EXPERT OPINION ON DRUG DISCOVERY, 2016

VOL. 11, NO. 5, 515–523

http://dx.doi.org/10.1517/17460441.2016.1160051

DRUG DISCOVERY CASE HISTORY

The Preclinical and Clinical Effects of Vilazodone for the Treatment of Major
Depressive Disorder
Zeyad T. Sahlia,b, Pradeep Banerjeec and Frank I. Tarazia
a
Department of Psychiatry and Neuroscience Program, Harvard Medical School, McLean Hospital, Belmont, MA, USA; bSchool of Medicine,
American University of Beirut, Beirut, Lebanon; cForest Research Institute, Jersey City, NJ, USA, an affiliate of Allergan Inc

ABSTRACT ARTICLE HISTORY

Introduction: Major depressive disorder (MDD) is the leading cause of disability worldwide, and Received 20 October 2015
according to the STAR*D trial, only 33% of patients with MDD responded to initial drug therapy. Accepted 26 February 2016
Augmentation of the leading class of antidepressant treatment, selective serotonin reuptake inhibitors Published online
(SSRIs), with the 5-HT1A receptor agonist buspirone has been shown to be effective in treating patients 15 March 2016
that do not respond to initial SSRI therapy. This suggests that newer treatments may improve the KEYWORDS
clinical picture of MDD. The US Food and Drug Administration (FDA) approved the antidepressant drug 5-HT1A receptor; clinical
vilazodone (EMD 68843), a novel SSRI and 5-HT1A receptor partial agonist. Vilazodone has a half-life trials; generalized anxiety
between 20–24 hours, reaches peak plasma concentrations at 3.7–5.3 hours, and is primarily metabo- disorder; major depressive
lized by the hepatic CYP450 3A4 enzyme system. disorder; serotonin
Areas covered: The authors review the preclinical and clinical profile of vilazodone. The roles of transporter; sexual
dysfunction; vilazodone
serotonin, the 5-HT1A receptor, and current pharmacotherapy approaches for MDD are briefly reviewed.
Next, the preclinical pharmacological, behavioral, and physiological effects of vilazodone are presented,
followed by the pharmacokinetic properties and metabolism of vilazodone in humans. Last, a brief
summary of the main efficacy, safety, and tolerability outcomes of clinical trials of vilazodone is provided.
Expert opinion: Vilazodone has shown efficacy versus placebo in improving depression symptoms in
several double-blind, placebo-controlled trials. The long-term safety and tolerability of vilazodone treat-
ment has also been established. Further studies are needed that directly compare patients treated with an
SSRI (both with and without an adjunctive 5-HT1A partial agonist) versus patients treated with vilaozodone.

1. Introduction 1.1 Role of the serotonergic system in MDD

Major depressive disorder (MDD) is the leading cause of dis- The serotonergic system has been implicated in having a
ability worldwide and affects more than 350 million people of major role in the pathophysiology of MDD. In 1987, fluoxetine
all ages.[1] In the U.S., approximately 14.8 million individuals became the first selective serotonin reuptake inhibitor (SSRI)
(or 6.7%) of the adult population (aged 18 years and older) to be approved by the U.S. Food and Drug Administration
have MDD.[2] More common in women than in men, diagnos- (FDA) for the treatment of MDD.[9] The serotonergic pathway
tic features include depressed mood, diminished interest and originates mainly from the raphe nuclei, and it plays a major
pleasure, sleep disturbance, psychomotor agitation, and inap- role in a wide range of brain functions, including mood reg-
propriate guilt, although patients present with a wide range of ulation, fear responses, sleep, appetite, and sexual behavior.
symptoms.[3] Despite its high prevalence, the pathophysiol- [10] It is important to a wide range of functions because of its
ogy of MDD remains largely unknown. MDD is a complex direct and indirect influence on other neurotransmitter sys-
disorder that does not result from either genetic or environ- tems, such as dopamine, norepinephrine, glutamate, acetyl-
mental stimuli alone but rather from both.[4] The pathophy- choline, histamine, and GABA, and autoregulation of its own
siology of MDD has been difficult to describe because of serotonergic pathways.[11,12] Not surprisingly, dysregulation
varied illness course and response to treatment. Current of the serotonergic system is implicated in several mental
pathophysiology models include monoamine deficiency, disorders including MDD.
altered glutamate transmission, reduced gamma-aminobutyric Several lines of evidence have implicated depletion of
acid (GABA) activity, decreased neurotrophic factor release, monoaminergic neurotransmitters, namely serotonin (5-HT),
and increased stress hormone release such as corticotropin- norepinephrine, epinephrine, and dopamine, in the pathophy-
releasing hormone.[5] Clinical and experimental evidence siology of depression, which has led to the monoamine deple-
strongly points to imbalances of the serotonergic and norepi- tion hypothesis of depression.[13] Long-term longitudinal
nephrine systems in the central nervous system.[6–8] studies have linked reductions of cerebrospinal fluid levels of

