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

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. Keywords: anxiety disorder, electroencephalography, generalized anxiety disorder, ketamine, social anxiety disorder; treatment resistance Introduction A wide range of “neurotic” disorders (Andrews et al., 1990), even ketamine on brain activity in patients resistant to other treat- when these are resistant to conventional treatment, respond ments for generalized anxiety and social anxiety; and suggest to ketamine. The neural basis for this therapeutic effect of that changes in right-frontal theta band rhythmicity may under - ketamine is not known. Here, we report widespread effects of lie changes in anxiety ratings. Received: February 6, 2018; Revised: March 15, 2018; Accepted: April 12, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 717 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 718 | International Journal of Neuropsychopharmacology, 2018 Significance Statement We report that ketamine decreases low-frequency brain rhythms and increases high ones in patients with treatment-resistant generalized anxiety and social anxiety disorders. Only the decrease in medium-low frequency (“theta”) power at right frontal sites predicted the improvement by ketamine in fear questionnaire scores. This is the first report of the effects of ketamine on brain rhythms and treatment-resistant anxiety and suggests that right frontal “theta” rhythmicity may be important for all types of anxiolytic action. Anxiety disorders such as generalized anxiety disorder (GAD) (Hamilton, 1959) and SAD with the Fear Questionnaire (FQ; and social anxiety disorder (SAD) are among the most preva- Marks and Mathews, 1979). We assessed EEG by quantitation of lent of mental health problems (Stein and Sareen, 2015). In the power in specific frequency bands and by measures that show United States, the prevalence of GAD has been reported to be as depression-related changes: frontal alpha asymmetry (FAA; high as 3.1% per year, and 5.7% over a patient’s lifetime (Stein Allen et  al., 2004; Stewart et  al., 2014; Mennella et  al., 2017) and Sareen, 2015). Further, 12% of the population is affected and increased Higuchi’s fractal dimension (HFD; Higuchi, 1988; by SAD, making it a leading cause of impairment and distress Bachmann et al., 2013; Akar et al., 2015). We predicted that keta- (Lipsitz and Schneier, 2000; Kessler et al., 2005). SAD, in particu- mine would produce dose-related improvements in symptoms, lar, has high economic burden, because it causes social impair - FAA, and HFD; show dose-related power decreases in the delta, ment, poor academic achievement, reduced work productivity, alpha, and beta bands; and power increases in the theta and and increased financial dependence on the government (Lipsitz gamma bands (Muthukumaraswamy et al., 2015). and Schneier, 2000). Conventional treatments can take weeks to produce their full effects and, worse, one-third of SAD patients Methods and Materials are treatment resistant (Kelly et al., 2015 Taylor et  ; al., 20152018 , ), which increases outpatient costs, doubles hospitalizations, Participants and produces substantial morbidity (Liebowitz et  al., 2003). We urgently need novel pharmaceutical agents that are both more We recruited 12 patients with refractory DSM-IV GAD and/or effective and act quickly (Liebowitz et al., 2003 Ta ; ylor et al., 2018). SAD. The Southern Health and Disabilities Ethics Committee Ketamine is an N-methyl-D-aspartate (NMDA) receptor approved this study (15/STH/86). Patient inclusion criteria antagonist that has been found to be rapidly effective in treat- included having a HAM-A score of ≥20, and/or an LSAS (Liebowitz, ing treatment-resistant depression (Zarate et al., 2006), possibly 1987) score of ≥60 at screening, and being aged 18  years or via a non-NMDA route (Zanos et al., 2016). Initial clinical stud- older. All had failed to respond to 2 courses of antidepressants. ies have also demonstrated rapid improvement in obsessive- Patients were excluded if there was evidence of severe acute or compulsive disorder (Rodriguez et  al., 2013) and posttraumatic chronic medical disorders or if they were pregnant or lactating; stress disorder (Feder et al., 2014). Converging neuroimaging and taking monoamine oxidase inhibitors, thyroxine, or stimulants, pharmacological evidence implicates glutamate abnormalities or had active suicidal ideation. To reduce the risk that changes in the pathophysiology of SAD (Freitas-Ferrari et al., 2010 Av; erill in anxiety ratings were confounded by comorbid depression, et al., 2017), and we have previously reported dose-related effects we excluded patients with Montgomery-Asberg Depression of ketamine on SAD and GAD in treatment-refractory patients Rating Scale (MADRS; Montgomery and Asberg, 1979) scores of (Glue et al., 2017). Taken together, these data suggest that keta- ≥20 at screening. All patients provided signed informed consent mine may be acting on a single fundamental mechanism to prior to enrollment and were assessed as suitable to partici- produce rapid changes in the broad class of “neurotic, stress- pate based on review of medical history, safety laboratory tests, related and somatoform disorders” (World Health Organization, and vital signs. Patients remained on their current medication 1992) even when these are resistant to conventional treatments. regimens and continued with ongoing psychotherapy. However, Anxiety and depression appear to share common changes in they started no new treatments and did not change doses/visit brain network activity (Pannekoek et al., 2015) and regional grey schedules. There were 3 ascending ketamine dose levels (0.25, matter (Van Tol et  al., 2010). In depressed patients, ketamine 0.5, and 1  mg/kg) and midazolam (0.01  mg/kg), administered specifically increases slow wave activity during sleep, especially double blind. Justification of the 3 ketamine doses is provided in those with low baseline slow waves, and this may mediate in Glue et  al. (2017) and for the midazolam dose in Loo et  al. its antidepressant effects (see Duncan and Zarate, 2013). In (2016). The choice of control treatment for ketamine studies in healthy participants, it can reduce delta (1–3 Hz), theta (4–7 Hz), mood disorders is complicated. Saline placebo has been criti- and alpha (8–15 Hz) band power, while increasing gamma (>32 cized for its lack of psychoactive effects, which essentially is Hz) band power (Hong et  al., 2010; de la Salle et  al., 2016). But unblinding. Therefore, we chose to use midazolam, which is it can also increase theta power while decreasing alpha power psychoactive, as an active control for ketamine. The 3 ketamine (Domino et  al., 1965; Schüttler et  al., 1987K ; ochs et  al., 1996), doses were administered in ascending order, with midazolam particularly at frontal sites (Muthukumaraswamy et  al., 2015); dosing randomly inserted into the dosing schedule. All medi- so changes in bands can be interleaved, with decreased delta, cations were injected subcutaneously in the upper arm, with alpha, and beta (16–31 Hz) mixed with increased theta and 1 week between doses. The study was registered prospectively gamma (Muthukumaraswamy et al., 2015; Rivolta et al., 2015). with the Australian New Zealand Clinical Trial Registry (ACTRN We therefore evaluated the effects of ketamine concur - 12615000617561; http://www.anzctr.org.au/). rently on symptoms of anxiety and EEG in treatment-resist- ant Diagnostic and