Venlafaxine Extended Release in Posttraumatic Stress Disorder

Article (PDF Available)inJournal of Clinical Psychopharmacology 26(3):259-67 · July 2006with97 Reads
DOI: 10.1097/01.jcp.0000222514.71390.c1 · Source: PubMed
Abstract
This 12-week, double-blind, multicenter trial evaluated the efficacy of venlafaxine extended release (ER), sertraline, and placebo in adult outpatients (N = 538) with a primary diagnosis of posttraumatic stress disorder (PTSD), as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, symptoms for 6 months or more and 17-item Clinician-administered PTSD Scale (CAPS-SX17) score of 60 or more. Patients were randomly assigned to receive placebo or flexible doses of venlafaxine ER (37.5-300 mg/d) or sertraline (25-200 mg/d) for 12 weeks or less. The primary outcome was the baseline-to-end point change in total CAPS-SX17 score (last observation carried forward). Secondary measures included CAPS-SX17 symptom cluster scores for reexperiencing/intrusion, avoidance/numbing, and hyperarousal; frequency of remission (CAPS-SX17 < or =20); and changes in Davidson Trauma Scale total score and symptom cluster scores for avoidance/numbing, hyperarousal, and reexperiencing/intrusion. Mean changes in CAPS-SX17 scores were -41.8, -39.4, and -33.9 for venlafaxine ER (P < 0.05 vs. placebo), sertraline, and placebo, respectively. Mean changes for venlafaxine ER, sertraline, and placebo in CAPS-SX17 cluster scores were -13.0, -11.7, and -11.0 for reexperiencing; -17.1, -16.8, and -13.7 (P < 0.05 both active treatments vs. placebo) for avoidance/numbing; and -11.8, -10.9, and -9.2 (P < 0.05 venlafaxine vs. placebo) for hyperarousal. Week 12 remission rates were venlafaxine ER 30.2% (P < 0.05 vs. placebo), sertraline 24.3%, and placebo 19.6%. The venlafaxine ER group had significantly better Davidson Trauma Scale total and cluster scores than placebo. Mean maximum daily doses were 225-mg venlafaxine ER and 151-mg sertraline. Both treatments were generally well tolerated. Study results suggest that venlafaxine ER is effective and well tolerated in the short-term treatment of PTSD.
Venlafaxine Extended Release in Posttraumatic
Stress Disorder
A Sertraline- and Placebo-controlled Study
Jonathan Davidson, MD,* Barbara O. Rothbaum, PhD,y Phebe Tucker, MD,z
Gregory Asnis, MD,x Isma Benattia, MD,k and Jeff J. Musgnung, MTk
Abstract: This 12-week, double-blind, multicenter trial evaluated the
efficacy of venlafaxine extended release (ER), sertraline, and placebo
in adult outpatients (N = 538) with a primary diagnosis of post-
traumatic stress disorder (PTSD), as defined in the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition,symptoms
for 6 months or more and 17-item Clinician-administered PTSD
Scale (CAPS-SX
17
) score of 60 or more. Patients were randomly
assigned to receive placebo or flexible doses of venlafaxine ER
(37.5300 mg/d) or sertraline (25200 mg/d) for 12 weeks or less.
The primary outcome was the baselinetoend point change in total
CAPS-SX
17
score (last observation carried forward). Secondary mea-
sures included CAPS-SX
17
symptom cluster scores for reexperiencing/
intrusion, avoidance/numbing, and hyperarousal; frequency of re-
mission (CAPS-SX
17
20); and changes in Davidson Trauma Scale
total score and symptom cluster scores for avoidance/numbing,
hyperarousal, and reexperiencing/intrusion. Mean changes in CAPS-
SX
17
scores were 41.8, 39.4, and 33.9 for venlafaxine ER ( P <
0.05 vs. placebo), sertraline, and placebo, respectively. Mean changes
for venlafaxine ER, sertraline, and placebo in CAPS-SX
17
cluster
scores were 13.0, 11.7, and 11.0 for reexperiencing; 17.1,
16.8, and 13.7 ( P < 0.05 both active treatments vs. placebo) for
avoidance/numbing; and 11.8, 10.9, and 9.2 ( P <0.05
venlafaxine vs. placebo) for hyperarousal. Week 12 remission rates
were venlafaxine ER 30.2% ( P < 0.05 vs. placebo), sertraline 24.3%,
and placebo 19.6%. The venlafaxine ER group had significantly
better Davidson Trauma Scale total and cluster scores than placebo.
Mean maximum daily doses were 225-mg venlafaxine ER and
151-mg sertraline. Both treatments were generally well tolerated.
Study results suggest that venlafaxine ER is effective and well
tolerated in the short-term treatment of PTSD.
(J Clin Psychopharmacol 2006;26:259267)
W
ith a lifetime prevalence of 7% to 12%, posttraumatic
stress disorder (PTSD) is a highly prevalent,
1–3
chronic,
1,4
and disabling
5,6
illness associated with increases
in physical symptoms and health care utilization,
7–10
as well
as substantial psychiatric comorbidity.
1,11,12
Patients with
PTSD are at increased risk for depression, alcoholism or
substance abuse, panic disorder, generalized anxiety disorder
and suicide,
1,11,12
and cooccurring medical illnesses.
13
According to the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV; American
Psychiatric Association, Washington, DC, 2000), PTSD is a
disorder that occurs after exposure to an ‘‘extreme traumatic
stressor’’ to oneself or someone close, accompanied by a
response of ‘‘fear, helplessness, or horror.’’ It is characterized
by persistent reexperiencing of intrusive and distressing
recollections of the event (reexperiencing/intrusion), avoid-
ance of cues associated with the event and ‘‘numbing of
general responsiveness’’ (avoidance/numbing), and increased
arousal (hyperarousal). The full symptom complex must be
present for at least 1 month and must cause significant distress
or impairment of social, occupational, or other areas of
functioning to fulfill the criteria for diagnosis (DSM-IV).
