EEG-vigilance regulation is associated with and predicts ketamine response in major depressive disorder.

Ketamine offers promising new therapeutic options for difficult-to-treat depression. The efficacy of treatment response, including ketamine, has been intricately linked to EEG measures of vigilance. This research investigated the interplay between intravenous ketamine and alterations in brain arousal, quantified through EEG vigilance assessments in two distinct cohorts of depressed patients (original dataset: n = 24; testing dataset: n = 24). Clinical response was defined as a decrease from baseline of >33% on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 h after infusion. EEG recordings were obtained pre-, start-, end- and 24 h post- infusion, and the resting EEG was automatically scored using the Vigilance Algorithm Leipzig (VIGALL). Relative to placebo (sodium chloride 0.9%), ketamine increased the amount of low-vigilance stage B1 at end-infusion. This increase in B1 was positively related to serum concentrations of ketamine, but not to norketamine, and was independent of clinical response. In contrast, treatment responders showed a distinct EEG pattern characterized by a decrease in high-vigilance stage A1 and an increase in low-vigilance B2/3, regardless of whether placebo or ketamine had been given. Furthermore, pretreatment EEG differed between responders and non-responders with responders showing a higher percentage of stage A1 (53% vs. 21%). The logistic regression fitted on the percent of A1 stages was able to predict treatment outcomes in the testing dataset with an area under the ROC curve of 0.7. Ketamine affects EEG vigilance in a distinct pattern observed only in responders. Consequently, the percentage of pretreatment stage A1 shows significant potential as a predictive biomarker of treatment response.Clinical Trials Registration: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000952-17/CZ Registration number: EudraCT Number: 2013-000952-17.

Glutamatergic abnormalities in the pregenual anterior cingulate cortex in obsessive-compulsive disorder using magnetic resonance spectroscopy: A controlled study.

In this study, we utilized proton magnetic resonance spectroscopy (MRS) to understand the role of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA) of OCD patients in the pregenual anterior cingulate cortex (pgACC). In total, 54 patients with OCD and 54 healthy controls (HC) matched for age and sex were included in the study. They underwent MRS in the pgACC region to calculate the concentrations of Glu, Gln, GABA, and Glu + Gln (Glx). After quality control of the MRS data, 21 OCD and 21 HC were statistically analyzed. The severity of symptoms were evaluated using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). In the statistical analysis, we compared differences between groups for the metabolites; in the OCD we analyzed the correlations with symptom severity, medication status, age, and duration of illness. A significant decrease in Glx, in Glu, and in Gln in the pgACC were observed in the OCD compared to HC. The correlation statistics showed a significant positive correlation between Glu levels and the YBOCS compulsions subscale. The results indicate that patients with OCD present a disturbance in glutamatergic metabolism in the pgACC. The results also demonstrate that these changes correlate with the severity of compulsions.

Spectroscopic abnormalities in the pregenual anterior cingulate cortex in obsessive-compulsive disorder using proton magnetic resonance spectroscopy: a controlled study.

BACKGROUND: The main aim of the present study is to determine the role of metabolites observed using proton magnetic resonance spectroscopy (1H-MRS) in obsessive-compulsive disorder (OCD). As the literature describing biochemical changes in OCD yields conflicting results, we focused on accurate metabolite quantification of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline-containing compounds (tCh), and myo-inositol (mI) in the anterior cingulate cortex (ACC) to capture the small metabolic changes between OCD patients and controls and between OCD patients with and without medication. METHODS: In total 46 patients with OCD and 46 healthy controls (HC) matched for age and sex were included in the study. The severity of symptoms in the OCD was evaluated on the day of magnetic resonance imaging (MRI) using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Subjects underwent 1H-MRS from the pregenual ACC (pgACC) region to calculate concentrations of tNAA, tCr, tCho, and mI. Twenty-eight OCD and 28 HC subjects were included in the statistical analysis. We compared differences between groups for all selected metabolites and in OCD patients we analyzed the relationship between metabolite levels and symptom severity, medication status, age, and the duration of illness. RESULTS: Significant decreases in tCr (U = 253.00, p = 0.022) and mI (U = 197.00, p = 0.001) in the pgACC were observed in the OCD group. No statistically significant differences were found in tNAA and tCho levels; however, tCho revealed a trend towards lower concentrations in OCD patients (U = 278.00, p = 0.062). Metabolic concentrations showed no significant correlations with the age and duration of illness. The correlation statistics found a significant negative correlation between tCr levels and YBOCS compulsions subscale (cor = -0.380, p = 0.046). tCho and YBOCS compulsions subscale showed a trend towards a negative correlation (cor = -0.351, p = 0.067). Analysis of subgroups with or without medication showed no differences. CONCLUSIONS: Patients with OCD present metabolic disruption in the pgACC. The decrease in tCr shows an important relationship with OCD symptomatology. tCr as a marker of cerebral bioenergetics may also be considered as a biomarker of the severity of compulsions. The study failed to prove that metabolic changes correlate with the medication status or the duration of illness. It seems that a disruption in the balance between these metabolites and their transmission may play a role in the pathophysiology of OCD.

