• Incidence of treatment emergence adverse events (TEAE) as assessed by local injection site [ Time Frame: First injection until Day 120 ]
  Injection site will be evaluated by observation and examination by appropriately trained personnel.
• Incidence of TEAEs as assessed by local injection site tolerability [ Time Frame: First injection at Day 1 until last injection administered at Day 85 ]
  Injection site tolerability will be measured by injection site grading for redness, induration, swelling and tenderness/pain.
• Incidence of TEAEs as assessed by changes in physical examination [ Time Frame: Time subjects sign the informed consent form throughout the study until EOS (Day 113) ]
  Targeted physical examination will be performed and clinically significant changes will be reported as adverse events (AE)
• Incidence of TEAEs as Assessed by Changes in Vital Signs [ Time Frame: Time subjects sign the informed consent form throughout the study until EOS (Day 113) ]
  Vital sign measurement will be performed, including orthostatic blood pressure, and clinically significant changes will be reported as adverse events (AE)
• Incidence of TEAEs as Assessed by Changes in ECG [ Time Frame: Time subjects sign the informed consent form throughout the study until EOS (Day 113) ]
  ECGs will be performed, and clinically significant changes in parameters will be reported as adverse events (AE)
• Incidence of TEAEs as Assessed by Changes in Body Weight [ Time Frame: Time subjects sign the informed consent form throughout the study until EOS (Day 113) ]
  Body weight, with shoes off, will be measured and clinically significant changes in parameters will be reported as adverse events (AE)
• Incidence of TEAEs as Assessed by Changes in Laboratory Testing [ Time Frame: Time subjects sign the informed consent form throughout the study until end of study (EOS) visit (Day 113) ]
  Laboratory testing will be performed and clinically significant changes from baseline will be reported as AEs
• Incidence of TEAEs as assessed by symptoms of anti-psychotic drug treatment [ Time Frame: Time subjects sign the informed consent form throughout the study until EOS (Day 113) ]
  Safety of treatment will be measured by administration of symptom questionnaires including AIMS, Barnes Akathisia Rating Scale (BARS) and Simpson-Angus Scale (SAS)
• Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Baseline, defined as last assessment prior to first injection, through Day 113 (EOS) ]
  Clinical outcome as measured by change from baseline in PANSS scores will be measured. PANSS is a medical scale designed to measure schizophrenia symptom severity utilizing a 30 item, 7-point rating scheme. The PANSS Is scored by a summation of ratings across items, with a total potential range of 7-49; higher results indicate greater severity of illness.
• Clinical Global Impression-Severity of Illness Scale (CGI-S) [ Time Frame: Baseline through EOS (Day 113) ]
  Clinical outcome as measured by change from baseline in CGI-S scores will be measured. The CGI-S is a measurement of the total severity of illness where one question is assessed. Responses range from 0 (not assessed) to 7 (most extremely ill).
• Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Screening through EOS (Day 113) ]
  Clinical outcome as measured by change from baseline in C-SSRS scores will be measured. The C-SSRS is based on a categorization of thoughts and behavior that are statistically identified as significantly related to suicidal behavior. The scale captures the occurrence, severity and frequency of suicide related thoughts and behaviours throughout lifetime at screening and for the time interval since last administration during a study. Questions solicit the type of information needed to determine if a suicide-related thought or behavior occurred.
• Assessment of minimum concentration of risperidone, 9-hydroxyrisperidone (9-OH) and total active moiety [ Time Frame: Calculated for timepoints 0-12 hours, 0-24 hours and 24-672 hours ]
  The key parameter of the minimum observed plasma concentration will be measured (oral and sc doses 1, 3 and 4)
• Assessment of maximum concentration of risperidone, 9-hydroxyrisperidone (9-OH) and total active moiety [ Time Frame: Calculated for timepoints 0-12 hours, 0-24 hours and 24-672 hours ]
  The key parameter of the maximum observed plasma concentration will be measured (oral and sc doses 1, 3 and 4)
• Assessment of average concentration of risperidone, 9-OH and total active moiety [ Time Frame: Time 0-672 hours post-dose ]
  Total exposure over the dosing interval divided by the time of the dosing interval to measure average risperidone concentration
• Assessment of area under the curve of risperidone, 9-OH and total active moiety [ Time Frame: Time 0 to 672 hours post-dose ]
  Area under the plasma concentration-time curve (AUC) will be measured
• Assessment of trough concentrations of risperidone, 9-OH and total active moiety [ Time Frame: Prior to dosing beginning at Day -6 to Day 85 (Injection 4) ]
  Trough plasma concentration will be measured pre-dose, directly before next dose administration, during the oral and SC administration periods
• Comparison of AUC between doses 3 and 4 for risperidone, 9-OH and total active moiety [ Time Frame: 0-28 days each after 3rd and 4th dose ]
  Data collected after the 4th dose (alternate site) for AUC will be compared against AUC data collected after 3rd dose (abdominal site)
• Comparison of peak parameters between doses 3 and 4 for of risperidone, 9-OH and total active moiety [ Time Frame: 0-28 days each after 3rd and 4th dose ]
  Initial, secondary, if applicable, and overall maximum observed concentrations (peak parameters) collected after the 4th dose (alternate site) will be compared against peak parameter data collected after 3rd dose (abdominal site)
• Comparison of Cavg between doses 3 and 4 for of risperidone, 9-OH and total active moiety [ Time Frame: 0-28 days each after 3rd and 4th dose ]
  Cavg collected after the 4th dose (alternate site) will be compared against average plasma concentration data collected after 3rd dose (abdominal site)

PERSERIS is an extended-release subcutaneous (SC) injectable suspension administered monthly for the treatment of schizophrenia in adults. PERSERIS was approved by the FDA at doses equivalent to 3 mg and 4 mg oral risperidone. Many patients require doses of 5-6 mg oral risperidone and above, and this study will test a higher dose of PERSERIS in order to meet this need.

