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Original Article |

Treatment of Posttraumatic Stress Disorder With Venlafaxine Extended Release:  A 6-Month Randomized Controlled Trial FREE

Jonathan Davidson, MD; David Baldwin, DM, FRCPsych; Dan J. Stein, MD; Enrique Kuper, BCETS, FAAETS; Isma Benattia, MD; Saeed Ahmed, MD; Ron Pedersen, MS; Jeff Musgnung, MT
[+] Author Affiliations

Author Affiliations: Duke University Medical Center, Durham, NC (Dr Davidson); Royal South Hants Hospital, Southampton, United Kingdom (Dr Baldwin); University of Cape Town and University of Stellenbosch, Cape Town, South Africa (Dr Stein); Centro de Stress Traumático, Buenos Aires, Argentina (Dr Kuper); Wyeth Pharmaceuticals, Collegeville, Pa (Drs Benattia and Ahmed and Messrs Pedersen and Musgnung).


Arch Gen Psychiatry. 2006;63(10):1158-1165. doi:10.1001/archpsyc.63.10.1158.
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Published online

Context  No large-scale posttraumatic stress disorder drug trials have been conducted to evaluate treatment effects beyond 12 weeks outside of those with selective serotonin reuptake inhibitors.

Objective  To evaluate the efficacy of venlafaxine extended release (ER), a serotonin norepinephrine reuptake inhibitor, in posttraumatic stress disorder.

Design  6-month, double-blind, placebo-controlled trial.

Setting  International study at 56 sites.

Patients  Adult outpatients (N = 329) with a primary diagnosis of posttraumatic stress disorder as defined in the DSM-IV, symptoms for 6 months or longer, and a 17-item Clinician-Administered Posttraumatic Stress Disorder Scale score of 60 or higher.

Intervention  Patients randomly assigned to receive flexible doses of venlafaxine ER (37.5-300 mg/d) or placebo for 24 weeks.

Main Outcome Measures  Primary measure was the change from baseline in the Clinician-Administered Posttraumatic Stress Disorder Scale score. Secondary measures included remission, defined as a Clinician-Administered Posttraumatic Stress Disorder Scale score of 20 or lower, and changes in symptom cluster scores, frequency of remission, and time to remission. Measures of stress vulnerability, resilience, depression, quality of life, functioning, and global illness severity were also taken.

Results  Mean changes from baseline in Clinician-Administered Posttraumatic Stress Disorder Scale total scores at end point were −51.7 for venlafaxine ER and −43.9 for placebo (P = .006). Improvement was significantly greater for the venlafaxine ER group than for the placebo group in cluster scores for reexperiencing (P = .008) and avoidance/numbing (P = .006), but not for hyperarousal. Remission rates were 50.9% for venlafaxine ER and 37.5% for placebo (P = .01). The venlafaxine ER group also showed significantly greater improvement at end point than the placebo group (P<.05) on all other reported outcome measures. The mean maximum daily dose of venlafaxine ER was 221.5 mg/d. Withdrawal rates were similar between groups with no significant difference in dropouts attributable to adverse events.

Conclusion  In this study, venlafaxine ER was effective and well tolerated in short-term and continuation treatment of patients with posttraumatic stress disorder.

Figures in this Article

Posttraumatic stress disorder (PTSD) is a condition characterized by intrusions of traumatic memories, symptoms of avoidance and numbing, and hyperarousal.1 The high prevalence,2 substantial psychiatric comorbidity,2 chronic course,2 and disabling effects3 of the illness are well documented. Selective serotonin reuptake inhibitors (SSRIs) have been shown to ameliorate symptoms of PTSD.4 However, SSRIs do not show a pattern of results in treatment studies of PTSD that is entirely consistent across patient types (combat veterans vs noncombat veterans), symptom clusters (avoidance/numbing, reexperiencing, or hyperarousal), or sex, even with drugs that have been approved for this indication.4,5

Some PTSD components are thought to be related to stress-induced increases in noradrenergic activity in patients with PTSD5; however, while the importance of the brain's noradrenergic pathways is recognized in the pathophysiology of PTSD, their exact role in the disorder is not clear.6,7 Venlafaxine extended release (ER), a serotonin norepinephrine reuptake inhibitor, has demonstrated efficacy in producing remission in patients with depression,8 generalized anxiety disorder,9 social anxiety disorder,10 and panic disorder.11 The purpose of this study was to assess the efficacy and safety of flexible-dose venlafaxine ER in the treatment of patients with moderate to severe PTSD.

Few large-scale, multicenter, randomized, placebo-controlled trials of non-SSRI agents for the treatment of PTSD have been conducted. We are aware of only 2 published studies, both short-term trials of the monoamine oxidase inhibitor brofaromine,12,13 an agent unavailable for clinical use and that is no longer in development, which failed to show statistically significant differences from placebo, and 1 short-term trial of venlafaxine ER.14

Although many patients show improvement following 12 weeks of pharmacotherapy, evidence suggests that further improvement occurs with longer-term treatment.15 Nonresponders to treatment with an SSRI at 12 weeks may become responders following 4 to 6 months of pharmacotherapy.15 Because of the high risk of relapse in patients with chronic PTSD, however, continuation of medication for at least 1 year is considered standard practice in the treatment of PTSD.16 The trial we report here is the first we know of to extend the acute-phase, double-blind treatment period to 6 months, thus addressing a clinically relevant issue. In addition, it is the first study we are aware of to examine the effect of a single agent on resilience and stress vulnerability. Of note, the maximum daily dose of venlafaxine ER used in this study was higher than the maximum dose of 225 mg recommended in the labeling for its Food and Drug Administration–approved indications (major depression disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder).

