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:
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.
Link changes in suicidal ideation pre-post ketamine treatment with changes in
suicide-related psychological features including hopelessness, psychological pain,
and perceived burdensomeness.
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.