Ketamine Effects on EEG during Therapy of Treatment-Resistant Generalized Anxiety and Social Anxiety

Background: Ketamine 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. Methods: Twelve 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. Results: Ketamine 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. Conclusions: Ketamine 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.