What is anhedonia

Anhedonia is the decreased ability to experience pleasure from positive stimuli such as social interaction, eating, or sex or a degradation in the recollection of pleasure previously experienced ¹⁾. Anhedonia is a facet of the broad personality trait domain ²⁾. Anhedonia is a lack of enjoyment from, engagement in or energy for life’s experiences; deficits in the capacity to feel pleasure or take interest in things ³⁾. This state is caused by a sheer lack of joy during extreme bouts of depression. One of the factors that has been linked to anhedonia is stress. Anhedonia has been the most extensively studied in major depression ⁴⁾, but, as it also constitutes one important negative symptom of schizophrenia, much literature has also been devoted to anhedonia in psychosis ⁵⁾. Anhedonia has in fact been studied in a large range of neuropsychiatrie disorders, including substance use disorder ⁶⁾, Parkinson’s disease ⁷⁾, overeating ⁸⁾ and various risky behaviors ⁹⁾.

Notably, anhedonic patients with affective disorders have a poorer treatment prognosis than their non-anhedonic counterparts ¹⁰⁾. Accumulating evidence suggests that standard treatments for depression do little to alleviate anhedonia ¹¹⁾ and may even cause reward and emotional blunting ¹²⁾, sexual anhedonia ¹³⁾ and anorgasmia ¹⁴⁾. Furthermore, the presence of anhedonia in a major depressive episode is a predictor of proximal suicide completion ¹⁵⁾. Critically, no US Food and Drug Administration-approved treatment currently exists specifically for anhedonia.

Social anhedonia is defined as an affective construct (less pleasure derived from social encounters) ¹⁶⁾, little is known about the emotional responsivity and expressivity of individuals with high levels of social anhedonia.

Anhedonia is a prominent symptom in neuropsychiatric disorders, most markedly in major depressive disorder and schizophrenia ¹⁷⁾. Based on the latest studies, anhedonia is a multidimensional construct and should not simply be considered as ‘loss of an ability to experience pleasure’ ¹⁸⁾. Deficits in other reward processes, such as valuation, motivation and decision-making, may lead to behaviors that can be interpreted as anhedonia ¹⁹⁾. Hence, distinguishing the deficits in different cognitive subcomponents of anhedonia is essential to identify its neurobiological substrates. Some investigators have suggested dichotomizing anhedonia into ‘consummatory anhedonia’ (the hedonic response to rewards) and ‘anticipatory anhedonia’ (diminished motivation to pursue rewards) ²⁰⁾. Others hold that studies should move away from conceptualization of anhedonia as a steady-state, mood-like phenomena, and instead focus on the reward-related motivational/decisional-making aspect ²¹⁾. Still others propose to bridge the gap between preclinical and clinical studies by isolating the neural substrates of various processes, such as sensing a pleasant stimulus or anticipating expected rewards, computing value and associated costs, determining effort required, deciding to obtain the reward, increasing motivation and performing the action ²²⁾. Changing research strategies and models demand more complicated and elaborate experimental designs to investigate the underlying neural bases of anhedonia.

Depressed patients must display one of two core symptoms of depression: anhedonia or feelings of sadness ²³⁾. Studies have shown that anhedonia and reduced reward learning ²⁴⁾ predict a poorer prognosis ²⁵⁾, with a higher prevalence of treatment failure among anhedonic patients ²⁶⁾. The number of depressed patients with anhedonia suggests that aberrant reward processing, perhaps due to changes in reward circuitry, is a core mechanism underlying depression pathophysiology ²⁷⁾. Recent neuroimaging studies in depressed patients show reduced activation of the reward circuitry in depression, specifically the nucleus accumbens and anterior cingulate cortex ²⁸⁾. Several studies have shown that deep brain stimulation of either the nucleus accumbens or anterior cingulate cortex ameliorates anhedonia in treatment-refractory depression ²⁹⁾. A greater understanding of the cellular mechanisms within brain reward circuitry is needed to provide insights into the anhedonic state and reveal new therapeutic targets.

In depression research, anhedonic depression has been suggested as a specific phenotype ³⁰⁾. Further, in the Research Domain Criteria framework, anhedonia has been suggested as a core construct in the cross-diagnostic study of psychopathology ³¹⁾. Hence, anhedonia might constitute a crossover phenotype between the affective and the trauma-related spectrum. The above mentioned findings motivate further research into symptoms bridging post-traumatic stress and depression such as anhedonia ³²⁾.

Anhedonia has been linked to reward functioning and deficits therein ³³⁾. Reward functioning is the ability to feel pleasure when consuming or collecting stimuli of positive valence. Further, it implies being motivated for obtaining such stimuli and promoting behaviour that produces them. As such, reward is pivotal for driving many human behaviours. Following this, different phases of reward functioning may be defined as distinct behaviors ³⁴⁾. Reward wanting is the anticipatory motivation towards obtaining the stimulus, whereas reward consumption is linked to the pleasure felt by obtaining the stimulus. Reward learning is the ability to increase the amount of obtained stimuli by predicting and performing reward-producing behaviors.

Anhedonia is a common symptom following exposure to traumatic stress and a feature of the post-traumatic stress disorder (PTSD) diagnosis ³⁵⁾. In recent factor analytic studies of PTSD, anhedonia has been found to constitute an independent symptom cluster of PTSD ³⁶⁾. Specifically, in a 7-factor model of PTSD, anhedonia consists of three symptoms, namely loss of interest, detachment and restricted range of affect ³⁷⁾. This anhedonia symptom cluster has been shown to be strongly associated with current depression, reduced mental functioning and quality of life as well as increased suicidal ideation ³⁸⁾. As such, anhedonia might not only suggest severe PTSD, but constitute a comorbidity link between PTSD and depression and be a useful predictor of mental dysfunction and reduced quality of life in trauma survivors ³⁹⁾.

Anhedonia is also common in addictive disorders, including cocaine, but also alcohol, opiate, amphetamine, and cannabis disorders ⁴⁰⁾. Across substances of abuse, the presence of anhedonia correlates with withdrawal symptom severity, craving, and likelihood of relapse, suggesting anhedonia may predict a more difficult course of addiction and worse treatment outcomes ⁴¹⁾. Several studies support the hypothesis that anhedonia is a poor prognostic sign in substance use disorders. For example, lifetime presence of anhedonia significantly predicts continued smoking during smoking cessation treatment, even after adjusting for the potential impact of co-occurring depressed mood ⁴²⁾. Another study found that opiate dependent individuals who were less aroused by pleasant, non-drug related pictures were more likely to continue using heroin during treatment ⁴³⁾.

Anhedonia, a lowered ability to experience pleasure, has been found to be associated with suicidal ideation or suicide attempts in various samples of university students, subjects with depressive spectrum disorders, depressed adolescents, and psychiatric patients ⁴⁴⁾. The search for a relationship between anhedonia and suicide has, however, provided mixed results ⁴⁵⁾. This discrepancy within literature can be explained by, for instance, taking into account the severity and the type of anhedonia. When anhedonia is severe and constitutes an acute dimension, as is the case in depressive disorders, anhedonia is associated with high risk of suicide ⁴⁶⁾. When anhedonia is chronic, as is the case in in non-psychiatric subjects or in stable negative schizophrenia subjects, anhedonia is associated with a low level of suicide compared to the studies’ control groups ⁴⁷⁾. Recently, anticipatory and consummatory anhedonia have been clearly defined as two separate entities ⁴⁸⁾. However, this distinction has not yet been explored in relation to suicidality. Still, several authors ⁴⁹⁾ previously suggested that recent change in anhedonia and particularly in its social component may be especially predictive of suicidal ideation. Two recent studies have explored this hypothesis.

In the first study, anhedonia was evaluated twice among 1529 psychiatric patients ⁵⁰⁾, once on admission and once 6 weeks later. Anhedonia was rated using a subscale from the Beck Depression Inventory (BDI-II) which comprised four items (loss of interest, loss of pleasure, loss of interest in sex and loss of energy). Suicidal ideation was rated using the “Suicidal thoughts and wishes” item of the BDI-II. These were separated from a subscale derived from the BDI-II which measured cognitive and affective symptoms of depression. Anhedonia was associated with suicidal ideation at baseline and termination even when the cognitive/affective dimension of depression was controlled for. However, symptom-level analyses showed that loss of interest and loss of pleasure were associated with a higher level of suicidal ideation at baseline and that loss of interest was associated with a higher level of suicidal ideation at termination. Winer et al. ⁵¹⁾ suggest that recent change of anhedonia, as rated by the anhedonia subscale of the BDI-II, is associated with suicidal ideation and that loss of interest is the most predictive factor. The authors suggest taking into account the different types of anhedonia when examining suicidal risk.

The second study, by the same team ⁵²⁾ used a sample of 1122 undergraduate students and examined the relationship between recent anhedonia change, suicidal ideation and suicide attempt. Winer et al. ⁵³⁾, used a total of three scales: the Specific Loss of Interest and Pleasure Scale (SLIPS, 11) that rates changes in the ability to take interest or pleasure in social experiences, the Center of Epidemiological Studies Depression Scale (CES-D), and the Suicidal Behaviors Questionnaire-Revised (SBQ-R). The Specific Loss of Interest Scale (SLIPS) was primarily designed to measure levels of interest over time (2 week period) ⁵⁴⁾. Each of the 23-items has a 3-point scale, with higher scores denoting increasing levels of anhedonia.

The Specific Loss of Interest and Pleasure Scale (SLIPS) rates both the anticipatory and consummatory components of anhedonia as accurately as the anhedonia subscale from the BDI-II ⁵⁵⁾. In a sample of 182 undergraduate students, one study reported significant correlations between the anticipatory or consummatory subscales of the Temporal Experience Pleasure Scale (TEPS) and the Specific Loss of Interest and Pleasure Scale (SLIPS) or the anhedonia subscale of the BDI-II ⁵⁶⁾. Another study in various samples or healthy or psychiatric subjects reported significant correlations between the different items of the anhedonia subscale of BDI and the anticipatory or consummatory subscales of the Temporal Experience Pleasure Scale (TEPS) ⁵⁷⁾.

Thus, changes in consummatory and anticipatory anhedonia and particularly in its social component were associated with suicidal ideation even when depressive symptoms were controlled for, although the association with suicide attempts was not significant.

Primary vs. secondary reward

The experience of pleasure can pertain to many stimuli that are instinctual (e.g. food, sex) versus non-instinctual (e.g. photography, reading). It could be argued that food and sex represent “primary” rewards (inherent rewards), whereas photography or money are secondary rewards (no inherent reward in itself and for which reward value must be learned). This distinction of “reward type” may complicate anhedonia research in two ways. First, neurobiological response to a primary reward may overlap with secondary reward, but may also have independent actions ⁵⁸⁾. In a meta-analysis of 87 studies to determine the overlapping and distinct brain areas activated in response to monetary, erotic and food rewards, there were some differences in activation within a common network, which included the ventromedial prefrontal cortex, ventral striatum, amygdala, anterior insula and mediodorsal thalamus ⁵⁹⁾. Notably, a study evaluating fluid and monetary incentives demonstrated that fluids were not as susceptible to contextual framing as secondary reward, and were more related to the experience of satiety or temperature ⁶⁰⁾, which also may affect distinctions in neural activation. In particular, the primary rewards (food and erotic) resulted in activation of the anterior insula and amygdala (in the case of erotic reward), while the monetary secondary reward activated the orbitofrontal cortex. Furthermore, the authors suggest that even within the neocortex there may be a difference in how primary and secondary rewards are encoded. Accordingly, the more phylogenetically recent anterior portion of the OFC was more likely to respond to monetary reward. While the same group previously demonstrated that the posterior OFC is more activated in response to primary stimuli (e.g. erotic) ⁶¹⁾, this requires replication due to some inconsistencies in findings ⁶²⁾. In contrast to the view of distinct activity with reward type, in a meta-analysis of 206 studies, Bartra and colleagues ⁶³⁾ reported that both primary and secondary rewards activated the same brain regions including the striatum and ventromedial prefrontal cortex. Based on these findings, the authors suggest that assertions of domain-based differences in functional activity should be interpreted with caution.

Second, the distinction of incentive type limits the translation from preclinical to clinical studies, considering most preclinical work uses primary reward as incentive while most human studies employ secondary rewards. Importantly, investigation of primary reward provides a more direct comparison with animal studies. The following sections will expand on this idea through a review of the preclinical and clinical methods that have been developed to measure anhedonia and will also evaluate their generalizability and ability to measure the different facets of anhedonia. Indeed, one of the ultimate difficulties in measuring anhedonia lies in devising measures that tap into the objective or subjective nature of this construct.

