Nancy B Lundin1, Linnea Sepe-Forrest2, Jessica R Gilbert3, Frederick W Carver4, Maura L Furey5, Carlos A Zarate3, Allison C Nugent6. 1. Section on the Neurobiology and Treatment of Mood Disorders, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA;; Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN, USA. 2. Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN, USA;; Magnetoencephalography Core Facility, National Institute of Mental Health, Bethesda, MD, USA. 3. Section on the Neurobiology and Treatment of Mood Disorders, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. 4. Magnetoencephalography Core Facility, National Institute of Mental Health, Bethesda, MD, USA. 5. Janssen Pharmaceuticals of Johnson and Johnson Inc., San Diego, CA, United States. 6. Section on the Neurobiology and Treatment of Mood Disorders, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA;; Magnetoencephalography Core Facility, National Institute of Mental Health, Bethesda, MD, USA;. Electronic address: nugenta@mail.nih.gov.
Abstract
BACKGROUND: The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD). However, ketamine's effects on emotional processing biases remain largely unknown, and understanding these processes may help elucidate ketamine's mechanism of action. METHODS: Magnetoencephalography (MEG) was used to investigate ketamine's effects on early visual responses to affective stimuli in individuals with MDD (n=31) and healthy volunteers (HVs; n=24). Participants were enrolled in a double-blind, placebo-controlled, crossover clinical trial and were assessed at baseline and after subanesthetic-dose ketamine and placebo-saline infusions. During MEG recording, participants completed an emotional evaluation task in which they indicated the sex or emotional valence (happy-neutral or sad-angry) of facial stimuli. Source-localized event-related field (ERF) M100 and M170 amplitudes and latencies were extracted from regions of interest. Linear fixed effects models examined interactions between diagnosis, stimulus valence, and drug session for behavioral and MEG data. RESULTS: In baseline behavioral analyses, MDD participants exhibited higher accuracy for sad-angry than happy-neutral faces, and HVs responded faster to happy-neutral than sad-angry faces. In the MEG post-infusion analyses, calcarine M100 amplitudes were larger in MDD than HV participants post-placebo but became more similar post-ketamine. Finally, fusiform M170 amplitudes were associated with antidepressant response in MDD participants. LIMITATIONS: The modest sample size and the need to collapse across responses to happy and neutral faces to increase statistical power limit the generalizability of the findings. CONCLUSIONS: Ketamine rapidly altered emotional stimulus processing in MDD, laying the groundwork for future investigations of biomarkers of antidepressant treatment response. CLINICAL TRIAL: Clinicaltrials.gov, NCT#00088699.
BACKGROUND: The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD). However, ketamine's effects on emotional processing biases remain largely unknown, and understanding these processes may help elucidate ketamine's mechanism of action. METHODS: Magnetoencephalography (MEG) was used to investigate ketamine's effects on early visual responses to affective stimuli in individuals with MDD (n=31) and healthy volunteers (HVs; n=24). Participants were enrolled in a double-blind, placebo-controlled, crossover clinical trial and were assessed at baseline and after subanesthetic-dose ketamine and placebo-saline infusions. During MEG recording, participants completed an emotional evaluation task in which they indicated the sex or emotional valence (happy-neutral or sad-angry) of facial stimuli. Source-localized event-related field (ERF) M100 and M170 amplitudes and latencies were extracted from regions of interest. Linear fixed effects models examined interactions between diagnosis, stimulus valence, and drug session for behavioral and MEG data. RESULTS: In baseline behavioral analyses, MDD participants exhibited higher accuracy for sad-angry than happy-neutral faces, and HVs responded faster to happy-neutral than sad-angry faces. In the MEG post-infusion analyses, calcarine M100 amplitudes were larger in MDD than HV participants post-placebo but became more similar post-ketamine. Finally, fusiform M170 amplitudes were associated with antidepressant response in MDD participants. LIMITATIONS: The modest sample size and the need to collapse across responses to happy and neutral faces to increase statistical power limit the generalizability of the findings. CONCLUSIONS: Ketamine rapidly altered emotional stimulus processing in MDD, laying the groundwork for future investigations of biomarkers of antidepressant treatment response. CLINICAL TRIAL: Clinicaltrials.gov, NCT#00088699.
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