Eligible subjects will initially be stabilized in the clinical unit on 6 mg oral risperidone for 5 days and transition to an approximate dose of PERSERIS by SC injection. PERSERIS will be administered every 28 days and subjects will be admitted to the clinical unit the day before, and remain in the unit for 3 days after each injection for pharmacokinetics (PK) and safety evaluations (a total of 8 days for the first injection including the stabilization period). Subjects will return to the clinic between injections for additional PK, safety and efficacy assessments at scheduled intervals until the next injection.

A total of 4 doses of PERSERIS will be administered. The 4th dose will evaluate an alternate site for injection, and will be administered in the back of the upper arm.

Subjects will return to the clinical unit for an end of study visit and will receive a follow up phone call to assess for adverse events one week after the end of study visit.

• Drug: PERSERIS
  PERSERIS is an extended-release SC injectable suspension administered once-monthly
  Other Name: long acting risperidone
• Drug: Risperidone
  Oral risperidone
  Other Name: Risperdal

Inclusion Criteria:

• Diagnosis of schizophrenia
• Clinically stable as defined as no hospitalizations for acute exacerbations within 3 months of screening and Screening PANSS score ≤70
• Total body mass index (BMI) between 18 and 35 kg/m2
• Given written informed consent

Exclusion Criteria:

• Received a once-monthly long-acting injectable (LAI) antipsychotic within 60 days of screening and a once every 3 month LAI antipsychotic within 120 days of screening

• Taking the following concurrent or over the counter (OTC) products:

  1. Inducers or inhibitors of CYP2D6 within 14 days or 5 half-lives whichever is greater prior to study screening
  2. Bupropion, chlorpheniramine, cimetidine, clomipramine, doxepin or quinidine within 30 days prior to study screening
  3. Clozapine, phenothiazines, aripiprazole, haloperidol or any other antipsychotic other than oral risperidone within 14 days prior to study screening
  4. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) within 30 days prior to study screening
  5. Opioids or opioid-containing analgesics within 14 days prior to study screening
  6. Medications, in the addition to those listed above which in the opinion of the Investigator in conjunction with the medical monitor, may be expected to significantly interfere with the metabolism or excretion of risperidone and/or 9-hydroxyrisperidone, that may be associated with a significant drug interaction with risperidone, or that may pose a significant risk to subjects' participation in the study. The medical monitor should be contacted with any questions regarding the use of CYP2D6 or 3A4 inducers or inhibitors in particular.
• History of cancer (with the exception of resected basal cell or squamous cell carcinoma of the skin) unless they have been disease free for ≥5 years.
• Another active medical condition or organ disease that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the study drug.
• Evidence or history of a significant hepatic disorder that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the study drug. Individuals with acute or chronic hepatitis (including but not limited to hepatitis B or C); or individuals with 1) total bilirubin >1.5x the upper limit of normal (ULN) and/or 2) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x ULN will be excluded.
• A history of renal disease, or a creatinine clearance of less than 60 mL/min (as determined by the Cockcroft-Gault formula).
• A history of orthostatic hypotension, syncope, significant low white blood cell (WBC) count (i.e., based on absolute neutrophil count or drug-induced leukopenia or other medical conditions including, but not limited to, history of heart attack (i.e., myocardial infarction) or brain injury (i.e., traumatic with loss of consciousness and/or cardiovascular accident) within a year of Screening and clinically significant low blood pressure or arrhythmias as interpreted by the principal investigator (PI).
• Corrected QT interval [Fridericia's calculation (QTcF)] >450 msec (male) or >470 msec (female) at screening or prior to administration of the 1st dose of PERSERIS, or with a known history of Torsades de Points, or family member with sudden unexplained cardiac death.
• Known to have AIDS (acquired immunodeficiency syndrome) or to be HIV (human immunodeficiency virus) positive.
• Suicidal ideation with intent and plan, as assessed by affirmative answers to C-SSRS questions 4 and 5 of the ideation section,or suicide attempts within the last 6 months as noted on the C-SSRS, or subjects with uncontrolled depression in the opinion of the Investigator.
• Known diagnosis of type 1 diabetes or subjects with Haemoglobin A1c (HbA1c) >8.0% at screening.
• Participated in a clinical trial within 30 days prior to study screening.
• Significant traumatic injury, major surgery or open biopsy within 30 days prior to study screening.
• Meet the criteria for the diagnosis of current moderate or severe substance use disorder.
• Prior allergic reactions, sensitivities, or other known contraindications to any component of PERSERIS.
• Women of childbearing potential who are pregnant or breastfeeding, seeking pregnancy or failing to use adequate contraceptive methods during the study.
• Positive urine drug screen (UDS) anytime through Day -1 for opioids, cocaine, amphetamines, methadone, cannabinoids, barbiturates, benzodiazepines, methamphetamine and phencyclidine, unless the positive screen is determined to be secondary to an allowable concomitant medication. If a positive UDS is possibly the result of a subject's use of OTC or prescription medications, a repeat urine drug screen may be permissible. Study site personnel should contact the medical monitor for approval to retest.
• Tardive dyskinesia as assessed by a score of ≥2 on Item 8 of the Abnormal Involuntary Movement Scale (AIMS) at Screening.
• Epilepsy or other seizure disorders, Parkinson's disease or dementia.
• History of neuroleptic malignant syndrome.
• Previously injected with PERSERIS within 6 months prior to screening.
• Unable, in the opinion of the PI, to comply fully with the study requirements.
• Determined to be poor metabolisers, intermediate metabolisers or ultra-rapid metabolisers for CYP2D6 genotype.