Underlying pharmacological mechanisms of psilocin-induced broadband desynchronization and disconnection of EEG in rats.

Introduction: Psilocybin is one of the most extensively studied psychedelic drugs with a broad therapeutic potential. Despite the fact that its psychoactivity is mainly attributed to the agonism at 5-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A receptors and indirectly modulates the dopaminergic system. Psilocybin and its active metabolite psilocin, as well as other serotonergic psychedelics, induce broadband desynchronization and disconnection in EEG in humans as well as in animals. The contribution of serotonergic and dopaminergic mechanisms underlying these changes is not clear. The present study thus aims to elucidate the pharmacological mechanisms underlying psilocin-induced broadband desynchronization and disconnection in an animal model. Methods: Selective antagonists of serotonin receptors (5-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 and 5-HT receptor antagonist, were used in order to clarify the underlying pharmacology. Results: Psilocin-induced broadband decrease in the mean absolute EEG power was normalized by all antagonists and antipsychotics used within the frequency range 1-25 Hz; however, decreases in 25-40 Hz were influenced only by clozapine. Psilocin-induced decrease in global functional connectivity and, specifically, fronto-temporal disconnection were reversed by the 5-HT2A antagonist while other drugs had no effect. Discussion: These findings suggest the involvement of all three serotonergic receptors studied as well as the role of dopaminergic mechanisms in power spectra/current density with only the 5-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics.

Psilocybin intoxication did not affect daytime or sleep-related declarative memory consolidation in a small sample exploratory analysis.

Psilocybin is investigated as a fast-acting antidepressant used in conjunction with psychotherapy. Intact cognitive functions, including memory, are one of the basic conditions of effective psychedelic-assisted therapy. While cognitive and memory processing is attenuated on various domains during psilocybin intoxication, the effect of psilocybin on the consolidation of memories learned outside of acute intoxication is not known. Thus the main aim of the current study was to test the effects of psilocybin on (A) memory consolidation of previously learned material just after the psilocybin session and (B) on overnight memory consolidation the night just after the psilocybin session. 20 healthy volunteers (10 M/10F) were enrolled in a placebo-controlled, double-blind, cross-over design. Effects on declarative memory consolidation in condition (A) The Groton Maze Learning Task and Rey Auditory Verbal Learning Test were used, and for (B) the Pair Associative Learning Test was used. We did not find psilocybin to improve memory consolidation. At the same time, we did not find psilocybin to negatively affect memory consolidation in any of the tests used. This evidence adds to the safety profile for the use of psilocybin.

Retrospective analysis of quantitative electroencephalography changes in a dissimulating patient after dying by suicide: A single case report.

