Evaluation of the Feasibility of Short-Term Discontinuation of Serotonin Reuptake Inhibitors in Patients with Hip and Knee Osteoarthritis Undergoing Arthroplasty

The primary objective of this study is to evaluate the **feasibility** of short-term temporary discontinuation of serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients scheduled for hip or knee arthroplasty. The focus is on assessing the potential for discontinuation syndrome and the relapse of depression and anxiety. This is clinically relevant as it addresses the management of psychiatric medications in the perioperative period, which can impact surgical outcomes and patient safety. No secondary objectives are specified for this study.

The clinical trial involves participants diagnosed with **hip and knee osteoarthritis**. The study population includes both male and female subjects aged 18 years and older. Participants are required to be planned for primary unilateral total hip arthroplasty (THA), total knee arthroplasty (TKA), or unicompartmental knee arthroplasty (UKA). They must be undergoing oral treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in any dose, as specified by certain ATC codes. All participants must understand written and spoken Danish and have provided signed written informed consent. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **feasibility** of short-term temporary discontinuation of serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients scheduled for hip or knee arthroplasty. This study employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to commence on April 1, 2024, and conclude by April 1, 2026, with an estimated duration of two years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older), planned primary unilateral total hip arthroplasty (THA), total knee arthroplasty (TKA), or unicompartmental knee arthroplasty (UKA), and current oral treatment with SSRIs or SNRIs. Following the screening, participants will be randomized and begin the intervention phase, which includes tapering off their medication under close supervision. Follow-up visits are scheduled at baseline, two weeks, five weeks (the day before surgery), and two months post-surgery to monitor the primary endpoint, which is the proportion of patients able to discontinue SSRI/SNRI therapy perioperatively.

The study will also assess secondary endpoints, including the proportion of patients who opt out of tapering due to discontinuation syndrome or relapse of depression or anxiety, and those who can reduce but not completely discontinue their medication. The Discontinuation-Emergent Signs and Symptoms (DESS), Major Depression Inventory (MDI), and Symptom Checklist 92 (SCL-92) scores will be evaluated at each follow-up visit to assess the psychological impact of discontinuation. The expected length of participant involvement is approximately six months, from the initial screening to the final follow-up visit.

Participants may be subject to early termination from the study if they experience severe adverse effects, fail to adhere to the study protocol, or withdraw consent. The trial is categorized as low-intervention, as it investigates the temporary discontinuation of well-tested drugs, with individual tapering plans based on current clinical practice. The study aims to provide valuable insights into the management of SSRI/SNRI therapy in the context of orthopedic surgery, with a focus on patient safety and well-being.

The clinical trial involves the administration of several **experimental medications** to evaluate the feasibility of short-term temporary discontinuation of serotonin reuptake inhibitors in patients undergoing hip or knee arthroplasty. The first experimental medication is **Duloxetine**, which is administered in an oral pharmaceutical form. The maximum daily dose for Duloxetine is 120 mg, and it is not formulated for pediatric use. The administration route is oral, and the treatment period is not specified with a maximum limit, indicating flexibility in dosing schedules. Participant compliance will be monitored to ensure adherence to the prescribed regimen.

Another experimental medication used in the trial is **Sertraline Hydrochloride**, also administered orally. The maximum daily dose for Sertraline Hydrochloride is 200 mg. Similar to Duloxetine, it is not a pediatric formulation and is administered orally. The treatment period is open-ended, allowing for adjustments based on individual patient needs. Monitoring of participant compliance is integral to the study to ensure accurate assessment of the medication's effects.

**Paroxetine Hydrochloride** is included as an experimental treatment, with an oral administration route. The maximum daily dose is set at 50 mg. This medication is not designed for pediatric use and is administered orally. The trial does not specify a maximum treatment period, providing flexibility in dosing. Compliance monitoring is essential to evaluate the medication's impact accurately.

The trial also involves the use of **Citalopram**, administered in an oral form. The maximum daily dose for Citalopram is 20 mg. It is not a pediatric formulation and is administered orally. The treatment period is not restricted, allowing for individualized dosing schedules. Participant compliance will be closely monitored to ensure the reliability of the study results.

Lastly, **Citalopram Hydrobromide** is used in the trial, with a maximum daily dose of 40 mg. It is administered orally and is not formulated for pediatric use. The treatment period is flexible, with no specified maximum duration. Monitoring of participant compliance is crucial to ensure the validity of the study findings.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients undergoing total hip arthroplasty (THA), total knee arthroplasty (TKA), or unicompartmental knee arthroplasty (UKA) who are able to discontinue **serotonin reuptake inhibitors (SSRIs)** or **serotonin-norepinephrine reuptake inhibitors (SNRIs)** therapy perioperatively. Secondary endpoints include the proportions of patients who opt out of tapering due to discontinuation syndrome, relapse of depression, relapse of anxiety, or other reasons, as well as those who are unable to completely discontinue but can reduce their doses.

Additional secondary endpoints involve the assessment of Discontinuation-Emergent Signs and Symptoms (DESS), Major Depression Inventory (MDI), and Symptom Checklist 92 (SCL-92) scores at baseline, after 2 weeks, the day before surgery (after 5 weeks), and 2 months post-surgery. The trial will also evaluate the proportion of patients who continue to use SSRIs/SNRIs 2 months after surgery, including those who were able to discontinue perioperatively. These efficacy parameters will be measured and collected at specified timepoints to ensure comprehensive analysis of the trial outcomes.