2012. Vol.3, No.10, 864-869
Published Online October 2012 in SciRes (
Copyright © 2012 SciRes.
A Dimensional Approach to Measuring Antidepressant
Response: Implications for Agomelatine
Sidney H. Kennedy1,2*, Anna Cyriac1
1Department of Psychiatry, University Health Network, Toronto, Canada
2Department of Psychiatry, University of Toronto, Toronto, Canada
Email: *
Received July 11th, 2012; revised August 12th, 2012; accepted September 10th, 2012
Current antidepressant treatments for Major Depressive Disorder (MDD) have limited efficacy and effec-
tiveness. While measurement of response and remission is typically based on overall symptom reduction,
the utilization of a dimensional approach, involving mood, cognitive and neurovegetative symptoms, may
be more effective in predicting response to different antidepressant classes. In addition to these dimen-
sions, evaluation of function is increasingly recognized as an important patient indicator of antidepressant
efficacy. This paper reviews the efficacy of second generation antidepressant classes across the proposed
symptom dimensions, and explores the potential benefits of agomelatine. While further research is re-
quired, agomelatine generally performed well in the mood dimension including measures of depressed
mood, anxiety and anhedonia without inducing emotional blunting. Improvements in daytime alertness
and clear thinking, combined with measures of subjective and objective sleep differentiate agomelatine
from other currently available antidepressants, and likely contribute to favourable functional outcomes.
Keywords: Symptom Dimensions; Major Depression; Antidepressants
A Dimensional Approach to Antidepressant
In general, the results of clinical trials and meta-analyses are
based on overall reduction of depression symptoms, and dem-
onstrate the limited efficacy and effectiveness of current anti-
depressants (Cipriani et al., 2010; Warden et al., 2007). Even in
remitted patients, specific residual symptoms are common and
contribute to poor outcomes and increased risk of relapse
(Conradi, Ormel, de Jonge, 2010; Fekadu et al., 2011). For
example, in a large study of patients treated with fluoxetine the
most frequent residual symptoms were impairments in interest,
mood, concentration, sleep, weight, and fatigue (Nierenberg et
al., 1999). These symptoms fall into the same dimensions of
mood, cognition, and neurovegetative symptoms that were
derived from factor analyses of individual items from several
depression rating scales (Korszun et al., 2004; Uher et al., 2008;
Brodbeck et al., 2011).
The utility of a factor-based approach to evaluate antide-
pressant response (see Table 1 Korszun et al., 2004) to differ-
ent antidepressant classes has also been demonstrated (Uher et
al., 2009). While there were no differences between nortrip-
tyline and escitalopram based on either the Hamilton Rating
Scale for Depression (HRSD; Hamilton 1960) or the Mont-
gomery-Asberg Depression Rating Scale (MADRS; Montgom-
ery & Asberg, 1979), there were significant differences in out-
come between nortriptyline and escitalopram on each of the
three symptom dimensions. Mood and cognition symptoms
improved more with escitalopram while neurovegetative sym-
ptoms including sleep, showed greater improvement in the
nortriptyline group (Uher et al., 2009). These findings suggest
that a dimensional approach to exploring differences between
antidepressants may help to personalize treatment strategies
based on symptom profile.
Each of these symptom dimensions is likely to influence so-
cial and occupational functioning which reflect patients’ per-
ceptions of favourable antidepressant outcome. For example,
when patients were asked to describe their concept of remission,
they identified optimism, self-confidence, emotional control,
success at school, work or home, and enjoying relationships as
being the most valued outcomes with antidepressant therapy
(Zimmerman et al., 2006). The Sheehan Disability Scale (SDS)
is a brief-three item self-report measure of satisfaction with
social, family and work or school function (Sheehan et al., 1996)
which has been used to compliment symptom rating scales and
to provide a more comprehensive profile of treatment outcome.
Agomelatine is the first melatonergic antidepressant with
MT1 and MT2 agonist and 5-HT2C antagonist properties
(Audinot et al., 2003; Millan et al., 2003): current evidence
suggests that synergy between these two mechanisms is re-
quired for antidepressant effect (Racagni et al., 2011). Agome-
latine differs from standard antidepressants in its lack of direct
effects on either serotonin or norepinephrine transporters (Mil-
lan et al., 2003).