PATIENT SAMPLE

Patients were enrolled in the study if they were at least 18 years of age, could provide legal consent, and were not currently hospitalized; met the DSM-IV1 criteria for a primary diagnosis of PTSD; had a score of at least 60 on the Clinician-Administered PTSD Scale, abbreviated 1-Week Symptom Status Version (CAPS-SX17)17; and had PTSD symptoms for at least the previous 6 months. In addition, they must have had a negative serum pregnancy test at screening (for women of childbearing potential); been in generally good health as determined by the investigator on the basis of medical history, physical examination, and screening laboratory results; been willing and able to return for all protocol-defined visits; been fluent in written and spoken forms of English, Spanish, or Portuguese; and been willing and able to provide written informed consent prior to admission.

Subjects were excluded if they had intolerance, hypersensitivity, or nonresponse to a previous adequate trial of venlafaxine; had inability to tolerate or respond to adequate trials of 3 antidepressants; had current primary major depression or panic disorder; had a current mental disorder due to a general medical condition or history of bipolar disorder, schizophrenia, or other psychotic disorder; abused or were dependent on alcohol or other drugs within 6 months of randomization or had a positive urine drug screen; showed a high risk of suicide or violence; used any investigational drug, antipsychotic, or monoamine oxidase inhibitor within 30 days of randomization; had electroconvulsive therapy within 3 months of randomization or likelihood of requiring electroconvulsive therapy during the study; used triptans or any other psychoactive drug, including fluoxetine, or herbal preparation within 7 days of randomization; had current involvement in criminal proceedings or compensation claims related to trauma; and, for women, were nursing, pregnant, or sexually active without acceptable birth control. Subjects who had initiated or changed psychotherapy of any kind within 3 months of study enrollment were also excluded.

The research was conducted at 56 outpatient psychiatric clinic sites in Argentina, Chile, Colombia, Denmark, Finland, Mexico, Norway, Portugal, South Africa, Spain, Sweden, and the United Kingdom in accordance with the Declaration of Helsinki and its amendments. Where necessary, the informed consent form and patient self-rating documents were translated to either Spanish or Portuguese by a US agency and certified as accurate. Local affiliate medical directors confirmed the accuracy of each translation prior to use. For each site, CAPS-SX17 training and testing to ensure correct scoring using 1 or more videotaped patient interviews were provided to the principal investigator and to an additional rater. No measure of interrater reliability was used during the study. All investigators were required to be fluent in English. The informed consent form, 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.

STUDY DESIGN

Patients were enrolled in the study by the site investigators. Following a washout period of at least 7 days, patients who met entry criteria were randomly assigned to 24 weeks of double-blind, parallel treatment with venlafaxine ER or placebo followed by a taper period of up to 2 weeks and poststudy evaluation (4-10 days after taper). The sponsor sent each site a table of computer-generated numbers randomized in blocks of 4, and patients were assigned packages linked to the randomization numbers in numerical order by the site investigator using the randomization tables. Investigators followed the protocol-specified medication dosing guidelines for venlafaxine ER (75-300 mg/d with a lead-in dose at baseline of 37.5 mg/d) and increased the dose to the next higher level based on tolerability for patients who did not achieve remission, which was operationally defined as a score of 20 or lower on the CAPS-SX17, a cutoff that has been used elsewhere.18,19 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. Study visits took place at baseline and at the end of study treatment weeks 1, 2, 4, 6, 8, 12, 18, and 24 and follow-up or at the time of discontinuation if before week 24.

EFFICACY ASSESSMENTS

The primary efficacy outcome in this study was the baseline to end point (week 24 or the time of discontinuation) last-observation-carried-forward (LOCF) change in the CAPS-SX17, which was measured at baseline and weeks 2, 4, 6, 8, 12, 18, and 24. This 17-item subset of the CAPS-SX17 assesses the 17 PTSD symptoms listed in the DSM-IV, divided into the re-experiencing, avoidance/numbing, and hyperarousal subscales. Secondary efficacy outcomes included changes from baseline to end point in CAPS-SX17 symptom cluster scores; frequency of remission (CAPS-SX17 score ≤20); and time to remission. Other secondary outcome measures included ratings from 3 clinician-administered instruments: the Clinical Global Impression–Severity of Illness scale20; the Global Assessment of Functioning1; and the 17-item Hamilton Rating Scale for Depression.21 Patient-rated secondary outcome measures included the Connor-Davidson Resilience Scale22 and Sheehan Vulnerability to the Effects of Stress Scale,23 a 1-item scale that rates the magnitude of setbacks to stressful events or personal problems experienced by patients from the time of their last visits.

Secondary assessments of patient-rated health outcomes included the Quality of Life Enjoyment and Life Satisfaction Short Form,24 a 16-item scale that assesses the degree of enjoyment and satisfaction in various areas of daily life, and the Sheehan Disability Scale,25 a 3-item scale that evaluates the extent to which PTSD symptoms have disrupted patients' work/school schedules, social life, and family life/home responsibilities. The Clinical Global Impression–Severity of Illness scale, Hamilton Rating Scale for Depression, and Sheehan Disability Scale were measured at baseline and weeks 2, 4, 6, 8, 12, 18, and 24; the Quality of Life Enjoyment and Life Satisfaction Short Form, Connor-Davidson Resilience Scale, and Sheehan Vulnerability to the Effects of Stress Scale, at baseline and weeks 4, 12, and 24; and the Global Assessment of Functioning, at baseline and weeks 12 and 24.

SAFETY ASSESSMENTS

Adverse events and use of concomitant treatments were recorded at all visits. Safety measurements 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 baseline and week 24; blood chemistry determinations, hematology tests, urinalysis, and urine toxicology tests at screening and week 24; and recording of last menstrual period for women of childbearing age.

