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PSYCHOPHARMACOLOGY BULLETIN: Vol. 44 · No. 3 • 15

The Safety and Tolerability Profile ofVilazodone, A Novel Antidepressant

for the Treatment of MajorDepressive Disorder

By Michael Liebowitz, Harry A. Croft,Daniel K. Kajdasz, Heidi Whalen, Susan Gallipoli,

Maria Athanasiou, Carol R. Reed

Dr. Liebowitz, MD, Affiliated with The Medical Research Network, LLC, New York, NY. Dr. Croft, MD,Affiliated with San Antonio Psychiatric Research Center, San Antonio, TX. Dr. Kajdasz, PhD andMs. Whalen, MHS, Affiliated with Dogwood Pharmaceuticals, A Subsidiary of Forest Laboratories, Inc.,New Haven, CT. Ms. Gallipoli, MSN, Former Full-Time Employee of Dogwood Pharmaceuticals,A Subsidiary of Forest Laboratories, Inc., New Haven, CT. Dr. Athanasiou, PhD, Affiliated with AthanasiouConsulting, LLC, Fond du Lac, WI. Dr. Reed, MD, Consultant to Forest Laboratories, Inc., New York, NY.To whom correspondence should be addressed: Michael Liebowitz, MD, 134 East 93rd Street, Suite201A, New York, NY 10128. Phone: 212 595-5012; Fax: 212 595-5013; E-mail: [email protected]

ABSTRACT ~ Objective: Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1Areceptor partial agonist approved for the treatment of major depressive disorder (MDD).This report summarizes the safety and tolerability of vilazodone 40 mg/day during short-and long-term treatment of adult MDD. Methods: Pooled data from two 8-week, double-blind studies of vilazodone (n � 436) vs placebo (n � 433) and data from one 52-week,open-label study (n � 616, vilazodone only) were analyzed. Patients aged 18-70 withDSM-IV-TR-defined MDD received vilazodone or placebo (8-week studies only) oncedaily, with food, titrated to 40 mg/day over 2 weeks. Safety and tolerability assessmentsincluded adverse events (AEs), laboratory tests, vital signs, electrocardiograms, and weight.Results: The most common AEs in all studies were diarrhea, nausea, and headache.Vilazodone-associated AEs in the two 8-week studies, defined as an incidence rate of �5%in the vilazodone group and at least twice that for placebo, were diarrhea (28.0% vs 9.2%),nausea (23.4% vs 5.1%), and insomnia (6.0% vs 2.1%), with the majority reported asmild to moderate and �5% of those patients requiring concomitant (directed) treatment forthese conditions. Discontinuation rates due to AEs were 7.1% (vilazodone) and 3.2%(placebo) in the 8-week studies and 20.7% in the 52-week study. Vilazodone had no clini-cally significant effects on vital signs, laboratory tests, or electrocardiograms. Conclusion:Vilazodone 40 mg/day was well tolerated during short- and long-term MDD treatmentin these trials. Safety profiles associated with 8- and 52-week exposure were consistent.Psychopharmacology Bulletin. 2011;44(3):15–33.

Key Words: treatment emergent adverse event, adverse event, sexual side effects, weight gain, antidepressant tolerability, antidepressant-induced suicidality

ORIGINAL RESEARCH

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INTRODUCTION

Features of the safety and tolerability profile of antidepressants ofteninfluence prescribing paradigms for major depressive disorder (MDD).1The American Psychiatric Association practice guideline for the treat-ment of MDD indicates initial antidepressant selection should be basedlargely on the individual’s presenting symptoms and anticipated adverseevents (AEs).2 The AE profile is also cited as a reason for noncompli-ance and premature discontinuation of treatment.3,4

Although practice guidance suggests that extended treatment is of ben-efit,2 as many as 35% of patients discontinue antidepressant therapy withinthe first few months,5 with weight gain, sexual dysfunction, and sleep dis-orders most often reported as the primary reason.3,4 Strategies for deter-mining the most appropriate treatment in relation to management of AEsare often unsuccessful but include changes in the daily drug schedule(fixed vs flexible schedule), symptom-directed therapies, antidepressantswitches, drug holidays, and dose reduction.6 Consequently, there is anunmet need for alternative antidepressants that offer reliable efficacy withan improved tolerability profile overall and for individual patients.