Statistical Manual of Mental Disorders, Assessments Volume IV (American Psychiatric Association, 2000) SAD and GAD patients using an active-control double-blinded design. We monitored patients in the clinic for 2 hours postdose, with We assessed GAD with the Hamilton Anxiety Scale/HAM-A vital signs obtained predose, and 15, 30, 60, 90, and 120 minutes Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Shadli et al. | 719 postdosing (data not reported). Anxiety assessments included Fractal dimension was calculated using Higuchi’s algorithm the FQ (score range 0–136; Marks and Mathews, 1979) and the with a k of 8 (Higuchi, 1988). After the eye-blink removal stage, max HAM-A (range 0–52; Hamilton, 1959) predose, at 1, 2, 24, 72, the data were subjected to an additional 2- to 36-Hz bandpass and 168 hours postdose. Tolerability assessments included filter, and sections with artefacts were manually removed. reported adverse events throughout the study, and Clinician The continuous data were then split into 2-second (256 sam- Administered Dissociative States Scale (Bremner et  al., 1998) ple) epochs with 50% overlap. Higuchi’s algorithm creates k max predose, 30, and 60 minutes postdose. Summary statistics were number of new time series (with k running from 1 to k ), each max calculated and reported for demographic, vital signs, and rating obtained by taking every kth sample of the original epoch. scale data. As EEG was only recorded predose and at 2 hours The length of the curve of each series is calculated and plot- postdose, we report only the predose and 2-hour postdose anxi- ted against k on a double logarithmic graph. If the length of the ety scale data here. curve and k are proportional, then the plotted data will fall on a straight line. The slope of this line is the fractal dimension. Electroencephalography Statistical Analysis A Waveguard EEG cap (ANT Neurotechnology) using the 10:20 sys- The data were submitted to ANOVA in SPSS with channel, fre- tem was used to record brain activity across the frontal lobes of quency, and dose as within-subjects variables. Polynomial the participants, specifically using channels Fp1, Fp2, F7, F3, Fz, F4, components of all factors were extracted with the MDZ active F8, and Cz, with left mastoid as the reference electrode. Depending control treated as 0 mg ketamine. on their head circumference, each participant was fitted with one of 3 appropriate cap sizes: large (head circumference 57–64  cm), medium (53–57 cm), and small (47–53 cm). The EEG cap was con- Results nected to a Bioradio (CleveMed: Cleveland Medical Devices Inc.). The Bioradio used Bluetooth to stream the recorded data (sam- Participants pled at 256 Hz) to a computer that stored the data for later offline The participants were 12 patients (4 male, 8 female; mean analysis using BioCapture (CleveMed, Cleveland Medical Devices age = 31  years, range 18–65). Mean duration of their anxiety Inc.). Participants were fitted with the EEG cap and a recording was disorders was 13.8  years. All 12 participants had SAD, 10 had made prior to study drug administration (predose recording). For GAD, and 2 panic disorder. Nine had past MDE but none were the predose recording, participants were asked to sit still to reduce depressed at the time of enrolment (mean MADRS 6.6). Baseline any noise interference and were then instructed to have their eyes HAMA score was 28.1 and mean LSAS was 91.3. Demographic open and then closed for alternating 1-minute intervals on request and diagnostic details are provided in Table 1, along with infor - for the next 10 minutes. There were, therefore, 5 recorded minutes mation about prior failed treatments for their anxiety disorders. of eyes open and 5 recorded minutes of eyes closed, with marks in the EEG file indicating the point of changeover. After the EEG pre- dose recording, the participants received their SC study drug dos- Changes in Anxiety Ratings ing and were supervised by registered nurses and psychiatrists for Overall, 8 of 12 patients (67%) reported a >50% reduction in the next 2 hours, after which participants underwent another EEG HAM-A and/or FQ scores after the 0.5- or 1-mg/kg doses of keta- recording (postdose recording) identical to the predose recording. mine at 2 hours postdose. Scores are shown in Table 2 and post- dose improvement relative to predose is shown in Figure  1A. EEG Processing There was a clear dose-related improvement in FQ scores with ketamine dose (dose, F(2.67, 29.41) = 3.80, P = .024, Greenhouse- The EEG data were analyzed using custom software written in Geisser corrected; dose[lin], F(1, 11) = 7.12, P = .022) with a trend to Visual Basic 6. The data were down-sampled to 128 Hz and sub- a ceiling effect or perhaps even reduction at 1.0 mg of ketamine mitted to a 3-point running mean as a low pass filter (effective (dose[quad], F(1, 11) = 4.68, P = .053). The very slight apparently 46 Hz cut off) and then submitted to an automated procedure for similar trend in HAM-A scores (Figure  1A) was not supported eye blink removal, based on the ballistic components of the eye statistically (all F ≤ 1.2, all P ≥ 0.3). blink, which left residual EEG (Zhang et al., 2017). For simple power analysis, the files were then manually pro- cessed and any remaining artefacts were replaced with missing Ketamine Reduced Low-Frequency and Increased values. The recordings were separated into single open/closed High-Frequency EEG Power but Did Not Improve minute segments and a serial Fast Fourier Transform with a HFD or FAA 1-second overlapping Hanning window was applied. The result- ant power spectra were log transformed to normalize error vari- For all analyses, we treated MDZ as equivalent to 0 mg of keta- ance and averaged. This segmented the file into 10 spectra, 5 mine. To simplify EEG power analysis, we averaged across fre- of which eyes were open and 5 of which eyes were closed. For quencies within each band. Figure 2A–B shows the effects (with the current analyses, these were then averaged over minutes statistics in the legend) of varying doses of ketamine on the to produce a single spectrum for each testing occasion for each post:pre difference in EEG power for the different frequency participant. Power was then averaged across frequencies within bands and channels. Across frontal sites (Figure 2A), higher doses each of the conventional bands to give a single power value for of ketamine significantly but nonlinearly reduced delta, and each of delta (1–3 Hz), theta (4–6 Hz), alpha1 (7–9 Hz), alpha2 sometimes theta, power at the lateral sites F7, F4, and particu- (10–12 Hz), beta (25–34 Hz), and gamma (41–53 Hz). larly F8, while generally increasing beta and particularly delta. Alpha asymmetry was calculated for both the alpha1 and From anterior to posterior (Figure  2B), there was a clear alpha2 bands by subtracting logarithmic power at left electrodes dose- and band-related (largest in the delta band) reduction in from their right-most counterparts [(ln(R) – ln(L)] for each of power at lower frequencies with ketamine at the fronto-polar F8:F7 and F4:F3. site, which diminished across the mid-frontal and central sites. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 720 | International Journal of Neuropsychopharmacology, 2018 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 1. General Demographic and Treatment Details for Participants Baseline Score Prior Ineffective Treatments Current Meds Diagnoses Anxiety No. Age Gender Employed Duration (y) HAMA LSAS MADRS Medication Psycho-therapy (mg/d) GAD SAD PD Past MDE Other 1 24 f y 8 39 78 6 SSRIs, TCAs, ven CBT, PRx Doth 50 mg, loraz X x x 4 mg 2 22 f n 7 22 97 6 Sert - Ven 150 mg X x 3 25 m n 5 26 118 6 Fluox, quet CBT, PRx Fluox 40 mg X x x 4 24 f n 12 33 105 6 Fluox, sert, cital PRx Ven 300 mg X x x 5 25 f n 12 32 68 5 SSRIs, mocl CBT, Ven 400 mg, VPA X x x x Past polysub- 400 mg, clon 2 mg stance use (opioids, cannabis) 6 33 m y 20 27 87 8 Fluox, cital CBT, PRx Ven 75 mg x x x 7 29 f y 19 36 80 8 SSRIs, mirt, busp - Ami 150 mg X x x 8 26 f n 16 14 88 5 SSRIs, mirt PRx Ven 300 mg, bup X x x 300 mg, diaz 10 mg 9 65 m n 15 38 101 8 SSRIs, ven, mirt, PRx Dox 75 mg, diaz X x x Past AUD TCAs 2 mg 10 27 f y 10 36 103 5 Ami PRx Cital 10 mg X x 11 18 f n 5 16 109 4 Parox, mirt PRx None x x EDNOS 12 52 m y 37 18 61 12 SSRIs PRx Parox 20 mg x x Abbreviations: ami, amitriptyline; AUD, alcohol use disorder; bup, buproprion; busp, buspirone; CBT, cognitive behavioural therapy; cital, citalopram; clon, clonazepam; diaz, diazepam; doth, dothi- epin; dox, doxepin; EDNOS, eating disorder not otherwise specified; fluox, fluoxetine; GAD, Generalised Anxiety Disorder; HAMA; Hamilton Anxiety; LSAS, Liebowitz Social Anxiety Scale; loraz, lor - azepam; MADRS, Montgomery Asberg Depression Rating Scale; mirt, mirtazapine; mocl, moclobemide; parox, paroxetine; PD, Panic Disorder; PRx, other psychotherapy; Quet, quetiapine; SAD, Social Anxiety Disorder; sert, sertraline; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; ven, venlafaxine; VPA, sodium valproate. Shadli et al. | 721 Table  2. Fear Questionnaire (FQ) and Hamilton Anxiety (HAM-A) Whereas, there was increased power at higher frequencies that Questionnaire Means Predose and 2 Hours Postdose for Midazolam tended to increase from frontal to central sites. Changes in HFD (MDZ) and Ketamine (K), with Values Showing Dose in mg (Figure  2C) were minimal, nonsignificant, and in the opposite direction to that predicted. There were no systematic changes Scale Time MDZ K0.25 K0.50 K1.00 in FAA for either F8:F7 or F4:F3. As there were no significant effects differentiating alpha1 and alpha2, the results are a -ver FQ Predose 45.33 54.33 49.67 42.00 +2h 35.92 37.75 28.13 24.17 aged across band in Figure 2D . HAM-A Predose 16.25 19.92 16.17 13.75 Posthoc calculation of statistical power for the mean differ - +2h 8.83 11.58 4.92 4.58 ences between ketamine 1 mg/kg and midazolam for each of the Figure 1. Predose vs postdose improvements in scale scores. (A) Variation with ketamine dose (K, mg) relative to midazolam (MDZ) for Fear (FQ) and Hamilton Anxiety (HAM-A) Questionnaires subjected to separate analyses. Curves are linear+quadratic trend lines (significant for FQ but not HAM-A). Bars are ±SEM and are approxi- mately equal (2.5 vs 2.2, respectively) for the 2 questionnaires in the case of MDZ. (B) Correlation of FQ change with power change in different frequency bands at differ - ent electrode sites. Values are signed (±) percent of variance accounted for (r × 100). Height of the grey zone represents the 95% CI uncorrected for multiple comparisons. *Significant effect within stepwise regression (P < .05). Figure 2. Post-pre effects (difference scores) for different doses of ketamine and midazolam (MDZ) on power in different frequency bands, on Higuchi’s fractal dimen- sion, and on alpha asymmetry at frontal-central electrodes. (A) Power data subjected to ANOVA for left-right effects across the frontal sites. The strongest reductions in power were at lateral sites and lower frequencies: dose[lin] x band[quad] x channel[quad], F (4, = 7) 5.04, P = .05); dose[cub] x band[lin] x channel[quad], F (4, 7) = 8.51, P = .022); dose[cub] x band[quad] x channel[cub], (F (4, 7)= 79.37, P =< .001); dose[cub] x band[quad] x channel[quad] (F (4, 7)= 30.52, P = .001. (B) Power data subjected to ANOVA for anterior-posterior effects. The strongest reduction was at Fp1 and in the delta band: dose[lin] x band[cub], F (4, = 11.65, 7) P = .011); dose[cub] x band[cub] x channel[lin] (F (4, 7)= 4.25, P = .077. (C) Higuchi’s Fractal Dimension (HFD, percent) shown for each of the 5 frontal electrode sites (bar is 2 × maxim um SE for the set of means). There were no reliable effects of ketamine. (D) Frontal Alpha Asymmetry (FAA) shown separately for the F8:F7 and F4:F3 pairs. Values are averaged across alpha1 and alpha2 as there were no significant effects associated with sub-band. There were no systematic effects of ketamine (bars are ±SEM). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 722 | International Journal of Neuropsychopharmacology, 2018 theta and gamma bands and at all 5 electrode positions showed asymmetry, it may be a characteristic that is linked to depressed that with sample sizes ranging from 3 to 11, there was >80% people but not to the depressed state itself. Benzodiazepines, power at alpha = 0.05. such as diazepam and lorazepam, often used to treat anxiety disorders but not depressive disorders, increase HFD in healthy humans (Chouvarda et al., 2009; Michail et al., 2010). We found Ketamine Effects on FQ Appear Related to Right-Frontal no such effect with midazolam in the current GAD and SAD Theta Power patient group. For each of the electrode sites, separately, we carried out a step- Our findings that ketamine rapidly reduces power in the wise regression of FQ change score with power-change scores alpha1, alpha2, and particularly delta bands in GAD and SAD for all the bands as predictors. The bulk of the simple correla- patients are broadly similar to previous findings (Hong et  al., tions (uncorrected for multiple comparisons) were well within 2010; de la Salle et al., 2016). However, the observed reduction in 95% confidence limits (Figure  1B). The lack of any obvious con- delta might seem opposite to the previously reported increase tribution to FQ change was particularly clear for the delta and in slow wave sleep activity (Duncan and Zarate, 2013). Given the gamma bands despite the fact that they were most affected consistent previous reduced waking delta and the very distinct- by ketamine (Figure  2A–B). All the highest correlations were ive EEG state occurring in deep slow wave sleep, it is possible obtained with the theta band with Fz and Cz achieving values that sleep delta is functionally distinct from waking delta. An that would have been significant uncorrected. F4 theta was the alternative is that the increase in sleep delta (which occurs dur - only power change that was extracted as a significant predictor ing the first night after dosing) is a rebound from the immediate by the stepwise analysis, with the other high values surrounding decrease (reported here 2 hours after dosing). it. To test the structure of these adjacent values we forced F3, Fz, Our increased gamma, unlike our increased beta, is as pre- F4, F8, and Cz into a multiple regression on FQ. The total predict- dicted. It seems likely that the variations in previous results ive power of the equation as a whole was 17%, about 5% greater and between our specific findings and our predicted pattern is than F4 alone, with the bulk of the additional explanatory power due to dose- and testing-related variations (note the decrease coming from a unique contribution (3%) from the contralateral in gamma at 0.25 mg) but could also be due to our use of a par - site F3. Of the remaining 14%, 9% was variance shared among Fz, ticular patient population (GAD/SAD) and also our small sample F4, F8, and Cz and 5% was unique to F4, with F8 and Cz having number. Other limitations include the lack of a placebo control no unique contribution. These results are consistent with the group, although there was an active control group; while we bulk of the effect of ketamine on FQ being mediated by a single obtained blood levels of drug, they were not analyzed. Further source close to F4, with some spread of activity to the immedi- work with carefully matched healthy controls is required to clar - ately adjacent electrodes, and a weak contribution from an inde- ify these points. However, if we take our data at face value, they pendent source in a similar location in the opposite hemisphere. 