Anhedonia causes

Anhedonia can arise from impairments in various facets of reward processing, including desire for reward, anticipation of reward, effort to attain reward, consummatory pleasure, as well as cognitive aspects of learning stimulus-reward associations ⁶⁴⁾. Evidence suggests that there are specific neuroanatomical areas that underlie various facets of reward processing, including the prefrontal cortex (orbitofrontal cortex, ventromedial prefrontal cortex and anterior cingulate cortex), dorsal striatum (caudate and putamen), nucleus accumbens and amygdala. While dopamine has been the main neurotransmitter investigated in relation to reward, there is also mounting evidence that systems other than dopamine are critically involved in the reward process. Specifically, opioids, glutamate, gamma-aminobutyric acid (GABA) and serotonin also play a significant role. Opioids and GABA, for example, may be particularly important in the experience of consummatory pleasure ⁶⁵⁾, while serotonin may be more associated with increased impulsivity and preference for immediate reward ⁶⁶⁾.

A significant body of literature suggests that inflammation or excessive immune activity, may underlie anhedonia across disorders ⁶⁷⁾. During acute inflammatory events, such as a cold, circulating inflammatory mediators produce “sickness behaviors” such as reduced activity, which serve the adaptive function of conserving energy and speeding healing ⁶⁸⁾. However, maladaptive chronic low-grade inflammation appears to be present in many psychiatric disorders, and has been implicated in symptoms of anhedonia seen in depression, schizophrenia, and cancer-related fatigue, among other conditions ⁶⁹⁾.

Anhedonia symptoms

Anhedonia is listed in the American Psychiatric Association, 2013, DSM-5 ⁷⁰⁾ among the main schizophrenia negative symptoms, and it is defined as “the decreased ability to experience pleasure from positive stimuli or a degradation in the recollection of pleasure previously experienced.” Similar concepts—loss of interest or pleasure, not feeling any enjoyment in activities that were previously considered pleasurable—are also reported among the main symptoms and criteria for the diagnosis of major depressive disorder ⁷¹⁾. These symptoms are often associated with “social withdrawal.” The condition of anhedonia, that is, in its stricter connotation, the loss of feeling pleasure, is the disruption of just one facet in a complex reward-processing phenomenon that encompasses pleasure expectation, reward evaluation, determination of the effort necessary to obtain it, and planning and deciding the appropriate strategy to repeat the pleasurable experience. A deficit in any of these aspects in the reward process may result in behaviors that could be interpreted as “anhedonia.” For instance, the expression “a degradation in the recollection of pleasure previously experienced” refers to pleasure-triggered cognitive processes codified in brain areas and by mechanisms very likely different from those underpinning pleasure perception ⁷²⁾, and this is true either for the recollection of a previous pleasurable experience or for its degradation. Thus, although several authors strongly sustain that the definition of anhedonia should be restricted to a well-defined neurobiological construct ⁷³⁾, the term is often used both in the clinical evaluation of patients and in basic science experimental contexts in a broader connotation.

Anhedonia test

Anhedonia measurement in depressed humans utilizes direct symptom scales or behavioral tasks ⁷⁴⁾. While scale methods provide direct evidence of patients’ experience, combining behavioral methods with neuroimaging offers an opportunity to disentangle different components of reward processing and identify neurobiological underpinnings associated with such abnormalities.

The four main validated self-report measures of anhedonia used in clinical research are the Snaith-Hamilton Pleasure Scale (SHAPS) ⁷⁵⁾, the Fawcett-Clark Pleasure Capacity Scale (FCPS) ⁷⁶⁾, the Revised Chapman Physical Anhedonia Scale (CPAS) and the Chapman Social Anhedonia Scale (CSAS) ⁷⁷⁾ (Table 1). Ideally, a scale quantifying anhedonia in the context of major depressive disorder should be able to measure different aspects of anhedonia, detect state versus trait differences, and take into account varying cultural beliefs and preferences (generalizability). Although all of these scales have been validated in clinical populations, they differ in their ability to meet these criteria ⁷⁸⁾.

