GABAergic Effects of Etifoxine and Alprazolam Assessed by Double Pulse TMS.

INTRODUCTION: There is a need for novel anxiolytics with improved side effect profiles compared to benzodiazepines. A promising candidate with alternative pharmacodynamics is the translocator protein ligand, etifoxine. METHODS: To get further insight into its mechanisms of action and side effects compared to the benzodiazepine alprazolam, we performed a double-blind, placebo-controlled, repeated-measures study in 36 healthy male subjects. Participants were examined for trait anxiety and side effects and underwent repeated transcranial magnetic stimulation (TMS) assessments, including motor evoked potentials (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). RESULTS: We observed attenuation of MEPs by alprazolam but not by etifoxine. SICI was not significantly affected by alprazolam or etifoxine. However, the response pattern indicated a lowered SICI threshold after the administration of etifoxine and alprazolam compared to the placebo. ICF and CSP were influenced by neither medication. Alprazolam led to higher sedation and subjective impairment of concentration compared to etifoxine. Individual anxiety trait scores did not affect TMS parameters. DISCUSSION: This study indicated a favorable side effect profile of etifoxine in healthy volunteers. Moreover, it revealed differential GABA-related effects on neuromuscular function by means of TMS. The side effects and TMS profile of etifoxine are compatible with the involvement of neurosteroidogenesis and a predominant α3 subunit modulation compared to alprazolam.

The Many Faces of Sleep Disorders in Post-Traumatic Stress Disorder: An Update on Clinical Features and Treatment.

Sleep disorders and nightmares are core symptoms of post-traumatic stress disorder (PTSD). The relationship seems to be bidirectional, and persistent disturbed sleep may influence the course of the disorder. With regard to sleep quality, insomnia and nocturnal anxiety symptoms, as well as nightmares and stressful dreams, are the most prominent sleep symptoms. Polysomnographic measurements reveal alterations of the sleep architecture and fragmentation of rapid eye movement sleep. In addition, sleep disorders, such as sleep-related breathing disorders and parasomnias are frequent comorbid conditions. The complex etiology and symptomatology of trauma-related sleep disorders with frequent psychiatric comorbidity require the application of multimodal treatment concepts, including psychological and pharmacological interventions. However, there is little empirical evidence on the effectiveness of long-term drug treatment for insomnia and nightmares. For nondrug interventions, challenges arise from the current lack of PTSD-treatment concepts integrating sleep- and trauma-focused therapies. Effective therapy for sleep disturbances may consequently also improve well-being during the day and probably even the course of PTSD. Whether early sleep interventions exert a preventive effect on the development of PTSD remains to be clarified in future studies.

Association of Chemokine (C-C Motif) Receptor 5 and Ligand 5 with Recovery from Major Depressive Disorder and Related Neurocognitive Impairment.

INTRODUCTION: Inflammatory processes play an important role in the pathophysiology of major depressive disorder (MDD), but their relevance for specific symptoms such as neurocognitive impairment is rarely investigated. METHODS: In this observational study, we investigated the changes of leukocyte chemokine (C-C motif) receptor 5 (CCR5) and ligand 5 (CCL5) mRNA levels and inflammatory cytokines in 60 MDD patients before (PRE) and after 5 weeks (W5) of antidepressive treatment in relation to therapy response and alterations in cognitive functions by means of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We hypothesized that elevated CCR5 and CCL5 levels in depressed patients would decrease upon treatment and could differ with regard to cognitive impairment associated with MDD. RESULTS: Both CCR5 and CCL5 levels were significantly decreased in the responder group compared to nonresponders even before treatment. The cytokine IL-6 as a marker of inflammation in depression did not show a difference before treatment in future responders versus nonresponders, but decreased significantly upon antidepressive therapy. Regarding neurocognitive impairment in MDD patients, an increased misperception of the emotion "anger" after 5 weeks of treatment proved to be associated with a more pronounced change in CCR5, and the perception of the emotion "disgust" became faster along with a stronger decrease in CCL5 over the same time. Executive functions typically impaired in MDD patients were not markedly associated with alterations in CCR5/CCL5. DISCUSSION: CCR5 and CCL5 are important in the targeting of immune cells by HIV. This is the first study providing valuable hints that both CCR5 and CCL5 might also serve as markers of therapy response prediction in MDD. Regarding neurocognitive impairment in depression, CCR5 and CCL5 did not reveal characteristic changes upon MDD treatment such as executive functions, which are probably delayed. However, changes of emotional perception appear to be an earlier responding feature.

