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The circadian rhythm hypothesis of bipolar disorder (BD) suggests a role for melatonin in regulating mood, thus extending the interest toward the melatonergic antidepressant agomelatine as well as type I (acute) or II cases of bipolar depression. Twenty-eight depressed BD-II patients received open label agomelatine (25 mg/bedtime) for 6 consecutive weeks as an adjunct to treatment with lithium or valproate, followed by an optional treatment extension of 30 weeks. Measures included the Hamilton depression scale, Pittsburgh Sleep Quality Index, the Clinical Global Impression Scale-Bipolar Version, Young Mania Rating Scale, and body mass index. Intent to treat analysis results demonstrated that 18 of the 28 subjects (64%) showed medication response after 6 weeks (primary study endpoint), while 24 of the 28 subjects (86%) responded by 36 weeks. When examining primary mood stabilizer treatment, 12 of the 17 (70.6%) valproate and six of the 11 (54.5%) lithium patients responded by the first endpoint. At 36 weeks, 14 valproate treated (82.4%) and 10 lithium treated (90.9%) subjects responded. At 36 weeks, there was a slight yet statistically significant (P = 0.001) reduction in body mass index and Pittsburgh Sleep Quality Index scores compared to respective baseline values, regardless of mood stabilizer/outcome. Treatment related drop-out cases included four patients (14.28%) at week 6 two valproate-treated subjects with pseudo-vertigo and drug-induced hypomania, respectively, and two lithium-treated subjects with insomnia and mania, respectively. Week 36 drop outs were two hypomanic cases, one per group. Agomelatine 25 mg/day was an effective and well-tolerated adjunct to valproate/lithium for acute depression in BD-II, suggesting the need for confirmation by future double blind, controlled clinical trials.
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Neuropsychiatric Disease and Treatment 2013:9 243–251
Neuropsychiatric Disease and Treatment
Adjunctive agomelatine therapy in the treatment
of acute bipolar II depression: a preliminary open
label study
Michele Fornaro1
Michael J McCarthy2,3
Domenico De Berardis4
Concetta De Pasquale1
Massimo Ta b aton5
Matteo Martino6
Salvatore Colicchio7
Carlo Ignazio Cattaneo8
Emanuela D’Angelo9
Pantaleo Fornaro6
1Department of Formative Sciences,
University of Catania, Catania, Italy;
2Department of Psychiatry, Veteran’s
Affairs San Diego Healthcare System,
3University of California San Diego,
La Jolla, CA, USA; 4Department of
Mental Health, Psychiatric Service
of Dia gno sis an d T rea tme nt,
“ASL 4”, Teramo, Italy; 5Department
of Internal Medicine and Medical
Specialties, University of Genova,
Genoa, Italy; 6Department of
Neurosciences, Section of Psychiatry,
University of Genova, Genoa, Italy;
7Unit of Sleep Medicine, Department
of Neuroscience, Catholic University,
Rome, Italy; 8National Health System,
“ASL 13”, Novara, Italy; 9National
Health System, “ASL 3”, Genoa, Italy
Correspondence: Michele Fornaro
Department of Formative Sciences at
the University of Catania, Via Teatro
Greco, 84, 95124, Catania, Italy
Tel 39-347-4140003
Fax 39-095-316792
Email dott.fornaro@gmail.com
Purpose: The circadian rhythm hypothesis of bipolar disorder (BD) suggests a role for mela-
tonin in regulating mood, thus extending the interest toward the melatonergic antidepressant
agomelatine as well as type I (acute) or II cases of bipolar depression.
Patients and methods: Twenty-eight depressed BD-II patients received open label ago-
melatine (25 mg/bedtime) for 6 consecutive weeks as an adjunct to treatment with lithium or
valproate, followed by an optional treatment extension of 30 weeks. Measures included the
Hamilton depression scale, Pittsburgh Sleep Quality Index, the Clinical Global Impression
Scale–Bipolar Version, Young Mania Rating Scale, and body mass index.
Results: Intent to treat analysis results demonstrated that 18 of the 28 subjects (64%) showed
medication response after 6 weeks (primary study endpoint), while 24 of the 28 subjects
(86%) responded by 36 weeks. When examining primary mood stabilizer treatment, 12 of
the 17 (70.6%) valproate and six of the 11 (54.5%) lithium patients responded by the first
endpoint. At 36 weeks, 14 valproate treated (82.4%) and 10 lithium treated (90.9%) subjects
responded. At 36 weeks, there was a slight yet statistically significant (P = 0.001) reduction in
body mass index and Pittsburgh Sleep Quality Index scores compared to respective baseline
values, regardless of mood stabilizer/outcome. Treatment related drop-out cases included four
patients (14.28%) at week 6 two valproate-treated subjects with pseudo-vertigo and drug-induced
hypomania, respectively, and two lithium-treated subjects with insomnia and mania, respectively.
Week 36 drop outs were two hypomanic cases, one per group.
Conclusion: Agomelatine 25 mg/day was an effective and well-tolerated adjunct to valproate/
lithium for acute depression in BD-II, suggesting the need for confirmation by future double
blind, controlled clinical trials.
Keywords: bipolar disorder type-II, acute bipolar depression, agomelatine, adjunctive
treatment
Introduction
Although the Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition
(DSM-IV)1 proposes mania as the hallmark of bipolar disorder (BD), depression
is the most enduring aspect of the illness,2 requiring intense treatment efforts.3
Moreover, the majority of patients with bipolar depression fail to respond adequately
to pharmacotherapy.4 For this reason, novel treatments for bipolar depression are
needed, and despite being controversial due to the uneven results reported in acute
and long-term follow-up clinical trials, antidepressant medications are commonly
used for bipolar depression.5 The antidepressant agomelatine is a norepinephrine and
dopamine disinhibitor drug, acting as a 5-HT2C/2B serotonin receptor antagonist and
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MT1/MT2 melatonin receptor agonist proven effective in the
treatment of major depressive disorder (MDD).6–9
In pilot studies of type I BD (BD-I), agomelatine showed
interesting results.10,11 Yet, to the best of our knowledge, no
equivalent information has been provided about depression
in type II BD (BD-II). Because there are important dif-
ferences between BD-I and BD-II in terms of prevalence,
clinical course, and antidepressant treatment implications,
the use of agomelatine in the latter condition also warrants
investigation.
