A Study to Compare the Efficacy, Safety, and Tolerability of JNJ-42847922 Versus Quetiapine Extended-Release as Adjunctive Therapy to Antidepressants in Adult Participants With Major Depressive Disorder Who Have Responded Inadequately to Antidepressant Therapy

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy of flexibly dosed JNJ-42847922 (20 milligram [mg] or 40 mg) compared to flexibly dosed quetiapine extended-release (XR) (150 mg or 300 mg) as adjunctive therapy to an antidepressant drug in delaying time to all-cause discontinuation of study drug over a 6-months (24 weeks) treatment period, in participants with major depressive disorder (MDD) who have had an inadequate response to current antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).

Official Title
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A 6-Month, Multicenter, Double-Blind, Randomized, Flexible-Dose, Parallel-Group Study to Compare the Efficacy, Safety, and Tolerability of JNJ-42847922 Versus Quetiapine Extended-Release as Adjunctive Therapy to Antidepressants in Adult Subjects With Major Depressive Disorder Who Have Responded Inadequately to Antidepressant Therapy

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: JNJ-42847922
* Drug: Placebo Matching to JNJ-42847922
* Drug: Quetiapine XR
* Drug: Placebo Matching to Quetiapine XR
* Drug: Selective Serotonin Reuptake Inhibitor (SSRI)
* Drug: Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female of non-childbearing potential (WONCBP) outpatients, aged 18 to 70 years (inclusive). A WONCBP is defined as: a).Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. b). Permanently sterile: Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy. c). If reproductive status is questionable, additional evaluation should be considered Meet Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) diagnostic criteria for major depressive disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the Structured Clinical Interview for DSM-5 Axis I Disorders- Clinical Trials Version (SCID-CT). The length of the current depressive episode must be less than or equal to (<=) 18 months Have had an inadequate response to at least 1 but no more than 3 antidepressants, administered at an adequate dose and duration in the current episode of depression, as assessed by the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire (MGH-ATRQ). An inadequate response is defined as less than (<)50 percent (%) reduction in depressive symptom severity, as assessed by the MGH-ATRQ. An adequate trial is defined as an antidepressant treatment for at least 4 weeks at or above the minimum therapeutic dose, as specified in the MGH-ATRQ, for any particular antidepressant. The inadequate response must include the participant's current antidepressant treatment Be receiving monotherapy treatment for depressive symptoms with 1 of the following selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants, in any formulation: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine at a stable dose (at or above the minimum therapeutic dose level) for at least 4 weeks, and for no greater than 12 months, at screening. Modification of an effective preexisting therapy should not be made for the explicit purpose of entering a participant into the study Have a Montgomery-Asberg Depression Rating Scale (MADRS) total score greater than or equal to (>=)25 (performed by independent, centralized remote raters) at screening and must not demonstrate a clinically significant improvement (that is, an improvement of greater than (>)20% on their MADRS total score) from the screening to baseline visit Have a Body Mass Index (BMI) between 18 and 35 kilogram per meter square (kg/m^2) inclusive (BMI equal to [=] weight/height^2) Must be otherwise healthy on the basis of physical examination, medical history, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population. If the results of the clinical laboratory tests are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed by the investigator Exclusion Criteria: Have Cushing's Disease, Addison's Disease, primary amenorrhea, or other evidence of significant medical disorders of the hypothalamic-pituitary-adrenal (HPA) axis Have a history of epilepsy, neuroleptic malignant syndrome (NMS) or Tardive Dyskinesia Have a history of previous non-response to an adequate trial of quetiapine as an adjunctive treatment for MDD (adequate trial defined as >=150 mg for 4 weeks or more) and/or a history of lack of response to 3 or more adequate antidepressant treatments and/or a history or evidence