Sleep apnea syndrome comorbid with and without restless legs syndrome: differences in insomnia specific symptoms.

OBJECTIVE: Sleep Apnea Syndrome (SAS) is frequently comorbid with Restless Legs Syndrome (RLS). Both disorders are associated with disturbed sleep. However, data about insomnia specific symptoms in patients suffering from both sleep disorders (SAS-RLS) are rare. METHODS: In a restrospective design, we investigated 202 patients suffering from SAS and SAS-RLS. All patients underwent polysomnography, performed a vigilance test (Quatember-Maly), and completed the Regensburg Insomnia Scale (RIS), Epworth Sleepiness Scale (ESS), Beck Depression Inventory-II (BDI-II), and a Morning Questionnaire (FZN). Differences in insomnia specific symptoms between SAS and SAS-RLS were calculated using ANOVA. In a secondary analysis, the differences in daytime sleepiness and depression were analyzed. RESULTS: Of 202 patients, 42 (21%) had SAS-RLS. The proportion of women (60%) with SASRLS was higher than for men (40%) while men had had a higher proportion (71%) of SAS alone compared to women (29%), p < 0.0005. The RIS score was higher in SAS-RLS than in SAS. No differences were found in PSG data, ESS, BDI-II, or vigilance tests. CONCLUSIONS: Patients with both disorders SAS and RLS show a higher degree of insomnia-specific symptoms than for SAS alone and may profit from additional insomnia specific treatment.

[Internet-based cognitive behavioral therapy of insomnia and nightmare disorder]. / Internetbasierte kognitive Verhaltenstherapie der Insomnie und Albtraumstörung.

Cognitive behavioral therapeutic interventions are considered to be one of the most effective forms of treatment of various mental disorders. Besides being very frequent, sleep disorders, such as insomnia and nightmare disorder are often not treated effectively and guideline-conform, mainly due to the lack of qualified psychotherapists. Implementation of modern technical options, such as web-based psychotherapy can help to overcome this problem. This article presents the current situation in the treatment of insomnia and nightmare disorders as particularly well-suited fields of application. For insomnia there are several English language and also recently German language options, which for example were also evaluated for the application to work-related stress and sleep disorders. In this respect, procedures with and without contact to a therapist or multicomponent procedures and single interventions can be differentiated. For nightmare disorders imagery rehearsal therapy provides a structure, which can also easily be transferred to an internet-based therapy program. The currently beginning use of internet-based treatment of sleep disorders does not yet utilize all theoretically available technical possibilities. The potential of internet-based therapy is extremely versatile and it remains for medical sleep experts to consider which method can be used for which indications.

[Recommendations on performing polygraphy or polysomnography in the fields of psychiatry and psychotherapy : Position paper of the working group on sleep medicine of the German Association for Psychiatry, Psychotherapy and Psychosomatics]. / Empfehlungen zur Durchführung einer Polygraphie oder Polysomnographie im Bereich Psychiatrie und Psychotherapie : Positionspapier des DGPPN-Referats Schlafmedizin.