The purpose of this review is to compare current second
generation antidepressants and agomelatine across dimensions
of mood, cognition and neurovegetative symptoms, and on
functional outcome, recognizing that dimensional analyses have
not been the primary focus of most trials.
Mood Dimension
The mood dimension of depression can be conceptualized to
include depressed mood, anxiety and loss of pleasure or interest
*Corresponding autho
Table 1.
Classification of symptom dimensions using factor analysis (Korszun et
al., 2004).
Factors Symtoms
1) Mood
Depressed mood, anhedonia, loss of hope, loss
of reactivity, loss of interest, low self esteem,
psychomotor retardation, loss of energy, loss of libido
2) Anxiety General anxiety, free floating anxiety, anxious
foreboding, general rating of phobias
3) Melancholia
Psychomotor agitation, pathological guilt, guilty ideas
of reference, suicidality, morning worsening of
4) Neurovegetative Loss of appetite, early morning waking inversely
correlated with increased appetite, hypersomnia
(anhedonia). In addition, loss of reactivity (emotional blunting)
has been increasingly explored in relation to SSRI treatment
and may cause additional burden for patients.
Depressed M o od
Since depressed mood is a pivotal criterion for the diagnosis
of a depressive episode, drug-placebo separation on this item is
given particular attention in evaluating antidepressant efficacy
and optimal dosing (Dunner & Dunbar, 1992; Mendels et al.,
1993). Bech (2001) evaluated the single “depressed mood” item
in a meta-analysis of 4 three arm trials (mirtazapine n = 182,
amitriptyline n = 187, placebo n = 184) which showed that both
mirtazapine and amitriptyline groups obtained an effect size
that was statistically significant against placebo as early as one
week after treatment. Change from baseline to endpoint on the
mood item was useful in discriminating between high and low
doses of paroxetine-controlled release (Trivedi et al., 2004) and
in evaluating the efficacy of paroxetine in adolescent depres-
sion (Keller et al., 2001). Interestingly, achieving a combined
score of zero on the mood and psychic anxiety items of the
HRSD after two weeks was predictive of achieving remission
during treatment with venlafaxine (Silverstone et al., 2002).
The “depressed mood” item was also assessed in a meta-
analysis of placebo-controlled agomelatine trials, there was a
significant mean difference between agomelatine and placebo
in the total population (0.29, p < .001) and in the subgroup with
higher baseline severity (baseline HRSD 5; 0.35, p < .001)
(Demyttenaere, 2011).
Anxiety symptoms or comorbid anxiety syndromes are pre-
valent in depression. The rate of “anxious depression” (defined
as a score 7 on the anxiety/somatization subscale of HRSD)
in large samples of MDD patients is approximately 50% (Pa-
pakostas & Larsen, 2011) and 40% of depressed individuals
have a comorbid anxiety disorder (Reiger et al., 1990). While
definitions of anxious depression differ, there is considerable
agreement that the prognosis is worse for depressed patients
with high levels of anxiety following treatment with currently
available antidepressants (Fava et al., 2008; Souery et al., 2007).
During a large 12-week trial involving over 500 MDD patients
treated with flexible dosing of fluoxetine, early symptom
changes were assessed in relation to treatment outcome (Fara-
baugh et al., 2010). Only early changes (defined as those ob-
served between baseline and week 1) in the “anxiety/soma-
tization” subscale on the HRSD predicted remission.
The effect of agomelatine in anxious and non-anxious de-
pression has been compared with placebo (Loo et al., 2002) and
against comparators in a recent meta-analysis (Stein & Kennedy,
2011). Compared to placebo, there was a separation of 3.43
points on the Hamilton Anxiety Rating Scale (HAM-A; Hamilton
1959) at endpoint (p = 0.011) and greater differences were ob-
served when only patients with high baseline levels of anxiety
(HRSD anxiety subscale 5) were included. Similarly, in the
trials comparing agomelatine with either an SSRI or an SNRI,
where the HAM-A was administered (Lemoine et al., 2007; Hale
et al., 2010; Kasper et al., 2010) there were significant advan-
tages in favour of agomelatine in both the total population (1.39
points, p < .0006) and in the subpopulation with higher base-
line anxiety (1.72 points, p = .032) (Stein and Kennedy, 2011).
