Subanesthetic-dose ketamine infusion may significantly reduce depression and suicidal ideation among patients with treatment-resistant major depressive disorder, according to study findings published in Journal of Affective Disorders.
Researchers conducted a secondary analysis of data from a crossover randomized trial (ClinicalTrials.gov Identifier: NCT00088699) that included 29 patients (19 women; mean age, 36.86±10.06 years) with treatment-resistant major depressive disorder without psychotic features who were not receiving medication. Of these patients, 12 had attempted suicide and 17 did not attempt suicide. Only baseline and postketamine periods were considered for the analysis.
Participants were experiencing a major depressive episode that lasted at least 4 weeks, were nonresponsive to at least 1 antidepressant during this episode, and had a score of at least 20 on the Montgomery-Asberg Depression Rating Scale (MADRS). Some participants were excluded due to imminent risk for suicide. All participants did not receive medications at least 2 weeks prior to the start of the study. Nonsuicidal self-injury was not considered.
At baseline, there were no significant differences in suicidal ideation or MADRS scores between those who attempted suicide and those who did not attempt suicide. A significant reduction for all participants was observed in suicidal ideation (baseline mean=0.351; 95% CI, 0.282-0.419; ketamine mean=0.253; 95% CI, 0.161-0.345) and depression (MADRS scores baseline mean=33.38; 95% CI, 31.43-35.33; ketamine mean=24.76; 95% CI, 20.38-29.14) several hours following ketamine infusion.
Participants were also given an attentional dot probe task with emotional face stimuli at baseline. Following ketamine infusion, participants who attempted suicide showed improved accuracy on task compared with participants who did not attempt suicide. There was a significant group-by-emotion-by-suicidal ideation interaction in the right-hemisphere subcortical and cortical structures. This was driven by a stronger negative association between theta power and suicidal ideation scores for happy faces relative to angry faces among those who did not attempt suicide and a slight positive association increase between theta power and suicidal thought scores for happy faces relative to angry faces among those who attempted suicide.
Gamma power in regions of the frontal and parietal cortices for participants in both groups had been positively associated with suicidal ideation. Indexed by theta power differences, participants who attempted suicide differed significantly in emotional reactivity to happy faces vs angry faces with or without ketamine in an extended amygdala-hippocampal region.
Researchers observed a significant reduction in the association between suicidal ideation and alpha power for happy faces compared with angry faces in a fronto-insular/anterior cingulate region with ketamine.
Limitations of the study include the nature of a secondary analysis, underpowered sample size, unaccounted suicidal ideation independent of depression, and unaccounted temporal variation in suicide risk.
Study authors concluded “Ketamine significantly reduced [suicidal ideation] SI in attempters and nonattempters, and attempters performed better on the dot probe task postketamine administration compared to nonattempters.” They added, “In an extended amygdala-hippocampal region, attempters demonstrated differences in emotional reactivity to angry faces compared to happy faces in theta power, and ketamine administration altered the association between alpha power and SI to angry relative to happy faces in a fronto-insular/anterior cingulate region important for regulating alertness and attentiveness to incoming stimuli.”
Gilbert JR, Gerner JL, Burton CR, Nugent AC, Zarate CA Jr, Ballard ED. Magnetoencephalography biomarkers of suicide attempt history and antidepressant response to ketamine in treatment-resistant major depression. J Affect Disord. September 1, 2022;312:188-197. doi:10.1016/j.jad.2022.06.025