Rapaport 2001.

Study characteristics
Methods	Design: multi‐centre multi‐phase double‐blind randomised placebo‐controlled study Prerandomisation phases Phase 0: 2‐week placebo run‐in Phase 1: 3 double‐blind acute treatments with sertraline 50 to 200 mg/d vs placebo (10 weeks) Phase 2: open‐label continuation treatment with sertraline at the same dose (52 weeks) Duration post randomisation: 28 weeks Aim: to investigate long‐term efficacy, prevention of relapse, and safety of sertraline for treatment of panic disorder
Participants	Country: USA Setting: community adults (outpatients from 31 clinical centres) Type of AD: sertraline Duration of antidepressant prerandomisation: 62 weeks Duration of antidepressant post stabilisation: 52 weeks Number of participants: 555 entered phase 1, 426 completed, 396 entered phase 2, 217 completed and responded to phase 2 Total number of randomised participants: 183 (placebo 90, sertraline 93) Primary diagnosis: panic disorder with or without agoraphobia Anxiety severity symptoms at randomisation (SD) PDSS score: 2.48 (2.6) placebo, 2.10 (2.0) antidepressant CGI severity: 1.73 (0.8) placebo, 1.71 (0.7) antidepressant HAM‐A: 5.97 (4.4) placebo, 6.04 (4.6) antidepressant Gender distribution (F): 62.2% placebo, 65.6% sertraline Mean age, years (SD): 40.30 (11.4) placebo, 41.00 (10.8) sertraline Inclusion criteria ‐ 18 years of age or older ‐ SCID‐I‐confirmed DSM‐III diagnosis of panic disorder with or without agoraphobia ‐ 4 or more panic attacks during the 4 weeks before screening, 3 or more panic attacks during a 2‐week placebo washout period, and HAM‐A total score ≥ 18 at baseline of phase 1 ‐ after 1 year, patients who met responder criteria were randomised to 28 weeks of double‐blind treatment with either sertraline or placebo Defintion of response/remission: CGI‐Improvement score of 1 (‘very much improved’) or 2 (‘much improved’) at Week 52 compared to baseline in the acute studies Exclusion criteria ‐ HDRS‐21 total score ≥ 18 at baseline of phase 1 ‐ current diagnosis of major depression, bipolar disorder, organic mental disorder, schizophrenic disorder; alcohol or substance abuse in the previous 6 months ‐ current principal diagnosis of dysthymia, obsessive‐compulsive disorder, any other anxiety disorder (besides panic disorder), or any personality disorder ‐ use of concomitant psychotropic medication (or a positive urine drug screen) ‐ previous treatment with sertraline ‐ females who are pregnant, nursing, or not practising a medically accepted form of birth control
Interventions	Intervention 1: placebo Tapering scheme: "discontinuation was immediate" Intervention 2: sertraline treatment 50 to 200 mg/d, with daily dose adjusted by 50‐mg increments on a weekly basis determined by clinical response and tolerability
Outcomes	Primary outcomes ‐ relapse Definition of relapse (1) CGI‐I ≥ 3 (reflecting, at best, minimal improvement from baseline in acute studies) at 3 consecutive visits at 2‐week intervals (additional visits were scheduled, if required) (2) meeting criteria for DSM‐III‐R panic disorder by the third visit; and (3) reporting more full symptom panic attacks during previous 4 weeks than during the last 4 weeks of open‐label treatment ‐ discontinuation due to insufficient clinical response, clinician rated. Any subject is discontinued from the double‐blind portion of the study by the investigator because of insufficient clinical response; this includes patients who meet the strict definition of relapse ‐ exacerbation of panic disorder symptoms Definition of exacerbation: 2 consecutive visits where there is: (1) CGI‐I ≥ 4 (no change or worsening from baseline in acute studies); (2) a 2‐point increase in CGI‐Improvement score (e.g. from 1, ‘very much improved’, to a minimum of 3, ‘minimally improved’); or (3) a score on at least 1 subscale of the PDSS that increased to 3 (‘severe’ or ‘definite’ discomfort) ‐ adverse events, observed and volunteered (rating instrument was not used)
Notes	Funding: study was supported by a grant from the pharmaceutical industry COI: not described
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: information insufficient to permit judgement
Allocation concealment (selection bias)	Unclear risk	Comment: information insufficient to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: information insufficient to permit judgement Quote: "double‐blind treatment"; "during double‐blind treatment, both groups were permitted to have their daily dose adjusted by 50‐mg increments on a weekly basis determined by clinical response and tolerability"
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: higher dropout rate in placebo group (50.6%) than in sertraline group (31.5%); last observation carried forward ('LCOF') analyses
Selective reporting (reporting bias)	High risk	Comment: study protocol not available; adverse events reported; no withdrawal symptoms measured
Other bias	Unclear risk	Comment: grant from the pharmaceutical industry