Pleasure and depression: anhedonia as a core feature

Dipartimento di Neuroscienze ed Imaging
Università G. D’Annunzio
Chieti, ITALY

Pleasure and depression: anhedonia as a core feature

by M. Di Giannantonio, Italy

Anhedonia is a condition in which the capacity to experience pleasure is totally or partially lost. Although anhedonia is a feature of major depressive disorder according to the diagnostic criteria for major depression in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, to date it has received relatively little attention in terms of clinical research. In the past, however, anhedonia has played an important role in theories of psychopathology. In this paper, we review anhedonia by starting with the different historical conceptualizations of pleasure, which have both practical and theoretical implications for the analysis of anhedonia. Anhedonia can refer both to a state symptom in various psychiatric disorders and a personality trait. The main methods utilized to investigate and assess anhedonia (or hedonic capacity) are presented. The neural system underlying reward is becoming increasingly well defined in humans, and there are multiple constructs embedded within the concept of pleasure. We review the neurobiology of anhedonia that reflects the deficits in hedonic capacity. Currently, there is no definitive specific pharmacological approach to the treatment of anhedonia in depression. Preliminary findings have described the efficacy of agomelatine in the treatment of anhedonia, and the effect of agomelatine on anhedonia may be a novel property among antidepressant agents, warranting further investigation. The efficacy of agomelatine on this dimension may hold particular importance for the treatment of patients with major depression.

Medicographia. 2013;35:292-298 (see French abstract on page 298)

The word anhedonia was coined by the French psychologist Théodule-Armand Ribot in 1896,1 and its meaning stems etymologically from the Greek αν- (an-; without) + ηδονη(hedone; pleasure). Ribot defined anhedonia as the inability to experience pleasure. Pleasure may be considered a specific sensation or a general quality of any state of consciousness. In the latter situation, emotions can be measured against a yardstick of pleasure or pain such that “one or the other of these opposites gives the basic feeling tone to each emotion.”2 Pleasure and pain are also believed to be essential forces for human motivation (ie, human beings seek one and avoid the other), and hence anhedonia might be expected to be accompanied by a reduction in the general energy of a person’s behavior. Ribot’s point of view was that pleasure was not a constitutive element of the various feelings, but rather a complex state derived from the satisfaction of certain tendencies.1 Obviously, different conceptualizations of pleasure have practical and theoretical implications for the analysis of anhedonia.

Anhedonia played an important role in theories relating to psychopathology at the beginning of the 20th century.3 For Kraepelin, loss of pleasure and interest and the annihilation of emotional activity were aspects of his wider concept of “indifference.”4 He spoke about anhedonia as a core symptom of a state of individual suffering that was a part of dementia praecox. Kraepelin described his patients as not feeling any real joy in life; according to him, the characteristic indifference of patients toward social interactions that would previously elicit emotion, the extinction of affection for family and friends, and the loss of satisfaction in their work and vocation and in recreation and pleasure were rather often the first symptoms to manifest, marking the onset of the disease. Bleuler, noting the indifference that some patients exhibited toward their friends, acquaintances, and colleagues, and toward life itself, defined anhedonia as a basic feature of their disease, « an external signal of their pathological condition.”5 What emerges when reading the works of Kraepelin and Bleuler is that they fundamentally interpreted the loss of the pleasure experience as only one facet of the deterioration of the patient’s emotional life. After the turn of the century, however, psychiatric interest in anhedonia faded, and Jaspers in his “Allgemeine Psychopathologie” does not mention it, considering loss of pleasure to be part of “apathy.”6

As far back as the original Feighner criteria published in 1972, anhedonia has, however, been presumed to be a core feature of major depressive disorder (MDD),7 and Klein’s concept in the 1970s of endogenomorphic depression revived interest in the notion of anhedonia.8 Klein’s definition of anhedonia was that of “a sharp, unreactive, pervasive impairment of the capacity to experience pleasure, or to respond affectively to the anticipation of pleasure.” From the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) onward, anhedonia has been considered a core symptom of major depression separate from depressed mood.9 Moreover, it is a necessary symptom for a diagnosis of depression with melancholic features. In 1992, anhedonia entered the lexicon of the International Classification of Diseases. The DSM (Fourth Edition, Text Revision; DSM-IV-TR) defines anhedonia as diminished interest or pleasure in response to stimuli that were previously perceived as rewarding during a premorbid state.10

