Vilazodone

Objective
1. Disease Profile
2. Treatment Options and Unmet needs
3. Serotonin and 5 HT1A Receptor
4. Vilazodone - Pharmacology
5. Vilazodone - Clinical Efficacy and Safety
6. Summary
2

They suffered from Depression
John Glenn 77 years
old, who made history
in 1962 when he
strapped himself into
anine-by-seven-foot
capsule
Sir Winston
Churchill
experienced
depression
Charles
Dickens was
affected by
depression
Florence
Nightingale
suffered
from
depression

Depression is a common mental disorder
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
India USA UK
(%)

Depression Described
1. Depression often comes with symptoms of anxiety
2. These problems can become chronic or recurrent
and lead to substantial impairments in an
individual’s ability to take care of his or her
everyday responsibilities

»

The Sad Truth about Depression - Suicidal Angle
1. At its worst, depression can lead to suicide.
2. Almost
due to suicide, which translates to 3000 suicide
deaths every day.
3. For every person who completes a suicide, 20 or
more may attempt to end his or her life (WHO,
2012).
4. Moreover, many people commit suicide by taking
their antidepressants

»

Depression – leading cause of
disability
 Depression is a significant contributor to the global
burden of disease and affects people in all
communities across the world.
» ‘Today, depression is estimated to affect 350 million people.
» The World Mental Health Survey conducted in 17 countries
found that on average about 1 in 20 people reported having
an episode of depression in the previous year.
 Depressive disorders often start at a young age; they
reduce people’s functioning and often are recurring.
 For these reasons, depression is the leading cause of
disability worldwide in terms of total years lost due
to disability.

Rank 20001 Rank Estimated 20202
1 Lower respiratory infections 1 Ischemic heart disease
2 Perinatal conditions 2 Unipolar major depression
3 HIV/AIDS 3 Road traffic accidents
4 Unipolar major depression 4 Cerebrovascular disease
5 Diarrheal diseases 5 Chronic obstructive
pulmonary disease
Depression: A Major Cause of
Disability Worldwide
1World Health Report 2001. Mental Health: New Understanding, New Hope. Geneva: World Health Organization; 2001.
2Murray CJL, Lopez AD, eds. The Global Burden of Disease. Boston: Harvard University Press; 1996.
National Ambulatory Care Medical Survey: 1997 summary. Adv Data 1999; 305: 1-28. In: Nurnberg GH, et al. JAMA 2003; 289: 56-64.
Martin Korn and Rachel Pollock, XXIIIrd Congress of the CINP; Judd LL, et al. Am J Psychiatry 1996
Burden in Disability-Adjusted Life Years (DALYs)
Year 2003 : Total cost of depression estimated to be $ 83 billion

Depression Burden in Women
While depression is the leading cause of disability for
both males and females, the burden of depression is
50% higher for females than males (WHO, 2008).
Research in developing countries suggests that
maternal depression may be a risk factor for poor
growth in young children (Rahman et al, 2008).

MDD: Indian Facts and Figures
The World Health Report 2001 accessed from http://www.who.
int/whr2001/2001/main/en/contents.htm. last accessed on 30.12.02
WHR 2001: Box 3.8 Two national approaches to suicide prevention
Total population
approx.103 crores
(2001 census)
Total no of
depressed patients
Depressed patients
per psychiatrist 9.1% (WHR 2001)

MDD: Indian Facts and Figures
The World Health Report 2001 accessed from http://www.who.
int/whr2001/2001/main/en/contents.htm. last accessed on 30.12.02
WHR 2001: Box 3.8 Two national approaches to suicide prevention
Total population
approx.120 crores
(2011 census)
Total no of
depressed patients

Depression Defined in DSM V
 MDD is a heterogeneous disease—every patient can present with different
symptoms
 Persistent depressed mood or loss of interest are common defining features of
MDD4*
 Other MDD symptoms are also persistent and vary by patient4*
» Insomnia or hypersomnia
» Weight gain or weight loss; increase or decrease in appetite
» Psychomotor agitation or psychomotor retardation
» Fatigue or loss of energy
» Feelings of worthlessness or excessive/inappropriate guilt
» Diminished ability to think/concentrate or indecisiveness
» Recurrent thoughts of death/suicide or suicide attempt
 *MDD diagnosis requires 5 (or more) of the symptoms listed above, which must
be present for at least 2 weeks, and represent a change from previous
functioning. At least one of the symptoms must be either depressed mood or
loss of interest or pleasure.
14 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
Washington, DC: American Psychiatric Association; 2013.

Overlap of MDD and Anxiety Disorders
sleep
concentration
fatigue
psychomotor
suicidality
appetite/
weight
guilt/
worthlessness
dep’d
mood Interest/
pleasure

irritability muscle
tension
compul-
sions
phobic
avoidance
panic
attacks
anxiety
worry
Overlap of MDD and Anxiety Disorders
sleep
concentration
fatigue
psychomotor

17
2. Treatment Options and Unmet needs

Depression Defeated
Treatment
Talk
therapy
Shock therapy
Pharmacotherapy
Pharmacotherapy
MAOIs,
TCAs
SSRIs,
NRI
SNRIs,
NDRIs
SPARI
18