The conceptualization of BD as a disorder of cycling,
possibly based on disturbances in circadian rhythms, has been
suggested for centuries. Reports of impaired daily rhythms in
“emotional disturbances” date back to Hippocrates, Galen,
Aretaeus of Cappadocia [“…vital tone was subject to typical
circadian variations”], and later Kraepelin.12 However, it was
not until after the discovery of melatonin in 1958 that the link
between the pineal gland and affective disorders, considered
by 17th century Cartesian theorists, found scientific biologi-
cal support.13 More recently, these observations have been
articulated into specific hypotheses of circadian rhythms as
the bases for mood disorders.14,15 Presently, changes in sleep
are included in the DSM-IV criteria for major depressive
episodes, including those associated with BD, and sleep
patterns have been proposed as predictors of manic relapses
in BD.16 Melatonergic modulation has been shown to be
relevant in regulating circadian rhythms and sleep patterns,
both in MDD17,18 and BD,19 and recent evidence suggests an
association between 5HTR2C gene polymorphisms and BD.20
Therefore, the circadian rhythm system represents a rational
target for novel antidepressant medications aiming to address
these clinical features of BD,21 and due to its unique receptor
binding profile, considerable interest has been generated
around the use of agomelatine.
The principal aim of this open label pilot study was to
assess the efficacy and safety of adjunctive agomelatine
pharmacotherapy in the treatment of acute major depression
in BD-II. As secondary aims, we examined whether there
were differences in sleep and/or body mass associated with
agomelatine treatment, and whether any of these outcomes
were differentially associated with concomitant lithium or
valproate therapy.
Methods
Participants
Participants aged 18–65 years old were recruited by five
experienced physicians between November 2010 and May
2012 through referrals to two main private outpatient practice
centers in Italy (Genoa and Pisa). Patients were referred by
general practitioners, psychiatrists, or self-referral. All met
the DSM-IV criteria for a primary diagnosis of BD-II and
a current major depressive episode, assessed by the means
of the Structured Clinical Interview for DSM-IV Axis-I
Disorders.22 Additional inclusion criteria were a Hamilton
Depression Rating-Scale 17-item (HAM-D-17)23 baseline
score $ 18; negative history for adrenal, thyroid, or liver
diseases; and continuously therapeutic blood levels of
lithium or valproate for at least 6 months. Exclusion criteria
included (I) lifetime diagnosis of BD-I, schizophrenia, or
other psychotic disorders, rapid-cycling or seasonal pat-
terns, history of treatment-resistant depression (defined
as non-response to two consecutive treatments of at least
4 weeks each with two different classes of antidepressants),
Axis-II comorbidity (including mental retardation), and
alcohol/drug use disorders; (II) severe medical comorbidi-
ties, including organic brain syndrome, clinically significant
drug interactions (eg, ciprofloxacin), pregnancy, nursing, or
a woman of childbearing potential who declined the use of
an adequate contraceptive; (III) concomitant use of another
mood altering medication in the previous 2 weeks, or 4 weeks
in the case of fluoxetine (low doses of benzodiazepines [eg,
lorazepam # 2.5 mg/day] were allowed during the first
2 weeks); and (IIII) concomitant psychological treatment.
Written informed consent was obtained from all patients
prior to enrollment in the study after procedures had been
fully explained by a senior study coordinator active in
patients’ recruitment and evaluation. A total of 50 subjects
were initially screened, and 28 were enrolled in the study
(F/M = 17/11). Excluded cases included those with sub-
optimal mood stabilizer blood levels (n = 16), those using
concomitant pharmacotherapies not allowed by the study
protocol (n = 5), and those with a serious medical illness
( Gilbert’s syndrome, n = 1). Of the 28 subjects who partici-
pated, 17 (60.7%) were on valproate and 11 (39.3%) were
taking lithium as their primary mood stabilizer therapy.
Study design
The efficacy of agomelatine as an adjunct to valproate
(blood levels of 50–125 µg/ml) or lithium (blood levels
0.6–1.1 mmol/L) in the treatment of an acute BD-II major
depressive episode was addressed using a 6 week open
parallel-group design. No blind assessment or placebo con-
trols were adopted, and the patients were regularly monitored
for safety, with clear instructions to report any unexpected
adverse events (AEs), including mood changes, to their treat-
ing physician at the earliest possible time.
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Pharmacotherapy
A fixed dose of agomelatine was used during the entire
study (25 mg at bedtime: 9:00–10:00 pm). Higher doses
(eg, 50 mg/day) were excluded due to the preliminary nature
of the study according to safety considerations. During the
initial period of 6 weeks, a psychiatrist performed clinical
evaluations every 2 weeks on each subject. Thereafter, the
patients who continued the trial were evaluated every 6 weeks
until week 36.
Clinical assessment
Demographic and clinical characteristics were recorded at
baseline; the HAM-D-17 was the primary measure of mood.
In all cases, “response” was defined as .50% decrease in
severity from the baseline HAM-D-17 score. Secondary
measures were the Severity and Impression modules of the
Clinical Global Impression Scale–Bipolar Version 24 starting
at the second week, the Young Mania Rating Scale (YMRS),25
and the Pittsburgh Sleep Quality Index (PSQI),26 which is a
self-report instrument used to subjectively measure sleep
across seven domains: quality, latency, duration, efficiency,
disturbances, use of medication, and daytime somnolence.