The anxiolytic effects of agomelatine have also been evalu-
ated using the Hospital Anxiety and Depression scale (HADS;
Zigmond & Snaith, 1983) in two 8-week, randomized pla-
cebo-controlled trials at fixed doses of 25 mg and 50 mg (Za-
jecka et al., 2010; Stahl et al., 2010). There was a statistically
significant anxiolytic effect in the 50 mg agomelatine group
from week 2 until endpoint (p = 0.016) in one trial (Zajecka et
al., 2010) and in the 25 mg agomelatine group in the other trial
(Stahl et al., 2011).
Anhedonia, as defined by the DSM-IV-TR, is characterized
by a diminished interest or pleasure in response to stimuli that
were previously perceived as rewarding in a premorbid state
(American Psychiatric Association, 2000). Although it is a core
symptom of depression, anhedonia has not been evaluated ex-
tensively. Nevertheless, there is emerging interest in exploring
the effects of different antidepressants on anhedonia, from both
clinical and neurobiological perspectives (Ossewaarde et al.,
2011). For example, in a comparison of atypical antipsychotics,
anhedonia and social function were improved significantly
more by aripiprazole than by risperidone (Liemburg et al.,
2011). This preferential antidepressant effect with aripiprazole
has been linked to its action on dopamine (D)-2 and serotonin
(5HT) receptors (Blier & Blondeau, 2011).
The impact of different antidepressants on reward processing
has also been investigated using a novel paradigm for pleasant
and aversive stimuli: volunteers who received an SSRI subjec-
tively reported and showed evidence on neuroimaging of a
blunted response to liquid chocolate placed on their tongue
(pleasure) and to pictures of mouldy strawberries and chocolate
(aversive) after receiving the SSRI citalopram compared with
those who received reboxetine (a norepinephrine reuptake in-
hibitor) (McCabe et al., 2010).
Greater severity of anhedonia predicted longer time to remis-
sion in a large “Treatment of Resistant Depression in Adoles-
cents” (TORDIA) clinical trial, comparing switch options in-
volving SSRI or venlafaxine alone or combined with CBT
(McMakin et al., 2012). Results of two small proofs of concept
agomelatine trials showed a significant reduction in anhedonia
scores on the Snaith-Hamilton Pleasure Scale (Snaith et al.,
1995) during treatment (see Di Giannantonio et al., in press).
Emotional Blunting
Among patients with SSRI-induced sexual dysfunction, 80%
reported emotional blunting. They described experiences of
reduced creativity, ability to cry, and care for the feelings of
others (Opobroek et al., 2002). This phenomenon has subse-
Copyright © 2012 SciRes. 865
quently been explored in a randomized controlled comparison
of escitalopram and agomelatine, in which significantly more
escitalopram-treated patients reported increased “lack of con-
cern for issues previously of high importance” and a “lack of
emotional intensity” (Corruble et al., 2011).
In an attempt to explore the effect of agomelatine on emo-
tional processing as a proxy for emotional blunting, Harmer and
colleagues (2011) evaluated the effect of agomelatine for 7
days in healthy volunteers, and demonstrated decreased recog-
nition of sad facial expressions and improved positive affective
memory in the agomelatine group. Although comparator drugs
were not included in this study, previous trials using the same
paradigms demonstrated impaired recognition of fear, anger
and disgust with SSRIs (Harmer et al., 2004), supporting the
hypothesis that agomelatine and SSRIs have disparate effects in
term of emotional reactivity.
Cognitive Dimension
There is considerable evidence to suggest that deficits in
memory function, executive function, attention, and psycho-
motor speed occur in patients with MDD (Austin, Mitchell, &
Goodwin, 2001; Fossati et al., 1999; Porter et al., 2003). All
medications with sedative effects have the potential to alter
cognitive function. For example, tricyclic induced sedative and
anticholinergic effects generally worsen pre-existing cognitive
symptoms (Amado-Boccara, Gougoulis, Poirier, Galinowski, &
Loo, 1992; Doraiswamy et al., 2003). Adverse effects of par-
oxetine on cognition have been linked to this drug’s additional
anticholinergic and sedative properties (Furlan et al., 2001).