Pharmacotherapy evolution
MAO
Inhibitors
TCAs SSRIs/
NDRI
SARI
NaSSA
SSRIs/
SNRIs
2000s
Escitalopram
Duloxetine
1980s
Fluoxetine
Sertraline
Paroxetine
Fluvoxamine
Citalopram
Bupropion
1960s
Imipramine
Clomipramine
Nortriptyline
Amitriptyline
Desipramine
1990s
Nefazodone
Mirtazapine
Venlafaxine
2011
Vilazodone
(USA)
2015
Vilazodone
(India)
Phenelzine
Isocarboxazid
Tranylcypromine

TCA - Side-effects (Drowsiness)
21
Weight gain Drowsiness
H1
INSERTED
H1
receptor
12
0

TCA - side-effects (postural hypotension)
22
Decreased
Blood pressure
Drowsiness
1
INSERTED
1
receptor

TCA -Side-effects (anticholinergic)
23
Dry Mouth Drowsiness
M1
INSERTED
M1
receptor
LAXATIVES E
P Q
Constipation
Blurred Vision

Limitations of SSRIs
Delayed onset of action
Moderate efficacy
GI Disturbance
Severe Sexual dysfunction
Paradoxical activation

Delayed action of SSRIs
Depression might be caused
by decreased 5-HT
neurotransmission
SSRIs are pharmacologically
active at their molecular and
cellular sites of action almost
immediately.
Antidepressant effects are
generally not seen until 2 to
4 weeks of continuous
treatment
26
5-
HT
5-
HT

Major Depression: Treatment Guidelines
 In the management of major depression, AHCPR treatment guidelines
recommend acute treatment for 12 weeks.
 To prevent the relapse of the current episode of major depression,
AHCPR treatment guidelines recommend that the antidepressant
treatment that produced a therapeutic response should then be
continued for a minimum of 4 to 9 months after remission.
27
Agency for Health Care Policy and Research
MaintenanceContinuationAcute
Full Recovery
Severity
Time
Response
Relapse
Recurrence
Treatment Phases
Symptoms
Remission
Syndrome
Relapse
No Depression

Major Depression: 5Rs
Response is usually defined as a 50%
improvement from baseline to end point on
depression rating scales such as the 17-item
Hamilton Depression Rating Scale (HAMD-17) or
the Montgomery-Åsberg Depression Rating
Scale (MADRS) or HAMAMaintenanceContinuationAcute
Full Recovery
Severity
Time
Response
Relapse
Recurrence
Treatment Phases
Symptoms
Remission
Syndrome
Relapse
No Depression
 Full remission is defined as a relatively free period during which the individual is
asymptomatic, and you should be aware that asymptomatic is not defined as a
complete absence of symptoms, but instead was defined as no more than minimal
symptoms.
 On the 17-item Hamilton Depression Scale, asymptomatic was operationalized as a
score of 7 and below.
• Full remission is associated with a much lower rate of subsequent relapse, and
much greater improvement in social and physical functioning.

The Sad Part of our Current Management
 Nearly one third of patients receive no benefit, and
one third do not experience complete remission
following an initial monotherapy trial with an
antidepressant.
 Treatment resistance therefore remains a
considerable problem
 The goal of treatment must be full remission, and not
just symptom improvement.
29

Unmet needs still exist -
No Treatment, No response, Significant Side effects
According to the National Institute of Mental Health:
of patients with MDD are not receiving any treatment
In the STAR*D Study
of patients were unresponsive to their initial treatment
of patients experienced significant side effects
Side effects such as weight gain, cognitive dulling, sexual
side effects, sedation or fatigue, and agitation may
represent different burdens to different individuals."
–American Psychiatric Association

31
3. Serotonin and 5 HT1A Receptor

32 1. The British Journal of Psychiatry 2008; 193: 229–234.
2. The Journal of Neuroscience 2004; 24(3):589 –591.

Serotonin and 5-HT1A receptors
 The 5-HT1A receptor is a subtype of serotonin receptor
located in presynaptic and postsynaptic regions.
 Activation of this receptor has been involved in the
mechanism of action of
» anxiolytic,
» antidepressant and
» antipsychotic medications.
 Others are responsible for many actions including
» GI disturbance
» Sexual dysfunction
 Optimal serotonin (not too cold not too hot) and
selective actions are desirable
33

Serotonin and 5-HT1A receptors
 Serotonin is a monoamine neurotransmitter that
interacts with 14 serotonin (5-HT) receptors that
can be subdivided into 7 classes

Role of 5HT1A receptors as inhibitory
autoreceptors
35
• 5HT1A receptors are expressed in the somatodendritic region of a
serotonergic neuron.

Autoreceptor that inhibits serotonergic
activity.
36
• There are 14 subtypes of serotonin receptors, the 5HT1A is one of them.
• When this receptor is stimulated it inhibits firing of serotonergic
neurons, this means that it works as an autoreceptor that inhibits
serotonergic activity.

Location
• 5-HT1A receptors can be found in the brain as:
Presynaptic autoreceptors on serotonergic cell bodies
in the raphe nuclei.
• Upon stimulation, these receptors inhibit firing of 5-
HT neurons .

38
4. Vilazodone - Pharmacology

SSRI or SPARI
 Vilano is indicated for the treatment of major
depressive disorder (MDD) in adults.
» Approved by US FDA and DCGI.
 Vilazodone is the first dual serotonin reuptake
inhibitor and 5HT1a receptor partial agonist.
» Selective Serotonin Reuptake Inhibitor/5-HT1a receptor
partial agonist (SPARI).
39

Ki values of various Antidepressants
5HT reuptake
transporter (nM)
NE reuptake
transporter (nM)
Vilazodone 0.5 -
Duloxetine 0.8 7.5
Imipramine 19 98
Venlafaxine 82 2483
Fluoxetine 7 1022
Vilazodone technically is not a selective serotonin
reuptake inhibitor (SSRI) because it has greater
affinity for the 5-HT1A receptor ( ) than it does
for the 5-HT reuptake pump ( )

Serotonergic Pathways and Depression-
Related Symptoms
 All serotonin in the
central nervous
system is produced
by neurons
emanating from the
raphe nuclei, which
project to nearly
every brain region.
 Serotonin-
innervated brain
structures that are
closely associated
with MDD
41

Basal Serotonergic Neurotransmission
(No Drug)
1. Serotonin released from the presynaptic cell (orange) activates 5-HT
heteroreceptors, causing a biological response in postsynaptic cells
(indicated by +).
2. Serotonin is removed from the synaptic cleft and other extracellular space
by the serotonin transporter, located on the presynaptic cell.
3. In MDD, synaptic levels of serotonin are lower than in a nondepressed state.
42
12
3
0

Effect of SSRI treatment on serotonergic
neurotransmission

» SSRI blocks the reuptake of serotonin through the serotonin
transporter, increasing the levels of serotonin in the synapse and
increasing the activation of nearby postsynaptic receptors (+)
43
Step 1: Inhibition of Serotonin Reuptake by Serotonin Transporter
1

neurotransmission

the increase in extracellular serotonin also
leads to stimulation of the presynaptic 5-HT1A autoreceptors,
creating a negative feedback loop (—) that decreases neuronal
activation (indicated by a smaller yellow arrow) and serotonin
release (indicated by fewer serotonin molecules in the synapse).
44
Step 2: Activation of Presynaptic Negative Feedback Loop Through
5-HT1A Autoreceptors
2

neurotransmission
 the negative feedback
pathway triggered by the activation of 5-HTIA autoreceptors
attenuates over time following the desensitization or down-
regulation of 5-HTIA autoreceptors, which takes approximately
a few weeks with standard SSRI treatment.
 Neuronal firing and serotonin release are then restored, while
serotonin transporter reuptake remains blocked.
45
3

Effect of Vilazodone on Serotonergic
Neurotransmission
1. As an SSRI, it blocks serotonin reuptake by the
serotonin transporter to increase serotonin
accumulation in the synapse, indirectly leading to
nonspecific 5-HT receptor activation.
46

Neurotransmission
2. As a 5-HT 1A partial agonist, it directly activates
5-HT1A autoreceptors as well as
postsynaptic heteroreceptors
47

Neurotransmission
3. also potentially hasten the desensitization of
the 5-HTIA autoreceptors.
» The faster autoreceptor desensitization lead to a
more rapid onset of therapeutic efficacy.
48

49
SSRIs - Delayed onset of action
1
2
3
Vilazodone – Rapid onset of action

Thus unique HYBRID action ensures ,
and
Optimal 5HT availability
resulting into
.

Mechanism of Action
 Serotonergic dysfunction itself play a role in MDD
and anxiety disorders and
» a receptor sites in the
in depressed patients may
be related to the increased consistent with
 Vilazodone - The FIRST and ONLY SSRI and 5-HT1A
receptor partial agonist
 Mechanism of action
» Selective inhibition of serotonin reuptake
» High-affinity 5-HT1A receptor partial agonist
» Favourable interplay with the HPA axis and 5-HT1A
51 1. Stahl S. Combining antidepressant therapies from the initiation of treatment: a paradigm shift for major depression. J Clin Psychiatry.
2009;70(11):1493–1494.

Favorable pharmacokinetics
 Bioavailability: 72% with food. Blood concentrations
(AUC) may be decreased by approximately 50% in a
fasting state.
 Metabolism: Extensively hepatic via CYP3A4 (major
pathway) and 2C19 and 2D6 (minor pathways)
 Excretion: 1% unchanged drug in the urine and 2%
unchanged drug in the feces
 Half-life elimination: Terminal ~ 25 hours
 Time to Peak Serum Concentration: 4-5 hours
 Protein Binding: Approximately 96-99%
52

Pharmacokinetics
Parameter Vilazodone Sertraline Citalopram
Metabolism
Hepatic via CYP3A4
(Primary), CYP2C19
and CYP2D6
(Minor); also possibly
by carboxylesterase
Hepatic via N-
demethylation
(Primary)
Hepatic via CYP3A4
and CYP2C19; N-
demethylation
(Primary)
Elimination
Urine (1%), feces
(2%) unchanged
Urine (40-45%) and
feces (40-45%)
with12-14%
unchanged
Urine (20%) with 12-
13% unchanged
Half-life ~25 hours ~24 hours ~35 hours
Protein
Binding
96-99% 99% 80%
Bioavailability 72% with food 100% 80%53

CLINICAL EFFICACY
Vilazodone (Vilano)
54

Consistent Efficacy Safety Vilazodone
Huge Clinical Experience – Int. Data
» Evaluated in 3007 patients: Includes
• 2 pivotal studies,
• 2 postmarketing studies, and a
• 1-year open-label safety study
» More than 170,000 prescribers
» Nearly 4,000,000 prescriptions filled

MADRS total score was clinical trials to assess
the severity of depressive symptoms
• Apparent Sadness • Reported Sadness
• Inner Tension • Reduced Sleep
• Reduced Appetite • Concentration Difficulties
• Lassitude • Inability to Feel
• Pessimistic Thoughts • Suicidal Thoughts
• MADRS is a widely used, physician-rated scale for assessing the severity of
depressive symptoms
• Each of the 10 symptoms on the MADRS is rated on a scale of 0-6; higher
numbers denote greater severity of symptoms
MADRS measures these 10 core symptoms of depression.