Difficulties in falling asleep and maintaining sleep, nonrestorative sleep and decreased daytime wakefulness represent very common but relatively unspecific health complaints. Around 100 specific sleep-related disorders will be classified in their own major chap. 7 (sleep wake disorders) for the first time in the upcoming 11th version of the International Classification of Diseases (ICD 11). With respect to the disciplines of psychiatry and psychotherapy there is a bidirectional relationship between mental health and sleep wake disorders. Sleep wake disorders can be an independent risk factor for the onset of a mental disorder and have a negative influence on the course of the disease. In addition, sleep wake disorders can also precede a mental disease as an early symptom and therefore be an important indication for early recognition. Many sleep wake disorders can be diagnosed based on the anamnesis and routine clinical investigations. In special cases, examination in a specialized sleep laboratory and treatment in a sleep medicine center following a staged care approach can be mandatory. Polysomnography represents the gold standard for the differential diagnostics; however, there is no legal foundation in the field of neuropsychiatric disorders for remuneration in the German healthcare system. This review summarizes the current guidelines with respect to the criteria for an investigation in a sleep laboratory from the perspective of the disciplines of psychiatry and psychotherapy. From this the requirements for guideline-conform diagnostics and treatment are derived.

The effect of partial sleep deprivation on computer-based measures of fitness to drive.

PURPOSE: Using a partial sleep deprivation paradigm, the aim of the study was to investigate the sensitivity of a computer-based test battery of fitness to drive to detect impairments related to sleepiness. METHODS: Forty-seven healthy subjects (34 females, mean age 26.0 ± 6.8 years) participated in a counterbalanced within-subject design of two conditions: (i) normal night sleep and (ii) partial sleep deprivation (PSD) with 4 h time in bed. For the assessment of fitness to drive, we used a validated traffic psychological test battery. Moreover, well-established measures of sleepiness highly responsive to sleep deprivation were applied: the Karolinska Sleepiness Scale (KSS), pupillography (Pupil Unrest Index (PUI) as physiological sleepiness indicator) and two sustained attention tasks (psychomotor Vigilance Task and Mackworth Clock Test). RESULTS: Subjective and physiological sleepiness were significantly increased after PSD, accompanied by large (d > 1.50 for KSS) and medium (d = 0.55 for PUI) effect sizes. Sleepiness-related performance decrements were found in both sustained attention tasks (d = 0.59-0.77). Assessing driving-related ability, PSD induced decrements only in the test domain Reaction Test (reaction time d = 0.54 and motor time d = 0.45). All other subtests-as well as the overall judgement of fitness to drive-were not significantly affected by PSD. CONCLUSION: In contrast to established tests of sustained attention and subjective sleepiness, computer-based test batteries of fitness to drive might lack sensitivity to core aspects of sleepiness as they mainly consist of short and stimulating subtests. Therefore, tasks that require sustained attention should be an essential part of traffic psychological test batteries when sleepiness is a potential issue.

Deep Brain Stimulation for Obsessive Compulsive Disorder Reduces Symptoms of Irritable Bowel Syndrome in a Single Patient.

Irritable bowel syndrome (IBS) is a frequent gastrointestinal disorder that is difficult to treat. We describe findings from evaluation of a woman (55 years old) with obsessive compulsive disorder, which was treated with bilateral deep brain stimulation in the anterior limb of the internal capsule, and IBS. After the brain stimulation treatment she reported substantial relief of her IBS symptoms. This reduction depended on specific stimulation parameters, was reproducible over time, and was not directly associated with improvements in obsessive compulsive disorder symptoms. These observations indicate a specific effect of deep brain stimulation on IBS. This observation confirms involvement of specific brain structures in the pathophysiology of IBS and shows that symptoms can be reduced through modulation of neuronal activity in the central nervous system. Further studies of the effects of brain stimulation on IBS are required.

Severe chronic insomnia is not associated with higher body mass index.

Short sleep duration is widely considered to be a risk factor for weight gain, suggesting that patients suffering from sleep disorders are a risk group. Despite some positive preliminary data on patients with organic sleep disorders, empirical evidence for an increased body mass index in patients with insomnia is scarce. Two-hundred and thirty-three patients with a confirmed diagnosis of severe and chronic insomnia without co-morbidity showing objectively impaired sleep quality were compared with respect to their body mass index with control data derived from a representative population survey matched in gender and age. As a result, patients with insomnia showed a lower body mass index (23.8 kg m(-2) versus 27.1 kg m(-2) ; P < 0.0005). Our findings suggest that patients with chronic insomnia do not exhibit overweight. These data are a valuable educational tool to calm patients' fears about the consequences of insomnia, and contribute to the understanding of chronically disturbed sleep and weight regulation.