of noncompliance with current antidepressant therapy Have taken a known moderate or strong inhibitor/inducer of cytochrome P450 (CYP)3A4 and CYP2C9 or a dual inhibitor/inducer of CYP3A4 and CYP2C9 within 14 days (or after washout that is, duration of 5 times the drug's half-life) before the first study drug administration on Day 1 until the follow-up visit. Fluvoxamine is a moderate CYP2C9 inhibitor and a mild CYP3A inhibitor, and will not be excluded from the study Have a history or current diagnosis of a psychotic disorder, bipolar disorder, intellectual disability, autism spectrum disorder, borderline personality disorder, somatoform disorders, or fibromyalgia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JNJ-42847922<br>Participants will receive 20 mg of JNJ-42847922 as a starting dose and matching placebo (1 capsule of 20 mg JNJ-42847922 and 1 capsule of matching placebo) once daily for 14 days. After Day 14, if needed, JNJ-42847922 dose can be increased to 40 mg (2*20 mg capsules) and flexible dose of JNJ-42847922 (20 or 40 mg) will be taken once daily until Day 167. Dose of JNJ-42847922 (20 or 40 mg) will be adjusted by investigator based on the participant's clinical response and tolerability. Participants will continue to take their baseline selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases. | Drug: JNJ-42847922<br>* Participants will receive JNJ-42847922 capsule orally.<br>* Other names: Seltorexant;Drug: Placebo Matching to JNJ-42847922<br>* Participants will receive placebo capsule matching to JNJ-42847922 orally.<br>Drug: Selective Serotonin Reuptake Inhibitor (SSRI)<br>* Participants will receive SSRI antidepressant (such as, citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, vilazodone or vortioxetine) as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases (approximately up to Week 26).<br>Drug: Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)<br>* Participants will receive SNRI antidepressant (such as duloxetine, milnacipran, levomilnacipran, venlafaxine, desvenlafaxine) as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases (approximately up to Week 26).<br>|
| Active Comparator: Quetiapine Extended-Release (XR)<br>Participants will receive 1 capsule of quetiapine XR 50 mg along with 1 capsule of matching placebo once daily for 2 days, followed by 1 capsule of quetiapine XR 150 mg along with 1 capsule of matching placebo once daily from Day 3 to Day 14. After Day 14, if needed, quetiapine XR dose can be increased to 300 mg (2*150 mg capsules) and flexible dose of quetiapine (150 or 300 mg) will be taken once daily until Day 167. Dose of quetiapine XR (150 or 300 mg) will be adjusted by investigator based on the participant's clinical response and tolerability. Participants will continue to take their baseline SSRI/SNRI antidepressant as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases. | Drug: Quetiapine XR<br>* Participants will receive quetiapine XR capsule orally.<br>Drug: Placebo Matching to Quetiapine XR<br>* Participants will receive placebo capsule matching to quetiapine XR orally.<br>Drug: Selective Serotonin Reuptake Inhibitor (SSRI)<br>* Participants will receive SSRI antidepressant (such as, citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, vilazodone or vortioxetine) as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases (approximately up to Week 26).<br>Drug: Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)<br>* Participants will receive SNRI antidepressant (such as duloxetine, milnacipran, levomilnacipran, venlafaxine, desvenlafaxine) as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases (approximately up to Week 26).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to All-Cause Discontinuation of Study Drug | Time to all-cause discontinuation of study drug is defined as the number of days from the first dose of study drug to the last dose of study drug. Participants who completed double-blind treatment were not considered to have discontinued. | Up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Remission up to Week 24 | Remission is defined as Montgomery-Asberg Depression Rating Scale (MADRS) total score of less than or equal to (<=) 12. A participant was defined as having achieved sustained remission if the MADRS total score was ≤12 at Week 12 and was sustained at Weeks 18 and 24. Participants with missing values at a given time point were imputed as non-evaluable for remission. MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. | Up to Week 24 | 