Other Scales Used:
HAM-D, CGI-I and CGI-S
 Hamilton Depression Rating Scale (HAM-D-
17): A clinician-rated 17-item checklist, ranked on a
0–4 or 0–2 scale that assesses the severity of
depressive symptoms in patients with primary
depressive illness and monitoring changes with
treatment.
 Clinical Global Impression (CGI) Scale:
Clinician-rated scale globally assessing response to
medication treatment. Scales measure improvement
(CGI-I) and severity of illness (CGI-S).
57

Patient Characteristics Across 4 Clinical
Studies
 Mean MADRS total
score at baseline: 31.2
 Episode of depression1-4
» Studies included patients
suffering from their first
or subsequent episodes
of depression
of patients were
suffering from their first
episode of depression

duration
1.Khan A, Cutler AJ, Kajdasz DK, et al. J Clin Psychiatry. 2011;72:441-447.
2.Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. J Clin Psychiatry. 2009;70(3):326-333.
3.Croft HA, Pomara N, Gommoll C, Chen D, Nunez R, Mathews M. J Clin Psychiatry. 2014 Nov;75(11):e1291-1298.
4.Mathews M, Gommoll C, Chen D, Nunez R, Khan A. Int Clin Psychopharmacol. 2015;30(2):67-74.
First
Episode,
26%
Second or
Subsequent
Episode,
74%

Patient Characteristics Across 4 Clinical
Studies
Duration of current
episode1-4
 Studies included
patients with
varying durations of
depression
of patients
were suffering from
their current
episode for 6
months or less

duration
3.Croft HA, Pomara N, Gommoll C, Chen D, Nunez R, Mathews M. J Clin Psychiatry. 2014 Nov;75(11):e1291-1298.
4.Mathews M, Gommoll C, Chen D, Nunez R, Khan A. Int Clin Psychopharmacol. 2015;30(2):67-74.
<1
month,
0.2%
1-6
months
, 52%
6-12
months
, 39%
>12
months
, 9%

Patient Characteristics – Pooled pivotal
studies
Severe,
28%
Moder
ate,
72%
Severity of
depression1,2
 Pivotal studies
included patients
with moderate or
severe depression
 ≈
patients suffered
from moderate
depression
severity

Study Design of Pivotal Trials
 Efficacy demonstrated through multiple studies
in adults with MDD
 Randomized, double-blind, placebo-controlled,
multicenter study to determine the efficacy and safety of
vilazodone in adults aged years who were
diagnosed with MDD.
 Primary endpoint was the change in MADRS total score
from baseline to week 8 in the intent-to-treat ( )
population ( ).
 Vilazodone treatment was initiated once daily at
» 10 mg for 7 days, followed by
» 20 mg for another 7 days, and
» 40 mg thereafter until the end of week 8.
 Vilazodone was administered with food
Rickels Pivotal Study Khan Pivotal Study

Primary Endpoint at week 8 : Significant improvement in
MADRS total score vs placebo at primary endpoint (P≤0.01)
 Onset of action from
• 42% IMPROVEMENT from baseline vs 31% for placebo1
• HAMD-17 also indicated early improvement that continued
throughout treatment period
1. Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. J Clin Psychiatry. 2009;70(3):326-333.
Rickels Pivotal Study –

Study Design of Postmarketing Study
vilazodone in adults aged 18-70 years who were
diagnosed with MDD.
from baseline to week 8 in the intent-to-treat (ITT)
population (MMRM analysis).
Croft Postmarketing Study

Primary Endpoint at week 8 :
 Significant
improvement in
MADRS total score vs
placebo at primary
endpoint (P≤0.01)
 52% IMPROVEMENT
from baseline
Croft Postmarketing Study

Study Design of Postmarketing Study
vilazodone in adults aged 18-70 years who were
diagnosed with MDD.
from baseline to week 10 in the intent-to-treat (ITT)
population (MMRM analysis).
1. Mathews M, Gommoll C, Chen D, Nunez R, Khan A. Int Clin Psychopharmacol. 2015;30(2):67-74.
Mathews Postmarketing Study

Primary Endpoint at week 10 : Significant improvement in
MADRS total score vs placebo at primary endpoint (P≤0.01)
Vilazodone 20 mg/day: Vilazodone 40 mg/day:
 56% IMPROVEMENT from
baseline
Matthews Postmarketing Study
 55% IMPROVEMENT from
baseline

Unique broad spectrum of efficacy &
Early improvement in depressive symptoms
 Remarkable efficacy across the range of depression severities
 Statistically significant separation from placebo on seven of ten MADRS single
items as early as Week 1 or Week 2.
67

Excellent Response Rate
 CGI-I score of less than 2 is also known as response
 60% of patients reported CGI-I score of less than 2
68

Remission
 48.8% patients reported remission (HAMA)
 Superior remission rate also noted with MADRS &
CGI scales
69

Switch Study
 Patkar et al reported in a poster at the American Society of
Clinical Psychopharmacology on an 8-week study
 71 patients were abruptly switched from ineffective SSRI or
SNRI medications to vilazodone 10, 20, or 40 mg/day.
 significant reduction in mean ± standard error of mean in
MADRS score from baseline ( ) to week 8 ( )
in the three groups combined (P<0.001)
 there were no significant differences between the three
vilazodone dose-initiation groups in mean changes in MADRS),
CGI-S , CGI-I , or HAMA scores
 ASEX scores showed a decrease from baseline ( ) to
end point ( ) among patients switched from
SSRI and SNRI medications to vilazodone
71
Patkar A, Rele S, Millet M, et al. A 8-week randomized, double-blind trial comparing efficacy, safety and tolerability of three
vilazodone dose initiation strategies following switch from SSRIs or SNRIs in major depressive disorder. 2014. Available
from: https://guidebook.com/guide/23750/poi/2064209. Accessed July 9, 2015.

Vilazodone, citalopram vs Placebo
 10-week Phase IV RCT comparing VC with P
» vilazodone 20 mg/day dose (n=288)
» vilazodone 40 mg/day dose (n=287)
» citalopram 40 mg/day (n=282)
» placebo (n=281),
 Mathews et al found that each of the active medication-treated groups were
superior to placebo.
 MADRS score improvement was significantly greater for VC compared with
placebo
» vilazodone 20 mg/day (least squares mean difference [LSMD] –2.57;
adjusted P=0.0073),
» vilazodone 40 mg/day (LSMD –2.82, adjusted P=0.0034), and
» citalopram (LSMD –2.74, adjusted P=0.0020).
 Mathews et al also showed a similar finding for symptom severity, as rated by
the CGI-S scale
72
1. Mathews M, Gommoll C, Chen D, Nunez R, Khan A. Efficacy and safety of vilazodone 20 and 40 mg in major
depressive disorder: a randomized, double-blind, placebo-controlled trial. Int Clin Psychopharmacol. Epub
December 12, 2014.

GAD
 Generalized anxiety disorder (GAD), a disorder
characterized by pervasive and highly distressing
worries, is associated with impairment that is
comparable to major depressive disorder (MDD).1
 Although numerous agents from various drug classes
are available to treat GAD, as many as 50% of
patients have inadequate response2
 Considerable unmet medical need
74
1. Int Clin Psychopharmacol 2000;15:319–328.
2. Expert Opin Pharmacother 2013;14:175–184.

GAD pharmacy
adjunctive
hypnotic CBT SDA/DPA
1st line
SNRIBZSSRI buspirone
2nd line
gabapentin/
pregabalin
TCA mirtazapine trazodone
Anxiety Disorder Treatment Options

–
Statistically significant improvements for vilazodone 40 mg/day
versus placebo were seen on the primary efficacy measure
76
Depression and Anxiety 2015; 32:451–459
A multicenter, double-blind, parallel-group, placebo-
controlled, fixed dose study in patients with GAD
randomized (1:1:1) to placebo (n = 223), or vilazodone
20mg/day (n = 230) or 40 mg/day (n = 227)

Phase III Study of Vilazodone in GAD
HAMA Responders
 ≥50% improvement from
baseline
CGI Responders
 CGI-I ≤ 2
77
53.9%
62.1%
Vilazodone 20 Vilazodone 40
64.0%
65.2%
CGI-I ≤2

Phase III Study of Vilazodone in GAD
HAMA Psychic Anxiety
 Change from baseline to
EOS
HAMA Somatic Anxiety
 Change from baseline to
EOS
78
-7.4
-7.7
-5.6
-5.9

Anxious Depression
 Approximately one-half of all patients diagnosed
with major depressive disorder (MDD) have
clinically meaningful levels of anxiety
» complicates clinical management and can affect treatment
outcomes
 Anxious depression is associated with
» more severe depressive symptoms,
» greater duration of current episode,
» suicidal ideation and history of suicide attempt, and
» more medical comorbidities
 Vilazodone is an effective treatment option for the
large proportion of patients with MDD who have
prominent anxiety symptoms80
International Clinical Psychopharmacology 2014, 29:351–356

52 49
68 74
Suicidal
Thoughts
Lifetime
DSM-III-R
Axis II
Disorder
Brown et al. Am J Psychiatry, 1996
Increased Severity of Symptoms
55.4
48.3
GAS Score
4.5
5.4
19.9
27.6
Beck Depression
P=0.02 P=0.04 P=0.0001
Hamilton Depression
Scale Anxiety
Subscale Score
P=0.002 P=0.0001
Major Depression with
Lifetime Anxiety Disorder
In Patients with MDD and Lifetime Anxiety Disorder:
When Compared to Patients with MDD Alone

Kessler et al, JAMA, 2003.
Lifetime Prevalence Rates
Comorbidity: MDD & Anxiety
Disorders
Anxiety
Disorders
Major
Depression
59%

Early and Significant improvement in
HAMD-17 anxiety/somatization subscale
83
International Clinical Psychopharmacology 2014, 29:351–356

Long-Term Efficacy Studies
Rating
Scores
Baseline Week 8 Week 24 1 year
MADRS 29.9 (4.5) 11.4 (7.6) 8.2 (7.1) 7.1 (7.4)
CGI-S 4.3 (0.5) 2.5 (1.1) … 1.7 (1.1)
CGI-I 3.5 (0.7) 1.9 (0.9) … 1.4 (0.8)
85

Health resource use and costs of vilazodone and
other SSRIs in treating MDD
 Compared with the vilazodone cohort (n=3,527), patients in the
citalopram (n=12,187), escitalopram (n=8,275), fluoxetine
(n=10,142), paroxetine (n=3,146), and sertraline (n=12,584)
cohorts had significantly
» more all-cause inpatient hospital visits,
» longer hospital stays and more frequent emergency
department visits, following the index date, after adjusting
for baseline characteristics.
 All-cause medical service costs (inpatient + outpatient +
emergency department visits) were significantly higher across
all other SSRI cohorts versus vilazodone
86
1. Zhou ZY, Sun S, Chopra P, Zhong Y, Totev T, Signorovitch J. Health resource use and costs of vilazodone and other selective
serotonin reuptake inhibitors in treating major depressive disorder. J Med Econ. 2015 Jun 29:1-36.

Contraindications
 Contraindications
» Vilano is contraindicated in patients taking, or within 14
days of stopping, monoamine oxidase inhibitors ( ),
because of an increased risk of serotonin syndrome.

Use in Special Population
 There are no adequate and well-controlled studies of
vilazodone in pregnant women so careful
consideration should be made when determining if
the potential benefits outweigh the potential risks of
treatment in pregnant women.
 Use in Breast Feeding – Vilazodone is excreted into
the milk of lactating rats. It is unknown as to
whether vilazodone is excreted into human breast
milk.
Pregnancy and Lactation

Pregnancy
 There is one published case report of the use of
vilazodone in pregnancy that reported that a 32-
year-old woman who unexpectedly became pregnant
while on 40 mg/day vilazodone
» continued medication, and gave birth to a healthy child.
 Child did not experience irritability or feeding or
respiratory difficulties, which have been reported in
neonates exposed to antidepressants during
pregnancy
89
1. Morrison CM. A case report of the use of vilazodone in pregnancy. Prim
Care Companion CNS Disord. 2013;16(2).

Adverse Event Profile
 The safety of Vilazodone was evaluated in 3007
patients (18 to 70 years of age) diagnosed with MDD
 The most frequent adverse effects reported during
clinical trials were nausea, diarrhea, and headache.
» Milder and titration to recommended dose reduces it even
more
» Class effect of SSRI
 It has a good safety profile in that it does not require
dose adjustment in renal or mild-to-moderate
hepatic impairment.
 It has minimal cardiac adverse effects.
90

Premature Discontinuation in
Placebo Controlled Trials
Khan et al. Rickels et al.
Vilazodone
N = 47
(19.6%)
Placebo
N = 46
(19.1%)
Vilazodone
N = 53
(25.9%)
Placebo
N = 51
(24.9%)
91
• In the Khan and colleagues study, a similar number of patients in each
group, 19.6% in the vilazodone group and 19.1% in the placebo group,
discontinued treatment prematurely.
•
• In the Rickels and associates study, a similar number of patients in each
group, 25.9% in the vilazodone group and 24.9% in the placebo group,
discontinued treatment prematurely.

Drug-Drug Interactions
1. Similar to escitalopram, it inhibits very few metabolic pathways
which should theoretically lead to fewer drug-drug interactions.
2. As with all antidepressants concomitant use with MAOIs is to be
avoided.
3. Concurrent use with NSAIDs may increase the risk of
gastrointestinal bleeding or bleeding in general.
4. Prolonged bleeding times may occur when used with anticoagulants
such as warfarin.
5. Concomitant use with potent CYP3A4 inhibitors may increase
vilazodone’s concentrations.
6. Vilazodone is highly bound to protein plasma and may increase the
free concentrations of other highly protein bound drugs.
7. No drug-lab interactions have been identified.
92

In 2 pivotal clinical studies, nausea and
diarrhea occurred early in treatment
93

Nervous System Disorders
Placebo
N=967
Vilazodone
29 mg/d
N=288
Vilazodone
40 mg/d
N=978
Headache 14% 15% 14%
Dizziness 5% 6% 8%
Somnolence 2% 4% 5%
Paresthesia 1% 1% 2%
94

Minimal Change in Weight Gain
 Pooled pivotal studies
95
8-week studies
Vilazodone
40 mg/day
N=436
Placebo
n=433
Mean change
(kg) from
baseline
+0.37 kg +0.10 kg
Percentage of patients with a
weight increase ≥7% from
baseline
1.2% 0.4%
Percentage of patients with a
weight decrease≥7% from
baseline
0.4% 0%

Minimal Change in Weight Gain
 Long-term study
» The mean weight change from baseline was +1.0 kg
 Postmarketing studies
96
8-week study 10-week study
Vilazodone
40 mg/day
N=255
Placebo
n=253
Vilazodone
20 mg/day
n=288
Vilazodone
20 mg/day
n=287
Placebo
n=281
Mean change
(kg) from
baseline
+0.37 kg +0.10 kg +0.59 kg +0.49 kg +0.39 kg
Percentage of
patients with a
weight increase
≥7% from
baseline
1.2% 0.4% 1.7% 2.1% 1.4%
Percentage of
patients with a
weight
decrease≥7%
from baseline
0.4% 0% 1.7% 0% 0.4%

Cardiac Parameters in Long-term study in 599 patients
 Systolic Blood Pressure, mmHg
» Baseline mean (SD): 121.6 (13.6)
» Week 52 mean (SD): 122.1 (13.2)
» (SD): (12.0)
 Diastolic Blood Pressure, mmHg
» Week 52 mean (SD): 78.6 (9.1)
» (SD): + (8.3)
 Pulse, beats per minute
» Week 52 mean (SD): 74.9 (10.0)
» (SD): + (11.0)97

Prevalence of erectile dysfunction
99
No erectile
dysfunction,
48%
Some erectile
dysfunction,
52%