Impact of overnight traffic noise on sleep quality, sleepiness, and vigilant attention in long-haul truck drivers: Results of a pilot study.

This study aimed to evaluate the impact of traffic noise along the motorway on sleep quality, sleepiness, and vigilant attention in long-haul truck drivers. This was a randomized, crossover, within-subject controlled study. Healthy long-haul truck drivers spent 6 consecutive nights in a real truck berth with full sleep laboratory equipment. During 3 nights, subjects were exposed to replayed traffic noise alongside motorways, whereas the other 3 nights were without traffic noise. Polysomnography was recorded during the nights and numerous sleepiness tests and vigilance examinations were performed during the following standardized working day. Outcome measures were compared between noisy and silent nights using the paired Wilcoxon test. Ten healthy long-haul truck drivers with a mean age of 36.3 ± 7.3 years completed the study as planned. On noisy nights, subjects had greater latencies to the rapid eye movement (REM) phase (90 ± 32 min vs 69 ± 16 min, P = 0.074) and higher percentages of sleep stage 1 (13.7 ± 5.5% vs 11.2 ± 4.4%; P = 0.059). Subjects also rated their sleep quality as having been better during nights without noise (28.1 ± 3.7 vs 30.3 ± 6.2, P = 0.092). The impact of these differences on daytime sleepiness and vigilance was rather low; however, mean Karolinska Sleepiness Scale (KSS) scores measured during the course of the following day were higher on six out of eight occasions after noisy nights. The effects of overnight traffic noise on sleep quality are detectable but unlikely to have any major impact on the vigilant attention and driving performance of long haul-truck drivers with low nocturnal noise sensitivity. This might not be true for subgroups prone to sleeping disorders.

Multimodal in-vehicle lighting system increases daytime light exposure and alertness in truck drivers under Arctic winter conditions.

Drowsiness while driving negatively impacts road safety, especially in truck drivers. The present study investigated the feasibility and alerting effects of a daylight-supplementing in-truck lighting system (DS) providing short-wavelength enriched light before, during, and after driving. In a within-participants design, eight truck drivers drove a fully-loaded truck under wintry Scandinavian conditions (low daylight levels) with a DS or placebo system for five days. Subjective and objective measures of alertness were recorded several times daily, and evening melatonin levels were recorded three times per study condition. DS significantly increased daytime light exposure without causing negative side effects while driving. In addition, no negative carry-over effects were observed on evening melatonin and sleepiness levels or on nighttime sleep quality. Moreover, objective alertness (i.e., psychomotor vigilance) before and after driving was significantly improved by bright light exposure. This effect was accompanied by improved subjective alertness in the morning. This field study demonstrated that DS was able to increase daytime light exposure in low-daylight conditions and to improve alertness in truck drivers before and after driving (e.g., during driving rest periods). Further studies are warranted to investigate the effects of daylight-supplementing in-cabin lighting on driving performance and road safety measures.

Prospective analyses of alertness, sleep, and fitness to drive one year after de novo multiple sclerosis diagnosis.

BACKGROUND: The prevalence and functional burden of the chronic demyelinating disease multiple sclerosis (MS) are well documented; however, little is known about the initial clinical course of alertness, sleep, cognitive, and psychological symptoms. OBJECTIVES: This exploratory, prospective, longitudinal study multidimensionally investigated the development and progression of alertness, sleep, fitness to drive, and psychological symptoms in the first year after de novo MS diagnosis. METHODS: Twenty-five people with MS (pwMS) were assessed cognitively, psychologically, and using polysomnography soon after diagnosis and one year later, with outcomes compared to matched healthy controls. RESULTS: In the early stage of the disease, psychological symptoms of pwMS were comparable with those of controls, and patient conditions did not deteriorate within the first disease year. A small percentage of pwMS experienced increased levels of anxiety and depression after diagnosis. Alertness, sustained attention, and fitness to drive were comparable between both groups, and fatigue levels remained low over the course of the year. CONCLUSIONS: This study highlights patient experiences within the initial clinical course of MS in a small group of patients. Further research is needed to understand the progression of symptoms and impairments in MS over a longer period and in different stages of the disease.