The scale is designed to assess both the initial quality and
ongoing comparative measurements of sleep quality, and has
a reliability Cronbach’s alpha = 0.83.
At every appointment, an assessment, including general
and psychiatric clinical examinations, was performed. These
included measurements of blood pressure, heart rate, and
body mass index (BMI). Routine laboratory tests included
monitoring of liver functioning (safety, including liver
enzyme levels, was a secondary endpoint of the study) and
blood levels of lithium or valproate. All AEs experienced
by participants were recorded at each study visit, based
on the clinical judgment of the investigator(s). Due to the
explorative nature of the study and safety considerations,
whenever an AE occurred (any degree of severity), this was
considered grounds for agomelatine discontinuation by the
investigators. In these cases, subjects were excluded from
further study.
Statistical analysis
The a priori sample size requirement for the study was
calculated to be at least 12 in each of the two mood sta-
bilizer groups ($24 patients in total), based on consid-
erations described previously for non-randomized pilot
studies.27 All statistical analyses were performed using
IBM® SPSS®Statistics®v.21.0.0 for Microsoft® Windows®8
Release Preview, Build 8400. Since data followed a normal
distribution, they were assessed using the Shapiro-Wilk
test. Parametric comparative analysis for demographic,
clinical, and course characteristics of the two groups were
performed using a Student’s two-tailed t-test for the con-
tinuous variables, and χ2 analysis for categorical variables,
performing bivariate correlation analysis for selected metrics.
Significance was set at P , 0.05. Intent to treat analysis was
performed for efficacy in those patients who took at least one
capsule of study medication and had at least one valid post-
baseline efficacy evaluation, either on the study medication
or within 3 days of drug discontinuation.
Results
Patient characteristics
Baseline demographic and clinical characteristics of the study
subjects are shown in Table 1. There were no significant dif-
ferences in patient characteristics between the lithium and
valproate treated subjects, although some numerical differences
may have led to statistical significance with a larger, “non-
pilot,” sample size. All were diagnosed with BD-II, but many
had secondary psychiatric disorders. Inter-rater reliability on the
DSM-IV diagnosis indicated substantial agreement among the
raters (Cohen’s κ = 0.75 [P , 0.0001], 95% CI = 0.65–0.37).
By adopting a conservative definition of severe depression
of HAM-D-17 scores . 2828, it was found that five patients
(17.9%) were severely depressed at study entry (n = 4 [23.5%]
for valproate and n = 1 [9.1%] for lithium).
Primary outcomes
Using intent to treat analysis, 12 of the 17 valproate treated
(70.6%) and 6 of the 11(54.5%) lithium treated patients
demonstrated clinical response to agomelatine augmenta-
tion at the 6 week primary study endpoint. Six valproate and
one lithium treated patients (25% of the total) responded as
early as the second week of treatment. Secondary analyses
conducted at the 6 week assessment are shown in Table 2.
At the 36 week endpoint, 14 of the 17 (82.4%) valproate
treated and 10 of the 11 (90.9%) lithium treated subjects had
a clinical response.
Secondary outcomes
PISQ scores were significantly reduced after 6 weeks com-
pared to baseline (t = 6.738 [27]; P , 0.001), and PISQ scores
remained lower at week 36 (t = 3.777 [27]; P = 0.001). The
PISQ reduction was similar in both the valproate and lithium
groups, and occurred independently of therapeutic response at
weeks 6 or 36. At week 36, a slight yet statistically significant
(t = 3.777; df = 27; P , 0.001) reduction in BMI score was
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Agomelatine adjunct in acute BD-II depression
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Table 1 Baseline characteristics of the patients included in the study
Included set
N = 28
Agomelatine +
valproate group
N = 17 (60.7%)
Agomelatine +
lithium group
N = 11 (39.3%)
F or χ2
(df = 2)
P
Sex F/M 17/11 9/8 8/3 0.295 (1) ns
Age in years,
Mean (SD); (range)
41.29 ± 13.60
(21–64)
41.94 ± 13.94
(23–64)
40.27 ± 13.66
(21–61)
0.174 ns
Age at rst diagnosis of BD,
mean (SD); (range)
26.21 ± 9.79
(13–59)
25.58 ± 7.68
(13–42)
27.18 ± 12.76
(14–59)
1.539 (26) ns
BMI score, mean (SD) 25.33 ± 2.62 25.17 ± 2.85 25.59 ± 2.33 0.610 (26) ns
Positive family history
for BD-II, N (%)
10 (35.7%) 6 (60%) 4 (40%) 0.003 (1) ns
First episode polarity
(depressive/hypomanic)
24 (85.7%)/4 (14.3%) 14 (82.4%)/3 (17.6%) 10 (90.9%)/1 (9.1%) 0.399 (1) ns
Reported number of depressive
episodes (previous 5 years)*
None, N = 16 (57.1%)
#3, N = 10 (35.7%)
$4, N = 2 (7.1%)
None, N = 9 (52.9%)
#3, N = 7 (41.2%)
$4, N = 1 (5.9%)
None, N = 7 (63.9%)
#3, N = 3 (27.3%)
$4, N = 1 (9.1%)
0.591 (2) ns
Duration of current depressive
episode days (SD); (range)
25.64 ± 18.54; (14–90) 26.18 ± 21.59; (14–90) 24.82 ± 13.47; (14–60) 10.781 (10) ns
HAM-D-17 score (SD); (range) 25.86 ± 3.19; (19–31) 26.53 ± 2.76; (21–31) 24.82 ± 3.65; (19–31) 14.374 (10) ns
YMRS score (SD) 3.46 ± 1.57 3.41 ± 1.73 3.54 ± 1.37 3.544 (6) ns
PSQI score (SD) 11.39 ± 5.31 10.70 ± 4.62 12.45 ± 6.33 12.453 (12) ns
CGI-BP-S (SD) 4.36 ± 1.37 3.94 ± 1.14 5 ± 1.48 5.372 (6) ns
Lifetime axis-I co-morbidity, N (%)
Generalized anxiety disorder 6 (21.4%) 4 (23.5%) 2 (18.2%) 0.113 (1) ns
Obsessive-compulsive disorder 7 (25%) 3 (17.6%) 4 (36.4%) 1.248 (1) ns
Panic disorder 5 (17.9%) 3 (17.6%) 2 (18.2%) 0.001 (1) ns
Specic phobias 8 (26.6%) 4 (23.3%) 4 (36.4%) 0.539 (1) ns
Impulse control disorder 4 (14.3%) 3 (17.6%) 1 (9.1%) 0.399 (1) ns
Anorexia nervosa 1 (3.6%) 1 (5.9%) 0 0.671 (1) ns
Bulimia nervosa 3 (10.7%) 2 (11.8%) 1 (9.1%) 0.050 (1) ns
Binge eating disorder 4 (14.3%) 3 (17.6%) 1 (9.1%) 0.399 (1) ns
Notes: For χ2 and relative, P-values refer to the comparison between the two groups, not versus the whole sample (+valproate vs +lithium). “Age at rst diagnosis of BD”
may differ from age at rst medical consultation for major depression or from actual age of onset of BD. *Current MDE excluded.
