JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 28, Number 1, 2018

Mary Ann Liebert, Inc.
Pp. 55–65
DOI: 10.1089/cap.2017.0099

Desvenlafaxine Versus Placebo in the Treatment

of Children and Adolescents with Major Depressive Disorder

Sarah Atkinson, MD,1 Shannon Lubaczewski, PharmD, MS,2 Sara Ramaker, BA,2
Richard D. England, MD, PhD,3 Dalia B. Wajsbrot, MSc,4
Richat Abbas, PhD,2 and Robert L. Findling, MD, MBA5

Abstract
Objective: To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and
adolescents with major depressive disorder (MDD).
Methods: Outpatient children (7–11 years) and adolescents (12–17 years) who met DSM-IV-TR criteria for MDD and had
screening and baseline Children’s Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8
weeks of treatment with placebo, low exposure desvenlafaxine (20, 30, or 35 mg/day based on baseline weight), or higher
exposure desvenlafaxine (25, 35, or 50 mg/day based on baseline weight). The primary efficacy endpoint was change from
baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy
assessments included Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement scales. Safety
assessments included adverse events and the Columbia-Suicide Severity Rating Scale.
Results: The safety population included 363 patients (children, n = 109; adolescents, n = 254). No statistical separation from
placebo was observed for either desvenlafaxine group for CDRS-R total score or for any secondary efficacy endpoint. At week
8, adjusted mean (standard error) changes from baseline in CDRS-R total score for the desvenlafaxine low exposure,
desvenlafaxine high exposure, and placebo groups were -23.7 (1.1), -24.4 (1.1), and -22.9 (1.1), respectively. The incidence
of adverse events was similar among groups.
Conclusion: Low and high exposure desvenlafaxine groups did not demonstrate efficacy for the treatment of MDD in children
and adolescents in this double-blind, placebo-controlled trial. Desvenlafaxine (20–50 mg/day) was generally safe and well
tolerated with no new safety signals identified in pediatric patients with MDD in this study.

Keywords: desvenlafaxine, major depressive disorder, treatment efficacy, clinical trial, children, adolescents

Introduction man et al. 1999; Fergusson and Woodward 2002; Marmorstein 2009;
Edwards et al. 2014). To address the significant morbidity and mor-

M ajor depressive disorder (MDD) is a primary cause of

disability in the United States, with prevalence rates of up to
*8% in adolescents and 2.5% in children (Birmaher et al. 1996).
tality associated with depression, the US Preventive Services Task
Force recommends screening for MDD in all pediatric patients 12–18
years of age (Siu 2016).
Depression in youth can substantially impair trajectories of de- Practice guidelines recommend antidepressant therapy, psycho-
velopment and overall quality of life (Siu 2016). Pediatric de- logical intervention, or both, for the treatment of children and ad-
pression can negatively impact social and family relationships, and olescents with moderate to severe depression (Birmaher et al. 2007;
frequently disrupts academic performance and activities (Puig- Cheung et al. 2007). The efficacy and safety of various selective
Antich et al. 1993; Birmaher et al. 1996, 2007; Fergusson and serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine
Woodward 2002). Furthermore, pediatric patients with depres- reuptake inhibitors (SNRIs) have been studied in pediatric patients
sion are at risk for substance abuse, suicidal behavior, medical with MDD (Emslie et al. 1997, 2007, 2009, 2014; Wagner et al. 2003,
and psychiatric hospitalization, and recurrence of depression (Weiss- 2004; Atkinson et al. 2014); however, only the SSRIs fluoxetine
1
Finger Lakes Clinical Research, Rochester, New York.
2
Pfizer Inc, Collegeville, Pennsylvania.
3
Pfizer Inc, Groton, Connecticut.
4
Pfizer Inc, New York, New York.
5
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University and Kennedy Krieger Institute, Baltimore, Maryland.
ª Sarah Atkinson et al. 2017; Published by Mary Ann Liebert, Inc. This article is available under the Creative Commons License CC-BY-NC (http://
creativecommons.org/licenses/by-nc/4.0). This license permits non-commercial use, distribution and reproduction in any medium, provided the original
work is properly cited. Permission only needs to be obtained for commercial use and can be done via RightsLink.

55
56 ATKINSON ET AL.