The AE profile of an individual antidepressant generally can be predictedby its receptor-binding profile.7 For example, selective serotonin reuptakeinhibitor (SSRI) therapy is associated with nausea, which is thought to becaused by stimulation of the 5-HT3 receptors. Similarly, the sexual dysfunc-tion associated with long-term SSRI therapy is thought to be attributable tochronic, unopposed stimulation of the postsynaptic 5-HT2 receptors.8

Vilazodone is a new molecule that is an SSRI and 5-HT1A receptorpartial agonist.9,10 Vilazodone has a 30-fold greater potency for sero-tonin reuptake inhibition than the SSRI fluoxetine with selectivity forthe inhibition of norepinephrine or dopamine reuptake inhibition com-parable to that of fluoxetine.11 The unique, dual mechanism of vila-zodone has been shown, in nonclinical studies, to enhance serotoninlevels. Additionally, it has been suggested that the high selectivity of vila-zodone for the 5-HT1A receptor may result in improved tolerability.10

Vilazodone has been approved by the United States (US) Food andDrug Administration (FDA) for the treatment of MDD. The efficacy oftreatment with vilazodone 40 mg once daily (qd) with food was estab-lished in two 8-week placebo-controlled studies, which showed signifi-cant improvements in depressive symptoms compared with placebo asmeasured by the Montgomery-Asberg Depression Rating Scale(MADRS).12,13 The efficacy of vilazodone was further supported by sig-nificant changes in MADRS-based therapeutic response rates and sig-nificant improvement on multiple other measures relating to depressionand global clinical improvement compared with placebo.12,13 Results

PSYCHOPHARMACOLOGY BULLETIN: Vol. 44 · No. 3

SAFETY AND TOLERABILITY PROFILE OF VILAZODONE

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from efficacy measures from an open-label, 40 mg qd 52-week study sup-ported findings of the 8-week placebo-controlled studies.12-14

This work summarizes findings from these three phase 3 studies ofvilazodone and characterizes the safety and tolerability profile of vila-zodone during both short- and long-term treatment of MDD in adults.

METHODS

Details of study design and conduct for the two phase 3, 8-week placebo-controlled studies (NCT00285376 and NCT00683592) and the 52-weeksafety study (NCT00644358) have been reported previously.12-14 All stud-ies were conducted in accordance with the Declaration of Helsinki andwith Good Clinical Practice guidelines. Protocols were approved by eachcenter’s institutional review board in accordance with the US Code ofFederal Regulations. All patients provided informed consent before anystudy procedures and were compensated for their time. The 52-week studywas not a continuation of the 8-week studies.

Patients

In brief, all three phase 3 studies included men and women 18 to 65 or70 years old with a diagnosis of MDD according to the Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Text Revision(DSM-IV-TR) criteria,15 with a 17-item Hamilton Rating Scale forDepression (HAMD-D17) score �22 (8-week studies) or �18 (52-weekstudy) at screening and baseline. For the two 8-week studies, patients hadto have a current major depressive episode (single or recurrent) with a dura-tion of �4 weeks and �2 years. Patients with a history of Axis 1 post-trau-matic stress disorder (PTSD), eating disorder, or obsessive compulsivedisorder (OCD) within the 6 months prior to screening were excluded aswere patients with any history of schizophrenia, schizoaffective disorder,or bipolar disorder. Patients with generalized anxiety disorder, social pho-bia, or simple phobia were permitted to enroll. Additionally, patientsexhibiting MDD with postpartum onset, psychotic features, or seasonalpattern; or those meeting the criteria for DSM-IV-TR substance abuse(alcohol or drugs) within 3 months of screening; or judged to pose a seri-ous suicidal risk were also excluded. Other exclusionary conditions includedpsychotherapy within the preceding 12 weeks, failure to respond to an ade-quate trial of 2 antidepressants of different drug classes during the sameepisode, or concurrent use of drugs, including psychotropics or migrainemedications, with a serotonergic mechanism of action. Patients with sig-nificant comorbid conditions that might interfere with trial participation



17Liebowitz, Croft,Kajdasz, et al.


were excluded at the investigators’ discretion. Exclusion criteria in the 52-week study were similar to those in the 8-week studies, except thatpatients were required to have a HAM-D score �18, were not excludedbecause of PTSD, eating disorder, OCD or a DSM-IV-TR MDD speci-fier, and they may not have met DSM-IV-TR criteria for substance abuseor dependence within 1 year of the baseline visit.

Study Design

Each study consisted of 3 periods: washout, screening, and a treatmentperiod, which was either 8 weeks, double-blind, placebo-controlled or52 weeks, open-label. The washout period in all studies was 4 weeks formonoamine oxidase inhibitors and fluoxetine, 12 weeks for depot neu-roleptics, and 2 weeks for all other antidepressants. After the washout andscreening periods, eligible patients underwent baseline assessments and,in the 8-week studies, were randomly assigned (1:1) to receive vilazodoneor placebo orally once daily. All patients in the 52-week study receivedvilazodone. In all studies, patients were treated with vilazodone accordingto a fixed-titration schedule of 10 mg qd for 7 days, followed by 20 mg qdfor the next 7 days, and then at the targeted dose of 40 mg qd, and wereinstructed to take study drug in the morning with food.