CONTACT Frank I. Tarazi [email protected] Harvard Medical School, McLean Hospital, Belmont, MA, USA
© 2016 The Author(s). Published by Taylor & Francis.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
516 Z. T. SAHLI ET AL.

been found to be lower in patients with MDD than in healthy

Article highlights patients.[21]
● Treatment options that include antidepressants with different
mechanisms of action may improve outcomes in patients with MDD.
● Vilazodone is an SSRI and 5-HT1A receptor partial agonist that was
1.3 Role of 5-HT1A receptors in antidepressant action
recently approved by the FDA for the treatment of MDD in adults.
● The efficacy of vilazodone in reducing depression symptoms was
Presynaptic 5-HT1A receptors are autoreceptors that provide
demonstrated in several phase III and IV, placebo-controlled, dou- an autoregulatory mechanism that inhibits 5-HT neurons.
ble-blind trials. Once activated, the receptor opens potassium channels, caus-
● Vilazodone was safe and well tolerated in trials of up to 52-weeks
showing relatively low incidence of weight gain and sexual
ing cell membrane hyperpolarization and a reduction in the 5-
dysfunction. HT cell firing rate.[22,23] The majority of antidepressant med-
ications acts by increasing the concentration of 5-HT in the
extracellular space through the inhibition of serotonin reup-
Table 1. Vilazodone pharmocological and clinical properties.
take transporters (SERTs). This increase in extracellular 5-HT
Dose 10–40 mg/day
preferentially takes place in the raphe nuclei over the frontal
Mechanism
Receptor action 5-HT1A receptor partial agonist
cortex. In the raphe nuclei, increased extracellular 5-HT leads
Absorption to greater negative feedback activation through the 5-HT1A
Tmax 3.7–5.3 h autoreceptors, which results in attenuation of 5-HT cell firing
Peak plasma 156 ng/ml
concentration
and terminal release of 5-HT.[24–26] Because of this attenua-
T1/2, hour 20–24 h tion, the activation of postsynaptic 5-HT receptors that is
Absolute bioavailability Bioavailability from 22 to 72% thought to be responsible for the therapeutic effect of SERT
(with food)
Food effect AUC0-24 h increased from 147 to 160% with high fat
blockade is lower than expected.[27,28] However, the efficacy
meals and 64 to 85% with light meals of 5-HT1A negative feedback becomes less marked following
Distribution long-term treatment with SSRIs, which is thought to be
% Protein binding 96–99%
Metabolism
mediated by desensitization of the presynaptic 5-HT1A auto-
Pathways CYP: primarily by the hepatic CYP450 3A4 enzyme receptors. Desensitization eventually leads to a recovery of 5-
system and secondarily by CYP2C19, CYP2D6 HT neuron firing in the dorsal raphe nucleus, and conse-
Non-CYP: mediated by carboxylesterases
Excretion 1% urine unchanged drug in urine
quently, to an increase in extracellular 5-HT release that is
2% unchanged drug in feces greater than that following a single or acute administration
Safety of SSRIs.[29,30]
Common adverse effects Diarrhea, nausea, headache
(>10%)
Pregnancy Category C
1.4 Role of 5-HT1A receptors in anxiolytic action
5-HT1A receptors, notably presynaptic 5-HT1A autoreceptors,
5-hydroxyindoleacetic acid (5-HIAA) and postmortem whole play a central role in the pathophysiology and treatment of
brain 5-HT concentrations in depressed patients and suicide anxiety disorders. Microinjection of buspirone, a 5-HT1A recep-
victims.[14] Also, 5-HT depletion through dietary tryptophan tor agonist, directly into limbic regions triggers a significant
restriction [15] or pharmacologically (i.e. reserpine or p-chlor- anxiolytic action.[31] Gene-targeting technology in mice
ophenylalanine) [16] induces relapse in depressed patients resulting in 5-HT1A receptor overexpression has been shown
who have responded to antidepressant treatment.[17] to reduce anxiety-like behavior in transgenic mice.[32]
Furthermore, drugs that effectively improve symptoms of Moreover, complete elimination of the 5-HT1A receptor in
depression elevate levels of one or more monoamines.[13] mice models leads to an increase in anxiety-like behavior
The monoamine hypothesis of depression has evolved over due to the impaired neuronal autoinhibitory response.[33]
the years, and it is now assumed that adaptive changes in Studies with human subjects have also demonstrated the
receptors play an increased role in antidepressant treatment importance of 5-HT1A receptors in anxiety disorders. Single
response; this may partially explain why a gradual clinical positron emission tomography scan using the 5-HT1A tracer
response is typically observed with antidepressants, while has shown a reduced presynaptic and postsynaptic 5-HT1A
the increase in the levels of extracellular monoamines is receptor binding in untreated patients with panic disorder in
rapid.[18] comparison with control subjects.[34]