We present the case of a 49-year-old man who was diagnosed with depressive disorder, with the first episode having a strong reactive factor. He was involuntarily admitted to a psychiatric hospital after a failed attempt at taking his own life, where he responded to psychotherapy and antidepressant therapy, as evidenced by a >60% reduction in his MADRS total score. He was discharged after 10 days of treatment, denied having suicidal ideations, and was motivated to follow the recommended outpatient care. The risk for suicide during hospitalization was also assessed using suicide risk assessment tools and psychological assessments, including projective tests. The patient underwent a follow-up examination with an outpatient psychiatrist on the 7th day after discharge, during which the suicide risk assessment tool was administered. The results indicated no acute suicide risk or worsening of depressive symptoms. On the 10th day after discharge, the patient took his own life by jumping out of the window of his flat. We believe that the patient had dissimulated his symptoms and possessed suicidal ideations, which were not detected despite repeated examinations specifically designed to assess suicidality and depression symptoms. We retrospectively analyzed his quantitative electroencephalography (QEEG) records to evaluate the change in prefrontal theta cordance as a potentially promising biomarker of suicidality, given the inconclusive results of studies published to date. An increase in prefrontal theta cordance value was found after the first week of antidepressant therapy and psychotherapy in contrast to the expected decrease due to the fading of depressive symptoms. As demonstrated by the provided case study, we hypothesized that prefrontal theta cordance may be an EEG indicator of a higher risk of non-responsive depression and suicidality despite therapeutic improvement.

The effect of low-frequency rTMS on auditory hallucinations, EEG source localization and functional connectivity in schizophrenia.

BACKGROUND: Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) diminishes auditory hallucinations (AHs). The aims of our study were a) to assess the efficacy of LF-rTMS in a randomized, sham-controlled double-blind alignment, b) to identify the electrophysiological changes accompanying the LF-rTMS, and c) to identify the influence of LF-rTMS on brain functional connectivity (FC). METHODS: Nineteen schizophrenia patients with antipsychotic-resistant AHs were randomized to either active (n = 10) or sham (n = 9) LF-rTMS administered over the left temporo-parietal region for ten days. The clinical effect was assessed by the Auditory Hallucination Rating Scale (AHRS). The localization of the differences in electrical activity was identified by standardized low resolution brain electromagnetic tomography (sLORETA) and FC was measured by lagged phase synchronization. RESULTS: AHRS scores were significantly improved for patients receiving active rTMS compared to the sham (median reduction: 40 % vs 12 %; p = 0.01). sLORETA revealed a decrease of alpha-2, beta-1,-2 bands in the left hemisphere in the active group. Active rTMS led to a decrease of the lagged phase connectivity in beta bands originating in areas close to the site of stimulation, and to a prevailing increase of alpha-2 FC. No significant differences in current density or FC were observed in the sham group. LIMITATIONS: Limitations to our study included the small group sizes, and the disability of LORETA to assess subcortical neuronal activity. CONCLUSIONS: LF-rTMS attenuated AHs and induced a decrease of higher frequency bands on the left hemisphere. The FC changes support the assumption that LF-rTMS is linked to the modulation of cortico-cortical coupling.

Psychosocial Impact of Huntington's Disease and Incentives to Improve Care for Affected Families in the Underserved Region of the Slovak Republic.

INTRODUCTION: Huntington's disease (HD) is often on the margin of standard medical practice due to its low prevalence, the lack of causal treatment, and the typically long premanifest window prior to the onset of the symptoms, which contrasts with the long-lasting burden that the disease causes in affected families. METHODS: To capture these socio-psychological aspects of HD and map the experiences of affected individuals, persons at risk of HD, and caregivers, we created a questionnaire using a qualitative research approach. The questionnaire containing 16 questions was conducted online for a period of three months through patient associations in Slovakia and their infrastructures. RESULTS: In total, we received 30 responses. The survey results, in particular, indicate insufficient counselling by physicians with explicitly missing information about the possibility of preimplantation genetic diagnostic. There was also a necessity to improve comprehensive social and health care in the later stages of the disease, raise awareness of the disease in the general health community, and provide more information on ongoing clinical trials. CONCLUSION: The psychosocial effects, as well as the burden, can be mitigated by comprehensive genetic counselling as well as reproductive and financial guidelines and subsequent therapeutic programs to actively support patients, caregivers, children, and adolescents growing up in affected families, preferably with the help of local HD community association. LIMITATIONS: We have used online data collection to reach a wider HD community, but at the same time, we are aware that the quality of the data we would obtain through face-to-face interviews would be considerably better. Therefore, future studies need to be conducted to obtain more detailed information.

