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Anhedonia and major depression: The role of agomelatine
European Neuropsychopharmacology (2012) 22, S505–S510
www.elsevier.com/locate/euroneuro
Anhedonia and major depression: The role of agomelatine Massimo Di Giannantonion, Giovanni Martinotti Department of Neuroscience and imaging c/o Mental Health Department, Viale Amendola, 47, 66100 Chieti, Italy Received 25 May 2012; received in revised form 10 July 2012; accepted 12 July 2012
1.
KEYWORDS
Abstract
Anhedonia; Agomelatine; Depression; Pleasure; SHAPS
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 DSM IV criteria for major depression diagnosis, so far it has received relatively little attention. The scale that is most commonly used in the measurement of anhedonia is the Snaith-Hamilton Pleasure Scale (SHAPS), a brief 14-item self-report questionnaire designed to measure hedonic tone and its absence. Two studies have described the efficacy of agomelatine in the treatment of anhedonia: an open-label study and a comparative trial versus the antidepressant venlafaxine XR. In both studies agomelatine significantly reduced anhedonia, as indicated using the SHAPS. This reduction was observed after the first week of treatment (Po0.05) and at different times until the end of the trial. Moreover, in the comparative trial, a significant difference between groups was observed in favor of agomelatine, after 1 (Po0.05), 2 (Po0.01), and 8 weeks (Po0.01). The possible effect of agomelatine on anhedonia may represent a novel area of interest among antidepressant agents and deserves further investigation, with larger samples and double-blind placebo-controlled designs. & 2012 Elsevier B.V. and ECNP. All rights reserved.
Introduction
The word anhedonia comes from the Greek: a n- an-, ‘‘without’’ +ZdonZ h¯ edon¯ e, ‘‘pleasure’’, and was introduced in psychiatry by Theodule-Armand Ribot in 1896 (Ribot, 1896). He defined anhedonia as the inability to experience pleasure, and it refers to both a state symptom in various psychiatric disorders and a personality trait (Loas and
n
Corresponding author. E-mail address: [email protected] (M. Di Giannantonio).
Pierson, 1989). The DSM-IV-TR defines anhedonia as diminished interest or pleasure in response to stimuli that were previously perceived as rewarding during a premorbid state (American Psychiatric Association, 2000). Anhedonia is a ‘‘core’’ symptom of major depression, whose severity could be influenced by it (Loas, 1996). Anhedonia played an important role in psychopathology theories at the beginning of the 20th century (Myerson, 1923). In particular, Kraepelin (1919) spoke of anhedonia as a core symptom of a state of individual suffering which was part of dementia praecox. Kraepelin described his patients as if they did not feel any real joy in life; according to him, the characteristic indifference of patients towards social
0924-977X/$ - see front matter & 2012 Elsevier B.V. and ECNP. All rights reserved. http://dx.doi.org/10.1016/j.euroneuro.2012.07.004
S506 interactions, which previously used to elicit emotion, the extinction of affection for family and friends, and the loss of satisfaction in their work and vocation, in recreation and pleasure, were rather often the first symptoms to manifest, marking the onset of the disease. Bleuler (1911), noting the indifference that some patients exhibited towards their friends, acquaintances, colleagues, and towards life itself, defined anhedonia as a basic feature of their disease, ‘‘an external signal of their pathological condition’’. What emerges by reading works by 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. Nevertheless, after the turn of the century, psychiatric interest in anhedonia faded, and Jaspers in his ‘‘Allgemeine ¨ Psychopathologie. Ein Leitfaden f¨ ur Studierende, Arzte und Psychologen’’ does not mention it except as an aspect of the more severe and pervasive loss of all emotional responses (Jaspers, 1913). Attention then focused on depressed mood as the pathognomonic feature of depressive illness. For most psychiatrists it was Klein’s concept of endogenomorphic depression that revived interest in the notion of anhedonia (Klein, 1984). Klein’s definition ‘‘a sharp, unreactive, pervasive impairment of the capacity to experience pleasure, or to respond affectively, to the anticipation of pleasure’’ was slightly modified to ‘‘a loss of interest or pleasure in all or almost all usual activities and pastimes’’ (Snaith, 1992). Furthermore, for the subtype of major depression, for which the term melancholia was resurrected, the anhedonic experience became essential to the definition. Anhedonia has been considered crucial for the diagnosis of depression (Klein, 1984; Schrader, 1997). It is, besides depressed mood, one of the two core symptoms of depression (Loas and Pierson, 1989). Moreover, lack of reactivity and anhedonia are key diagnostic criteria for the DSM-IV-TR melancholic subtype of major depression (Klein, 1984), and anhedonia is also one of the most important negative symptoms frequently observed in schizophrenia (Mason et al., 2004), although the differences between the anhedonic symptoms observed in mood disorders and schizophrenia is profound from both the clinical and neurobiological points of view. Although anhedonia plays a very important role in depression and schizophrenia, it is not limited to them. In fact, anhedonia has been linked to anxiety and adjustment disorders (Silverstone, 1991), suicidal ideation (Oei et al., 1990), successful suicide (Fawcett, 1993), alcohol and substance abuse (Martinotti et al., 2009; Janiri et al., 2005). On the other hand, in the model proposed by Loas (1996), a genetically determined low hedonic capacity was regarded as a specific character trait, which, together with aspects like introversion, obsessive-compulsivity, pessimism, and passivity, could represent a risk factor which could lead, under stress conditions, to unipolar endogenomorphic depression. Moreover, anhedonia is also present in other disorders and dysfunctional behaviors, such as Parkinson’s disease (Isella et al., 2003), overeating (Davis and Woodside, 2002), and risky behaviors in general (Franken et al., 2006).
M. Di Giannantonio, G. Martinotti
2.
Diagnosing anhedonia
Although anhedonia is regarded as an important symptom in psychopathology, so far it has received relatively little attention. This limited attention could be the result of the low availability of short, well-validated, and easy-to-use instruments (Snaith, 1993). In general, two main approaches have been utilized to investigate and assess anhedonia (or hedonic capacity): laboratory-based measures and questionnaires. The first approach utilizes laboratory-based measures of anhedonia, involving signal-detection methodology, physiologic measures, and subjective hedonic response to pleasant stimuli (Berlin et al., 1998). Besides these behavioral measures, anhedonia can also be evaluated using hemodynamic (Keedwell et al., 2005) and electrophysiological (Franken et al., 2006) measures. The second approach to the diagnosis of anhedonia involves the use of questionnaires. Several scales have been developed to assess anhedonia or hedonic capacity. Specific scales for the measurement of anhedonia are the Revised Chapman Physical Anhedonia Scale (CPAS) and Social Anhedonia Scale (SAS) (Chapman et al., 1976), the Fawcett-Clark Pleasure Scale (FCPS) (Fawcett et al., 1983), and the Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al., 1995). Other rating instruments can be employed to evaluate anhedonia within broader psychopathological dimensions, such as those of depression, with the Bech-Rafaelsen Melancholia Scale (BRMS) (Bech, 2002), and negative symptoms of schizophrenia, with the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1989) and particularly the Subscale for Anhedonia (SANSanh). Furthermore, it is worth mentioning the 10-cm VAS (Mottola, 1993) for pleasure and the Temporal Experience of Pleasure Scale (TEPS) (Gard et al., 2006), which was developed to assess anticipatory and consummatory pleasure. The scale most commonly used in the measurement of anhedonia is the SHAPS (Snaith et al., 1995), a brief 14-item self-report questionnaire designed to measure hedonic tone and its absence, anhedonia. These 14 items cover four domains of hedonic experience: interest/pastimes (items 1, 4, and 9), social interaction (items 2, 7, 8, 13, and 14), sensory experience (items 5, 6, 11, and 12), and food/drink (items 3 and 10). The SHAPS instructs participants to agree or disagree with statements of hedonic response in pleasurable situations, which are likely to be encountered by most people (e.g., ‘‘I would enjoy my favourite television or radio programme’’; ‘‘I would enjoy being with family or close friends’’; ‘‘I would be able to enjoy my favourite meal’’, etc.). 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 answers to each item, therefore going 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 the SHAPS are instructed to respond based on their ability to experience pleasure ‘‘in the last few days’’. The SHAPS has shown adequate overall psychometric properties in clinical and student samples (Snaith et al.,
Agomelatine’s effect in anhedonia 1995; Gilbert et al., 2002; Leventhal et al., 2006). SHAPS was found to be highly reliable in terms of internal consistency and test–retest stability. Furthermore, the SHAPS correlated in a theoretically meaningful way with other measures of affect and personality. Patients with depression, psychosis, or substance dependence scored significantly higher on the SHAPS than non-patient controls, while patients with depression displayed the highest SHAPS score (Franken et al., 2007). Since it is a brief scale, it seems to be a very useful instrument for measuring anhedonia in clinical and research settings. Its discriminant validity has been supported by its lack of association with MADRS Depressed Mood and Anxiety items (Snaith et al., 1995).