1.2 Serotonin receptors 1.5 Current pharmacotherapies for MDD

There are 14 types of 5-HT receptors in the brain, and each has Patients who achieve acute response or remission from a first
roles in a wide range of functions throughout the body, episode of MDD with pharmacotherapy typically receive 4–
including mood, body temperature, anxiety, sleep, memory, 9 months of continuation treatment to prevent relapse;
and nausea.[19] The most widespread 5-HT receptor is 5-HT1A, patients with recurrent MDD may receive long-term mainte-
which is located mostly in the raphe nuclei (presynaptic), nance therapy.[35] Current antidepressant drugs can be
hippocampus, frontal cortex, dorsal horn of the spinal cord, divided into five major categories: SSRIs, serotonin norepi-
the lateral septum, and amygdala (postsynaptic).[20] The den- nephrine reuptake inhibitors (SNRIs), tricyclic antidepressants
sity of 5-HT1A receptors in the amygdala and hippocampus has (TCAs), monoamine oxidase inhibitors (MAOIs), and
 EXPERT OPINION ON DRUG DISCOVERY 517

multimodal antidepressants (e.g. bupropion, mirtazapine, and autoreceptor downregulation; this process reduces the nega-
vortioxetine).[36] Agomelatine, a new antidepressant agent, tive feedback mechanism and prevents increased extracellular
acts through a combination of antagonist activity at 5-HT2C 5-HT release.[21] Accordingly, vilazodone has been shown to
receptors and agonist activity at melatonergic MT1/MT2 recep- reduce the sensitivity of 5-HT1A autoreceptors in the dorsal
tors. It is unique in that it does not possess a monoaminergic raphe nuclei more rapidly than the SSRIs fluoxetine and par-
component and has no ability to interfere with the neuronal oxetine.[54] Unlike vilazodone, administration of 5-HT1A recep-
reuptake of 5-HT, norepinephrine, or dopamine.[37] tor agonists or partial agonists such as buspirone, 8-hydroxy-2-
No drug class has proven to be effective in all patients; for (dipropylamino)tetralin hydrobromide (8-OH-DPAT), and MKC-
instance, SSRIs and SNRIs typically achieve 25–35% and 242 caused an increase in extracellular dopamine and norepi-
25–45% remission rates, respectively.[38–40] Furthermore, nephrine in the rat brain.[55–58] Molecular experiments using
many patients may experience a lag phase until efficacy is ligand-facilitated binding of [35S]GTPγS to Gi proteins together
observed. The lag phase is thought to be due to the action of with the 5-HT1A receptor expressed in SF9 cells showed that
a 5-HT1A presynaptic receptor-mediated negative feedback compared to vehicle, vilazodone (partial agonist) increased
system, and clinical effect may require up to 6 weeks of binding by fourfold, whereas the full agonist 8-OH-DPAT
continuous treatment until receptor desensitization leads to increased binding by eightfold.[59]
a recovery of 5-HT neuron firing.[41–43] This approximate 6- Vilazodone has high affinity for SERT and achieved 100%
week lag phase that is associated with SSRIs is believed to occupancy at 10 mg/kg and 50% occupancy at 1–3 mg/kg in
represent the time required for desensitization of the 5-HT1A rat cortex and hippocampus ex vivo.[59] This differs from in
receptor.[41] SSRIs also increase synaptic levels of 5-HT in vivo occupancy, which is difficult to assume, because intrinsic
forebrain regions, including the cortex, hippocampus, and activity depends on the receptor reserve available and con-
striatum, which in turn stimulates presynaptic 5-HT1A recep- centration of endogenous agonist (i.e. 5-HT); notably, vilazo-
tors to decrease 5-HT levels.[44–47] In addition, coadministra- done (1 and 10 mg/kg) caused no change in extracellular
tion of pindolol, a mixed 5-HT1A/β-adrenergic receptor partial levels of norepinephrine or dopamine.[59] Moreover, the