Effects of rapid eye movement sleep deprivation on fear extinction recall and prediction error signaling.

In a temporal difference learning approach of classical conditioning, a theoretical error signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative prediction error signal, which is the initial step towards successful extinction and may therefore be relevant for fear extinction recall. As studies in rodents have observed a bidirectional relationship between fear extinction and rapid eye movement (REM) sleep, we aimed to test the hypothesis that REM sleep deprivation impairs recall of fear extinction through prediction error signaling in humans. In a three-day design with polysomnographically controlled REM sleep deprivation, 18 young, healthy subjects performed a fear conditioning, extinction and recall of extinction task with visual stimuli, and mild electrical shocks during combined functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. Compared to the control group, the REM sleep deprivation group had increased SCR scores to a previously extinguished stimulus at early recall of extinction trials, which was associated with an altered fMRI time-course in the left middle temporal gyrus. Post-hoc contrasts corrected for measures of NREM sleep variability also revealed between-group differences primarily in the temporal lobe. Our results demonstrate altered prediction error signaling during recall of fear extinction after REM sleep deprivation, which may further our understanding of anxiety disorders in which disturbed sleep and impaired fear extinction learning coincide. Moreover, our findings are indicative of REM sleep related plasticity in regions that also show an increase in activity during REM sleep.

Low Sleep Satisfaction Is Related to High Disease Burden in Tinnitus.

Previous studies have shown a high prevalence of sleep disturbances in tinnitus patients. However, no study has yet evaluated subjective sleep satisfaction. The present study aimed to investigate associations of self-reported sleep satisfaction with sociodemographic factors, tinnitus-related distress, depression, and self-reported quality of life. This is a retrospective analysis of 2344 outpatients with tinnitus presenting at a tertiary German tinnitus clinic from 2010 to 2020. Patients who filled in five questionnaires (Tinnitus Handicap Inventory (THI), Tinnitus Questionnaire (TQ), Major Depression Inventory (MDI), Tinnitus Sample Case History Questionnaire (TSCHQ), and the World Health Organization Quality of Life Brief Version (WHOQOL-Bref)) were included. Based on the question about sleep satisfaction in the WHOQOL-Bref, group classification into (I) sleep-satisfied, (II) neither satisfied or dissatisfied, and (III) sleep-dissatisfied patients was performed. Associations between sleep satisfaction and quality of life, depression, tinnitus distress, and tinnitus characteristics were analyzed by group differences and a multinomial regression model with elastic net penalization. A total of 42.38% of patients were satisfied or very satisfied with sleep, whereas 40.91% of patients were dissatisfied or very dissatisfied with sleep. The remaining patients reported being neither satisfied nor dissatisfied with sleep. Sleep-dissatisfied patients were significantly more burdened in questionnaires on depressive symptoms (MDI), tinnitus distress (TQ, THI), and quality of life (WHOQOL-Bref). In addition, they suffered significantly more often from comorbidities such as headache, neck pain, or temporomandibular joint disorder (TMJ). The elastic net regression based on sum scores of THI, TQ, MDI, the four domains of WHOQOL-Bref, as well as all individual questions from the TSCHQ was able to classify patients satisfied with their sleep with an accuracy of 79%, 87.8% sensitivity, and 70.4% specificity. The model could not identify patients indifferent with the quality of their sleep (neither satisfied nor dissatisfied) (sensitivity: 0%; specificity: 100%). The accuracy of the model to predict patients dissatisfied with their sleep was 80.7%, with 83% sensitivity and 78.4% specificity. Poor physical and mental health (Domain I/II WHOQOL-Bref) as well as tinnitus distress were the strongest predictors of sleep dissatisfaction. Conversely, for sleep satisfaction, good physical and mental health as well as low tinnitus distress were the strongest predictors. The division into sleep-satisfied and sleep-dissatisfied tinnitus patients allows a very good discrimination regarding disease burden as indicated by depression, tinnitus distress, quality of life, and pain-related comorbidities. Physical and mental health as well as tinnitus distress seem to be strongly related to sleep satisfaction underscoring the concept of "tinnitus" versus "tinnitus disorder", but also the importance of sleep satisfaction as a global health indicator. Moreover, these data indicate the relevance of addressing sleep disorders in the therapeutic management of chronic tinnitus patients.

