Table 1 Inclusion and exclusion criteria

1. Age ≥ 12 and < 25 years at randomization

2. Meets criteria for schizophrenia or related disorder, in the range in the range ICD-10v2016 F20.x, F22.x-F29.x

3. Meets criteria for treatment resistance, defined as:

  a. Previous trials of at least two different antipsychotic drugs with adequate adherence (estimated < 20% missed doses), both treatment trials to exceed 6 weeks at therapeutic dose (≥ 600 mg chlorpromazine equivalent)

  b. At least 1 of these trials must be with a second-generation drug

  c. Failure to respond to NICE-recommended psychological treatment OR failure to engage in same

4. PANSS total ≥ 70, at least 2 items > 4

5. CRS > 3

6. Capacity to give informed consent OR has a legal representative able to give consent to the trial

7. English or Welsh language sufficient to participate

1. Psychosis predominantly caused by substance misuse

2. Pregnancy

3. Breastfeeding

4. Contra-indications to clozapine as listed in SmPC as follows:

 a. Hypersensitivity to the active substance or to any of the excipients

 b. Patients unable to undergo regular blood tests

 c. History of toxic or idiosyncratic granulocytopenia/ agranulocytosis (except for granulocytopenia/ agranulocytosis from previous chemotherapy)

 d. History of clozapine-induced agranulocytosis

 e. Impaired bone marrow function

 f. Uncontrolled epilepsy

 g. Alcoholic and other toxic psychoses, drug intoxication, comatose conditions

 h. Circulatory collapse and/or CNS depression of any cause

 i. Severe renal or cardiac disorders (e.g., myocarditis)

 j. Active liver disease associated with nausea, anorexia or jaundice, progressive liver disease, hepatic failure

 k. Paralytic ileus

 l. Clozapine treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged

5. Previous adequate trial of clozapine, as defined by TRIPP working group consensus guidelines, i.e. duration of at least 3 months following attainment of therapeutic plasma levels or a minimum dose of 500 mg/day (if no plasma level available)

6. CNS disorders (ICD-10 G00-26; G40-41, G45-46; G80-94, G97)

7. Concurrent medications with documented interactions with antipsychotics^a

8. Participation in a medicinal trial involving an unlicensed, investigational medical product within the last 3 month

9. Positive test for COVID-19 within the past 10 days

10. For participation in the substudy MRI scan only, standard contraindications to MRI at 3 Tesla such as ferromagnetic or electronic implants