Abbreviations: BMI, body mass index; CGI-BP-I/S, Clinical Global Impression/Severity scales for Bipolar Disorder; HAM-D-17, Hamilton Depression Rating-Scale 17-item;
MDE, major depressive episode; PSQI, Pittsburgh Sleep Quality Index; SD, standard deviation; YMRS, Young Mania Rating Scales.
Table 2 Comparison of clinical measures at week-6 of the study (last post-baseline value)
Included set
N = 28
+valproate group
N = 17 (60.7%)
+lithium group
N = 11 (39.3%)
F or χ2
(df = 2)
P
HAM-D-17 mean score (SD) 10.71 (4.52) 10.23 (3.99) 11.45 (5.35) 11.58 (12) ns
YMRS mean score (SD) 7.89 (5.14) 6.94 (3.38) 9.36 (7.01) 10.531 (8) ns
BMI score, mean (SD) 25.27 (3.26) 25.59 (3.21) 24.77 (3.43) 16.610 (15) ns
CGI-BP-S mean (SD) 4.18 (1.28) 3.82 (1.13) 4.73 (1.35) 4.742 (5) ns
CGI-BP-I mean (SD) 2.78 (1.64) 2.88 (1.87) 2.64 (1.29) 2.306 (6) ns
PSQI mean (SD) 4.61 (1.42) 4.88 (1.41) 4.18 (1.40) 3.835 (5) ns
Abbreviations: BMI, body mass index; CGI-BP-I/S, Clinical Global Impression/Severity scales for Bipolar Disorder; HAM-D-17, Hamilton Depression Rating-Scale 17-item;
PSQI, Pittsburgh Sleep Quality Index; SD, standard deviation; YMRS, Young Mania Rating Scales.
observed in the intent to treat population (24.32 ± 2.26 vs
baseline 25.33 ± 2.62) regardless of the primary mood sta-
bilizer treatment. Specifically, mean BMI scores at week
36 were 24.73 ± 2.12 among valproate treated subjects and
23.68 ± 2.43 among lithium treated subjects. Also, at week
36, there was a trend toward a negative correlation between
BMI and HAM-D-17 score (r = –0.16; P = ns). There was
no correlation between BMI and PISQ (r = –0.06; P = ns).
Additional information about the trend of specific clinical
variables within the trial is reported in Figure 1.
Adverse events
Four patients (14.28% of the total) dropped out due to a
treatment-related AE by week 6. In the valproate group, these
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CGI_BP_I_36
CGI_BP_I_W6
PSQI_W36
CGI_BP_SW36
YMRS_baseline
CGI_BP_S_W6
CGI_BP_S_baseline
PSQI_W6
HAM_D_17_W36
YMRS_W36
YMRS_W36
HAM_D_17_W6
PSQI_baseline
BMI_week_36
BMI_week_6
BMI_baseline
HAM_D_17_baseline
0.00
Lithium
Valproate
10.0020.00
Mean score
Assigned mood-stabilizer
30.00
Figure 1 Trend of different rating and clinical parameters at weeks 6 and 36 between the two groups.
Note: While the gure fails to show any substantial differences between groups, this highlights the fact that the effect of agomelatine add-on therapy was substantially
maintained within week 6 and week 36, independent of the ongoing mood stabilizer treatment.
Abbreviations: BMI, body mass index; CGI-BP-I/S, Clinical Global Impression/Severity scales for Bipolar Disorder; HAM-D-17, Hamilton Depression Rating-Scale 17-item;
PSQI, Pittsburgh Sleep Quality Index; YMRS, Young Mania Rating Scales.
included a single case each of pseudo-vertigo and hypomania;
in the lithium group, these included a single case of insomnia
and mania (YMRS = 30).
Two additional cases left the study at week 36 due to
hypomania. These included one each in both the valproate
(YMRS = 17) and lithium (YMRS = 16) treated groups.
Notably, whenever an AE occurred, this was judged as severe
and considered responsible for drop out.
Discussion
Overview and limits of the study
Our results suggest that adjunctive agomelatine may be useful
in the treatment of acute depression in BD-II. During both
the short- and longer-term periods of the trial, agomelatine
treatment was associated with improvements in depression
and sleep quality and was well tolerated.