Although research from randomized controlled trials
has shown the efficacy of selective serotonin reuptake
inhibitors (SSRIs) in improving the symptoms of PTSD,
14 19
it appears that their efficacy may not extend to all
populations.
20
In addition, there is evidence that neuro-
transmitters other than serotonin, such as norepinephrine,
may be involved in the pathophysiology of PTSD.
21
The serotonin norepinephrine reuptake inhibitor ven-
lafaxine extended release (ER) has been studied for ame-
liorating major depressive disorder,
22,23
generalized anxiety
disorder,
24 27
social anxiety disorder,
28
panic disorder,
29
and
mixed
30
or comorbid anxiety and depression.
31
It is currently
approved in the United States for the first 4 disorders. We
report here on a large multicenter trial of venlafaxine ER in
the treatment of patients with moderate to marked symp-
toms of PTSD using sertraline, a drug that is approved in
the United States for the treatment of PTSD, as an active
comparator.
MATERIALS AND METHODS
Patient Sample
The subjects were male and female outpatients aged
18 years or older who met DSM-IV criteria for a primary
Original Contribution
Journal of Clinical Psychopharmacology
Volume 26, Number 3, June 2006 259
*Department of Psychiatry and Behavioral Sciences, Duke University
Medical Center, Durham, NC; yDepartment of Psychiatry and Be-
havioral Sciences, Emory University School of Medicine, Atlanta, GA;
zDepartment of Psychiatry, Oklahoma University Health Science Center,
Oklahoma City, OK; xDepartment of Psychiatry and Behavioral
Sciences, Albert Einstein College of Medicine/Montefiore Medical
Center, Bronx, NY and kWyeth Pharmaceuticals, Collegeville, PA.
Received January 20, 2005; accepted after revision March 20, 2006.
Address correspondence and reprint requests to Jonathan Davidson, MD,
Department of Psychiatry and Behavioral Sciences, Duke University
Medical Center, Trent Drive, 4th Floor, Room 4082B, Durham, NC
27710. E-mail: david011@mc.duke.com.
Copyright n 2006 by Lippincott Williams & Wilkins
ISSN: 0271-0749/06/2603-0259
DOI: 10.1097/01.jcp.0000222514.71390.c1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
diagnosis of PTSD based on the Structured Clinical Inter-
view for DSM-IV.
32
Additional inclusion criteria included a
score of at least 40 on the Davidson Trauma Scale (DTS);
7,33
a score of at least 60 on the 17-item Clinician-administered
PTSD Scale (CAPS-SX
17
), 1-week symptom status version;
34
PTSD symptoms for at least the previous 6 months; a negative
serum pregnancy test at screening (for women of childbearing
potential); generally good health based on medical history,
physical examination, and screening laboratory results; and
likelihood of complying with protocol.
Excluded were subjects with a decrease of more than
25% on the DTS between screening and baseline; intoler-
ance, hypersensitivity, or nonresponse to a previous adequate
trial of venlafaxine or sertraline; inability to tolerate or
respond to adequate trials of 3 or more antidepressants;
current primary major depression or panic disorder (deter-
mined using the structured Mini-International Neuropsychi-
atric Interview);
35
a current mental disorder due to a general
medical condition or history of bipolar disorder, schizophre-
nia, or other psychotic disorder; alcohol or drug abuse or
dependence within 6 months of randomization or a positive
urine drug screen; and a high risk of suicide or violence.
Additional exclusion criteria included use of any investiga-
tional drug, antipsychotic, or monoamine oxidase inhibitor
within 30 days of randomization; electroconvulsive therapy
within 3 months of randomization or likelihood of requiring
electroconvulsive therapy during the study; triptans or any
other psychoactive drug (including SSRIs or tricyclic anti-
depressants) or herbal preparation within 7 days of ran-
domization; initiation of or change in psychotherapy within
3 months of randomization; current involvement in criminal
proceedings or compensation claims related to trauma; and
for women, nursing, pregnancy, or sexual activity without
acceptable birth control.
Patients who began or received any of the prohibited
treatments described above during the study were considered
protocol deviators. These patients were evaluated by the
sponsor on a case-by-case basis for possible exclusion from
the study. Permitted medications included zaleplon or
zolpidem, 1 dose nightly as needed for insomnia, for up to
6 nights, during the 14 days after the baseline evaluation
only. The use of any alternative hypnotics required prior
approval of the sponsor. Short-term treatments for allergies,
colds, or flu were permitted, provided the medications used
had minimal psychotropic effects.
The research was conducted at 59 outpatient centers in
the United States in accordance with the Declaration of
Helsinki and its amendments. The protocol and amendments
received independent ethics committee/institutional review
board approval before the study began. Written informed
consent was obtained from all patients before study
enrollment. Once a patient was determined to be eligible
for participation in the study, he or she was randomized to
1 of 3 treatment groups in a 1:1:1 ratio.
Study Design
After a washout period of at least 7 days, patients who
met entry criteria were randomly assigned to 12 weeks of
double-blind, parallel treatment with venlafaxine ER, sertra-
line, or placebo, followed by a taper period of up to 3 weeks
and poststudy evaluation (410 days after taper). Inves-
tigators followed the protocol-specific medication dosing
guidelines for venlafaxine ER (75300 mg/d, with a lead-in
dose at baseline of 37.5 mg/d) and the within-label dosing
guidelines for sertraline for PTSD (50 200 mg/d, with a
lead-in dose at baseline of 25 mg/d) and increased the dose to
the next higher level, based on efficacy and tolerability, for
patients who did not achieve remission, which was opera-
tionally defined as a score of 20 or less on the CAPS-SX
17
.
Venlafaxine ER dosing was increased to a maximum dose of
75 mg/d at day 5, 150 mg/d at day 14, 225 mg/d at day 28,
and 300 mg/d at day 42. Sertraline dosing increased to a
maximum dose of 50 mg/d at day 5, 100 mg/d at day 14,
150 mg/d at day 28, and 200 mg/d at day 42.
