BackgroundKetamine is swiftly effective in a range of neurotic disorders that are resistant to conventional antidepressant and anxiolytic drugs. The neural basis for its therapeutic action is unknown. Here we report the effects of ketamine on the EEG of patients with treatment-resistant generalized anxiety and social anxiety disorders.MethodsTwelve patients with refractory DSM-IV generalized anxiety disorder and/or social anxiety disorder provided EEG during 10 minutes of relaxation before and 2 hours after receiving double-blind drug administration. Three ascending ketamine dose levels (0.25, 0.5, and 1 mg/kg) and midazolam (0.01 mg/kg) were given at 1-week intervals to each patient, with the midazolam counterbalanced in dosing position across patients. Anxiety was assessed pre- and postdose with the Fear Questionnaire and HAM-A.ResultsKetamine dose-dependently improved Fear Questionnaire but not HAM-A scores, decreased EEG power most at low (delta) frequency, and increased it most at high (gamma) frequency. Only the decrease in medium-low (theta) frequency at right frontal sites predicted the effect of ketamine on the Fear Questionnaire. Ketamine produced no improvement in Higuchi’s fractal dimension at any dose or systematic changes in frontal alpha asymmetry.ConclusionsKetamine may achieve its effects on treatment-resistant generalized anxiety disorder and social anxiety disorder through related mechanisms to the common reduction by conventional anxiolytic drugs in right frontal theta. However, in the current study midazolam did not have such an effect, and it remains to be determined whether, unlike conventional anxiolytics, ketamine changes right frontal theta when it is effective in treatment-resistant depression.

Depression is a major cause of health disability. EEG measures may provide one or more economical biomarkers for the diagnosis of depression. Here we compared frontal alpha asymmetry (FAA), posterior alpha asymmetry (PAA), and Higuchi’s fractal dimension (HFD) for their capacity to predict PID-5 depressivity and for the specificity of these predictions relative to PID-5 anxiousness. University students provided 8 or 10 minutes of resting EEG and PID-5 depressivity and PID-5 anxiousness questionnaire scores. FAA and PAA had no significant correlations with the measures at any electrode pair. There were distinct frontal and posterior factors underlying HFD that correlated significantly with anxiousness and with each other. Posterior HFD also correlated significantly with depressivity, though this was weaker than the correlation with anxiousness. The portion of depressivity variance accounted for by posterior HFD was not unique but shared with anxiousness. Inclusion of anxiety disorder patients into the sample rendered the frontal factor somewhat more predictive than the posterior one but generally strengthened the prior conclusions. Contrary to our predictions, none of our measures specifically predicted depressivity. Previous reports of links with depression may involve confounds with concurrent anxiety. Indeed, HFD may be a better measure of anxiety than depression; and its previous linkage to depression may be due to a confound between the two, given the high incidence of depression in cases of severe anxiety.