Risk of Breakthrough Symptoms With Long-Acting Injectable Medications

Study Overview
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Brief Summary
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This prospective longitudinal cohort study will follow patients with schizophrenia who are treated with second generation long-acting injectable antipsychotic medications (LAIs) for 48 weeks to determine the risk of psychotic symptom relapse when treatment adherence is established. The study is designed to minimize the other factors that have contributed to breakthrough psychotic symptoms in patients treated with LAIs including poor adherence, substance use, concurrent mood disorders, poor treatment response, failed cross-titration, and insufficient dosing. Eligible subjects will undergo a screening visit to document that inclusion criteria are met and those meeting exclusion criteria are excluded. Participants will be assessed every 12 weeks to determine whether they remain in remission or meet criteria for a relapse. More comprehensive assessment will be completed at the beginning of the study (baseline visit), at the 24-week study midpoint and the 48-week study endpoint. Plasma antipsychotic levels will be measured at these three study time points to investigate associations between plasma levels and remission/relapse status as well as side effects. Plasma prolactin will also be measured to assess the association with sexual side effects. Hemoglobin A1c and measures of total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol will be obtained to assess the effects of SGA LAIs on these measures.

Detailed Description
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Rationale and Study Objectives In this study, we aim to determine the likelihood that relapse of psychosis will occur when patients with schizophrenia who have experienced a remission of their psychotic symptoms are adherent to treatment with a second generation antipsychotic (SGA) LAI on which they have been stable at a therapeutic dose for at least three months. Primary objective: 1. To estimate the rate of psychotic relapse in patients with schizophrenia whose psychotic symptoms have remitted and who are adherent with second generation LAIs for maintenance treatment. Secondary objectives: 1. To determine whether the risk of psychotic relapse is associated with antipsychotic plasma levels in patients treated with second generation LAIs. Study design: This prospective longitudinal cohort study will follow patients with schizophrenia who are treated with the second generation LAIs (paliperidone palmitate, risperidone or aripiprazole) for 48 weeks to determine the risk of psychotic symptom relapse when treatment adherence is established. The study is designed to minimize the other factors that have contributed to breakthrough psychotic symptoms in patients treated with LAIs including poor adherence, concurrent mood disorders, poor treatment response, failed cross-titration, and insufficient dosing. Laboratory tests: The following laboratory tests will be carried out at the baseline visit, 24-week visit and 48-week visit: Urine drug screen - to document use of cannabis and other common recreational drugs. This will allow us to determine whether substance use is associated with the risk of relapse in remitted patients with established adherence to LAIs. Plasma antipsychotic levels - to determine whether trough (pre-injection) plasma levels are associated with risk of relapse and medication side effects Plasma prolactin - to determine whether the incidence and severity of sexual dysfunction is associated with antipsychotic plasma levels The following laboratory tests will be carried out at the baseline visit and 48-week visit: Hemoglobin A1c - to determine the effects of LAIs on blood sugar levels Lipid panel - to determine the effects of LAIs on total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol The target population is individuals diagnosed with schizophrenia whose psychotic symptoms have remitted and are receiving outpatient care at the Centre for Addiction and Mental Health (CAMH) in Toronto, Ontario, Canada. Patients who have been stabilized on long-acting injectable forms of either paliperidone palmitate, risperidone or aripiprazole with be invited to participate in this study. Participants will be recruited from CAMH outpatient treatment teams in Toronto, Ontario, Canada, that provide follow-up to individuals diagnosed with schizophrenia including: Downtown Central Flexible Assertive Community Treatment (DC-FACT) Downtown West Flexible Assertive Community Treatment (DW-FACT) Downtown East Flexible Assertive Community Treatment (DE-FACT) Slaight Centre Early Intervention Service (SCEIS) Forensic Outpatient Program for Schizophrenia (FOPS) Psychosis Coordinated Care Service (PCCS) General Psychosis Service (GPS) All outpatients of the above clinics who are receiving treatment with LAI paliperidone, risperidone, or aripiprazole will be invited to participate in this study if they are considered to meet inclusion criteria and do not meet any of the exclusion criteria listed below. A screening visit will be scheduled for potential participants who express interest in the study. The study and procedures involved with be explained to eligible participants and informed consent will be obtained for study participation by the study research coordinator or research assistant. A baseline visit will then be scheduled. Study Duration: The study duration will be 48 weeks rather than 52 weeks as participants treated with LAIs are most commonly administered medication at intervals of two, three, four or twelve weeks. Each of these intervals would fit with major assessments as 24 weeks (study mid-point) and 48 weeks (study end-point). Study Visit: At the screening visit, the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) will be administered to determine if the subject meets criteria for schizophrenia and that they do not meet diagnoses that would exclude them from study participation. Screening for other exclusion criteria including medical disorders, concomitant medications, and suicide attempts or hospitalizations in the past 3 months, will be completed at this visit. Subjects who do not meet inclusion criteria or who meet exclusion criteria will be informed and will not participate in further assessments. Following the Screening visit, all subjects will be assessed at the following time points: Baseline, 12-week, 24-week, 36-week and 48-week visits, with more comprehensive assessments carried out at baseline, 24 weeks and 48 weeks. The following laboratory tests will be carried out at the baseline visit, 24-week visit and 48-week visit: urine drug screen, plasma antipsychotic levels, plasma prolactin. Height will be collected at baseline and weight and waist circumference will be collected at these time points. Hemoglobin A1c and a lipid panel will be obtained at baseline and 48 weeks.