Study visits took place at baseline and at the end of
study treatment weeks 1, 2, 4, 6, 8, and 12 or at the time of
discontinuation, if before week 12.
Efficacy Assessments
The primary efficacy outcome in this study was the
baselineto end point (week 12 or the time of discontin-
uation) last-observation-carried-forward (LOCF) change in
the CAPS-SX
17
, which was measured at baseline and weeks
2, 4, 6, 8, and 12. This 17-item subset of the CAPS-SX
17
assesses the 17 DSM-IV PTSD symptoms divided into the
reexperiencing, avoidance/numbing, and hyperarousal sub-
scales. Secondary efficacy outcomes included baseline
toend point changes in CAPS-SX
17
symptom cluster scores
and frequency of remission (CAPS-SX
17
20). Other sec-
ondary outcome measures included ratings from 3 clinician-
administered instruments: the Clinical Global Impression
Severity of Illness (CGI-S) Scale,
36
the Global Assessment of
Functioning (GAF; DSM-IV), and the 17-item Hamilton
Rating Scale for Depression (HAM-D
17
).
37
Patient-rated sec-
ondary outcome measures included the DTS, a 17-item scale
that evaluates the frequency and severity of PTSD symptoms
over the past week, and the Sheehan Vulnerability to the
Effects of Stress Scale (SVS),
38
a 1-item scale that evaluates
how much subjects were set back by stressful events or per-
sonal problems since their last visit.
Secondary assessments of patient-rated health out-
comes included the Quality of Life Enjoyment and Life
Satisfaction Short Form (Q-LES-Q-SF),
39
a 16-item scale
that evaluates the degree of enjoyment and satisfaction in
various areas of daily life; and the Sheehan Disability Scale
(SDS),
40
a 3-item scale that evaluates how PTSD symptoms
have disrupted patients’ work/school schedule, social life, and
family life/home responsibilities. The CGI-S, HAM-D, DTS,
and SDS were measured at baseline and weeks 2, 4, 6, 8, and
12; the Q-LES-Q-SF and SVS, at baseline and weeks 4 and
12; and the GAF, at baseline and week 12.
Safety Assessments
Adverse events (AEs) were assessed, and use of con-
comitant treatments was recorded at all visits. Measurements
to assess safety included weight at baseline and week 12, and
resting pulse rate and 2 sitting blood pressure readings at all
visits. Other evaluations included physical examination at
260 n 2006 Lippincott Williams & Wilkins
Davidson and Associates Journal of Clinical Psychopharmacology
Volume 26, Number 3, June 2006
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
baseline and week 12; blood chemistry determinations,
hematology, urinalysis, and urine toxicology at screening
and week 12; and recording of last menstrual period for
women of childbearing age.
Statistical Methods
Inferential analyses of efficacy variables were per-
formed on the intent-to-treat population, which consisted of all
randomized patients who received at least 1 dose of study
medication and had at least 1 postbaseline efficacy assess-
ment. Safety analyses were also performed on the intent-to-
treat population. For patients who discontinued before study
completion, the efficacy analyses of baseline toend point
changes were calculated using their final recorded score.
The CAPS-SX
17
total score was the primary outcome
measure, and the primary analysis compared venlafaxine ER
with placebo on the mean change in CAPS-SX
17
total score
from baseline to week 12 (LOCF). Additional planned com-
parisons were performed between the sertraline and placebo
treatment groups, and between the venlafaxine ER and
sertraline treatment groups. Last-observation-carried-forward
values at week 12 were used for analysis of CAPS-SX
17
symptom cluster scores, and LOCF values at the final visit,
defined as the last nonmissing postbaseline assessment (which,
in a few cases, occurred after week 12), were used for the
analysis of remission rates and other secondary outcomes. In
addition to the analyses based on LOCF values, the observed
changes (ie, the changes observed only for those patients who
had nonmissing values at each visit) were summarized.
Post hoc tests were performed to evaluate the effect of
baseline HAM-D
17
scores and compare effect sizes of both
active treatments and placebo on the change from baseline in
CAPS-SX
17
scores at end point, and to examine the effects of
treatment on DTS cluster scores at end point. A post hoc
analysis of the effect of treatment on SDS total score was
also conducted. Because no adjustments were made for
multiple comparisons, the P values for secondary analyses
should be interpreted with caution.
The statistical model for hypothesis testing was an
analysis of covariance on the change from baseline, with
treatment group as the main effect, and the baseline value as
the covariate, with no adjustment for center. The continuous
secondary efficacy end points were analyzed by the same
method. Categorical variables, such as the frequency of re-
mission, were analyzed using x
2
tests. The incidence of AEs
and premature discontinuations were analyzed using x
2
tests.
The sample size estimate of 525 patients was based on
attaining a power of more than 90% to detect a difference of
0.35 SD between the venlafaxine ER and placebo groups.
Statistical tests were 2-sided using the 0.05 level of
significance. Version 6.12 of the SAS System (SAS, Cary,
NC) was used for all statistical analyses.
RESULTS
Demographic and Clinical Characteristics
A total of 538 patients of the 889 patients screened for
participation met study entry criteria and were randomized to
treatment (7 of whom discontinued before receiving the
study drug). Of the 531 patients who received treatment, 350
(66%) completed the study. There were no clinically im-
portant differences between the 3 treatment groups in the
proportion of patients in each group who completed the
study. Of the 181 treated patients (34%) who withdrew from
the trial, primary reasons for early withdrawal included
failure to return (70 patients [13%]) and AEs (58 patients
[11%]). There were no clinically important differences
between the 3 treatment groups in reasons for early with-
drawal. The 3 groups also had no important differences in
baseline demographic or baseline clinical characteristics
(details available on request). Most common types of pri-
mary trauma were nonsexual abuse (26.2%), adult sexual
abuse (15.8%), childhood sexual abuse (14.9%), unexpected
death (12.6%), accidental injury (11.9%), and combat
(9.0%). One hundred fifty-four patients (86%) in each of
the venlafaxine ER and placebo groups and 140 patients
(81%) in the sertraline group received at least 1 concomitant
medication during the study. Overall, the types and
frequencies of concomitant medications received were
similar among the 3 groups. The most frequently used
concomitant medications were ibuprofen, acetaminophen,
acetylsalicylic acid, and multivitamins.