and escitalopram are approved in the United States for the treatment treatment of children and adolescents with MDD. Patients who
of MDD in children ‡8 years of age (fluoxetine) and adolescents completed this acute-phase study were eligible to participate in a
12–17 years of age (escitalopram) (Prozac Package Insert, 2014; 6-month, open-label extension study of desvenlafaxine. Eligible
Lexapro Package Insert, 2014). Currently available antidepressants patients were randomly assigned (1:1:1) to placebo, desvenlafaxine
may not be safe and effective for all children and adolescents with low exposure (based on body weight at baseline), or desvenlafaxine
MDD; thus, there is an unmet need for additional treatment options. higher exposure (based on body weight at baseline) arms, and
Desvenlafaxine (administered as desvenlafaxine succinate) is an stratified by age group (child [7–11 years] or adolescent [12–17
SNRI approved for the treatment of adults with MDD at the re- years]) and country. (Country was not included as a factor in sta-
commended therapeutic dose of 50 mg/day (Pristiq Package Insert, tistical analyses because only one subject was enrolled in Chile.)
2016). Treatment with desvenlafaxine doses lower than 50 mg has Eligible patients received 8 weeks of double-blind treatment. Pa-
not demonstrated significant clinical benefit versus placebo in adults tients not continuing into the extension study completed a 1-week
(Iwata et al. 2013; Liebowitz et al. 2013). The safety and tolerability blinded treatment taper.
of desvenlafaxine in children and adolescents with MDD were as-
sessed in a small, 8-week, open-label, fixed-dose phase 2 study Study treatment
(Findling et al. 2014). Desvenlafaxine doses ranging from 10 to
The selection of doses was based on two factors: first, the highest
200 mg/day were generally safe and well tolerated in that study.
dose used in the study was 50 mg/day because no efficacy benefit
Although efficacy endpoints were exploratory, children and ado-
has been demonstrated at doses higher than 50 mg/day in adults and
lescents treated with desvenlafaxine demonstrated improvements
tolerability decreases at doses higher than 50 mg/day (Thase et al.
from baseline in depressive symptoms assessed using the Children’s
2009). Second, pharmacokinetic data from a phase 2a study in
Depression Rating Scale-Revised (CDRS-R) (Poznanski et al. 1985)
pediatric patients with MDD have shown that desvenlafaxine ex-
total score (Findling et al. 2014). However, the study did not include
posure may be predicted by body weight in this population (Find-
a placebo control group for comparison. Improvements observed at
ling et al. 2016). Therefore, dosing for low and high desvenlafaxine
the end of the 8-week open-label study appeared to be maintained
exposure groups in this study was based on each patient’s body
among children and adolescents who participated in the 6-month,
weight at baseline, starting at 50 mg/day for the highest body
flexible-dose extension study (Findling et al. 2014). To further as-
weight group in the ‘‘high exposure’’ desvenlafaxine arm. For the
sess the efficacy and safety of desvenlafaxine in pediatric patients
‘‘high exposure’’ desvenlafaxine group, patients weighing 20 to
with MDD, the sponsor (Pfizer, Inc.) planned a total of four phase 3
<35 kg, 35 to <70 kg, and >70 kg at baseline received desvenla-
studies, including two short-term and two corresponding 6-month
faxine doses of 25, 35, and 50 mg, respectively. Patients in the ‘‘low
extension studies. Pharmacokinetic data obtained using desvenla-
exposure’’ desvenlafaxine group received desvenlafaxine doses of
faxine doses ranging from 10 to 200 mg in the phase 2 study
20, 25, and 35 mg, respectively. Patients received a titration dose
(Findling et al. 2016) served as the basis for informing the des-
during the first week on-therapy. Desvenlafaxine dosing during
venlafaxine exposure levels studied in the phase 3 studies.
titration, treatment, and taper (when applicable) are provided in
This study (NCT01371734) is the second of two similar short-term,
Supplementary Table S1 (Supplementary Data are available online
double-blind, placebo-controlled studies of desvenlafaxine for the
at www.liebertpub.com/cap).
treatment of pediatric patients with MDD. Findings from the first of
these short-term studies (NCT01372150) have been published (Weihs
Study patients
et al. 2017), and results of the extension studies will be reported sep-
arately. The objectives of this study were to evaluate the efficacy, Eligible study participants were male and female outpatients ‡7 to
safety, and tolerability of desvenlafaxine in the treatment of children <18 years of age who weighed ‡20 kg at the screening and baseline
and adolescents with MDD. An additional objective was to evaluate the visits. All enrolled patients met Diagnostic and Statistical Manual of
population pharmacokinetics of desvenlafaxine in children and ado- Mental Disorders, Fourth Edition (Text Revision) criteria for MDD
lescents with MDD; results of that analysis will be reported separately. as the primary diagnosis, as assessed by the Schedule for Affective
Disorders and Schizophrenia for School-Age Children–Present and
Methods Lifetime Version (Kaufman et al. 1997) [K-SADS-PL] and clinical
interview. A comprehensive diagnostic psychiatric evaluation, in-
Patients were randomized at 33 sites in the United States and
cluding collection of psychiatric history and treatments and confir-
Chile. Principal investigators were child and adolescent, or general
mation of the MDD diagnosis, was performed by a psychiatrist at
psychiatrists with experience in the diagnosis and treatment of pe-
screening. Enrolled patients were required to have at least moder-
diatric depression and in conducting industry-sponsored studies. The
ately severe depressive symptoms for ‡30 days before screening, and
study was conducted from August 2011 to September 2015 in ac-
a CDRS-R score >40 and Clinical Global Impressions-Severity scale
cordance with the International Council for Harmonisation Guideline
(CGI-S) (Guy 1976) score ‡4 at screening and baseline. Eligible
for Good Clinical Practice (International Council for Harmonisation
patients were judged, in the investigator’s opinion, to be likely to
1998) and the ethical principles that have their origin in the De-
respond to antidepressant therapy without the need for concomitant
claration of Helsinki. The study protocol and any amendments re-
psychotherapy.
ceived institutional review board or independent ethics committee
Key exclusion criteria included history or presence of MDD with
approval. Written informed consent and assent were obtained
psychotic features or any psychotic disorder, bipolar disorder (or
from legal guardians and study participants, respectively, before
first-degree relative with bipolar disorder), manic episodes or other
any protocol-required procedures were performed.
comorbid primary psychiatric conditions, or high risk of suicide
(including first-degree relative who committed suicide). Detailed
Study design
exclusion criteria and prohibited treatments are listed in Supple-
This was a phase 3, multicenter, randomized, double-blind, mentary Data S1. Nonpsychopharmacologic drugs with psycho-
placebo-controlled, parallel-group study of desvenlafaxine in the tropic effects were permitted if the patient had been taking a stable
DESVENLAFAXINE IN PEDIATRIC MDD 57