| Percentage of Participants With Sustained Response up to Week 24 | A participant was defined as having achieved a sustained response if there was at least a 50% improvement from baseline in the MADRS total score at Week 12, and that response was maintained at Week 18 and Week 24. Participants who did not meet such criterion were considered as non-sustained responders. MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. | Up to Week 24 | 
| Change From Baseline in MADRS Total Score in Participants With Significant Insomnia (Baseline Insomnia Severity Index [ISI] Score >=15) Versus Those Without Significant Insomnia (Baseline ISI Score Less Than [<] 15) at Week 12 | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. The ISI has 7 questions, each rated on a 5-point Likert scale ranging from 0 to 4. The total score is calculated as the sum of the 7 items ranging from 0 to 28. Higher scores represent a more severe condition. | Baseline and Week 12 | 
| Change From Baseline in MADRS Total Score in Participants With Significant Insomnia (Baseline ISI Score >=15) Versus Those Without Significant Insomnia (Baseline ISI Score <15) at Week 18 | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. The ISI has 7 questions, each rated on a 5-point Likert scale ranging from 0 to 4. The total score is calculated as the sum of the 7 items ranging from 0 to 28. Higher scores represent a more severe condition. | Baseline and Week 18 | 
| Change From Baseline in MADRS Total Score in Participants With Significant Insomnia (Baseline ISIscore >=15) Versus Those Without Significant Insomnia (Baseline ISI Score 15) at Week 24 | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. The ISI has 7 questions, each rated on a 5-point Likert scale ranging from 0 to 4. The total score is calculated as the sum of the 7 items ranging from 0 to 28. Higher scores represent a more severe condition. | Baseline and Week 24 | 
| Change From Baseline in the Hamilton Anxiety Rating Scale (HAM-A) Total Score at Weeks 12, 18, and 24 | HAM-A is a 14-item scale designed to measure anxiety in individuals. Each question reflects a symptom of anxiety and physical as well as mental symptoms are represented. Each of the 14-items in the scale is scored on a 5-point scale, ranging from 0 (a complete lack of that symptom) to 4 (a very severe show of anxiety with that symptom). The total score ranges from 0 to 56 which is calculated by adding the scores of all 14 items, where 0-13 indicates normal range, 14-17 indicates mild severity, 18 -24: mild to moderate severity, 25 -30: moderate to severe, and >=31: severe. Higher score indicates worsening. Negative change in score indicates improvement. | Baseline, Weeks 12, 18, and 24 | 
| Percentage of Participants With Weight Gain of >=7% of Baseline Body Weight at Week 24 | Percentage of participants with weight gain of >=7% of baseline body weight at Week 24 were reported. | At Week 24 | 
| Percentage of Participants With Shifts in Triglycerides From Normal to High | Percentage of participants with shifts in triglycerides from normal to high (<150 milligrams per deciliter [mg/dL] at baseline to >=200 mg/dL at any post-baseline assessment) were reported. | Up to Week 24 | 
| Percentage of Participants With Shifts in Triglycerides From Borderline to High | Percentage of participants with shifts in triglycerides from borderline to high (>=150 to <200 mg/dL at baseline to >=200 mg/dL at any post-baseline assessment) were reported. | Up to Week 24 | 
| Percentage of Participants With Shifts in Triglycerides From Normal to Very High | Percentage of participants with shifts in triglycerides from normal to very high (<150 mg/dL at baseline to >=500 mg/dL at any post-baseline assessment) were reported. | Up to Week 24 | 
| Percentage of Participants With Shifts in Triglycerides From Borderline to Very High | Percentage of participants with shifts in triglycerides from borderline to very high (>=150 mg/dL to <200 mg/dL at baseline to >=500 mg/dL at any post-baseline assessment) were reported. | Up to Week 24 | 
| Percentage of Participants With Shifts in Triglycerides From High to Very High | Percentage of participants with shifts in triglycerides from high to very high (>=200 mg/dL to <500 mg/dL at baseline to >=500 mg/dL at any post-baseline assessment) were reported. | Up to Week 24 | 
| Percentage of Participants With Shifts in Fasting Blood Glucose From Normal to Borderline | Percentage of participants with shifts in fasting blood glucose from normal to borderline (<100 mg/dL at baseline to between >=100 and <126 mg/dL at any post-baseline assessment) were reported. | Up to Week 24 | 