Nonetheless, the study was limited by several important
factors that warrant discussion, especially in light of the
potential “publication and outcome reporting” biases that
have arisen regarding randomized controlled studies involv-
ing agomelatine in the treatment of MDD.29
Additionally, the pharmacodynamics of agomelatine
need to be better characterized in human samples. In fact,
by inhibiting 5-HT2C receptors, agomelatine secondarily
increases norepinephrine and dopamine in the frontal cortex
of the brain of animals, while the drug binding and coupling
profiles of h5-HT2B and h5-HT2C receptors are similar, and
agomelatine also blocked 5-HT-induced [3H]PI depletion
at h5-HT2B sites.30 However, 5-HT2B receptors are poorly
represented in the central nervous system, wherein their
functional significance remains substantially obscure.31
Due to safety reasons and the preliminary nature of the
study, raters also participated in the clinical management
and were therefore not blind to treatment assignments
(“measurement bias”). Moreover, because agomelatine is
not yet supplied for free by the National Health System in
Italy (unlike many medications), this naturalistic study may
suffer from an additional selection bias, favoring recruitment
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Agomelatine adjunct in acute BD-II depression
Neuropsychiatric Disease and Treatment 2013:9
of patients who were more financially stable and/or motivated
for treatment, potentially influencing both the drop-out rate
and medication adherence (“under/over-reporting bias”),
especially in the optional 30 week extension period. Despite
these limitations, our results should stimulate further inves-
tigation of agomelatine and BD-II.
On the other hand, since the ultimate goal of treatment in
“acute” bipolar depression should be establishing long-term
mood stability,32 the lack of additional follow up, ideally
beyond 52 weeks,11 needs to be noted, although very few
pilot studies would indeed follow this criterion. However, it
is worthy of notice that during both the acute and extension
periods of the trial, adjunctive agomelatine treatment was
associated with improvement in depression, with favorable
safety and tolerability profiles, including sensitive issues such
as liver (there was no clinically relevant enzyme modification
within the trial) and sexual function,29,33,34 although these lat-
ter outcomes were not assessed by ad hoc instruments, and
improvement of subjective sleep quality – when initially
impaired was not assessed by actigraphic techniques or
by other objective neurophysiological measurements due to
the very preliminary nature of the study, whereas lithium or
valproate may have contributed both to the antidepressant
response and, possibly, to modulation of MT1/MT2 melaton-
ergic receptors as already documented in animal models.35,36
Finally, the fact that the mean duration of depression was
less than 4 weeks (with a lower range of 2 weeks) cannot
exclude the chance of spontaneous improvement due to
the natural course of depression for those subjects judged
as “responders”; equally, the eventual predictive role of
anxious co-morbidity (when present) could not be evinced
at this time due to the small sample size and methodological
limits of this preliminary study, although agomelatine has
been anecdotally reported to have a promising modulating
role in anxious disorders.37–43
Agomelatine, sleep, and depression
The effects of agomelatine on sleep have already been
documented by different studies on MDD samples. Among
others, a comparative study with venlafaxine highlighted a
statistically significant improvement of sleep with agomela-
tine,44 a faster improvement of the “circadian rest-activity
cycle” compared to sertraline,45 and a better rapid eye move-
ment profile – but not short wave sleep profile, possibly due
to 5-HT2C antagonism in comparison to escitalopram,46
although the degree to which 5-HT2C receptor antagonism
explains or contributes to the antidepressant or sleep effect
of agomelatine has been questioned in humans.47
Sleep disturbances are a core aspect of BD and may
often predict subsequent manic switch.48 In our study and
in others, agomelatine led to sustained subjective improve-
ments in sleep quality in association with either lithium or
valproate, beginning as early as 2 weeks into treatment.
The concomitant use of benzodiazepines during the first
2 weeks may have influenced these results, but is unlikely
to account for the effect since only a minority patients used
these medications (n = 3/28; 10.7%), and no patients used
them beyond the second week. Improved sleep quality may
have important clinical implications for BD-II, but may
not necessarily improve mood.49 While insomnia has been
reported as a major predictor of depression,50 abnormalities
in sleep architecture, including disturbances of sleep consoli-
dation, slow-wave sleep, and rapid eye movement sleep are
common during antidepressant treatments, suggesting sleep
quality and mood state are dissociable.51,52 Paradoxically,
four patients (14.3%) experienced insomnia while taking
agomelatine. This problem was effectively managed after
exclusion from the study by switching the time of agomela-
tine administration from bedtime to early morning, without
any subsequent manic switch. While not described in previous
trials, this unexpected insomnia may be related to circadian
phase abnormalities associated with depression. In seasonal
depression, most patients are thought to be phase delayed and
respond to the phase advancing effects of evening melatonin.
In contrast, 30% may be phase advanced.53 In these latter
cases, evening melatonin receptor stimulation may lead to a
worsening of the circadian abnormality by further advancing
phase, perhaps disrupting sleep onset and causing nighttime
insomnia. If these findings generalize to bipolar depression,
among the minority of subjects with advanced phase, morn-
ing agomelatine would correct the abnormality by delaying
phase to a more optimal time.