Efficacy Analysis
Results for the main primary and secondary PTSD
outcome measures at the final study end point are shown
in Table 1. Venlafaxine ER showed significantly greater
immprovement than placebo on the change in CAPS-SX
17
total score (P = 0.0147). There were no significant between-
group differences in baseline to end point changes on
reexperiencing cluster B, but the venlafaxine ER group
showed significantly greater improvement than the placebo
group on avoidance/numbing cluster C (P = 0.0208) and
hyperarousal cluster D (P = 0.0241). Venlafaxine ER
treated patients showed greater improvement than placebo-
treated patients on the final visit DTS total score (P =
0.0146) and intrusion (P = 0.0348), avoidance and numbing
(P = 0.0328), and hyperarousal clusters (P = 0.0238), as well
as in SVS score (P = 0.0208). The venlafaxine ER treated
group showed greater improvement than the placebo-treated
group on the CGI-S (P = 0.0068) but not on the GAF.
Secondary depressive symptoms also showed significantly
greater improvement with venlafaxine ER than with placebo,
as measured by HAM-D
17
total scores ( P = 0.0392).
Sertraline-treated patients showed significantly greater
improvement than placebo-treated patients on the CAPS-
SX
17
cluster C (P = 0.0325) and on the CGI-S (P = 0.0465).
Patient self-ratings of functioning, satisfaction, and
quality of life were less consistent, as shown in Table 2. At
the final visit, venlafaxine ERtreated patients showed sig-
nificantly greater improvement than placebo-treated patients
on Q-LES-Q-SF total (P = 0.0327), overall life satisfaction
(P = 0.0023), and general activities (P = 0.0288) scores. No
statistically significant differences were observed between the
3 groups in work/school or family/home subscales of the SDS,
but venlafaxine ERtreated patients showed significantly
n 2006 Lippincott Williams & Wilkins 261
Journal of Clinical Psychopharmacology
Volume 26, Number 3, June 2006 Venlafaxine ER in Posttraumatic Stress Disorder
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
TABLE 1. Change Scores and Effect Sizes for Selected Outcome Measures at End Point (LOCF)
Mean Change from Baseline (95% CI) Effect Size P
Predictors
Venlafaxine ER
(n = 179)
Sertraline
(n = 173)
Placebo
(n = 179)
Ven ER
vs. Pbo
Sert
vs. Pbo
Ven ER
vs. Sert
Ven ER
vs. Pbo
Sert
vs. Pbo
Ven ER
vs. Sert
CAPS-SX
17
Total score 41.51 (45.66 to 37.36) 39.44 (43.67 to 35.21) 34.17 (38.33 to 30.01) 0.266 0.191 0.075 0.015 0.081 0.494
Cluster scores
Reexperiencing 12.54 (13.94 to 11.14) 11.89 (13.32 to 10.47) 11.23 (12.63 to 9.83) 0.141 0.071 0.070 0.195 0.515 0.525
Avoidance 16.99 (18.85 to 15.12) 16.78 (18.68 to 14.87) 13.87 (15.74 to 12.00) 0.252 0.235 0.017 0.021 0.033 0.878
Hyperarousal 11.57 (12.92 to 10.23) 10.90 (12.27 to 9.53) 9.38 (10.73 to 8.03) 0.245 0.170 0.075 0.024 0.121 0.491
DTS
Total score 42.86 (47.56 to 38.17) 38.92 (43.69 to 34.16) 34.59 (39.27 to 29.91) 0.267 0.140 0.127 0.015 0.203 0.248
Cluster scores
Intrusion 12.77 (14.26 to 11.27) 11.11 (12.62 to 9.59) 10.44 (11.93 to 8.94) 0.236 0.068 0.168 0.031 0.534 0.127
Avoidance/numbing 17.07 (19.17 to 14.97) 15.85 (17.98 to 13.71) 13.76 (15.85 to 11.66) 0.238 0.150 0.088 0.029 0.171 0.423
Hyperarousal 12.95 (14.47 to 11.42) 11.89 (13.44 to 10.34) 10.48 (12.00 to 8.96) 0.245 0.140 0.105 0.025 0.202 0.339
SVS 2.58 (3.05 to 2.10) 2.35 (2.84 to 1.86) 1.79 (2.26 to 1.31) 0.257 0.182 0.075 0.021 0.106 0.508
CGI-S 1.60 (1.79 to 1.41) 1.51 (1.70 to 1.31) 1.23 (1.42 to 1.04) 0.296 0.220 0.076 0.007 0.046 0.492
GAF 14.16 (12.16 16.16) 13.63 (11.57 15.70) 11.41 (9.32 13.49) 0.220 0.178 0.042 0.062 0.136 0.720
HAM-D
17
* 7.09 (8.13 to 6.05) 6.42 (7.48 to 5.37) 5.54 (6.58 to 4.50) 0.224 0.128 0.096 0.039 0.244 0.379
P values are based on the pairwise comparisons from the analysis of covariance model using baseline-adjusted values, unless otherwise noted. CAPS-SX
17
total and cluster scores are from week 12.
Scores for all other outcomes are from the final visit.
CI indicates confidence interval; Ven ER, venlafaxine extended release; Sert, sertraline; Pbo, placebo.
*Analysis of variance.
262 n 2006 Lippincott Williams & Wilkins
Davidson and Associates Journal of Clinical Psychopharmacology
Volume 26, Number 3, June 2006
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
greater improvement than placebo-treated patients on the so-
cial life subscale (P = 0.0251). A post hoc analysis also
showed significantly greater improvement for venlafaxine
ERtreated patients than for placebo-treated patients on the
SDS total score (P = 0.025) but no significant differences for
other between-group comparisons of total score. Sertraline-
treated patients showed significantly greater improvement
than placebo-treated patients on overall life satisfaction (P =
0.0065) and medication satisfaction (P = 0.0158).