Among the SSRIs, sertraline has been associated with im-
provement in various neurocognitive components including
attention, psychomotor speed and memory (Bandareff et al.,
2000), and this may be associated with sertraline’s additional
dopaminergic effects. The favorable effects of SNRI antide-
pressants such as duloxetine on verbal memory (Raskin et al.,
2007) and venlafaxine on a wider range of cognitive tasks
(Cunningham et al., 1994) have been linked to positive norepi-
nephrine effects on cognition. Similarly, effects on both nore-
pinephrine and dopamine have been cited as possible mecha-
nisms for bupropion’s enhancement of attention, executive
function, and psychomotor speed (Gualtieri & John, 2007).
Overall, these findings suggest that improvement in cognition is
not purely mediated by changes in depressive symptomatology,
and that there are direct positive and negative effects of antide-
pressants on cognitive function.
To date, there are no published reports on the effects of
agomelatine on specific aspects of cognitive function. However,
subjective reports after one week of treatment reveal significant
advantages on measures of “daytime alertness” and “feeling
good” for patients receiving agomelatine compared to venla-
faxine (Lemoine et al., 2007). In comparison with escitalopram,
patients who received agomelatine reported a gradual progres-
sion of improvement in “clear thinking” during 24 weeks of
treatment, which was not achieved in the escitalopram group
(Quera-Salva et al., 2011). Similarly, “wellness on waking”
improved more with agomelatine compared with escitalopram,
also suggesting better alertness (Corruble et al., 2011). Future
studies should evaluate the effect of agomelatine on all aspects
of neurocognition.
Neurovegetative Dimension
The neurovegetative dimension includes symptoms such as
sleep, energy, appetite, weight, libido and sexual function. The
conventional cutoff score of 7 or less on the HRSD to describe
remission (Frank et al., 1991) does not reflect the biases in
symptom reduction that may occur during treatment. For exam-
ple, an 8-week open-label study of fluoxetine therapy showed
that responders who have not achieved remission had signifi-
cantly more somatic symptoms than remitters (Denninger et al.,
2006). Similarly, in an open-label treatment trial of SSRIs,
venlafaxine, mirtazapine and bupropion, non-remitting re-
sponders had significantly smaller reductions in somatic items
on both the HRSD and MADRS (McIntyre et al., 2006). Even
among remitters, fatigue and sleep disturbance were the two
most common residual symptoms following treatment with
fluoxetine (Nierenberg et al., 1999). There is also evidence to
suggest that antidepressants from distinct classes differentially
affect somatic symptoms. Patients who did not respond to
SSRIs had a significant reduction in somatic symptoms after
treatment with mirtazapine (Fava et al., 2001).
Sleep and Alertness
Traditional antidepressants, including tricyclic and monoamine
oxidase inhibitor agents, as well as Serotonin Reuptake Inbi-
tiors and Serotonin Norepinephrine Reuptake Inhibitors fre-
quently disrupt sleep. For example, desimpramine reduces sleep
efficiency and increases wake time following sleep onset while
SSRIs tend to disrupt continuity of sleep and may exacerbate
bruxism and Restless Leg Syndrome (Wilson & Nutt, 2005).
The melatonergic action of agomelatine is particularly effec-
tive in the sleep-related disturbances of depressed patients. In a
randomized controlled trial, primarily designed to evaluate the
effect of agomelatine and sertraline on the rest-activity cycle,
depressed patients receiving agomelatine reported significant
benefits in “getting to sleep” and “quality of sleep” during the
first week of treatment compared with sertraline (Kasper et al.,
2010). In a comparison of agomelatine and escitalopram with
polysomnography recordings, treatment with agomelatine was
associated with a significant reduction in sleep latency from
week 2 and an improvement in sleep efficiency (Quera-Salva et
al., 2011). Somatic symptoms, as evaluated by the HAM-D
scale, are also reduced by agomelatine in a metaanalysis of
placebo-controlled trials (Demyttenaere, 2011). There is addi-
tional evidence from a large open-label trial that agomelatine
improves energy and fatigue, where there was a 51% drop in
the number of patients reporting daytime tiredness after 12
weeks of treatment (Table 2; Laux, 2011).
Libido and Sexual Fu n c ti o n
Evaluation of sexual function incorporates desire, arousal
and orgasm. While loss of sexual desire is present in approxi-
mately 70% of untreated depressed patients, treatment emergent
adverse effects on all aspects of sexual function are associated
Table 2.