The incidence of erectile dysfunction increased with age in this study of normal
men between the ages of 40 and 70, from 39% at age 40 to 67% at age 70
100
0%
10%
20%
30%
40%
50%
60%
70%
40 50 60 70
39%
48%
57%
65%
FrequencyofErectileDysfunction(%)
Age
Association between prevalence of ED and Age –
Massachusetts Male Aging Study

Erectile dysfunction is associated with depression
and increases in frequency as depression worsens
Among severely depressed men, some studies
suggest that over 90% are impotent
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Mild Depression Moderate Depression Severe Depression
25%
59%
90%
FrequencyofErectileDysfunction(%)
Axis Title
Association between prevalence of ED and Depression –
Massachusetts Male Aging Study

Frequency of Sexual Dysfunction between
Paroxetine and Duloxetine
0%
10%
20%
30%
40%
50%
60%
70%
Study 1 Study 2
29%
47%
35%
62.80%
FrequencyofSexualDysfunction(%)
Duloxetine
Paroxetine
102

103
Human Sexual Response
Libido
• Desire
for sex
Arousal
• Erection for
men
• Genital
lubrication
and
swelling for
women
Orgasm
• Ejaculation
in men
Dopamine + + +
“5HT1A receptors act as an accelerator for
dopamine release” – Stephen Stahl

Frequency of Antidepressant induced
Sexual Dysfunction
0%
10%
20%
30%
40%
50%
60%
70%
Escitalopram Paroxetine Venlafaxine Fluoxetine Mirtazapine
70%
54% 55%
46%
18%
FrequencyofSexualDysfunction(%)
104

Sexual Dysfunction in Untreated Male MDD
 In a study of patients with untreated MDD, the
prevalence of men reporting decreased desire was
42%, less vigorous erections 34%, inability to sustain
an erection 46%, delayed ejaculation 22%, and
premature ejaculation 12%
 The prevalence of women reporting decreased sexual
desire was 50%, diminished sexual arousal 50%,
difficulty obtaining vaginal lubrication 40%, and
difficulty having orgasm 15%
105

Sexual Dysfunction in Untreated Male MDD
 In a study of patients with untreated MDD, the
prevalence of men reporting decreased desire was
42%, less vigorous erections 34%, inability to sustain
an erection 46%, delayed ejaculation 22%, and
premature ejaculation 12% [3].
 The prevalence of women reporting decreased sexual
desire was 50%, diminished sexual arousal 50%,
difficulty obtaining vaginal lubrication 40%, and
difficulty having orgasm 15%
106

 In the meta-analysis, treatment-emergent sexual
dysfunction in the active SSRI groups ranged from
25.8% (fluvoxamine) to 80.3% (sertraline)
 The rates of treatment-emergent sexual dysfunction
observed among patients who were functional at
baseline in the vilazodone groups are relatively low
and closer to that of placebo than the rates
reported for most SSRIs (citalopram, escitalopram,
fluoxetine, fluvoxamine, paroxetine, sertraline).
107
1. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: A meta-analysis. J Clin Psychopharmacol 2009;29:259–66.

Treatment emengent Sexual Dysfunction
108
1. Williams VS, Baldwin DS, Hogue SL, Fehnel SE, Hollis KA, Edin HM. Estimating the prevalence and impact of antidepressant-induced sexual dysfunction in 2 European countries: A cross-sectional patient survey. J Clin Psychiatry 2006;67:204–10.
2. McGahuey CA, Gelenberg AJ, Laukes CA, Moreno FA, Delgado PL, McKnight KM, Manber R. The Arizona Sexual Experience Scale (ASEX): Reliability and validity. J Sex Marital Ther 2000;26:25–40.
3. Clayton AH, Pradko JF, Croft HA, Montano CB, Leadbetter RA, Bolden-Watson C, Bass KI, Donahue RM, Jamerson BD, Metz A. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 2002;63:357–66.
4. Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord 2006;91:27–32.
5. Matuszczyk JV, Larsson K, Eriksson E. Subchronic administration of fluoxetine impairs estrous behavior in intact female rats. Neuropsychopharmacology 1998;19:492–8.
6. Hull EM, Muschamp JW, Sato S. Dopamine and serotonin: Influences on male sexual behavior. Physiol Behav 2004;83:291–307.
7. Alcantara AG. A possible dopaminergic mechanism in the serotonergic antidepressant-induced sexual dysfunctions. J Sex Marital Ther 1999;25:125–9.

ASEX Scale
 The ASEX is a five-item rating scale (score of 1–6 per item) that
quantifies
 Total scores can range from 5 to 30, with increasing scores indicating
diminishing sexual function.
 Sexual dysfunction is defined as
» a total score 19
» a score 5 on any item
» a score 4 on at least three items
111
1 2 3 4 5 6
sex drive
arousal
vaginal lubrication/penile erection
ability to reach orgasm
satisfaction from orgasm
Diminishing Sexual Function

112
+0.23
+0.23
+0.42
+0.08
+0.25

Change in Sexual Function Questionnaire
 The 14-item self-report version of the CSFQ
 Total score is derived by summing the scores from 14
items (score of 1–5 per item)
 Total scores can range from 14 to 70, with higher
scores indicating better sexual functioning.
 Global sexual dysfunction is defined as a total score
of 47 in men and 41 in women
114

 Half of men and two thirds of women with MDD had
sexual dysfunction at baseline
 Sexual function improved on average in both
vilazodone and placebo groups
115 J Sex Med 2013;10:2465–2476

Dosage and Administration
Initiation of treatment
The
dose for
vilazodone is 40
mg once daily.
When starting
vilazodone, the
drug must be
.
The
daily dose is 40
mg/day.
Taking Vilano on an empty stomach can reduce plasma concentrations (AUC) by approximately 50% and may diminish effectiveness
Vilano should be taken with food

Titration
Start at 10 mg
once daily for 7
days…
…followed by 20
mg once daily
for an additional
7 days…
…and then
increased to 40
mg once daily.