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. Discussion Our observation of reduced theta power is consistent with Our main finding is that ketamine produced a dose-related some previous reports and opposite to others. There is a sug- decrease, maximal at 0.5 mg, in theta frequency frontal power at gestion in Figure 2 that the theta decrease is greater at F8 than the right frontal site F4 that appears to mediate its therapeutic other sites, and so the variable results reported in this band effects on GAD and SAD, as measured by the FQ. Similar power may depend on site of recording (Muthukumaraswamy et  al., changes in the theta range at adjacent sites appeared to be less 2015), method of testing (Kochs et  al., 1996), and the dose of involved in controlling FQ, while larger decreases in power in the ketamine. Given our inverse-U dose-response curve with the FQ delta range and large increases in power in the gamma range and the largely linear dose-response for most bands and elec- appeared to make no contribution to changes in FQ. Ketamine trode sites, our current data suggest that the observed effect produced no sign of an improvement in HFD scores at any dose of ketamine most likely to be related to its therapeutic effect and no systematic or reliable changes in FAA. Reduced anxiety is at right frontal sites, particularly F4. Critically, F4 is the only has previously been reported with ketamine (Glue et  al., 2017; site for which we have clear evidence that changes in the theta Taylor et al., 2018); however, we saw significant changes only in band (and no other) relate to FQ changes. Despite large dose- FQ and no large changes in HAM-A scores. related changes in power in the delta and gamma bands, there Our alpha asymmetry results are against our prediction but was no evidence that these changes were linked to therapeutic not entirely surprising. FAA has previously been linked to av -er action (as opposed, say, to residual effects of dissociation). sion/withdrawal/pessimism/introversion in general (Wacker A much larger sample and much more detailed analysis would et al., 2010; De Pascalis et al., 2013W ; acker, 2017) and not depres- be needed to confirm these observations. sion or anxiety (Bruder et al., 1997 Mathersul et  ; al., 2008 Adolph ; Our recently developed human anxiolytic biomarker and Margraf, 2017) in particular. It shows a trait-like reliability (McNaughton, 2017), goal-conflict rhythmicity, is obtained and stability that (over months) is not related to changes in in the theta (spreading to alpha1) band at right frontal sites depressed state in patients with major depression (Debener (McNaughton et al., 2013Shadli et  ; al., 2015). It is possible, there- et al., 2000; Allen et al., 2004) and may be a predictor of future fore, that the therapeutic effects reported with ketamine here disorder rather than a biomarker of current disorder (Smith and reflect an action on the same brain system, which is potentially Bell, 2010). homologous with the rodent theta that is a uniquely reliable test Our fractal dimension results are also against our predic- of anxiolytic action (McNaughton et  al., 2007) and is known to tion. This measure has so far been linked only to depression be reduced by ketamine (Engin et al., 2009). However, in healthy (Bachmann et  al., 2013; Akar et  al., 2015), and it is possible humans and rats, this biomarker has been defined by conven- that it is specifically linked to this rather than more gener - tional anxiolytics given in single, low, doses. In our GAD and ally linked to the neurotic spectrum. This may also be true of SAD patients, MDZ had little effect on rhythmicity and no effect alpha asymmetry (Gordon et al., 2010). Alternatively, like alpha at all on theta at right frontal sites. This lack of effect could be Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Shadli et al. | 723 an explanation of the patients’ resistance to such treatments. quantitative electroencephalographic study. Biol Psychiatry However, it is just as likely that ketamine in the current experi- 41:939–948. ments is acting on a quite distinct right frontal system, which Chouvarda I, Michail E, Kokonozi A, Staner L, Domis N, also requires theta-frequency rhythmicity, to that activated by Maglaveras N (2009) Investigation of sleepiness induced by our existing biomarker paradigm insomnia medication treatment and sleep deprivation. In: We have reported a dose-related effect of ketamine on rat- Foundations of augmented cognition. Neuroergonomics and ings of anxiety and EEG recordings in patients with treatment operational neuroscience: 5th International Conference, FAC refractory anxiety disorders. In particular, we found that right 2009 held as part of HCI International 2009 San Diego, CA, frontal slow-wave (theta) EEG changes predicted reduced inten- USA, July 19–24, 2009 Proceedings (Schmorrow DD, Estabrooke sity of phobic anxiety ratings. These novel double-blind findings IV, Grootjen M, eds), pp120–127. Berlin, Heidelberg: Springer in patients are consistent with earlier preclinical and human Berlin Heidelberg. data that link diverse anxiolytic treatments with right frontal Debener S, Beauducel A, Nessler D, Brocke B, Heilemann H, EEG changes, which may represent a plausible biomarker of Kayser J (2000) Is resting anterior EEG alpha asymmetry a anxiolytic action. trait marker for depression? 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Within the last 3  years, Duncan WC Jr, Zarate CA Jr (2013) Ketamine, sleep, and depres- P. Glue has participated in an advisory board for Janssen Pharma sion: current status and new questions. Curr Psychiatry Rep and N. McNaughton has had a confidential disclosure and con- 15:394. sulting agreement with Janssen Research & Development, LLC. Engin E, Treit D, Dickson CT (2009) Anxiolytic- and antidepres- The other authors declare no potential conflicts of interest with sant-like properties of ketamine in behavioral and neuro- respect to the research, authorship, and/or publication of this physiological animal models. Neuroscience 161:359–369. article. 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Rivolta D, Heidegger T, Scheller B, Sauer A, Schaum M, Birkner K, Zhang S, McIntosh J, Shadli SM, Neo PS, Huang Z, McNaughton Singer W, Wibral M, Uhlhaas PJ (2015) Ketamine dysregulates N (2017) Removing eye blink artefacts from EEG-A single- the amplitude and connectivity of high-frequency oscilla- channel physiology-based method. J Neurosci Methods tions in cortical-subcortical networks in humans: evidence 291:213–220. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Neuropsychopharmacology Oxford University Press

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

