Trial Examining Methods for Antidepressant Discontinuation

Rationale: For discontinuation, two fundamentally different ways of antidepressant discontinuation exist: 1) a conventional 2-step reduction, halving dosages with available dosage-units and then stop over 2-4 weeks (currently treatment as usual), and 2) more gradual reduction (dose reduction with progressively smaller dosage-units). The crucial difference between these ways of antidepressant discontinuation are free-fall vs. linear decreases of SERT occu¬pancies, respectively. These two ways have not been directly compared in a double-blind RCT. This lack of evidence leaves patients, clinicians, pharmacists and policy-makers uncertain about rational methods to discontinue antidepressants. Objective: TEMPO will compare two tapering strategies in patients with remitted MDD who use either paroxetine (PAR) or venlafaxine (VLX). We will evaluate effectiveness (number of patients that can discontinue their antidepressant; depression-scores and discontinuation symptoms), pharmacokinetics during the course of discontinuation, relapse rates during 6 months of follow-up after deblinding, patients attitudes and perceived difficulty during discontinuation and cost-effectveness. Study design: Multicenter randomized (1:1) clinical trial of 200 patients with remitted major depressive disorder (MDD, retrospectively assessed by semi-structured interview) using paroxetine (PAR, 20-50mg, n=100) or venlafaxine (VLX, 75-375mg, n=100). After double blind discontinuation of antidepressants, we will follow patients up for ≥6 months (no medication or blindng). Study population: Patients (18-75 years) with stable 6-month remission of MDD with confirmed >6 months use of PAR (20-50mg, N=100) or VLX (75-375mg, N=100). Exclusion criteria are psychotic/bipolar disorder, severe drug/alcohol addiction, insufficient mastery of Dutch language. Intervention: Concealed randomization by computer (1:1) to either of the two tapering strategies. Main study parameters/endpoints: Rate of failure to successfully discontinue antidepressant: defined as significant deviation from discontinuation antidepressant protocol (e.g. switching to rescue medication, stopping with discontinuation medication) or significant withdrawal symptoms during the double blind phase.

Succes-rate of discontinuation is higher with more gradual tapering of paroxetine or venlafaxine

Multicenter double-blind randomized (1:1) clinical trial of 200 patients with remitted MDD (assessed with semi-structured interview) using paroxetine (PAR, 20-50mg, n=100) or venlafaxine extended release (VLX, 75-375mg, n=100). The double-blind discontinuation phase is followed by an open label phase without medication, while blinding of tapering-method is maintained. With patients who drop-out during discontinuation, after unblinding, we will discuss an alternative, open label discontinuation plan, chosen via shared decision making, to enable another (prospectively monitored) discontinuation attempt.

We compare two active tapering strategies