Figure 1 shows a significantly greater change from
baseline for the venlafaxine ER group than for the placebo
group on the CAPS-SX
17
from week 2 onward. The ser-
traline group showed a significant difference from the
placebo group only at week 6. The observed-cases analysis at
week 12 showed no between-group differences. Figure 2
shows remission rates for each group, where remission was
defined as a CAPS-SX
17
total score of 20 or less. The
percentage of patients who achieved remission was higher in
the venlafaxine ER group than in the placebo group at weeks
4, 6, and 12, but there were no differences between the
sertraline and placebo groups at any time point.
A post hoc analysis of between-group differences in
mean CAPS-SX
17
scores at end point was performed using
3 levels of severity of depressive symptoms, defined by
baseline HAM-D
17
scores. CAPS-SX
17
scores at end point
were 37.2, 34.4, and 30.0 for placebo, sertraline, and
venlafaxine ER, respectively, for the least severely depressed
group; 48.6, 43.3, and 41.4 for placebo, sertraline, and
venlafaxine ER, respectively, for the intermediate group; and
53.0, 46.9, and 49.6 for placebo, sertraline, and venlafaxine
ER, respectively, for the most severely depressed group.
CAPS-SX
17
total score at baseline (F = 7.18; P = 0.008) and
TABLE 2. Change Scores and Effect Sizes for Measures of Quality of Life and Functioning (Final Visit, LOCF)
Mean Change from Baseline (95% CI) Effect Size P
Predictors
Venlafaxine ER
(n = 179)
Sertraline
(n = 173)
Placebo
(n = 179)
Ven ER
vs. Pbo
Sert
vs. Pbo
Ven ER
vs. Sert
Ven ER
vs. Pbo
Sert
vs. Pbo
Ven ER
vs. Sert
Q-LES-Q-SF
Total score 11.54 (9.73 13.35) 11.17 (9.30 13.04) 8.75 (6.94 10.56) 0.237 0.206 0.031 0.033 0.068 0.782
Cluster scores
General activities 8.59 (7.03 10.15) 8.22 (6.61 9.83) 6.13 (4.57 7.69) 0.243 0.206 0.036 0.029 0.067 0.748
Medication satisfaction 0.30 (0.04 to 0.64) 0.57 (0.20 0.94) 0.13 (0.51 to 0.26) 0.422 0.683 0.261 0.100 0.012 0.300
Overall life satisfaction 0.90 (0.74 1.06) 0.87 (0.71 1.03) 0.55 (0.400.71) 0.340 0.308 0.032 0.002 0.007 0.774
SDS
Total score* 8.54 (9.78 to 7.29) 8.17 (9.43 to 6.90) 6.52 (7.76 to 5.29) 0.245 0.200 0.045 0.025 0.068 0.683
Cluster scores
Family/home 2.90 (3.35 to 2.44) 2.80 (3.26 to 2.34) 2.28 (2.73 to 1.83) 0.205 0.174 0.031 0.060 0.113 0.777
Social life 3.15 (3.60 to 2.69) 2.97 (3.43 to 2.50) 2.41 (2.86 to 1.95) 0.244 0.184 0.059 0.025 0.093 0.589
Work/school 2.46 (2.92 to 2.01) 2.48 (2.94 to 2.03) 1.93 (2.37 to 1.48) 0.183 0.189 0.006 0.096 0.087 0.957
P values are based on the pairwise comparisons from the analysis of covariance model (LOCF) using baseline-adjusted values.
*Post hoc analysis.
FIGURE 1. P value are based on pairwise comparisons from
analysis of covariance model with treatment as the main effect
and baseline as the covariate. For the observed cases analysis
at week 12, n = 113 for the placebo group, n = 111 for the
sertraline group, and n = 125 for the venlafaxine ER. group.
Values plotted are unadjusted. *P < .01 venlafaxine ER vs.
placebo; yP < 0.05 sertraline vs. placebo; zP < 0.001 venlafax-
ine ER vs. placebo; xP < 0.05 venlafaxine ER vs. placebo. LOCF
indicates last observation carried forward.
n 2006 Lippincott Williams & Wilkins
263
Journal of Clinical Psychopharmacology
Volume 26, Number 3, June 2006 Venlafaxine ER in Posttraumatic Stress Disorder
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
treatment (F = 3.26; P = 0.039) significantly affected
improvement in PTSD symptoms, as measured by the CAPS-
SX
17
total scores at end point. However, the effects of HAM-
D severity at baseline on CAP-SX
17
score (F = 1.85; P =
0.159) and the baseline HAM-D
17
severity by treatment (F =
0.31; P = 0.872) interaction were not significant.
Treatment and Tolerability
The mean average prescribed daily doses were
164.4 mg/d for venlafaxine ER and 110.2 mg/d for sertraline.
The mean maximum prescribed daily dose was 224.6 mg/d
(range, 37.5 375.0 mg/d) for venlafaxine ER and 151.4 mg/d
(range, 25.0200.0 mg/d) for sertraline. Roughly 47% (84/
179) of patients in the venlafaxine ER group and 49% (85/
173) of patients in the sertraline group achieved maximum
dosing.
The most commonly reported treatment-emergent AEs
(those reported by at least 10% of patients in at least 1 of the
active treatment groups) in the venlafaxine ER, sertraline,
and placebo groups, respectively, were headache (53 patients
[29%], 57 patients [32%], and 55 patients [29%]), nausea
(45 patients [24%], 39 patients [23%], and 27 patients
[14%]), diarrhea (22 patients [12%], 47 patients [26%],
and 25 patients [13%]), dry mouth (34 patients [18%], 26
patients [15%], and 27 patients [15%]), somnolence (21
[12%], 18 [10%], and 24 [13%]), fatigue (19 patients [11%],
24 patients [14%], and 17 patients [9%]), dizziness (24
patients [13%], 21 patients [10%], and 14 patients [8%]),
insomnia (24 patients [13%], 18 patients [10%], and 16
patients [9%]), constipation (21 patients [12%], 12 patients
[7%], and 18 patients [10%]), and appetite decrease (21
patients [12%], 13 patients [8%], and 11 patients [6%]).
