Study of Brexpiprazole as Adjunctive Treatment of Irritability in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

Study Overview
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Brief Summary
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To explore the anti-impulsive and anti-aggressive properties of brexpiprazole in a naturalistic setting of depressed patients with irritability.

Official Title
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Interventional, Open-label, Flexible-dose, Exploratory Study of Brexpiprazole as Adjunctive Treatment of Irritability in Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Therapy

Conditions
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Major Depressive Disorder, Irritability

Intervention / Treatment
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* Drug: Brexpiprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Main selection criteria at screening visit: The patient has a Major Depressive Episode (MDE) associated to Major Depressive Disorder (MDD) diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR™). The current MDE should be confirmed using the Mini International Neuropsychiatric Interview (MINI) The patient has an inadequate response to at least one antidepressant treatment (including the treatment the patient is taking at screening) in the current MDE, as documented by self-report as less than a pre-defined percentage response on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ). Pre-defined MADRS total score Pre-defined CGI-S total score The patient has had the current MDE for ≥10 weeks The patient is receiving a SSRI or SNRI antidepressant treatment for ≥6 weeks, at same dosage for ≥2 weeks Pre-defined Inventory of Depressive Symptomatology - Clinician-Rated - 30 items (IDS-C 30) Item 6 Mood (irritable) score Main inclusion criteria at baseline visit: The patient still fulfils DSM-IV-TR™ criteria for MDE Pre-defined MADRS total score Pre-defined CGI-I (Lead-in period) score The patient received the same SSRI or SNRI antidepressant treatment at adequate doses during the entire lead-in period The patient has less than a pre-defined percentage decrease in MADRS score at the end of the lead-in period as compared to the screening visit The patient still has the pre-defined IDS-C 30 Item 6 Mood (Irritable) score Exclusion Criteria: The patient has any current psychiatric disorder or Axis I disorder (DSM-IV-TR™ criteria), established as the principal diagnosis, other than MDD. All anxiety disorders, impulse-control disorders such as intermittent explosive disorder, as well as non-suicidal self-injury are not excluded diagnoses as far as they are not considered as principal diagnosis. The patient has a current Axis II (DSM-IV-TR™) diagnosis of antisocial, borderline, paranoid, schizoid, schizotypical, or histrionic personality disorder. The patient has experienced/experiences hallucinations, delusions, or any psychotic symptomatology in the current MDE. The patient, in the opinion of the investigator or based on C-SSRS rating, is at significant risk of suicide. The patient has started formal cognitive or behavioural therapy or systematic psychotherapy within 6 weeks prior to screening, or plans to start such therapy during the study. Any ongoing formal psychotherapy initiated more than 6 weeks prior to screening should be continued with the same methodology and at the same frequency and intensity during the entire study. The patient has a current diagnosis or history of substance abuse or dependence (excluding nicotine or caffeine) or alcohol abuse or dependence (DSM-IV-TR™ criteria) <6 months prior to the Screening Visit. The patient reports adjunctive treatment with an antipsychotic medication together with an antidepressant for 3 weeks or more during the current MDE. The patient has received electroconvulsive therapy (ECT) <6 months prior to the Screening Visit or at any time during the current MDE (if its duration is longer than 6 months). The patient has had vagus nerve stimulation or a deep brain stimulation device implanted for the management of depression. Other inclusion and exclusion criteria may apply.

