The purpose of the study is to determine the efficacy, safety and pharmacokinetics of inhaled Esketamine in participants with treatment-resistant depression (TRD) in the course of Major Depressive Disorder (MDD). The study is to determine the efficacy and dose response of three Esketamine doses, compared with placebo.

This is a randomized, multiple dose, placebo-controlled, double-blind, multicentre study of Esketamine DPI, inhalation powder delivered via dry powder inhaler (DPI) in participants with TRD in the course of MDD. There are 3 study phases: Screening phase, a two weeks double-blind treatment phase and a 6-week follow-up phase. Participants are to be randomized in 1:1:1:1 ratio to receive placebo or one of the three doses of Esketamine DPI. Participants from each group will receive different dosing sequences, consider as a single dose, corresponding to low, medium, high Esketamine dose or placebo. Participants will undergo one cycle of treatment consisting of four doses of Esketamine DPI or placebo over 14-day period. Participants safety will be monitored throughout the study.

Inclusion Criteria:

1. Gender: female or male,
2. Age: 18 - 65 years old, inclusive, on the day of Screening,
3. Participant must meet Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria for major depressive disorder, without psychotic features, confirmed by the Mini International Neuropsychiatric Interview (MINI),
4. Participant must have in Montgomery-Asberg Depression Rating Scale (MADRS) total score of >= 25 at Screening and predose on Day 1,
5. Participant is treatment resistant, defined as having an inadequate response to at least 2 antidepressants administered for the sufficient duration and dose, both in the current episode of depression,
6. Participant must be on stable monotherapy with antidepressant drug (listed in the protocol) remain non-responsive to it and continue on non-investigational antidepressant therapy from Screening to at least the duration of the double-blind treatment phase,
7. Participant agrees to be hospitalized voluntarily for a period of 12 h before first administration and until the Day 6 of treatment phase. Hospitalization from Day 6 up to the end of treatment phase on Day 14 is up to Investigator discretion, with exception of mandatory hospitalization from 12 h before each administration until 24 h post each administration and from evening on Day 13 until the end of examinations on Day 14,
8. Participant must be medically stable on the basis of clinical laboratory tests, physical examination, vital signs, 12-lead ECG,
9. Participant agrees to blood sample collection for DNA analysis,
10. Participant of childbearing potential willing to use acceptable forms of contraception.

Exclusion Criteria:

1. Participant has a current DSM-5 diagnosis, according to MINI, of any other than MDD disorder,
2. Participant has suicidal ideation in MADRS 'suicidal thoughts' subscale score greater or equal to 2 and/or in C-SSRS score greater or equal to 4 at Screening and/or has a history of suicidal thoughts within 6 months prior to Screening and/or history of suicidal attempt within 1 year prior to Screening,
3. Participant has a history or current signs and symptoms of chronic obstructive pulmonary disease (COPD), asthma, liver or renal insufficiency, significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, hematologic, neurologic, rheumatologic or metabolic disturbances that are uncontrolled with medication change during last three months before Screening and/or that could influence the present general health condition at the Investigator's discretion,
4. Participant has uncontrolled hypertension,
5. Upper respiratory tract and/or chest infection and/or inflammation within 2 weeks preceding the first administration and during the treatment phase,
6. Participant took part in other clinical trial within 90 days preceding the Screening,
7. Known allergy or hypersensitivity, intolerance or contraindication to Esketamine/ketamine or its derivatives and/or to any study product excipients,
8. Blood drawn within 30 days prior to inclusion to the study,
9. History of drug, alcohol, chemical, sedatives or sleeping medications abuse or dependence (except nicotine or caffeine) within 2 years prior to Screening,
10. Lifetime abuse or dependence on ketamine or phencyclidine,
11. Positive results from pregnancy test for female participants,
12. Lactation in female participants,
13. Positive drug screen (except benzodiazepines evaluation during follow-up) or alcohol breath test.