More than twice as many patients in the sertraline group
experienced diarrhea compared with the venlafaxine ER
group. Overall, the types and frequencies of AEs in the 3
treatment groups were similar.
Adverse events led to discontinuation from the study as
follows: venlafaxine ER (n = 17), sertraline (n = 22), and
placebo (n = 19). One patient randomized to the venlafaxine
ER group died during the study, secondary to the serious AE
of acute coronary insufficiency, which the investigator con-
sidered unrelated to study medication: an obese 62-year-old
veteran who was a smoker with an undisclosed history of
treated type 2 diabetes, elevated cholesterol, and cardiac
problems.
No clinically significant laboratory values were noted
during treatment. However, at baseline, the median values of
total cholesterol were 5.04 mmol/L for the venlafaxine ER
group, 5.02 mmol/L for the sertraline group, and 4.94 mmol/L
for the placebo group. There were increases from baseline to
week 12 for the venlafaxine ER group (+0.06 mmol/L; P =
0.0076 vs. placebo) and the sertraline group (+0.14 mmol/L;
P = 0.0001 vs. placebo) and a decrease from baseline to week
12 for the placebo group (0.15 mmol/L).
The mean weight change from baseline to week 12 was
0.5 kg in the venlafaxine ER group and 0.3 kg in the
sertraline group, compared with +0.9 kg in the placebo
group. The difference in weight change between both active
treatment groups compared with placebo was statistically
significant (P = 0.0064 and P = 0.0242, for venlafaxine ER
and sertraline, respectively, vs. placebo). Moreover, the
proportion of patients with a gain or loss of 7% or more of
body weight was similar among the 3 groups. The mean
pulse rate change from baseline to week 12 was +3.0 beats
per minute (bpm) in the venlafaxine ER group, +0.1 bpm in
the sertraline group, and +0.6 bpm in the placebo group ( P =
0.0010 and P = 0.0017, for venlafaxine ER vs. placebo and
sertraline, respectively, with no significant difference
between sertraline and placebo). At week 12, there was an
increase in mean systolic blood pressure in the venlafaxine
ER group (+2.4 mm Hg) and decreases in the sertraline
(0.2 mm Hg) and placebo (1.7 mm Hg) groups, with a
statistically significant difference only between the venla-
faxine ER and placebo groups (P = 0.0030). At week 12,
there was an increase in mean diastolic blood pressure in the
venlafaxine ER group (+1.8 mm Hg) and decreases in the
sertraline group (0.3 mm Hg) and in the placebo group
(1.2 mm Hg), with significant differences between the
venlafaxine ER group and placebo and sertraline groups
(P = 0.0013 and 0.0187, respectively) only.
DISCUSSION
The results of this study provide support for the
efficacy of venlafaxine ER relative to placebo in the
treatment of PTSD. Mean changes in total CAPS-SX
17
score showed significantly greater improvement for the
venlafaxine ER group than for the placebo group, beginning
at week 2, as did change scores for avoidance/numbing
and hyperarousal clusters (but not reexperiencing). The
observed-cases analysis at end point, which used fewer
patients than the LOCF analysis, showed a significant
FIGURE 2. P value for the treatment differences are based on
the Pearson x
2
test. Remission = CAPS-SX
17
total score 20.
*P<0.05 venlafaxine ER vs placebo; yP <0.01 venlafaxine vs.
sertraline; zP<0.001 venlafaxine ER vs. placebo; xP<0.05
venlafaxine ER vs. sertraline.
264 n 2006 Lippincott Williams & Wilkins
Davidson and Associates Journal of Clinical Psychopharmacology
Volume 26, Number 3, June 2006
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
difference between the 2 groups on avoidance/numbing but
not on other symptom clusters or on the CAPS-SX
17
total
score. Remission rates at the final visit (LOCF) were
significantly higher for the venlafaxine ER group than for
the placebo group.
Two of the 3 secondary clinician-administered scales
showed superiority for venlafaxine ER over placebo. CGI-S
scores were significantly lower at the final visit, indicating
lower levels of overall symptom severity, whereas signifi-
cantly greater reductions in HAM-D
17
scores showed the
effectiveness of venlafaxine ER in treating depressive and
anxiety symptoms. There was no difference in GAF scores
between the venlafaxine ER and placebo groups.
Patient-rated measures showed a similar pattern of
results (Table 1). Reductions in DTS total scores were
significantly greater for venlafaxine ERtreated patients
than for placebo-treated patients on all symptom clusters.
The observed-cases analysis confirmed the superiority of
venlafaxine ER relative to placebo on the DTS total score
(venlafaxine ER, 50.4 ± 32.20; placebo, 39.2 ± 28.45; P =
0.0243) and on the avoidance and numbing (venlafaxine ER,
20.3 ± 14.83; placebo, 15.6 ± 13.77; P = 0.0282)
symptom cluster but not on the intrusion (venlafaxine ER,
15.1 ± 10.73; placebo, 11.5 ± 9.03; P = 0.0676) or
hyperarousal (venlafaxine ER, 15.0 ± 10.47; placebo,
12.1 ± 9.68; P = 0.0742) clusters. Improvement in the SVS
was also significantly greater for venlafaxine ER than for
placebo, suggesting a resilience-enhancing effect similar to
an earlier study that compared fluoxetine with placebo in the
treatment of PTSD.
18
A post hoc analysis of between-group differences in
mean CAPS-SX
17
scores at end point was performed to
determine whether the statistically significant differences in
PTSD symptoms might be accounted for by a nonspecific
antidepressant effect, because the study population, on
average, had clinically significant depression and the
venlafaxine ER group showed a statistically significant
improvement in HAM-D
17
scores at the end of the study.
