Journal Club Presentation
Efficacy of the Novel Antidepressant Agomelatine on the
Circadian Rest-Activity Cycle and Depressive and Anxiety
Symptoms in Patients With Major Depressive Disorder:
A Randomized, Double-Blind Comparison With Sertaline
Mohammed Almoslem Pharm.D. Candidate
King Saud University & King Khalid University Hospital
Psychiatric Rotation
Supervised by: Dr. Solafa Fatani Ms.c.
Outline
• Introduction
• Relevance
• Validity
– Method
– Statistical analysis
• Results
• Strengths
• Limitations
• Conclusion
• Final Message
Introduction
Paper Information
• Title:
– Efficacy of the Novel Antidepressant Agomelatine on the Circadian
Rest-Activity Cycle and Depressive and Anxiety Symptoms in Patients
With Major Depressive Disorder: A Randomized, Double-Blind
Comparison With Sertaline
• Journal:
– The journal of clinical psychiatry
• Authors:
– Kasper S, Hajak G, et al
• Study Design:
– International, Randomized, double-blind, parallel-group
• Funding:
– This study was sponsored by Servier (Courbevoie,France)
Introduction
Major Depressive Disorder (MDD)
• 16.2% of the population had a history of Major Depressive Disorder
• More than 6.6% had episodes in one year.
• MDD medication are classified as following:
– Monoamine Oxidase Inhibitors (MAOIs)
• Hypertensive crisis, food interaction
– Tricyclic Antidepressants (TCAs)
• Anticholenergic, orthostatic hypotension
– Selective Serotonin Reuptake inhibitors (SSRIs)
• Wait gain, sexual dysfunction
– Serotonin-Norepinephrine Reuptake inhibitors (SNRIs)
• Hypertension, liver toxicity
– Atypical antidepressants
• Liver toxicity, psychosis
Dipiro, et al, pharmacotherapy a pathophysiological approach 7th edition
Introduction
Agomelatine
•
•
•
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The first melatonergic antidepressant
Potent MT1/ MT2 receptor agonist
5-HT2C receptor antagonist
Resynchronize altered circadian rhythm in depressive or healthy
individuals
Introduction
Circadian Rhythm
• Endogenous physiological processes that regulates the cycle
of 24 hour in living beings
• Circa: around or approximately
• Diem or dies: day
Introduction
Circadian Rhythm
Introduction
Actigraphy
• A useful proved method that measures the circadian rest
and activity patterns
• Indirectly measurement of sleep and characterize 24-hour
sleep-wake cycle
Introduction
Objective
• Primary:
Demonstrate that agomelatine (25–50 mg/d) improved the circadian
rest-activity cycle faster than sertraline in MDD outpatients
• Secondary:
Assess the efficacy and tolerability of agomelatine on depressive and
anxiety symptoms compared with sertraline through its effect on
sleep efficacy and latency
Relevance
• Sleep disruption is a major symptom in depression, with over
90% of patients suffering from sleep complaints
• There is a close link between the regulation of sleep and
circadian rhythms and the regulation of mood
Thase ME. Antidepressant treatment of the depressed patient with insomnia. J Clin Psychiatry. 1999;60(suppl 17):28–31, discussion 46–48. PubMed
Birchler-Pedross A, Schroder CM, Munch M, et al. Subjective well-being is modulated by circadian phase, sleep pressure, age and gender. J Biol Rhythms. 2009;24(3):232–242. PubMed doi:10.17/07487304093546
Boivin DB, Czeisler CA, Dijk DJ, et al. Complex interaction of the sleepwake cycle and circadian phase modulates mood in healthy subjects. Arch Gen Psychiatry. 997;54(2):145–152
Validity
Method
• Hypothesis:
The nocturnal disturbances of sleep onset, continuity, and/or
awakening, together with daytime retardation and napping, lead
to a reduced Relative Amplitude, and that improvement of the
former leads to increase of the latter.
Validity cont.
Method
• Randomization:
– International, double-blind, parallel-group
– Conducted from 2005-2006 in 37 centers in 6 European
countries
• (France, Germany, Austria, Spain, Italy, and Poland)
Validity cont.
Method
• Allocation:
– Inclusion criteria
• MDD diagnosed male and female outpatients aged 18 to 60 years
• Confirmed by the Mini-International Neuropsychiatric Interview
• Match the items standard of Hamilton Depression Rating Scale
(HDRS)
• Single or recurrent episodes that match the criteria of DSM-IV-TR
• The current episode had already lasted at least 4 weeks
• Should not have seasonal pattern, psychotic features, or
catatonic symptoms and were not postpartum
Validity cont.
Method
• Allocation:
– Exclusion criteria
•
•
•
•
•
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•
•
•
•
•
•
High risk of suicide or a previous suicide attempt within 6 months
Bipolar disorder
Anxiety symptoms
Drug abuse or dependency within the past 12 months
Previous antidepressants resistance
ECT therapy or formal psychotherapy within 3 months
Light-therapy started within 2 weeks
Positive screened for sleep disorders
Neurologic disorders
Obesity with functional impairment
Serious or not stabilized organic
Other antidepressants were prohibited for washout
ECT: electroconvulsive therapy
Validity cont.
Method
• Allocation:
– Disposition of included patients:
Validity cont.
Method
• Attrition
– 6 patients were not included in
the Full Analysis Set
• 4 in agomelatine group
• 2 in sertaline group
Due to absence of treatment
intake or no postbaseline
efficacy assessment
– The Actigraphy Analysis Set
comprised only (73%) 233 pts.
• 117 (76%) of the agomelatine
• 116 (73%) of sertaline
Validity cont.
Method
• Demographic
characteristics:
Validity cont.
Method
• Blindness and concealment
– Blindness:
• All patients took orally 2 tablets once a day in the evening
• Daily dosage irrespective to the treatment
• Same appearance and the taste of the study treatment during
the study period for all patients
• The packaging and the labeling were identical
• Statistical analysis group ??????
– Concealment:
• Three hundred seventy-two patients were screened, and 313
patients were randomly assigned to receive
– Agomelatine (154 patients)
– Sertaline (159 patients).
• The concealment was NOT mentioned in the study.
Validity cont.
Method
• Intention to treat:
– The actigraphy analysis set (AAS), defined, for objective sleep
criteria analyses, as all randomized patients who took at least 1
dose of study treatment and had 1 reliable baseline value and
at least 1 reliable postbaseline value for the RA
– The full analysis set (FAS), defined, for other efficacy criteria
analyses, as all randomized patients who took at least 1 dose
of study treatment and had at least 1 postbaseline efficacy
assessment (other than actigraphic) over the 6-week
treatment period.
Validity cont.
Statistical Analysis
• Actigraphy Analysis Set (AAS)
– For sleep data analysis
• Mixed-effects model with repeated measures (MMRM)
• Full Analysis Set (FAS)
– For depression data analysis
• Hamilton Depression Rating Scale (HDRS)
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2-way analysis of covariance
2-sided Student t test
X2 test
Post hoc analysis
• Clinical Global Impressions scale (CGI)
• Leeds Sleep Evaluation Questionnaire (LSEQ)
– For anxiety data analysis
• Hamilton Anxiety Rating Scale (HARS)
– 1-way analysis of covariance
– Post hoc analysis
Results cont.
Efficacy on the Circadian Rest-Activity Cycle
Mean ± SD
P-value
Mean RA 1st week
.010
AAS evolution of the
mean RA over time
.023
Mean RA 2nd week
.148
Mean RA 3rd week
.521
Mean M10
Mean L5
Agomelatine
(386.6 ± 6914.9)
Sertraline
( - 430.5 ± 5934.2)
Agomelatine
(-120.8 ± 1302.8)
Sertraline
( - 366.8 ± 1367.1)
RA: relative amplitude. M10: activity of maximum 10 hours. L5: activity of minimum 5 hours.
.006
.121
Results cont.
Efficacy on Actigraphy-Derived Sleep Parameters
• Baseline and Difference in Sleep Efficiency (A) and Sleep Latency (B)
Between Treatment Groups Over Each Postbaseline 7-Day Period in the
Actigraphy Analysis Set
Results cont.
Efficacy on Subjective Sleep
• Change in LSEQ Getting to Sleep (A) and Quality of Sleep (B) Scores (mm)
From Baseline to Last Postbaseline Value Over the Week 0–Week 6
Period in the Full Analysis Set
a: P value, treatment effect: 2-sided Student t test for independent samples.
Abbreviation: LSEQ = Leeds Sleep Evaluation Questionnaire
Results cont.
Efficacy on Depressive symptoms
• Change in HDRS Total Score From Baseline to Last Postbaseline
Assessment Over the 6-Week Period (week 0–week 6) in the Full Analysis
Set
a: Two-way analysis of covariance with treatment and center (as random effect) as factors and week 0 HDRS total score as
covariate.
b: Estimate (standard error) of the difference between adjusted treatment group means: sertraline minus agomelatine.
c: 95% CI of the difference.
d: P value of treatment effect.
Abbreviation: HDRS = Hamilton Depression Rating Scale.
Results cont.
Clinical Global Impressions scale
• The data will be provided later on
Results cont.
Efficacy on Anxiety Symptoms
• The data will be provided later on
Results cont.
• Most Frequently Reported Emergent Adverse Events (≥ 5.0% of patients
in any treatment group), Expressed as Percentage of Affected Patients
Among Exposed Patients During the Double-Blind Treatment Period in
the Safety Set
The safety data were not statistically analyzed and only emergent adverse
events (EAEs) that reported by less than 5% of the patients were NOT provided
Study Strengths
• .
Study Limitations
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Study Conclusion
• .
Final Message
• .
Thank You …