agonist, with SSRIs enhanced the levels of extracellular 5-HT. SSRI activity of vilazodone is 30 times more potent than
[46–50] fluoxetine, which likely contributes to a faster proposed
According to the National Institute of Mental Health’s onset of action.[60] Page et al. (2002) compared brain 5-HT
STAR*D trial, only 33% of patients with MDD responded to levels in response to systemic injection with fluoxetine or
initial drug therapy, and each subsequent treatment was likely vilazodone in rats. In that study, 5-HT levels measured 3 h
be less successful than the previous one.[21,51] Additionally, after injection revealed that acute administration of vilazo-
33% of patients continued to have significant symptoms after done produced larger maximal increases of extracellular 5-HT
1 year of successive treatments with a new antidepressant than the SSRI fluoxetine in both the ventral hippocampus (558
drug.[21,51] On the basis of the STAR*D trial, augmentation vs. 274%) and the frontal cortex (527 vs. 165%).[61] Despite
of SSRIs with buspirone has been shown to be effective in these encouraging results, there is currently no clinical data
treating patients who do not respond to initial SSRI therapy, that compares the onset of action of vilazodone to other
suggesting that addition of 5-HT1A partial agonism to 5-HT antidepressants.
reuptake inhibition may improve the clinical picture in MDD.
The antidepressant drug vilazodone (EMD 68843), which
2.2 Behavioral and physiological effects of vilazodone in
shows SSRI and 5-HT1A partial agonist activity (Table 1), was
rodents
approved by the FDA on 21 January 2011 for the treatment of
MDD in adults.[19,52] Several experiments in rats have been conducted to further
establish the mechanism of action of vilazodone. Vilazodone
administration inhibited ultrasonic vocalization, which is a
2. Pharmacological profile of vilazodone behavioral model for anxiolytic activity that is mediated by
presynaptic 5-HT1A receptor activation.[61] The reduction in
2.1 Mechanism of action
ultrasonic vocalization was blocked by coadministration with
Vilazodone is an indolalkylamine that acts as both a potent the potent 5-HT1A receptor antagonist WAY 100,635.[62] In
SSRI (IC50 = 0.2 nM, Ki = 0.1 nM) and a 5-HT1A receptor partial contrast, administration of fluoxetine had no effect on ultra-
agonist (IC50 = 0.5 nM). While vilazodone exhibits high affinity sonic vocalization.[62] Vilazodone also demonstrated dose-
toward the 5-HT1A reuptake site, it does not bind to the dependent anxiolytic efficacy in both the predator-induced
norepinephrine (Ki = 56 nM) or dopamine (Ki = 37 nM) reup- stress paradigm (20–40 mg/kg) and the shock probe test
take sites as avidly.[19] It has also been suggested that the 5- (10–40 mg/kg); the latter measures defensive burying beha-
HT1A partial agonist activity of vilazodone may eliminate the vior in response to a shock from a stationary electrified probe.
efficacy lag phase observed with SSRIs, thereby effectively [62] Vilazodone blocked the predator-induced stress response
reducing patient response time.[19] both 90 min before and 10 min after exposure to the predator.
Vilazodone is 60 times more selective for the 5-HT1A recep- [62] However, no significant anxiolytic effects were observed
tor than buspirone, the only 5-HT1A receptor partial agonist on the elevated plus maze (EPM); in the EPM test, the animal is
that is approved for clinical use as an antidepressant.[53] paced in the center of an elevated four-arm maze that has two
Overstimulation of presynaptic 5-HT1A receptors is interpreted open and well-lit arms and two closed and dimly lit arms. This
by the neuron as toxic activity, and it leads to 5-HT1A outcome may not be surprising because the EPM test is
518 Z. T. SAHLI ET AL.