Psilocybin-Mediated Attenuation of Gamma Band Auditory Steady-State Responses (ASSR) Is Driven by the Intensity of Cognitive and Emotional Domains of Psychedelic Experience.

Psilocybin is a classical serotoninergic psychedelic that induces cognitive disruptions similar to psychosis. Gamma activity is affected in psychosis and is tightly related to cognitive processing. The 40 Hz auditory steady-state responses (ASSR) are frequently used as indicators to test the ability to generate gamma activity. Based on previous literature, we studied the impact of psilocybin on 40 Hz ASSR in healthy volunteers. The study was double blind and placebo controlled with a crossover design. A sample of 20 healthy subjects (10M/10F) received psilocybin orally 0.26 mg/kg or placebo. Participants were measured four times in total, one time before ingestion of psilocybin/placebo and one time after ingestion, during the peak of intoxication. A series of 500 ms click trains were used for stimulation. Psilocybin induced a psychedelic effect and decreased 40 Hz ASSR phase-locking index compared to placebo. The extent of the attenuation was related to Cognition and Affect on the Hallucinogen Rating Scale. The current study shows that psilocybin lowers the synchronization level and the amplitude of 40 Hz auditory steady-state responses, which yields further support for the role of gamma oscillations in cognitive processing and its disturbance.

Apnea Detection in Polysomnographic Recordings Using Machine Learning Techniques.

Sleep disorders are diagnosed in sleep laboratories by polysomnography, a multi-parameter examination that monitors biological signals during sleep. The subsequent evaluation of the obtained records is very time-consuming. The goal of this study was to create an automatic system for evaluation of the airflow and SpO2 channels of polysomnography records, through the use of machine learning techniques and a large database, for apnea and desaturation detection (which is unusual in other studies). To that end, a convolutional neural network (CNN) was designed using hyperparameter optimization. It was then trained and tested for apnea and desaturation. The proposed CNN was compared with the commonly used k-nearest neighbors (k-NN) method. The classifiers were designed based on nasal airflow and blood oxygen saturation signals. The final neural network accuracy for apnea detection reached 84%, and that for desaturation detection was 74%, while the k-NN classifier reached accuracies of 83% and 64% for apnea detection and desaturation detection, respectively.

Electrophysiological correlates of suicidality.

Suicidal risk assessment is still a major challenge not only in psychiatric practice. Clinical investigation of suicidality can be significantly improved by using standardized scales for assessing suicide risk. The choice of a method for assessing suicidality also has significant implications for the search of valid available biomarker of suicidal behavior, where a less complex suicidality assessment procedure yields inaccurate results. This article offers an overview and analyzes in detail clinical studies of suicidality by electrophysiological methods since 2005 to 5/2020, especially in connection with presumed pathophysiological mechanism of the "suicidal brain" and the chosen method of sucidality assessment. Electrophysiological methods such as quantitative electroencephalography indicators, event-related potential, loudness dependence of the auditory evoked potential, polysomnography and heart rate variability offer a robust battery of easily available methods for assessing impaired emotional regulation. Nowadays it is unfortunately very difficult to point out the optimal electrophysiological examination of suicidal behaviour because of conflicting conclusion of presented studies which have been probably caused by various suicidal risk assessments, not always available data on affecting medication prior to testing and small samples of suicidal participants among studies. The most consistent and hopeful results are presented by evaluation of theta power by quantitative electroencephalography, although there are also few conflicting conclusions. The authors of this paper believe that this article could be good starting point for further research of electrophysiological methods in the field of suicidality.

Is short-term memory capacity (7±2) really predicted by theta to gamma cycle length ratio?

Several studies suggest that EEG parameters, reflecting top-down processes in the brain, may predict cognitive performance, e.g. short-term memory (STM) capacity. According to Lisman and Idiart's model, STM capacity is predicted by theta and gamma EEG waves and their ratio. This model suggests that the more periods of gamma band waves fit into one period of theta band waves, the more information can be stored. We replicated the study by Kaminski et al. (2011), which recorded spontaneous EEG activity and measured verbal STM capacity with a modified digit span task from the Wechsler battery. Our study included more subjects and two EEG recording sessions. We discuss the possible limits of EEG correlates of STM capacity as EEG parameters were not stable across the two measurements and no correlation was found between the theta/gamma ratio and performance in the digit span task.