dose for at least 90 days before study baseline. Previous formal randomized subjects would fail to qualify for the primary analysis.
psychotherapy for MDD was allowed only if it occurred more than Based on findings from a planned interim analysis (Supplementary
30 days before screening. Supportive nonbehavioral psychother- Data S2), the sample size was increased from N = 333 to N = 360
apy, family therapy, counseling, or play therapy with a focus other (i.e., nine participants added to each treatment group).
than on depressive symptoms were also permitted, provided that no
changes in intensity or frequency were made within 90 days before Efficacy. Efficacy evaluations were conducted in the intent-
study baseline and no change was anticipated for the duration of the to-treat (ITT) population, defined as all patients who were ran-
study. domly assigned to treatment, received at least one dose of study
drug, and had a baseline and at least one postbaseline primary
Study assessments efficacy assessment. Change from baseline in CDRS-R (primary
analysis) was assessed using a mixed-effects model for repeated
Efficacy. The primary efficacy outcome was change from
measures (MMRM) with terms for treatment, week, interaction of
baseline in CDRS-R total score at week 8. Total scores on the 17-
treatment and week, age group, gender, and baseline CDRS-R
item CDRS-R scale range from 17 to 113, with lower scores indi-
score. Change from baseline in CGI-S score was assessed using the
cating lower symptom intensity. Other efficacy outcomes included
same approach as used with the CDRS-R total score. A Hochberg
change from baseline in CGI-S (key secondary efficacy outcome),
step-up procedure was used to control for multiplicity associated
distribution of Clinical Global Impressions-Improvement (CGI-I)
with study-wise type I error across comparisons between each
scores, and CGI-I response (defined as a CGI-I score of 1 or 2). All
desvenlafaxine treatment group and placebo. If both desvenlafax-
efficacy assessments were administered at weeks 1, 2, 3, 4, 6, and 8,
ine treatment groups had p-values £0.05, both were considered
and/or at early termination in the double-blind phase. Individuals
statistically significant; if one had a p-value >0.05 and the other had
completing the CDRS-R, CGI-S, and CGI-I were qualified, trained
a p-value £0.025, the latter desvenlafaxine treatment group alone
by the sponsor, and approved as evaluators before conducting the
was considered statistically significant. At each visit, the CGI-I was
assessments. Individuals completing the K-SADS-PL, CDRS-R,
analyzed as a categorical variable using the Cochran-Mantel-
CGI-S, and CGI-I were qualified (with a minimum of 2 years of
Haenszel row-mean-score-difference test using ridit scores, con-
clinical experience with pediatric MDD), trained by the study
trolling for age groups. Response rates at each visit, based on a
sponsor, and approved as evaluators before conducting the assess-
CGI-I score of 1 or 2, were analyzed using a logistic regression
ments. Individuals completing the CDRS-R had at least 2 years’
model with treatment and age group as factors. Sensitivity analyses
experience using the scale and were certified by the sponsor by a two-
were conducted and are described in Supplementary Data S2.
step process: raters had to (1) meet predefined inter-rater reliability
criteria against the gold standard scores using video-taped assess-
Safety. The safety population included all patients who were
ments and (2) complete a one-on-one training on CDRS-R interview
randomly assigned to treatment and received at least one dose of
technique (applied training) by the rater training vendor, achieving
study drug. The incidence of treatment-emergent adverse event
acceptable technique and reliability in accordance with prespecified
(TEAE), discontinuations due to AEs, and serious AEs were sum-
criteria using the Rater Applied Performance Scale (Kobak et al.
marized by treatment group. Vital signs, laboratory evaluations,
2005). The protocol recommended that, whenever possible, the same
ECG parameters, C-SSRS data, and Tanner assessments were
rater performed a given scale for a patient at each assessment.
summarized descriptively. The incidence rates of prespecified AEs
of clinical interest for desvenlafaxine (tier-1 AEs) were compared
Safety. Adverse events’ (AEs, MedDRA v18), vital sign as-
between treatment groups using risk difference and exact 95%
sessments’, and Columbia-Suicide Severity Rating Scale (C-SSRS)
confidence intervals.
(Posner et al. 2011) evaluations were performed at each study visit.
A physical examination with Tanner assessment and laboratory
Results
evaluations were conducted at screening and week 8, with serum
lipids and liver function tests also assessed at week 4. Electro- Study patients
cardiogram (ECG) was performed at screening, baseline, and week
Of 573 individuals screened, 363 were randomly assigned to
8. Potential clinically important (PCI) findings were identified
treatment, took at least one dose of study drug, and were included in
based on categorical changes in vital signs, ECG results, and lab-
the safety population (desvenlafaxine low exposure, n = 122; des-
oratory findings defined according to criteria prespecified by the
venlafaxine high exposure, n = 121; and placebo, n = 120) (Fig. 1).
sponsor (Supplementary Table S2).
The safety population comprised 109 children and 254 adolescents;
Individuals completing the C-SSRS and Tanner assessments
the ITT population included 109 children and 251 adolescents (total,
were qualified, trained by the study sponsor, and approved as
360 patients). A total of 59 patients discontinued treatment early
evaluators before conducting those assessments. The protocol re-
(desvenlafaxine low exposure, 19 [16%]; desvenlafaxine high ex-
commended that, whenever possible, the same rater administer the
posure, 17 [14.0%]; and placebo, 23 [19%]). Overall, the most
Tanner assessment for the patient at each study visit.
common reasons for discontinuation were AEs (19 [5.2%]) and no
longer willing to participate in the study (16 [4.4%]).
Statistical analysis The safety population was 56.5% female and median age was 14
Sample size determination. The sample size estimate was years. Mean (SD) CDRS-R total score at baseline was 58.09 (9.19),
conducted for the change from baseline in CDRS-R total score at reflecting moderately severe depression; baseline CDRS-R total
week 8. It was estimated that 111 participants per treatment arm scores ranged from 40 to 87 (one child with a baseline CDRS-R
(N = 333) was sufficient to demonstrate a 5-point difference in the total score equal to 40 was enrolled; the child was excluded from
primary endpoint between the desvenlafaxine and placebo groups the per-protocol population analysis due to the violation). Patient
at a significance level of 5% and a power of 85%, assuming a demographics and baseline clinical characteristics were similar
pooled standard deviation (SD) of 12, and that no more than 5% of among treatment groups (Table 1). Overall, 24.8% (90) of patients
 FIG. 1. Study flow and patient disposition ITT. ITT, intent-to-treat.

Table 1. Demographic and Baseline Characteristics by Treatment and Age Group, Safety Population

Treatment Age group

Desvenlafaxine Desvenlafaxine
Placebo low exposure high exposure Children Adolescents
(n = 120) (n = 122) (n = 121) (n = 109) (n = 254)

Age, mean (SD), years 13.15 (2.68) 13.07 (2.80) 12.87 (3.01) 9.36 (1.32) 14.61 (1.55)
Sex, n (%)
Female 60 (50.0) 69 (56.56) 76 (62.81) 46 (42.20) 159 (62.60)
Male 60 (50.0) 53 (43.44) 45 (37.19) 63 (57.80) 95 (37.40)
Race, n (%)
Asian 1 (0.83) 1 (0.82) 0 0 2 (0.79)
Black 25 (20.83) 31 (25.41) 33 (27.27) 40 (36.70) 49 (19.29)
White 85 (70.83) 86 (70.49) 78 (64.46) 59 (54.13) 190 (74.80)
Other 9 (7.50) 4 (3.28) 10 (8.26) 10 (9.17) 13 (5.12)
Ethnic origin, n (%)
Hispanic/Latino 18 (15.0) 23 (18.85) 18 (14.88) 18 (16.51) 41 (16.14)
Not Hispanic/Latino 102 (85.0) 99 (81.15) 103 (85.12) 91 (83.49) 213 (83.86)
Height, mean (SD), cm 159.43 (12.68) 158.26 (13.18) 155.80 (14.60) 141.92 (9.61) 164.65 (8.24)
Weight, mean (SD), kg 61.39 (22.18) 58.04 (19.96) 59.82 (24.12) 41.94 (14.18) 67.38 (20.48)
BMI, mean (SD), kg/m2 23.64 (6.38) 22.64 (5.45) 23.96 (7.29) 20.46 (5.38) 24.68 (6.43)
Duration of current episode, 12.85 (12.10) 11.23 (11.21) 12.42 (13.24) 11.39 (11.01) 12.50 (12.68)
mean (SD), months
Baseline CDRS-R total score, 57.28 (8.94) 58.52 (9.18) 58.45 (9.45) 56.43 (8.73) 58.80 (9.30)
mean (SD)
Baseline CGI-S score, mean (SD) 4.55 (0.58) 4.61 (0.61) 4.61 (0.58) 4.59 (0.58) 4.59 (0.59)

BMI, body mass index; CDRS-R, Children’s Depression Rating Scale-Revised; CGI-S, Clinical Global Impressions-Severity; SD, standard deviation.

