Rickels 2010.

Study characteristics
Methods	Design: single‐centre multi‐phase double‐blind randomised placebo‐controlled trial Prerandomisation phases Phase 1: for all participants: open‐label treatment with venlafaxine extended release (ER) (70 to 225 mg) (24 weeks) Phase 2: for participants with 12 months' treatment before randomisation: open‐label treatment with venlafaxine extended release (ER) (70 to 225 mg) (24 weeks) and continuation treatment with venlafaxine extended release (ER) (70 to 225 mg) (24 weeks) Duration post randomisation: 24 weeks Aim: to examine the long‐term efficacy of venlafaxine XR in patients with chronic GAD who responded therapeutically to 6‐month or 12‐month venlafaxine XR treatment
Participants	Country: USA Setting: community adults (recruited by research psychiatrists in 4 primary care practices, recruited by media advertising, or were treated in our central clinic at University of Pennsylvania) Type of antidepressant: venlafaxine ER (70 to 225 mg) Duration of antidepressant treatment prerandomisation AD: 24 weeks or 48 weeks Duration of antidepressant treatment post stabilisation: 0 weeks or 24 weeks Primary diagnosis: generalised anxiety disorder Number of participants: 286 entered phase 1, 158 completed phase 1, 136 entered phase 2 Total number of randomised participants: 136 participants with 6 months' antidepressant before randomisation (54 placebo, 82 antidepressant) and 49 participants with 12 months'  before randomisation (15 venlafaxine ER, 34 placebo) Severity of anxiety symptoms at randomisation (HAM‐A), mean (SD): participants with 6 months' antidepressant before randomisation: 4.17 (3.10); participants with 12 months antidepressant before randomisation: 3.89 (3.43) Severity of depression symptoms at randomisation (HAM‐D), mean (SD): participants with 6 months' antidepressant before randomisation: 3.71 (3.08); participants with 12 months' antidepressant before randomisation: 3.17 (2.45) Gender distribution (F): participants with 6 months' antidepressant before randomisation: 62.5%; participants with 12 months' antidepressant before randomisation: 59.3% Mean age, years (SD): participants with 6 months' antidepressant before randomisation: 49.8 (15.8); participants with 12 months' antidepressant before randomisation: 59.3 (15.0) Inclusion criteria ‐ ≥ 18 years of age ‐ meeting the criteria for generalised anxiety disorder (determined by the SCID‐I for DSM‐IV criteria) ‐ sufficient symptoms to require anxiolytic drug therapy, including HAM‐A ≥ 20 at screen and CGI‐S ≥ 4 at baseline ‐ responders to 6 months' open‐label treatment (at least moderately improved (CGI‐I score ≤ 2) from baseline) or 6 months' open‐label treatment and open‐label and continuation treatment with venlafaxine extended release (ER) (70 to 225 mg) (24 weeks) Definition of response: CGI‐I score ≤ 2 Exclusion criteria ‐ eating disorder such as bulimia and anorexia, substance abuse, or dependence during the past 6 months ‐ any current anxiety spectrum DSM‐IV diagnosis other than GAD ‐ an episode of MDD in the previous 6 months or depressive symptoms at study intake (HAM‐D score ≥ 18) ‐ current or past history of dementia, bipolar disorder, schizophrenia, or other psychotic disorders ‐ positive urine drug screens for amphetamines, cocaine, phencyclidine hydrochloride, methadone hydrochloride, or barbiturates were immediate exclusion criteria, as were uncontrolled medical conditions and hypersensitivity to venlafaxine, as well as pregnancy, breastfeeding, or a positive urine pregnancy test
Interventions	Intervention 1: placebo Tapering scheme: tapering over 1 to 3 weeks. Study dosage was reduced by 75 mg weekly, with reduction to 37.5 mg during the last week. Depending on the patient’s study drug daily dose, this taper could last from 1 to 3 weeks. Gradual tapering was facilitated with a patient diary Intervention 2: venlafaxine 75 to 225 mg per day Results were separately reported for participants with 6 months' antidepressants before randomisation and for participants with 12 months' antidepressants before randomisation
Outcomes	Primary outcomes ‐ relapse Definition of relapse: meeting symptom criteria for a Structured Clinical Interview for DSM‐IV GAD diagnosis with HAM‐A score ≥ 16, a CGI, CGI‐S score ≥ 4 (moderate or higher), and CGI‐I score of 6 or 7 (worse or very much worse) compared with baseline of the double‐blind relapse phase, and present for 2 successive visits, spaced 2 weeks apart, with the last visit conducted at least 3 weeks after taper completion ‐ remission Defintion of remission: CGI of 1 or HAM‐A ≤ 7 Secondary outcomes ‐ HAM‐A, CGI‐S, CGI‐I, patient‐rated Hospital Anxiety and Depression Scale (biweekly for the first 8 weeks and monthly thereafter) ‐ HAM‐D, Sheehan Disability Scale, and quality of life assessed by General Health Questionnaire ‐ adverse events were assessed at each visit by an open‐ended approach, which was facilitated by the use of a physician‐completed medication problem checklist. Adverse events were rated by severity, duration, and association with study medication (probably related, possibly related, or non‐related) ‐ potential withdrawal symptoms were assessed at selective time points using a patient‐completed withdrawal checklist, which was based on a checklist developed by Fava et al
Notes	Funding: study was supported by a grant from the pharmaceutical industry. Pharmaceutical company provided all study medication COI: 2 study authors (including principal author) received grants from the pharmaceutical company that provided study medication for this trial
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: information insufficient to permit judgement Quote: "responders to 6 months of open‐label venlafaxine XR treatment were randomised to double‐blind treatment in a 60:40 ratio of drug to placebo"; "a stratified randomisation was used, including level of secondary depressive symptoms at intake and improvement status after 6 months of venlafaxine XR therapy“
Allocation concealment (selection bias)	Unclear risk	Comment: information insufficient to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: study described as double‐blind trial; however information insufficient to permit judgement Quote: "double‐blind treatment in a 60:40 ratio of drug to placebo"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: information insufficient to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: dropout rates high and not balanced across groups: 14/54 (25%) dropouts in placebo group and 18/82 (21%) dropouts in antidepressant group. Reasons for dropout reported
Selective reporting (reporting bias)	High risk	Comment: study protocol not available; adverse events reported but incompletely (not all adverse events for each treatment group reported); no information on withdrawal symptoms reported
Other bias	Unclear risk	Comment: grant from the pharmaceutical industry