This randomised, double-blind, active placebo-controlled study (n=12) investigated the effects of 3 ascending ketamine dose levels (17.5/35/70mg/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.
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.
Anxiety disorders such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are common, often persistent, and frequently resistant to conventional treatments; one-third of SAD patients, for example, remain treatment resistant, producing substantial impairment and economic burden. Ketamine, an NMDA receptor antagonist, has shown rapid efficacy across several treatment-resistant neurotic conditions including depression, obsessive–compulsive disorder, and post‑traumatic stress disorder, but the neural mechanisms underlying its anxiolytic effects remain unclear. Prior human and animal work has reported mixed effects of ketamine on EEG rhythms (reductions in delta, theta and alpha, with increases in gamma in some studies), and neuroimaging and pharmacological evidence implicates glutamatergic dysfunction in SAD; these observations motivated the current study. Shadli and colleagues set out to examine concurrent changes in anxiety symptoms and frontal EEG in treatment-refractory GAD and SAD patients after double‑blind administration of three ascending ketamine doses and an active control (midazolam). The primary aim was to test whether ketamine produces dose-related symptom improvements together with specific EEG changes, in particular alterations in frontal alpha asymmetry and Higuchi's fractal dimension, and band‑specific power shifts (decreases in delta/alpha/beta and increases in theta/gamma) that might relate to clinical response.
This was a double‑blind, within‑subject study in which 12 patients with treatment‑refractory DSM‑IV GAD and/or SAD received three ascending subcutaneous ketamine doses (0.25, 0.5, and 1.0 mg/kg) and an active control, midazolam (0.01 mg/kg). Midazolam was randomly inserted into the dosing sequence and the ketamine doses were given in ascending order, with one week between sessions. The study had ethics approval and was prospectively registered; participants remained on their existing psychotropic medications but did not change doses or start new treatments during the trial. Inclusion criteria included age ≥18 years, HAM‑A ≥20 and/or LSAS ≥60, failure to respond to at least two antidepressant courses, and absence of current depression (MADRS <20). Exclusions covered severe medical conditions, pregnancy/lactation, certain medications (MAOIs, thyroxine, stimulants), and active suicidal ideation. Twelve participants (4 male, 8 female; mean age 31 years) completed the protocol; all had SAD, 10 had GAD, and two had panic disorder. Clinical assessments comprised the Fear Questionnaire (FQ) and the Hamilton Anxiety Rating Scale (HAM‑A) administered predose and at 1, 2, 24, 72, and 168 hours postdose; EEG was recorded only predose and at 2 hours postdose. Tolerability and dissociative symptoms were monitored, and vital signs were measured up to 2 hours postdose. For analysis, midazolam was treated analytically as equivalent to 0 mg/kg ketamine. EEG was recorded from frontal and central leads (Fp1, Fp2, F7, F3, Fz, F4, F8, Cz) referenced to the left mastoid, using a cap and a 256 Hz sampling rate, then downsampled to 128 Hz for offline processing. Participants alternated 1‑minute eyes‑open and eyes‑closed epochs for a total of 10 minutes. Processing included blink removal, artefact rejection, FFT with overlapping Hanning windows, log transformation of power, and averaging to yield band powers for delta (1–3 Hz), theta (4–6 Hz), alpha1 (7–9 Hz), alpha2 (10–12 Hz), beta (25–34 Hz), and gamma (41–53 Hz). Frontal alpha asymmetry (FAA) was computed as ln(R) − ln(L) for F8:F7 and F4:F3, and Higuchi fractal dimension (HFD) was calculated with kmax = 8. Statistical analysis used repeated‑measures ANOVA (channel, frequency, dose as within‑subjects factors) and polynomial contrasts; stepwise and multiple regression analyses assessed relationships between EEG changes and symptom change.
The data were submitted to ANOVA in SPSS with channel, frequency, and dose as within-subjects variables. Polynomial components of all factors were extracted with the MDZ active control treated as 0 mg ketamine.