58
DESVENLAFAXINE IN PEDIATRIC MDD 59

in the safety population had a psychiatric condition other than for children (7–11 years) and adolescents (12–17 years) across
MDD in their medical history, and the percentages of patients treatment groups (Supplementary Fig S1).
across treatment groups were 27.3%, 23.0%, and 24.2% in the
desvenlafaxine high exposure, desvenlafaxine low exposure, and Secondary efficacy endpoints. The results based on CGI-S
placebo groups, respectively. The most common psychiatric con- and CGI-I scores for the desvenlafaxine groups versus placebo
ditions (reported in >5% of patients) included ADHD (high expo- were generally consistent with those for the CDRS-R total score,
sure, 9.9%; low exposure, 9.8%; and placebo, 7.5%), self-injurious with no statistically significant differences observed (Table 2).
behavior (high exposure, 9.1%; low exposure, 4.9%; and placebo, Although the proportion of responders were numerically higher
6.7%), and insomnia (high exposure, 5.8%; low exposure, 7.4%; in the desvenlafaxine groups (desvenlafaxine low exposure, 56.2%,
and placebo, 4.2%). A total of 13 (3.6%) patients in the safety and desvenlafaxine high exposure, 62.3%) compared with placebo
population received some type of supportive therapy (e.g., psy- (placebo, 55.9%), there were no statistically significant differences
chotherapy, behavioral therapy, family therapy, or counseling) between groups in the proportion of patients who were much im-
during study participation (desvenlafaxine high exposure, 5.0%; proved or very much improved at week 8 LOCF.
desvenlafaxine low exposure, 1.6%; and placebo, 4.2%). In 3 of
these 13 subjects, the supportive therapy was prohibited per pro- Safety and tolerability
tocol, as the therapy was focused on the patient’s depressive Adverse events. A total of 235/363 (64.7%) patients expe-
symptoms. Those patients were noted as having protocol deviation rienced 1 or more AE during the on-therapy period (desvenlafaxine
in the study report. low exposure, 81 [66.4%]; desvenlafaxine high exposure, 81
[66.9%]; and placebo, 73 [60.8%]). Most AEs were mild or mod-
Efficacy erate in severity. Moderate AEs considered by the investigator to be
Children’s Depression Rating Scale-Revised. At week 8, related to study medication were reported by 43 patients (desven-
the adjusted mean (standard error) changes from baseline in CDRS- lafaxine low exposure, 17 [13.9%]; desvenlafaxine high exposure,
R score were -23.7 (1.1), -24.4 (1.1), and -22.9 (1.1) for the 14 [11.6%]; and placebo, 12 [10.0%]). A total of two patients, both
desvenlafaxine low exposure, desvenlafaxine high exposure, and in the desvenlafaxine low exposure group, reported severe AEs that
placebo groups, respectively. The adjusted mean difference versus were considered by the investigator to be related to study treatment
placebo (95% CI) in change from baseline in CDRS-R score at (tension headache and initial insomnia [adolescent]; and suicide
week 8 did not differ statistically from placebo for either the des- attempt [adolescent]). The patient who made the suicide attempt
venlafaxine low exposure (0.85 [-2.23, 3.94]) or desvenlafaxine (involving overdose of amitriptyline prescribed to a relative) was
high exposure (1.52 [-1.56, 4.61]) groups (Fig. 2). Overall, the treated in the emergency department, admitted to the intensive care
profile of change from baseline in CDRS-R score during the course unit for observation, and then transferred to an in-patient psychi-
of the 8-week treatment phase was similar for the three treatment atric facility. Study drug was stopped after the event, and the patient
groups. Point differences were statistically significant between the was stabilized on treatment with sertraline.
desvenlafaxine low exposure group and placebo group at week 3 Overall, 17 patients (4.7%) experienced AEs resulting in dis-
( p = 0.013), and between the desvenlafaxine high exposure group continuation (6 children and 11 adolescents), including 7 patients
and placebo group at week 3 ( p = 0.034). For all other time points (5.7%) in the desvenlafaxine low exposure group (palpitations, liver
(weeks 1, 2, 4, 6, and 8), no statistically significant differences were function test abnormal, sedation, aggression, hypomania, irritabil-
found between the active groups and placebo. Results were similar ity, and suicide attempt); 3 patients (2.5%) in the desvenlafaxine

FIG. 2. Adjusted mean (SE) change from baseline in CDRS-R score in children and adolescents; MMRM analysis, ITT population.
*p = 0.013, desvenlafaxine low exposure versus placebo; p = 0.034, desvenlafaxine high exposure versus placebo. Adjusted mean
difference vs placebo (95% CI), week 8: desvenlafaxine low exposure, 0.85 (-2.23, 3.94); desvenlafaxine high exposure, 1.52 (-1.56,
4.61). CDRS-R, Children’s Depression Rating Scale-Revised; MMRM, mixed-effects model for repeated measures; SE, standard error.
60 ATKINSON ET AL.