Results showed that the initial severity of PTSD-specific
symptoms, measured by the mean CAPS-SX
17
total score at
baseline (F = 7.18; P = 0.008), and type of treatment (F =
3.26; P = 0.039) had a statistically significant effect on
improvement of PTSD symptoms at end point, measured by
the CAPS-SX
17
. However, the effects of HAM-D severity at
baseline on CAP-SX
17
score (F = 1.85; P = 0.159) and the
baseline HAM-D
17
severity by treatment (F = 0.31; P =
0.872) interaction were not significant, suggesting that the
improvement in PTSD symptoms was not mediated by
improvement in depressive symptoms.
Patient-reported health outcomes were not fully con-
sistent with the findings for the clinician- and patient-rated
symptom and global measures of treatment efficacy. The
venlafaxine ER group showed significantly greater improve-
ment than the placebo group on the Q-LES-Q-SF total score
and on individual items measuring overall life satisfaction
and general activities but not on medication satisfaction.
Venlafaxine ER was associated with significantly greater
efficacy than placebo on the SDS social life subscale and
total score (post hoc) but not on the work/school or family
life subscales.
Sertraline was superior to placebo on 2 measures and
showed a trend on the primary outcome. However, the
magnitude of the differences in improvement between the
venlafaxine ER and sertraline groups on both the primary
and secondary outcome measures was very small and
clinically insignificant, as can be seen from the effect sizes
shown in Table 1, which suggests that the 2 drugs are
broadly similar. The following considerations may help us
interpret our findings. In this trial, the protocol-specified
maximum dosing for venlafaxine ER (300 mg/d) was higher
than the dosage recommended in the product labeling
(250 mg/d) for its Food and Drug Administrationapproved
indications, whereas maximum dosing for sertraline was
within the dosage specified for its approved PTSD indica-
tion. Moreover, 2 published, pivotal, 12-week, large-scale,
multicenter, randomized, double-blind, placebo-controlled
studies found a significant difference between the sertraline
and placebo groups on the CAPS-2 (which was later renamed
the CAPS—Symptom Status Version, or CAPS-SX, but
includes the same 17-item checklist of potentially traumatic
experiences, based on the DSM-IV criteria—hence ‘‘CAPS-
SX
17
’’).
14,15
In both of these studies, mean CAPS-2 (CAPS-
SX
17
) total scores at baseline were roughly 75 for both
the sertraline and placebo groups. In our study, CAPS-SX
17
total scores at baseline were 84.0 (SD, ±14.97), 82.0 (SD,
±15.49), and 81.6 (SD, ±14.66) for the venlafaxine ER,
sertraline, and placebo groups, respectively. Moreover, more
than 75% of patients in the sertraline group in these earlier
studies were women, compared with roughly 65% in our
study, and both earlier studies had a higher proportion of
white subjects (>80% compared with <70% in the current
study). Thus, differences in baseline PTSD illness severity,
sex, or racial/ethnic factors may explain the lack of a
significant difference relative to placebo in outcome on the
CAPS-SX
17
for sertraline found in this study compared with
previously published large-scale, randomized, controlled
trials. Other differences between these studies and the pres-
ent investigation, such as the distribution of various types
of trauma or duration of illness, may have also influenced
the results.
The improvement in CAPS-2 (now referred to as the
CAPS-SX
17
) scores found in these previously published
sertraline studies was also lower for both the placebo and
active treatment groups than the improvement in CAPS-SX
17
scores found in our study. In the first of these studies,
14
the
adjusted mean change score at end point for the CAPS-2 was
33.0 for the sertraline group and 23.2 for the placebo
group (P = 0.02). In the second study,
15
the mean change
score for the CAPS-2 was 33.0 (SD, ±2.4) for the sertraline
group and 26.2 (SD, ±2.3) for the placebo group (P =
0.04). In our study, the mean change scores on the CAPS-
SX
17
were 41.51 for venlafaxine ER, 39.44 for sertraline,
and 34.17 for placebo. The relatively small effect size for
venlafaxine ER on the primary outcome measure, although
significantly greater than that for placebo, and low effect sizes
on the secondary outcome measures for both venlafaxine ER
n 2006 Lippincott Williams & Wilkins 265
Journal of Clinical Psychopharmacology
Volume 26, Number 3, June 2006 Venlafaxine ER in Posttraumatic Stress Disorder
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
and sertraline might be attributable to the high response rate
among patients treated with placebo.
Although clinician-administered and patient-rated
measures of improvement in symptom and global measures
were generally in agreement, health outcomes measures
(quality of life, life satisfaction, functioning, and health care
utilization) did not parallel the improvements in symptom
and global measures found in other 12-week studies of
sertraline
14
or other SSRIs, such as fluoxetine
18,19
and
paroxetine.
16,17
There is some suggestion, however, that the
patients in our study may have had higher baseline levels of
PTSD illness severity than the patients in most of these
published studies, which may, in part, explain this inconsis-
tency. Moreover, a longer period of observation may have
been required for differences between groups in the efficacy
of treatment to fully emerge. Recently, an international
expert consensus panel for PTSD recommended treatment of
chronic PTSD for a minimum of 12 to 24 months.
41
In addition to the short duration of the trial, additional
limitations of this study include the exclusion of patients
with a recent history of alcohol or drug abuse, insufficient
power to perform a head-to-head comparison between
venlafaxine ER and sertraline, and insufficient power to
evaluate the influence of potentially clinically important
variables such as sex, severity or duration of illness, type of
trauma, or presence of comorbidity on treatment response.
Few studies have examined the mediating effects of patient
characteristics on treatment outcomes, and even fewer have
identified predictor variables that may mediate treatment
effects.
42 45
Secondary analyses of several potential predic-
tor variables will be provided in a follow-up report using
data from the current trial and a second, successful 2-arm
international study of venlafaxine ER and placebo.
The differences in mean weight change between both
active treatment groups and the placebo group, during the
course of the study, were not clinically significant. The
clinical significance of the small but statistically significant
differences in mean pulse rate and systolic blood pressure
between venlafaxine ER and placebo is unclear, as is the
small but statistically significant difference between ven-
lafaxine ER and the other 2 treatment groups in mean
diastolic blood pressure. Safety assessments showed that the
overall safety profiles of venlafaxine ER and sertraline were
consistent with the safety results observed in other trials of
these agents.
Together, the results of this study suggest that
venlafaxine ER, a serotonin norepinephrine reuptake inhib-
itor, is safe and generally well tolerated and may be effective
in the treatment of patients with PTSD. Although the
differences in improvement between venlafaxine ER and
placebo groups on the primary and most secondary efficacy
measures were statistically significant, the effect sizes were
generally small. These small effect sizes, as well as the lack
of a significant difference between the group of patients
treated with sertraline, an agent with established efficacy for
the treatment of PTSD, and the placebo group on the primary
outcome measure, and absence of robust differences relative
to placebo on the secondary outcome measures, suggest that
the patient population used in this trial may have differed in
important respects from populations used in earlier published
studies. These findings should encourage additional explo-
ration of the role of norepinephrine and other neurotrans-
mitters in the pathophysiology and treatment of PTSD and
stimulate further investigation of patient characteristics that
may influence the efficacy of treatment.
ACKNOWLEDGMENTS
Funding was provided by Wyeth Pharmaceuticals.
The authors thank Michael Rennert, PhD, for his
editorial assistance.
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Volume 26, Number 3, June 2006 Venlafaxine ER in Posttraumatic Stress Disorder
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    • "During the consultations, medication is initiated in accordance with the medical treatment algorithm of the clinic, which constitutes the pharmaceutical part of TAU. The algorithm is based on the present knowledge on treatment of traumatised refugees [5, 50, 51] . In accordance with this, sertraline is first choice medication, and venlafaxine second choice of medication. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Treatment of traumatised refugees is one of the fields within psychiatry, which has received little scientific attention. Evidence based treatment and knowledge on the efficiency of the treatment for this complex patient group is therefore scarce. This leads to uncertainty as to which treatment should be offered and potentially lowers the quality of life for the patients. Chronic pain is very common among traumatised refugees and it is believed to maintain the mental symptoms of trauma. Hence, treating chronic pain is believed to be of high clinical value for this patient group. In clinical studies, physical activity has shown a positive effect on psychiatric illnesses such as depression and anxiety and for patients with chronic pain. However, scientific knowledge about physical activity as part of the treatment for traumatised refugees is very limited and no guidelines exist on this topic. Methods/design: This study will include approximately 310 patients, randomised into three groups. All three groups receive psychiatric treatment as usual for the duration of 6-7 months, consisting of consultations with a medical doctor including pharmacological treatment and manual-based Cognitive Behavioural Therapy. The first group only receives treatment as usual while the second and the third groups receive either Basic-Body Awareness Therapy or mixed physical activity as add-on treatments. Each physical activity is provided for an individual 1-hour consultation per week, for the duration of 20 weeks. The study is being conducted at the Competence Centre for Transcultural Psychiatry, Mental Health Centre Ballerup in the Capital Region of Denmark. The primary endpoint of the study is symptoms of Post Traumatic Stress Disorder; the secondary endpoints are depression and anxiety as well as quality of life, functional capacity, coping with pain, body awareness and physical fitness. Discussion: This study will examine the effect of physical activity for traumatised refugees. This has not yet been done in a randomised controlled setting on such a large scale before. Hereby the study will contribute to important knowledge that is expected to be used in future clinical guidelines and reference programs. Trial registration: ClinicalTrials.gov NCT01955538 . Date of registration: 18 September 2013.
    Full-text · Article · Oct 2015
    • "During the consultations, medication is initiated in accordance with the medical treatment algorithm of the clinic, which constitutes the pharmaceutical part of TAU. The algorithm is based on the present knowledge on treatment of traumatised refugees[5,50,51]. In accordance with this, sertraline is first choice medication, and venlafaxine second choice of medication. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: The aim of the study was to investigate refugee experiences of individual Basic Body Awareness Therapy (BBAT) and the level of transference into daily life. Method: Qualitative research using semi-structured interviews. Malterud's version of Giorgi's 4-step analysis was used to analyse the data. Participants: Three traumatised refugees with PTSD who had completed 14-20 individual BBAT sessions. Results: The participants experienced the movements in BBAT as small and simple with big effects. BBAT was found to relieve pain and tension, bring peace of mind and body, and make it easier to sleep. Regular practice was necessary, as were instructions from a physiotherapist, to get the effect from BBAT. Positive changes in the contact to oneself and others were experienced and new coping strategies were developed. Conclusion: Traumatised refugees experienced positive effects from BBAT and transference into daily life was experienced to a great extent.
    Full-text · Article · Oct 2015 · Journal of Psychopharmacology
    • "There is some evidence that tricyclics are more effective in men and SSRI in women whom have depression (Kornstein et al., 2000). 5. Further studies are needed to investigate the dose effects, safety and to establish whether tricyclic drugs are superior to SSRI. The only study that compared a SSRI against a SNRI in PTSD shows that the SNRI, but not the SSRI, is superior to placebo; and remission rates show a pattern in which the SSRI was intermediate and not differing from either comparator (Davidson et al., 2006). "
    [Show abstract] [Hide abstract] ABSTRACT: Serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitors (SSRI) are the first-line recommended drug treatments for post-traumatic stress disorder (PTSD); but despite their benefits, much residual pathology remains and no new drugs have yet emerged with a clearly demonstrated benefit for treating the disorder. A case is made that tricyclic drugs deserve a closer look, based on their ability to affect several of the main neurotransmitters that are relevant to PTSD. Their promising efficacy, which was shown 30 years ago, had not been followed up, until a recent trial of desipramine found advantages over a SSRI in PTSD with comorbid alcohol dependence. Opportunities exist for studying newer and purportedly safer tricyclic formulations, as well as further the work with older, established compounds. A reappraisal of their risk:benefit ratio seems in order, when treating PTSD. © The Author(s) 2015.
    Full-text · Article · Jan 2015
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