Mavissakalian 1999.

Study characteristics
Methods	Design: multi‐phase double‐blind randomised placebo‐controlled trial Prerandomisation phases Phase 0: single‐blind placebo run‐in (2 weeks) Phase 1: acute open‐label treatment with imipramine (24 weeks) Duration post randomisation: 52 weeks Aim: to assess the 12‐month cumulative risk of relapse specifically due to discontinuation of imipramine and to test the hypothesis that maintenance treatment with imipramine protects patients with panic disorder and agoraphobia from such reversals
Participants	Country: USA Setting: community adults (outpatients from Phobia and Anxiety Disorders Clinic, Ohio State University Medical Center, Columbus; either trough clinical referrals or in response to media coverage or advertisement) Type of AD: imipramine Duration of antidepressant treatment prerandomisation: 24 weeks Duration of antidepressant treatment post stabilisation: 0 weeks Number of participants: 110 entered phase 1, 59 were in stable remission after phase 1 Total number of randomised participants: 56 (27 placebo, 29 antidepressant) Primary diagnosis: panic disorder with agoraphobia Severity of anxiety symptoms at randomisation, mean (SD) GAS: 1.37 (0.49) placebo, 1.59 (0.5) antidepressant Self‐rating severity: placebo 0.81 (0.92), 1.1 (0.82) antidepressant 17‐HRDS: placebo 3.85 (3.5), 3.9 (2.88) antidepressant Comorbidity: 1 or 2 concurrent anxiety disorders (%): 37% placebo, 27.6% antidepressant Gender distribution (F): 20% placebo, 18% antidepressant Mean age, years (SD): 37.89 (9.92) placebo, 34.28 (8.23) antidepressant Inclusion criteria ‐ patients who met operationalised response criteria at both 16‐ and 24‐week assessments after 24 weeks of imipramine were entered into phase 2 of the trial ‐ meeting SCI DSM‐III‐R diagnostic criteria for panic disorder with agoraphobia ≥ moderate severity and 3 months’ duration and experiencing active recurrent panic attacks at the time of initial evaluation ‐ free of psychotropic drug use for 14 days before treatment began, except patients who were unable to stop using benzodiazepines initially (and have to taper off gradually, starting at Week 4 and discontinued by Week 16 assessment) to qualify for randomisation to the maintenance study. 3 patients in each group began treatment while taking benzodiazepines Definition of response/remission: ≥ 50% improvement from pretreatment scores or a cutoff score signifying mild to absent symptoms simultaneously on 6 or all of these measures Exclusion criteria ‐ evidence of organic mental disorders ‐ psychotic, bipolar, and OCD ‐ primary or current major depression with melancholia ‐ suicidal intention or score ≥ 18 on HDRS‐17 ‐ PTSD somatisation disorder, severe personality disorders (borderline, schizotypal), and substance abuse disorder (current or in remission for < 6 months). In addition, patients had to be in good general health, have no contraindications for the use of imipramine because of illness or because of treatment necessary for the illness, and had to demonstrate compliance during an initial 2‐week single‐blind placebo run‐in
Interventions	Intervention 1: placebo (4 identical looking tablets) Tapering scheme: 25% decrements in dose each week so that dose of 0 mg was reached on the 22nd day of randomisation. Identical‐looking tablets daily at bedtime Intervention 2: imipramine at same dose (10 mg, 25 mg, 50 mg, or 75 mg), identical looking tablets daily at bedtime. Target dose of 2.25 mg/kg per day Co‐intervention: no additional psychological or psychiatric treatments, but if participants had problems, additional visits for supportive intervention were provided (brief 1‐ or 2‐session, crisis‐type intervention)
Outcomes	‐ relapse: based on composite index of End‐State (ESF range 0 to 7) derived from 7 measures Global assessment of severity (1 to 5) Self‐rating of severity (0 to 8) Phobic avoidance and anxiety (0 to 8) Fear questionnaire, agoraphobia (0 to 40) Behavioural assessment test (0 to 8) Panic severity, patient related (0 to 8) Panic severity, clinician related (0 to 4) ‐ definition of worsening: ESF ≤ 4 signified at least a 33% decline in ESF Defnition of relapse ‐ at which time patients exited the study, also required that worsening be accompanied by insistent requests for therapeutic action and/or that worsening still be present in a repeated confirmatory assessment 2 weeks later ‐ survival analysis for worsening ‐ survival time without relapse, worsening, exiting (months) ‐ number of panic attacks (DSM‐III definition of panic attacks, 2‐week diary, monthly) ‐ depressive symptoms assessed by 17‐HDRS
Notes	COI: not reported Funding: supported by grant from the National Institute of Mental Health
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: random sequence generation by computer random number generator Quote: “hospital pharmacist, who used computer numbers to randomly assign patients to same‐dose imipramine continuation or placebo substitution”
Allocation concealment (selection bias)	Low risk	Comment: central allocation Quote: "treatment condition was known only by the hospital pharmacist, who used computer numbers"; “hospital pharmacist, who used computer numbers to randomly assign patients to same‐dose imipramine continuation or placebo substitution”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: blinding of participants and key study personnel ensured; unlikely that the blinding could have been broken Quote: "dated packets prepared by the hospital pharmacist, each containing four identical looking tablets composed of placebo or 10, 25, 50, or 75 mg of imipramine hydrochloride to be taken at bedtime"; "treatment condition was only known by the hospital pharmacist"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: information insufficient to permit judgement Quote: "same clinical psychologist administered all diagnostic and clinical assessments"
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 62% of placebo and 31% of imipramine patients did not complete
Selective reporting (reporting bias)	High risk	Comment: adverse events and withdrawal symptoms are not reported and are fundamental outcomes in drug discontinuation studies. Panic attack/HAM‐D 17 measures reported only for participants who had relapse after discontinuation of antidepressant
Other bias	Low risk	None