Predictive value of heart rate in treatment of major depression with ketamine in two controlled trials.

OBJECTIVE: Ketamine has been shown to be effective in treatment of episodes of major depressive disorder (MDD). This controlled study aimed to analyse the predictive and discriminative power of heart rate (HR) and heart rate variability (HRV) for ketamine treatment in MDD. METHODS: In 51 patients, HR and HRV were assessed at baseline before and during ketamine infusion and 24 hours post ketamine infusion. Montgomery-Åsberg Depression Rating Scale (MADRS) was used to assess changes of depressive symptoms. A 30% or 50% reduction of symptoms after 24 hours or within 7 days was defined as response. A linear mixed model was used for analysis. RESULTS: Ketamine infusion increased HR and HRV power during and after infusion. Responders to ketamine showed a higher HR during the whole course of investigation, including at baseline with medium effect sizes (Cohen's d = 0.47-0.67). Furthermore, HR and HRV power discriminated between responders and non-responders, while normalized low and high frequencies did not. CONCLUSION: The findings show a predictive value of HR and HRV power for ketamine treatment. This further underlines the importance of the autonomous nervous system (ANS) and its possible malfunctions in MDD. SIGNIFICANCE: The predictive power of HR and HRV markers should be studied in prospective studies. Neurophysiological markers could improve treatment for MDD via optimizing the choice of treatments.

Special Report on the Impact of the COVID-19 Pandemic on Clinical EEG and Research and Consensus Recommendations for the Safe Use of EEG.

INTRODUCTION: The global COVID-19 pandemic has affected the economy, daily life, and mental/physical health. The latter includes the use of electroencephalography (EEG) in clinical practice and research. We report a survey of the impact of COVID-19 on the use of clinical EEG in practice and research in several countries, and the recommendations of an international panel of experts for the safe application of EEG during and after this pandemic. METHODS: Fifteen clinicians from 8 different countries and 25 researchers from 13 different countries reported the impact of COVID-19 on their EEG activities, the procedures implemented in response to the COVID-19 pandemic, and precautions planned or already implemented during the reopening of EEG activities. RESULTS: Of the 15 clinical centers responding, 11 reported a total stoppage of all EEG activities, while 4 reduced the number of tests per day. In research settings, all 25 laboratories reported a complete stoppage of activity, with 7 laboratories reopening to some extent since initial closure. In both settings, recommended precautions for restarting or continuing EEG recording included strict hygienic rules, social distance, and assessment for infection symptoms among staff and patients/participants. CONCLUSIONS: The COVID-19 pandemic interfered with the use of EEG recordings in clinical practice and even more in clinical research. We suggest updated best practices to allow safe EEG recordings in both research and clinical settings. The continued use of EEG is important in those with psychiatric diseases, particularly in times of social alarm such as the COVID-19 pandemic.

The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action.

Serotonergic agonist psilocybin is a psychedelic with antidepressant potential. Sleep may interact with psilocybin's antidepressant properties like other antidepressant drugs via induction of neuroplasticity. The main aim of the study was to evaluate the effect of psilocybin on sleep architecture on the night after psilocybin administration. Regarding the potential antidepressant properties, we hypothesized that psilocybin, similar to other classical antidepressants, would reduce rapid eye movement (REM) sleep and prolong REM sleep latency. Moreover, we also hypothesized that psilocybin would promote slow-wave activity (SWA) expression in the first sleep cycle, a marker of sleep-related neuroplasticity. Twenty healthy volunteers (10 women, age 28-53) underwent two drug administration sessions, psilocybin or placebo, in a randomized, double-blinded design. Changes in sleep macrostructure, SWA during the first sleep cycle, whole night EEG spectral power across frequencies in non-rapid eye movement (NREM) and REM sleep, and changes in subjective sleep measures were analyzed. The results revealed prolonged REM sleep latency after psilocybin administration and a trend toward a decrease in overall REM sleep duration. No changes in NREM sleep were observed. Psilocybin did not affect EEG power spectra in NREM or REM sleep when examined across the whole night. However, psilocybin suppressed SWA in the first sleep cycle. No evidence was found for sleep-related neuroplasticity, however, a different dosage, timing, effect on homeostatic regulation of sleep, or other mechanisms related to antidepressant effects may play a role. Overall, this study suggests that potential antidepressant properties of psilocybin might be related to changes in sleep.