Recent reports estimate that approximately 37% of patients with MDD experience clinically significant anhedonia.11 Compared with MDD patients without anhedonia, MDD patients with anhedonia have been found to demonstrate greater social impairment, have higher scores on measures of depression and hopelessness, be less neurotic, be younger, and be more often female than male.12 There is also evidence to suggest a correlation between anhedonia and psychomotor retardation among adults with MDD.13 Different studies have found that anhedonia can precede the onset of a depressive episode14 and is a common residual symptom after treatment.15

Table I
Table I. Classification of various types of anhedonia.

The term anhedonia can refer both to a state symptom in various psychiatric disorders and a personality trait.16 For example, anhedonia is one of the negative symptoms of schizophrenia. There are, however, important differences between the anhedonic symptoms in mood disorders and those in schizophrenia as regards time course and degree of insight. Anhedonia has also been linked to anxiety and adjustment disorders,17 suicidal ideation,18 successful suicide,19 and Parkinson disease.20 Moreover, in various disorders and dysfunctional behaviors such as overeating and eating disorders in general,21 alcohol and substance abuse,22 and impulse control disorders,23 anhedonia is often considered to be a prodromal state (Table I).

Diagnosing anhedonia

The limited attention that anhedonia has received to date in terms of clinical research could, in part, be the result of the low availability of short, well-validated, and easy-to-use tools for its assessment and investigation.24

There are two methods that are utilized the majority of the time to investigate and assess anhedonia (or hedonic capacity): laboratory-based measures and rating scales. The first approach involves signal-detection methodology, physiological measures, and subjective hedonic response to pleasant stimuli. Besides these behavioral measures, anhedonia can also be evaluated using hemodynamic and electrophysiological measures. The second approach is primarily diagnostic and involves the use of questionnaires. Anhedonia forms the subject of a subsection of questions on certain popular rating instruments like the Bech-Rafaelsen Melancholia Scale (BRMS), used in depression evaluation, and the Scale for the Assessment of Negative Symptoms (SANS), used in schizophrenia evaluation. The first attempts to assess anhedonia alone go back to the end of the 1960s,with the Reinforcement Survey Schedule (RSS) and the Pleasant Events Schedule (PES). Since then, many researchers have attempted to operationalize the concept, and several scales have been developed to assess anhedonia or hedonic capacity. Specific scales in use for the measurement of anhedonia are: the Physical and Social Anhedonia Scales (PAS and SAS, respectively), self-administered tests that consider anhedonia above all as a trait; the Fawcett-Clark Pleasure Scale (FCPS), a 36-item scale in which subjects have to imagine potentially rewarding situations; the two scales developed by Brown and colleagues, one self-administered (Pleasurable Activity Self-Rating Scale [PASRS]) and the other administered by an observer (Pleasurable Activity Observer Rating Scale [PAORS]); the Mood- Related Pleasant Events Schedule (MRPES), derived from the PES; and the Snaith-Hamilton Pleasure Scale (SHAPS). Furthermore, it is worth mentioning the 10-cm visual analog scale (VAS) for pleasure and the Temporal Experience of Pleasure Scale (TEPS), which was developed to assess anticipatory and consummatory pleasure.

Of these scales, the one that has been used most in the past few years is SHAPS,25 a 14-item self-report questionnaire designed to measure hedonic tone. SHAPS has shown adequate overall psychometric properties in clinical and student samples, and was found to be highly reliable in terms of internal consistency and test-retest stability. Its discriminant validity has been supported by its lack of association with items related to depressed mood and anxiety on the Montgomery- Asberg Depression Rating Scale (MADRS).25 Furthermore, SHAPS has been found to correlate in a theoretically meaningful way with other measures of affect and personality. Patients with depression, psychosis, or substance dependence scored significantly higher on SHAPS than healthy controls, while patients with depression displayed the highest SHAPS score. The items on SHAPS cover four domains of hedonic experience: interest/pastimes, social interaction, sensory experience, and food/drink. SHAPS instructs participants to agree or disagree with statements of hedonic response in pleasurable situations. Four responses are possible: strongly disagree, disagree, agree, or strongly agree. If the subject answers “strongly agree” or “agree,” the item is assigned a score of zero, while for “disagree” or “strongly disagree,” the score is 1. A total score can be derived by summing the scores for the answers to each item, thereby producing a total score ranging from 0 (absence of anhedonia) to 14 (complete anhedonia). Thus, higher SHAPS total scores indicate greater anhedonia, and a score of 3 or more indicates a significant reduction in hedonic capacity and seems to discriminate between healthy and clinically depressed patients. Participants completing SHAPS are instructed to respond on the basis of their ability to experience pleasure “in the last few days.”