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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. Keywords: anxiety disorder, electroencephalography, generalized anxiety disorder, ketamine, social anxiety disorder; treatment resistance Introduction A wide range of “neurotic” disorders (Andrews et al., 1990), even ketamine on brain activity in patients resistant to other treat- when these are resistant to conventional treatment, respond ments for generalized anxiety and social anxiety; and suggest to ketamine. The neural basis for this therapeutic effect of that changes in right-frontal theta band rhythmicity may under - ketamine is not known. Here, we report widespread effects of lie changes in anxiety ratings. Received: February 6, 2018; Revised: March 15, 2018; Accepted: April 12, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 717 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 718 | International Journal of Neuropsychopharmacology, 2018 Significance Statement We report that ketamine decreases low-frequency brain rhythms and increases high ones in patients with treatment-resistant generalized anxiety and social anxiety disorders. Only the decrease in medium-low frequency (“theta”) power at right frontal sites predicted the improvement by ketamine in fear questionnaire scores. This is the first report of the effects of ketamine on brain rhythms and treatment-resistant anxiety and suggests that right frontal “theta” rhythmicity may be important for all types of anxiolytic action. Anxiety disorders such as generalized anxiety disorder (GAD) (Hamilton, 1959) and SAD with the Fear Questionnaire (FQ; and social anxiety disorder (SAD) are among the most preva- Marks and Mathews, 1979). We assessed EEG by quantitation of lent of mental health problems (Stein and Sareen, 2015). In the power in specific frequency bands and by measures that show United States, the prevalence of GAD has been reported to be as depression-related changes: frontal alpha asymmetry (FAA; high as 3.1% per year, and 5.7% over a patient’s lifetime (Stein Allen et  al., 2004; Stewart et  al., 2014; Mennella et  al., 2017) and Sareen, 2015). Further, 12% of the population is affected and increased Higuchi’s fractal dimension (HFD; Higuchi, 1988; by SAD, making it a leading cause of impairment and distress Bachmann et al., 2013; Akar et al., 2015). We predicted that keta- (Lipsitz and Schneier, 2000; Kessler et al., 2005). SAD, in particu- mine would produce dose-related improvements in symptoms, lar, has high economic burden, because it causes social impair - FAA, and HFD; show dose-related power decreases in the delta, ment, poor academic achievement, reduced work productivity, alpha, and beta bands; and power increases in the theta and and increased financial dependence on the government (Lipsitz gamma bands (Muthukumaraswamy et al., 2015). and Schneier, 2000). Conventional treatments can take weeks to produce their full effects and, worse, one-third of SAD patients Methods and Materials are treatment resistant (Kelly et al., 2015 Taylor et  ; al., 20152018 , ), which increases outpatient costs, doubles hospitalizations, Participants and produces substantial morbidity (Liebowitz et  al., 2003). We urgently need novel pharmaceutical agents that are both more We recruited 12 patients with refractory DSM-IV GAD and/or effective and act quickly (Liebowitz et al., 2003 Ta ; ylor et al., 2018). SAD. The Southern Health and Disabilities Ethics Committee Ketamine is an N-methyl-D-aspartate (NMDA) receptor approved this study (15/STH/86). Patient inclusion criteria antagonist that has been found to be rapidly effective in treat- included having a HAM-A score of ≥20, and/or an LSAS (Liebowitz, ing treatment-resistant depression (Zarate et al., 2006), possibly 1987) score of ≥60 at screening, and being aged 18  years or via a non-NMDA route (Zanos et al., 2016). Initial clinical stud- older. All had failed to respond to 2 courses of antidepressants. ies have also demonstrated rapid improvement in obsessive- Patients were excluded if there was evidence of severe acute or compulsive disorder (Rodriguez et  al., 2013) and posttraumatic chronic medical disorders or if they were pregnant or lactating; stress disorder (Feder et al., 2014). Converging neuroimaging and taking monoamine oxidase inhibitors, thyroxine, or stimulants, pharmacological evidence implicates glutamate abnormalities or had active suicidal ideation. To reduce the risk that changes in the pathophysiology of SAD (Freitas-Ferrari et al., 2010 Av; erill in anxiety ratings were confounded by comorbid depression, et al., 2017), and we have previously reported dose-related effects we excluded patients with Montgomery-Asberg Depression of ketamine on SAD and GAD in treatment-refractory patients Rating Scale (MADRS; Montgomery and Asberg, 1979) scores of (Glue et al., 2017). Taken together, these data suggest that keta- ≥20 at screening. All patients provided signed informed consent mine may be acting on a single fundamental mechanism to prior to enrollment and were assessed as suitable to partici- produce rapid changes in the broad class of “neurotic, stress- pate based on review of medical history, safety laboratory tests, related and somatoform disorders” (World Health Organization, and vital signs. Patients remained on their current medication 1992) even when these are resistant to conventional treatments. regimens and continued with ongoing psychotherapy. However, Anxiety and depression appear to share common changes in they started no new treatments and did not change doses/visit brain network activity (Pannekoek et al., 2015) and regional grey schedules. There were 3 ascending ketamine dose levels (0.25, matter (Van Tol et  al., 2010). In depressed patients, ketamine 0.5, and 1  mg/kg) and midazolam (0.01  mg/kg), administered specifically increases slow wave activity during sleep, especially double blind. Justification of the 3 ketamine doses is provided in those with low baseline slow waves, and this may mediate in Glue et  al. (2017) and for the midazolam dose in Loo et  al. its antidepressant effects (see Duncan and Zarate, 2013). In (2016). The choice of control treatment for ketamine studies in healthy participants, it can reduce delta (1–3 Hz), theta (4–7 Hz), mood disorders is complicated. Saline placebo has been criti- and alpha (8–15 Hz) band power, while increasing gamma (>32 cized for its lack of psychoactive effects, which essentially is Hz) band power (Hong et  al., 2010; de la Salle et  al., 2016). But unblinding. Therefore, we chose to use midazolam, which is it can also increase theta power while decreasing alpha power psychoactive, as an active control for ketamine. The 3 ketamine (Domino et  al., 1965; Schüttler et  al., 1987K ; ochs et  al., 1996), doses were administered in ascending order, with midazolam particularly at frontal sites (Muthukumaraswamy et  al., 2015); dosing randomly inserted into the dosing schedule. All medi- so changes in bands can be interleaved, with decreased delta, cations were injected subcutaneously in the upper arm, with alpha, and beta (16–31 Hz) mixed with increased theta and 1 week between doses. The study was registered prospectively gamma (Muthukumaraswamy et al., 2015; Rivolta et al., 2015). with the Australian New Zealand Clinical Trial Registry (ACTRN We therefore evaluated the effects of ketamine concur - 12615000617561; http://www.anzctr.org.au/). rently on symptoms of anxiety and EEG in treatment-resist- ant Diagnostic and Statistical Manual of Mental Disorders, Assessments Volume IV (American Psychiatric Association, 2000) SAD and GAD patients using an active-control double-blinded design. We monitored patients