The Snaith-Hamilton Pleasure Scale (SHAPS) ⁷⁹⁾ remains the gold standard for measuring anhedonia in depression ⁸⁰⁾. It is recommended that any scale should be validated in the population of interest prior to use. While the Revised Chapman Physical Anhedonia Scale (CPAS) and Chapman Social Anhedonia Scale (CSAS) have been used in to assess anhedonia in studies of depression, only the Snaith-Hamilton Pleasure Scale (SHAPS) ⁸¹⁾, Fawcett-Clark Pleasure Capacity Scale (FCPS) ⁸²⁾ and Dimensional Anhedonia Rating Scale (DARS) ⁸³⁾ have undergone empirical scale validation procedures in major depressive disorder samples. Although the SHAPS only measures consummatory pleasure, it does so across several domains and with limited cultural biases. Considering consummatory reward is not consistently impaired in depression, the SHAPS may be useful to identify subgroups within major depressive disorder or test specific effects of treatment, but may not have the sensitivity to be utilized as a predictor of treatment response. Further study is needed to determine whether deficits in reward responding are dependent on reward type (e.g. social, food, physical), for which the Dimensional Anhedonia Rating Scale (DARS) ⁸⁴⁾ may be able to tease apart any potential differences given its component structure is based on reward type. Most importantly, in light of emerging evidence indicating that different facets of reward processing are subserved by partially dissociable neurobiological systems (Der-Avakian & Markou, 2012), it will be imperative for future scale development to evaluate desire, motivation, effort, and consummatory pleasure across different domains of anhedonia, as well as measuring the stability of the construct.

Table 1. First generation scales to measure anhedonia

In the last 8 years there has been a resurgence in refining anhedonia scales with at least 4 new published self-report questionnaires (Table 2), which attempt to take into account different facets of reward function instead of only consummatory pleasure. All of these scales take approximately 5-10 minutes to complete.

Table 2. Second generation scales to measure anhedonia

Anhedonia treatment

No effective treatments for anhedonia have been found to date. Ketamine, recently the focus of research ⁹⁶⁾ as a rapid-acting antidepressant that can ease symptoms within hours instead of weeks, is now being studied as a fast-acting mood-lifter to treat bipolar patients. To test their theory, the researchers infused Ketamine or a placebo into 36 patients in the depressive phase of bipolar disorder ⁹⁷⁾. They then detected any mood changes using rating scales for anhedonia and depression. By isolating scores on anhedonia from scores on other depression symptoms, the researchers discovered that ketamine was triggering a strong anti-anhedonia effect sooner — and independent of — the other effects, they report in the study, which was published in the journal Translational Psychiatry. Levels of anhedonia plummeted within 40 minutes in patients who received ketamine, compared with those who received the placebo, according to the researchers, who add the effect was still detectable in some patients two weeks later.

Other depressive symptoms improved within two hours, the researchers noted. The anti-anhedonic effect remained significant even in the absence of other antidepressant effects, suggesting a unique role for the drug.

Next, the researchers scanned the brains of a subset of the ketamine-infused patients, using positron emission tomography (PET), which shows what parts of the brain are active by tracing the destinations of radioactively-tagged glucose — the brain’s fuel.

The scans showed that ketamine jump-started activity not in the middle brain area they had expected, but rather in the dorsal (upper) anterior cingulate cortex, near the front middle of the brain, and putamen, deep in the right hemisphere.

Boosted activity in these areas may reflect increased motivation towards or ability to anticipate pleasurable experiences, according to the researchers.

Depressed patients typically experience problems imagining positive, rewarding experiences, which would be consistent with impaired functioning of this dorsal anterior cingulate cortex circuitry, they said.

However, confirmation of these findings must await results of a similar NIMH (National Institute of Mental Health) ketamine trial nearing completion in patients with unipolar major depression, the researchers noted.

Other evidence suggests that ketamine’s action in this circuitry is mediated by its effects on the brain’s major excitatory neurotransmitter, glutamate, as well as downstream effects on a key reward-related chemical messenger, dopamine.

The findings add to mounting evidence in support of the antidepressant efficacy of targeting this neurochemical pathway, according to the researchers. Ongoing research is exploring, for example, potentially more practical delivery methods for ketamine and related experimental antidepressants, such as a nasal spray, they noted.

Recent 2016 meta analysis ⁹⁸⁾, which drew data from several clinical trials of ketamine in individuals with treatment-resistant major depressive disorder or bipolar disorder, found an association between reductions in suicidal thoughts and anhedonia that occurred independently of depressive symptoms. The authors also found that anhedonia, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS), was associated with suicidal thoughts independent of depressive symptoms both before and after ketamine administration ⁹⁹⁾. One day post-ketamine administration, improvements on the SHAPS accounted for an additional 13% of the variance in suicidal thought reduction, beyond the influence of depressive symptoms. The Beck Depression Inventory (BDI) anhedonia subscale was not significantly associated with suicidal thoughts after adjusting for depressive symptoms. They concluded that suicidal thoughts may be related to symptoms of anhedonia independent of other depressive symptoms. These results have implications for the potential mechanisms of action of ketamine on suicidal thoughts ¹⁰⁰⁾.