STATISTICAL METHODS

Analyses of efficacy variables were performed on the intent-to-treat population (ie, on all randomized patients who had received at least 1 dose of study medication and had at least 1 postbaseline evaluation). The primary efficacy variable was the change from baseline to week 24 in the CAPS-SX17 score. For patients who discontinued participation before study completion, the last postdose observed value was used for end point analysis (LOCF). In addition to the LOCF value, the observed changes at each visit were computed.

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 score and baseline score × treatment interaction as the covariates. All inferential analyses of treatment effects were 2-sided and were performed at the α = .05 level of significance. An α level of .10 was used to evaluate interactions. The continuous secondary efficacy end points were analyzed by the same method as the primary end point. No adjustment was made for multiple analyses.

Post hoc effect-size analyses using Cohen d were performed on the values of the outcome measures at end point to compare the difference in effect size between venlafaxine ER and placebo. A post hoc analysis comparing the response rate (defined as the proportion of patients who showed a ≥30% decrease in CAPS-SX17 score) between the active treatment and placebo groups was also performed. Categorical variables, such as the frequency of remission, were analyzed by using χ2 tests. A post hoc analysis of the number needed to treat, a measure of how many patients must be treated with a specific intervention relative to another intervention to achieve a desired outcome in 1 additional patient,26 was used to compare active treatment with placebo for the rate of remission. Time to remission was analyzed using Kaplan-Meier methodology. Version 8.2 of the SAS system (SAS Inc, Cary, NC) was used for all statistical analyses.

DEMOGRAPHIC AND CLINICAL CHARACTERISTICS

As shown in Figure 1, 442 patients were screened, 329 were randomized, and 224 (68%) completed the study. There were no clinically important differences in the proportion of patients in each group who completed the study. There were no unexpected differences between the venlafaxine ER and placebo groups in the reasons given for early withdrawal (Figure 1) or clinically important differences in baseline demographic or clinical characteristics (Table 1). Withdrawal rates were 30.4% for venlafaxine ER and 33.3% for placebo with no significant difference in dropouts attributable to adverse events. The venlafaxine ER group had 15 discontinuations attributed to adverse events compared with 9 discontinuations for the placebo group; 5 patients in the venlafaxine ER group withdrew because of unsatisfactory response compared with 18 patients in the placebo group. The types of trauma experienced by all randomized patients are outlined in Table 2.

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Figure 1.

Study flowchart. ER indicates extended release.

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Table Graphic Jump LocationTable 1. Baseline and Demographic Characteristics (ITT Population)
Table Graphic Jump LocationTable 2. Frequency of Trauma by Category
EFFICACY ANALYSIS

Results for the main primary and secondary PTSD outcome measures at the final study end point are listed in Table 3. Venlafaxine ER–treated patients showed significantly greater improvement than placebo-treated patients on the change in CAPS-SX17 total score (P = .006). The differences between active treatment and placebo in changes from baseline to end point were significant for reexperiencing cluster B (P = .008) and avoidance/numbing cluster C (P = .006), but not for hyperarousal cluster D (P = .06). As indicated in Table 4, the venlafaxine ER group showed significantly greater improvement than the placebo group in Clinical Global Impression–Severity of Illness scale scores (P = .004), Hamilton Rating Scale for Depression total scores (P = .007), and Global Assessment of Functioning mean scores (P = .03).

Table Graphic Jump LocationTable 3. Effects of Treatment on Total PTSD and Cluster Scores (LOCF)
Table Graphic Jump LocationTable 4. Effect Sizes for Selected Outcomes*

Ratings of resilience and stress vulnerability by patients exhibited a similar pattern of results. Venlafaxine ER–treated patients showed greater improvement than placebo-treated patients on the final visit Connor-Davidson Resilience Scale (P = .002) and Sheehan Vulnerability to the Effects of Stress Scale (P = .01) total scores (Table 4). At the final visit, the venlafaxine ER group showed significantly greater improvement than the placebo group on Quality of Life Enjoyment and Life Satisfaction Short Form total (P = .007), overall life satisfaction (P = .04), and general activities (P = .007) scores, but not on medication satisfaction (P = .08). The venlafaxine ER group showed significantly greater improvement than placebo on the Sheehan Disability Scale total (P = .03) and family life/home responsibilities (P = .01) items, but not on the work/school (P = .05) or social life (P = .08) items. None of the utilization and cost items showed a significant difference between the venlafaxine ER and placebo groups. Differences between the venlafaxine ER and placebo groups on the work questionnaire for the days lost during the last month (P = .07) and days underproductive during the last month items, both evaluated using analysis of variance, were not significant. The number needed to treat for remission was 8 at the study end point, and effect sizes for the outcome measures appear in Table 4.

Figure 2 demonstrates that on the primary outcome measure, venlafaxine ER showed significantly greater improvement than placebo from week 4 onward (LOCF). Mean ± SD week 12 LOCF change scores from baseline were −47.5 ± 25.86 and −37.6 ± 27.55 for the venlafaxine ER and placebo groups, respectively (P<.001), and −51.7 ± 27.16 and −43.9 ± 28.93, respectively, at week 24 (P = .006). For completers, the mean ± SD week 24 change scores from baseline for the venlafaxine ER and placebo groups were −59.2 ± 23.76 and −54.0 ± 23.63, respectively, at week 24, a difference that was not statistically significant (P = .06). Figure 3 shows remission rates for each group. The percentage of patients who achieved remission was higher in the venlafaxine ER group than in the placebo group at weeks 6, 12, and 24 (LOCF) and at end point for completers. Week 12 LOCF remission rates were 42.9% (69/161) and 28.0% (47/168) for the venlafaxine ER and placebo groups, respectively (P = .005), and 50.9% (82/161) and 37.5% (63/168), respectively, at week 24 (P = .01). Among completers, remission rates for the venlafaxine ER and placebo groups were 40.4% (65/165) and 27.4% (46/168), respectively, at week 12 and 44.7% (72/161) and 33.3% (56/168), respectively, at week 24 (P = .04).

