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Testing Ulotaront Added to Antidepressants for Adults with Major Depressive Disorder Who Did Not Respond Well to Initial Treatment

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This study involves people who have Major Depressive Disorder, a condition where a person experiences persistent feelings of sadness and loss of interest in activities that affects daily life. The study will test a medication called Ulotaront, also known by its code name SEP-363856, which will be given as an additional treatment alongside standard antidepressant medications. The antidepressants that may be used in this study include venlafaxine, citalopram, sertraline, duloxetine, fluoxetine, and paroxetine. Some people in the study will receive placebo instead of the study medication. The purpose of this study is to find out if SEP-363856 works better than placebo when added to standard antidepressant treatment in helping people whose depression has not improved enough with their current antidepressant medication.

The study is divided into two phases and lasts for about 14 weeks in total. During the first phase, which lasts 8 weeks, all people in the study will receive one of the standard antidepressant medications mentioned above. This phase helps to confirm that the depression has not improved enough with the antidepressant alone. During the second phase, which lasts 6 weeks, people will continue taking their antidepressant medication and will also receive either SEP-363856 or placebo. All medications are taken by mouth. The study will measure changes in depression symptoms using rating scales that assess mood, daily functioning, and overall well-being.

Throughout the study, regular check-ups will be conducted to monitor safety. These check-ups include physical examinations, measurements of body weight, blood pressure, heart rate, and body temperature. Blood and urine samples will be collected to check general health and how the body is processing the medications. Heart activity will be monitored using a test that records the electrical signals of the heart. The study will also assess other aspects such as movement-related side effects, sleep quality, sexual functioning, and thoughts about self-harm. People in the study will be asked about any unwanted effects they may experience.

The research process

The trial runs in 4 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Initial treatment period with assigned antidepressant

    This phase lasts 8 weeks and is called Phase A.

    You will receive one assigned antidepressant medication from the following options: venlafaxine, escitalopram, sertraline, duloxetine, fluoxetine, or paroxetine.

    The medication will be taken by mouth.

    The purpose of this phase is to assess your response to the antidepressant treatment.

    At the end of this 8-week period, your response to the treatment will be evaluated at a Week 8 visit.

  2. Step 2

    Additional treatment period with study medication or placebo

    This phase lasts 6 weeks and is called Phase B.

    You will continue taking the same antidepressant medication from Phase A.

    In addition to your antidepressant, you will receive either ulotaront or a placebo. A placebo is an inactive substance that looks like the real medication but contains no active ingredient.

    The assignment to ulotaront or placebo will be done randomly, meaning it will be determined by chance, similar to flipping a coin.

    If you receive ulotaront, the dose will be flexible, ranging from 50 to 75 mg per day.

    The ulotaront or placebo will be taken by mouth in the form of a tablet.

    This phase will end at the Week 14 visit, where your condition will be assessed again.

  3. Step 3

    Assessments during the trial

    Throughout the trial, your depression symptoms will be measured using standardized rating scales.

    The main assessment tool is the Montgomery-Åsberg Depression Rating Scale, which measures the severity of depression symptoms.

    Another scale used is the 17-item Hamilton Depression Rating Scale, which also evaluates depression symptoms.

    The change in your depression scores from the end of Phase A to the end of Phase B will be the main measure of how well the treatment is working.

  4. Step 4

    Safety monitoring throughout the trial

    Your safety will be monitored regularly throughout the entire trial period.

    This will include recording any adverse events, which are any unwanted or unexpected medical occurrences.

    Physical examinations will be performed, including measurements of your body weight and waist circumference.

    Vital signs will be checked, including blood pressure, heart rate, and body temperature.

    Electrocardiograms will be performed to monitor your heart's electrical activity.

    Laboratory tests will be conducted on your blood and urine to check various health parameters, including blood cell counts, organ function, prolactin levels, blood sugar control, and blood clotting factors.

    Additional safety assessments will include evaluations for suicidal thoughts and behavior, involuntary movements, restlessness, sexual function, and sleep quality.

Who can join the trial?

8 criteria

  • You must be between 18 and 65 years old at the time you agree to join the study
  • You must have major depressive disorder, which is a medical condition that causes persistent feelings of sadness and loss of interest in daily activities, as your main diagnosis
  • You must currently be experiencing a major depressive episode, which is a period of at least two weeks with symptoms of depression
  • Your current major depressive episode must have lasted for at least 8 weeks but less than 2 years
  • You must have tried at least 1 but no more than 3 antidepressant medications for your current depressive episode, and these medications did not work well enough for you
  • You must score 18 or higher on a depression rating scale called the Hamilton Depression Rating Scale at both the screening visit and the baseline visit. This scale measures how severe your depression symptoms are
  • Your diagnosis will be confirmed using a structured interview and a clinical psychiatric assessment to make sure you meet the criteria for major depressive disorder
  • Both men and women can participate in this study

Who cannot join the trial?

1 criterion

  • The study does not include information about specific reasons why patients cannot participate in this clinical trial at this time.
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Investigated drugs

  • SEP 363856

    is an investigational medication being studied as an additional treatment for major depressive disorder. In this trial, it is given alongside a standard antidepressant therapy to see if it can help people who have not responded well enough to their antidepressant medication alone. This medication is being tested to determine if it is safe and effective when used in combination with other depression treatments.

  • Antidepressant therapy

    refers to standard medications used to treat depression. In this trial, participants continue taking their assigned antidepressant medication throughout the study. The antidepressant serves as the main treatment, while the study medication is added to see if it provides additional benefit for people whose depression symptoms have not improved enough with the antidepressant alone.

What is already known about the treatment

SEP-363856 – SEP-363856 is an experimental medication currently being studied in clinical trials as an add-on treatment to standard antidepressants for adults with major depressive disorder who have not responded well to their current antidepressant therapy alone. It is taken orally in flexible doses ranging from 50 to 75 mg per day. The medication works through a unique mechanism that targets specific receptors in the brain called TAAR1 and 5-HT1A receptors, which help regulate mood and emotional responses without blocking the dopamine receptors that traditional antipsychotic medications typically affect. SEP-363856 belongs to a new class of psychiatric medications being investigated for their potential to enhance the effects of antidepressants in patients who need additional support beyond their primary depression treatment.

Investigated diseases

Major Depressive Disorder – Major depressive disorder is a mental health condition characterized by persistent feelings of sadness, hopelessness, and loss of interest in activities that were once enjoyable. People with this disorder experience these symptoms for at least two weeks, and the symptoms significantly interfere with daily functioning. Common signs include changes in sleep patterns, appetite changes, difficulty concentrating, fatigue, and feelings of worthlessness. The disorder affects how a person thinks, feels, and handles daily activities such as working, sleeping, or eating. Major depressive disorder can occur as a single episode or recur multiple times throughout a person's life. The severity of symptoms can vary from mild to severe, impacting the person's ability to function in social, occupational, and other important areas of life.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IVTrial ID2022-500538-27-00Protocol code382-201-00001Estimated enrolment944 patientsSponsorOtsuka Pharmaceutical Development & Commercialization Inc.

sourced from the EU Clinical Trials Register and site verification

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