My small effort to present an article with PPT presentation for learning purpose. Color codes in the article PDF document: 1) Green for positive criticism 2) Red for negative criticism 3) Yellow for important points 3)

1. Critical Appraisal of A Journal
Article
Dr. Shakeeb Dhorajiwala,
MBBS, MD. Pharmacology, DM 1st year resident- Department Of Clinical Pharmacology
Former Scientist B in project “Covishield”,
Presentation for: Dept. of Clinical Pharmacology, Seth GSMC & KEM hospital, Parel, Mumbai.

2. Link to the article
https://s.docworkspace.com/d/AAHGiCOfprJbqaG2_OedFA
• Disclaimer: For Educational Purpose only (non-commercial use)
11-02-2021 2

3. Introduction(1/5)
Major depressive disorder widespread debilitating illness.
Prevalence: 300 million1
High rate of :
• medical,
• psychiatric co-morbidity,
• functional impairment
• Personal and societal cost
F:M= 1.5:1
Leading cause of disability in both
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1. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C,et al. Disability-adjusted life years (DALYs) for 291 diseases
andinjuries in 21 regions, 1990-2010: A systematic analysis for the global burden of disease study 2010. Lancet
2012;380:2197-223
3

4. Cont’d(2/5)
Treatments available:
11-02-2021 SSRI: selective serotonin reuptake inhibitors SNRIs: serotonin and noradrenaline reuptake inhibitors 4

5. Limitations of existing treatment(3/5)
TCAs SSRIs
• commonly prescribed too
• Lack of efficacy and tolerability non-
compliance
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6. Test Drug- Vilazodone(4/5)
less disruption of other neurotransmitter system.2
greater tolerability
high selectivity
high affinity for 5-HT receptor
5HT partial agonist reuptake= 5-HT reuptake inhibition + 5-HT1A partial agonism
MOA:
11-02-2021 2. Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 2003;53:193-203. 6

7. Rationale for the study(5/5)
Efficacy at 40 mg/day in MDD proved2
Nearly half of patients diagnosed with MDD  anxiety problem too
Residual anxiety  increased risk of MDD relapse
Also proven efficacy in GAD, MDD and MDD with anxiety
Scarcity of studies done on Indian population
No direct head-to-head comparison of efficacy and tolerability
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GAD: Generalized anxiety disorder
2.Croft HA, Pomara N, Gommoll C, Chen D, Nunez R, Mathews M. Efficacy and safety of vilazodone in major depressive disorder: A
randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2014;75:e1291-8.
7

8. Methodology: Study Design(1/7)
Randomized, prospective, comparative, parallel-group, open-label
Period: February 2016 - October 2017
Site: Psychiatry OPD of a tertiary care teaching hospital.
Approved by the IEC
in accordance with ICH-GCP guidelines and the ethical principles as mentioned in the DoH.
WIVC in vernacular language with detailed history and physical examinations done
11-02-2021 WIVC: written informed valid consent IEC: institutional ethics committee 8

9. Outcome Measure (2/7)
Efficacy:
• 1o : ΔHAMD-17 score from
baseline to wk 12
• >20 % improvement in first
2 weeks from baseline:
Clinically meaningful
• 2o: ΔMADRS and HAM-A
from baseline to wk 12
Safety:
• Modified Hartwig and Siegel
scale- AE severity
• Naranjo ADR Probability
Scale- Causality
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10. Cont’d(3/7)
f/u visits: 2, 4 and 12 weeks
Compliance was assessed by empty blister packets
Rescue management:
• i/c/o no response or worsening: withdrawal from study with
subsequent psychiatric care
No post-trial access
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11. Selection Criteria (4/7)
Inclusion
Newly diagnosed patients :MDD (DSM-5)
Either gender,
Aged :18 - 60 years
HAMD-17 score ≥22
Exclusion
Patients of :
• severe depression who may not respond to
pharmacotherapy
• on ECT within 3 months
• suffering from any other psychiatric disorders except
GAD;
• impaired renal/hepatic function;
• requiring other psychotropic/active medications, or
other systemic disorder;
• taken investigational drug or participated in an
investigational drug trial within past 30 days;
• Pregnant, lactating women and women of reproductive
age group
11-02-2021 HAMD-17: 17-item Hamilton Depression Rating Scale 11

12. Study groups (5/7)
Vilazodone 20 mg
n=17
Escitalopram 20 mg
n= 16
Amitriptyline 75 mg
n= 17
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13. Statistical Analysis (6/7)
sample size calculated based on change in HAMD score from baseline to week 12 and standard
deviation (SD) = 10.38 from previous studies,
α = 5% and 1-β= 80%.
required sample size : 20/ group with dropout rate of 20%,
Power and Sample Size Calculation software version 3.0.43
Categorical data: Chi-square test
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14. Statistics cont’d (7/7)
continuous variables: one-way ANOVA
1o and 2o efficacy parameters analyzed by Friedman test  Dunn’s test: within-group comparison at
different follow-up visits
Kruskal–Wallis test  Dunn’s test : between groups comparison.
P < 0.05 :statistically significant.
GraphPad Prism version 5.01 (GraphPad software Inc., California, USA) for analysis.
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15. Results(1/6)
N= 60 randomized and
allocated to 3 groups,
50 completed study as
per protocol
10 dropouts:
3 in amitriptyline group
(2-ADRs & 1-lack of
efficacy),
4 in escitalopram group
(1-ADRs,
1-lack of efficacy, 2 lost
to follow-up),
3 in vilazodone group (1-
ADRs and 2-lost to
follow-up).
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16. 11-02-2021 16