Place holder to copy figure label and caption
Figure 2.

Change in score on the Clinician-Administered Posttraumatic Stress Disorder Scale, the abbreviated 1-Week Symptom Status Version, from the baseline score. All values represent last observation carried forward unless otherwise stated. ER indicates extended release. P values are based on pairwise comparisons from an analysis of covariance model with treatment as the main effect and baseline as the covariate. Asterisk indicates P<.05; dagger, P<.01; and double dagger, P<.001.

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Place holder to copy figure label and caption
Figure 3.

Patients who achieved remission (last observation carried forward). Remission is defined as a total score of 20 or lower on the Clinician-Administered Posttraumatic Stress Disorder Scale, the abbreviated 1-Week Symptom Status Version. ER indicates extended release; OCs, observed cases. Asterisk indicates P<.05; dagger, P<.01.

Graphic Jump Location
SAFETY AND TOLERABILITY

The mean average daily dose of venlafaxine ER was 181.7 mg/d, and the mean maximum dose was 221.5 mg. At the final visit, 4.3% (7/161) of patients were receiving 37.5 mg/d, 13.7% (22/161) were receiving 75.0 mg/d, 23.6% (38/161) were receiving 150 mg/d, 23.0% (37/161) were receiving 225 mg/d, and 35.4% (57/161) were receiving 300 mg/d, the maximum protocol-specified dose level. The percentage of patients with at least 1 adverse event was 78% (125/161) in the venlafaxine ER group and 69% (114/168) in the placebo group.

The most common treatment-emergent adverse events reported by at least 5% of patients in the venlafaxine ER group appear in Table 5. A total of 15 patients receiving venlafaxine ER experienced adverse events leading to discontinuation compared with 9 patients in the placebo group. The most frequently reported adverse events leading to discontinuation in the venlafaxine ER group were mild to severe nausea experienced by 6 patients followed by moderate dizziness experienced by 5 patients. No clinically relevant differences between groups on changes from baseline to end point in cholesterol levels or vital signs were noted during treatment (Table 6); only the change in cholesterol levels showed a statistically significant difference between active treatment and placebo groups (P = .04). Weight change of 7% or greater was the most common treatment-emergent clinically significant abnormality, occurring in 20 patients (12%) in the venlafaxine ER group and 12 patients (7%) in the placebo group. For all other vital signs measures, the frequency of clinically significant values was less than 5%.

Table Graphic Jump LocationTable 5. Treatment-Emergent Adverse Events*
Table Graphic Jump LocationTable 6. Vital Signs and Cholesterol Levels at Final Visit (Week 24, LOCF)

In this study, the efficacy of venlafaxine ER was observed on all main reported measures with the exception of the CAPS-SX17 hyperarousal symptom cluster, which fell just short of statistical significance. Our findings are, therefore, consistent with a number of other randomized trials of pharmacotherapy for PTSD; of the 5 previously published short-term placebo-controlled trials of SSRIs (sertraline,27,28 paroxetine,18,29 and fluoxetine30) only 218,29 showed significant superiority of active treatment over placebo on all 3 clusters. The failure to find completely consistent results across all CAPS-SX17 symptom clusters in this study and in previous studies may also represent an inability of SSRIs or serotonin norepinephrine reuptake inhibitors to adequately control the full range of PTSD symptoms, or it may reflect a deficiency of the rating scale itself. It is also possible that drugs with noradrenergic-enhancing effects may promote arousal, as suggested by animal data.31,32

Treatment with venlafaxine ER was also associated with greater improvement than treatment with placebo in overall quality of life and disability. Drug effects on some social and work-related measures fell just short of statistical significance but were consistent with the overall pattern of findings. The lack of benefit for satisfaction with medication may be attributable to drug-related adverse events.

Resilience and stress vulnerability have both been largely overlooked in the treatment of depression and anxiety yet play an important role in PTSD, which is characterized by conspicuously low resiliency scores.22 A possible link between the extent of norepinephrine transporter but not serotonin transporter, inhibition, and improvement in Connor-Davidson Resilience Scale score in patients with depression treated with venlafaxine ER33 has been suggested, providing 1 possible neurobiological explanation for our finding. Of interest, enhancement of resiliency did not emerge until after 4 weeks of treatment by which time a statistically significant effect had already been observed for PTSD symptoms. The effect sizes for drug-placebo differences in the outcome measures at end point were generally low to modest, in line with earlier reports for sertraline34 and paroxetine,18,29 but it is of interest that the measure showing the greatest effect size was improvement in resiliency, even though it occurred later than symptom improvement.

The 6-month duration of this trial is unique for placebo-controlled evaluation of drug efficacy in the treatment of PTSD, and it reveals that the superiority of active treatment at week 12 persists at the week 24 study end point, although without further widening the separation between groups. Remission rates at week 12 for both drug and placebo were about 10% to 15% higher than what has been previously reported using identical criteria for sertraline and paroxetine in the treatment of PTSD.14,19 This suggests that subjects in the present study may have been more treatment responsive for reasons that remain unclear but may reflect sampling characteristics.

In a 12-week, multicenter trial of 2 fixed doses of paroxetine (20 mg/d and 40 mg/d) in the treatment of PTSD,29 response rates on the CAPS were 54% to 62% for patients taking paroxetine compared with 37% for patients taking placebo. A flexible-dose study by Tucker and coworkers18 found response rates of 60% and 40% for paroxetine (20-50 mg) and placebo groups, respectively. Flexible-dose studies of sertraline (50-200 mg) by Brady et al27 and Davidson et al28 found drug response rates on the CAPS of 53% and 60%, respectively, for active treatment compared with 32% and 38%, respectively, for placebo. In the present study, the response rate at 12 weeks (defined as the percentage of patients who showed a ≥30% decrease in CAPS-SX17 score) was 78% in the venlafaxine ER group compared with 63.8% in the placebo group, a difference that was statistically significant (P<.01). The extent to which sampling factors account for the difference in the results of this study compared with the results of SSRI studies is hard to determine. There were somewhat more survivors of accidental injury and combat trauma in this study but fewer survivors of violent assault as well as differences in how trauma categories were defined between studies. It should also be noted that more recent published trials of antidepressants in depressed patients reveal higher response rates in patients treated with placebo or active treatment than do earlier trials, and a similar pattern may hold for efficacy studies in patients with PTSD.35

The number needed to treat for remission at the 6-month end point in our study was 8, indicating that for every 8 patients treated with venlafaxine ER, 1 additional patient would achieve remission relative to treatment with placebo, which could be considered a moderate effect of treatment. Remission rates were 50.9% for the venlafaxine ER group and 37.5% for the placebo group (LOCF). By comparison, in a study of patients treated for generalized anxiety disorder, Allgulander and colleagues (2002)36 found that the 6-month remission rate among patients receiving venlafaxine ER was 43% compared with 19% among patients receiving placebo. In a study of patients with social anxiety disorder, remission rates at 6 months were 31% for patients who received venlafaxine ER compared with 16% for those who received placebo.37 Our results, therefore, suggest that the remission rate in patients with PTSD following 6 months of treatment with venlafaxine ER or placebo is higher than the remission rate for patients with generalized anxiety disorder or social anxiety disorder.

Early withdrawal rates were similar for drug and placebo, although for somewhat different reasons. The maximum dose of venlafaxine ER in our study was higher than that used in other studies of this agent and exceeded the dose recommended in the product label. In designing the study, however, experts advised that allowing dosing as high as 300 mg would maximize the chance of achieving efficacy and would be consistent with standard clinical practice at that time.

Limitations of this study include the lack of statistical significance for the completer analysis of the CAPS-SX17 and the lack of a PTSD self-rating, which may be associated with greater effect-size differences between drug and placebo.34 Strengths include the 6-month duration, the higher dose of drug, the inclusion of stress-coping and resiliency measures, and the fact that this study forms part of the first major clinical trial program of a dual reuptake inhibitor in PTSD.

In the patient population we studied, made up of men and women presenting with diverse primary trauma types, we found that venlafaxine ER was effective and well tolerated during 6-month treatment of PTSD and had beneficial effects on PTSD and depression symptoms, resilience and stress vulnerability, functioning, quality of life, global well-being, and remission rate. Changes from baseline in response to treatment were similar between sexes with mean ± SD score changes of −50.6 ± 29.11 for men and −52.5 ± 25.64 for women in the group treated with venlafaxine ER and −43.6 ± 28.38 for men and −44.2 ± 29.57 for women in the group treated with placebo. Further pooled analyses of our data from this trial and the previous trial of venlafaxine ER in the treatment of patients with PTSD are under way to explore potential predictors of response and remission, including sex and type of trauma. From these analyses, as well as from a broader appraisal of serotonin norepinephrine reuptake inhibitors in general, we hope to gain a better understanding of the role played by this class of agents in the treatment of PTSD.

Correspondence: Jonathan Davidson, MD, Department of Psychiatry and Behavioral Sciences, Box 3812, Duke University Medical Center, Trent Drive, Fourth Floor, Room 4082B, Durham, NC 27710 (david011@mc.duke.edu).

Accepted for Publication: February 28, 2006.

Financial Disclosure: Dr Davidson has received honoraria as a speaker from Solvay, Pfizer, GlaxoSmithKline, Wyeth, Lichtwer Pharma, Forest, the American Psychiatric Association, the Henry Jackson Foundation, the University of Hawaii, the University of Utah, the University of North Carolina, the University of Chicago, the North Carolina Psychiatric Association, the Psychiatric Society of Virginia, the Texas Society of Psychiatric Physicians, the Massachusetts Psychiatric Society, and Duke University Medical Center. Dr Davidson has received research support from Pfizer, Solvay, Eli Lilly, GlaxoSmithKline, Wyeth, Organon, Forest, PureWorld, Allergan, Nutrition 21, Bristol Myers Squibb, Johnson and Johnson, Cephalon, AstraZeneca, Parke Davis, Pharmacia, Upjohn, UCB, Merck, Janssen, Roche, Ayerst, Boiron, Deutsche Homoopathie Union, the National Institute of Mental Health, the National Center for Complementary and Alternative Medicine, the Anxiety Disorders Association of America, the International Psychopharmacology Algorithm Project, and the Department of Veterans Affairs. Dr Davidson owns stock in Procter and Gamble. Dr Davidson has served as an advisor to Actelion, Solvay, Pfizer, GlaxoSmithKline, Forest, Eli Lilly, Ancile, Roche, MediciNova, Jazz, Novartis, Organon, Boehringer Ingelheim, MedTap, Research Triangle Institute, AstraZeneca, Johnson and Johnson, Wyeth, Bristol Myers Squibb, Boots, UCB, Sanofi, Cephalon, Alexza, Janssen, and Brain Cells. Dr Davidson has received study drug supplies from Eli Lilly, Schwabe, PureWorld, and Pfizer. Dr Davidson has received royalties from MultiHealth Systems Inc, Guilford Publications, the American Psychiatric Association, Penguin Putnam, Current Medical Science, Martin Dunitz, and Taylor and Francis. Dr Davidson has served as an expert witness in class actions against the Royal Ulster Constabulary and the Ministry of Defense (United Kingdom) and in cases of medical malpractice, patent litigation, and personal injury. Dr Baldwin has acted as a consultant to Asahi, Cephalon, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, Pfizer, Pharmacia, Pierre Fabre, Roche, Servier, Sumitomo, and Wyeth. Dr Baldwin holds or has held research grants (on behalf of his employer) from Cephalon, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, Pfizer, Pharmacia, Roche, and Wyeth. Dr Baldwin has accepted paid speaking engagements in industry-supported satellite symposia at international and national meetings. Dr Stein has received research grants and/or consultancy honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, and Wyeth. Drs Benattia and Ahmed and Messrs Pedersen and Musgnung are employees of Wyeth and as such receive stock options from Wyeth.