known to result in highly variable responses with other ser- metabolism occurs in the liver, with only 1 and 2% unchanged
otonergic drugs.[63] vilazodone recovered in urine and feces, respectively. A study
Antidepressant efficacy of vilazodone in rats was assessed by Boinpally et al. (2013) compared the pharmacokinetics of
using the forced swim test (FST). Prior to the FST, rats were vilazodone 20 mg in 32 subjects with mild to moderate kidney
injected intraperitoneally with three doses of vilazodone (1, 3, impairment with that in healthy controls; total drug clearance,
or 10 mg/kg). All three treatment groups showed reduced mean drug recovery in urine, AUC, Cmax, and half-life para-
immobility and increased swimming behavior, which indicated meters were found to be not significantly different. Also, no
antidepressant-like response, although only the 1-mg/kg dos- vilazodone dosage change was needed in patients with renal
ing group exhibited significant changes.[64] Core body tem- or hepatic impairment.[71] A gradual withdrawal from vilazo-
perature change, which is mediated by postsynaptic 5-HT1A done is suggested to prevent 5-HT discontinuation syn-
receptor activity, was not observed after vilazodone adminis- drome.[21]
tration in rats.[65] However, intraperitoneal vilazodone (1–
10 mg/kg) exhibited a significant dose-dependent hypother-
2.4 Metabolism of vilazodone
mic response in mice and also attenuated stress-induced
hyperthermia in mice. These effects of vilazodone were Vilazodone is metabolized primarily by the hepatic CYP450
reversed by WAY 100635, a potent 5-HT1A receptor antagonist 3A4 enzyme system and secondarily by CYP2C19, CYP2D6,
[66], suggesting that vilazodone may have thermoregulatory and other non-CYP pathways that are mediated by carboxy-
effects that can be attributed to its partial 5-HT1A receptor lesterases.[72,73] For this reason, the vilazodone dose should
agonism. Symptoms of 5-HT syndrome were not observed in not exceed 20 mg if coadministered with moderate CYP3A4
rats with the highest doses of vilazodone, in contrast to high enzyme inhibitors (e.g. erythromycin or ketoconazole) in
doses of the full 5-HT1A receptor agonist 8-OH-DPAT, which patients who experienced intolerable adverse events due to
did cause 5-HT syndrome symptoms. These differences were a 50% increase in observed plasma concentration.[70] Because
likely mediated by full (8-OH-DPAT) versus partial (vilazodone) of this drug interaction, vilazodone in combination with strong
5-HT1A receptor agonist activity.[61] CYP3A4 inhibitors such as ketoconazole may warrant up to a
50% decrease of vilazodone dosage. Equally, the maximum of
80 mg/day dosage of vilazodone should be considered when
2.3 Pharmacokinetics of vilazodone in humans
given in combination with strong CYP3A4 inducers such as
Vilazodone is available in 10-, 20-, and 40-mg tablets for daily carbamazepine.[74] However, no vilazodone dose adjustment
treatment to be taken preferably in the morning with food. is necessary when it is coadministered with mild inhibitors of
Initial dosage is recommended at 10 mg once daily for the first CYP3A4 (e.g. cimetidine). Conversely, inducers of CYP3A4 have
