Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression After a First-time Treatment Failure

Inclusion criteria

• \. In- or out patients, at least 18 years of age up until 70 (SZ study sample), 65 years (MDD study sample) and no limit for the BD study..
• 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.
• \. Female subjects of child bearing potential must be willing to ensure that they use effective contraception during the trial and as per the requirements in the protocol (section 8.2.1).Male subjects that will use valproate acid during the trial must use effective contraceptive measures during the trial.
• \. Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, major depressive disorder (without psychotic features) or bipolar depression (bipolar disorder type I and II currently in a depressive episode), according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
• \. Subject experiences a treatment failure due to lack of efficacy in the current episode, as confirmed by a CGI-I ≥3; preferably 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). However, other lines of treatment are accepted as well.
• \. Subject and clinician intend to change pharmacotherapeutic treatment. 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 for SZ subjects is at least 2 PANSS positive or negative items with a score of 4, or at least one PANSS positive or negative item with a score of 5.
• The minimum symptom severity threshold for MDD is a score of ≥ 20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
• The minimum symptom severity threshold for BD is a score of ≥20 on the Montgomery Åsberg Depression Rating Scale (MADRS)
• For all study samples: 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

• Being pregnant or breastfeeding.
• Subject has failed previously on the EIPT study medication (i.e. SZ: clozapine; MDD: esketamine intranasal/(es)ketamine IV) Treatment duration as ≥ 4 weeks within an efficacious dose range according to the SmPC.
• Subject has a known intolerance to clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only) or to all medication options for a study sample (related to the TAU treatment arms) or all EIPT medications (BD study sample).
• Meeting any of the contraindications of clozapine (SZ only), esketamine intranasal/ (es)ketamine IV (MDD only) or quetiapine (BD only), or to all medication options for a study sample (related to the TAU treatment arms), or all EIPT medications (BD study sample), as specified within the applicable SmPC.
• 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.
• 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
• 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.
• Subjects have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• Subjects dependent on the sponsor, investigator or trial site must be excluded from participation in advance.
• For the SZ sample only: schizophrenia subjects cannot meet the modified Andreasen criteria for remission.
• For the SZ sample only: Subjects that have any clinically significant abnormal values on the local laboratory test (especially ANC/WBC and liver values), electrocardiogram (ECG) or physician examinations.
• For the BD sample only: a score of 12 or higher on the Young Mania Rating Scale (YMRS) in order to exclude subjects with predominant manic symptoms or mixed symptoms.
• For the BD study sample only: Subjects with a history of antidepressant-induced mania or hypomania or recent rapid cycling (based on the medical file of the potential participant or the clinical judgment of the clinician).
• For the BD study sample only: Subjects with pre-existing severe liver damage (as tested within the local laboratory test at visit 1).