Neurobiology of pleasure and anhedonia

The neural system underlying reward is quite well defined in animals and humans: the euphoric response to dextroamphetamine, cocaine-induced euphoria, monetary reward, and even pleasurable responses to music, pictures, and attractive faces have all been associated with activity within the nucleus accumbens (NAcc), ventral caudate, and ventral putamen.26 More specifically, release of dopamine (DA) within the ventral striatum may be involved in the anticipation and generation of motor responses associated with future rewards, the so-called “wanting.”27 On the other hand, the main mediators of pleasurable hedonic experience (“liking”) appear to be the endogenous opioids, particularly in the shell of the NAcc and the ventral pallidum.28 The orbitofrontal cortex (OFC) and anterior cingulate cortex also play important roles in the neural reward system. The former is implicated in the subjective representation of incentive salience, hedonic impact, and hedonic experience; the latter is primarily involved in evaluating the costs and benefits of a given set of options.29 Finally, other cerebral structures such as the amygdala are also involved in the reward system, as are neurotransmitters such as serotonin and γ-aminobutyric acid (GABA). Serotonin, for example, has a recognized effect on the modulation of DA and opioid release: serotonin reuptake inhibitors raise the threshold for brain stimulation reward and reduce the firing rate of DA neurons in the ventral tegmental area.30

L-3,4-dihydroxyphenylalanine (L-DOPA) alterations in the striatum are present in depressed individuals with flat affect or psychomotor slowing, but not in depressed individuals without these symptoms.31 One study restricted to patients with MDD and anhedonic symptoms reported decreased DA transport binding in the striatum.32 Data supporting a role of DA in MDD come from studies of DA turnover, in which it has been observed that individuals with MDD have decreased cerebrospinal fluid levels of homovanillic acid, the primary metabolite of DA.28 These studies suggest the presence of a reduced basal dopaminergic tone in MDD. Additionally, pharmacological interventions that block or deplete DA can induce or deepen depressive symptoms in currently depressed or remitted individuals, further implicating DA dysfunction in MDD. Moreover, in animal models of depression, several lines of evidence support the role of DA dysfunction.33 Studies investigating the effects of a deficient endogenous opioid system in depression and anhedonia have by contrast produced largely equivocal findings,34 and to date, no studies have specifically evaluated opioid systems in reward liking or other aspects of reward processing in MDD patients. In MDD, both the OFC and the anterior cingulate cortex have shown a variety of alterations in gross morphology, neuronal structure, function, connectivity, and neurochemistry.28

Figure 1
Figure 1. Putative agomelatine mechanism of action in relieving

Abbreviations: 5-HT2C, serotonin 2C; α2R, α2-adrenergic receptor; BDNF,
brain-derived neurotrophic factor; DA, dopamine; D2R, dopamine receptor 2;
MT1 and MT2, melatonergic receptor subtypes; NA, norepinephrine.

The deficit in DA transmission could be associated with decreased availability of brain-derived neurotrophic factor (BDNF) and increased glucocorticoid signaling.35 BDNF has been shown in particular to regulate DA neurons in the ventral tegmental area, and alterations in BDNF concentrations can influence mesolimbic DA responses to reward and resiliency to stress.36 Treatment with antidepressant medication increases BDNF concentrations, stimulates neurogenesis, and reverses the inhibitory effects of stress, particularly in the hippocampus.37 In recent preclinical studies, the new-generation antidepressant agomelatine showed the ability to enhance BDNF levels38 and modulate neuronal plasticity, both in the hippocampus and the prefrontal cortex.39 These effects seem to be associated with antidepressant-like effects and an increase in motor activity and exploratory behavior, hypothetically reversing a deficit in motivational drive and reward (Figure 1).39

Treating anhedonia in major depression

Currently, there is no definitive specific pharmacological approach to the treatment of anhedonia in depression. An important issue concerns whether patients with anhedonia have a different pattern of symptoms to patients without anhedonia. Such differential symptom expression could have important implications regarding the etiology of MDD and its prevention and treatment.

Despite it having been shown in the 1970s that the presence of anhedonia is predictive of antidepressant response,8 studies in the current literature often neglect to assess anhedonia in the evaluation of antidepressant response, and efficacy data on this specific dimension are sparse.Boyer showed a late effect of sertraline on anhedonia (over 21 to 56 days), which occurred after its effects on depression and anxiety,40 while in a study by Tomarken, the catecholaminergic effects of bupropion SR 300 tended to produce more robust effects than placebo on anhedonia/positive affect, particularly during a 6-week initial treatment phase.41

However, for many authors, anhedonia is considered a particularly difficult symptom to treat, as accruing evidence suggests that current first-line pharmacotherapies (eg, selective serotonin reuptake inhibitors [SSRIs]) do not adequately address motivational and reward-processing deficits in depression.42 Indeed, their ability to improve diminished positive affect by relieving symptoms of low energy, decreased motivation, and anhedonia has been questioned.43 A related issue is that some patients associate their SSRI treatment with an experience of emotional blunting, whereby emotional responses to both aversive and pleasurable experiences are diminished.42 Thus, increases in serotonin function produced by SSRIs could produce a form of “emotional constraint” in which the salience of both rewarding and aversive stimuli is lost.44 Considering the widespread use of SSRIs, such an effect could have considerable personal, clinical, and social implications, and the presence of anhedonic symptoms is considered a predictor of poor treatment response.45 Moreover, investigating the effect of SSRIs on emotional responses in depressed patients is difficult, because loss of pleasure may persist even during clinical remission.46 In addition, modest degrees of emotional blunting might be difficult for individuals to subjectively detect or report.

Agomelatine (S20098, N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide) has a novel neurochemical mechanism that is unlike that of other antidepressants. It is an MT1 and MT2 melatonergic receptor agonist and a selective antagonist of the 5-HT2C receptors. The main hypothesis explaining the antidepressant action of agomelatine is that it acts synergistically on both the melatonergic and the 5-HT2C receptors. This synergy may resynchronize circadian rhythms. Agomelatine causes the release of DA specifically in the prefrontal cortex (no release in the NAcc or striatum) and norepinephrine in the prefrontal cortex and hippocampus, without affecting extracellular levels of serotonin.47,48 Evidence from preclinical and clinical studies suggests that agomelatine has antidepressant properties, alleviates symptoms of anxiety associated with depression, and rapidly relieves symptoms compared with placebo.49 In addition, the tolerability and safety profile of agomelatine includes a low propensity to cause sexual dysfunction, absence of discontinuation symptoms upon withdrawal, and improvement in daytime functioning and quality of sleep associated with depression.49

Table II
Table II. Agomelatine efficacy in the various dimensions of depression.

Abbreviations: HAM-A, Hamilton Anxiety Scale; HAM-D, Hamilton Depression Rating Scale;
LSEQ, Leeds Sleep Evaluation Questionnaire; QOL, quality of life; SHAPS, Snaith-Hamilton
Pleasure Scale.
After reference 51: Di Giannantonio et al. J Biol Regul Homeost Agents. 2011;25(1):109-114.
© 2011, BIOLIFE, s.a.s.