7 days, 20 mg once daily for 7 days (to minimize the potential the potential to reduce systemic vilazodone exposure,
for adverse gastrointestinal side effects), and finally 20 or although this has not been systematically evaluated. And
40 mg once daily to achieve the recommended maintenance finally, coadministration with CYP2C8 substrates has been
dose.[41,67] shown to disrupt the metabolism of vilazodone in vitro [70];
The pharmacokinetics of vilazodone was investigated in this has not been evaluated in vivo. M17 and M10 are two
healthy volunteers with doses ranging from 2.5 to 80 mg. major inactive metabolites of vilazodone that are formed as a
Serum concentrations were found to be dose dependent, with by-product of hepatic metabolism. M17 is under postapproval
mean maximum concentrations of 1.5 ng/ml for 2.5-mg dose surveillance for human embryofetal toxicity. The projected
and 156 ng/ml for 80-mg dose.[68] Peak plasma concentrations exposures to M10 and M17 represented more than 10% of
were observed at 3.7–5.3 h, and the half-life was between 20 total circulating vilazodone-related species at steady state
and 24 h (Table 1). Vilazodone must be ingested with food in after a single 20-mg dose to healthy male subjects.[75]
order to increase its bioavailability from 22 to 72% and to Because of the action of 5-HT in platelet function, the use
protect the gastrointestinal system.[21,36] Vomiting after 7 h of SSRIs may increase the risk of upper gastrointestinal bleed-
decreased absorption by 25%; however, no replacement ing; coadministration of nonsteroidal anti-inflammatory drugs
dosage was required.[69] Once absorbed, it was widely distrib- or aspirin may potentiate the risk of bleeding. Increased bleed-
uted throughout the body, with 96–99% of vilazodone being ing has occurred when SSRIs and SNRIs were coadministered
protein bound. This high level of protein binding may tempora- with warfarin. No significant adverse effects of vilazodone
rily disrupt digoxin or Coumadin binding, as it displaces these 20 mg were found in healthy volunteers on biotransformation
drugs into a nonprotein-bound, free plasma state that increases of substrates for CYP1A2 (caffeine), CYP2C9 (flurbiprofen),
their availability and activity.[21] For this reason, caution is CYP2D6 (debrisoquine), and CYP3A4 (nifedipine).[36]
needed when vilazodone is taken with other highly protein-
bound drugs, including phenytoin and warfarin.[70]
2.5 Drug interactions
After daily doses of vilazodone 40 mg with food, the mean
maximum plasma concentration (Cmax) at steady state was Because of the mechanism of action of vilazodone and its
156 ng/ml, and the mean area-under-the-curve (AUC0-24h) effect on increased extracellular 5-HT release, many drugs
concentration was 1645 ng•h/ml; AUC0-24 h increased from should not to be taken with vilazodone. These include
147 to 160% and 64 to 85% when patients had either a MAOIs, SSRIs, SNRIs, buspirone (Buspar, Bristol-Myers Squibb),
high-fat or light meal, respectively. Neither the Cmax nor AUC tramadol (Ultram, Janssen/PriCara), triptans, and tryptophan, a
of vilazodone was affected by ethanol intake.[69] Vilazodone 5-HT precursor. The combination of vilazodone with 5-HT-
 EXPERT OPINION ON DRUG DISCOVERY 519

