Mohammed Almoslem Pharm.D . Candidate King Saud University & King Khalid University Hospital

1. 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.

2. Outline • Introduction • Relevance • Validity • Method • Statistical analysis • Results • Strengths • Limitations • Conclusion • Final Message

3. 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)

4. 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

5. IntroductionAgomelatine • The first melatonergic antidepressant • Potent MT1/ MT2 receptor agonist • 5-HT2C receptor antagonist • Resynchronize altered circadian rhythm in depressive or healthy individuals

6. IntroductionCircadian Rhythm • Endogenous physiological processes that regulates the cycle of 24 hour in living beings • Circa: around or approximately • Diem or dies: day

7. IntroductionCircadian Rhythm

8. IntroductionActigraphy • A useful proved method that measures the circadian rest and activity patterns • Indirectly measurement of sleep and characterize 24-hour sleep-wake cycle

9. 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

10. 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

11. 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.

12. 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)

13. 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

14. 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

15. Validity cont.Method • Allocation: • Disposition of included patients:

16. 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

17. Validity cont.Method • Demographiccharacteristics:

18. 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.

19. 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.

20. 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

21. Results cont.Efficacy on the Circadian Rest-Activity Cycle RA: relative amplitude. M10: activity of maximum 10 hours. L5: activity of minimum 5 hours.

22. 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

23. 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

24. 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.

25. Results cont.Clinical Global Impressions scale • The data will be provided later on

26. Results cont.Efficacy on Anxiety Symptoms • The data will be provided later on

27. 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

28. Study Strengths • .

29. Study Limitations • .

30. Study Conclusion • .

31. Final Message • .

32. Thank You …