Effects of agomelatine on sleep (Laux, 2011).
Circadian Screen Baseline (%) 12 weeks (%)
Difficulty falling asleep 74 12
Repeated awakenings 78 15
Daytime tiredness 62 11
Ability to carry out daily activities 33 61
Copyright © 2012 SciRes.
with most SSRI and SNRI antidepressants (Kennedy & Rizvi,
2009). Since direct effects of serotonin on 5-HT2C receptors is
thought to contribute to sexual side effects, it is not surprising
that antidepressants with 5-HT2C antagonist properties are less
likely to be associated with sexual dysfunction (Keltner et al.,
2002). Mirtazapine has antagonistic effects on alpha-2 adrener-
gic, 5-HT2 and 5-HT3 receptors and agonist effects on post-
synaptic 5-HT1A receptors. The 5-HT2 blockade is thought to
be associated with low rates of sexual dysfunction (Waldinger,
Zwinderman, Olivier, 2003).
Since agomelatine also has antagonist effects on 5HT2C, it
was hypothesized that its effects on sexual function would be
more favorable than venlafaxine in a randomized comparator
trial. Results indicated a significant advantage of agomelatine
in measures of desire in sexually active men and women who
achieved remission, where approximately 20% in the venla-
faxine group reported deterioration in desire, compared with
4% of those receiving agomelatine (Kennedy, Rizvi, Fulton,
Rasmussen, 2008). In a subsequent study of healthy male vol-
unteers, the effects of agomelatine at daily doses of 25 mg and
50 mg on sexual function were compared to paroxetine 20 mg
in a placebo-controlled trial. The reported sexual side effects of
agomelatine at both 25 mg and 50 mg were equivalent to pla-
cebo, whereas over 50% of patients on paroxetine reported
treatment-emergent sexual side effects (Montejo et al., 2010).
Functional Outcom es
While the specific interactions among depression symptoms
and function have not been empirically investigated, ultimately,
all symptom dimensions have a potential impact on overall
functioning. This concept is recognized in the DSM-IV defini-
tion of a major depressive episode, which requires a decline in
function due to depressive symptoms, and is supported by high
rates of patient reported dysfunction in occupational and social
domains even after “remission” of a major depressive episode
(Agosti & Stewart, 1998; Keller et al., 1987). Furthermore, the
improvement of function is cited as a main goal of treatment
based on clinical guidelines (Lam et al., 2009), and according
to depressed patients, is perceived as a proxy for remission
(Zimmerman et al., 2006). However, less than 5% of antide-
pressant clinical trials evaluate function as a treatment out-
come (McKnight & Kashdan, 2009). The consequence of this is
a failure to capture pertinent information that is different from
basic symptom improvement. For example, in a 24-week study
comparing duloxetine and escitalopram the remission rates did
not differ at treatment end (73% vs 70%, respectively), al-
though escitalopram treatment resulted in increased functioning
based on the overall SDS score, as wel as the work subscale
(Wade et al., 2007).
There is also evidence of improved function in several ago-
melatine trials in MDD (Stahl et al., 2010; Zajecka et al., 2010).
In the MDD studies there was a significant improvement in over-
all functioning across work, social life, and family/home re-
sponsibility with agomelatine 25 mg (Stahl et al., 2010) and 50
mg (Zajecka et al., 2010) compared with placebo. Improvement
in social functioning from the first week of treatment has also
been demonstrated in an observational study with 111 depressed
patients treated with 25 - 50 mg agomelatine (Novotny, 2011).
Further support for improved functioning with agomelatine is
derived from a large naturalistic study of over 3300 outpatients
who received agomelatine 25 - 50 mg for 12 weeks. Treatment
effects on sleep and daily activity using a patient screening
questionnaire were assessed in addition to conventional scale
scores. At baseline, only 33% of patients were able to fulfill
their normal daily activities, compared with 61% after 12 weeks
of treatment (Laux, 2011).
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restricted to changes in total scores on symptom scales such as
HRSD or MADRS. The evaluation of symptom dimensions as
well as function provides additional information that may dis-
criminate between antidepressant agents and has the potential to
refine treatment selection and improve outcomes. These ap-
proaches should be considered in the evaluation of new and
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