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

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.

Time frame: Week 6

Population: Full-analysis set (FAS), this endpoint presents descriptive statistics for CGI-I based on patients who have CGI-I score observed at Week 6; the number of participants analysed is therefore smaller than the defined FAS.

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.

Time frame: Week 6

Population: full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: full-analysis set (FAS). Only patients who have observed data at Week 6 were included in the ANCOVA analysis; the number of participants analysed is therefore smaller than the defined FAS.

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.

Time frame: Baseline and Week 6

Population: full-analysis set (FAS). Only patients who have observed data at Week 6 were included in the ANCOVA analysis; the number of participants analysed is therefore smaller than the defined FAS.

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS)

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.

Time frame: Week 6 and Week 10

Population: Completer's-analysis set (CAS). Only patients who have observed data at Week 10 were included in the ANCOVA analysis.

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.

Time frame: Week 6 and Week 10

Population: Completer's-analysis set (CAS)

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.

Time frame: Week 6 and Week 10

Population: Completer's-analysis set (CAS). Only patients who have observed data at Week 10 were included in the ANCOVA analysis; the number of participants analysed is therefore smaller than the defined CAS.

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.

Time frame: Week 6 and Week 10

Population: Completer's-analysis set (CAS)

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.

Time frame: Week 6 and Week 10

Population: Completer's-analysis set (CAS)

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.

Time frame: Week 6 and Week 10

Population: Completer's-analysis set (CAS). Only patients who have observed data at Week 10 were included in the ANCOVA analysis; the number of participants analysed is therefore smaller than the defined CAS.

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.

Time frame: Week 6 and Week 10

Population: Completer's-analysis set (CAS)

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.

Time frame: Baseline and Week 6

Population: Full-analysis set (FAS) and OC. Only patients who have both baseline and Week 6 data observed were included; the number of participants analysed is therefore smaller than the defined FAS.