P.3.020 How ketamine changes the neurophysiology of depressive patients' brains: a randomised controlled trial

Clinical neuropsychopharmacology P.3.020 How ketamine changes the neurophysiology of depressive patients’ brains: a randomised controlled trial P. Sos1 ° , M. Klirova1 , M. Brunovsky2 , J. Horacek1 , T. Novak1 , B. Kohutova1 , M. Bares1 , M. Kopecek1 , 1 Prague Psychiatric Centre, Psychiatric V. Krajca3 . Clinic, Prague, Czech Republic; 2 Prague Psychiatric Centre, EEG laboratory, Prague, Czech Republic; 3 Faculty Hospital Na Bulovce, Department of Neurology, Prague, Czech Republic Objective: Administration of subanaesthetic doses of the non-competitive NMDA (N-methyl-D-aspartic acid) antagonist, ketamine hydrochloride, was found in numerous studies to lead to a rapid-onset (hours), but relatively short (days) antidepressive-like effect [1]. The maximum mood improvement within a period from 2 hours to 3 days after administration was significantly better with ketamine than with placebo. Functional imaging studies have found a consistently abnormal type of metabolism or perfusion in the dorsolateral prefrontal cortex and/or the anterior cingular cortex in depressive depression. These structures are functionally and neuroanatomically linked. Theta activity (4−8 Hz) in EEGs from prefrontal regions reflects both the activity of the dorsolateral prefrontal cortex and the projection of rhythms generated in the anterior cingulum. Increased glucose metabolism in the rostral part of the anterior cingulum (Brodmann area 24/32) before treatment is predictive of response, and hyperactivity (higher current density in the theta frequency band) in the same regions is connected with the response rate in depressive patients. These findings support the use of QEEG (quantitative electroencephalography) cordance for assessing regional cerebral activity. QEEG cordance combines complementary information from absolute and relative EEG spectra in an algorithm that was developed in the mid-1990s by Leuchter and Cook at UCLA (University of California, Los Angeles). The cordance value correlates much better with regional cerebral perfusion and metabolism than other QEEG indicators. Previous studies have demonstrated the predictive value of prefrontal QEEG cordance reduction in depressive patients treated with different antidepressants. Congruently with previous findings we hypothesised in our compressed model that a decrease of prefrontal QEEG theta cordance in 10 minutes of ketamine hydrochloride infusion is predictive of antidepressant response the following day. Methods: 14 patients with depressive disorder (6 female, 8 male) diagnosed with a moderate to severe depressive episode without psychotic symptoms (F32.1, F32.2 according to ICD-10) were included. All participants received a single 30-minute infusion with a subanaesthetic

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dose of ketamine hydrochloride solution (0.54 mg/kg). Depressive symptoms and overall clinical state were ˚ assessed using MADRS (Montgomery–Asberg Depression Rating Scale) and BDI (Beck Depression Inventory). Response to treatment was defined as a 50% reduction of MADRS scores. EEG measurements at baseline and after 10 and 30 minutes of infusion were used to compute prefrontal QEEG theta cordance. Results: Nine subjects (64.3%) showed a response the day after a single ketamine hydrochloride infusion. 88.9% (8) of the responders had decreased prefrontal QEEG theta cordance. Repeated measures ANOVA found no significance (F2.36; df = 2.24; p < 0.11); however, in subsequent pair comparisons a significant difference was found between cordance values at baseline and after 10 minutes of ketamine infusion in responders (F = 4.12; p < 0.003) without correction for repeated measures. Conclusions: Preliminary results suggest that a decrease in prefrontal QEEG cordance during infusion is predictive of response to ketamine hydrochloride. A larger sample size is needed for assessing the sensitivity and specificity of cordance values. The combination of the latest QEEG method with the fast-acting antidepressantlike effect of ketamine in this trial is unprecedented. Reference(s) [1] Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 2000;47(4):351–354. [2] Leuchter AF, Cook IA, Lufkin RB, Dunkin J, Newton TF, Cummings JL, et al. Cordance: a new method for assessment of cerebral perfusion and metabolism using quantitative electroencephalography. Neuroimage 1994;1(3):208–219. [3] Bares M, Brunovsky M, Novak T, Kopecek M, Stopkova P, Sos P, et al. The change of prefrontal QEEG theta cordance as a predictor of response to bupropion treatment in patients who had failed to respond to previous antidepressant treatments. European Neuropsychopharmacology 2010.