1. Update the serious adverse event (SAE) and pregnancy reporting information (Title page and Section 9.4). 2. Add detail to the process of washout of prior psychiatric medications (Protocol Summary and Sections 3 and 8.2). 3. Increase the length of the safety follow-up period from 1 week to 4 weeks, adding an additional follow-up visit (throughout the document). 4. Add assessment of remission as a separate row in the Schedule of Visits and Procedures. 5. Clarify the timing of the pharmacogenetic consent and sampling (Table 1 and Section 6.4). 6. Decrease the suicidality-related MADRS score for exclusion at Screening or Baseline from 5 to 4 (exclusion criterion #9). 7. Add exclusion criterion and prohibitions for patients who are taking concomitant cytochrome P450 3A4 (CYP3A4) inducers/inhibitors (exclusion criterion #13 and Section 4.8.2). 8. Clarify the definitions for remission and stability criteria (Section 4.5). 9. Modify the relapse criterion related to initiation of psychiatric medication (Protocol Summary and Sections 3 and 4.7) 10. Clarify use of the 1.5 mg dose of cariprazine (Section 5.1) 11. Clarify treatment compliance evaluation (Section 5.6). 12. Add an additional efficacy parameter to the study (PSP) (Section 6.2.2.3 and Attachment 12.9) 13. Add a quality-of-life measure to the study: Work Productivity and Activity Impairment-Bipolar Disorder (WPAI-BD) (Sections 6.5 and Attachment 12.12).

14. Clarify planned analyses for additional efficacy parameters (Sections 7.2.3 and 7.3.3) 15. Clarify planned safety analyses (Sections 7.3.4) 16. Clarify the timing and details of visits and associated procedures (Sections 8.4 and 8.7) 17. Add details about the Safety Follow-up (SFU) Visits (Section 8.4.7). 18. Modify the discontinuation reason for disallowed medications; add a new reason for discontinuation: postbaseline finding of cataracts; and to delete the discontinuation reason for consecutively missed doses; (Section 8.9).

1. Depressed episode to depressive episode. (Global change for clarity) 2. Removed patients with a postbaseline cataracts was to be discontinued from the study. (Global change) 3. Replaced the scale used to make the diagnostic assessment from Mini International Neuropsychiatric Interview (MINI) to Structured Clinical Interview for DSM-5 (SCID-5). (Operational Change) 4. Changed doses (Open-Label Period – Changed from 4.5 mg to 3.0 mg; DB Period: 2 Cariprazine Dose arms are now: 3.0 mg and 1.5 mg). (applicable sections of protocol) 5. Inclusion of depressed patients was added in addition to manic patients. manic or depressed patients may either be “with or without mixed features” (related inclusion criterion incorporated). (applicable sections of protocol) 6. Sample size was changed. 7. Day 4 and Day 10 study visits were deleted and a Day 22 visit was added. Study Visits have been renumbered throughout entire amendment 2. Study days have been renumbered to allow 1 full week of dosing before Visit 3. (applicable sections of protocol) 8. Exclusion criteria around urine drug screen has been clarified. 9. Removal of Symbol Digit Coding (SDC) – additional efficacy assessment. (applicable sections of protocol) 10. MADRS total score was changed from MADRS total score ≥ 17 to ≥ 20. (applicable sections of protocol) 11. Added open-label safety-follow-up (OL SFU) population will consist of patients in the OL safety population who were not randomized. 12. The primary analysis was updated to use stratified log-rank test instead of unstratified log-rank test and updated the first sensitivity analyses. 13. Changed period for reporting of pregnancies during the study from 30 days after last dose to 3 months following last dose. (Section 9.4) 14. Deleted the words “formerly” and “popular” when describing Snellen (Appendix 12.10)

1. Corrected Backup Serious Adverse Event Reporting Fax Number. (global change) 2. Changed Forest Laboratories to AbbVie Sales. (global change) 3. Added text to clarify the location of the Emergency Telephone Numbers. (Title page) 4. Added text to clarify that psychotropic medications, not listed as rescue medications, may not be newly initiated or reinstated. (Protocol Summary, Screening/Washout period) 5. Added text to clarify that Day 8 is Visit 3. (Protocol Summary, Screening/Washout period) 6. Added visit windows of +3 days for Visit 2/Baseline and ± 3 days for Visits 3 through 33 to the table header. (Protocol Summary, Table 1) 7. Changed “Blood Alcohol Level” to “Blood Alcohol Concentration by Breathalyzer”. (Protocol Summary, Table 1) 8. Added serum pregnancy test at Visits 7, 18, 24, and 33. (Protocol Summary, Table 1) 9. Added text to clarify the timing of visits. (Protocol Summary, Table 1) 10. Added text to clarify that psychotropic medications, not listed as rescue medications, may not be newly initiated or reinstated. (Section 3. Study Design) 11. Added text to clarify that Day 8 is Visit 3. (Section 3. Study Design) 12. Added text to clarify that the patient must meet the same criterion at both the screening and baseline visits. (Section 4.3 Inclusion Criteria) 13. Added text to clarify the need to use birth control for 12 weeks after the last dose of investigational product. (Section 4.3 Inclusion Criteria) 14. Added text to clarify that the serum pregnancy test is qualitative. (Section 4.3 Inclusion Criteria) 15. Added text to clarify use disorders. (Section 4.4 Exclusion Criteria) 16. Added text to clarify that a positive urine drug screen (UDS) is not exclusionary if the drug was used as rescue medication during washout. (Section 4.4 Exclusion Criteria) 17. Added text to exclude moderate CYP3A4 inhibitors. (Section 4.4 Exclusion Criteria) 18. Changed example of endocrinological disease. (Section 4.4 Exclusion Criteria)