Table 2. Summary of Secondary Efficacy Outcomes at Week 8, Intent-to-Treat Population

Adjusted mean Difference in adjusted

CGI-S N change (SE) means (placebo active) 95% CI p

Placebo 102 -1.49 (0.11)

Desvenlafaxine low exposure 105 -1.51 (0.11) 0.015 -0.29, 0.32 0.923
Desvenlafaxine high exposure 106 -1.65 (0.11) 0.161 -0.14, 0.47 0.302

Very much Much Minimally No change CMH test

CGI-Ia N improved (%) improved (%) improved (%) (%) p-value

Placebo 102 22 (21.6) 35 (34.3) 29 (28.4) 16 (15.7)

Desvenlafaxine low exposure 105 20 (19.0) 39 (37.1) 26 (24.8) 19 (18.1) 0.696
Desvenlafaxine high exposure 106 27 (25.5) 39 (36.8) 23 (21.7) 16 (15.1) 0.462

CGI-I responseb Proportion responders % Adjusted odds ratio Wald 95% CI p

Placebo 57/102 55.9

Desvenlafaxine low exposure 59/105 56.2 0.97 0.56, 1.69 0.925
Desvenlafaxine high exposure 66/106 62.3 0.76 0.44, 1.33 0.342
a
CGI-I scored as 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much
worse; 1 patient in each desvenlafaxine group scored 5 at week 8 and no patient scored 6 or 7 at week 8.
b
CGI-I response was defined as CGI-I score of 1 (very much improved) or 2 (much improved).
CGI-I, Clinical Global Impressions-Improvement; CGI-S, Clinical Global Impressions-Severity; CI, confidence interval; CMH, Cochran-Mantel-
Haenszel; SE, standard error.

high exposure group (mydriasis, suicidal ideation, and dermatitis in Supplementary Table S4]). A total of 39/360 (10.8%) patients had
allergic); and 7 patients (5.8%) in the placebo group (anxiety, de- treatment-emergent suicidal ideation, and two patients (0.6%) also
pression, oppositional defiant disorder, screaming, and dermato- had treatment-emergent suicidal behavior. Both suicidal behavior
myositis). events were categorized as actual attempt, one reported in a placebo-
treated adolescent and the other in an adolescent treated with low
Treatment-emergent adverse events. TEAEs were re- exposure desvenlafaxine (Supplementary Table S4). The desvenla-
ported by 81 patients (66.4%) in the desvenlafaxine low exposure faxine low exposure-treated patient was discontinued due to a serious
group, 81 patients (66.9%) in the desvenlafaxine high exposure AE of suicide attempt, and the placebo-treated patient remained in
group, and 73 patients (60.8%) in the placebo group. The most the study as described above (‘‘Deaths and SAEs’’ section).
common TEAEs reported by at least 5% in any treatment group are New-onset self-injurious behavior without suicidal intent was
summarized by age group in Table 3. No statistically significant reported for one patient (0.8%) in the desvenlafaxine low exposure
differences were observed between desvenlafaxine low exposure, group, one patient (0.8%) in the desvenlafaxine high exposure
desvenlafaxine high exposure, and placebo in the incidence of any group, and three patients (2.5%) in the placebo group.
tier-1 TEAE (Supplementary Table S3).
Other safety measures. A total of 202 patients had on-
Deaths and SAEs. No deaths occurred during the study. therapy PCI vital sign values (low exposure desvenlafaxine, 76/120
Seven randomized patients (1.9%) experienced SAEs: three assigned [63.3%]; high exposure desvenlafaxine, 66/121 [54.5%]; and pla-
to the desvenlafaxine low exposure group (aggression [child; dis- cebo, 60/119 [50.4%]). Upon data review by the medical monitor,
continued]; homicidal ideation and suicidal ideation [adolescent; PCI vital sign findings in 43 patients were considered to be clini-
events occurred after last on-therapy dose, discontinued]; and suicide cally important. The most common clinically important findings
attempt [adolescent; discontinued, as described above]), one as- were postural hypotension (desvenlafaxine low and high exposure,
signed to the desvenlafaxine high exposure group (appendicitis and n = 14 each; and placebo, n = 9), weight gain (desvenlafaxine low
abscess [adolescent; temporarily discontinued for treatment]), and exposure, n = 1; desvenlafaxine high exposure, n = 3; and placebo,
three assigned to placebo (suicidal ideation [adolescent; event oc- n = 1), weight loss (desvenlafaxine low exposure, n = 2; desvenla-
curred after last on-therapy dose, discontinued], dermatomyositis faxine high exposure, n = 1; and placebo, n = 1), and abnormal
[adolescent; discontinued], and suicide attempt and suicidal ideation blood pressure (desvenlafaxine low and high exposure, n = 1 each).
[adolescent]; suicide attempt involving ibuprofen overdose with Mean changes from baseline in vital signs and weight are reported
vomiting, no change to study drug during the event, recovered from by age group in Table 5.
suicide attempt, and study drug stopped *1 week later due to in- Expected shifts associated with development assessed by Tanner
sufficient response; suicidal ideation occurred after the patient staging were observed during the study. No clinically important
stopped taking study drug, hospitalized]). ECG findings were reported, and no clinically meaningful differ-
ences between treatment groups were observed.
Suicidality. Treatment-emergent suicidal ideation or suicidal A total of 253 patients had at least 1 on-therapy PCI laboratory
behavior, which included both new onset and worsening suicidal test result (low exposure desvenlafaxine, 86/117 [73.5%]; high
ideation or behavior, was reported for 39 (10.8%) of 360 patients who exposure desvenlafaxine, 87/116 [75.0%]; and placebo, 80/115
had a C-SSRS assessment at baseline and at 1 or more postbaseline [69.6%]). Of these, clinically important changes in laboratory
time points (Table 4 [treatment-emergent events; full data presented findings were observed in 18 patients, including 11 patients in the
 Table 3. Number (%) of Patients Reporting Treatment-Emergent Adverse Events with Incidence ‡5%
in Any Treatment Group, On-Therapy Period, Safety Population

Children Adolescents Overall

Desvenlafaxine Desvenlafaxine Desvenlafaxine Desvenlafaxine Desvenlafaxine Desvenlafaxine
Placebo low exposure high exposure Placebo low exposure high exposure Placebo low exposure high exposure
(n = 36) (n = 37) (n = 36) (n = 84) (n = 85) (n = 85) (n = 120) (n = 122) (n = 121)

Any TEAE 21 (58.3) 24 (64.9) 24 (66.7) 52 (61.9) 57 (67.1) 57 (67.1) 73 (60.8) 81 (66.4) 81 (66.9)
Abdominal pain, upper 4 (11.1) 3 (8.1) 5 (13.9) 5 (6.0) 4 (4.7) 6 (7.1) 9 (7.5) 7 (5.7) 11 (9.1)
Accidental overdose 1 (2.8) 0 2 (5.6) 0 0 1 (1.2) 1 (0.8) 0 3 (2.5)
Aggression 0 2 (5.4) 0 0 0 0 0 2 (1.6) 0
Blood triglycerides increased 0 2 (5.4) 0 0 0 0 0 2 (1.6) 0
Cough 2 (5.6) 1 (2.7) 1 (2.8) 3 (3.6) 1 (1.2) 2 (2.4) 5 (4.2) 2 (1.6) 3 (2.5)
Decreased appetite 1 (2.8) 0 3 (8.3) 5 (6.0) 6 (7.1) 3 (3.5) 6 (5.0) 6 (4.9) 6 (5.0)
Diarrhea 0 2 (5.4) 2 (5.6) 2 (2.4) 1 (1.2) 1 (1.2) 2 (1.7) 3 (2.5) 3 (2.5)

