This randomized, double-blind, active placebo-controlled study (n=12) investigated the effects of 3 ascending ketamine dose levels (17.5, 35 & 70 mg/70kg) and midazolam (0.7mg/70kg) on electrophysiological brain activity in patients with anxiety. While ketamine increased high-frequency brain rhythms and decreased low-frequency rhythms in a dose-dependent manner, only decreases within the frontal theta frequency band were related to improvements in anxiety.
Abstract
“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.”
Authors: Shabah Mohammad Shadli, Tame Kawe, Daniel Martin, Neil McNaughton, Shona Neehoff & Paul Glue
Summary
Ketamine is effective in treating patients with treatment-resistant generalized anxiety disorder and social anxiety disorder, but the neural basis for its therapeutic action is unknown.
Questionnaire and HAM-A.
Ketamine improved Fear Questionnaire scores, decreased EEG power at low (delta) frequency, and increased it most at high (gamma) frequency, but did not improve Higuchi’s fractal dimension at any dose or systematic changes in frontal alpha asymmetry.
Keywords: anxiety disorder, treatment resistance
Introduction
Ketamine has a widespread therapeutic effect on a wide range of “neurotic” disorders, including generalized anxiety and social anxiety.
Anxiety disorders such as generalized anxiety disorder and social anxiety disorder are prevalent mental health problems. Conventional treatments take weeks to produce their full effects, and one-third of SAD patients are treatment resistant, increasing outpatient costs, doubleing hospitalizations, and producing substantial morbidity.
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been found to be rapidly effective in treating treatment-resistant depression, obsessive-compulsive disorder, and posttraumatic stress disorder. It may be acting on a single fundamental mechanism.
Ketamine increases slow wave activity during sleep in depressed patients and decreases delta, alpha, and beta band power, while increasing gamma band power. It can also increase theta power while decreasing alpha power, particularly at frontal sites.
We evaluated the effects of ketamine on symptoms of anxiety and EEG in treatment-resistant SAD and GAD patients using an active-control double-blinded design. Ketamine produced dose-related improvements in symptoms, frontal alpha asymmetry, and Higuchi’s fractal dimension.
Participants
We recruited 12 patients with refractory DSM-IV GAD and/or SAD, and administered 3 ascending ketamine dose levels and midazolam doses double blind. All patients remained on their current medication regimens and continued with ongoing psychotherapy. The choice of control treatment for ketamine studies in mood disorders is complicated. Midazolam was used as an active control, and 3 ketamine doses were administered in ascending order, with 1 week between doses.
Assessments
We monitored patients for 2 hours postdose, obtained vital signs predose, 15, 30, 60, 90, and 120 minutes postdose, and assessed anxiety and tolerance predose, 1, 2, 24, 72, and 168 hours postdose.
Electroencephalography
A Waveguard EEG cap was used to record brain activity across the frontal lobes of the participants prior to study drug administration. The postdose recording was identical to the predose recording and was performed 2 hours after study drug administration.
EEG Processing
The EEG data was analyzed using custom software written in Visual Basic 6, and then submitted to an automated procedure for eye blink removal.
For simple power analysis, the recordings were manually processed and the resulting spectra were log transformed to normalize error variance and averaged. Alpha asymmetry was calculated for both the alpha1 and alpha2 bands by subtracting logarithmic power at left electrodes from their right-most counterparts.
Fractal dimension was calculated using Higuchi’s algorithm with a k max of 8. The data were split into 2-second (256 sample) epochs with 50% overlap, and Higuchi’s algorithm created k max number of new time series.
Participants
12 patients with anxiety disorders were enrolled; 4 had SAD, 10 had GAD, and 2 panic disorder. All had past MDE but none were depressed at the time of enrolment.
Changes in Anxiety Ratings
Overall, ketamine reduced HAM-A and FQ scores in 8 of 12 patients (67%) at 2 hours postdose, with a trend to a ceiling effect or reduction at 1.0 mg of ketamine.
Ketamine Reduced Low-Frequency and Increased High-Frequency EEG Power but Did Not Improve HFD or FAA
We treated MDZ as equivalent to 0 mg of ketamine for all analyses and averaged across frequencies within each band. Ketamine reduced delta and theta power at the lateral sites, while increasing beta and particularly delta, and increasing power at higher frequencies.
Ketamine Effects on FQ Appear Related to Right-Frontal Theta Power
We carried out stepwise regression analysis on FQ change scores for each electrode site, separately. Theta band power-change scores were the only significant predictors of FQ change, with the other high values surrounding it. The total predictive power of the equation was 17%, with the bulk of the additional explanatory power coming from a unique contribution (3%) from the contralateral site F3.
Discussion
Ketamine decreased theta frequency frontal power at the right frontal site F4 and appeared to mediate its therapeutic effects on GAD and SAD, as measured by the FQ. Ketamine produced no improvement in HFD scores at any dose.
Our alpha asymmetry results are against our prediction, but not entirely surprising. Alpha asymmetry has been linked to aversion/withdrawal/pessimism/introversion in general, and not to depression or anxiety in particular, and may be a predictor of future disorder rather than a biomarker of current disorder.
Ketamine rapidly reduces power in the alpha1, alpha2, and particularly delta bands in GAD and SAD patients, but increases slow wave sleep activity. It is possible that sleep delta is functionally distinct from waking delta.
Our data suggest that ketamine produces a decrease that is greatest at lower frequencies and an increase that is greatest at higher frequencies, although further work with carefully matched healthy controls is required to clarify these points.
We observed reduced theta power in the right frontal cortex after ketamine administration, and the decrease was greater at F8 than other sites. The decrease was largely linear in dose-response and site, and was most likely related to therapeutic action at F4.
A human anxiolytic biomarker, goal-conflict rhythmicity, is obtained in the theta band at right frontal sites. Ketamine may act on a similar brain system to that activated by theta-frequency rhythmicity, but this system is different from the one activated by conventional anxiolytics.
We found that ketamine reduced anxiety in patients with treatment refractory anxiety disorders, and that right frontal slow-wave (theta) EEG changes predicted reduced intensity of phobic anxiety ratings.
Statement of Interest
The authors declare potential conflicts of interest: P. Glue has a contract with Douglas Pharmaceuticals, N. McNaughton has a confidential disclosure and consulting agreement with Janssen Research & Development, LLC.