A Randomized Controlled Trial Comparing Tapering Strategies for Discontinuation of Paroxetine Hydrochloride and Venlafaxine in Remitted Major Depressive Disorder

The primary objective of the Trial Examining Methods for Antidepressant Discontinuation (TEMPO) is to evaluate the optimal strategy for discontinuing **antidepressants** in patients with stable remitted **Major Depressive Disorder** (MDD). This double-blind, placebo-controlled randomized controlled trial (RCT) will compare two tapering strategies in patients using either **paroxetine hydrochloride** or **venlafaxine**. The clinical relevance of this study lies in its potential to inform best practices for safely discontinuing antidepressant therapy, thereby minimizing withdrawal symptoms and relapse risk in patients with MDD.

The clinical trial focuses on individuals diagnosed with **Major Depressive Disorder** (MDD) who are in stable remission. The study population includes both male and female participants aged between 18 and 75 years. Participants are required to have a stable remission of MDD for at least six months, or one year in cases of recurrent MDD, as confirmed by a score of 12 or lower on the Patient Health Questionnaire 9 (PHQ-9). Eligible participants must be current users of paroxetine (20-50mg) or venlafaxine (75-375mg) and have had a previous MDD episode with current remission confirmed through a semi-structured psychiatric interview (MINI). The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. Participants must be willing and able to provide informed consent and adhere to the study procedures. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations.

The clinical trial is designed as a **double-blind**, placebo-controlled, randomized controlled trial (RCT) to evaluate the optimal strategies for discontinuing antidepressants in patients with **Major Depressive Disorder** (MDD) who are in stable remission. The trial will compare two tapering strategies for patients using either **paroxetine hydrochloride** or **venlafaxine**. The trial is expected to run until August 31, 2026, with recruitment having commenced on January 2, 2023. Participants will be involved in the study for a maximum treatment period of 24 to 26 weeks, depending on the medication used.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit, or screening, will confirm eligibility based on criteria such as age (18-75 years), stable remission of MDD for at least six months (or one year for recurrent MDD), and current use of the specified antidepressants. Eligibility will be further confirmed through a semi-structured psychiatric interview and a Patient Health Questionnaire 9 (PHQ-9) score of 12 or lower. Participants must also provide informed consent and demonstrate the ability to adhere to study procedures.

Following the inclusion visit, participants will undergo a series of follow-up visits to monitor their progress and adherence to the discontinuation protocol. These visits will assess the primary endpoint, which is the rate of failure to successfully discontinue the antidepressant. This is defined by significant deviations from the protocol, such as switching to rescue medication for five or more days or experiencing significant withdrawal symptoms, indicated by an increase in the modified 15-item Discontinuation-Emergent Signs and Symptoms (DESS) scale from baseline by four or more points for two consecutive assessments during Phase II.

The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged. Participants may be terminated early from the study if they experience severe adverse effects, are unable to comply with the study protocol, or choose to withdraw consent. The trial's design and procedures are meticulously structured to ensure the collection of robust data while maintaining participant safety and adherence to ethical standards.

The clinical trial involves the use of **paroxetine hydrochloride** as one of the experimental medications. Paroxetine hydrochloride is administered in an oral pharmaceutical form, identified by the code PHF00082MIG. The maximum daily dose for this medication is 50 mg, with a total treatment period not exceeding 24 weeks. The medication has been modified to resemble a placebo, and dosages lower than those authorized for marketing are applied. The administration route is oral, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is **venlafaxine**. This medication is also administered orally, with a pharmaceutical form identified by the code PHF00131MIG. The maximum daily dose for venlafaxine is 375 mg, and the treatment period can extend up to 26 weeks. Similar to paroxetine hydrochloride, venlafaxine has been modified to resemble a placebo, with dosages lower than those authorized for marketing. The oral route of administration is maintained, and participant compliance is closely monitored to ensure proper adherence to the prescribed dosing regimen.

Both medications are part of a double-blind, placebo-controlled randomized controlled trial (RCT) aimed at investigating the optimal strategies for discontinuing antidepressants in patients with stable remitted major depressive disorder (MDD). The trial compares two tapering strategies, ensuring that the administration of the medications is consistent with the study's objectives and protocols.

The efficacy of the clinical trial titled "Trial Examining Methods for Antidepressant Discontinuation (TEMPO)" will be assessed primarily through the **rate of failure to successfully discontinue antidepressant**. This is defined as a significant deviation from the discontinuation protocol, such as switching to rescue medication for five or more days in total, stopping the discontinuation medication, or experiencing significant withdrawal symptoms. Withdrawal symptoms are quantified by an increase in the modified 15-item Discontinuation-Emergent Signs and Symptoms (DESS) scale from baseline by four or more points for two consecutive assessments during Phase II of the trial.