61
Dizziness 0 1 (2.7) 0 3 (3.6) 4 (4.7) 6 (7.1) 3 (2.5) 5 (4.1) 6 (5.0)
Dysmenorrheaa 0 0 0 1 (2.1) 1 (1.8) 4 (7.1) 1 (1.7) 1 (1.4) 4 (5.3)
Fatigue 1 (2.8) 2 (5.4) 2 (5.6) 1 (1.2) 2 (2.4) 7 (8.2) 2 (1.7) 4 (3.3) 9 (7.4)
Feeling jittery 0 0 2 (5.6) 0 1 (1.2) 2 (2.4) 0 1 (0.8) 4 (3.3)
Viral gastroenteritis 2 (5.6) 0 1 (2.8) 0 2 (2.4) 2 (2.4) 2 (1.7) 2 (1.6) 3 (2.5)
Headache 2 (5.6) 8 (21.6) 5 (13.9) 13 (15.5) 14 (16.5) 20 (23.5) 15 (12.5) 22 (18.0) 25 (20.7)
Insomnia 0 (0) 3 (8.1) 3 (8.3) 1 (1.2) 4 (4.7) 1 (1.2) 1 (0.8) 7 (5.7) 4 (3.3)
Nausea 2 (5.6) 2 (5.4) 4 (11.1) 5 (6.0) 10 (11.8) 10 (11.8) 7 (5.8) 12 (9.8) 14 (11.6)
Nasopharyngitis 1 (2.8) 3 (8.1) 1 (2.8) 1 (1.2) 5 (5.9) 6 (7.1) 2 (1.7) 8 (6.6) 7 (5.8)
Psychomotor hyperactivity 0 1 (2.7) 3 (8.3) 0 0 1 (1.2) 0 1 (0.8) 4 (3.3)
Pyrexia 0 3 (8.1) 1 (2.8) 0 0 1 (1.2) 0 3 (2.5) 2 (1.7)
Skin abrasion 0 0 2 (5.6) 0 0 0 0 0 2 (1.7)
Upper respiratory tract infection 1 (2.8) 0 0 2 (2.4) 4 (4.7) 6 (7.1) 3 (2.5) 4 (3.3) 6 (5.0)
Vomiting 0 0 3 (8.3) 4 (4.8) 1 (1.2) 6 (7.1) 4 (3.3) 1 (0.8) 9 (7.4)
a
Percentage calculated using number of females as denominator.
TEAE, treatment-emergent adverse event.
62 ATKINSON ET AL.

Table 4. Summary of Treatment-Emergent Suicidal Ideation and Behavior Reported on the Columbia-Suicide
Severity Rating Scale at Any Postbaseline Assessment, Safety Population

Desvenlafaxine Desvenlafaxine
Placebo low exposure high exposure Total
(n = 119) (n = 120) (n = 121) (N = 360)

Treatment-emergent SIBa, n/N (%) 16/119 (13.4) 9/120 (7.5) 14/121 (11.6) 39/360 (10.8)
New-onset SIBb 14/107 (13.1) 9/113 (8.0) 13/108 (12.0) 36/328 (11.0)
Worsening SIBc 2/12 (16.7) 0/113 (0) 1/13 (7.7) 3/32 (9.4)
Treatment-emergent SId, n/N (%) 16/119 (13.4) 9/120 (7.5) 14/121 (11.6) 39/360 (10.8)
New-onset SIe 14/107 (13.1) 9/113 (8.0) 13/108 (12.0) 36/328 (11.0)
Wish to be dead 5 5 5 15
Nonspecific active suicidal thoughts 4 3 4 11
Active suicidal ideation with any methods 4 0 4 8
(no plan) without intent to act
Active suicidal ideation with specific plan 1 1 0 2
and intent
Worsening SIf 2/12 (16.7) 0 1/13 (7.7) 3/32 (9.4)
Shift to nonspecific active suicidal thoughts 1 0 0 1
Shift to active suicidal ideation with any methods 0 0 1 1
(no plan) without intent to act
Shift to active suicidal ideation with specific 1 0 0 1
plan and intent
Treatment-emergent SBg, n/N (%) 1/119 (0.8) 1/120 (0.8) 0/121 (0) 2/360 (0.6)
New-onset suicidal behaviorh 1/119 (0.8) 1/120 (0.8) 0/121 (0) 2/360 (0.6)
Suicide attempt 1 1 0 2
Worsening SBi 0 0 0 0

There was one poststudy suicide attempt reported as a serious adverse event that was not captured on the C-SSRS; C-SSRS was not performed
following that event. N represents the number of subjects in this analysis, that is, subjects who had a baseline and a postbaseline C-SSRS assessment.
a
Treatment-emergent SIB is defined as (1) new-onset SI or SB, (2) worsening SI or SB, or (3) postbaseline SB on subjects reporting SI at baseline.
b
New-onset SIB is defined as any SI or SB reported postbaseline on subjects who reported no SI and no SB at baseline.
c
Worsening SIB is defined as (1) shift from SI at baseline to a more severe SI postbaseline, (2) shift from SI at baseline (and no SB at baseline) to any
SB postbaseline, or (3) shift from SB at baseline to a more severe SB postbaseline
d
Treatment-emergent SI is defined as new-onset SI or worsening SI.
e
New-onset SI is defined as any SI reported postbaseline on subjects who reported no SI at baseline.
f
Worsening SI is defined as shift to a more severe SI postbaseline on subjects reporting SI at baseline.
g
Treatment-emergent SB is defined as new-onset SB or worsening SB.
h
New-onset SB is defined as any SB reported postbaseline on subjects who reported no SB at baseline.
i
Worsening SB is defined as shift to a more severe SB postbaseline on subjects reporting SB at baseline.
C-SSRS, Columbia-Suicide Severity Rating Scale; SI, suicidal ideation; SB, suicidal behavior; SIB, suicidal ideation or behavior.