Our main finding is that ketamine produced a dose-related decrease, maximal at 0.5 mg, in theta frequency frontal power at the right frontal site F4 that appears to mediate its therapeutic effects on GAD and SAD, as measured by the FQ. Similar power changes in the theta range at adjacent sites appeared to be less involved in controlling FQ, while larger decreases in power in the delta range and large increases in power in the gamma range appeared to make no contribution to changes in FQ. Ketamine produced no sign of an improvement in HFD scores at any dose and no systematic or reliable changes in FAA. Reduced anxiety has previously been reported with ketamine; however, we saw significant changes only in FQ and no large changes in HAM-A scores. Our alpha asymmetry results are against our prediction but not entirely surprising. FAA has previously been linked to aversion/withdrawal/pessimism/introversion in generaland not depression or anxietyin particular. It shows a trait-like reliability and stability that (over months) is not related to changes in depressed state in patients with major depressionand may be a predictor of future disorder rather than a biomarker of current disorder. Our fractal dimension results are also against our prediction. This measure has so far been linked only to depression, and it is possible that it is specifically linked to this rather than more generally linked to the neurotic spectrum. This may also be true of alpha asymmetry. Alternatively, like alpha asymmetry, it may be a characteristic that is linked to depressed people but not to the depressed state itself. Benzodiazepines, such as diazepam and lorazepam, often used to treat anxiety disorders but not depressive disorders, increase HFD in healthy humans. We found no such effect with midazolam in the current GAD and SAD patient group. Our findings that ketamine rapidly reduces power in the alpha1, alpha2, and particularly delta bands in GAD and SAD patients are broadly similar to previous findings. However, the observed reduction in delta might seem opposite to the previously reported increase in slow wave sleep activity. Given the consistent previous reduced waking delta and the very distinctive EEG state occurring in deep slow wave sleep, it is possible that sleep delta is functionally distinct from waking delta. An alternative is that the increase in sleep delta (which occurs during the first night after dosing) is a rebound from the immediate decrease (reported here 2 hours after dosing). Our increased gamma, unlike our increased beta, is as predicted. It seems likely that the variations in previous results and between our specific findings and our predicted pattern is due to dose-and testing-related variations (note the decrease in gamma at 0.25 mg) but could also be due to our use of a particular patient population (GAD/SAD) and also our small sample number. Other limitations include the lack of a placebo control group, although there was an active control group; while we obtained blood levels of drug, they were not analyzed. Further work with carefully matched healthy controls is required to clarify these points. However, if we take our data at face value, they suggest that, at least under some conditions, ketamine produces a decrease that is greatest at lower frequencies and an increase that is greatest at higher frequencies. Our observation of reduced theta power is consistent with some previous reports and opposite to others. There is a suggestion in Figurethat the theta decrease is greater at F8 than other sites, and so the variable results reported in this band may depend on site of recording, method of testing, and the dose of ketamine. Given our inverse-U dose-response curve with the FQ and the largely linear dose-response for most bands and electrode sites, our current data suggest that the observed effect of ketamine most likely to be related to its therapeutic effect is at right frontal sites, particularly F4. Critically, F4 is the only site for which we have clear evidence that changes in the theta band (and no other) relate to FQ changes. Despite large doserelated changes in power in the delta and gamma bands, there was no evidence that these changes were linked to therapeutic action (as opposed, say, to residual effects of dissociation). A much larger sample and much more detailed analysis would be needed to confirm these observations. Our recently developed human anxiolytic biomarker, goal-conflict rhythmicity, is obtained in the theta (spreading to alpha1) band at right frontal sites. It is possible, therefore, that the therapeutic effects reported with ketamine here reflect an action on the same brain system, which is potentially homologous with the rodent theta that is a uniquely reliable test of anxiolytic actionand is known to be reduced by ketamine. However, in healthy humans and rats, this biomarker has been defined by conventional anxiolytics given in single, low, doses. In our GAD and SAD patients, MDZ had little effect on rhythmicity and no effect at all on theta at right frontal sites. This lack of effect could be an explanation of the patients' resistance to such treatments. However, it is just as likely that ketamine in the current experiments is acting on a quite distinct right frontal system, which also requires theta-frequency rhythmicity, to that activated by our existing biomarker paradigm We have reported a dose-related effect of ketamine on ratings of anxiety and EEG recordings in patients with treatment refractory anxiety disorders. In particular, we found that right frontal slow-wave (theta) EEG changes predicted reduced intensity of phobic anxiety ratings. These novel double-blind findings in patients are consistent with earlier preclinical and human data that link diverse anxiolytic treatments with right frontal EEG changes, which may represent a plausible biomarker of anxiolytic action.