Adverse events and manic switch
While relatively few in number, our study did have AEs to
report, including four mood switches to (hypo-) mania. The
rate of manic/hypomanic switch was lower than expected
based on previous clinical experience with other antidepres-
sants added to mood stabilizers in the treatment of acute
depression in BD-II, yet was still remarkable compared to
other established antidepressants.54 Nonetheless, the profile
of agomelatine with regard to manic switching is consistent
with preliminary reports from BD-I;10 since the safety of
antidepressants in bipolar depression is of great interest in
modern clinical psychiatry, further research on this issue is
needed for agomelatine to reliably compare corresponding
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Neuropsychiatric Disease and Treatment 2013:9
data coming from controlled trials on other antidepressants,
ideally looking at long-term treatment compliance and
stability.55
The occurrence of “pseudo-vertigo” (dizziness not
involving a sense of rotation, which is common in the
course of panic disorders, hyperventilation, and orthostatic
hypotension) in three patients was another unexpected AE
that was encountered. Of note, a previous case report sug-
gested an interaction between agomelatine and the melaton-
ergic neurons of the cerebellum in a minority of sensitive
individuals.38 Larger studies are required to determine the
rate of AE associated with this problem.
Implications for the circadian rhythm
hypothesis of BD
With the associated disruptions in sleep and daily activity
cycles, circadian rhythm abnormalities have been proposed
to play a role in the etiology of mood disorders, including
BD. Both lithium and valproate, the mood stabilizers used in
our study, have effects on circadian rhythms,56–58 and genetic
variants in clock genes have been associated with lithium
response.59 BD patients have been reported to be particularly
sensitive to environmental events,60,61 a feature that has also
been associated with circadian instability,62 suggesting that
biological rhythms play a critical role in the emotional dys-
regulation at the center of BD.19,63,64 Central to the circadian
effects on mood is the availability of light. Differential
outcomes in antidepressant response are associated with
specific changes in retinal physiology, suggesting that proper
timing of light input into the central nervous system may be
an important aspect of antidepressant response.65
In this context, it is interesting to consider the implica-
tions of our agomelatine findings with respect to the circadian
clock hypothesis of mood disorders. We found changes in
sleep quality and BMI, the latter presumably reflecting
differences in dietary intake and/or motor activity. It is
interesting to note that regardless of the use of drugs that
affect the clock in distinct ways (lithium and valproate), the
effects of agomelatine on rhythmically influenced behaviors
did not differ by the concomitant mood stabilizer. Of inter-
est, previous reports have described melatonergic neurons
outside the central nervous system, including those in the
gastrointestinal tract, that are influenced both by light/dark
cycles and environmental stressors.66–69 Collectively, these
findings lend support to the supposed interaction between
melatonergic regulation on mood and the “gut-clock”.70
If further evidence supports the hypothesis that agomela-
tine functions as core “rhythm regulator,71 it could play
a therapeutic role for those BD patients with prominent
imbalances in eating rhythms, and may extend the concept
of rhythm disturbances in mood disorder to include feeding
behavior and metabolic activity in addition to sleep/wake
behavior.72–75 This could be in marked contrast to standard
antidepressants, with their propensity toward causing weight
gain via serotonergic stimulation of 5-HT2A receptors
rather than selective antagonism of 5-HT2C.9,51,76,77 It will be
of interest in the future to determine whether agomelatine
affects excessive or atypical eating behaviors in the context
of depression, especially in the view that animal studies have
reported that 5-HT2B agonists concur with hyperphagia and
reduce grooming in rodents,78 whereas stimulation of 5-HT2B
sites exerts actions in animal peripheral tissues, especially in
development. However, there is no evidence for a functional
effect of antagonists at these sites79 and agomelatine is yet to
be characterized in this regard in human samples.
Concluding remarks
Adjunctive agomelatine treatment with lithium or valproate
in the acute phase of BD-II major depression led to substan-
tial positive results in our preliminary open label trial. Large
double-blind randomized controlled studies are warranted
and will be essential to providing more definitive evidence of
the efficacy, safety, and optimal dose-range profile compared
to MDD usage.80
Disclosure
The authors report no conflicts of interest in this work.
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Agomelatine adjunct in acute BD-II depression
... After removing duplicates, we screened the remaining 82 unique articles by title and abstract and excluded 35 unrelated records. Subsequently, we conducted a full-text review and identified 6 studies that met the final inclusion criteria (Calabrese et al., 2007;Fornaro et al., 2013;Tiuvina Nas, 2012;ushkalova et al., 2015;Verbitskaya et al., 2022;Yatham et al., 2016). The specific process of screening is shown in Figure 1. ...
... Table 1 presents an overview of the study characteristics. One study was a RCT , while the other five were open-label studies (Calabrese et al., 2007;Fornaro et al., 2013;Tiuvina Nas, 2012;ushkalova et al., 2015;Verbitskaya et al., 2022). The majority of the studies were conducted in Russia (k = 3) (Tiuvina Nas, 2012;ushkalova et al., 2015;Verbitskaya et al., 2022). ...
... Three studies initiated an extension period (46/30/44 weeks) following adjunctive therapy for acute bipolar depression to evaluate long-term efficacy, the proportion achieving a response was 68.4% (117/171). In open-label studies (Calabrese et al., 2007; Fornaro et al., 2013), the efficacy and safety of AGO treatment were sustained during the optional extension period. While in the RCT study , there was still no significant difference from placebo. ...
Article
Introduction: The controversy of antidepressant use in bipolar depression remains controversial. Agomelatine (AGO) is an effective antidepressant in major depressive disorder (MDD), but its application in bipolar depression was little discussed. We aimed to provide a comprehensive systematic review of clinical evidence from studies examining the efficacy and safety of AGO for bipolar depression. Methods: We conducted a systematic review about AGO trials for the treatment of bipolar patients. We searched PubMed, MEDLINE, Embase, and Cochrane for relevant studies published since each database's inception. We synthesised evidence regarding efficacy (mood and rhythm) and tolerability across studies. Results: We identified 6 studies including 272 participants (44% female). All studies used 25-50 mg AGO per day for treatment combined or not combined with mood stabilisers (MS). Across all 6 studies, there were improvements in depression evaluated by depression rating scores and response rate over time. The response rates varied from 43% to 91% within 6-12 weeks. Although AGO was found of better efficacy in bipolar depression compared to recurrent depression, its efficacy remains controversial. Most studies have shown AGO to be effective after just about a week. AGO was reasonably well tolerated both in acute and extension period, without obvious risk in inducing mood switching. Conclusion: AGO is promising in treating bipolar depression with significant efficacy and well tolerability. However, more strictly designed and large-sample trials are needed in further research with homogeneity within intervention and treatment groups.