3.
Treating anhedonia in major depression
At the moment there is no definite and specific pharmacological approach to the treatment of anhedonia in depression, although it is clear that all antidepressants, treating depressive symptoms as a whole, act on anhedonia to a certain degree. The assessment of anhedonia in the evaluation of the other antidepressants was often neglected and no conclusion can be drawn regarding their efficacy on this symptom of depression. Boyer et al. (2000) showed a late effect (over 21 to 56 days) of sertraline on anhedonia occurring after its effects on depression and anxiety, while in the study of Tomarken the catecholaminergic effects of bupropion SR 300 tended to produce more robust effects on anhedonia/ positive affect than placebo, particularly during a 6-week initial treatment phase. Unlike other antidepressants, agomelatine (S20098, N-[2(7-methoxynaphth-1-yl)ethyl]acetamide) has a novel neurochemical mechanism. 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 (Racagni et al., 2011). This synergy may resynchronize circadian rhythms. Evidence from pre-clinical (Tardito et al., in press; Kasper and Hamon, 2009; De Bodinat et al., 2010) and clinical studies (Loo et al., 2002; Zajecka et al., 2010; Stahl et al., 2010; Goodwin et al., 2009; Kennedy and Rizvi, 2010; Hickie and Rogers, 2011) suggests that agomelatine has antidepressant properties, alleviates symptoms of anxiety associated with depression, and rapidly relieves symptoms compared with placebo. In addition, the tolerability and safety profile of agomelatine includes a low propensity to cause sexual dysfunction (Kennedy et al., 2008), absence of discontinuation symptoms upon withdrawal (Montgomery et al., 2004), and improvement in daytime functioning and quality of sleep associated with depression (Lemoine et al., 2007, Kasper et al., 2010). 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. Nevertheless, the specific effect of circadian rhythm resynchronization may contribute to the regulation of hedonic capacity (Hasler
S507 et al., 2010; Monteleone et al., 2011; Farina et al., 2002). Because of this, 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. The first, an open-label 8-week study by Di Giannantonio et al. (2011) was conducted at 2 sites: Universita ‘‘G. D’Annunzio’’ in Chieti and Casa di Cura Neuropsichiatrica ‘‘Villa Maria Pia’’ in Rome. The study lasted 8 weeks and included 30 male and female outpatients aged 18 to 60 years old with a DSM-IV diagnosis of major depressive disorder. The primary endpoints were reduction in depressive and anxiety symptoms, expressed by the scores of each of the Hamilton Depression and Anxiety Rating Scales (HAM-D; HAM-A). The secondary endpoints were related to the reduction in the degree of anhedonia and insomnia. In this open-label study agomelatine proved to be a possible therapeutic option for patients with major depressive disorder. In line with previous studies, in which agomelatine was associated with early clinical improvement (Olie and Kasper, 2007; Stahl et al., 2010), 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. Moreover, agomelatine proved efficacious in the treatment of anhedonia. As to SHAPS scores, a reduction of 1.6 points from baseline was observed after the first week of treatment (Po0.05), increasing at different times until the end of the trial, where the level of significance was even greater (Po0.01) (Figure 1). This was the first study in which the efficacy of agomelatine in treating anhedonia was studied. In another study by the same group (Martinotti et al., 2012), the effects of agomelatine on anhedonia were compared with those of venlafaxine XR, an antidepressant of proven efficacy for the treatment of major depression (Stahl et al., 2002; De Berardis et al., 2010). In this openlabel, 8-week parallel-group, pilot study, patients with major depressive disorder were randomly started on agomelatine at a dose of 25 mg/d (N patients =30) or on venlafaxine XR 75 mg/d (N patients = 30). The agomelatine dosage regimen involved the administration of 25 mg/d, a single dose at 08:00 pm. In the event of no clinical response, and based on the clinician’s judgment, the dosage could be increased to 50 mg/d, administered in a single dose.