No dose adjustment is recommended for a
range of populations
Dose adjustment in patients with impaired kidney function
• No dosage adjustment is recommended in mild, moderate, or severe renal
impairment.
Dose adjustment in hepatic impairment
• Mild-to-moderate impairment: No dosage adjustment is recommended.
Dose adjustment based on sex
. Not required
Dose adjustment in the elderly
• No dose adjustment is recommended on the basis of age.

Type of Patients
1. Recommended as a as its combined
SPARI mechanism offers a unique initial antidepressant
approach when compared to SSRI, SNRI, etc.
2. Likely be used in those who do not
or given
their prevalence and ease of use as well as potential for faster
titration and lower gastrointestinal side effect profiles.
3. Especially useful if the patient develops
on SSRI/SNRI
4. Should strongly be considered, if patients cannot tolerate or
risk intervention with an atypical second generation
due to
weight gain, sedation, extrapyramidal symptoms, or
dyslipidemia.
119

Type of Patients
 Given that other agents with SSRI activity and 5-
HT1A receptor activity carry approvals for depression,
GAD, obsessive compulsive disorder (OCD), social
anxiety disorder (SAD), panic disorder,
posttraumatic stress disorder, eating disorders, and
premenstrual disorders, it would follow that
vilazodone conceptually has the pharmacodynamic
mechanisms necessary to alleviate symptoms
attributed to these disorders as well.
120
1. Stahl S. Essential Psychopharmacology: The Prescriber’s Guide. Cambridge, UK:
Cambridge University Press; 2011.
2. Stahl S. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical
Applications. Cambridge, UK: Cambridge University Press; 2008.

PS. Future Direction Unfolding
 Compounds possessing balanced 5-HT1A receptor
agonism and D2 antagonism are efficacious
antipsychotics
 5-HT1A receptor activation is required for the
cortical DA release by antipsychotics
» this effect is regionally selective and is only seen in
frontocortical regions, but not the nucleus accumbens or
striatum
 Partial agonists at 5-HT1A receptors reduce negative
symptoms in schizophrenics treated with haloperidol
 Antipsychotics are used in depression and we may
see the reversal antidepressant used in schizophrenia
122

Antidepressant
Vilazodone
Second-generation (atypical) antipsychotics
Clozapine
Ziprasidone
Aripiprazole
Antianxiety agent
Buspirone

Q: Children
 No reported data on the use of vilazodone in children
or adolescents either
 ClinicalTrials.gov lists one study, which is listed as
currently recruiting:
» Safety and Efficacy of Vilazodone in Adolescent Patients
with Major Depressive Disorder
» Vilazodone (15 or 30 mg/day) will be compared to placebo
» 8-week study
» 495 adolescents aged

Q: Elderly
 2 Pivotal studies - 18-65 years
 2 Post-marketing studies : 18-70 years
 Clinical- Trials.gov lists one 12-week study, which is
listed as currently recruiting:
» Vilazodone for Treatment of Geriatric Depression,
» vilazodone will be studied in years of
age
• Vilazodone up to 40 mg/day or
• paroxetine up to 30 mg/day

Summary
 Depression affects millions of people in India
 MDD is the #2 contributor to disability worldwide
 Available Treatment Options has several limitations
» Delayed onset of action
» Moderate efficacy
» GI disturbance
» CNS side effects
» Weight gain
» Sexual dysfunction
 Need for newer antidepressant with unique MOA
127

Summary
 Compared to SSRI’s, vilazodone has a faster onset
due to its partial agonism at 5HT1a receptors
 Vilazodone has demonstrated superior efficacy when
compared to placebo for major depressive disorder
» Fast onset of action
» Superior response and remission
» Sustained efficacy in long-term trials
 Broad spectrum efficacy
 Recent Findings
» Vilazodone 20 mg/day: 55% IMPROVEMENT from baseline vs
47% for placebo
» Vilazodone 40 mg/day: 56% IMPROVEMENT from baseline vs
47% for placebo
128

Summary
 Overall, it did appear to produce less sexual side effects than
most other SSRIs.
» Its activity on the 5HT1a receptor is believed to be responsible for
its decrease in sexual side effects when compared to other SSRIs.
 It also appeared to produce less somnolence than other
medications in its class as well.
 Similar to escitalopram, it inhibits very few metabolic pathways
which should theoretically lead to fewer drug-drug interactions.
 No lab-drug interactions, No effect on ECG and vital signs
 It has minimal cardiac adverse effects or weight gain
 Dosage Range: 10-40mg once daily.
129

References
1. Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. J Clin Psychiatry. 2009;70(3):326-
333.
2. Khan A, Cutler AJ, Kajdasz DK, et al. J Clin Psychiatry. 2011;72:441-447.
3. Croft HA, Pomara N, Gommoll C, Chen D, Nunez R, Mathews M. J Clin Psychiatry. 2014 Nov;75(11):e1291-1298.
5. VIIBRYD (vilazodone HCl) [package insert]. Cincinnati, OH: Forest Pharmaceuticals, Inc.

Vilazodone

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