in the clinic for 2 hours postdose, with We assessed GAD with the Hamilton Anxiety Scale/HAM-A vital signs obtained predose, and 15, 30, 60, 90, and 120 minutes Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Shadli et al. | 719 postdosing (data not reported). Anxiety assessments included Fractal dimension was calculated using Higuchi’s algorithm the FQ (score range 0–136; Marks and Mathews, 1979) and the with a k of 8 (Higuchi, 1988). After the eye-blink removal stage, max HAM-A (range 0–52; Hamilton, 1959) predose, at 1, 2, 24, 72, the data were subjected to an additional 2- to 36-Hz bandpass and 168 hours postdose. Tolerability assessments included filter, and sections with artefacts were manually removed. reported adverse events throughout the study, and Clinician The continuous data were then split into 2-second (256 sam- Administered Dissociative States Scale (Bremner et  al., 1998) ple) epochs with 50% overlap. Higuchi’s algorithm creates k max predose, 30, and 60 minutes postdose. Summary statistics were number of new time series (with k running from 1 to k ), each max calculated and reported for demographic, vital signs, and rating obtained by taking every kth sample of the original epoch. scale data. As EEG was only recorded predose and at 2 hours The length of the curve of each series is calculated and plot- postdose, we report only the predose and 2-hour postdose anxi- ted against k on a double logarithmic graph. If the length of the ety scale data here. curve and k are proportional, then the plotted data will fall on a straight line. The slope of this line is the fractal dimension. Electroencephalography Statistical Analysis A Waveguard EEG cap (ANT Neurotechnology) using the 10:20 sys- The data were submitted to ANOVA in SPSS with channel, fre- tem was used to record brain activity across the frontal lobes of quency, and dose as within-subjects variables. Polynomial the participants, specifically using channels Fp1, Fp2, F7, F3, Fz, F4, components of all factors were extracted with the MDZ active F8, and Cz, with left mastoid as the reference electrode. Depending control treated as 0 mg ketamine. on their head circumference, each participant was fitted with one of 3 appropriate cap sizes: large (head circumference 57–64  cm), medium (53–57 cm), and small (47–53 cm). The EEG cap was con- Results nected to a Bioradio (CleveMed: Cleveland Medical Devices Inc.). The Bioradio used Bluetooth to stream the recorded data (sam- Participants pled at 256 Hz) to a computer that stored the data for later offline The participants were 12 patients (4 male, 8 female; mean analysis using BioCapture (CleveMed, Cleveland Medical Devices age = 31  years, range 18–65). Mean duration of their anxiety Inc.). Participants were fitted with the EEG cap and a recording was disorders was 13.8  years. All 12 participants had SAD, 10 had made prior to study drug administration (predose recording). For GAD, and 2 panic disorder. Nine had past MDE but none were the predose recording, participants were asked to sit still to reduce depressed at the time of enrolment (mean MADRS 6.6). Baseline any noise interference and were then instructed to have their eyes HAMA score was 28.1 and mean LSAS was 91.3. Demographic open and then closed for alternating 1-minute intervals on request and diagnostic details are provided in Table 1, along with infor - for the next 10 minutes. There were, therefore, 5 recorded minutes mation about prior failed treatments for their anxiety disorders. of eyes open and 5 recorded minutes of eyes closed, with marks in the EEG file indicating the point of changeover. After the EEG pre- dose recording, the participants received their SC study drug dos- Changes in Anxiety Ratings ing and were supervised by registered nurses and psychiatrists for Overall, 8 of 12 patients (67%) reported a >50% reduction in the next 2 hours, after which participants underwent another EEG HAM-A and/or FQ scores after the 0.5- or 1-mg/kg doses of keta- recording (postdose recording) identical to the predose recording. mine at 2 hours postdose. Scores are shown in Table 2 and post- dose improvement relative to predose is shown in Figure  1A. EEG Processing There was a clear dose-related improvement in FQ scores with ketamine dose (dose, F(2.67, 29.41) = 3.80, P = .024, Greenhouse- The EEG data were analyzed using custom software written in Geisser corrected; dose[lin], F(1, 11) = 7.12, P = .022) with a trend to Visual Basic 6. The data were down-sampled to 128 Hz and sub- a ceiling effect or perhaps even reduction at 1.0 mg of ketamine mitted to a 3-point running mean as a low pass filter (effective (dose[quad], F(1, 11) = 4.68, P = .053). The very slight apparently 46 Hz cut off) and then submitted to an automated procedure for similar trend in HAM-A scores (Figure  1A) was not supported eye blink removal, based on the ballistic components of the eye statistically (all F ≤ 1.2, all P ≥ 0.3). blink, which left residual EEG (Zhang et al., 2017). For simple power analysis, the files were then manually pro- cessed and any remaining artefacts were replaced with missing Ketamine Reduced Low-Frequency and Increased values. The recordings were separated into single open/closed High-Frequency EEG Power but Did Not Improve minute segments and a serial Fast Fourier Transform with a HFD or FAA 1-second overlapping Hanning window was applied. The result- ant power spectra were log transformed to normalize error vari- For all analyses, we treated MDZ as equivalent to 0 mg of keta- ance and averaged. This segmented the file into 10 spectra, 5 mine. To simplify EEG power analysis, we averaged across fre- of which eyes were open and 5 of which eyes were closed. For quencies within each band. Figure 2A–B shows the effects (with the current analyses, these were then averaged over minutes statistics in the legend) of varying doses of ketamine on the to produce a single spectrum for each testing occasion for each post:pre difference in EEG power for the different frequency participant. Power was then averaged across frequencies within bands and channels. Across frontal sites (Figure 2A), higher doses each of the conventional bands to give a single power value for of ketamine significantly but nonlinearly reduced delta, and each of delta (1–3 Hz), theta (4–6 Hz), alpha1 (7–9 Hz), alpha2 sometimes theta, power at the lateral sites F7, F4, and particu- (10–12 Hz), beta (25–34 Hz), and gamma (41–53 Hz). larly F8, while generally increasing beta and particularly delta. Alpha asymmetry was calculated for both the alpha1 and From anterior to posterior (Figure  2B), there was a clear alpha2 bands by subtracting logarithmic power at left electrodes dose- and band-related (largest in the delta band) reduction in from their right-most counterparts [(ln(R) – ln(L)] for each of power at lower frequencies with ketamine at the fronto-polar F8:F7 and F4:F3. site, which diminished across the mid-frontal and central sites. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 720 | International Journal of Neuropsychopharmacology, 2018 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 1. General Demographic and Treatment Details for Participants Baseline Score Prior Ineffective Treatments Current Meds Diagnoses Anxiety No. Age Gender Employed Duration (y) HAMA LSAS MADRS Medication Psycho-therapy (mg/d) GAD SAD PD Past MDE Other 1 24 f y 8 39 78 6 SSRIs, TCAs, ven CBT, PRx Doth 50 mg, loraz X x x 4 mg 2 22 f n 7 22 97 6 Sert - Ven 150 mg X x 3 25 m n 5 26 118 6 Fluox, quet CBT, PRx Fluox 40 mg X x x 4 24 f n 12 33 105 6 Fluox, sert, cital PRx Ven 300 mg X x x 5 25 f n 12 32 68 5 SSRIs, mocl CBT, Ven 400 mg, VPA X x x x Past polysub- 400 mg, clon 2 mg stance use (opioids, cannabis) 6 33 m y 20 27 87 8 Fluox, cital CBT, PRx Ven 75 mg x x x 7 29 f y 19 36 80 8 SSRIs, mirt, busp - Ami 150 mg X x x 8 26 f n 16 14 88 5 SSRIs, mirt PRx Ven 300 mg, bup X x x 300 mg, diaz 10 mg 9 65 m n 15 38 101 8 SSRIs, ven, mirt, PRx Dox 75 mg, diaz X x x Past AUD TCAs 2 mg 10 27 f y 10 36 103 5 Ami PRx Cital 10 mg X x 11 18 f n 5 16 109 4 Parox, mirt PRx None x x EDNOS 12 52 m y 37 18 61 12 SSRIs PRx Parox 20 mg x x Abbreviations: ami, amitriptyline; AUD, alcohol use disorder; bup, buproprion; busp, buspirone; CBT, cognitive behavioural therapy; cital, citalopram; clon, clonazepam; diaz, diazepam; doth, dothi- epin; dox, doxepin; EDNOS, eating disorder not otherwise specified; fluox, fluoxetine; GAD, Generalised Anxiety Disorder; HAMA; Hamilton Anxiety; LSAS, Liebowitz Social Anxiety Scale; loraz, lor - azepam; MADRS, Montgomery Asberg Depression Rating Scale; mirt, mirtazapine; mocl, moclobemide; parox, paroxetine; PD, Panic Disorder; PRx, other psychotherapy; Quet, quetiapine; SAD, Social Anxiety Disorder; sert, sertraline; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; ven, venlafaxine; VPA, sodium valproate. Shadli et al. | 721 Table  2. Fear Questionnaire (FQ) and Hamilton Anxiety (HAM-A) Whereas, there was increased power at higher frequencies that Questionnaire Means Predose and 2 Hours Postdose for Midazolam tended to increase from frontal to central sites. Changes in HFD (MDZ) and Ketamine (K), with Values Showing Dose in mg (Figure  2C) were minimal, nonsignificant, and in the opposite direction to that predicted. There were no systematic changes Scale Time MDZ K0.25 K0.50 K1.00 in FAA for either F8:F7 or F4:F3. As there were no significant effects differentiating alpha1 and alpha2, the results are a -ver FQ Predose 45.33 54.33 49.67 42.00 +2h 35.92 37.75 28.13 24.17 aged across band in Figure 2D . HAM-A Predose 16.25 19.92 16.17 13.75 Posthoc calculation of statistical power for the mean differ - +2h 8.83 11.58 4.92 4.58 ences between ketamine 1 mg/kg and midazolam for each of the Figure 1. Predose vs postdose improvements in scale scores. (A) Variation with ketamine dose (K, mg) relative to midazolam (MDZ) for Fear (FQ) and Hamilton Anxiety (HAM-A) Questionnaires subjected to separate analyses. Curves are linear+quadratic trend lines (significant for FQ but not HAM-A). Bars are ±SEM and are approxi- mately equal (2.5 vs 2.2, respectively) for the 2 questionnaires in the case of MDZ. (B) Correlation of FQ change with power change in different frequency bands at differ - ent electrode sites. Values are signed (±) percent of variance accounted for (r × 100). Height of the grey zone represents the 95% CI uncorrected for multiple comparisons. *Significant effect within stepwise regression (P < .05). Figure 2. Post-pre effects (difference scores) for different doses of ketamine and midazolam (MDZ) on power in different frequency bands, on Higuchi’s fractal dimen- sion, and on alpha asymmetry at frontal-central electrodes. (A) Power data subjected to ANOVA for left-right effects across the frontal sites. The strongest reductions in power were at lateral sites and lower frequencies: dose[lin] x band[quad] x channel[quad], F (4, = 7) 5.04, P = .05); dose[cub] x band[lin] x channel[quad], F (4, 7) = 8.51, P = .022); dose[cub] x band[quad] x channel[cub], (F (4, 7)= 79.37, P =< .001); dose[cub] x band[quad] x channel[quad] (F (4, 7)= 30.52, P = .001. (B) Power data subjected to ANOVA for anterior-posterior effects. The strongest reduction was at Fp1 and in the delta band: dose[lin] x band[cub], F (4, = 11.65, 7) P = .011); dose[cub] x band[cub] x channel[lin] (F (4, 7)= 4.25, P = .077. (C) Higuchi’s Fractal Dimension (HFD, percent) shown for each of the 5 frontal electrode sites (bar is 2 × maxim um SE for the set of means). There were no reliable effects of ketamine. (D) Frontal Alpha Asymmetry (FAA) shown separately for the F8:F7 and F4:F3 pairs. Values are averaged across alpha1 and alpha2 as there were no significant effects associated with sub-band. There were no systematic effects of ketamine (bars are ±SEM). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 722 | International Journal of Neuropsychopharmacology, 2018 theta and gamma bands and at all 5 electrode positions showed asymmetry, it may be a characteristic that is linked to depressed that with sample sizes ranging from 3 to 11, there was >80% people but not to the depressed state itself. Benzodiazepines, power at alpha = 0.05. such as diazepam and lorazepam, often used to treat anxiety disorders but not depressive disorders, increase HFD in healthy humans (Chouvarda et al., 2009; Michail et al., 2010). We found Ketamine Effects on FQ Appear Related to Right-Frontal no such effect with midazolam in the current GAD and SAD Theta Power patient group. For each of the electrode sites, separately, we carried out a step- Our findings that ketamine rapidly reduces power in the wise regression of FQ change score with power-change scores alpha1, alpha2, and particularly delta bands in GAD and SAD for all the bands as predictors. The bulk of the simple correla- patients are broadly similar to previous findings (Hong et  al., tions (uncorrected for multiple comparisons) were well within 2010; de la Salle et al., 2016). However, the observed reduction in 95% confidence limits (Figure  1B). The lack of any obvious con- delta might seem opposite to the previously reported increase tribution to FQ change was particularly clear for the delta and in slow wave sleep activity (Duncan and Zarate, 2013). Given the gamma bands despite the fact that they were most affected consistent previous reduced waking delta and the very distinct- by ketamine (Figure  2A–B). All the highest correlations were ive EEG state occurring in deep slow wave sleep, it is possible obtained with the theta band with Fz and Cz achieving values that sleep delta is functionally distinct from waking delta. An that would have been significant uncorrected. F4 theta was the alternative is that the increase in sleep delta (which occurs dur - only power change that was extracted as a significant predictor ing the first night after dosing) is a rebound from the immediate by the stepwise analysis, with the other high values surrounding decrease (reported here 2 hours after dosing). it. To test the structure of these adjacent values we forced F3, Fz, Our increased gamma, unlike our increased beta, is as pre- F4, F8, and Cz into a multiple regression on FQ. The total predict- dicted. It seems likely that the variations in previous results ive power of the equation as a whole was 17%, about 5% greater and between our specific findings and our predicted pattern is than F4 alone, with the bulk of the additional explanatory power due to dose- and testing-related variations (note the decrease coming from a unique contribution (3%) from the contralateral in gamma at 0.25 mg) but could also be due to our use of a par - site F3. Of the remaining 14%, 9% was variance shared among Fz, ticular patient population (GAD/SAD) and also our small sample F4, F8, and Cz and 5% was unique to F4, with F8 and Cz having number. Other limitations include the lack of a placebo control no unique contribution. These results are consistent with the group, although there was an active control group; while we bulk of the effect of ketamine on FQ being mediated by a single obtained blood levels of drug, they were not analyzed. Further source close to F4, with some spread of activity to the immedi- work with carefully matched healthy controls is required to clar - ately adjacent electrodes, and a weak contribution from an inde- ify these points. However, if we take our data at face value, they pendent source in a similar location in the opposite hemisphere. 