Figure 1 Anhedonia score at different times for patients treated with agomelatine 25–50 mg (n=30), n Po0.05; nn Po0.01.
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Figure 2 Anhedonia scores at different times for patients treated with agomelatine or venlafaxine, n Po0.05; nn Po0.01.
The venlafaxine XR dosage regimen involved the administration of 75 mg/d, a single dose at 08:00 am. In the case of no clinical response, and based on the clinician’s judgment, the dosage could be increased to 150 mg/d, administered in a single dose. Treatment outcome, in terms of improvement in anhedonia (SHAPS), depression, and anxiety scores (HAMD; HAM-A), was assessed after 1 (W1), 2(W2), and 8 (W8) weeks. A significant reduction in times for the SHAPS was observed in both the agomelatine (F =20.74; Po0.001) and the venlafaxine XR (F=3.27; Po0.5) groups. However, a significant difference between groups was observed in favor of agomelatine, at W1 (Po0.05), W2 (Po0.01), and W8 (Po0.01) (Figure 2), with a Number Needed to Treat of eight subjects in favor of agomelatine, considering the presence or absence of an anhedonic state (SHAPSZ3) at the end of the study. A significant reduction in HAM-D and HAM-A scores was observed for both groups (Po0.05), with no difference between groups, whereas only patients treated with agomelatine showed a statistically significant improvement in CGI scores (t =2.94; Po0.05). The improvements in anhedonia scores detected as early as 1 week after treatment initiation were a beneficial characteristic of agomelatine, especially given the usually relatively slow onset of antidepressant efficacy with current agents. In these two studies agomelatine did not determine the onset of hypomanic or manic symptoms. 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. These results regarding agomelatine and anhedonia appear difficult to compare with those from other clinical studies. Anhedonia is a dimension poorly characterized in all the major clinical trials regarding the treatment of major depressive disorder, where anhedonia, despite being one of the two ‘‘core’’ symptoms of depression, is only considered as one of a large range of symptoms. This warrants further study.
4.
Conclusion
Different studies have found that anhedonia can precede the onset of a depressive episode (Dryman and Eaton, 1991),
influence its severity, predicts poor outcome 12 months later (Spijker et al., 2001), is a common residual symptom after treatment (Taylor et al., 2010), and is associated with dysfunction in the brain reward system (Keedwell et al., 2005). Therefore, the efficacy of agomelatine on this dimension may hold particular importance for the treatment of patients with major depression. Differentiating patients into subtypes, in line with the typology of symptoms and the phenomenological approach, may represent the future of the psychopharmacological approach, leading to the choice of the right antidepressant for the specific symptom. The original effect of agomelatine on anhedonia is a novel property among antidepressant agents and deserves further investigation, with larger samples and double-blind placebo-controlled designs.
Role of the funding source The manuscript was produced with an educational grant from Servier.
Contributors The authors wrote all the drafts and revisions of the manuscript.
