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Randomized Controlled Trial
. 2022 Sep 1:312:188-197.
doi: 10.1016/j.jad.2022.06.025. Epub 2022 Jun 18.

Magnetoencephalography biomarkers of suicide attempt history and antidepressant response to ketamine in treatment-resistant major depression

Jessica R Gilbert  1 , Jessica L Gerner  2 , Courtney R Burton  2 , Allison C Nugent  3 , Carlos A Zarate Jr  2 , Elizabeth D Ballard  2
Affiliations
Randomized Controlled Trial

Magnetoencephalography biomarkers of suicide attempt history and antidepressant response to ketamine in treatment-resistant major depression

Jessica R Gilbert et al. J Affect Disord. .

Abstract

Background: This study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and following subanesthetic-dose ketamine infusion.

Methods: Twenty-nine drug-free TRD patients (12 suicide attempters/17 non-attempters) participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Mixed models were used to test for clinical, behavioral, and electrophysiological effects of group, emotion, session, and SI score.

Results: Ketamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness.

Limitations: Limitations include a small sample size of attempters.

Conclusions: The findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history.

Keywords: Ketamine; Magnetoencephalography; Suicidal ideation; Suicide attempt; Treatment-resistant depression.

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Conflict of interest statement

Declaration of Interest

Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise.

Figures

Figure 1:
Figure 1:. Clinical Measures and Behavioral Performance.
Clinically, there were no differences in baseline (BL) levels of suicidal ideation (SI) and depression (MADRS) between attempters (att) and non-attempters (non-att). There was a significant main effect of ketamine (KET) on both SI and MADRS scores, but no group-by-session interactions. Behaviorally, non-attempters had higher accuracy rates than attempters. In addition, non-attempters were more accurate at baseline compared to post-ketamine, while attempters were more accurate post-ketamine compared to baseline.
Figure 2:
Figure 2:. Group-by-suicidal ideation (SI) Interactions.
Significant group-by-SI interactions were identified across large-scale brain regions in the theta, alpha, beta, and gamma frequencies.
Figure 3:
Figure 3:. Group-by-Emotion-by-Suicidal Ideation (SI) Interaction – Theta Frequency.
Right-hemisphere subcortical and cortical structures, including the ventral striatum, amygdala, hippocampal cortex, and insula showed a significant group-by-emotion-by-SI interaction in the theta frequency. Extracting theta power estimates in this region showed a stronger negative association between theta power and SI score for angry relative to happy faces for non-attempters and a slight increase in the positive association between theta power and SI score for angry relative to happy faces for attempters.
Figure 4:
Figure 4:. Suicidal Ideation (SI) and Gamma Power.
A significant main effect of SI on gamma power within regions of the left inferior frontal gyrus, middle frontal gyrus, superior frontal gyrus, and supramarginal gyrus were identified. Plotting the z-score for the effect, gamma power within these regions was positively associated with SI score across the entire sample.
Figure 5:
Figure 5:. Session-by-Suicidal Ideation (SI) Interactions.
Significant session-by-SI interactions were identified across large-scale brain regions in the theta, alpha, beta, and gamma frequencies.
Figure 6:
Figure 6:. Group-by-Emotion-by-Session-by-Suicidal Ideation (SI) Interaction – Alpha Frequency.
Left-hemisphere subcortical and cortical structures, including the anterior temporal lobe, striatum, anterior insula, and anterior cingulate, showed a significant group-by-emotion-by-session-by-SI interaction in the alpha frequency. Extracting theta power estimates in this region showed that ketamine flattened the relationship between alpha power and SI score for angry faces in this region while increasing the negative association between alpha power and SI score for happy faces in attempters. For non-attempters, ketamine non-selectively decreased the negative association between alpha power and SI score for both emotional face types.
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References

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    1. Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, Brutsché NE, Ameli R, Furey ML, Zarate CAJ, 2014a. Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety. J Psychiatr Res 58, 161–166. - PMC - PubMed
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