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

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brexpiprazole<br>Brexpiprazole adjunct to open-label commercially available Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin Norepinephrine Reuptake Inhibitor (SNRI) antidepressant treatment (ADT) | Drug: Brexpiprazole<br>* 2-3 mg/day, once daily dose, tablets, for oral use. The patients received 1mg/day brexpiprazole during Week 1 and 2mg/day during Week 2 (up-titration) and from Weeks 3 to 6 they received 3mg/day; depending on tolerability the dose could be reduced to 2mg/day based on the investigator's judgement.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 6 in SIS Total Score | The Sheehan Irritability Scale (SIS) is a patient-rated scale designed to measure irritability. The SIS consists of 7 subscales assessing irritability, frustration, edginess/impatience/overreaction, moodiness, anger with self, anger with others, and temper. The subscales are summarised to give the total score which ranges from 0 to 70, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in SIS Item 1 Score | The Sheehan Irritability Scale (SIS) is a patient-rated scale designed to measure irritability. The SIS item 1 assess how much the patient has suffered from irritability in the past week. The SIS item 1 ranged from 0 to 10 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in IDS-C30 Item 6 Score | The 30-item Inventory of Depressive Symptomatology - Clinician-Rated (IDS-C30) is a clinician-rated scale designed to assess the severity of depressive symptoms. The IDS-C30 item 6 measures mood (irritable) and is rated on a 4-point anchored scale from 0 (least severe) to 3 (most severe) with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in Delay Discounting - Log-transformed MCQ Scores | The Monetary Choice Questionnaire (MCQ) is a patient-completed questionnaire designed to measure delay discounting, an index of impulsive behaviour. The MCQ consists of 27 choices between immediate and delayed rewards. The patients choose repeatedly between two hypothetical sums of money: a smaller amount now or a larger amount in the future (for example, ''Would you prefer $27 today or $50 in 21 days?). The answers provide an estimate of the patient's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicate impulsivity. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in BIS-11 Total Score | The Barratt Impulsiveness Scale, Version 11 (BIS-11) is a patient-rated scale designed to assess impulsive personality traits. The BIS-11 consists of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). The total score ranges from 30 to 120 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in KSQ Anger-hostility Subscore | The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ anger-hostility subscale score ranges from 0 to 23 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Shift From Baseline to Week 6 in Anger Attacks (AAQ) | The Anger Attacks Questionnaire (AAQ) is a patient-rated scale designed to assess the presence of anger attacks over a period of time. The AAQ consists of 7 items. Patients are classified as having anger attacks when exhibiting the following 4 criteria: 1) irritability, 2) overreaction to minor annoyances, 3) occurrence of anger attacks (at least one of which occurred within the period), and 4) experienced 4 or more specific symptoms during at least one of the attacks. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in IDS-C30 Total Score | The 30-item Inventory of Depressive Symptomatology - Clinician-Rated (IDS-C30) is a clinician-rated scale designed to assess the severity of depressive symptoms. The IDS-C30 consists of 30 items assessing the symptoms of depression, as well as commonly associated symptoms (for example, anxiety, irritability), and topics relevant to melancholic or atypical features; the patient rates only one of the 2 items assessing appetite (decreased or increased), and only one of the 2 items assessing weight (loss or gain). Each of the items is rated on a 4-point anchored scale from 0 (least severe) to 3 (most severe). The total score is the sum of the 28 scored items, and ranges from 0 to 84, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in KSQ Depression Subscore | The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ depression subscale score ranges from 0 to 23, with higher values indicating worse outcome . As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in MADRS Total Score | The Montgomery and Åsberg Depression Rating Scale (MADRS) is a 10-item rating scale designed to assess the severity of the symptoms in depressive illness and to be sensitive to treatment effects. Symptoms are rated on a 7-point scale from 0 (no symptom) to 6 (severe symptom). The total score of the 10 items ranges from 0 to 60, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in CPFQ Total Score | The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) is a patient-rated scale designed to assess cognitive and executive dysfunction including symptoms of fatigue in mood and anxiety disorders. The CPFQ consists of 7 items, each rated on a scale from 1 (greater than normal functioning) to 6 (poorer than normal functioning). The total score of the 7 items ranges from 7 to 42, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in CGI-S Score | The Clinical Global Impression severity of illness (CGI-S) provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill patients). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| CGI-I Score at Week 6 | The Clinical Global Impression - global improvement CGI-I provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). In all cases, the assessment should be made independent of whether the rater believes the improvement is drug-related or not. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 | 