Assessments

Safety measures for all studies included reported AEs, clinical labora-tory evaluations (chemistry, hematology, and urinalysis), electrocardio-grams (ECG), and vital signs (systolic blood pressure [SBP]; diastolicblood pressure [DBP], heart rate, respiration, and weight). AEs werecollected via patient self-reporting as well as general investigator solic-itation. AEs starting on or after the date of initial study drug adminis-tration, preexisting events that worsened in severity after the start ofstudy drug, and AEs that started within 30 days of the discontinuationof study medication were considered treatment emergent (TEAE) forthese integrated evaluations. AE coding was based on the MedicalDictionary for Regulatory Activities (MedDRA; version 11.1).

Additional safety assessments relevant to antidepressant use were con-ducted and included (1) suicidality as evaluated via AE reporting andcomprehensive text string search (TSS) results;16 (2) the development ofserotonin syndrome as identified through evaluations of TEAEs associ-ated with the clinical features defined by Hunter Serotonin ToxicityCriteria17; (3) the development of mania or hypomania as identified viareview of TEAEs associated with substance-induced mood disorder withmanic features; and (4) changes in sexual function as assessed by either



18Liebowitz, Croft,

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the Arizona Sexual Experience Scale (ASEX)18 or the Change in SexualFunctioning Questionnaire (CSFQ).19

Analyses

For these analyses, the safety population was defined as all randomizedor enrolled patients who received study drug and had at least 1 post-base-line safety assessment. Data for the two 8-week trials were pooled, andtreatment group evaluations were based on treatment as received.Informational P values from statistical tests from the pooled 8-week studydata are also provided.

TEAEs, serious adverse events (SAEs), and TEAEs leading to studydiscontinuation were tabulated by MedDRA System Organ Class (SOC)and Preferred Term for each treatment group. Stratifications by sex, age(�55 vs �55), and race (Caucasian vs not Caucasian) were evaluated toidentify any potential demographic differences in AE profiles. In thepooled 8-week database, TEAEs attributed to vilazodone were defined asevents that occurred at an incidence rate of 5% or more in the 40-mg/dayvilazodone treatment group and at least twice the rate for placebo.

Safety analyses included summarization of quantitative and qualitativechanges from baseline to end of treatment (EOT). EOT was defined aseach patient’s last study visit. This corresponded to week 8 or 52 forpatients completing the short- or long-term studies, respectively. The lastvisit at or prior to study termination was used for those patient who dis-continued prematurely.

For the analyses of clinical laboratory evaluations, vital signs, and ECGs,the percentage of patients with potentially clinically significant (PCS) high orlow values while on study were summarized according to predefined criteria.Treatment group comparisons of the incidence of TEAEs and PCS occur-rences for vital signs and weight were evaluated using the Fisher exact test.

For continuous safety measures in the pooled 8-week studies, treatmenteffects were estimated by the difference in least-squares mean (LSM)changes from baseline to EOT. LSM changes were estimated from ananalysis of covariance (ANCOVA) model containing terms for treatmentgroup and study, with the baseline measurement included as a covariate.

The incidences of suicidal ideation and behavior were derived by map-ping comprehensive text string search (TSS) results16 to the ColumbiaClassification Algorithm for Suicide Assessment (C-CASA).20 AE ver-batim terms, MedDRA Preferred Terms, and all comment fields withinthe study databases were included in the text string search. Odds ratios(ORs) for suicidal behavior and ideation were estimated using a condi-tional logistic regression model containing terms for treatment group andstudy for the pooled placebo-controlled data.





