Amendment 1 to the protocol was issued before any patients were enrolled into the study. Following the voluntary harmonization procedure protocol assessment, the primary reasons for this amendment were to limit the duration of treatment with study drug to 52 weeks and to clarify the use of permitted medications and prohibited tricyclic antidepressants. The following major procedural changes were made to the protocol: • Treatment with study drug was limited to 52 weeks. • Butriptyline and mianserin were removed from the list of allowed antidepressants, and trimipramine and mirtazapine were removed to clarify the use of the permitted medications and prohibited tricyclic and tetracyclic antidepressants. • Clarification of the assessment time points following the limitation of the study drug treatment duration to 52 weeks.

Amendment 2 to the protocol was issued after 94 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The primary reason for this global amendment was to implement the following major procedural changes made to the protocol: • The 2 telephone calls for safety evaluation at weeks 18 and 38 were added, including C-SSRS and an abbreviated PBA-s assessment. • The treatment duration in the study was extended by an additional period of 52 weeks (for a total of 104 weeks). • Q-Motor assessments were added to the protocol as an efficacy measure. • Suicidal thoughts and ideations were defined as protocol-defined adverse events for expedited reporting.