| Percentage of Participants With Shifts in Fasting Blood Glucose From Borderline to High | Percentage of participants with shifts in fasting blood glucose from borderline to high (>=100 to <126 mg/dL at baseline to >=126 mg/dL at any post-baseline assessment) were reported. | Up to Week 24 | 
| Percentage of Participants With Shifts in Fasting Blood Glucose From Normal to High | Percentage of participants with shifts in fasting blood glucose from normal to high (<100 mg/dL at baseline to >=126 mg/dL at any post-baseline assessment) were reported. | Up to Week 24 | 
| Change From Baseline in the Clinical Global Impression-Severity (CGI-S) Scale Score at Weeks 12 and 24 | The CGI-S provides an overall clinician-determined summary measure of the severity of the participant's illness that takes into account all available information, including knowledge of the participant's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the participant's ability to function. The CGI-S is a 7-point global assessment scale that measures the clinician's impression of the severity of illness exhibited by a participant, rating according to: 1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=among the most extremely ill participants. Higher scores indicate worsening. Negative change in score indicates improvement. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in the Patient Global Impression Severity (PGI-S) Scale Score at Weeks 12 and 24 | The PGI-S is a self-report scale to measure severity of illness (1=none, 2=mild, 3=moderate, 4=severe). Higher score indicates more illness severity. Negative change in score indicates improvement. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Quality of Life in Depression Scale (QLDS) Score at Weeks 12 and 24 | The QLDS is a disease specific patient-reported outcome (PRO) designed to assess health related quality of life in participants with major depressive disorder (MDD). The instrument has a recall period of at the present time, contains 34-items with true/not true response options. Each statement on the QLDS is given a score of 1 (adverse quality of life) or 0 good quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition. Negative change indicates improvement. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Patient Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD) Short Form 8a at Weeks 12 and 24 | The PROMIS-SD Short Form 8a subscale consists of a static 8 item questionnaire. It assesses the concepts of sleep initiation (2 items), quality of sleep (3 items), early morning feelings (2 items) and worrying about sleep (1 item). Responses to each of the 8 items range from 1 to 5, and the range of possible summed raw scores is 8 to 40. Higher scores on the PROMIS-SD indicate more of the concept measured (disturbed sleep). Negative change in score indicates improvement. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Patient Reported Outcomes Measurement Information System-Sleep Related Impairment (PROMIS-SRI) Short Form 8a at Weeks 12 and 24 | The PROMIS-SRI Short Form 8a subscale consists of a static 8 item questionnaire and use five-point likert scale to capture the participant's impressions. It assesses sleep-related impairment over the past 7 days. Responses to each of the 8 items range from 1 (less impairment) to 5 (more impairment), and the range of possible summed raw scores is 8 to 40. Lower scores indicate less sleep related impairment. Negative change in score indicates improvement. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) Score at Weeks 12 and 24 | The SMDDS assesses participant-reported symptoms associated with MDD. This 16-item instrument has a 7-day recall period, and participants respond to each question using a rating scale between 0 (Not at all or Never) to 4 (Extremely or Always). Before summing the items to create a total score, item 11 (how often did you have a poor appetite) and item 12 (how often did you over eat) are combined into a single score by selecting the highest severity on either item. The total score is then created by summing the responses on the 15 items. The total score ranges from 0 to 60 with a higher score indicating more severe depressive symptomatology. Negative change in score indicates improvement. | Baseline, Weeks 12 and 24 | 