... In contrast, the self-reported measures in this study, such as the QIDS-self report for depressive symptoms and the Altman Self-Rating Mania scale for manic symptoms, decreased. Long-term prescription of adjunct agomelatine can improve depressive symptoms; however, it can cause a switch to hypomania (Fornaro et al., 2013). The distinction between these measures signified a subtle improvement in symptoms by MEL and was distinguished by the participants. ...
... In people with BD, differences in neuronal circadian rhythms from patient-derived pluripotent stem cells predict lithium response [54], and psychosocial therapy for mood disorders decreases REM density while improving symptoms [55][56][57]. Preliminary research shows benefits of pharmacological agents, such as the selective melatonin receptor type I and II agonists ramelteon and agomelatine, as mood stabilizers, suggesting potential therapeutic actions via alterations in circadian rhythms in sleep [58,59]. ...
Article
Full-text available
Background The primary objective of this trial is to examine the mechanisms of time-restricted eating (TRE) as an adjunct to psychiatric care for people with bipolar disorder (BD) with sleep or circadian disruptions. This study builds on prior studies of circadian disruption in BD as well as growing evidence that TRE improves circadian functioning. Methods One-hundred fifty participants diagnosed with BD 1 or II will be recruited via advertising in the local community. Main inclusion criteria include: obtaining medical treatment for BD; current sleep or circadian problems; self-reported eating period of ≥ 12 h; no eating disorder or other health conditions that would hinder or limit the safety of following TRE; and not currently experiencing a mood episode, acute suicidality, psychosis, alcohol or substance use disorder. Participants will be asked to complete a baseline period in which daily food intake is logged online for two weeks. After baseline, participants will be asked to follow TRE for 8 weeks and to continue to complete daily food logging during this time. Symptom severity interviews will be conducted by phone or videoconference at baseline, mid-intervention (6 weeks post-baseline), end of intervention (10 weeks post-baseline), and 6 months post-baseline. Self-rated symptom severity and quality of life data will be gathered online at the same time points as symptom severity interviews, and at 16 weeks post-baseline (6 weeks after the TRE period ends). To assess potential mechanisms of change, we will examine the change in diurnal amplitude of ‘clock’ gene expression as a primary mediator at 8 weeks compared to baseline. We will further test whether diurnal amplitude of clock gene expression is predictive above and beyond the role of two covariate potential mediators, glucose tolerance and inflammation at 8 weeks relative to baseline. To provide an index of whether TRE successfully decreases emotional lability, participants will be asked to complete 5 mood assessments per day for 7 days at baseline and at 10 weeks. These mood assessments will be optional. Discussion The planned research will provide novel and important information on whether TRE improves sleep/circadian rhythm problems, along with reductions in mood symptoms and improvements in quality of life, for individuals with BD. Trial registration ClinicalTrials.gov ID: NCT06555406.
... Ramelteon, an M1/M2 melatonin receptor agonist, has a significant effect in preventing recurrence of bipolar disorder [73]. Additive therapy using agomelatine, another M1/M2 melatonin receptor agonist, affects mood symptoms by advancing the circadian rhythm [74]. Light therapy, which is mainly used as an adjunct to drug therapy, was found to be effective in improving depressive symptoms without increasing the risk of manic switch in bipolar disorder [75]. ...
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Sleep disturbance and abnormal circadian rhythm might be closely related to bipolar disorder. Several studies involving disturbed sleep/wake cycle, changes in rhythms such as melatonin and cortisol, clock genes, and circadian preference have shown the relationship between bipolar disorder and circadian rhythm. The results differed across different studies. In some studies, a delay in the circadian rhythm was observed in the depressive episode and advanced circadian rhythm was observed during the manic episode. In other studies, a delay in circadian rhythm was observed independent of mood episodes. Accordingly, circadian rhythm disorder was proposed as a trait marker for bipolar disorder. The altered circadian rhythm may represent a pathological mechanism that contributes to the mood episodes. However, a prospective cohort study is needed for further clarification.
... It was approved by the European Medicines Agency (EMA) in 2009 and the Therapeutic Goods Administration in Australia in 2010 [1,2]. This molecule is also effective in the treatment of generalized anxiety disorder (GAD) [2][3][4], as well as in bipolar depression, alcohol abuse, and migraines [2,5,6]. ...
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Introduction: Bipolar disorder (BD) is a severe and chronic medical condition typified by episodic recurrent mania (or hypomania) in addition to major depression. BD is associated with a number of negative outcomes including premature death, reduced quality of life and can also lead to other complications including impaired cognitive function. Unfortunately, the currently available pharmacological treatments for BD are insufficient for many with the condition. Areas covered: This review focuses on known therapeutic targets of mood stabilizing drugs including: the glycogen synthase kinase-3 (GSK-3), the phosphoinositide pathway and protein kinase C (PKC), the brain-derived neurotrophic factor (BDNF), and histone deacetylases (HDACs). This article also presents new promising therapeutic targets including: the glutamatergic pathway, mitochondrial modulators, neuropeptide-converting endopeptidases, the insulin transduction pathway, the purinergic system and the melatoninergic system. Expert opinion: Challenges in improving methods and tools to generate, integrate and analyze high-dimensional data are required to allow opening novel routes to BD drug discovery. Through the application of systems biology approaches and the use of bioinformatical tools to integrate all omics data, it will be possible in the near future to gain deeper insights into pathophysiology of BD. This will in turn lead to the identification and exploitation of new potential therapeutic approaches.
