Trial Examining Methods for Antidepressant Discontinuation

Two different ways of antidepressant discontinuation currently exist: 1) a
conventional reduction which halves dosages with available dosage-units and
stop over the course of weeks (currently treatment as usual), and 2) a more
gradual dose reduction with progressively smaller dosage-units over a longer
period. However, it is currently unknown whether one method is preferred about
the other, and these two ways of antidepressant discontinuation 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.

This study has been transitioned to CTIS with ID 2024-511997-66-00 check the CTIS register for the current data.

TEMPO will directly compare i) conventional 2-step reduction with ii) gradual
tapering in patients with remitted MDD who use either the antidepressant
paroxetine (PAR) or venlafaxine (VLX). We will evaluate the number of patients
that can successfully discontinue PAR or VLX between arms, based on either
discontinuation symptoms or relapse of major depressive disorder (MDD).

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.

Concealed stratified block randomization by computer (1:1) to: i) conventional
tapering strategy (N=100 [~50 PAR/~50 VLX]) or ii) gradual tapering strategy
(N=100 [~50 PAR/~50 VLX]) over a 16-week period.

Discontinuation of antidepressants can cause withdrawal symptoms and relapse
patterns might be less favorable when antidepressants are discontinued less
slowly compared to gradual tapering, which is unknown and a secondary outcome
of this study. However, these risks are not higher during this study than those
of antidepressant discontinuation in daily clinical practice. Because the
clinical population under study is vulnerable for recurrences of depression, we
classify the risk as moderate. To decrease the risk of experiencing withdrawal
symptoms, we use relatively slow tapering of the antidepressant dose in the
conventional arm, which is also done in current clinical practice and in line
with Dutch clinical guidelines and the multidisciplinary document *Afbouwen
SSRI*s en SNRI*s'.
The burden of the study for patients consists of making time to visit the study
center 6-9 times during a year, have an additional 12-14 telephone assessments
and fill out questionnaires regularly from their own home and on their
smartphone. Furthermore, it may be confronting for depressed individuals to be
asked about their mood and possible suicidal ideation. There will be two blood
draws, done by a fieldworker or researcher who is qualified to draw blood
thereby minimalizing the risk of injury.
Adverse side effects and withdrawal symptoms, medication adherence, and
depressive and suicidal symptoms will be closely monitored with structured
measurement instruments. SAEs and SUSARs will be closely monitored as well.
There will be close contact between the physicians/pharmacists of the TEMPO
research team and the patient*s own physician in case of relapse or severe
withdrawal symptoms. Overall we consider the risk of this study as moderate.