This is an open-label, parallel-group study to evaluate the safety and efficacy of ropanicant in participants with moderate to severe Major Depressive Disorder (MDD).

Approximately 36 participants will be randomly assigned to receive ropanicant either Dose 1 qd, Dose 2 bid, or Dose 3 mg bid for 2 weeks, in a ratio of 1:1:1 (12 participants in each treatment group). Following a screening period of up to 4 weeks, the participants will be treated for 2 weeks.

Inclusion Criteria:

• Participants must meet the DSM-5 criteria for MDD without psychotic features and diagnosis confirmed by the Mini-International Neuropsychiatric Interview (MINI).
• Participants with a current major depressive episode of at least 4 weeks of duration prior to the screening visit.
• Participants must have an MADRS score of ≥25 at the screening and the baseline visits.
• Participants must have a score of ≥4 on Clinical Global Impression - Severity (CGI-S) Scale at the screening and the baseline visits.

Exclusion Criteria:

• Participants who meet criteria for treatment-resistant depression during the current major depressive episode, which will be defined as being non-responders (less than 50% of symptom improvement) to 2 or more depression treatment periods of adequate dose and duration as defined by the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ).
• Participants taking antidepressant treatment (SSRIs and SNRIs) or any medication that is contraindicated with the use of monoamine oxidase inhibitors (eg, opioids, stimulants) within 2 weeks (or 5 half-lives, whichever is longer) prior to baseline and until the end of study visit.
• Participants who do not agree to avoid tyramine rich diet from the start of dosing and until 2 weeks following last study drug administration.
• Participants who are habitual smokers or using nicotine products.