*2.1. Participants*

We analyzed data from eight multicenter CTN trials that included 2543 participants [32–39]. Only 2541 participants were included in the analysis (2 participants were excluded due to missing data). Included studies: (1) were completed in the last 10 years (2012–2021), (2) used the CHRT-SR as a measure to assess suicidality of patients at baseline, prior to

treatment, and (3) captured overdose events via the adverse event form, death form, and/or hospital utilization form. Trial characteristics are described in Table 1. While each of these eight multisite trials secured approval from their respective Institutional Review Board, the current study only used de-identified data and therefore was exempt from ethical review.


**Table 1.** Selected CTN Trial Characteristics.

RCT: Randomized Controlled Trial. \* The CTN 0049 population assessed in this analysis includes only those unduplicated patients (*N* = 688 of 801 total) who were not re-randomized to CTN 0064 (*N* = 113).

#### *2.2. Independent Variable: Suicidality*

The independent variable analyzed as the predictor was the baseline suicidality score as measured by the 12-item CHRT-SR [24] that evaluates suicide propensity, ideation, and

intent. Items assess signs and symptoms, including characteristics such as pessimism, lack of social support, helplessness, and despair; the last three items assess active suicidal ideation and behavior. Responses are measured by a 5-point Likert scale ranging from strongly disagree (1) to strongly agree (5), with total scores ranging from 12 to 60. The CHRT-SR was also used to create a binary indicator of suicidality if a participant responded "Yes" to any of the three following items indicative of suicidal thoughts: "I have been having thoughts of killing myself", "I have thoughts about how I might kill myself", or "I have a plan to kill myself". The Cronbach's alpha for CHRT-SR was acceptable for all trials (CTN0037: 0.86; CTN0049: 0.91; CTN0051: 0.87; CTN0053: 0.89; CTN0054: 0.87; CTN0064: 0.90; CTN0067: 0.86; CTN0068: 0.89).

#### *2.3. Dependent Variable and Adjudication Process: Overdose Events*

An overdose event during the study period, the outcome of interest, was defined as a binary outcome (Present: yes/Absent: no). Responses were determined through a review of the dataset for: (1) MedDRA-Preferred Terms captured in Adverse Event forms, (2) primary cause of death reported on death form, or (3) hospital utilization due to overdose reported on hospitalization forms. Through a rigorous adjudication process, a panel of experts consisting of a subgroup of study co-authors (VEH, RDS, DB, KH, JF, ST) followed explicit steps and key terms recommended by a CTN medical monitor (RK) as they reviewed the recorded adverse events, deaths, and hospitalizations. The key recommended term for adverse event forms was "overdose", but related terms such as acute amphetamine toxidrome, respiratory depression and drug intoxication were considered where the term overdose was not recorded but suspected. For these overdose suspected cases, the medical monitor reviewed narratives from the study forms for an indication of involved substances which were then discussed by the panel to reach consensus on the adjudication of the outcome. For the 2 trials where both the hospitalization and death forms were used (CTN 0049 [33,41] and CTN 0064 [37,45]), the panel reviewed all causes for hospitalization (primary discharge diagnosis) and the primary cause of death as recorded in the database. Deaths due to overdose were listed as "Drug Use/Overdose" or "Substance Use". Key terms used to search the hospitalization events included "Overdose", "Abuse", "Intoxication", and "Detox"; however, all primary discharge diagnoses were considered individually by the panel.