Funding/Support: This study was supported in part by Wyeth Pharmaceuticals.

Previous Presentations: This study was presented as a poster at the 43rd Annual Meeting of the American College of Neuropsychopharmacology (ACNP); December 12, 2004; San Juan, Puerto Rico; 8th Annual Meeting of the College of Psychiatric and Neurologic Pharmacists (CPNP); March 10, 2005; San Diego, Calif; Regional and International Congress of the World Psychiatric Association/Hellenic Psychiatric Association (WPA/HPA); March 12, 2005; Athens, Greece; 25th Annual Meeting of the Anxiety Disorders Association of America (ADAA); March 17, 2005; Seattle, Wash; 158th Annual Meeting of the American Psychiatric Association (APA); May 21, 2005; Atlanta, Ga; 45th Annual Meeting of the New Clinica Drug Evaluation Unit (NCDEU); June 6, 2005; Boca Raton, Fla; 8th World Congress of the World Federation of Societies of Biological Psychiatry (WFSBP); June 28, 2005; Vienna, Austria; 13th World Congress of the World Psychiatric Association (WPA); September 10, 2005; Cairo, Egypt; 18th Annual Meeting of the European College of Neuropsychopharmacology (ECNP); October 22, 2005; Amsterdam, the Netherlands; Annual Meeting of the American College of Clinical Pharmacy (ACCP); October 23, 2005; San Francisco, Calif; 21st Annual Meeting of the International Society for Traumatic Stress Studies (ISTSS); November 2, 2005; Toronto, Ontario; 18th Annual Meeting of the US Psychiatric and Mental Health Congress (USPMH); November 7, 2005; Las Vegas, Nev; and 40th Annual Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP); December 4, 2005; Waikoloa, Hawaii.

Acknowledgment: We acknowledge Michael P. Rennert, PhD, for his editorial assistance on this manuscript.

American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Kessler  RCSonnega  ABromet  EHughes  MNelson  CB Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;521048- 1060
PubMed Link to Article
Brunello  NDavidson  JRDeahl  MKessler  RCMendlewicz  JRacagni  GShalev  AYZohar  J Posttraumatic stress disorder: diagnosis and epidemiology, comorbidity and social consequences, biology and treatment. Neuropsychobiology 2001;43150- 162
PubMed Link to Article
Asnis  GMKohn  SRHenderson  MBrown  NL SSRIs versus non-SSRIs in post-traumatic stress disorder: an update with recommendations. Drugs 2004;64383- 404
PubMed Link to Article
Southwick  SMBremner  JDRasmusson  AMorgan  CA  IIIArnsten  ACharney  DS Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry 1999;461192- 1204
PubMed Link to Article
Kimble  MKaufman  M Clinical correlates of neurological change in posttraumatic stress disorder: an overview of critical systems. Psychiatr Clin North Am 2004;2749- 65
PubMed Link to Article
McFarlane  ACYehuda  RClark  CR Biologic models of traumatic memories and post-traumatic stress disorder: the role of neural networks. Psychiatr Clin North Am 2002;25253- 270
PubMed Link to Article
Thase  MEEntsuah  ARRudolph  RL Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001;178234- 241
PubMed Link to Article
Gelenberg  AJLydiard  RBRudolph  RLAguiar  LHaskins  JTSalinas  E Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: a 6-month randomized controlled trial. JAMA 2000;2833082- 3088
PubMed Link to Article
Allgulander  CMangano  RZhang  JDahl  AALepola  USjodin  IEmilien  G Efficacy of venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine. Hum Psychopharmacol 2004;19387- 396
PubMed Link to Article
Bradwejn  JAhokas  AStein  DJSalinas  EEmilien  GWhitaker  T Venlafaxine extended-release capsules in panic disorder: flexible-dose, double-blind, placebo-controlled study. Br J Psychiatry 2005;187352- 359
PubMed Link to Article
Baker  DGDiamond  BIGillette  GHamner  MKatzelnick  DKeller  TMellman  TAPontius  ERosenthal  MTucker  P A double-blind, randomized, placebo-controlled, multi-center study of brofaromine in the treatment of post-traumatic stress disorder. Psychopharmacology (Berl) 1995;122386- 389
PubMed Link to Article
Katz  RJLott  MHArbus  PCrocq  LHerlobsen  PLingjaerde  OLopez  GLoughrey  GCMacFarlane  DJMcIvor  R Pharmacotherapy of post-traumatic stress disorder with a novel psychotropic. Anxiety 1994;1169- 174
PubMed Link to Article
Davidson  JRothbaum  BOTucker  PAsnis  GBenattia  IMusgnung  JJ Venlafaxine extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled study. J Clin Psychopharmacol 2006;26259- 267
PubMed Link to Article
Londborg  PDHegel  MTGoldstein  SGoldstein  DHimmelhoch  JMMaddock  RPatterson  WMRausch  JFarfel  GM Sertraline treatment of posttraumatic stress disorder: results of 24 weeks of open-label continuation treatment. J Clin Psychiatry 2001;62325- 331
PubMed Link to Article
 The Post-Traumatic Stress Disorder Algorithm.  International Psychopharmacology Algorithm Project (IPAP)2005;http://www.ipap.orgAccessed on December 8, 2005
Blake  DDWeathers  FWNagy  LMKaloupek  DGGusman  FDCharney  DSKeane  TM The development of a Clinician-Administered PTSD Scale. J Trauma Stress 1995;875- 90
PubMed Link to Article
Tucker  PZaninelli  RYehuda  RRuggiero  LDillingham  KPitts  CD Paroxetine in the treatment of chronic posttraumatic stress disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 2001;62860- 868
PubMed Link to Article
Ballenger  JC Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry 2004;651696- 1707
PubMed Link to Article
Guy  W 028 CGI Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology, Revised 1976.  Bethesda, Md US Dept of Health, Education and Welfare, National Institute of Mental Health1976;217- 222
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Connor  KMDavidson  JR Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety 2003;1876- 82
PubMed Link to Article
Sheehan  DVRaj  ABSheehan  KHSoto  S Is buspirone effective for panic disorder? J Clin Psychopharmacol 1990;103- 11
PubMed Link to Article
Endicott  JNee  JHarrison  WBlumenthal  R Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull 1993;29321- 326
PubMed
Sheehan  DV The Anxiety Disease.  New York, NY Charles Scribners Sons1983;
Cook  RJSackett  DL The number needed to treat: a clinically useful measure of treatment effect [erratum in: BMJ. 1995;310:1056]. BMJ 1995;310452- 454
PubMed Link to Article
Brady  KPearlstein  TAsnis  GMBaker  DRothbaum  BSikes  CRFarfel  GM Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA 2000;2831837- 1844
PubMed Link to Article
Davidson  JRRothbaum  BOvan der Kolk  BASikes  CRFarfel  GM Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry 2001;58485- 492
PubMed Link to Article
Marshall  RDBeebe  KLOldham  MZaninelli  R Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 2001;1581982- 1988
PubMed Link to Article
Martenyi  FBrown  EBZhang  HPrakash  AKoke  SC Fluoxetine versus placebo in posttraumatic stress disorder. J Clin Psychiatry 2002;63199- 206
PubMed Link to Article
Hunsley  MSPalmiter  RD Norepinephrine-deficient mice exhibit normal sleep-wake states but have shorter sleep latency after mild stress and low doses of amphetamine. Sleep 2003;26521- 526
PubMed
Hunsley  MSPalmiter  RD Altered sleep latency and arousal regulation in mice lacking norepinephrine. Pharmacol Biochem Behav 2004;78765- 773
PubMed Link to Article
Davidson  JWatkins  LOwens  MKrulewicz  SConnor  KCarpenter  DKrishnan  RNemeroff  C Effects of paroxetine and venlafaxine XR on heart rate variability in depression. J Clin Psychopharmacol 2005;25480- 484
PubMed Link to Article
Davidson  JRTFarfel  GM Effect sizes of rating scales in two multicenter trials of sertraline and placebo in posttraumatic stress disorder [poster].  Presented at: 12th Annual Meeting of the European College of Neuropsychopharmacology September 21, 1999 London, England
Walsh  BTSeidman  SNSysko  RGould  M Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002;2871840- 1847
PubMed Link to Article
Allgulander  CHirschfeld  RMNutt  DJ Long-term treatment strategies in anxiety disorders. Psychopharmacol Bull 2002;3679- 92
PubMed
Liebowitz  MDavidson  JBlanco  CTummala  RJiang  Q Pooled analysis of response and remission rates with venlafaxine ER in social anxiety disorder [poster].  Presented at: Annual Meeting of the American College of Neuropsychopharmacology December 11-16, 2005 Waikoloa, Hawaii