Given its novel neurochemical mechanism, the antidepressant activity of agomelatine may have different and specific effects on the broad range of symptoms usually observed in a depressive syndrome. The specific effect of circadian rhythm resynchronization may contribute to the regulation of hedonic capacity.50 In view of the latter, a line of studies was inaugurated to test the possible use of agomelatine in the treatment of anhedonia. Two studies have described the efficacy of agomelatine in the treatment of anhedonia.51,52 The first, an open-label 8-week study, included 30 male and female outpatients aged 18 to 60 years old, with a DSM-IV diagnosis of MDD. The primary end points were reduction in depressive and anxiety symptoms, expressed by the scores on the Hamilton Depression and Anxiety Rating Scales (HAM-D; HAM-A). The secondary end points were related to the reduction in the degree of anhedonia and insomnia. In this open-label study, agomelatine was shown to be a possible therapeutic option for patients with MDD. In line with previous studies in which agomelatine was associated with early clinical improvement, this study also provided evidence of an early response (first week of treatment) and improvement in depression scores following an increase in the agomelatine dose, with a good tolerability profile (Table II).51 Moreover, agomelatine was shown to be efficacious in the treatment of anhedonia. A reduction of 1.6 points from baseline was observed on SHAPS after the first week of treatment (P<0.05), with the reduction increasing at different time points until the end of the trial, whereupon the level of significance was even greater (P<0.01).51

In the second study, the effects of agomelatine on anhedonia were compared with those of venlafaxine XR. In this open-label, 8-week parallel-group pilot study, patients with MDD were randomly started on either agomelatine at a dose of 25-50 mg/day (n=30) or venlafaxine XR at a dose of 75-150 mg/ day (n=30). Treatment outcomes in terms of improvement in anhedonia (SHAPS), depression, and anxiety scores (HAM-D; HAM-A) were assessed after 1 (T1), 2 (T2), and 8 (T3) weeks. A significant reduction over time was observed in SHAPS scores in both the agomelatine (F=20.74; P<0.001) and the venlafaxine XR (F=3.27; P<0.5) groups. However, there was a significant difference between groups in favor of agomelatine at T1 (P<0.05), T2 (P<0.01), and T3 (P<0.01), with the number needed to treat being 8 subjects in favor of agomelatine in terms of the presence or absence of an anhedonic state (SHAPS ≥3) at study end (Figure 2).52 A significant reduction in HAM-D and HAM-A scores was observed for both groups (P<0.05), with no difference between groups, but onlypatients who were treated with agomelatine showed a statistically significant improvement in scores on the Clinical Global Impression (CGI) scale (t=2.94; P<0.05). Improvements in anhedonia scores were detected as early as 1 week after treatment initiation with agomelatine, which was a beneficial characteristic, especially given the usually relatively slow onset of antidepressant efficacy with current agents. In both of these studies, use of agomelatine did not determine the onset of hypomanic or manic symptoms.52

Figure 2
Figure 2.
Agomelatine versus venlafaxine in treating anhedonia.

Abbreviations: HAM-A, Hamilton Anxiety Scale; HAM-D, Hamilton Depression Rating Scale; SHAPS, Snaith-Hamilton Pleasure Scale.
After reference 52: Martinotti et al. J Clin Psychopharmacol. 2012;32(4):487-491. © 2012, Lippincott Williams & Wilkins.

The results of these two studies need to be interpreted with caution due to some limitations. First, the small sample size does not allow for firm conclusions to be drawn. Second, the absence of a placebo group and the open design are weaknesses that temper the interpretation of the results. The results regarding agomelatine and anhedonia are difficult to compare with those from other clinical studies, as anhedonia is a dimension that has been poorly characterized in all the major clinical trials involving treatment of MDD.


Different studies have found that anhedonia can precede the onset of a depressive episode,14 influence its severity, and predict poor outcome 12 months later.45 Moreover, anhedonia is considered to be a common residual symptom after treatment15 and is associated with dysfunction in the brain reward system.26

The limited attention that anhedonia has so far received in terms of clinical research could be the main explanation for the fact that there is currently no definitive specific pharmacological approach to the treatment of anhedonia in depression. Anhedonia has been poorly characterized in all the major clinical trials involving treatment of MDD, where it has only been considered as one of a large range of symptoms, despite beingone of the two core symptoms of major depression. Anhedonia warrants further study, as an important issue concerns whether patients with anhedonia have a different pattern of symptoms to patients without anhedonia: such differential symptom expression could have important implications with respect to the etiology of MDD and its prevention and treatment. Differentiating patients into subtypes in line with their symptom typology and the phenomenological approach may represent the future of psychopharmacology, resulting in the right choice of antidepressant for the specific symptom(s). Given its novel neurochemical mechanism, the antidepressant activity of agomelatine may have different specific effects on the broad range of symptoms usually observed in a depressive syndrome, and the specific effect of circadian rhythm resynchronization may contribute to the regulation of hedonic capacity. The original effect of agomelatine on anhedonia is a novel property among antidepressant agents and may hold particular importance for the treatment of patients with major depression: it thus deserves further investigation with larger samples and double-blind, placebo-controlled designs. _

