AEs were graded by the investigator for severity on a three-point scale: mild, moderate and severe. Causality is graded as either related or not related. A serious adverse event (SAE) is an AE resulting in death, a life-threatening adverse event, hospitalization, a persistent or significant disability/incapacity, a congenital anomaly/birth defect, or an important medical event that may require medical intervention to prevent any of the previous results.

Protocol-defined adverse events requiring expedited reporting included skin rash, hypersensitivity reaction, emergent suicidal ideation or suicide attempt, and psychosis.

Safety population

Summary of serum chemistry tests in which at least one participant had a during study value that was clinically significant abnormal. The test name and criterion for clinically significant abnormal appear in each row.

• ULN=upper limit of normal
• BUN=Blood Urea Nitrogen; Uric acid has a normal range of 125-494 μmol/L. Criterion for clinically significant abnormal are different for men and women.
• GGT = gamma-glutamyl transpeptidase with a normal range of 4-61 U/L
• ALT = alanine aminotransferase with a normal range of 6-43 U/L
• BUN = blood urea nitrogen with a normal range of 1.4-8.6 mmol/L
• AST = aspartate aminotransferase with a normal range of 9-36 U/L

Safety population with post-baseline serum chemistry assessments

Summary of hematology tests in which at least one participant had a during study value that was clinically significant abnormal. The test name and criterion for clinically significant abnormal appear in each row.

• ULN=upper limit of normal
• WBC - white blood cell counts with a normal range of 3.8-10.7 10^9/L.
• Hemoglobin with a normal range of 115-181 g/L
• Hematocrit with a normal range of 0.34-0.54 L/L
• Platelet counts with a normal range of 130-400 10^9/L
• ANC= absolute neutrophil counts with a normal range of 1.96-7.23 10^9/L

Safety population with post-baseline hematology assessments

Summary of urinalysis tests in which at least one participant had a during study value that was clinically significant abnormal. Criterion for clinically significant abnormal urinalysis tests was >=2 unit increase from baseline.

Safety population with post-baseline urinalysis assessments

Summary of vital signs tests in which at least one participant had a during study value that was clinically significant abnormal. Criterion for clinically significant abnormal vital signs are based on FDA Neuropharmacological Division criteria:

• Pulse high: >=120 beats per minute (bpm) and increase of >=15 bpm from baseline
• Pulse low: <=50 bpm and decrease of >=15 bpm from baseline
• Sitting systolic blood pressure high: >=180 mm Hg and increase of >=20 mm Hg from baseline
• Sitting systolic blood pressure low: <=90 mm Hg and decrease of >=20 mm Hg from baseline
• Sitting diastolic blood pressure high: >=105 mm Hg and increase of >=15 mm Hg from baseline
• Sitting diastolic blood pressure low: <=50 mm Hg and decrease of >=15 mm Hg from baseline

Safety population with post-baseline vital signs assessments

ECG was conducted at baseline which was before the first dose of study drug in the double-blind study, and at the month-6 visit of the open-label study (or early termination).

RR= inter-beat intervals

Safety population of treated participants with both baseline and post-baseline ECG assessments

Baseline is the day prior to double-blind treatment. Assessments are summarized as normal or abnormal. The first assessment is the baseline assessment followed by the endpoint assessment. For example 'normal/abnormal' indicates participants who were normal at baseline and abnormal at endpoint.

HEENT = Head, Eye, Ear, Nose and Throat exam

Safety population of treated participants with baseline and endpoint assessments Participants n=: General appearance 785, HEENT 784, Chest and lungs 785, Heart 785, Abdomen 785, Musculoskeletal 785, Skin 785, Lymph nodes 780, Neurological 784

The IDS-C30 is a standardized 30-item, clinician-rated scale to assess the severity of a participant's depressive symptoms. Every effort was made to have the same rater evaluate a participant across all visits.

Total scores range from 0-84, with a score of 0 indicating no depression and a score of 84 indicating the most severe depression. Negative change from baseline values indicate improvement in the severity of depression.

Baseline was the score before the first dose of study drug in the double-blind study.

Full analysis set

Baseline was the score before the first dose of study drug in the double-blind study.

Safety population of treated participants with both baseline and post-baseline assessments.

The YMRS is a clinician-rated, 11-item checklist used to measure the severity of manic episodes. Information for assigning scores is gained from the participant's subjective reported symptoms over the previous 48 hours and from clinical observation during the interview. Seven items are ranked 0 through 4 and have descriptors associated with each severity level. Four items (irritability, speech, content, and disruptive-aggressive behavior) are scored 0 through 8 and have descriptors for every second increment. The total scale is 0-60. A score of ≤12 indicates remission of manic symptoms, and higher scores indicate greater severity of mania. Negative change from baseline scores indicate a decrease in severity of mania.

Baseline was the score before the first dose of study drug in the double-blind study.

The safety analysis set includes randomized participants who took 1 or more doses of study drug. The number analyzed includes participants with both baseline (double-blind study) and treatment assessments during the open-label study.

The C-SSRS is a clinician-rated scale that assesses suicidality from ideation to behaviors and monitors the potential emergence of suicidality in clinical studies. The number of participants who had findings on any of the C-SSRS-SLV (SLV=since last visit) categories at any of the time frames are indicated.

- C-SSRS=Columbia Suicide Severity Rating Scale

Safety population; only 19 participants were asked the last three questions as the inclusion of these questions depends on physician assessment.

The QIDS-C16 was derived from specified items in the IDS-C30, clinician-rated scale to assess the severity of a participant's depressive symptoms. Total scores range from 0-27, with a score of 0 indicating no depression and a score of 27 indicating the most severe depression. Negative change from baseline values indicate improvement in the severity of depression.

Baseline was the score before the first dose of study drug in the double-blind study.

Full analysis set

The CGI-S is an observer-rated scale that measures illness severity on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill patients). Negative change from baseline values indicate improvement in the severity of depression.

Baseline was the score before the first dose of study drug in the double-blind study.

Full analysis set

The Global Assessment of Functioning (GAF) is a numeric scale (1 through 100) used by mental health clinicians and physicians to rate subjectively the social, occupational, and psychological functioning of adults, e.g., how well or adaptively one is meeting various problems-in-living. Ratings of 1 - 10 mean the participant is in persistent danger of severely hurting self or others (e.g., recurrent violence) or persistent inability to maintain minimal personal hygiene or serious suicidal act with clear expectation of death. Ratings of 91 - 100 indicate no symptoms, and the participant exhibits superior functioning in a wide range of activities, life's problems never seem to get out of hand, is sought out by others because of his or her many positive qualities. Positive change from baseline values indicate improvement in functioning.

Baseline was the score before the first dose of study drug in the double-blind study.

Full analysis set of participants with both a baseline and post-baseline assessment.

The ISI is a participant-rated, 7-item questionnaire designed to assess the severity of the participant's insomnia. Each item is ranked 0 (none) through 4 (very severe) and has a descriptor associated with each severity level. Total range is 0 (no insomnia) to 28 (very severe insomnia). Responses to each item are added to obtain a total score to determine the severity of insomnia. Negative change from baseline scores indicate a decrease in severity of insomnia. Baseline was the assessment before the first dose of study drug in the double-blind study.

Safety population of treated participants with both a baseline and post-baseline assessment.

HAM-A measures the severity of anxiety symptoms. The scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Negative change from baseline scores indicate a decrease in severity of anxiety.

Baseline was the score before the first dose of study drug in the double-blind study.

Safety population of participants with both a baseline and post-baseline assessment.