stimulating drugs is contraindicated. When use of an MAOI to-head studies comparing efficacy against other anxiolytic
and vilazodone is necessary, administration should occur at agents published.
least 14 days apart. The use of SSRIs and antipsychotic drugs
or SNRIs may cause fatal neuroleptic malignant syndrome
(NMS)-like reactions or 5-HT syndrome.[69] 4. Tolerability and safety of vilazodone
4.1 Tolerability
3. Clinical profile of vilazodone Studies have shown that vilazodone is generally well tolerated
under doses of 40 mg per day; according to the FDA, doses of
3.1 MDD vilazodone higher than 40 mg may be poorly tolerated.[85] In
FDA approval of vilazodone came after two, 8-week placebo- a phase III clinical study, 23.9% of patients taking vilazodone
controlled phase III trials with adult patients with MDD and a reported diarrhea and 18.5% reported nausea compared to 7.3
current depressive episode between 4 weeks and 2 years in and 4.4%, respectively, in the placebo group. The majority of
duration.[76,77] In both of these studies, the mean change these adverse events was labeled as mild or moderate in
from baseline to week 8 on the Montgomery-Åsberg intensity and were self-limiting, with a median duration of 4
Depression Rating Scale (MADRS), the primary efficacy para- or 5 days. Only 18 vilazodone-treated patients (8.8%) and 11
meter, showed significant improvements with vilazodone placebo-treated patients (5.4%) complained of severe symp-
treatment compared to placebo. Response rates in the two toms.[76] Although no cases of hyponatremia were associated
studies (≥50% MADRS score decrease) were determined to be with vilazodone therapy in clinical studies, hyponatremia is
40 and 28% (p = .007), for vilazodone and placebo, respec- known to occur as a result of treatment with SSRIs and SNRIs.
tively [76], and 44 and 30% (p = .002), for vilazodone and Activation of mania or hypomania can occur with vilazodone
placebo, respectively.[77] These results were similar to other therapy; therefore, patients should be screened for bipolar
antidepressant drugs trials, including TCAs (39 vs. 28% pla- disorder.[69]
cebo) and the SSRI escitalopram (52 vs. 37% placebo).[78] The In a 52-week open-label study designed to assess the safety
efficacy of vilazodone 40 mg/day was further supported in two and tolerability of vilazodone 40 mg/day in 616 adult patients
double-blind, randomized phase IV trials. One of these trials with MDD, 51% completed at least 6 months of the study and
had a vilazodone 20-mg/day treatment arm, with positive 41% completed 1 year.[65] Overall, 20.7% patients discontin-
results supporting the efficacy of vilazodone at lower doses. ued the trial because of adverse effects, which were mostly
In both trials, all vilazodone-treated groups showed significant gastrointestinal (diarrhea, 35.7%; nausea, 31.6%) and headache
improvement relative to placebo in MADRS score starting at (20.0%). Similar to the adverse effects observed in the short-
week 2 and persisting to the end of double-blind treatment. term trials, the majority of side effects was considered mild or
[79,80] A 52-week open-label study to assess the safety and moderate in intensity, with 14.9% of patients reporting severe
tolerability of vilazodone 40 mg/day in 616 adult patients with adverse events (gastrointestinal = 21 patients; headache = 7
MDD reported the mean change in MADRS score to be –18.5 patients). No abnormal changes were recorded in liver enzyme
at week 8, –21.7 at week 24, and –22.8 at week 52, which elevations, blood pressure, heart rate, or electrocardiograms.
suggested that long-term efficacy was maintained with vilazo- The mean weight increase over the 52 weeks was only 1.7 kg,
done.[81] There are currently no head-to-head studies com- which may have been due to vilazodone’s lack of effects on
paring efficacy against other antidepressant agents published. histamine blockade and 5-HT2 receptor antagonism.[86] The
52-week study showed that vilazodone 40 mg/day was safe
and well tolerated; however, the lack of a placebo group limits
3.2 Generalized anxiety disorder conclusions about the long-term effectiveness of vilazodone.
Positive results have been reported for vilazodone in three of [81] There are no reported head-to-head studies comparing
three, double-blind, randomized, placebo-controlled, 8-week tolerability of vilazodone against other antidepressant agents.
trials in adult patients with generalized anxiety disorder (GAD).
One study evaluated fixed-dose vilazodone 20 or 40 mg/day 4.2 Cardiovascular adverse events
[82], and two studies evaluated flexibly dosed vilazodone
20–40 mg/day.[83,84] The primary outcome measure in each Effects on cardiac health were investigated in a phase I study
study was change from baseline to week 8 in Hamilton enrolling 45 placebo-treated and 66 vilazodone-treated
Anxiety Rating Scale (HAMA) total score. In the fixed-dose patients who received daily doses of vilazodone that increased
study, vilazodone 40 mg/day was significantly superior to every 3 days (10, 20, 40, 60, and finally 80 mg) for 15 days total
placebo on the primary efficacy measure; the difference in vilazodone treatment; there was no significant change in QTc
mean reduction in HAMA score between vilazodone 20 mg/ interval from baseline (range, –1.3 to 2.7 ms).[87]
day and placebo did not reach statistical significance. In both
flexible-dose studies, statistically significant improvement in
4.3 Pregnancy and pediatrics
HAMA total score was seen for vilazodone 20–40 mg/day
relative to placebo. Given the high comorbidity between Vilazodone may be taken during pregnancy if the benefits
MDD and GAD, proven efficacy in GAD may make vilazodone outweigh the potential risks, despite its observed adverse
a favorable treatment option for patients with depression and effect on animal fetuses and lack of information in human
prominent symptoms of anxiety. There are currently no head- trials.[67,88] Higher need for intensive care treatment and
520 Z. T. SAHLI ET AL.

