General Practitioner & Pharmacist Support for Discontinuing Long-term Antidepressants in Clinically Stable Patients

• GPS-AD intervention (Behavioral), also known as AD discontinuation, AD deprescribing: The GPS-AD intervention is a structured collaboration between GPs and community pharmacists designed to support the safe discontinuation of long-term AD use in clinically stable adults. The intervention incorporates behavioural activation, motivational support, shared decision-making, personalised tapering schedules, and collaborative care. It follows a stepped-care model and clearly defines the roles of both the GP and pharmacist. It starts with an invitation letter and educational brochure that encourages patients to book an appointment with their GP to review their AD use. This is followed by at least one consultation with the GP to discuss the option of tapering AD. If the patient is ready, a personalised tapering plan will be started in collaboration with the pharmacist. The pharmacist provides an initiation consultation, including medication review, tapering plan, potential withdrawal symptoms, motivational support, and a closing consultation focused on future coping.

Primary outcomes

• AD discontinuation (superiority) [12 months post-randomisation]: Proportion of participants who have stopped antidepressant medication for ≥2 consecutive months at the 12-month follow-up assessment, based on participant self-report. This is a binary measure (yes/no).
• Depressive symptom severity (inferiority) [12 months post-randomisation]: PHQ-9 total score (range 0-27; higher scores indicate more severe depressive symptoms) at 12 months post-randomisation; this is a continuous metric. Difference in baseline-corrected mean between groups will be evaluated, with 95% CI. Non-inferiority will be assessed using a prespecified non-inferiority margin of 2 points. In this trial, we use co-primary endpoints. The trial will conclude effectiveness only if (1) discontinuation is superior and (2) PHQ-9 is non-inferior.

Secondary outcomes

• AD discontinuation [6, 18 and 24 months post-randomisation]: Proportion of participants who have stopped antidepressant medication for ≥2 consecutive months at the 6-month follow-up assessment, based on participant self-report. This is a binary measure (yes/no) at 6, i.e. short-term, 18 and 24, i.e. long-term, months.
• Depressive symptom severity [6, 18 and 24 months post-randomisation]: PHQ-9 total score
• Suicidal ideation [6, 12, 18, and 24 months]: Patient-reported suicidal ideation assessed using item 9 of the Patient Health Questionnaire-9 (PHQ-9), scored 0-3, with higher scores indicating more frequent suicidal thoughts.
• Health-related quality of life [6, 12, 18 and 24 months]: Health-related quality of life measured using the EQ-5D-5L questionnaire, summarized as a country-specific index value derived from the five dimensions
• Mental wellbeing [6, 12, 18, and 24 months post-randomisation]: Mental wellbeing assessed using the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS), with higher total scores indicating better mental wellbeing.

Other outcomes

• Safety: adverse effects of AD [6, 12, 18, 24 months post-randomisation]: Patient-reported adverse effects of antidepressants assessed using the Antidepressant Side-Effect Checklist (ASEC). The ASEC includes 21 predefined side effects
• Safety: relapse or new depressive episode [6, 12, 18 and 24 months post-randomisation]: Occurrence of relapse or new depressive episode during the preceding 6 months, assessed by the GP based on clinical evaluation and electronic health record review (Yes/No).
• Safety: withdrawal symptoms [6 and 12 months]: Patient-reported antidepressant withdrawal symptoms assessed using an abbreviated version of the Discontinuation Emergent Signs and Symptoms (DESS) questionnaire.
• Safety: clinician-assessed withdrawal symptoms [6 and 12 months post-randomisation]: GP-reported occurrence of antidepressant withdrawal symptoms during the preceding 6 months, based on clinical evaluation and electronic health record review (Yes/No).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

Patients will be eligible for inclusion in the study if they meet all of the following criteria:

* Are 18 years or older and capable of providing informed consent.
* Have their Global Medical File (GMD) managed by one of the participating GPs.
* Have been prescribed AD (any type) by their GP for the treatment of depression, with:

  * at least 6 months of continuous daily use following a first depressive episode, or
  * at least 2 years of continuous daily use in the context of a relapsed depression/recurrent episode
* Are judged by their GP as no longer meeting the criteria for a current depressive disorder.

Exclusion Criteria:

Patients will be excluded from participation in the study if they meet any of the following criteria:

* AD discontinuation is considered contra-indicated by the treating GP.
* The patient is judged by the GP to be at high risk of relapse. This includes any of the following:

  * Current significant depressive symptoms, defined as a score of ≥12 on the PHQ-9
  * Current significant anxiety symptoms, defined as a score of ≥10 on the Generalised Anxiety Disorder-7 (GAD-7) scale.
  * Current suicidal ideation, defined as a score >0 on item 9 (suicidality) of the PHQ-9.
  * The patient is currently receiving only psychiatric treatment (out- or inpatient) for depression

In addition to the criteria increasing the risk of relapse, the following will also be an exclusion criteria:

* The patient has a current psychiatric comorbidity (e.g. bipolar disorder, psychosis, substance use)
* The patient has a diagnosis of dementia or significant cognitive impairment (assessed by GP judgement) or is living in a nursing home.
* The AD is prescribed for a primary indication other than depression, such as anxiety alone without comorbid depressive disorder, or chronic pain.
* The patient has insufficient language proficiency in Dutch or French to participate in the study procedures (e.g. providing consent, completion of questionnaires, interviews).
* use of trazodon as AD as this is mainly used for sleep problems

• Ellen Van Leeuwen, MD, PhD, Principal investigator, University Ghent