RESULTS

Baseline Demographics and Primary Disease Characteristics

Demographic and baseline disease characteristics are summarized inTable 1. Mean age at baseline was 41 years for the 8-week studies and43 years for the 52-week study. Women were more common amongthe study population (59.5% in the 8-week studies and 67.9% in the52-week study), and the majority of patients were Caucasian (81.2%



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TABLE 1

BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS (SAFETY POPULATIONS)

POOLED 8-WK STUDIES 52-WK STUDYVILAZODONE PLACEBO VILAZODONE

CHARACTERISTIC n � 436 n � 433 N � 599

Sex, n (%)Men 170 (39.0) 182 (42.0) 192 (32.1)Women 266 (61.0) 251 (58.0) 407 (67.9)

Race, n (%)Caucasian 360 (82.6) 346 (79.9) 479 (80.0)Black or African American 54 (12.4) 66 (15.2) 101 (16.9)Asian 10 (2.3) 10 (2.3) 10 (1.7)Other/Unknown 12 (2.8) 11 (2.5) 9 (1.5)

Age, mean (SD), y 40.6 (12.2) 41.3 (12.6) 42.8 (12.5)18–39, n (%) 196 (45.0) 197 (45.5) 234 (39.1)40–54, n (%) 180 (41.3) 157 (36.3) 252 (42.1)�55, n (%) 60 (13.8) 79 (18.2) 113 (18.9)

Mean BMI, mean (SD), kg/m2 30.2 (7.9) 30.1 (6.8) 31.6 (8.0)Underweight (BMI �18.5), n (%) 5 (1.1) 3 (0.7) 3 (0.5)Normal (BMI 18.5–�25.0), n (%) 128 (29.4) 105 (24.2) 119 (19.9)Overweight

(BMI 25.0–�30.0), n (%) 111 (25.5) 138 (31.9) 163 (27.2)Obese (BMI � 30.0), n (%) 192 (44.0) 182 (42.0) 311 (51.9)Unknown 0 5 (1.2) 3 (0.5)

Duration of current episode,months, n (%)

�1 1 (0.2) 0 01–�6 214 (49.1) 226 (52.2) 215 (35.9)6–12 128 (29.4) 137 (31.6) 172 (28.7)�12 93 (21.3) 70 (16.2) 212 (35.4)

Baseline MADRS and HAMD-D17total scores, mean (SD)

MADRS 31.4 (3.7) 31.4 (3.8) 29.9 (4.4)HAMD-D17 24.9 (2.4) 25.2 (2.5) 23.1 (3.3)BMI, body mass index; HAMD-D17, 17-item Hamilton Rating Scale for Depression;MADRS, Montgomery-Asberg Depression Rating Scale; SD, standard deviation; wk, week.





in the 8-week studies and 80.0% in the 52-week study). Within the 8-week studies, differences in demographics and disease characteristicsbetween the placebo and vilazodone groups were not considered clini-cally relevant. Mean baseline MADRS scores were 31.4 in the 8-weekstudies and 29.9 in the 52-week study, indicating depression of moder-ate severity on average. The duration of the current episode was morethan 6 months for approximately 50% of patients in both treatmentgroups in the 8-week studies and 64% of patients in the 52-week study.

Patient Disposition and Vilazodone Exposure

In the 8-week studies, 436 patients were exposed to vilazodone for atotal of 59.5 patient-years. During the 52-week study, 599 patientswere exposed to vilazodone for a total of 348.2 patient-years, with 314patients (52.4%) exposed for a minimum of 6 months and 118 patients(19.7%) exposed for a minimum of 12 months.

Figure 1 shows the patient disposition for the 8-week studies and the52-week study. For the 8-week studies, the percentages of patients dis-continued prematurely (20.9% vilazodone and 19.4% placebo) weresimilar between groups. In the 52-week study, the percentage ofpatients who completed the study was 42.4%.

Patients who received vilazodone discontinued early from the 8-weekstudies primarily because they were lost to follow-up (7.3%), had anAE (7.1%), or withdrew consent (2.8%). Patients in the placebo groupdiscontinued primarily because they were lost to follow-up (6.7%),withdrew consent (3.7%), had a lack of efficacy (3.7%) or had an AE(3.2%). The most frequent reasons for early discontinuation from the52-week study were AEs (20.7%), lost to follow-up (15.9%), with-drawal of consent (9.7%), and lack of efficacy (6.5%).

Treatment-Emergent Adverse Events

The incidence of patients reporting TEAEs in the 8-week studies wassignificantly greater (P � 0.001) in the vilazodone group (358 of 436patients, 82.1%) than in the placebo group (280 of 433 patients, 64.7%).Table 2 shows all TEAEs that occurred in �5.0% of patients. In theplacebo group, 91.4% of patients reporting TEAEs reported a maximumseverity of mild to moderate compared with 90.8% of patients in the vila-zodone group, with 55.4% of all TEAEs reported as mild in the placebogroup compared with 60.4% in the vilazodone group. The 3 most com-mon TEAEs overall in the vilazodone group were diarrhea (28.0% vs9.2% in the placebo group), nausea (23.4% vs 5.1% in the placebo group),and headache (13.3% vs 12.0% in the placebo group). Diarrhea and




22Liebowitz, Croft,

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nausea occurred in �5% of vilazodone patients and at least at twice therate of placebo, as did insomnia (6.0% vs 2.1% in the placebo group).