| Change From Baseline in Symbol Digit Modalities Test (SDMT) at Weeks 6, 12, and 24 | SDMT is a widely used, paper-and-pencil assessment of complex scanning and visual tracking, requiring elements of attention, visuoperceptual processing, working memory, and cognitive/psychomotor speed. The test is viewed as a robust screening test for adult neuropsychological impairment and is sensitive to impairments in cognitive function associated with MDD. The SDMT measured the time to pair abstract symbols with specific numbers. The test included a coding key consisting of 9 abstract symbols, each paired with a number ranging from 1 to 9. Following the key, the participant was presented with randomly ordered symbols and was required to write the number corresponding to each symbol as fast as possible. The number of correct substitutions within 90 seconds was recorded and total score derived from the total number of correct responses with a minimum possible score of 0 and maximum of 110 where high scores indicate better outcome. Positive change in score indicates improvement. | Baseline, Weeks 6, 12, and 24 | 
| Change From Baseline in Trail Making Test - Part B (TMT-Part B) at Weeks 6, 12, and 24 | The TMT-Part B measures divided attention and executive function (tracking and sequencing). The participant is instructed to draw a line to connect a set of 25 consecutively numbered and lettered circles, alternating sequentially between numbers and letters (that is, 1 A 2 B). The participant is instructed to work as quickly as possible while still maintaining accuracy. Score included time (seconds) to completion and number of errors in performing the test which ranges from 0 (no errors) to 25 (more errors), where shorter time and less number of errors indicates better performance. The TMT-Part B is sensitive to cognitive decline associated with MDD. Negative change in score indicates improvement. | Baseline, Weeks 6, 12, and 24 | 
| Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) at Weeks 6, 12, and 24 | The HVLT-R measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. The delayed recall requires free recall of any words remembered. The recognition trial is composed of 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the three learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0 -12); the total number of true-positive errors (0-12); and the recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score indicates higher cognition. | Baseline, Weeks 6, 12, and 24 | 
| Change From Baseline in Salivary Cortisol Levels as Measured at Home Upon Awakening and During the Evening at Weeks 6 and 24 | Change from baseline in salivary cortisol levels as measured upon awakening and at home during the evening at Weeks 6 and 24 were reported. | Baseline, Weeks 6 and 24 | 
| Percentage of Participants With Treatment-emergent Adverse Events as a Measure of Safety and Tolerability | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent AEs were AEs with onset during the double-blind treatment phase or that were a consequence of a preexisting condition that worsened since baseline. | Up to 24 weeks | 
| Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Events of Special Interest | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence that at any dose may result in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. AESIs were significant AEs that were judged to be of special interest because of clinical importance, known or suspected class effects, or based on nonclinical signals. Adverse events of special interest were cataplexy, sleep paralysis, complex, and sleep-related behaviors (parasomnias). | Up to 24 weeks | 
| Percentage of Participants With Abnormalities in Vital Sign Parameters | Percentage of participants with abnormalities in vital sign parameters (pulse, supine and standing blood pressure [systolic and diastolic], body temperature, and body weight) were reported. Abnormally low values for parameters included pulse (beats per minute)- decrease value from baseline (>=) 15 to <=50; Systolic Blood Pressure (BP) (mmHg [Millimeter of mercury])- decrease value from baseline >=20 to <=90; Diastolic BP- decrease value from baseline >=15 to <=50; weight (Kilogram[Kg])- decrease from baseline of >=7%; Body temperature (Celsius [C])- <35.5. Abnormally high values for parameters included pulse- increase value from baseline >=15 to >=100; Systolic BP(mmHg)- increase from baseline of >=20 to >=180; Diastolic BP- increase value from baseline >=15 to >=105; weight(Kg)- increase from baseline of >=7%; body temperature (C)- >37.5. | Up to 24 weeks | 
| Percentage of Participants With Abnormalities in Electrocardiogram (ECG) Parameters | Percentage of participants with abnormalities in ECG parameters were reported. | Up to 24 weeks | 