Restless Legs Syndrome Prevalence and Clinical Correlates Among Psychiatric Inpatients: A Multicenter Study.

Background: There are only limited reports on the prevalence of restless legs syndrome (RLS) in patients with psychiatric disorders. The present study aimed to evaluate the prevalence and clinical correlates in psychiatric inpatients in Germany and Switzerland. Methods: This is a multicenter cross-sectional study of psychiatric inpatients with an age above 18 years that were diagnosed and evaluated face-to-face using the International RLS Study Group criteria (IRLSSG) and the International RLS severity scale (IRLS). In addition to sociodemographic and biometric data, sleep quality and mood were assessed using the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Epworth Sleepiness Scale (ESS), and the Patient Health Questionnaire (PHQ-9). In addition to univariate statistics used to describe and statistically analyze differences in variables of interest between patients with and without RLS, a logistic model was employed to identify predictors for the occurrence of RLS. Results: The prevalence of RLS in a sample of 317 psychiatric inpatients was 16.4%, and 76.9% of these were diagnosed with RLS for the first time. RLS severity was moderate to severe (IRLS ± SD: 20.3 ± 8.4). The prevalences in women (p = 0.0036) and in first-degree relatives with RLS (p = 0.0108) as well as the body mass index (BMI, p = 0.0161) were significantly higher among patients with RLS, while alcohol consumption was significantly lower in the RLS group. With the exception of atypical antipsychotics, treatment with psychotropic drugs was not associated with RLS symptoms. Regarding subjective sleep quality and mood, scores of the PSQI (p = 0.0007), ISI (p = 0.0003), and ESS (p = 0.0005) were higher in patients with RLS, while PHQ-9 scores were not different. A logistic regression analysis identified gender (OR 2.67; 95% CI [1.25; 5.72]), first-degree relatives with RLS (OR 3.29; 95% CI [1.11; 9.73], ESS score (OR 1.09; 95% CI [1.01; 1.17]), and rare alcohol consumption (OR 0.45; 95% CI [0.22; 0.94] as predictors for RLS. Conclusions: Clinically significant RLS had a high prevalence in psychiatric patients. RLS was associated with higher BMI, impaired sleep quality, and lower alcohol consumption. A systematic assessment of restless legs symptoms might contribute to improve the treatment of psychiatric patients.

Rapid eye movements during sleep in mice: high trait-like stability qualifies rapid eye movement density for characterization of phenotypic variation in sleep patterns of rodents.

BACKGROUND: In humans, rapid eye movements (REM) density during REM sleep plays a prominent role in psychiatric diseases. Especially in depression, an increased REM density is a vulnerability marker for depression. In clinical practice and research measurement of REM density is highly standardized. In basic animal research, almost no tools are available to obtain and systematically evaluate eye movement data, although, this would create increased comparability between human and animal sleep studies. METHODS: We obtained standardized electroencephalographic (EEG), electromyographic (EMG) and electrooculographic (EOG) signals from freely behaving mice. EOG electrodes were bilaterally and chronically implanted with placement of the electrodes directly between the musculus rectus superior and musculus rectus lateralis. After recovery, EEG, EMG and EOG signals were obtained for four days. Subsequent to the implantation process, we developed and validated an Eye Movement scoring in Mice Algorithm (EMMA) to detect REM as singularities of the EOG signal, based on wavelet methodology. RESULTS: The distribution of wakefulness, non-REM (NREM) sleep and rapid eye movement (REM) sleep was typical of nocturnal rodents with small amounts of wakefulness and large amounts of NREM sleep during the light period and reversed proportions during the dark period. REM sleep was distributed correspondingly. REM density was significantly higher during REM sleep than NREM sleep. REM bursts were detected more often at the end of the dark period than the beginning of the light period. During REM sleep REM density showed an ultradian course, and during NREM sleep REM density peaked at the beginning of the dark period. Concerning individual eye movements, REM duration was longer and amplitude was lower during REM sleep than NREM sleep. The majority of single REM and REM bursts were associated with micro-arousals during NREM sleep, but not during REM sleep. CONCLUSIONS: Sleep-stage specific distributions of REM in mice correspond to human REM density during sleep. REM density, now also assessable in animal models through our approach, is increased in humans after acute stress, during PTSD and in depression. This relationship can now be exploited to match animal models more closely to clinical situations, especially in animal models of depression.