19. Added: 30. Absolute neutrophil count < 1000 per mm^3 at screening; 31. Hemoglobin A1c (HbA1c) > 7% at screening; 32. Blood alcohol concentration ≥ 0.02 g/dL at Visit 1 as measured by breathalyzer (Section 4.4. Exclusion Criteria) 20. Changed text to clarify that an additional barrier method must be used if hormonal contraception is used by a female patient, and added text to state that contraception must be used for 12 weeks after the last dose of study drug. (Section 4.8.1 Permissible Medications/Treatments) 21. Added phenazepam to list of prohibited psychotropic medications. (Section 4.8.2 Prohibited Medications/Treatments) 22. Added text to clarify that moderate CYP3A4 inhibitors are also prohibited. (Section 4.8.2 Prohibited Medications/Treatments) 23. Added Suvorexant (maximum of 20 mg/d) to the list of allowed medications for insomnia. (Section 4.8.3. Rescue Medications) 24. Added Biperiden to permissible rescue medications for extrapyramidal symptoms (EPS) or akathisia and removed dosing guidance. (Section 4.8.3. Rescue Medications) 25. Added: All investigational products (IPs) will be taken orally as a single daily dose at approximately the same time of day (morning or evening). The dosing time can be switched if there are tolerability problems. Any switch must allow at least 24 hours between 2 consecutive doses and must be documented in the eCRF. (Section 5.5 Treatment Regimen and Dosing) 26. Added text to state that any patient who misses ≥ 4 consecutive doses of IP must be discontinued from the study. (Section 5.6 Treatment Compliance) 27. Changed text to state that the rating scale must be administered by a trained rater. (Section 6.2.1.2 Montgomery-Asberg Depression Rating Scale) 28. Changed text to state that the rating scale must be administered by a trained rater (Section 6.2.1.3 Clinical Global Impressions-Severity)

29. Changed text to state that the rating scale must be administered by a trained rater (Section 6.2.2.1 Clinical Global Impressions-Improvement) 30. Changed text to state that the rating scale must be administered by a trained rater (Section 6.2.2.2 Personal and Social Performance Scale) 31. Added text to correct the timing of urine myoglobin testing (Section 6.6.3 Clinical Laboratory Determinations, Table 3) 32. Added text to include a serum pregnancy test at Visit 33 (Section 6.6.3 Clinical Laboratory Determinations, Table 3) 33. Replaced “Blood Alcohol Level” with “Blood alcohol concentration as measured by breathalyzer” (Section 6.6.3 Clinical Laboratory Determinations, Table 3) 34. Changed text to state that the rating scale must be performed by a trained rater (Section 6.6.7.2 Columbia-Suicide Severity Rating Scale) 35. Deleted text stating that, for Clinical Global Impressions (CGI)-Improvement Scale (I), the OL baseline CGI-Severity Scale (S) value will be used as the baseline variable (Section 7.3.3 Other Efficacy Analyses) 36. Replaced all text to define how AEs and treatment emergent AEs will be coded and summarized (Section 7.3.4.1 Adverse Events) 37. Added text to clarify that psychotropic medications, not listed as rescue medications, may not be newly initiated or reinstated (Section 8.2 Washout Intervals/Run-in) 38. Added text to clarify that Day 8 is Visit 3 (Section 8.2 Washout Intervals/Run-in) 39. Added text to allow rescreening under certain situations after consultation with the AbbVie medical monitor (Section 8.3 Procedures for Final Study Entry) 40. Added text to clarify that the serum pregnancy test is qualitative (Section 8.3 Procedures for Final Study Entry) 41. Added text to clarify the timing of visits (Section 8.4 Visits and Associated Procedures)

42. Changed text to clarify how blood alcohol concentration is assessed (Section 8.4.1 Screening/Visit 1) 43. Changed text to clarify how blood alcohol concentration is assessed (Section 8.4.4 End of OL Period/Randomization Visit) 44. Edited text to make serum pregnancy test mandatory at Visit 33. (Section 8.4.7 Safety Follow-up Visits 32 and 33) 45. Added text to clarify the timing of visits (Section 8.7 Compliance with Protocol) 46. Added text to clarify that Day 8 is Visit 3 (Section 8.9. Withdrawal Criteria) 47. Added text to number 6 to clarify that a patient with a positive UDS after enrollment should only be withdrawn if the positive test is confirmed at the next scheduled visit and to cross reference to Section 4.8.3 (Section 8.9. Withdrawal Criteria) 48. Added text to number 9 to clarify the timing of repeat testing and that the patient should be discontinued if his or her neutrophil values are not normalized or are not increasing (Section 8.9. Withdrawal Criteria) 49. Changed 3 months to 12 weeks (Section 9.4 Reporting of Pregnancies Occurring During the Study) 50. Added text to clarify that source documents must follow Attributable, Legible, Contemporaneous, Original, Accurate, and Complete (ALCOA-C) principles (Section 10.4.1 Source Documents) 51. Changed interval 40 – 31 to Severe difficulties in 1 and marked difficulties in at least 1 of areas a-c, or marked difficulties in d (Section 12.9. Personal and Social Performance [PSP] Scale, Guidelines for PSP Total Score)

1. There is no longer a distinct SAE reporting form and AESI reporting form. It is a combined SAE/AESI form. (Global) 2. Exclusion Criterion #24a revised. (4.4 Exclusion Criteria) 3. Text revised to clarify which pregnancy outcomes or genetic abnormalities are considered SAEs. (9.1.2 Serious Adverse Events)

1. Sample size calculation updated. (Protocol Summary and Section 7.5) 2. Coronavirus Disease 2019 (COVID-19) addendum was incorporated into Protocol Amendment 5. (Attachment 12.13)