desvenlafaxine low exposure group (urine protein [n = 4], triglyc- CDRS-R total score at week 8. Findings for the secondary efficacy
erides [n = 4], prolactin [n = 2], abnormal liver function tests [n = 1], endpoints (CGI-S; CGI-I) were similar to and consistent with the
and fasting glucose [n = 1]), 5 patients in the desvenlafaxine high primary (CDRS-R total score) findings. Desvenlafaxine was gen-
exposure group (urine protein [n = 4] and triglycerides [n = 1], and erally well tolerated in children and adolescents, with no new safety
2 patients in the placebo group (prolactin [n = 1] and triglycerides signals identified. Safety results were consistent with previous adult
[n = 1]). Mean changes from baseline for selected laboratory values and pediatric desvenlafaxine MDD trials.
are reported by age group Supplementary Table S5. The findings in this study are consistent with the previously
published small, open-label study in pediatric patients in which
desvenlafaxine doses of 10–100 mg/day in children (n = 27) and
Discussion
25–200 mg/day in adolescents (n = 24) were shown to be generally
In this phase 3 multicenter, randomized, double-blind, placebo- safe and well tolerated (Findling et al. 2014). Exploratory efficacy
controlled, 8-week, parallel-group study of children and adoles- findings from that study demonstrated that improvements from
cents with MDD, there was no statistically significant difference for baseline in CDRS-R at the end of the fixed-dose study were
either desvenlafaxine exposure group compared with placebo on maintained during a 6-month flexible dosing extension (Findling
the primary efficacy measure, or other efficacy measures, at week 8. et al. 2014). Results of this study are also comparable with those of
Efficacy of desvenlafaxine for treating MDD in pediatric patients a companion study (NCT01372150) that assessed the efficacy and
therefore was not demonstrated in this study. A large placebo re- tolerability of desvenlafaxine (n = 115), fluoxetine (n = 112), and
sponse was observed across all measures of efficacy; this likely placebo (n = 112) in pediatric patients with MDD (Weihs et al. 2017).
reduced the ability to detect a statistically significant difference In that study, all treatment groups (including placebo) showed im-
between the desvenlafaxine low exposure, desvenlafaxine high proved CDRS-R total scores from baseline (primary endpoint), with
exposure, and placebo groups on the primary or secondary efficacy no differences observed between groups for any of the primary or
endpoints. Patients in all treatment groups demonstrated substantial secondary efficacy endpoints due to the large placebo effect. The study
improvement from baseline in depressive symptoms based on the was deemed inconclusive with regard to desvenlafaxine efficacy,
DESVENLAFAXINE IN PEDIATRIC MDD 63

Table 5. Physical and Vital Sign Results, Mean Change from Baseline
at Final On-Therapy Evaluation, Safety Population

Children Adolescents
Desvenlafaxine Desvenlafaxine Desvenlafaxine Desvenlafaxine
Placebo low exposure high exposure Placebo low exposure high exposure
(n = 36) (n = 37) (n = 36) (n = 84) (n = 85) (n = 85)

Systolic BP, supine (mm Hg) 0.6 0.1 0.5 0.3 -0.1 -0.4
Diastolic BP, supine (mm Hg) -0.6 -0.4 1.9 0.2 0.9 0.1
Pulse, supine (beats/min) 1.5 3.7 -1.4 2.1 1.7 1.4
Systolic BP, orthostatic (mm Hg) 0.9 0.4 -0.3 -1.3 -0.6 -0.2
Diastolic BP, orthostatic (mm Hg) -0.1 2.3 -0.3 -0.1 0 0
Pulse, orthostatic (beats/min) 1.4 1.1 4.3 -2.0 1.1 2.5
Weight (kg) 1.0 0.1 0.5 0.4 -0.2 0.2
BMI (kg/m2) 0.3 -0.1 0.1 0 -0.2 -0.1
Height (cm) 0.6 0.5 0.5 0.4 1.7 0.5

BMI, body mass index; BP, blood pressure.

given that even the active comparator, fluoxetine, which has well- with MDD (Clark et al. 2012). Thus, for pediatric patients, the
established efficacy in the pediatric MDD population, also did not potential therapeutic effect of simply participating in a clinical trial
separate from placebo. may partly explain why no separation was observed for active
The mean changes in CDRS-R scores observed with desvenla- treatment (desvenlafaxine) from placebo. In addition, the study
faxine in this study (-23.7 and–24.4 for the low and high exposure protocol allowed randomization of patients who participated in
groups, respectively) are comparable with antidepressant drug re- previous psychotherapy sessions (greater than 30 days before
sponse observed in positive clinical trials of pediatric patients with screening), and also allowed other types of therapy in which the
MDD (Emslie et al. 1997, 2002, 2009; Wagner et al. 2003, 2004). focus was not on depressive symptoms (e.g., supportive nonbe-
However, the large placebo response observed in this study (-22.9) havioral psychotherapy, family therapy, counseling, or play ther-
was similar to that reported in negative or inconclusive trials of apy) as long as the intensity and frequency of sessions were stable
paroxetine (Emslie et al. 2006), duloxetine (Atkinson et al. 2014; for 90 days before treatment with no anticipated change throughout
Emslie et al. 2014), and venlafaxine (Emslie et al. 2007) for pediatric the duration of the study. However, only 13 patients (3.6%) re-
MDD, and may have influenced study outcomes. Factors associated ceived such supportive therapy.
with placebo response and potential strategies for reducing placebo This study had several limitations. The use of inclusion and ex-
response have been identified and discussed in the published litera- clusion criteria to enroll individuals without comorbid psychiatric
ture (Bridge et al. 2009; Enck et al. 2013; Rief et al. 2016). Several of conditions, other unstable medical illnesses, or a risk for suicide
those strategies, including limiting number of treatment arms, re- limited the study population to one that did not reflect the larger
quiring rater certification for the CDRS-R, and using the same rater pediatric MDD population. In addition, the inclusion of two des-
for a given patient whenever possible, were used in this trial, but it is venlafaxine arms in the study design may have increased expectation
not clear that any of these was effective. The placebo response rate of treatment success, enhancing the placebo response (Rutherford
for CGI-I in this trial (55.9%) fell in the range of placebo response and Roose 2013). This study did not include an active control to
rates reported in a review of other industry-sponsored trials for pe- provide assay sensitivity, which may have increased understanding
diatric depression (50%–60%) (Walkup 2017). of factors contributing to the efficacy outcome (Temple and Ellen-
In this study, a possible contributor to the large placebo effect berg 2000). Finally, this study did not use independent raters for
was the actual process of clinician-administration of the CDRS-R. efficacy evaluations. It may be that the use of centralized raters could
This process alone may have provided a therapeutic impact for reduce placebo response (Kobak et al. 2010), but data suggest that
patients comparable with a cognitive behavior therapy session. The rater competence and reliability may be more critical than whether
potential for psychological assessment procedures to emerge as a raters are site based or centralized (Targum et al. 2013).
therapeutic tool was described in a recent evaluation of children
with mood disorders (including MDD), who were participating in
Conclusions
clinical trials (Young et al. 2016). The authors reported significant,
clinically meaningful improvements in mood severity following In this phase 3, double-blind, placebo-controlled study, low
psychodiagnostic screening assessments (such as CDRS-R), but doses (20–35 mg/day based on baseline weight) and higher doses
before randomization or administration of study treatment (Young (25–50 mg/day based on baseline weight) of desvenlafaxine did not
et al. 2016). However, while a potential psychotherapeutic effect of demonstrate efficacy for the treatment of MDD in children and
the CDRS-R assessments may have contributed to the placebo re- adolescents. Statistically significant differences between desven-
sponse in this study, it cannot fully explain the failure of desven- lafaxine and placebo were not observed for any efficacy measure
lafaxine to separate from placebo. Several positive pediatric studies assessed. Throughout the study, similar improvements in depres-
with lower placebo response rates have also used the CDRS-R as- sive symptoms were observed in all three treatment groups, with no
sessment (Emslie et al. 1997, 2002, 2009; Wagner et al. 2003, 2004). meaningful differences observed between patients who received
Nonpharmacological interventions (i.e., psychotherapy) are desvenlafaxine versus placebo. These results, and those from a
recognized as an effective treatment option for pediatric patients similarly designed sister study (Weihs et al. 2017), provide no
64 ATKINSON ET AL.