Computer-Assisted Avatar-Based Treatment for Dysfunctional Beliefs in Depressive Inpatients: A Pilot Study.

Dysfunctional cognitions are a crucial part of depression. Cognitive therapy aims to modify dysfunctional beliefs. Typically, dysfunctional beliefs are questioned, and patients are trained to think of alternative functional beliefs. We developed a computer-assisted, avatar-based adjunct for cognitive therapy that aims to reduce dysfunctional beliefs and symptom severity. Besides, it aims to promote alternative functional beliefs. In a randomized controlled trial with 34 patients diagnosed with major depression currently undergoing inpatient treatment at the university psychiatric hospital in Regensburg, Germany, participants were randomly assigned to receive either treatment as usual (TAU) or computer-assisted avatar-based treatment for dysfunctional beliefs (CAT-DB) in addition to TAU. In CAT-DB participants are faced with a virtual avatar expressing their personal dysfunctional beliefs. Participants are asked to contradict these and express alternative functional beliefs. Assessments of conviction of dysfunctional beliefs, functional beliefs and symptom severity were done shortly before the intervention (pre-treatment), right after the intervention (post-treatment) and 14 days later (follow-up). The reduction in conviction of dysfunctional beliefs and symptom severity, and the increase in conviction of alternative functional beliefs at post-treatment and follow-up were significantly greater for the group receiving CAT-DB. Our study provides an indication in favor of the effectiveness of CAT-DB for depressive patients. It is a simple tool that could support classical cognitive therapy. Further studies at different centres, with larger sample sizes and varying therapeutic contexts are required to prove the effectiveness of our intervention.

A direct comparison of neuronavigated and non-neuronavigated intermittent theta burst stimulation in the treatment of depression.

OBJECTIVE: To investigate whether a four-week course of neuronavigated intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is superior to the non-neuronavigated F3-EEG method of positioning. METHODS: We conducted a single-center, two-arm, randomized and double-blinded study (clinicaltrials.gov NCT03953521). 37 inpatients with an at least moderate depressive episode were randomized to receive either neuronavigated or 10-20-EEG-system based F3 guided iTBS. Both groups received twenty week daily sessions of iTBS while continuing to receive standard-of-care treatment by their ward physicians. For navigated iTBS, we used magnetic resonance imaging to target the border between the anterior and middle third of the middle frontal gyrus considered to represent the left dorsolateral prefrontal cortex (lDLPFC). Differences in the treatment arms were blinded by completely mimicking the procedures of the respective other treatment group. Rating physicians were not involved in the treatment procedure. Primary outcome was defined as the change of the 21-item version of the Hamilton Depression Score (HAMD) from baseline to end of treatment at week 4. Secondary outcomes included HAMD score during the treatment, Patient Health Questionnaire-9, WHO Quality of Life-BREF and Clinical Global Impression. For primary outcome, we used a planned group comparison for the absolute change in the HAMD. For secondary outcome measures we calculated analyses of variance (ANOVAs) with the within-subjects factor time (primary: baseline vs. week 4; secondary: all visits) and the between-subjects factor group (navigated vs. F3 guided group). We also did planned contrasts between both groups for all variables and all treatment and follow-up visits with the aim not to oversee any group differences. For group contrasts we used Student T-tests for metric and chi-square tests for categorial variables. Significance threshold was set to 5% uncorrected for multiple comparisons. RESULTS: Enrolment of 80 patients with interim analysis was planned. Interim analysis was performed after 37 patients (intention to treat). 6 patients dropped out, leaving 31 for analysis. With respect to primary outcome criteria, absolute change in the HAMD did not differ significantly between groups. In accordance, relative change and number of responders and remitters were not significantly different. Overall number of responders was 53% and of remitters was 60%. On a descriptive level, the results favor the clinical effects of the F3 group for the absolute and relative change in the HAMD and the number of responders. Number of remitters were exactly the same for both groups. Therefore, we decided to stop the trial due to the added burden of magnetic resonance imaging and neuronavigated treatment in relation to the effect. Secondary outcomes did also not differ significantly between groups. Patients did not differ in their baseline characteristics nor with respect to intake of medication during the trial period and all had access to the same therapeutic interventions. CONCLUSION: We noticed a high antidepressive effect of add-on iTBS treatment to standard inpatient treatment but failed to demonstrate a clinical superiority of neuronavigated localization. The non-navigated, F3 guided iTBS treatment used as a control group may be sophisticated enough to dilute potential added benefits, and the difference between the localization approaches is either negligible or too small to justify the additional efforts of navigation. The effects of concomitant treatment may mask effects, but our patient population reflects clinical reality in an inpatient setting. Further prospective studies are warranted to compare neuronavigated with surface-based approaches.