Official Title
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Risk of Breakthrough Symptoms On Antipsychotic Maintenance Medication When Remitted Patients Are Treated With Long-Acting Injectable Medications

Conditions
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Schizophrenia, Schizophrenia Relapse

Intervention / Treatment
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* Drug: Second Generation Long-Acting Injectable Antipsychotic Medications


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DSM-5 Schizophrenia Age 18-65 years On SGA LAI: paliperidone palmitate (4-week or 12-week formulations), risperidone or aripiprazole Receiving LAI injections through clinical services based at CAMH History of improvement in psychotic symptoms with antipsychotic medication as evidenced by a rating of mild or less on the Clinical Global Impression - Severity (CGI-S) for Positive symptoms Demonstrated adherence to LAIs defined as not having received any injections more that 7 days past its due date in the past 3 months On stable dose of LAI for 3 months or longer Capable of providing informed consent for participation in this study Exclusion Criteria: Current DSM-5 major depressive episode or manic episode Receiving any oral antipsychotic medication in the past 3 months History of organic brain disease (e.g. cerebrovascular accident, Huntington's Disease, Parkinson's Disease, epilepsy, etc.) History of untreated or unstable medical illness (e.g. thyroid disease, cancer) History of electroconvulsive therapy (ECT) in the past year History of suicide attempt in the past 3 months History of psychiatric hospitalization in the past 3 months Inability to read and communicate in English