1. Ribot T. La psychologie des sentiments. Paris, France: Felix Alcan; 1896.
2. Tracy TJ. Physiological Theory and the Doctrine of the Mean in Plato and Aristotle. The Hague, The Netherlands: Mouton; 1969.
3. Myerson A. Anhedonia. Am J Psychiatry. 1923;2:87-103.
4. Kraepelin E. Dementia Praecox and Paraphrenia. Barclay BM, trans. Edinburgh, England: E. & S. Livingstone; 1919.
5. Bleuler E. Dementia Praecox. Leipzig and Vienna: Franz Deuticke; 1911.
6. Jaspers K. Allgemeine Psychopathologie. 5th ed. Berlin, Germany: Springer- Verlag; 1948.
7. Feighner JP, Robbins E, Guze SB, Woodruff RA Jr, Winokur G, Munoz R. Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry. 1972;26: 57-63.
8. Klein DF. Endogenomorphic depression. A conceptual and terminological revision. Arch Gen Psychiatry. 1974;31:447-454.
9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.
10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
11. Pelizza L, Ferrari A. Anhedonia in schizophrenia and major depression: state or trait? Ann Gen Psychiatry. 2009;8:22.
12. Fawcett J, Clark DC, Scheftner WA, Hedeker D. Differences between anhedonic and normally hedonic depressive states. Am J Psychiatry. 1983;140:1027- 1030.
13. Lemke MR, Puhl P, Koethe N, Winkler T. Psychomotor retardation and anhedonia in depression. Acta Psychiatr Scand. 1999;99:252-256.
14. Dryman A, Eaton WW. Affective symptoms associated with the onset of major depression in the community: findings from the US National Institute of Mental Health Epidemiologic Catchment Area Program. Acta Psychiatr Scand. 1991; 84(1):1-5.
15. Taylor DJ, Walters HM, Vittengl JR, et al. Which depressive symptoms remain after response to cognitive therapy of depression and predict relapse and recurrence? J Affect Disord. 2010;123(1-3):181-187.
16. Loas G, Pierson A. Anhedonia in psychiatry: a review. Ann Med Psychol (Paris). 1989;147:705-717.
17. Silverstone PH. Is anhedonia a good measure of depression? Acta Psychiatr Scand. 1991;83:249-250.
18. Oei TI, Verhoeven WM, Westenberg HG, Zwart FM, van Ree JM. Anhedonia, suicide ideation and dexamethasone nonsuppression in depressed patients. J Psychiatr Res. 1990;24:25-35.
19. Fawcett J. The morbidity and mortality of clinical depression. Special issue: Affective disorders: current and future perspectives. Int Clin Psychopharmacol 1993;8:217-220.
20. Isella V, Iurlaro S, Piolti R, et al. Physical anhedonia in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2003;74:1308-1311.
21. Davis C, Woodside DB. Sensitivity to the rewarding effects of food and exercise in the eating disorders. Compr Psychiatry. 2002;43:189-194.
22. Martinotti G, Carli V, Tedeschi D, et al. Mono- and polysubstance dependent subjects differ on social factors, childhood trauma, personality, suicidal behaviour, and comorbid Axis I diagnoses. Addict Behav. 2009;34(9):790-793.
23. Franken IH, Van Strien JW, Nijs I. Effect of hedonic tone on event-related potential measures of cognitive processing. Psychiatry Res. 2006;142:233-239.
24. Snaith RP. Anhedonia: a neglected symptom of psychopathology. Psychol Med. 1993;23:957-966.
25. Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone: the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167:99-103.
26. Keedwell PA, Andrew C,Williams SC, Brammer MJ, Phillips ML. The neural correlates of anhedonia in major depressive disorder. Biol Psychiatry. 2005;58: 843-853.
27. Elliott R, Newman JL, Longe OA, William Deakin JF. Instrumental responding for rewards is associated with enhanced neuronal response in subcortical reward systems. Neuroimage. 2004;21:984-990.
28. Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35(3):537-555.
29. Rushworth MF, Behrens TE. Choice, uncertainty, and value in prefrontal and cingulate cortex. Nat Neurosci. 2008;11:389-397.
