Patients who demonstrated 50% reduction from screening in HAM-D total score and had a HAM-D total score 15 at all visits during this prospective lead-in period were eligible to continue to the double-blind study. randomized to receive adjunctive BUP/SAM 2 mg/2 mg or placebo for 6 weeks. The primary end point was change in MontgomeryC?sberg Depression Rating Scale (MADRS)-10 total score from randomization at baseline to the end of the 6-week treatment period. Results Least-squares mean change in MADRS-10 score at end of treatment was -4.8 (SE 0.67) in the BUP/SAM 2 Choline Chloride mg/2 mg group and -4.6 (SE 0.66) in the placebo group (mean difference -0.3 [SE 0.95], (DSM-IV-TR) criteria and a current major depressive episode of 8 weeks to 24 months. Additionally, all patients had a 17-item Hamilton Rating Scale for Depression (HAM-D) total Cav1.3 score 18 and a Clinical Global Impression C severity (CGI-S) score 4. Patients were eligible to enter the double-blind period if they demonstrated an inadequate response to one or two courses of ADT during the current episode. This criterion could be met either historically or prospectively. Patients who did not have sufficient historical evidence of one or two inadequate responses to ADT and whose HAM-D total score was 22 were allowed to enter the prospective lead-in period, during which ADT was administered open-label for 8 weeks. Patients who demonstrated 50% reduction from screening in HAM-D total score and had a HAM-D total score 15 at all visits during this prospective lead-in period were eligible to continue to the double-blind study. At randomization, all patients would have then received ADT treatment for 8 weeks Choline Chloride at an adequate dose that was stable over the last 4 weeks. Key exclusion criteria included any primary axis I disorder besides MDD, the use of adjunctive treatments during the current episode (except as noted in the Supplementary material), imminent suicide risk, and evidence of an alcohol- or substance-use disorder within the past year. Suicide risk was deemed imminent based on one or more of a recent history of suicide attempt (past 2 years), acknowledgment of current suicidal ideation with intent, with or without a plan (based on the Columbia Suicide Severity Rating Scale [CSSRS]), and investigator clinical assessment. Patients were also excluded if they had a current axis II diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder. Detailed patient-inclusion and -exclusion criteria are included in the Supplementary material. At the start of the double-blind treatment period, patients were stratified according to their baseline HAM-D total score. Patients with a baseline HAM-D total score 20 (group 1) received double-blind placebo for 4 weeks, and thereafter placebo nonresponders were randomized to BUP/SAM 2 mg/2 mg or placebo as a sublingual tablet once daily, in addition to continuing their current ADT, for a further 6 weeks. Data from these patients were used to evaluate efficacy. Placebo responders remained on placebo for the duration of the double-blind treatment period. Patients with a baseline HAM-D total score of 18C19 (group 2) were randomized to BUP/SAM 2 mg/2 mg or placebo, in addition to continuing their current ADT, for the duration of the 10-week double-blind treatment period. Group 2 patients were included in the study to provide additional blinding of the existence of the placebo run-in period for group 1 patients and to minimize baseline-score inflation by allowing patients with lower HAM-D scores into the study. After the double-blind treatment period, patients in both groups entered a long-term safety study (FORWARD-2, ClinicalTrials.gov “type”:”clinical-trial”,”attrs”:”text”:”NCT02141399″,”term_id”:”NCT02141399″NCT02141399) or completed a 2-week safety follow-up period. See Figure S1 for a schema of the FORWARD-3 study design. All investigative staff were blinded to the existence of two groups, Choline Chloride the existence of the placebo run-in, the timing of randomization, and the.