Figures

Place holder to copy figure label and caption
Figure 1.

Study flowchart. ER indicates extended release.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Change in score on the Clinician-Administered Posttraumatic Stress Disorder Scale, the abbreviated 1-Week Symptom Status Version, from the baseline score. All values represent last observation carried forward unless otherwise stated. ER indicates extended release. P values are based on pairwise comparisons from an analysis of covariance model with treatment as the main effect and baseline as the covariate. Asterisk indicates P<.05; dagger, P<.01; and double dagger, P<.001.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Patients who achieved remission (last observation carried forward). Remission is defined as a total score of 20 or lower on the Clinician-Administered Posttraumatic Stress Disorder Scale, the abbreviated 1-Week Symptom Status Version. ER indicates extended release; OCs, observed cases. Asterisk indicates P<.05; dagger, P<.01.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline and Demographic Characteristics (ITT Population)
Table Graphic Jump LocationTable 2. Frequency of Trauma by Category
Table Graphic Jump LocationTable 3. Effects of Treatment on Total PTSD and Cluster Scores (LOCF)
Table Graphic Jump LocationTable 4. Effect Sizes for Selected Outcomes*
Table Graphic Jump LocationTable 5. Treatment-Emergent Adverse Events*
Table Graphic Jump LocationTable 6. Vital Signs and Cholesterol Levels at Final Visit (Week 24, LOCF)