In the 52-week study, 562 of 599 (93.8%) patients experienced one ormore TEAE. The most frequent TEAEs were diarrhea (35.9%), nau-sea (31.6%), and headache (20.4%). TEAEs occurring in the 52-weekstudy were mostly mild (55.6%) with 84.2% of patients reporting aTEAE reporting a maximum severity of mild to moderate.

(B)

PATIENT DISPOSITION THROUGH (A) THE POOLED 8-WEEK STUDIES AND

(B) THE 52-WEEK STUDY

FIGURE 1

(A)


Initial Onset and Duration of the Most Common Adverse Events

The time to initial onset of either diarrhea or nausea was significantlyshorter on average for the vilazodone group compared with the placebogroup (P � 0.001 for both TEAEs). Most cases of diarrhea and nauseain the vilazodone group had onset during the titration period (i.e., withinthe first 2 weeks).The median onset of the first occurrence of diarrhea forvilazodone and placebo was 2 days and 8 days, with a median duration of8 days and 4 days, respectively. Only 3.7% of vilazodone patients experi-encing diarrhea required treatment with concomitant medications andnone of these episodes were reported as severe. Four patients discontin-ued due to diarrhea (0.9%). Median onset of the first occurrence of nau-sea was 2 days for vilazodone and 6.5 days for placebo (P � 0.001) with




TABLE 2

TREATMENT-EMERGENT ADVERSE EVENTS OCCURRING IN �5.0% OF PATIENTS

IN ANY TREATMENT GROUP IN PHASE 3 STUDIES BY PREFERRED TERM

POOLED 8-WK STUDIESVILAZODONE PLACEBO

PREFERRED TERMa n � 436 n � 433

Patients with �1 TEAE, n (%) 358 (82.1) 280 (64.7)Diarrhea 122 (28.0) 40 (9.2)Nausea 102 (23.4) 22 (5.1)Headache 58 (13.3) 52 (12.0)Dizziness 37 (8.5) 20 (4.6)Dry mouth 35 (8.0) 22 (5.1)Insomnia 26 (6.0) 9 (2.1)Nasopharyngitis 23 (5.3) 20 (4.6)Upper respiratory tract infection 19 (4.4) 33 (7.6)

52-WK STUDY—VILAZODONE, N � 599

Patients with �1 TEAE, n (%) 562 (93.8)PREFERRED TERM,a n (%)

Diarrhea 215 (35.9) Dizziness 64 (10.7) Nasopharyngitis 45 (7.5)Abnormal

Nausea 189 (31.6) dreams 62 (10.4) Vomiting 44 (7.3)Headache 122 (20.4) Somnolence 59 (9.8) Anxiety 36 (6.0)Upper

respiratory Weight Urinary tract tract infection 82 (13.7) increase 57 (9.5) infection 35 (5.8)

Increased Insomnia 76 (12.7) appetite 54 (9.0) Back pain 33 (5.5)Dry mouth 66 (11.0) Fatigue 49 (8.2)

MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event; wk, week.aMedDRA, version 11.1.


a median duration, respectively, of 5 days and 4.5 days. Few patients(n � 5; 1.1%) who experienced nausea required treatment for the AE andfew discontinued as a result (n � 2; 0.5%).

In the 52-week study, median onset of the first occurrence andmedian duration were 4 days and 7 days for diarrhea and 5 days and7 days for nausea. As in the 8-week studies, �5% of patients (n � 29)received concomitant drug therapy for diarrhea; 2 of these patientsexperienced diarrhea reported as severe. Similarly, 3.7% of patients tookconcomitant medications to treat nausea and 8 of these patientsreported nausea as severe.

For the evaluations of onset and duration of insomnia,TEAEs coding tothe MedDRA Preferred Terms of “insomnia,” “initial insomnia,” “middleinsomnia,” “early morning waking,” and “hyposomnia” were groupedtogether.The median onset of the first occurrence of insomnia for the vila-zodone and placebo groups was 11 days and 9 days, respectively, and themedian duration was 10 days and 14 days, respectively, in the 8-week stud-ies. In the 52-week study, median onset of the first insomnia occurrenceand median insomnia duration were 19 days and 25 days, respectively.No cases of hyposomnia occurred in any of the 3 studies.

