Davidson 2006a.

Study characteristics
Methods	NEW TRIAL ADDED TO UPDATED REVIEW Design: multi‐centre trial, randomised, placebo‐controlled, parallel arm, flexible dose, double‐blind Duration of intervention: 24 weeks, followed by a taper period of up to 2 weeks and post‐study evaluation (4 ‐ 10 days after taper) Placebo run‐in: washout period of at least 7 days Post‐treatment: Not specified
Participants	Setting: Quote: “International study at 56 outpatient psychiatric clinic sites in Argentina, Chile, Colombia, Denmark, Finland, Mexico, Norway, Portugal, South Africa, Spain, Sweden, and the United Kingdom" Sample size: 329 randomised to venlafaxine ER and placebo Mean age: 41.35 (18.60) years Sex: 151 men and 178 women, 40 combat Diagnostic measure: DSM‐IV Inclusion criteria: Quote: “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‐IV 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); 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" Exclusion criteria: Quote: "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" Comorbidity: Not specified Dropouts: 105/329 (49/161 in the venlafaxine ER and 56/168 in the placebo group)
Interventions	Pharmacological intervention: Quote: “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 cut off 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"
Outcomes	Primary outcomes: CAPS‐SX‐17 Secondary outcomes: CGI‐S, GAF, HDRS‐17, CD‐RISC, SVS, a 1‐item scale that rates the magnitude of setbacks to stressful events or personal problems experienced by participnts from the time of their last visits, Q‐LES‐Q‐SF, a 16‐item scale that assesses the degree of enjoyment and satisfaction in various areas of daily life, SDS, 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 Time points: Quote: “The primary outcome was measured at baseline and weeks 2, 4, 6, 8, 12,18, and 24. The CGI‐S, HDRS‐17 and the SDS were measured at baseline and weeks 2, 4, 6, 8, 12, 18, and 24; the Q‐LES‐Q‐SF, CD‐RISC and the SVS, at baseline and weeks 4, 12, and 24; and the GAF, at baseline and weeks 12 and 24" Data estimation: LOCF, completer analysis
Notes	Dates of trial: Not stated Industry‐funded: Yes. Quote: "This study was supported in part by Wyeth Pharmaceuticals" Medication provided by industry: No Any of the authors work for industry: Yes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "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"
Allocation concealment (selection bias)	Low risk	Quote: "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"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	The study was described as "double‐blind", although no information was provided on which parties were blinded and how blinding was achieved. Quote: "Design: 6‐month, double‐blind, placebo‐controlled trial"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	The study was described as "double‐blind", although no information was provided on blinding of outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Low risk	A similar proportion of participaents withdrew from the venlafaxine ER group (49/161, 30%) compared to the placebo group (56/168; 33%). The 2 groups did not differ by sample characteristics at baseline. The ITT population was used at baseline and LOCF at endpoint Quote: "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. For patients who discontinued participation before study completion, the last post dose observed value was used for end point analysis (LOCF). In addition to the LOCF value, the observed changes at each visit were computed"
Selective reporting (reporting bias)	Unclear risk	The study protocol was not available for this study
Other bias	Unclear risk	Funding for study provided by industry Quote: "This study was supported in part by Wyeth Pharmaceuticals"