evidence for the use of desvenlafaxine as a first-line treatment for pressive disorder. J Child Adolesc Psychopharmacol 24:180–189,
MDD in pediatric patients. Treatment with desvenlafaxine 20– 2014.
50 mg/day was generally safe and well tolerated in this study with Birmaher B, Brent D, Bernet W, Bukstein O, Walter H, Benson RS,
no new safety signals observed. The safety and tolerability profile Chrisman A, Farchione T, Greenhill L, Hamilton J, Keable H,
of desvenlafaxine was consistent with that observed in previ- Kinlan J, Schoettle U, Stock S, Ptakowski KK, Medicus J: Practice
ous clinical trials of children, adolescents, and adults with MDD parameter for the assessment and treatment of children and ado-
(Findling et al. 2014; Carrasco et al. 2016). lescents with depressive disorders. J Am Acad Child Adolesc
Psychiatry 46:1503–1526, 2007.
Clinical Significance Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J, Dahl
RE, Perel J, Nelson B: Childhood and adolescent depression: A
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PhD, at Peloton Advantage, LLC, and funded by Pfizer Inc. The e1313–e1326, 2007.
authors would like to thank the patients and family members who Clark MS, Jansen KL, Cloy JA: Treatment of childhood and adoles-
contributed their time to this study. Site investigators, coordinators, cent depression. Am Fam Physician 86:442–448, 2012.
as well as study monitors, data managers, and data analysts were Edwards AC, Joinson C, Dick DM, Kendler KS, Macleod J, Munafo
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Emslie GJ, Findling RL, Yeung PP, Kunz NR, Li Y: Venlafaxine ER
Study design: S.R., S.L., R.D.E., R.L.F., and D.W. (SAP for the treatment of pediatric subjects with depression: Results of
amendment). Study investigator: S.A. and R.L.F. Enrolled patients: two placebo-controlled trials. J Am Acad Child Adolesc Psychiatry
S.A. and R.L.F. Collection and assembly of data: S.R. and S.L. Data 46:479–488, 2007.
analysis: D.B.W. (statistical analysis). Data review: R.D.E. (med- Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE,
ical monitoring), S.L., S.R., and R.A. Data interpretation: All au- Brown E, Nilsson M, Jacobson JG: Fluoxetine for acute treatment
thors. Article preparation: All authors. Article review and revisions: of depression in children and adolescents: A placebo-controlled,
All authors. Final approval of article: All authors. randomized clinical trial. J Am Acad Child Adolesc Psychiatry 41:
1205–1215, 2002.
Disclosures Emslie GJ, Prakash A, Zhang Q, Pangallo BA, Bangs ME, March JS:
A double-blind efficacy and safety study of duloxetine fixed doses
S.A.: Receives or has received research support from Pfizer, in children and adolescents with major depressive disorder. J Child
Acadia, Allergan [Forest, Naurex, Actavis], Blackthorn, Roche, Adolesc Psychopharmacol 24:170–179, 2014.
Janseen, NIMH, SYNRX, AssureRX, Axsom, Boehringer In- Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW,
gelheim, Otsuka, and Sunovion. S.L. and S.R.: Employee of Pfizer, Carmody T, Rintelmann J: A double-blind, randomized, placebo-
Inc., and has Pfizer stock and Pfizer stock options. R.D.E., D.B.W., controlled trial of fluoxetine in children and adolescents with de-
and R.A.: Employee of Pfizer, Inc., owns Pfizer stock, and has Pfizer pression. Arch Gen Psychiatry 54:1031–1037, 1997.
stock options. R.L.F.: Receives or has received research support, Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S: Escitalopram in
acted as a consultant and/or served on a speaker’s bureau for Actavis, the treatment of adolescent depression: A randomized placebo-
Akili, Alcobra, American Academy of Child & Adolescent Psy- controlled multisite trial. J Am Acad Child Adolesc Psychiatry 48:
chiatry, American Psychiatric Press, Bracket, CogCubed, Cognition 721–729, 2009.
Group, Coronado Biosciences, Elsevier, Epharma Solutions, Forest, Emslie GJ, Wagner KD, Kutcher S, Krulewicz S, Fong R, Carpenter
Genentech, GlaxoSmithKline, Guilford Press, Ironshore, Johns DJ, Lipschitz A, Machin A, Wilkinson C: Paroxetine treatment in
Hopkins University Press, KemPharm, Lundbeck, Medgenics, children and adolescents with major depressive disorder: A ran-
Merck, NIH, Neurim, Novartis, Otsuka, PCORI, Pfizer, Physicians domized, multicenter, double-blind, placebo-controlled trial. J Am
Postgraduate Press, Purdue, Rhodes Pharmaceuticals, Roche, Sage, Acad Child Adolesc Psychiatry 45:709–719, 2006.
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