| Change From Baseline to Week 6 in KSQ Total Score | The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ consists of 92 items which form the basis for the four subscales: depression, anxiety, anger-hostility, and somatic; of which 68 items indicate symptoms (symptom subscales) and 24 items are antonyms of some of the symptoms and indicate well-being (well-being subscales). A yes or true response on the symptom subscales scores 1, and a no or false on the well-being subscales scores 1. The maximum score for each symptom subscale is 17, and the maximum score for each well-being subscale is 6. The score of each subscale ranges from 0 to 23 (the sum of the symptom subscale and the well-being subscale). A higher score indicates more distress. The total score ranges from 0 to 92. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in Delay Discounting - Log-transformed EDT DPDT Scores | DPDT consists of approximately 110 choices between an immediate reward or a higher delayed reward, and between an immediate reward or a higher reward that only comes with a certain probability. The tasks are scored independently of each other and do not yield a total score. There will be two derived variables from this task; a delayed discounting rate and a probability discounting rate. The delay discounting value takes values from 0 and up, a higher delay discounting value indicates greater impulsivity. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in Delay Discounting - EDT DRT Score | DRT consists of 60 choices between an immediate reward or a higher delayed reward. The number of impulsive choices will be a continuous variable estimated from how many immediate choices based on 60 possible. The number ranges between 0 and 60, with a higher value indicating more impulsivity. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Week 6 to Week 10 in SIS Total Score | The Sheehan Irritability Scale (SIS) is a patient-rated scale designed to measure irritability. The SIS consists of 7 subscales assessing irritability, frustration, edginess/impatience/overreaction, moodiness, anger with self, anger with others, and temper. The patient rates the extent to which they have suffered from these symptoms. Each subscale has verbal descriptors (not at all, mildly, moderately, markedly, and extremely) as well as numerical scores from 0 (not at all) to 10 (extremely) that provide more precise levels of the verbal descriptors. One additional question assesses number of days impaired by irritability over the period. The subscales are summarised to give the total score which ranges from 0 to 70, with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 and Week 10 | 
| Change From Week 6 to Week 10 in SIS Item 1 Score | The Sheehan Irritability Scale (SIS) is a patient-rated scale designed to measure irritability. The SIS item 1 assess how much the patient has suffered from irritability in the past week, using verbal descriptors (not at all, mildly, moderately, markedly, and extremely) as well as numerical scores from 0 (not at all) to 10 (extremely) that provide more precise levels of the verbal descriptors. The SIS item 1 ranged from 0 to 10 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 and Week 10 | 
| Change From Week 6 to Week 10 in Delay Discounting - MCQ Scores | The Monetary Choice Questionnaire (MCQ) is a patient-completed questionnaire designed to measure delay discounting, an index of impulsive behaviour. The MCQ consists of 27 choices between immediate and delayed rewards. The patients choose repeatedly between two hypothetical sums of money: a smaller amount now or a larger amount in the future (for example, ''Would you prefer $27 today or $50 in 21 days?). The answers provide an estimate of the patient's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicate impulsivity. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 and Week 10 | 
| Change From Week 6 to Week 10 in BIS-11 Total Score | The Barratt Impulsiveness Scale, Version 11 (BIS-11) is a patient-rated scale designed to assess impulsive personality traits. The BIS-11 consists of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). The scores provide information to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance, and cognitive instability impulsiveness) and 3 second-order factors (motor impulsiveness, non-planning impulsiveness, and attentional impulsiveness). The total score ranges from 30 to 120 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 and Week 10 | 
| Change From Week 6 to Week 10 in KSQ Anger-hostility Subscore | The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ anger-hostility subscale score ranges from 0 to 23 with higher values indicating worse outcome. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 and Week 10 | 
| Change From Week 6 to Week 10 in KSQ Depression Subscore | The Kellner Symptom Questionnaire (KSQ) is a patient-rated scale designed to assess distress using symptoms of depression, anxiety, anger-hostility, and somatization. The KSQ depression subscale score ranges from 0 to 23, with higher values indicating worse outcome . As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 and Week 10 | 
| Change From Week 6 to Week 10 in CGI-S Score | The Clinical Global Impression severity of illness (CGI-S) provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill patients). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 and Week 10 | 
| Change From Baseline to Week 6 in MADRS Total Score in Patients With a Pre-defined Baseline BIS-11 Total Score | The Montgomery and Åsberg Depression Rating Scale (MADRS) is a 10-item rating scale designed to assess the severity of the symptoms in depressive illness and to be sensitive to treatment effects. Symptoms are rated on a 7-point scale from 0 (no symptom) to 6 (severe symptom). The total score of the 10 items ranges from 0 to 60, with higher values indicating worse outcome. Subgroup analyses were performed for the change from Baseline to Week 6 in MADRS total score based on the patients' BIS-11 total score at Baseline. The subgroups denoted BIS-11_HIGH had a BIS-11 total score at Baseline ≥median at baseline and the subgroups denoted BIS-11_LOW had a BIS-11 total score <median at baseline. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| Change From Baseline to Week 6 in CGI-S Score in Patients With a Pre-defined Baseline BIS-11 Total Score | The subgroups denoted BIS-11_HIGH had a BIS-11 total score at Baseline ≥median at baseline and the subgroups denoted BIS-11_LOW had a BIS-11 total score <median at baseline. The Clinical Global Impression severity of illness (CGI-S) provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill patients). As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Baseline and Week 6 | 
| CGI-I Score at Week 6 Patients With a Pre-defined Baseline BIS-11 Total Score | The subgroups denoted BIS-11_HIGH had a BIS-11 total score at Baseline ≥median at baseline and the subgroups denoted BIS-11_LOW had a BIS-11 total score <median at baseline. The Clinical Global Impression - global improvement CGI-I provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). In all cases, the assessment should be made independent of whether the rater believes the improvement is drug-related or not. As this was an open-label exploratory study, all outcomes should be considered as exploratory outcomes. | Week 6 |