Simultaneous fMRI-EEG-Based Characterisation of NREM Parasomnia Disease: Methods and Limitations.

Functional magnetic resonance imaging (fMRI) techniques and electroencephalography (EEG) were used to investigate sleep with a focus on impaired arousal mechanisms in disorders of arousal (DOAs). With a prevalence of 2-4% in adults, DOAs are significant disorders that are currently gaining attention among physicians. The paper describes a simultaneous EEG and fMRI experiment conducted in adult individuals with DOAs (n=10). Both EEG and fMRI data were validated by reproducing well established EEG and fMRI associations. A method for identification of both brain functional areas and EEG rhythms associated with DOAs in shallow sleep was designed. Significant differences between patients and controls were found in delta, theta, and alpha bands during awakening epochs. General linear models of the blood-oxygen-level-dependent signal have shown the secondary visual cortex and dorsal posterior cingulate cortex to be associated with alpha spectral power fluctuations, and the precuneus with delta spectral power fluctuations, specifically in patients and not in controls. Future EEG-fMRI sleep studies should also consider subject comfort as an important aspect in the experimental design.

Predicting Sex From EEG: Validity and Generalizability of Deep-Learning-Based Interpretable Classifier.

Explainable artificial intelligence holds a great promise for neuroscience and plays an important role in the hypothesis generation process. We follow-up a recent machine learning-oriented study that constructed a deep convolutional neural network to automatically identify biological sex from EEG recordings in healthy individuals and highlighted the discriminative role of beta-band power. If generalizing, this finding would be relevant not only theoretically by pointing to some specific neurobiological sexual dimorphisms, but potentially also as a relevant confound in quantitative EEG diagnostic practice. To put this finding to test, we assess whether the automatic identification of biological sex generalizes to another dataset, particularly in the presence of a psychiatric disease, by testing the hypothesis of higher beta power in women compared to men on 134 patients suffering from Major Depressive Disorder. Moreover, we construct ROC curves and compare the performance of the classifiers in determining sex both before and after the antidepressant treatment. We replicate the observation of a significant difference in beta-band power between men and women, providing classification accuracy of nearly 77%. The difference was consistent across the majority of electrodes, however multivariate classification models did not generally improve the performance. Similar results were observed also after the antidepressant treatment (classification accuracy above 70%), further supporting the robustness of the initial finding.

The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication.

The rapid antidepressant effect of ketamine has become a breakthrough in the research and treatment of depression. Although predictive and modulating factors of the response to ketamine are broadly studied, little is known about optimal concurrent medication protocols. Concerning gamma-aminobutyric acid neurotransmission being a shared target for both ketamine and benzodiazepines (BZD), we evaluated the influence of BZD on the antidepressant effect of a single ketamine infusion in depressed patients. Data from 47 patients (27 females) with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) who participated in two previous studies (EudraCT Number: 2009-010625-39 and 2013-000952-17) entered the analysis. All of the subjects were given an infusion of a subanesthetic dose of racemic ketamine (0.54 mg per kg) as an add-on medication to ongoing antidepressant treatment. Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis. The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001). RM-ANOVA revealed a different time pattern of response to ketamine between the BZD+ (>8mg of DZ equivalent) and BZD- (≤8mg of DZ equivalent) groups, with a significantly worse outcome in BZD+ on day 3 (p=0.04) and day 7 (p=0.02). The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine's antidepressant effect. The pathophysiological, clinical and methodological implications of this finding should be considered in future research and ketamine treatment.