Conflict of interest The supplement that this article appears in was produced with an educational grant from Servier.
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Anhedonia and major depression: The role of agomelatine Massimo Di Giannantonion, Giovanni Martinotti Department of Neuroscience and imaging c/o Mental Health Department, Viale Amendola, 47, 66100 Chieti, Italy Received 25 May 2012; received in revised form 10 July 2012; accepted 12 July 2012
1.
KEYWORDS
Abstract
Anhedonia; Agomelatine; Depression; Pleasure; SHAPS
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 DSM IV criteria for major depression diagnosis, so far it has received relatively little attention. The scale that is most commonly used in the measurement of anhedonia is the Snaith-Hamilton Pleasure Scale (SHAPS), a brief 14-item self-report questionnaire designed to measure hedonic tone and its absence. Two studies have described the efficacy of agomelatine in the treatment of anhedonia: an open-label study and a comparative trial versus the antidepressant venlafaxine XR. In both studies agomelatine significantly reduced anhedonia, as indicated using the SHAPS. This reduction was observed after the first week of treatment (Po0.05) and at different times until the end of the trial. Moreover, in the comparative trial, a significant difference between groups was observed in favor of agomelatine, after 1 (Po0.05), 2 (Po0.01), and 8 weeks (Po0.01). The possible effect of agomelatine on anhedonia may represent a novel area of interest among antidepressant agents and deserves further investigation, with larger samples and double-blind placebo-controlled designs. & 2012 Elsevier B.V. and ECNP. All rights reserved.
Introduction
The word anhedonia comes from the Greek: a n- an-, ‘‘without’’ +ZdonZ h¯ edon¯ e, ‘‘pleasure’’, and was introduced in psychiatry by Theodule-Armand Ribot in 1896 (Ribot, 1896). He defined anhedonia as the inability to experience pleasure, and it refers to both a state symptom in various psychiatric disorders and a personality trait (Loas and
n
Corresponding author. E-mail address: [email protected] (M. Di Giannantonio).
Pierson, 1989). The DSM-IV-TR defines anhedonia as diminished interest or pleasure in response to stimuli that were previously perceived as rewarding during a premorbid state (American Psychiatric Association, 2000). Anhedonia is a ‘‘core’’ symptom of major depression, whose severity could be influenced by it (Loas, 1996). Anhedonia played an important role in psychopathology theories at the beginning of the 20th century (Myerson, 1923). In particular, Kraepelin (1919) spoke of anhedonia as a core symptom of a state of individual suffering which was part of dementia praecox. Kraepelin described his patients as if they did not feel any real joy in life; according to him, the characteristic indifference of patients towards social
0924-977X/$ - see front matter & 2012 Elsevier B.V. and ECNP. All rights reserved. http://dx.doi.org/10.1016/j.euroneuro.2012.07.004
S506 interactions, which previously used to elicit emotion, the extinction of affection for family and friends, and the loss of satisfaction in their work and vocation, in recreation and pleasure, were rather often the first symptoms to manifest, marking the onset of the disease. Bleuler (1911), noting the indifference that some patients exhibited towards their friends, acquaintances, colleagues, and towards life itself, defined anhedonia as a basic feature of their disease, ‘‘an external signal of their pathological condition’’. What emerges by reading works by 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. Nevertheless, after the turn of the century, psychiatric interest in anhedonia faded, and Jaspers in his ‘‘Allgemeine ¨ Psychopathologie. Ein Leitfaden f¨ ur Studierende, Arzte und Psychologen’’ does not mention it except as an aspect of the more severe and pervasive loss of all emotional responses (Jaspers, 1913). Attention then focused on depressed mood as the pathognomonic feature of depressive illness. For most psychiatrists it was Klein’s concept of endogenomorphic depression that revived interest in the notion of anhedonia (Klein, 1984). Klein’s definition ‘‘a sharp, unreactive, pervasive impairment of the capacity to experience pleasure, or to respond affectively, to the anticipation of pleasure’’ was slightly modified to ‘‘a loss of interest or pleasure in all or almost all usual activities and pastimes’’ (Snaith, 1992). Furthermore, for the subtype of major depression, for which the term melancholia was resurrected, the anhedonic experience became essential to the definition. Anhedonia has been considered crucial for the diagnosis of depression (Klein, 1984; Schrader, 1997). It is, besides depressed mood, one of the two core symptoms of depression (Loas and Pierson, 1989). Moreover, lack of reactivity and anhedonia are key diagnostic criteria for the DSM-IV-TR melancholic subtype of major depression (Klein, 1984), and anhedonia is also