17. 11-02-2021 17

18. 11-02-2021 18

19. Assessment of Safety (5/6)
Amitriptyline
(total 9 events)
• Constipation
n= 2
• Sedation n= 7
Escitalopram
(total 4 events)
• Nausea n= 2
• Headache
• n= 2
Vilazodone
(total 5 events)
• Nausea n= 2
• Headache
• n= 3
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20. Safety evaluation (6/6)
Modified Hartwig
and Siegel scale:
for severity
assessment
Mild- level 1
Naranjo scale:
Probable
Constipation Sedation Nausea
Possible
Headache
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21. Discussion: Study findings(1/9)
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Finding no.1: significant
reduction in HAMD-17
and/or MADRS scores
compared to baseline at
4 weeks
Finding no.2: reduction in
scores at two weeks
significantly more than
amitriptyline but similar to
escitalopram.
Inference: at 2 weeks,
vilazodone more
efficacious than
amitriptyline.
Finding no.3: reduction in
HAMD-17 and MADRS
scores highest
compared to other two
groups at week 4 and
week 12,
Inference: vilazodone is
more efficacious than the
other two study drugs.

22. Cont’d (2/9)
Finding no. 4:
MADRS-sustained response
- MADRS score ≤12 for at
least the last two
consecutive visits
comparable with
escitalopram group
significantly higher than the
amitriptyline group at 12
weeks
Inference: treatment
benefits are maintained
beyond a single time point
Finding 5:
Reduction in HAM-A score
at 4th and 12 weeks
compared to baseline
Inference: beneficial effect
of vilazodone in anxiety.
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23. What other studies showed(3/9)
Vilazodone at 40 mg/day statistically significant decrease in HAMD-17 and/or MADRS scores
following 8-week treatment all placebo-controlled studies
Effects reported as early as 1 or 2 weeks
Studies supportive of sustained effect (4th finding)of vilazodone. However, effect compared only to
escitalopram.
Therapeutic effect of vilazodone in dose of 20 mg/40 mg/day in generalized anxiety disorder has
been demonstrated in double-blind, randomized, placebo-controlled clinical trials supporting 5th
finding.5
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5. Durgam S, Gommoll C, Forero G, Nunez R, Tang X, Mathews M, et al. Efficacy and safety of vilazodone in patients with generalized anxiety
disorder: A Randomized, double-blind, placebo-controlled, flexible-dose trial. J Clin Psychiatry 2016;77:1687-94.
23

24. Justification for Dose Selection(4/9)
studies comparing
doses of 20 mg and
40 mg/day reported-
• statistically significant beneficial effects with 20 and
40mg
• no significant differences between the different
vilazodone doses.3
• One study even reported that dose of vilazodone above
20 mg/day did not yield additional benefit.4
• one study reported better tolerability with 20 mg dose3
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3. Mathews M, Gommoll C, Chen D, Nunez R, Khan A. Efficacy and safety of vilazodone 20 and 40mg in major depressive disorder: A randomized,
double-blind, placebo-controlled trial. Int Clin Psychopharmacol 2015;30:67-74
4. Laughren TP, Gobburu J, Temple RJ, Unger EF, Bhattaram A, Dinh PV, et al. Vilazodone: Clinical basis for the US food and drug administration’s
24

25. Proposed mechanism (5/9)
11-02-2021 Taken from : Goodman & Gillman ed. 13 25

26. Evaluation of Safety Profile (6/9)
Adverse effects with antidepressant drugs are common
negatively impact patient outcomes.
vilazodone (29.41%) and escitalopram (25%) groups comparable
amitriptyline group (52.94%) significantly higher
Intolerability to medication is one of the most common reasons of discontinuation of antidepressant
treatment.[29]
Constipation and sedation were major adverse events
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27. Cont’d (7/9)
Nausea and headache major adverse events in escitalopram and vilazodone
groups.
GI s/e of mild severity and transient.
Sexual dysfunction is a common adverse effect of SSRIs which are currently the
most commonly used antidepressants.[4]
Sexual dysfunction as a s/e reported by none.
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28. Limitations (8/9)
open-label study
small sample size restricts generalizability of study
results
Third, assessing adverse effects on sexual functions
difficult since they did not use any measurable criteria
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29. Conclusion (9/9)
Although results
of their study
show that
vilazodone is
more efficacious
antidepressant
compared to
escitalopram
and
amitriptyline:
• small sample size of this study does not allow
generalization of results
• High cost of vilazodone another hindrance
• Hence, they suggested that vilazodone be
considered as a treatment option in selected
group of MDD patients with coexisting anxiety not
responding satisfactorily to standard drugs.
• However, even this needs to be substantiated by
large-scale studies with larger sample size and
having an active comparator group.
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