The Effect of a Six Week Intensified Pharmacological Treatment for Major Depressive Disorder Compared to Treatment as Usual in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.

Inclusion Criteria:

1. In- or outpatients, at least 18 years of age up until 65.
2. Being willing and able to provide written informed consent. Having a legal guardian to cosign is allowed. Informed consent will be signed at visit 1, before any study procedure.
3. Female subjects of child bearing potential must use effective contraception during the trial as per the requirements of the applicable SmPCs and should have a negative pregnancy test at visit 1 or 2 (before randomisation).
4. Meeting diagnostic criteria for a primary diagnosis of major depressive disorder (without psychotic features), according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
5. Subject experiences a treatment failure due to lack of efficacy in the current episode, as confirmed by a CGI-I ≥3; perferably, this treatment is a first-line pharmacotherapeutic agent for the primary DSM-5 diagnosis, and was prescribed for at least 4 weeks within an effective dose range as specified in the Summary of Product Characteristics (SmPCs).
6. Subject and clinician intend to change pharmacotherapeutic treatment. However, other lines of treatment are allowed as well.
7. A minimum symptom severity threshold needs to be present (moderate level; see below) and subject needs to experience functional impairment.

   * The minimum symptom severity threshold is a score of ≥20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
   * Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).

Exclusion criteria:

1. Being pregnant or breastfeeding.
2. Subject has used (es)ketamine previously for the treatment of depressive symptoms.
3. Subject has a known intolerance to (es)ketamine or to all TAU medication.
4. Meeting any of the contraindications for (es)ketamine, or to all TAU medication options, as specified within the applicable SmPC, supported by clinically significant abnormal values on local laboratory tests, electrocardiogram (ECG) or physical examinations.
5. Subject has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit 1.
6. Subject experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the subjects at risk because of participation in the trial, or may influence the result of the trial, or the subject's ability to participate in the trial.
7. Subjects with active suicidal ideation with some intent to act, without specific plan ("Yes" to question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS)) or active suicidal ideation with specific plan and intent ("Yes" to question 5 of the C-SSRS), followed by an assessment by the treating clinician who determines it is not safe for the subject to participate in the study
8. Subject meets criteria for current substance use disorder, as confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2). Nicotine dependency is allowed, as well as mild and moderate alcohol and/or cannabis use disorder (as defined by MINI v7.0.2). Severe alcohol and/or cannabis use disorder are not allowed.
9. Subjects have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
10. Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance.