• Change from baseline in MADRS total score at each other than Day 14 timepoint [ Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12 and week 3, 4, 5, 6, 7 and 8 ]
  The MADRS is a clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment. The test consists of 10 items, each scored from 0 (symptoms not present or normal) to 6 (severe or continuous presence of the symptoms). Total score is 60. The higher MADRS total score, the more severe depression.
• Number of participants with clinical response (>= 50% decrease in MADRS baseline score) [ Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and up to 6 weeks after the treatment phase ]
  Clinical response is to be defined as greater than or equal to 50 % decrease in MADRS baseline score at Day 14 and every other timepoint.
• Onset of clinical response that was sustained through the end of the 2-week, double-blind, treatment phase [ Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 ]
• Change from baseline in depression severity, measured by Hamilton Depression Rating Scale (HDRS) at every timepoint [ Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and week 3, 4, 5, 6, 7 and 8 ]
  HDRS is a questionnaire used to rate the severity of depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss and somatic symptoms. HDRS consists of 17 questions with maximum 4-points scale. The higher HDRS total score, the more severe depression.
• Number of participants with clinical remission (MADRS total score <= 10) [ Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and up to 6 weeks after the treatment phase ]
  Clinical remission, defined as MADRS total score less than or equal to 10.
• Time to relapse [ Time Frame: Day 14 and week 3, 4, 5, 6, 7 and 8 ]
  Relapse assessed for responders and remitters and defined when MADRS total score in 2 consecutive assessments after Day 14 exceeds 50% MADRS baseline total score value.
• Change from baseline in Clinical Global Impression - Severity (CGI-S) score at Day 14 and every other timepoint [ Time Frame: Day 1, 2, 4, 5, 8, 9, 11, 12, 14 and week 3, 4, 5, 6, 7 and 8 ]
  CGI-S scale is a physician-rated scale that is designed to rate the severity of the patient's illness at the time of assessment. It is a 7-point assessment where 1 = normal (not at all ill) and 7 = among the most extremely ill patients.
• Change from baseline in Columbia Suicide Severity Rating Scale (C-SSRS) at Day 14 and every other timepoint [ Time Frame: Day 1, 14 and week 5, 8 ]
  C-SSRS is a suicide ideation rating scale created by researchers at Columbia University.
• Change from baseline in the Clinician Administered Dissociative States Scale (CADSS) at each day of administration [ Time Frame: up to 24 hours following the start of each administration ]
  CADSS is a scale designed to assess dissociative symptoms. CADSS consists of 23 questions with 4-points scale, where 1=normal (not at all) and 4=Extremely. The higher CADSS total score, the more severe symptoms.
• Change from baseline in the Brief Psychiatric Rating Scale (BPRS) at each day of administration [ Time Frame: up to 24 hours following the start of each administration ]
  BPRS is a scale designed to rate psychotomimetic effects. BPRS consists of 18 questions with 7-points scale, from 1 (not present) to 7 (extremaly severe). The higher BPRS total score, the more severe effects.
• Potential withdrawal symptoms after Esketamine treatment, as measured by the 20-item Physician Withdrawal Checklist (PWC-20) [ Time Frame: Day 0, week 3, 4 and 5 ]
  PWC-20 is a method to assess discontinuation symptoms.
• Potential Esketamine effect on cognition as measured by Montreal Cognitive Assessment (MoCA) [ Time Frame: Day 0, week 4 and 8 ]
  MoCA is a screening assessment for detecting cognitive impairment.
• Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: up to 8 weeks ]
• Esketamine AUC0-24h - area under the plasma concentration - time curve from time 0 to 24 h [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Esketamine Cmax - maximum plasma concentration [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Esketamine AUC0-inf - area under the plasma concentration - time curve from time 0 to infinity [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Esketamine Kel - terminal elimination rate constant [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Esketamine t1/2 - plasma elimination half-life [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Esketamine Tmax - time to reach maximum concentration in plasma [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Esnorketamine AUC0-24h - area under the plasma concentration - time curve from time 0 to 24 h [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Esnorketamine Cmax - maximum plasma concentration [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Esnorketamine Tmax - time to reach maximum concentration in plasma [ Time Frame: up to 24 hours following the start of first and fourth administration ]
• Changes between predose and postdose values for each administration in hematology and biochemistry [ Time Frame: up to 6 weeks ]
• Changes between predose and postdose values for each administration in vital signs (heart rate, blood pressure, respiratory rate) and urinalysis [ Time Frame: up to 8 weeks ]
• Changes between predose and postdose values for each administration in SpO2 (blood oxygen saturation) [ Time Frame: up to 2 hours following the start of each administration ]

• Drug: Esketamine DPI - low dose
  Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to low Esketamine dose.
• Drug: Esketamine DPI - medium dose
  Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to medium Esketamine dose.
• Drug: Esketamine DPI - high dose
  Esketamine DPI is to be administered via dry powder inhaler. Each dose correspond to high Esketamine dose.
• Drug: Placebo DPI
  Placebo DPI is to be administered via dry powder inhaler.

• Experimental: Esketamine low dose
  Participants are to receive four doses of Esketamine DPI administered over 14-day period (on Day 1, 4, 8 and 11).
  Intervention: Drug: Esketamine DPI - low dose
• Experimental: Esketamine medium dose
  Participants are to receive four doses of Esketamine DPI administered over 14-day period (on Day 1, 4, 8 and 11).
  Intervention: Drug: Esketamine DPI - medium dose
• Experimental: Esketamine high dose
  Participants are to receive four doses of Esketamine DPI administered over 14-day period (on Day 1, 4, 8 and 11).
  Intervention: Drug: Esketamine DPI - high dose
• Placebo Comparator: Placebo
  Participants are to receive four doses of Placebo DPI administered over 14-day period (on Day 1, 4, 8 and 11).
  Intervention: Drug: Placebo DPI

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.