Please select the eligibility criteria that correspond to the clinical trial below.
Title: International Study of Improving Treatment for the Most Severely Ill With Schizophrenia
Brief Summary: This is a 9 week, multicentre, randomized, double-blind, placebo-controlled trial with two parallel groups. There is also an open-label extension phase of 18 weeks. Both medications to be used in the study, clozapine and risperidone, are fully approved for the treatment of schizophrenia.


Options:
A: Inclusion Criteria:

1. Current treatment with clozapine for the primary indication of schizophrenia (clinical diagnosis, guided by DSM-IV criteria).
2. Treatment with clozapine for at least six months at a stable dose of 400 mg or more per day, unless the size of the dose was limited by side-effects.
3. Unsatisfactory benefit from clozapine treatment, as indicated by the presence of positive symptoms (delusions, hallucinations, abnormal behaviour, clinical diagnosis)
4. Age 18 and above.
5. Agreement between investigator and patient to enter the study.
6. The patient is normally resident in Italy.
7. It is considered clinically reasonable to try combination treatment with clozapine and aripiprazole or with clozapine and haloperidol.
8. Uncertainty about which trial treatment would be best for the participant.
9. No medical disorder or condition contraindicates either of the investigational drugs.
10. Agreement between investigator and patient to discontinue any antipsychotic drugs other than clozapine (including long-acting antipsychotic drugs).
B: Inclusion Criteria:

* Subjects who are able to provide written informed consent and/or consent obtained from a legally acceptable representative (as required by Institutional Review Board/Independent Ethics Committee \[IRB/IEC\]), prior to the initiation of any protocol-required procedures.
* Male and female subjects 18 to 60 years of age, inclusive, at time of informed consent.
* Subjects with a current diagnosis of schizophrenia as defined by Diagnostic and Statistical Manual of Mental Disorders, version 4, Text Revision (DSM-IV-TR) criteria and a history of the illness for at least 3 years prior to screening.
* Subjects who, in the investigator's judgment, require chronic treatment with an anti-psychotic medication.
* Subjects able to understand the nature of the study and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, IM depot injection, discontinuation of prohibited concomitant medications, who can read and understand the written word in order to complete patient-reported outcome measures, and who can be reliably rated on assessment scales.

Exclusion Criteria:

* Subjects with a current DSM-IV-TR diagnosis other than schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic, or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
* Subjects with schizophrenia that are considered resistant/refractory to antipsychotic treatment by history or response only to clozapine.
* Subjects with a significant risk of violent behavior or a significant risk of committing suicide based on history or investigator's judgment.
* Subjects who currently meet DSM-IV-TR criteria for substance dependence; including alcohol and benzodiazepines, but excluding caffeine and nicotine, or 2 positive drug screens for cocaine.
* Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones, or hypersensitivity to anti-psychotic agents, including aripiprazole.
* Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia at screening.
* Subjects with uncontrolled thyroid function abnormalities.
* Subjects with a history of seizures, neuroleptic malignant syndrome, clinically significant tardive dyskinesia, or other medical condition that would expose the subject to undue risk or interfere with study assessments.
* Subjects who are involuntarily incarcerated.
* Subjects who have undergone electroconvulsive therapy within 180 days of entry into Phase 2.
* Subjects who have used an investigational agent within 30 days of screening; and prior participation in a clinical study with aripiprazole IM depot.
* Subjects with clinically significant abnormalities in laboratory test results, vital signs, or ECG results.
* Subjects hospitalized for more than 30 days in the 90 days prior to Phase 1 (or Phase 2 for subjects bypassing Phase 1).
* Subjects requiring more than 1 benzodiazepine beyond screening (eg, lorazepam and oxazepam).
* Subjects who fail to wash-out from prohibited concomitant medications, including the use of CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers, antipsychotics, antidepressants (including monoamine oxidase inhibitors \[MAOI\]), and mood stabilizers, during screening and Phase 1.
C: Inclusion Criteria include:

1. Male and female subjects between the ages of 18 to 65 years, inclusive.
2. Subjects who are on stable, oral, chronic (\>2 mos) antipsychotic medication regimen and who are able to tolerate the rapid oral dose taper and substitution regimen.

Exclusion Criteria include:

1. Subjects who are currently treated with injectable depot neuroleptics within one dose interval must be excluded.
2. Subjects who have received loxapine or amoxapine within the last 30 days must be excluded.
3. Subjects with a history of allergy or intolerance to dibenzoxazepines (loxapine and amoxapine) must be excluded.
4. Subjects with a history of movement disorders including Parkinson's disease or a history of neuroleptic malignant syndrome must be excluded.
5. Subjects who have a history within the past year of drug or alcohol dependence or abuse as defined by DSM-4 must be excluded.
D: Inclusion Criteria:

* Subjects treated with clozapine for the indication of poor response to other antipsychotic medications.
* Treatment with clozapine is at a stable dose for at least 12 weeks. Dose must be 400 mg/day or more, unless side effects limited increase of dose.

Exclusion Criteria:

* Subjects with significant alcohol or substance abuse in the past 3 months.
* Subjects with a previous trial of risperidone augmentation of clozapine
* Subjects who are pregnant, breast-feeding, or women of child-bearing potential not using adequate contraception
* Subjects requiring treatment with anticonvulsants.
* Subjects with known hypersensitivity or allergy to risperidone.
* Subjects with hematological or other contraindications to continued clozapine treatment.

Answer: D