References

American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Kessler  RCSonnega  ABromet  EHughes  MNelson  CB Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;521048- 1060
PubMed Link to Article
Brunello  NDavidson  JRDeahl  MKessler  RCMendlewicz  JRacagni  GShalev  AYZohar  J Posttraumatic stress disorder: diagnosis and epidemiology, comorbidity and social consequences, biology and treatment. Neuropsychobiology 2001;43150- 162
PubMed Link to Article
Asnis  GMKohn  SRHenderson  MBrown  NL SSRIs versus non-SSRIs in post-traumatic stress disorder: an update with recommendations. Drugs 2004;64383- 404
PubMed Link to Article
Southwick  SMBremner  JDRasmusson  AMorgan  CA  IIIArnsten  ACharney  DS Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry 1999;461192- 1204
PubMed Link to Article
Kimble  MKaufman  M Clinical correlates of neurological change in posttraumatic stress disorder: an overview of critical systems. Psychiatr Clin North Am 2004;2749- 65
PubMed Link to Article
McFarlane  ACYehuda  RClark  CR Biologic models of traumatic memories and post-traumatic stress disorder: the role of neural networks. Psychiatr Clin North Am 2002;25253- 270
PubMed Link to Article
Thase  MEEntsuah  ARRudolph  RL Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001;178234- 241
PubMed Link to Article
Gelenberg  AJLydiard  RBRudolph  RLAguiar  LHaskins  JTSalinas  E Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: a 6-month randomized controlled trial. JAMA 2000;2833082- 3088
PubMed Link to Article
Allgulander  CMangano  RZhang  JDahl  AALepola  USjodin  IEmilien  G Efficacy of venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine. Hum Psychopharmacol 2004;19387- 396
PubMed Link to Article
Bradwejn  JAhokas  AStein  DJSalinas  EEmilien  GWhitaker  T Venlafaxine extended-release capsules in panic disorder: flexible-dose, double-blind, placebo-controlled study. Br J Psychiatry 2005;187352- 359
PubMed Link to Article
Baker  DGDiamond  BIGillette  GHamner  MKatzelnick  DKeller  TMellman  TAPontius  ERosenthal  MTucker  P A double-blind, randomized, placebo-controlled, multi-center study of brofaromine in the treatment of post-traumatic stress disorder. Psychopharmacology (Berl) 1995;122386- 389
PubMed Link to Article
Katz  RJLott  MHArbus  PCrocq  LHerlobsen  PLingjaerde  OLopez  GLoughrey  GCMacFarlane  DJMcIvor  R Pharmacotherapy of post-traumatic stress disorder with a novel psychotropic. Anxiety 1994;1169- 174
PubMed Link to Article
Davidson  JRothbaum  BOTucker  PAsnis  GBenattia  IMusgnung  JJ Venlafaxine extended release in posttraumatic stress disorder: a sertraline- and placebo-controlled study. J Clin Psychopharmacol 2006;26259- 267
PubMed Link to Article
Londborg  PDHegel  MTGoldstein  SGoldstein  DHimmelhoch  JMMaddock  RPatterson  WMRausch  JFarfel  GM Sertraline treatment of posttraumatic stress disorder: results of 24 weeks of open-label continuation treatment. J Clin Psychiatry 2001;62325- 331
PubMed Link to Article
 The Post-Traumatic Stress Disorder Algorithm.  International Psychopharmacology Algorithm Project (IPAP)2005;http://www.ipap.orgAccessed on December 8, 2005
Blake  DDWeathers  FWNagy  LMKaloupek  DGGusman  FDCharney  DSKeane  TM The development of a Clinician-Administered PTSD Scale. J Trauma Stress 1995;875- 90
PubMed Link to Article
Tucker  PZaninelli  RYehuda  RRuggiero  LDillingham  KPitts  CD Paroxetine in the treatment of chronic posttraumatic stress disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 2001;62860- 868
PubMed Link to Article
Ballenger  JC Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry 2004;651696- 1707
PubMed Link to Article
Guy  W 028 CGI Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology, Revised 1976.  Bethesda, Md US Dept of Health, Education and Welfare, National Institute of Mental Health1976;217- 222
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Connor  KMDavidson  JR Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety 2003;1876- 82
PubMed Link to Article
Sheehan  DVRaj  ABSheehan  KHSoto  S Is buspirone effective for panic disorder? J Clin Psychopharmacol 1990;103- 11
PubMed Link to Article
Endicott  JNee  JHarrison  WBlumenthal  R Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull 1993;29321- 326
PubMed
Sheehan  DV The Anxiety Disease.  New York, NY Charles Scribners Sons1983;
Cook  RJSackett  DL The number needed to treat: a clinically useful measure of treatment effect [erratum in: BMJ. 1995;310:1056]. BMJ 1995;310452- 454
PubMed Link to Article
Brady  KPearlstein  TAsnis  GMBaker  DRothbaum  BSikes  CRFarfel  GM Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA 2000;2831837- 1844
PubMed Link to Article
Davidson  JRRothbaum  BOvan der Kolk  BASikes  CRFarfel  GM Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry 2001;58485- 492
PubMed Link to Article
Marshall  RDBeebe  KLOldham  MZaninelli  R Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 2001;1581982- 1988
PubMed Link to Article
Martenyi  FBrown  EBZhang  HPrakash  AKoke  SC Fluoxetine versus placebo in posttraumatic stress disorder. J Clin Psychiatry 2002;63199- 206
PubMed Link to Article
Hunsley  MSPalmiter  RD Norepinephrine-deficient mice exhibit normal sleep-wake states but have shorter sleep latency after mild stress and low doses of amphetamine. Sleep 2003;26521- 526
PubMed
Hunsley  MSPalmiter  RD Altered sleep latency and arousal regulation in mice lacking norepinephrine. Pharmacol Biochem Behav 2004;78765- 773
PubMed Link to Article
Davidson  JWatkins  LOwens  MKrulewicz  SConnor  KCarpenter  DKrishnan  RNemeroff  C Effects of paroxetine and venlafaxine XR on heart rate variability in depression. J Clin Psychopharmacol 2005;25480- 484
PubMed Link to Article
Davidson  JRTFarfel  GM Effect sizes of rating scales in two multicenter trials of sertraline and placebo in posttraumatic stress disorder [poster].  Presented at: 12th Annual Meeting of the European College of Neuropsychopharmacology September 21, 1999 London, England
Walsh  BTSeidman  SNSysko  RGould  M Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002;2871840- 1847
PubMed Link to Article
Allgulander  CHirschfeld  RMNutt  DJ Long-term treatment strategies in anxiety disorders. Psychopharmacol Bull 2002;3679- 92
PubMed
Liebowitz  MDavidson  JBlanco  CTummala  RJiang  Q Pooled analysis of response and remission rates with venlafaxine ER in social anxiety disorder [poster].  Presented at: Annual Meeting of the American College of Neuropsychopharmacology December 11-16, 2005 Waikoloa, Hawaii

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