30. Gorwood P. Neurobiological mechanisms of anhedonia. Dialogues Clin Neurosci. 2008;10(3):291-299.
31. Bragulat V, Paillere-Martinot ML, Artiges E, Frouin V, Poline JB, Martinot JL. Dopaminergic function in depressed patients with affective flattening or with impulsivity: [18F]fluoro-L-dopa positron emission tomography study with voxelbased analysis. Psychiatry Res. 2007;154:115-124.
32. Sarchiapone M, Carli V, Camardese G, et al. Dopamine transporter binding in depressed patients with anhedonia. Psychiatry Res. 2006;147:243-248.
33. Yadid G, Friedman A. Dynamics of the dopaminergic system as a key component to the understanding of depression. Prog Brain Res. 2008;172:265-286.
34. Hegadoren KM, O’Donnell T, Lanius R, Coupland NJ, Lacaze-Masmonteil N. The role of β-endorphin in the pathophysiology of major depression. Neuropeptides. 2009;43(5):341-353.
35. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23:477-501.
36. Cordeira JW, Frank L, Sena-Esteves M, Pothos EN, Rios M. Brain-derived neurotrophic factor regulates hedonic feeding by acting on themesolimbic dopamine system. J Neurosci. 2010;30:2533-2541.
37. Masi G, Brovedani P. The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression. CNS Drugs. 2011;25(11):913-931.
38. Calabrese F, Molteni R, Gabriel C, Mocaer E, Racagni G, Riva MA. Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine. Psychopharmacology (Berl). 2011;215 (2):267-275.
39. Ladurelle N, Gabriel C, Viggiano A, Mocaër E, Baulieu EE, Bianchi M. Agomelatine (S20098) modulates the expression of cytoskeletal microtubular proteins, synaptic markers and BDNF in the rat hippocampus, amygdala and PFC. Psychopharmacology (Berl). 2012;221(3):493-509.
40. Boyer P, Tassin JP, Falissart B, Troy S. Sequential improvement of anxiety, depression and anhedonia with sertraline treatment in patients with major depression. J Clin Pharm Ther. 2000;25:363-371.
41. Tomarken AJ, Dichter GS, Freid C, Addington S, Shelton RC. Assessing the effects of bupropion SR onmood dimensions of depression. J Affect Disord. 2004; 78:235-241.
42. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study. Br J Psychiatry. 2009;195:211-217.
43. McCabe C, Mishor Z, Cowen PJ, Harmer CJ. Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment. Biol Psychiatry. 2010;67(5):439-445.
44. Zald DH, Depue RA. Serotonergic functioning correlates with positive and negative affect in psychiatrically healthy males. Pers Individ Dif. 2001;30:71-86.
45. Spijker J, Bijl RV, de Graaf R, Nolen WA. Determinants of poor 1-year outcome of DSM-III-R major depression in the general population: results of the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Acta Psychiatr Scand. 2001;103:122-130.
46. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004;29:1765-1781.
47. Millan MJ, Gobert A, Lejeune F, et al. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther. 2003;306(3):954-964.
48. Millan MJ, Brocco M, Gobert A, Dekeyne A. Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl). 2005;177(4):448-458.
49. De Berardis D, Di Iorio G, Acciavatti T, et al. The emerging role of melatonin agonists in the treatment of major depression: focus on agomelatine. CNS Neurol Disord Drug Targets. 2011;10(1):119-132.
50. Monteleone P, Martiadis V, Maj M. Circadian rhythms and treatment implications in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(7):1569- 1574.
51. Di Giannantonio M, Di Iorio G, Guglielmo R, et al. Major depressive disorder, anhedonia and agomelatine: an open-label study. J Biol Regul Homeost Agents. 2011;25(1):109-114.
52. Martinotti G, Sepede G, Gambi F, et al. Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study. J Clin Psychopharmacol. 2012;32(4):487-491.

Keywords: agomelatine; anhedonia; depression; pleasure; SHAPS