one of the most important negative symptoms frequently observed in schizophrenia (Mason et al., 2004), although the differences between the anhedonic symptoms observed in mood disorders and schizophrenia is profound from both the clinical and neurobiological points of view. Although anhedonia plays a very important role in depression and schizophrenia, it is not limited to them. In fact, anhedonia has been linked to anxiety and adjustment disorders (Silverstone, 1991), suicidal ideation (Oei et al., 1990), successful suicide (Fawcett, 1993), alcohol and substance abuse (Martinotti et al., 2009; Janiri et al., 2005). On the other hand, in the model proposed by Loas (1996), a genetically determined low hedonic capacity was regarded as a specific character trait, which, together with aspects like introversion, obsessive-compulsivity, pessimism, and passivity, could represent a risk factor which could lead, under stress conditions, to unipolar endogenomorphic depression. Moreover, anhedonia is also present in other disorders and dysfunctional behaviors, such as Parkinson’s disease (Isella et al., 2003), overeating (Davis and Woodside, 2002), and risky behaviors in general (Franken et al., 2006).
M. Di Giannantonio, G. Martinotti
2.
Diagnosing anhedonia
Although anhedonia is regarded as an important symptom in psychopathology, so far it has received relatively little attention. This limited attention could be the result of the low availability of short, well-validated, and easy-to-use instruments (Snaith, 1993). In general, two main approaches have been utilized to investigate and assess anhedonia (or hedonic capacity): laboratory-based measures and questionnaires. The first approach utilizes laboratory-based measures of anhedonia, involving signal-detection methodology, physiologic measures, and subjective hedonic response to pleasant stimuli (Berlin et al., 1998). Besides these behavioral measures, anhedonia can also be evaluated using hemodynamic (Keedwell et al., 2005) and electrophysiological (Franken et al., 2006) measures. The second approach to the diagnosis of anhedonia involves the use of questionnaires. Several scales have been developed to assess anhedonia or hedonic capacity. Specific scales for the measurement of anhedonia are the Revised Chapman Physical Anhedonia Scale (CPAS) and Social Anhedonia Scale (SAS) (Chapman et al., 1976), the Fawcett-Clark Pleasure Scale (FCPS) (Fawcett et al., 1983), and the Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al., 1995). Other rating instruments can be employed to evaluate anhedonia within broader psychopathological dimensions, such as those of depression, with the Bech-Rafaelsen Melancholia Scale (BRMS) (Bech, 2002), and negative symptoms of schizophrenia, with the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1989) and particularly the Subscale for Anhedonia (SANSanh). Furthermore, it is worth mentioning the 10-cm VAS (Mottola, 1993) for pleasure and the Temporal Experience of Pleasure Scale (TEPS) (Gard et al., 2006), which was developed to assess anticipatory and consummatory pleasure. The scale most commonly used in the measurement of anhedonia is the SHAPS (Snaith et al., 1995), a brief 14-item self-report questionnaire designed to measure hedonic tone and its absence, anhedonia. These 14 items cover four domains of hedonic experience: interest/pastimes (items 1, 4, and 9), social interaction (items 2, 7, 8, 13, and 14), sensory experience (items 5, 6, 11, and 12), and food/drink (items 3 and 10). The SHAPS instructs participants to agree or disagree with statements of hedonic response in pleasurable situations, which are likely to be encountered by most people (e.g., ‘‘I would enjoy my favourite television or radio programme’’; ‘‘I would enjoy being with family or close friends’’; ‘‘I would be able to enjoy my favourite meal’’, etc.). 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 answers to each item, therefore going 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 the SHAPS are instructed to respond based on their ability to experience pleasure ‘‘in the last few days’’. The SHAPS has shown adequate overall psychometric properties in clinical and student samples (Snaith et al.,
Agomelatine’s effect in anhedonia 1995; Gilbert et al., 2002; Leventhal et al., 2006). SHAPS was found to be highly reliable in terms of internal consistency and test–retest stability. Furthermore, the SHAPS correlated in a theoretically meaningful way with other measures of affect and personality. Patients with depression, psychosis, or substance dependence scored significantly higher on the SHAPS than non-patient controls, while patients with depression displayed the highest SHAPS score (Franken et al., 2007). Since it is a brief scale, it seems to be a very useful instrument for measuring anhedonia in clinical and research settings. Its discriminant validity has been supported by its lack of association with MADRS Depressed Mood and Anxiety items (Snaith et al., 1995).