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Agomelatine is an antidepressant with a novel mechanism of being a selective melatonergic MT1/MT2 receptor agonist with serotonin 5-HT2c receptor antagonist activities. Although the vast majority of the clinical data concerning the effectiveness of agomelatine concern its antidepressant properties, there is also preliminary evidence of anxiolytic effects. The purpose of the study was to perform a review of studies that investigated the efficacy of agomelatine in the treatment of anxiety disorders (ADs) and a discussion of the clinical utility of agomelatine in this clinical population. Previous clinical data indicated that agomelatine was more efficacious than both placebo and comparator drugs in reducing anxiety symptoms in depressed patients. Moreover, agomelatine effectiveness in the treatment of AD patients was observed in 2 double-blind, randomized trials, in a case series and in 3 case reports. Greater clinical evidence was observed with generalized AD patients. Agomelatine was efficacious both in reducing anxiety symptoms and in preventing relapses after a 6-month follow-up. However, concerning other ADs, evidence of agomelatine's effects on anxiety was found only in isolated case descriptions. Nevertheless, those case reports emphasized the drug's favorable side effect profile (in comparison to serotonin reuptake inhibitors) and its effectiveness in treatment-refractory patients. Considering the high incidence of poor efficacy and tolerability of the first-line agents in the treatment of ADs, agomelatine seems to be a promising option in cases of treatment failure, and it could be used as a second or third option, as monotherapy or as augmentation treatment. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
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Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain’s primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks in mood disorders.
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Background Subjective reports of insomnia and hypersomnia are common in bipolar disorder (BD). It is unclear to what extent these relate to underlying circadian rhythm disturbance (CRD). In this study we aimed to objectively assess sleep and circadian rhythm in a cohort of patients with BD compared to matched controls. Method Forty-six patients with BD and 42 controls had comprehensive sleep/circadian rhythm assessment with respiratory sleep studies, prolonged accelerometry over 3 weeks, sleep questionnaires and diaries, melatonin levels, alongside mood, psychosocial functioning and quality of life (QoL) questionnaires. Results Twenty-three (50%) patients with BD had abnormal sleep, of whom 12 (52%) had CRD and 29% had obstructive sleep apnoea. Patients with abnormal sleep had lower 24-h melatonin secretion compared to controls and patients with normal sleep. Abnormal sleep/CRD in BD was associated with impaired functioning and worse QoL. Conclusions BD is associated with high rates of abnormal sleep and CRD. The association between these disorders, mood and functioning, and the direction of causality, warrants further investigation.
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Management of bipolar disorder has traditionally emphasized the acute treatment of mania. Although acute treatment of mania is a critical aspect of care, this emphasis has tended to over-shadow other important phases of bipolar disorder, such as depression, hypomania, and subsyndromal symptoms. We offer a reconceptualization of bipolar disorder that highlights unmet needs and the importance of differential spectra of efficacy. In this reconceptualization, bipolar disorder can be viewed as an aberration of mood, behavior. and cognition from baseline (euthymia). "Below baseline" is characterized by depression and subsyndromal depression. "Above baseline" is characterized by mania. mixed states, hypomania. and subsyndromal mood elevation. In contrast to the treatment options for mania, the options for depression are limited. This new nomenclature emphasizes the need to develop mood stabilizers that possess the ability to stabilize mood "from below baseline," either alone or in combination with other agents. In this article, the treatment options for bipolar disorder, with a focus on depression and rapid cycling, are discussed according to this new conceptualization of management from below and above baseline.
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Introduction: Despite the clinical and social relevance of depression, and the availability of numerous antidepressants and non-pharmacological interventions, response rates remain unsatisfactory and novel therapeutic targets are being explored. Areas covered: This review starts with a brief overview of the evolution of the current antidepressant drug scenario and ends with a focus on the potential influence of the underestimation of bipolarity on the exploration of novel antidepressant drugs. Expert opinion: The field of antidepressant drug development has suffered from a relative decline recently and, with the exception of agomelatine, innovative non-monoaminergic antidepressants have yet to be developed. The need for more effective compounds is evident. Clinicians and researchers should pay greater attention to the impact of bipolarity in depression. The ultimate goal of this review is not to discourage the use of antidepressants but rather to encourage judicious prescriptions, and also to solicit a better collaboration between clinicians and preclinical researchers so that more reliable diagnostic criteria can be adopted.
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Pooled analysis of individual patient data was used to compare the antidepressant efficacy of agomelatine with that of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). We sought head-to-head, double-blind, randomized studies without a placebo arm using antidepressant doses in the licensed range and primary evaluation on the Hamilton scale (HAM-D17). Six studies were identified versus venlafaxine, sertraline, fluoxetine, paroxetine or escitalopram. Estimates of differences between treatments were calculated on parameters expressed as the last postbaseline value (6, 8 or 12 weeks). A total of 2034 patients were randomized (age 47.6±14.9 years; 73% women; HAM-D17 total score 26.9±3.0). The full analysis set included 1997 patients (1001 agomelatine; 996 SSRI/SNRI). There was a significant difference between HAM-D17 total scores, with a greater reduction with agomelatine than with SSRI/SNRI [E(SE), 0.86 (0.35), 95% confidence interval 0.18-1.53, P=0.013], and better rates of response on the HAM-D17 (P=0.012) and the Clinical Global Impression-Improvement scales (P=0.032). Similar results were found in patients with severe depression. Agomelatine was associated with better tolerability than SSRI/SNRI. Agomelatine has favourable efficacy and tolerability versus a range of SSRIs and SNRIs - including agents considered to have superior efficacy - and may deserve benefit-risk analysis as a first-line treatment of major depressive disorder.