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Glue, P., Medlicott, N. J., Harland, S. et al. · Journal of Psychopharmacology (2017)
Taylor, J. H., Landeros-Weisenberger, A., Coughlin, C. et al. · Neuropsychopharmacology (2017)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
Papers in Blossom that reference this study
Asim, M., Wang, B., Hao, B. et al. · Neurochemistry International (2021)
Twelve participants completed the protocol. Clinically, 8 of 12 patients (67%) showed >50% reduction in HAM‑A and/or FQ scores at 2 hours after the 0.5 or 1.0 mg/kg ketamine doses. The FQ showed a dose‑related improvement: ANOVA reported a significant dose effect (F(2.67,29.41) = 3.80, P = .024) and a significant linear trend (F(1,11) = 7.12, P = .022), with a quadratic trend approaching significance suggesting a possible ceiling or reduction at 1.0 mg (F(1,11) = 4.68, P = .053). By contrast, HAM‑A scores did not change significantly (all F ≤ 1.2, all P ≥ 0.3). The extracted text notes that only predose and 2‑hour postdose anxiety data are considered alongside EEG. EEG analyses indicated dose‑related decreases in low‑frequency power and increases in higher frequencies. Specifically, ketamine significantly but nonlinearly reduced delta power, and sometimes theta, at lateral frontal sites (F7, F4 and particularly F8), while higher frequencies (beta and especially gamma) tended to increase; the greatest low‑frequency reductions were observed at fronto‑polar sites and diminished more posteriorly. Changes in Higuchi fractal dimension were minimal, non‑significant, and opposite to the hypothesis, and there were no systematic changes in frontal alpha asymmetry for either alpha1 or alpha2 bands. Analyses linking EEG to clinical response identified theta changes at right frontal locations as the most relevant predictor. Stepwise regressions across sites and bands extracted change in theta power at F4 as the single significant predictor of FQ change. Forcing F3, Fz, F4, F8 and Cz into a multiple regression produced a model explaining 17% of variance in FQ change, about 5% more than F4 alone; within that model, a small unique contribution (3%) was attributed to contralateral F3, about 9% variance was shared among Fz, F4, F8 and Cz, and 5% was unique to F4, with F8 and Cz contributing no unique variance. The authors report that delta and gamma bands, though substantially altered by ketamine, showed little or no correlation with FQ improvement. A post‑hoc power note indicated >80% power at alpha = 0.05 for mean differences between ketamine 1 mg/kg and midazolam for theta and gamma bands with sample sizes ranging from 3 to 11 (per electrode/band comparisons reported).
Shadli and colleagues interpret their principal finding as a dose‑related reduction in right frontal theta (maximal at F4 and around 0.5 mg/kg) that appears to mediate ketamine’s rapid anxiolytic effect on phobic anxiety as measured by the FQ. They emphasise that although ketamine produced larger changes in other bands (notably decreases in delta and increases in gamma), these did not predict clinical improvement, suggesting a specific role for right frontal theta reductions in the therapeutic effect. The lack of change in frontal alpha asymmetry and in Higuchi fractal dimension ran counter to the investigators’ predictions. They note that FAA may reflect a trait vulnerability (related to aversion/withdrawal) rather than a state marker of anxiety, and that HFD has been more consistently linked to depression than to anxiety. The absence of an HFD or FAA effect with ketamine, and the absence of an HFD increase with midazolam, are discussed in this context. The authors consider consistency and discrepancies with prior literature: reductions in waking delta and increases in gamma are broadly similar to some earlier reports, but the reported waking delta decrease differs from findings of increased slow‑wave activity during sleep after ketamine; the investigators suggest this may reflect functional differences between waking and sleep delta or a rebound increase in sleep following an acute daytime reduction. They also attribute variability across studies to differences in dose, recording site, patient population and small samples. Methodological limitations are acknowledged explicitly: small sample size, lack of a true inert placebo (the study used an active control), and that measured blood drug levels were not analysed. They recommend further work with larger samples and carefully matched healthy controls. Finally, the authors relate their results to an anxiolytic biomarker they have developed (goal‑conflict rhythmicity), which is manifest in the theta band at right frontal sites; they suggest ketamine’s right frontal theta effect could reflect action on a similar brain system that is homologous to rodent anxiolytic‑related theta. They caution, however, that midazolam produced little effect in their patients and that it is therefore unclear whether ketamine is acting on the same theta‑dependent system as conventional anxiolytics or on a related but distinct right‑frontal mechanism. Overall, the investigators conclude that right frontal theta changes are a plausible biomarker of anxiolytic action and that their double‑blind patient data support preclinical and human evidence linking right frontal EEG changes to anxiolytic treatments.