Serious Adverse Events

In the 8-week studies, 9 SAEs were reported for 7 of 433 patients (1.6%)receiving placebo and 11 SAEs were observed for 9 of 436 patients(2.1%) receiving vilazodone. The only SAEs that occurred in more than1 patient were suicidal ideation (0 with vilazodone; 3 with placebo) anddepression (1 with vilazodone; 2 with placebo). Depression was the onlySAE deemed possibly related and all others were judged unlikely or notrelated to study medication.

In the 52-week study, 23 of 599 patients (3.8%) experienced 33 SAEswhile taking vilazodone. Infections and infestations was the most commonsystem organ class (5 patients, 0.8%), including pneumonia in 2 patients(0.3%). All other SAEs occurred in single patients. Serotonin syndromeand panic attack were deemed probably and chest discomfort was deemedpossibly related to study medication. All other SAEs were judged unlikelyor not related to study medication. There was no pattern to SAEs withregard to MedDRA Preferred Terms or SOCs.

Treatment-Emergent Adverse Events Leading to Discontinuation

TEAEs led to discontinuation for 31 of 436 patients (7.1%) receivingvilazodone and 14 of 433 patients (3.2%) receiving placebo in the 8-week studies and no specific TEAE led to discontinuation in �1%



24Liebowitz, Croft,

Kajdasz, et al.


of patients receiving vilazodone. TEAEs leading to discontinuation inmore than 1 patient in the vilazodone group were diarrhea and palpita-tions (4 patients each) and nausea, depression, and fatigue (2 patientseach). In the placebo group, suicidal ideation and headache (3 patientseach) were reported in �1 patient.

During the 52-week study, 124 of 599 patients (20.7%) experienced aTEAE that led to discontinuation. Specific TEAEs leading to discon-tinuation in �1% of patients were nausea (8 patients, 1.3%), diarrhea(7 patients, 1.2%), and anxiety (6 patients, 1.0%).

Clinical Laboratory Evaluations

In the 8-week studies, few patients (n � 6 for any parameter) in eithergroup had PCS abnormalities for any of the evaluated clinical chemistry,hematology, or urinalysis parameters. PCS elevations in liver function testswere observed in 4 patients in the vilazodone group: aspartate amino-transferase and gamma glutamyl transpeptidase, 1 patient (0.3%) each (�3times the upper limit of normal [ULN] range); bilirubin, 2 patients (0.5%)(�1.5 � ULN), compared with 3 patients in the placebo group: gammaglutamyl transpeptidase, 1 patient (0.3%); bilirubin, 2 patients (0.5%).

Similarly, few patients treated with vilazodone (n � 9 for any param-eter) had PCS abnormalities for any of the evaluated laboratory param-eters in the 52-week study (including liver function abnormalities). Nopatients in the 8-week or 52-week studies met the criteria for Hy’s law(�3 � ULN for aspartate aminotransferase and �2 � ULN for totalbilirubin, a prognostic indicator of drug-induced liver injury).21

Vital Signs and ECG

Changes from baseline to EOT in vital signs are tabulated by treatmentgroup for the 8- and 52-week studies in Table 3. The incidences of PCShigh or low vital signs and ECG values while on study are shown inTable 4 along with the PCS criteria that were utilized. LSM changesfrom baseline to EOT in PR interval (PR), QRS interval (QRS), andQTc (Fridericia) interval corrected for heart rate (QTc) for vilazodonecompared with placebo are shown in Table 5.

Mean body weight change from baseline to EOT was 0.2 kg in bothtreatment groups in the 8-week studies (Table 3). PCS weight increases�7% were observed in 4 vilazodone patients (0.9%) and 5 placebo patients(1.2%), and weight PCS decreases �7% were seen in 6 patients (1.4%) forboth groups (Table 4). In the 52-week study, the mean change in bodyweight at EOT was 1.0 kg for all patients and, for patients remaining inthe study at week 52, was 1.7 kg. PCS weight increases were observed in







26Liebowitz, Croft,

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92 patients (15.4%), and PCS weight reductions were observed in 36patients (6.0%). Assessed at 6 months, mean (SD) weight change forpatients with normal baseline weight (body mass index [BMI] of 18.5to �25.0 kg/m2; n � 95) was 1.3 (3.5) kg; for overweight (BMI of 25.0 to�30.0 kg/m2; n � 136) and obese (BMI �30.0 kg/m2; n � 258) patients,mean (SD) weight increases were 1.6 (3.7) kg and 1.0 (5.9) kg, respec-tively. The reported incidences of TEAEs of weight increase and weightdecrease were 9.5% (57 patients) and 1.7% (10 patients), respectively.14

Adverse Events of Special Interest

In the 8-week studies, 1 patient (0.2%) each in the vilazodone andplacebo groups met the C-CASA criteria for suicidal behavior based onTSS. C-CASA-defined suicidal ideation was identified for 1 patient(0.2%) in the vilazodone group and 3 patients (0.7%) in the placebogroup based on TSS. There was no increased likelihood in either suici-dal ideation (OR � 0.3, P � 0.337) or behavior (OR � 1.0, P � 0.997)associated with vilazodone treatment. In the 52-week study, suicidalideation and suicidal behavior were identified for 7 patients (1.2%) and2 patients (0.3%), respectively. No completed suicides occurred.