| Percentage of Participants With Abnormalities in Clinical Laboratory Parameters | Percentage of participants with abnormalities in clinical laboratory parameters were reported. | Up to 24 weeks | 
| Percentage of Participants With Sexual Dysfunction as Determined by Arizona Sexual Experiences Scale (ASEX) Total Score | Sexual dysfunction is defined as an ASEX total score of 19 or greater, or a score of 5 or greater on any item, or a score of 4 or greater on any 3 items. ASEX is a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Each of the 5 items is rated on a 6-point Likert scale, ranging from 1 to 6. The 5 items are summed to create a total score, ranging from 5 to 30, with the higher scores indicating more sexual dysfunction. | Up to Endpoint (Up to 24 weeks) | 
| Percentage of Participants With Clinically Relevant Changes in Extrapyramidal Symptoms Assessed by the Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) Score | The ESRS-A is an abbreviated manualized version of the ESRS, a semi-structured interview that rates parkinsonian symptoms, dystonia, dyskinesias, and akathisia over the previous 7 days. The ratings include a motor examination for rigidity, tremor, reduced facial expression or speech, impaired gait/posture, postural instability, and bradykinesia/hypokinesia. Twenty-four individual items are rated on a 6-point scale: 0=Absent, 1=Minimal, 2=Mild, 3=Moderate, 4=Severe, or 5=Extreme. Frequency is included as an index of severity. | Up to Endpoint (Up to 24 weeks) | 
| Percentage of Participants With Suicidality Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) Score | C-SSRS is a clinician-rated instrument that reports severity and frequency of suicide-related ideation and behaviors. Suicidal ideation was classified on a 5-item scale: 1 (wish to be dead), 2 (non-specific active suicidal thoughts), 3 (active suicidal ideation with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). Suicidal behavior is classified on a 5-item scale: 6 (preparatory acts or behavior), 7 (aborted attempt), 8 (interrupted attempt), 9 (actual attempt [non-fatal]), and 10 (completed suicide [only applicable for post baseline]). Minimum total score 0, maximum total score 10; higher total scores indicate more suicidal ideation and/or suicidal behavior. If no events qualify for score of 1 to 10, score of 0 was assigned (0= no event that can be assessed on the basis of C-SSRS). Higher scores indicate greater severity. | Up to Endpoint (Up to 24 weeks) | 
| Percentage of Participant With Potential Withdrawal Effects Assessed by the Physician Withdrawal Checklist (PWC) | Intensity of discontinuation symptoms was assessed (anxiety-nervousness, dysphoric mood/depression, Depersonalization-Derealization, , Diaphoresis, Diarrhea, Difficulty Concentrating, Remember, Dizziness-Lightheadedness, Fatigue-Lethargy-Lack of Energy, Headaches, Increased Acuity Sound Smell Touch, Irritability, Loss of Appetite, Muscle Aches or Stiffness, Nausea-Vomiting, Paresthesias, Poor Coordination, Restlessness-Agitation, Tremor-Tremulousness, Weakness), using the Physician Withdrawal Checklist (PWC-20) administered by a trained clinician/rater. Symptoms are rated on a scale of 0 (no symptom present), 1 (mild), 2 (moderate), and 3 (severe). Total scores range from 0 (no symptom) to 24 (severe symptom) calculated by adding the scores of following 8 items: Nausea-Vomiting, Diarrhea, Poor Coordination, Diaphoresis, Tremor-Tremulousness, Dizziness-Lightheadedness, Increased Acuity Sound Smell Touch, Paresthesias. Higher scores indicates more severe symptoms. | Up to 26 weeks | 
| Change From Baseline in MADRS Total Score Over Time | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. | Baseline, Weeks 2, 4, 6, 12, 18, 24 | 
| Change From Baseline in MADRS Total Score Over Time, by Mode Dose | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score range of 0-60 which is calculated by adding the scores of all 10 items. Higher scores represent a more severe condition. Negative change in score indicates improvement. | Baseline, Weeks 2, 4, 6, 12, 18, 24, and 26 | 
| Change From Baseline in MADRS-6 Score Over Time | MADRS-6 is the depression subscale of the full MADRS, including the following 6 items: apparent sadness, reported sadness, inner tension, lassitude, inability to feel, pessimistic thoughts. Each item is scored from 0 (absence of symptom) to 6 (severe symptom); the overall score ranges from 0 to 36 which is calculated by adding the scores of all 6 items. Higher scores represent a more severe condition. | Baseline, Weeks 2, 4, 6, 12, 18, 24, and 26 |