risks of pulmonary hypertension and neonatal behavioral syn- 5. Conclusions

drome have been reported in some infants born to mothers
Vilazodone is an SSRI and 5-HT1A partial agonist that is
taking SSRIs.[89] The black box warning label emphasizes that
approved for the treatment of MDD in adults. Acute treatment
vilazodone is not indicated for pediatric use.[69]
(8–10 weeks) with vilazodone 20–40 mg/day versus placebo
resulted in significantly greater improvements from baseline in
MADRS total score (predefined primary efficacy parameter)
4.4 Sexual dysfunction and significantly higher percentages of patients with MADRS
response (≥50% total score improvement from baseline).
Sexual dysfunction is a common symptom of MDD, with
[76,77,79,80] In a multicenter open-label study, MADRS total
untreated male and female patients reporting decreased
score decreased by approximately 20 points after 8 weeks of
libido (42 and 50%, respectively), inability to sustain an erec-
treatment; similar decreases were observed at subsequent
tion in men (46%), and difficulty in obtaining vaginal lubrica-
study visits up to 52 weeks, suggesting that long-term efficacy
tion in women (40%).[90,91] Antidepressant drugs can also
was maintained in MDD patients treated with vilazodone
negatively affect sexual functioning in patients with MDD
40 mg/day.[81]
due to changes in 5-HT, dopamine, and norepinephrine synap-
Acute treatment with vilazodone 20–40 mg/day has also
tic release and signaling.[92–94] Activation of 5-HT1A receptors
been shown to reduce anxiety symptoms in adults with GAD,
has been shown to reverse inhibited sexual function by
as demonstrated by the significantly greater mean improve-
increasing libido and facilitating ejaculation.[92,95]
ments from baseline with vilazodone versus placebo in HAMA
The effects of vilazodone and prototypical SSRIs (citalopram
total score in three randomized, double-blind, placebo-con-
and paroxetine) on copulatory and ejaculatory behaviors in
trolled trials.[82–84] The results from these GAD studies, along
male rats were recently investigated.[96] After 7 and 14 days
with the improvements in anxious depression that were found
of treatment with citalopram (10 and 30 mg/kg) or paroxetine
in a post hoc analysis of the MDD studies [100], suggest that
(10 mg/kg), impaired sexual behaviors were observed, includ-
vilazodone may be a suitable treatment option in patients
ing reduced ejaculatory frequency and copulatory efficiency.
with comorbid MDD and GAD, or in MDD patients with pro-
In contrast, vilazodone (1–10 mg/kg) did not exhibit significant
minent anxiety symptoms.
changes in sexual behaviors as compared to vehicle controls.
The clinical trials with vilazodone, including the 52-week
Audoradiographic assays performed after 14 days of treatment
study in MDD patients [81], indicate that this medication is
showed that chronic administration of vilazodone resulted in
generally safe and tolerable at doses up to 40 mg/day. In both
smaller reductions in 5-HT transporter (5-HTT) levels in the
MDD and GAD patients, gastrointestinal disturbances (e.g.
forebrain as compared to citalopram and paroxetine.[96]
nausea, diarrhea, and vomiting), headache, and dizziness
Chronic vilazodone treatment also decreased 5-HT1A receptor
were the most common treatment-emergent adverse events.
density in cortical and hippocampal regions, whereas both
In contrast to prototypical SSRIs, vilazodone has not been
SSRIs increased 5-HT1A receptors in the same regions. These
associated with treatment-emergent sexual difficulties or dys-
differential effects on 5-HTT and 5-HT1A levels may be related
function. No clinically significant changes in blood pressure,
to the ability of vilazodone to limit SSRI-induced sexual side
heart rate, electrocardiograms, or laboratory tests were
effects.
observed. However, more studies are needed to further eval-
A post hoc pooled investigation by Clayton et al. (2013) on
uate the long-term safety of vilazodone in both MDD and GAD
the effects of vilazodone on sexual function was conducted in
patients.
869 patients from placebo-controlled studies and 599 from the
open-label vilazodone study.[97] In the placebo-controlled
studies, 91.2% of male and 92.9% of female vilazodone-treated
6. Expert opinion
patients displayed either improved or stable sexual function,
which was similar to the rates observed in placebo-treated A number of pharmacological options are available for the
male (90.8%) and female (95.6%) patients. In the open-label treatment of MDD and GAD, with SSRIs and SNRIs often used
vilazodone study, 87.9% of men and 91.8% of women showed as first-line therapies. However, as no single medication is
either improved or stable sexual function from baseline, which effective in all patients, the ongoing discovery and develop-
was also similar to the rates in placebo-treated patients.[97] In ment of medications for these disorders are merited. The
a placebo- and active-controlled phase IV study, baseline sex- approval of vilazodone for the treatment of MDD in adults
ual function was improved in men and women, MDD respon- was based on the efficacy and safety of this drug in four
ders, and patients with baseline sexual dysfunction following double-blind, placebo-controlled trials and one long-term,
10 weeks of treatment with vilazodone.[98] open-label study.[69] The results of these studies adequately
In the GAD studies, the Changes in Sexual Functioning demonstrate the clinical benefits of vilazodone in MDD
Questionnaire (CSFQ) [99], a prospective measure of sexual patients, but the unique pharmacological profile of this drug
functioning, was used in each trial. Small and similar mean also warrants some consideration.
changes in CSFQ total score were seen for men and women in In addition to being an SSRI, vilazodone is a potent 5-HT1A
the vilazodone (range, –0.3 to +1.9) and placebo (range, +0.5 receptor partial agonist. As decreased 5-HT1A density has been
to +1.8) groups in all three studies, suggesting that the effect found in patients with MDD, targeted activation of these
of treatment on sexual functioning was similar for vilazodone receptors may help to restore their modulatory effects on 5-
and placebo. HT neurotransmission. In preclinical studies, partial 5-HT1A
 EXPERT OPINION ON DRUG DISCOVERY 521

receptor agonism has been shown to decrease the lag •• Review of neurobiological theories, pharmacotherapies and
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