3.
Treating anhedonia in major depression
At the moment there is no definite and specific pharmacological approach to the treatment of anhedonia in depression, although it is clear that all antidepressants, treating depressive symptoms as a whole, act on anhedonia to a certain degree. The assessment of anhedonia in the evaluation of the other antidepressants was often neglected and no conclusion can be drawn regarding their efficacy on this symptom of depression. Boyer et al. (2000) showed a late effect (over 21 to 56 days) of sertraline on anhedonia occurring after its effects on depression and anxiety, while in the study of Tomarken the catecholaminergic effects of bupropion SR 300 tended to produce more robust effects on anhedonia/ positive affect than placebo, particularly during a 6-week initial treatment phase. Unlike other antidepressants, agomelatine (S20098, N-[2(7-methoxynaphth-1-yl)ethyl]acetamide) has a novel neurochemical mechanism. 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 (Racagni et al., 2011). This synergy may resynchronize circadian rhythms. Evidence from pre-clinical (Tardito et al., in press; Kasper and Hamon, 2009; De Bodinat et al., 2010) and clinical studies (Loo et al., 2002; Zajecka et al., 2010; Stahl et al., 2010; Goodwin et al., 2009; Kennedy and Rizvi, 2010; Hickie and Rogers, 2011) suggests that agomelatine has antidepressant properties, alleviates symptoms of anxiety associated with depression, and rapidly relieves symptoms compared with placebo. In addition, the tolerability and safety profile of agomelatine includes a low propensity to cause sexual dysfunction (Kennedy et al., 2008), absence of discontinuation symptoms upon withdrawal (Montgomery et al., 2004), and improvement in daytime functioning and quality of sleep associated with depression (Lemoine et al., 2007, Kasper et al., 2010). 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. Nevertheless, the specific effect of circadian rhythm resynchronization may contribute to the regulation of hedonic capacity (Hasler
S507 et al., 2010; Monteleone et al., 2011; Farina et al., 2002). Because of this, 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. The first, an open-label 8-week study by Di Giannantonio et al. (2011) was conducted at 2 sites: Universita ‘‘G. D’Annunzio’’ in Chieti and Casa di Cura Neuropsichiatrica ‘‘Villa Maria Pia’’ in Rome. The study lasted 8 weeks and included 30 male and female outpatients aged 18 to 60 years old with a DSM-IV diagnosis of major depressive disorder. The primary endpoints were reduction in depressive and anxiety symptoms, expressed by the scores of each of the Hamilton Depression and Anxiety Rating Scales (HAM-D; HAM-A). The secondary endpoints were related to the reduction in the degree of anhedonia and insomnia. In this open-label study agomelatine proved to be a possible therapeutic option for patients with major depressive disorder. In line with previous studies, in which agomelatine was associated with early clinical improvement (Olie and Kasper, 2007; Stahl et al., 2010), 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. Moreover, agomelatine proved efficacious in the treatment of anhedonia. As to SHAPS scores, a reduction of 1.6 points from baseline was observed after the first week of treatment (Po0.05), increasing at different times until the end of the trial, where the level of significance was even greater (Po0.01) (Figure 1). This was the first study in which the efficacy of agomelatine in treating anhedonia was studied. In another study by the same group (Martinotti et al., 2012), the effects of agomelatine on anhedonia were compared with those of venlafaxine XR, an antidepressant of proven efficacy for the treatment of major depression (Stahl et al., 2002; De Berardis et al., 2010). In this openlabel, 8-week parallel-group, pilot study, patients with major depressive disorder were randomly started on agomelatine at a dose of 25 mg/d (N patients =30) or on venlafaxine XR 75 mg/d (N patients = 30). The agomelatine dosage regimen involved the administration of 25 mg/d, a single dose at 08:00 pm. In the event of no clinical response, and based on the clinician’s judgment, the dosage could be increased to 50 mg/d, administered in a single dose.
