia”, and highlight the neurobiological networks that may underlie impaired decision-making in the context of reward. These distinctions have been largely overlooked in the extant empirical literature on MDD, which may explain why this literature is replete with inconsistent findings (Forbes, 2009). We suggest that a crucial next step in the field is to refine our assessment and diagnostic tools to better reflect the multi-faceted nature of reward deficits in MDD.
This strategy is not entirely new, and indeed echoes decades-old theoretical models and clinical observations. Neurobiological models of personality have previously emphasized dissociations between “approach” and “consumption” of rewards, with the former constituting a behavioral activation system. These models further posited that DA is primarily linked with approach emotions, and might therefore underlie individual differences in reward seeking behaviors and psychopathology (Cloninger, 1987, Depue and Collins, 1999, Depue and Iacono, 1989, Gray, 1987). Similarly, this dissociation has been noted in the clinical literature; the psychiatrist Donald Klein noted that many patients with depression and anhedonia appeared to enjoy rewards that were readily available, yet complained bitterly about feeling no desire to obtain them (Klein, 1987). While these theories and observations have existed for some time, they have yet to be integrated with the substantial animal literature on the neurobiology of reward processing into a comprehensive framework.
It is the goal of this review to provide such an integrative framework. Central to our approach is the claim that symptom definitions should be grounded in a neurobiological context. In the sections that follow, we begin by summarizing the available empirical literature regarding reward-processing deficits in depression. We argue that the distinction between motivation and pleasure has critical implications for both interpreting the existing literature and for the design of future studies of MDD. Following this review, we summarize the preclinical literature regarding the neural mechanisms of motivational, hedonic and decisional aspects of reward, and compare these mechanisms to neurobiological studies of human MDD. Based on existing preclinical and clinical data of reward processing we suggest that multiple nodes involved in reward circuits are impacted in MDD, and that this dysfunction may underlie differential expression of anhedonic symptoms.
Section snippets
Diagnostic and behavioral studies of anhedonia in depression
In his original definition, Theodule Ribot described anhedonia as the inability to experience pleasure (Ribot, 1896). However, across multiple domains of the social and neural sciences, it has become clear that embedded within the idea of pleasure are multiple constructs, including reinforcement, desire, predicted utility, subjective pleasure, experienced utility, remembered utility, and so forth, each of which describes a unique aspect of reward processing. Attention to these distinctions is
Neurobiological bases of motivational and consummatory anhedonia
In a striking contrast to the behavioral literature, which has largely focused on deficits in hedonic capacity (‘liking’), preclinical neurobiological studies of anhedonia have primarily targeted neural substrates involved in motivation and reinforcement (‘wanting’). Across a variety of studies, ‘liking’ and ‘wanting’ have been linked to a variety of brain regions, neural circuits and neurotransmitters. These include the neurotransmitter dopamine and opioid neuropeptides, sub-cortical
Wanting, liking, choosing: the case for decisional anhedonia
Up to this point, we have considered anhedonia as a steady-state, mood-like phenomenon, in which individuals exhibit a general tendency to feel unmotivated or lack experienced pleasure. However, this conceptualization presents limitations when attempting to link anhedonic symptoms to underlying neurobiological mechanisms, as preclinical neurobiological studies typically examine behavior within a significantly narrower temporal window than is captured by self-report measures in humans. Indeed,
Anhedonia reconsidered
The fundamental goal of this paper has been to emphasize the crucial importance of developing symptom definitions that are aligned with both their clinical presentation and biological basis. In the case of anhedonia in depression, we have noted that while behavioral studies of anhedonia in MDD have largely focused on positively valenced affective stimuli, biological studies have focused on neural substrates that are more closely involved in motivation and decision-making. This mismatch between
Conclusion
In the present review we have argued that studies of anhedonia in MDD should be informed by animal models of reward processing. Specifically, we suggest that current clinical definitions of anhedonia are too broad. As the processes of reward wanting and liking are found to rely on separate neural systems, depression research must attend to these distinctions in order to develop specific neurobiological models and novel treatment targets. As a multi-faceted construct, anhedonia requires a more
Acknowledgements
This manuscript was produced with the support of the National Institute of Mental Health (F31MH087015) to MTT and the National Institute on Drug Abuse (R01DA019670) to DHZ. The authors report no conflict of interest. The authors wish to thank Joshua Buckholtz for thoughtful commentary, and Gabriel Dichter, Andrew Tomarken, Steven Hollon and Richard Shelton for points of inspiration.
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