A randomised, controlled trial to investigate the effect of a six-week intensified pharmacological treatment for schizophrenia compared to treatment as usual in subjects who had a first-time treatment failure on their first-line treatment.

Prior treatment

• Participant has participated in another clinical trial in which the subject received an experimental or investigational drug or agent within 30 days before visit 1.
• Meeting any of the contraindications of clozapine * or to all TAU medication options, as specified within the applicable SmPC.
• Partcipant has a known intolerance to clozapine or to all TAU medication options.

Other illness

• Participant experiences any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.
• Participant 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.

Lab values

• Participants that have any clinically significant abnormal values on the local laboratory test (especially ANC/WBC and liver values), electrocardiogram (ECG) or physician examinations.

Other

• Being pregnant or breastfeeding.
• Participants 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
• Participants dependent on the sponsor, investigator or trial site must be excluded from participation in advance.
• Participants have not been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• Participants who meet the modified Andreasen criteria for remission.
• Participant has used clozapine in the past.

• In- or out patients, at least 18 years of age up until 70.
• 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 participants 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; section 8.2).
• Meeting diagnostic criteria for a primary diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder, according to DSM-5. The primary diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI v7.0.2).
• Participant experiences his/her first treatment failure due to lack of efficacy in the current episode, as confirmed by CGI-I ≥3; 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. However, other treatments are accepted as long as they are in line with clinical guidelines and protocols for schizophrenia.
• Participant and clinician intend to change pharmacotherapeutic treatment.
• 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 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 - Functional impairment is defined as a score of 5 or higher on any of the three scales of the Sheehan Disability Scale (SDS).