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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

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JournalClubPresentation

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 AlmoslemPharm.D. Candidate

King Saud University & King Khalid University Hospital

Psychiatric Rotation

Supervised by: Dr. SolafaFataniMs.c.

outline
Outline
  • Introduction
  • Relevance
  • Validity
    • Method
    • Statistical analysis
  • Results
  • Strengths
  • Limitations
  • Conclusion
  • Final Message
introduction paper information
IntroductionPaper 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
IntroductionMajor 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
IntroductionAgomelatine
  • 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
IntroductionCircadian Rhythm
  • Endogenous physiological processes that regulates the cycle of 24 hour in living beings
  • Circa: around or approximately
  • Diem or dies: day
introduction actigraphy
IntroductionActigraphy
  • 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
IntroductionObjective
  • 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
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
ValidityMethod
  • 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
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 method1
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 method2
Validity cont.Method
  • Allocation:
    • Exclusion criteria
      • 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 method3
Validity cont.Method
  • Allocation:
    • Disposition of included patients:
validity cont method4
Validity cont.Method
  • Attrition
    • 6 patients were not included inthe Full Analysis Set
      • 4 in agomelatine group
      • 2 in sertaline group

Due to absence of treatmentintake or no postbaselineefficacy assessment

    • The Actigraphy Analysis Setcomprised only (73%) 233 pts.
      • 117 (76%) of the agomelatine
      • 116 (73%) of sertaline
validity cont method5
Validity cont.Method
  • Demographiccharacteristics:
validity cont method6
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 method7
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
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)
        • 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
Results cont.Efficacy on the Circadian Rest-Activity Cycle

RA: relative amplitude. M10: activity of maximum 10 hours. L5: activity of minimum 5 hours.

results cont efficacy on actigraphy derived sleep parameters
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
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
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
Results cont.Clinical Global Impressions scale
  • The data will be provided later on
results cont efficacy on anxiety symptoms
Results cont.Efficacy on Anxiety Symptoms
  • The data will be provided later on
results cont
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 adverseevents (EAEs) that reported by less than 5% of the patients were NOT provided