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. Discussion Our observation of reduced theta power is consistent with Our main finding is that ketamine produced a dose-related some previous reports and opposite to others. There is a sug- decrease, maximal at 0.5 mg, in theta frequency frontal power at gestion in Figure 2 that the theta decrease is greater at F8 than the right frontal site F4 that appears to mediate its therapeutic other sites, and so the variable results reported in this band effects on GAD and SAD, as measured by the FQ. Similar power may depend on site of recording (Muthukumaraswamy et  al., changes in the theta range at adjacent sites appeared to be less 2015), method of testing (Kochs et  al., 1996), and the dose of involved in controlling FQ, while larger decreases in power in the ketamine. Given our inverse-U dose-response curve with the FQ delta range and large increases in power in the gamma range and the largely linear dose-response for most bands and elec- appeared to make no contribution to changes in FQ. Ketamine trode sites, our current data suggest that the observed effect produced no sign of an improvement in HFD scores at any dose of ketamine most likely to be related to its therapeutic effect and no systematic or reliable changes in FAA. Reduced anxiety is at right frontal sites, particularly F4. Critically, F4 is the only has previously been reported with ketamine (Glue et  al., 2017; site for which we have clear evidence that changes in the theta Taylor et al., 2018); however, we saw significant changes only in band (and no other) relate to FQ changes. Despite large dose- FQ and no large changes in HAM-A scores. related changes in power in the delta and gamma bands, there Our alpha asymmetry results are against our prediction but was no evidence that these changes were linked to therapeutic not entirely surprising. FAA has previously been linked to av -er action (as opposed, say, to residual effects of dissociation). sion/withdrawal/pessimism/introversion in general (Wacker A much larger sample and much more detailed analysis would et al., 2010; De Pascalis et al., 2013W ; acker, 2017) and not depres- be needed to confirm these observations. sion or anxiety (Bruder et al., 1997 Mathersul et  ; al., 2008 Adolph ; Our recently developed human anxiolytic biomarker and Margraf, 2017) in particular. It shows a trait-like reliability (McNaughton, 2017), goal-conflict rhythmicity, is obtained and stability that (over months) is not related to changes in in the theta (spreading to alpha1) band at right frontal sites depressed state in patients with major depression (Debener (McNaughton et al., 2013Shadli et  ; al., 2015). It is possible, there- et al., 2000; Allen et al., 2004) and may be a predictor of future fore, that the therapeutic effects reported with ketamine here disorder rather than a biomarker of current disorder (Smith and reflect an action on the same brain system, which is potentially Bell, 2010). homologous with the rodent theta that is a uniquely reliable test Our fractal dimension results are also against our predic- of anxiolytic action (McNaughton et  al., 2007) and is known to tion. This measure has so far been linked only to depression be reduced by ketamine (Engin et al., 2009). However, in healthy (Bachmann et  al., 2013; Akar et  al., 2015), and it is possible humans and rats, this biomarker has been defined by conven- that it is specifically linked to this rather than more gener - tional anxiolytics given in single, low, doses. In our GAD and ally linked to the neurotic spectrum. This may also be true of SAD patients, MDZ had little effect on rhythmicity and no effect alpha asymmetry (Gordon et al., 2010). Alternatively, like alpha at all on theta at right frontal sites. This lack of effect could be Downloaded from https://academic.oup.com/ijnp/article-abstract/21/8/717/4989167 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Shadli et al. | 723 an explanation of the patients’ resistance to such treatments. quantitative electroencephalographic study. Biol Psychiatry However, it is just as likely that ketamine in the current experi- 41:939–948. ments is acting on a quite distinct right frontal system, which Chouvarda I, Michail E, Kokonozi A, Staner L, Domis N, also requires theta-frequency rhythmicity, to that activated by Maglaveras N (2009) Investigation of sleepiness induced by our existing biomarker paradigm insomnia medication treatment and sleep deprivation. In: We have reported a dose-related effect of ketamine on rat- Foundations of augmented cognition. Neuroergonomics and ings of anxiety and EEG recordings in patients with treatment operational neuroscience: 5th International Conference, FAC refractory anxiety disorders. In particular, we found that right 2009 held as part of HCI International 2009 San Diego, CA, frontal slow-wave (theta) EEG changes predicted reduced inten- USA, July 19–24, 2009 Proceedings (Schmorrow DD, Estabrooke sity of phobic anxiety ratings. These novel double-blind findings IV, Grootjen M, eds), pp120–127. Berlin, Heidelberg: Springer in patients are consistent with earlier preclinical and human Berlin Heidelberg. data that link diverse anxiolytic treatments with right frontal Debener S, Beauducel A, Nessler D, Brocke B, Heilemann H, EEG changes, which may represent a plausible biomarker of Kayser J (2000) Is resting anterior EEG alpha asymmetry a anxiolytic action. trait marker for depression? Findings for healthy adults and clinically depressed patients. Neuropsychobiology 41:31–37. de la Salle S, Choueiry J, Shah D, Bowers H, McIntosh J, Ilivitsky V, Acknowledgments Knott V (2016) Effects of ketamine on resting-state EEG activ- ity and their relationship to perceptual/dissociative symp- Shabah Shadli was supported by funding from the Health Research Council of New Zealand (14/129). toms in healthy humans. Front Pharmacol 7:348. De Pascalis V, Cozzuto G, Caprara GV, Alessandri G (2013) Relations among EEG-alpha asymmetry, BIS/BAS, and dispo- Statement of Interest sitional optimism. Biol Psychol 94:198–209. Domino EF, Chodoff P, Corssen G (1965) Pharmacologic effects of The authors declare the following potential conflicts of inter - CI-581, a new dissociative anesthetic, in man. Clin Pharmacol est: P.  Glue has a contract with Douglas Pharmaceuticals to Ther 6:279–291. develop novel ketamine formulations. Within the last 3  years, Duncan WC Jr, Zarate CA Jr (2013) Ketamine, sleep, and depres- P. Glue has participated in an advisory board for Janssen Pharma sion: current status and new questions. Curr Psychiatry Rep and N. McNaughton has had a confidential disclosure and con- 15:394. sulting agreement with Janssen Research & Development, LLC. Engin E, Treit D, Dickson CT (2009) Anxiolytic- and antidepres- The other authors declare no potential conflicts of interest with sant-like properties of ketamine in behavioral and neuro- respect to the research, authorship, and/or publication of this physiological animal models. Neuroscience 161:359–369. article. 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