Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
Journal of psychopharmacology (Oxford, England)
August 1, 2021
Rachael L Sumner, Emme Chacko, Rebecca McMillan et al.
68 citations
Ketamine, given at 0.44 mg/kg to 32 volunteers with major depressive disorder in a crossover design with the active-placebo remifentanil, produced psychedelic experiences that correlated with greater antidepressant response at 24 hours. Specifically, higher scores on spirituality, experience of unity, and insight were linked to larger reductions in depression ratings. Qualitative interviews revealed perceptual changes, loss of control, emotional shifts, a psychedelic afterglow, and lasting changes in perspective on life, people, problems, and depression. The findings suggest the psychedelic experience and afterglow contribute to ketamine's antidepressant effects, and that standard questionnaires may not fully capture these properties.
Reviews in the Neurosciences
May 5, 2020
Rebecca McMillan, Suresh Muthukumaraswamy
53 citations
Ketamine has multiple uses—as an anesthetic, a model of psychosis, and an antidepressant—but its physiology is complex because it acts on several sites at clinically relevant doses. This review examines ketamine's acute effects on the resting brain, moving from its pharmacology through in vitro and in vivo electrophysiology to EEG/MEG and neuroimaging studies (MRI and PET). The picture of ketamine's effects is complicated and sometimes confusing, likely due to differences in species, doses, and analytical methods. The authors suggest strategies for future research to address these issues.
Human Brain Mapping
October 21, 2019
Bhim M. Adhikari, Juergen Dukart, Joerg F. Hipp et al.
24 citations
Ketamine, given at subanesthetic doses to healthy volunteers, produces psychosis-like symptoms and reduces functional connectivity in the salience network, auditory network, and default mode network (DMN). Midazolam, a sedative, only reduces DMN connectivity. The pattern of connectivity deficits caused by ketamine positively correlates with the pattern seen in schizophrenia, whereas midazolam's effects do not. After subtracting midazolam's effects, the remaining ketamine-specific disconnectivity pattern still correlates with schizophrenia deficits. This suggests that ketamine's psychosis-like effects have a brain functional basis that overlaps with schizophrenia-related connectivity disruptions.
Journal of Psychopharmacology
January 21, 2019
Rebecca McMillan, Anna Forsyth, Doug Campbell et al.
23 citations
Ketamine infusion in healthy men increases blood-oxygen-level dependent signals across the cortex and decreases them in the subgenual anterior cingulate cortex, but the decrease is largely due to physiological noise, especially cardiac pulsatility, rather than neural activity. Modeling the pharmacological MRI response with a single time course misses the full range of neural dynamics; using simultaneously recorded electroencephalography power time series reveals distinct temporal responses to ketamine, though no EEG band correlated with the subgenual anterior cingulate cortex decrease.
Human Brain Mapping
December 6, 2019
Anna Forsyth, Rebecca McMillan, Doug Campbell et al.
19 citations
The validity of fMRI functional connectivity as a drug biomarker was tested by comparing seven preprocessing pipelines and by simultaneously measuring EEG and fMRI in a placebo-controlled, three-way crossover study with ketamine and midazolam. Independent components analysis (ICA)-denoising produced stronger reductions in connectivity after ketamine and weaker increases after midazolam than pipelines using physiological noise modelling or averaged signals from cerebrospinal fluid or white matter. This indicates that pipeline decisions should match a drug's unique noise structure; when unknown, extensive ICA denoising may sacrifice some signal but increase confidence in remaining results. No significant relationship was found between changes in electrophysiological and hemodynamic correlation structures, cautioning against cross-modal comparisons of pharmacologically-modulated functional connectivity.