Understanding and Treating Suicidal Ideation With Ketamine

This innovative, mixed-method study will combine treatment, neuroimaging, and qualitative interview approaches in a clinical sample enriched for suicide-related outcomes and selected for the presence of active suicidal thoughts. For study participants, ketamine may offer a rapid strategy to alleviate suicidal ideation and provide a window of opportunity to engage in other, longer-term strategies to decrease suicide risk. Collecting longitudinal diffusion MRI data while patients undergo ketamine treatment will further the understanding of the key brain circuitry involved in suicidal ideation, and the mechanisms underlying ketamine's antisuicidal effects. This work may identify new targets for intervention and suicide prevention. Finally, seeking patient perspectives on their change in suicidal thinking with ketamine may allow them to gain insight into their own thought patterns and how they change with lessening of suicidal ideation. These unique findings have the potential to inform future research directions, provide support for existing theories of suicide, and may even lead to new theories. The overarching goal of this project is to treat active suicidal ideation in patients with MDD using ketamine and to harness ketamine's rapid antisuicidal effects to understand suicidal ideation by examining biological mechanisms using MRI, and psychological mechanisms through validated clinical scales and qualitative interviews. The central hypothesis is that ketamine will reduce suicidal ideation in a significant proportion of study participants and that reduction in suicidal ideation will be accompanied by rapid changes in neuroimaging biomarkers assessed using advanced diffusion MRI. The specific aims of the study are to: 1. Measure changes in advanced diffusion MRI biomarkers (white matter microstructure, extracellular free water, and neurite density index) pre-post repeated ketamine treatment in association with changes in suicidal ideation. 2. Link changes in suicidal ideation pre-post ketamine treatment with changes in suicide-related psychological features including hopelessness, psychological pain, and perceived burdensomeness. 3. Explore patient perceptions of change in suicidal ideation while undergoing ketamine treatment through qualitative interviews. This phase III, prospective, longitudinal study involves clinical assessment, neuroimaging, and qualitative interviews in participants undergoing repeated IV ketamine treatment for active suicidal ideation. The study is open-label and non-randomized. There is no use of a comparative agent. Participants will receive four IV ketamine infusions administered twice weekly for two weeks. Ketamine infusions will be administered at the BMO Innovative Clinic for Depression, a facility within the Royal Ottawa Mental Health Centre (ROMHC) that has safely administered over 500 intranasal esketamine treatments. Participants will undergo two identical MRI scans: 1) within 48 hours prior to starting treatment, and 2) 24 hours (+/-6 hours) after the fourth ketamine infusion. Suicidal ideation and depressive symptoms will be assessed prior to each imaging session alongside additional self-report measures. A short qualitative interview will occur within 72 hours after the fourth ketamine treatment. Each participants study duration is expected to be approximately 3 weeks total. The entire study will enroll participants over an 18 month period. Anticipated start date is MAR 2025 and anticipated end date is JAN 2026. Thirty-six (36) participants will be recruited into the study. Systematic reviews and meta-analyses of the acute antisuicidal effects of ketamine report medium-large and large effect sizes. Despite calls for the reporting of standardized effect sizes in neuroimaging studies, existing preliminary diffusion MRI studies failed to report effect sizes for changes observed post-ketamine treatment. Nevertheless, assuming a medium effect size (Cohen's d=0.5), 80% power, a p value of 0.05, a power calculation shows a total sample size of 34 will allow detection of the primary outcome, pre-post treatment change in free water corrected fractional anisotropy. This sample size will inform future work. Early withdrawals will be replaced with new enrollments to allow 36 participants to complete the study. The study team has extensive experience with longitudinal trials, and minimal attrition rate of participants is anticipated as the provision of treatment is expected to increase retention. Allowances have been made for participant withdrawal, incidental findings, or incomplete data by targeting a large enough sample size to inform future trials.