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| SGA-LAI<br>Outpatients with schizophrenia treated with second generation long-acting injectable antipsychotics whose psychotic symptoms have remitted. | Drug: Second Generation Long-Acting Injectable Antipsychotic Medications<br>* Patients who have been stabilized on long-acting injectable formulations of paliperidone palmitate, risperidone and aripiprazole will be followed for 48 weeks to determine the rate of relapse when adherence is established. Blood samples to measure plasma antipsychotic levels and prolactin levels, and urine samples for drug screen will be collected at baseline and at the 24-week and 48-week time points.<br>* Other names: paliperidone palmitate, risperidone, aripiprazole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impressions Schizophrenia Scale (CGI-SCH) - Positive Symptoms Change subscale | Subjects will be considered to have relapsed during the study if they are assessed as having a change score of 6 (much worse) or 7 (very much worse) on the Clinical Global Impressions Schizophrenia Scale (CGI-SCH) - Positive Symptoms Change subscale (Haro et al., 2003). The minimum score on this scale is 1 - Very much improved and the maximum score is 7 - Very much worse. A higher score means a worse outcome. | Assessed at 12 weeks, 24 weeks, 36 weeks and 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression Schizophrenia scale | Clinical Global Impression Schizophrenia scale (CGI-SCH) (Haro et al., 2003) The minimum score is 1 - Normal, not ill and the maximum score is 7 - Among the most severely ill. A higher score means a worse outcome. | Assessed at 24 weeks and 48 weeks | 
| Brief Psychiatric Rating Scale | Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) This scale measures psychiatric symptoms on a scale from 1-7, where 1 is the least severe and 7 is the most severe. The 24 signifies that it is the longer version of the assessment which includes 24 questions. The minimum score is 24 and the maximum score is 168. A higher score means more severe symptoms/ worse outcome. | Assessed at 24 weeks and 48 weeks | 
| Calgary Depression Scale | Calgary Depression Scale (CDS) (Addington et al., 1993) This scale is a nine-item structured interview that assesses the level of depression in people with schizophrenia. Items are measured on a 4-point Likert-scale from 0 to 3 where higher ratings indicate more depressive symptoms and a worse outcome. The minimum total score for the scale is 0 and the maximum score is 27 with higher scores indicating more severe depressive symptoms. | Assessed at 24 weeks and 48 weeks | 
| VAGUS Insight Into Psychosis Scale | VAGUS Insight Into Psychosis Scale (Gerretsen et al., 2014) The VAGUS is a 10-item self-report scale that uses 10-point Likert scales to capture subtle changes in degree of insight into illness. The minimum score is 0 and the maximum score is 10. Higher scores reflect better insight and lower scores indicate poorer insight. | Assessed at 24 weeks and 48 weeks | 
| Personal and Social Performance Scale | Personal and Social Performance Scale (PSP) (Morosini et al., 2000) This scale assesses a patient's degree of impairment in four domains. Each domain is rated on a six-point scale from absent to very severe. Using the ratings on the four sub-dimensions, one total score on a 100-point scale is created, where 100 is no impairment and 0 is the most severely impaired. | Assessed at 24 weeks and 48 weeks | 
| Satisfaction with Life Scale | Satisfaction with Life Scale (SWLS) (Diener et al., 1985) This is a 5-item instrument designed to measure global cognitive judgments of satisfaction with one's life. Each item is rated from 0 to 7 with total scores ranging from 0 to 35. Higher scores indicate better outcomes. | Assessed at 24 weeks and 48 weeks | 
| Single-Item Happiness Questionnaire | Single-Item Happiness Questionnaire (SIQ) (Abdel-Khalek, 2006) This scale involves answering a single question with ratings ranging from 0 to 10 with higher scores indicating better outcomes/greater happiness. | Assessed at 24 weeks and 48 weeks | 
| Quality of Life Scale | Quality of Life Scale (QLS) (Heintichs et al., 1984) This is a 21-item assessment that evaluates the adequacy of an individual's psychosocial functioning over the past month on 7-point Likert scales (items rate from 0 to 6) with a higher score meaning better functioning. The minimum total score is 0 and the maximum score is 126 with higher scores indicating better outcomes. | Assessed at 24 weeks and 48 weeks | 
| UKU Side Effect Rating Scale | Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale (Lingjaerde et al., 1987) The scale involves rating 48 side effects on a 4-point scale from 0 to 3 with higher scores indicating more severe side effects. | Assessed at 24 weeks and 48 weeks | 
| Subjective Well-Being Under Neuroleptics Scale | Subjective Well-Being Under Neuroleptics Scale (SWN) (Naber et al., 2001) This is a self-rated scale consisting of 20 items that are assessed on a 6-point Likert scale. Each item is rated from 1 to 6. The minimum score is 20 and the maximum score is 120. Higher scores indicate better subjective well-being. | Assessed at 24 weeks and 48 weeks | 
| Barnes Akathisia Scale | Barnes Akathisia Scale (BAS) (Barnes, 1989) This scale is scored on Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness. Each are rated on a 4-point scale from 0 to 3 and are summed to yield a total score ranging from 0 to 9, with 9 being the most severely affected. There is also a Global Clinical Assessment of Akathisia item that is rated from 0 - Absent to 5 - Severe Akathisia. | Assessed at 24 weeks and 48 weeks | 
| Arizona Sexual Experiences Scale | Arizona Sexual Experiences Scale (ASEX) (McGahuey et al., 2000) This is a five-item rating scale assessing sexual dysfunction with each item rated from 1 to 6. Possible scores range from 5 to 30, with the lower scores indicating better sexual functioning and higher scores indicating worse sexual functioning (i.e. more sexual dysfunction). | Assessed at 24 weeks and 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Relapse, Long-acting injectable antipsychotics, Remission