No patients in the 8-week studies experienced serotonin syndromeaccording to Hunter’s criteria. One patient in the 52-week studyexperienced severe serotonin syndrome due to an overdose with studydrug associated with non-adherence to study drug scheduling. Nopatients in the 8-week studies were identified as potentially havingmania or manic symptoms associated with vilazodone. Two patients(0.3%) in the 52-week study experienced mania or manic symptomsassociated with vilazodone. Both patients withdrew from the study.

In the first 8-week study,12 LSM change from baseline to EOT inASEX total score in the vilazodone group vs the placebo group was 0.8versus –1.0 (P � 0.011) for men and –1.2 versus 0.1 (P � 0.054) forwomen (decrease indicates improved score). In the second 8-week study,LSM change from baseline to EOT in CSFQ score in the vilazodonegroup vs the placebo group was 0.5 versus 1.7 (P � 0.211) for men and1.9 versus 2.2 (P � 0.682) for women (increase indicates improved score).In the 52-week study, mean change in CSFQ total score during vila-zodone treatment was 1.5 in men and 2.7 in women.

During the 8-week studies, 8.0% of patients in the vilazodone groupand 0.9% in the placebo group reported at least one TEAE related tosexual function, with libido decrease the most frequently reported: 3.7%of the vilazodone group (males, 4.7%; females, 3.0%) and 0.2% of theplacebo group (males, 0%; females, 0.4%). In the 52-week study, 15.1%of patients reported at least one TEAE related to sexual function. As in





the 8-week studies, libido decreased was the most commonly reported:4.3% of the total population (males, 5.7%; females, 3.7%).

Safety Evaluations of Demographic Subgroups

In Phase 3 studies, there were no clinically meaningful differences insubgroups defined by age, sex, and race from the patterns observed inthe total population for TEAEs, SAEs, or TEAEs leading to discon-tinuation. Diarrhea was more frequent in older patients (�55 years ofage) and nausea was more frequent in younger patients. Dizziness wasalso reported more frequently in younger patients. Vomiting and som-nolence were observed at a higher percentage in non-Caucasians com-pared with Caucasians. Female patients reported gastrointestinalTEAEs more often than male patients (nausea was reported more oftenfor females and diarrhea more often for males). Females also reportednervous system TEAEs (especially headache) and infections and infes-tations (particularly nasopharyngitis) more often than males.

With regard to SAEs and TEAEs leading to discontinuation, SAEsoccurred more often in patients �55 years of age during 8 weeks of vila-zodone treatment and more often in males during 52 weeks of vila-zodone treatment. TEAEs leading to discontinuation in the 8-weekstudies were greater for patients who were �55 years of age orCaucasian. In the 52-week study, TEAEs leading to discontinuationoccurred more often for patients who were �55 years of age, female, orCaucasian.

DISCUSSION

This analysis of safety and tolerability data from the phase 3 studies foundthat in adult patients with MDD, vilazodone 40 mg/day is generally welltolerated during up to 52 weeks of treatment. In the 8-week studies, themost common TEAEs associated with vilazodone occurring at least attwice the rate as with placebo were diarrhea, nausea, and insomnia, whichare commonly reported with serotonergic medications. TEAEs were typ-ically mild to moderate and most patients did not require directed treat-ment with concomitant medications. Most diarrhea and/or nausea firstoccurred during the initial 2 weeks of titration and were not a cause forstudy discontinuation. Similarly, the percentage of subjects who experi-enced an SAE while taking vilazodone was low, and there was no appar-ent pattern to SAEs based on SOC or preferred term.

No clinically concerning effect of vilazodone on laboratory test resultsor vital signs was observed. Changes from baseline in SBP, DBP, andpulse were similar between the vilazodone and placebo groups in the



30Liebowitz, Croft,

Kajdasz, et al.


8-week studies and incidences of PCS high or low values during bothshort- and long-term treatment were low in the vilazodone groups withall incidence rates �0.5% in the 8-week studies and �0.8% in the 52-week study. Change in weight with vilazodone in the 8-week studieswas the same as that with placebo (0.2 kg). Mean weight change in the52-week study was 1.0 kg for the safety population and 1.7 kg for thesubset of patients completing the study, which compares favorably withaverage gains of 6.8 to 10.8 kg reported after 6 to 12 months of therapywith other SSRIs.22 However, the 15.4% of patients who experienceda �7% increase in body weight during up to 1 year of exposure suggeststhat a subset of patients may be prone to weight gain. Further study isneeded to determine whether this weight gain is a direct result of vila-zodone treatment or an indirect result of clinical improvement.

Vilazodone did not demonstrate any clinically significant effects onECG parameters or any signal of proarrhythmic potential. This findingis consistent with those from a phase 1, thorough QT study designed tomore rigorously evaluate the effects of supertherapeutic doses of vila-zodone on the ECG compared with placebo and moxifloxacin.22

Evaluations of drug class effects were specifically conducted for suici-dality, serotonin toxicity, and activation of mania/hypomania. The find-ings for these topics were not of clinical concern and were consistentwith those for other antidepressants.

Understanding the impact of vilazodone on sexual function based oninterpretation of currently available data is challenging. Results from bothAE reporting and scale data suggest a differential effect by sex associatedwith vilazodone treatment. Men were more likely to experience AEsassociated with sexual functioning and less overall improvement based onscale results when compared with women. Further studies with appropri-ate active comparators are needed to determine whether the impact ofvilazodone on sexual function is benign or at least less severe than that ofother antidepressants known to negatively impact sexual function.

It should be noted that the safety profiles for the 8-week and 52-weekstudies were similar. No new safety findings or concerns emerged dur-ing the 52-week study compared with the 8-week studies, and nolonger-term safety concerns were identified.

This work summarizes phase 3 information from both short- andlonger-term vilazodone use, all at the indicated dose of 40 mg qd.Although a considerable number of patients (n � 2177; 551.7 subjectyears of exposure) were studied, with any safety assessment the abilityto detect or to find signals for rare AEs is limited. Only a small per-centage of patients were �65 years of age; therefore, findings may notaccurately reflect the safety and tolerability profile of vilazodone in theelderly. Nevertheless, the findings presented here support that vila-





zodone is generally well tolerated during both short-term and long-term treatment of MDD in adults.✤

ACKNOWLEDGMENTS

The authors acknowledge the writing and editorial assistance provided byNorma Padilla, PhD, an employee of ApotheCom (supported by fundingfrom Dogwood Pharmaceuticals, a subsidiary of Forest Laboratories,Inc.), in the development and submission of this manuscript.

AUTHOR DISCLOSURES

M. Liebowitz—Equity: Pherin Pharmaceuticals and Liebowitz SocialAnxiety Scale; Consultancy: AstraZeneca, Pfizer, Takeda, Pherin, Otsuka,and Eisai; Speaker: Wyeth, Pfizer, and Pherin Pharmaceuticals; Licensingsoftware or LSAS: GlaxoSmithKline, Pfizer, Avera, Tikvah, Endo, Eli Lilly,Indevus, and Servier; Clinical Trial Contracts: Pfizer, GlaxoSmithKline,AstraZeneca, Forest, Tikvah, Avera, Eli Lilly, Novartis, Sepracor, Horizon,Johnson & Johnson, Allergan, PGX Health, Abbott, Jazz, MAP, Takeda,Wyeth, Cephalon, Indevus, Endo, Ortho-McNeil, Gruenthal, PurduePharma, and Lundbeck; Investigator-Initiated Trial Support: Pfizer.

H.A. Croft—Research Grants: Croft Research Center from Boehringer-Ingelheim, Bristol-Myers-Squibb, Cephalon, Forest, GlaxoSmithKline,Eli Lilly, Labopharm, Merck, Organon, Otsuka, Pfizer, sanofi-aventis,and Takeda; Speaking Honoraria: AstraZeneca, Bristol-Myers Squibb,Forest, GlaxoSmithKline, Eli Lilly, Angelini-Labopharm, Pfizer, Sanofi-Aventis, and Wyeth; Consultancy: Forest, GlaxoSmithKline, Clin Data,Forest, Eli Lilly, and Pfizer; Advisory Board: GlaxoSmithKline, Clin Data,Forest, Eli Lilly, and Pfizer.

D.K. Kajdasz, H. Whalen, S. Gallipoli, M. Athanasiou, and C.R. Reedare all former employees of Dogwood Pharmaceuticals, a subsidiary ofForest Laboratories, Inc.

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