Figure 1 Anhedonia score at different times for patients treated with agomelatine 25–50 mg (n=30), n Po0.05; nn Po0.01.
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M. Di Giannantonio, G. Martinotti
Figure 2 Anhedonia scores at different times for patients treated with agomelatine or venlafaxine, n Po0.05; nn Po0.01.
The venlafaxine XR dosage regimen involved the administration of 75 mg/d, a single dose at 08:00 am. In the case of no clinical response, and based on the clinician’s judgment, the dosage could be increased to 150 mg/d, administered in a single dose. Treatment outcome, in terms of improvement in anhedonia (SHAPS), depression, and anxiety scores (HAMD; HAM-A), was assessed after 1 (W1), 2(W2), and 8 (W8) weeks. A significant reduction in times for the SHAPS was observed in both the agomelatine (F =20.74; Po0.001) and the venlafaxine XR (F=3.27; Po0.5) groups. However, a significant difference between groups was observed in favor of agomelatine, at W1 (Po0.05), W2 (Po0.01), and W8 (Po0.01) (Figure 2), with a Number Needed to Treat of eight subjects in favor of agomelatine, considering the presence or absence of an anhedonic state (SHAPSZ3) at the end of the study. A significant reduction in HAM-D and HAM-A scores was observed for both groups (Po0.05), with no difference between groups, whereas only patients treated with agomelatine showed a statistically significant improvement in CGI scores (t =2.94; Po0.05). The improvements in anhedonia scores detected as early as 1 week after treatment initiation were a beneficial characteristic of agomelatine, especially given the usually relatively slow onset of antidepressant efficacy with current agents. In these two studies agomelatine did not determine the onset of hypomanic or manic symptoms. 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. These results regarding agomelatine and anhedonia appear difficult to compare with those from other clinical studies. Anhedonia is a dimension poorly characterized in all the major clinical trials regarding the treatment of major depressive disorder, where anhedonia, despite being one of the two ‘‘core’’ symptoms of depression, is only considered as one of a large range of symptoms. This warrants further study.
4.
Conclusion
Different studies have found that anhedonia can precede the onset of a depressive episode (Dryman and Eaton, 1991),
influence its severity, predicts poor outcome 12 months later (Spijker et al., 2001), is a common residual symptom after treatment (Taylor et al., 2010), and is associated with dysfunction in the brain reward system (Keedwell et al., 2005). Therefore, the efficacy of agomelatine on this dimension may hold particular importance for the treatment of patients with major depression. Differentiating patients into subtypes, in line with the typology of symptoms and the phenomenological approach, may represent the future of the psychopharmacological approach, leading to the choice of the right antidepressant for the specific symptom. The original effect of agomelatine on anhedonia is a novel property among antidepressant agents and deserves further investigation, with larger samples and double-blind placebo-controlled designs.
Role of the funding source The manuscript was produced with an educational grant from Servier.
Contributors The authors wrote all the drafts and revisions of the manuscript.
Conflict of interest The supplement that this article appears in was produced with an educational grant from Servier.
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