Bifrontal high-frequency transcranial random noise stimulation is not effective as an add-on treatment in depression.

BACKGROUND: Depressive disorders are linked to dysfunction in prefrontal cortical areas. Hence, non-invasive neurostimulation of the prefrontal cortex has demonstrated antidepressant efficacy. In the present study, we investigated the efficacy of high frequency transcranial random noise stimulation (hf-tRNS) as an add-on treatment for depression in a sham-controlled randomized trial. METHODS: Forty in-patients with depression were randomized and treated with real or sham hf-tRNS (100-650 Hz) with 0 mA offset. The electrodes were mounted over the left and right dorsolateral prefrontal cortex. The Hamilton Depression Rating Scale (primary outcome), the Major Depression Inventory, the Clinical Global Impression scale and the Global Assessment of Functioning scale were used for assessment at baseline, after 3 weeks of intervention (end of treatment), and 9 weeks after intervention. Safety parameters included cognitive functioning and reported side-effects. RESULTS: Comparison of real and sham treatment at the planned interim analysis showed an amelioration of symptoms in both groups for all outcomes with numeric but not statistically significant superiority of the sham arm for the primary outcome. Thus, the study was terminated prematurely after an interim analysis. There were no systematic differences with respect to safety parameters. LIMITATIONS: The negative finding might be related to the specific stimulation parameters used in this study. CONCLUSIONS: Our study suggests that prefrontal hf-tRNS is safe but not effective as an add-on treatment of depression. The challenge for future studies employing transcranial electric stimulation remains to identify effective stimulation parameters for the treatment of depression.

Dissociation of endocrine responses to the Trier Social Stress Test in Virtual Reality (VR-TSST) by the benzodiazepine alprazolam and the translocator protein 18 kDa (TSPO) ligand etifoxine.

BACKGROUND: Activity of the two major stress systems, the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) axis, has already been shown to be modulated by different compounds that bind to the central benzodiazepine receptor. Less is known about ligands that modulate the peripheral benzodiazepine receptor - meanwhile known as the translocator protein 18 kDa (TSPO) - which constitute promising candidates in the search of novel anxiolytics. To close this gap, the present study compared the effects of the benzodiazepine alprazolam and the TSPO ligand etifoxine on responses of the HPA and SAM axes to the Trier Social Stress Test, a standardized paradigm to induce acute psychosocial stress in humans, performed in Virtual Reality (VR-TSST). METHODS: Sixty healthy males, aged between 18 and 55 years, were randomly assigned to receive either a daily dose of 1.5 mg alprazolam, 150 mg etifoxine, or placebo over five days. On the last day of intake, they were exposed to the VR-TSST. We assessed changes of salivary cortisol, allopregnanolone, (nor-) epinephrine in serum, TSPO expression in platelets as well as heart rate (HR), skin conductance level (SCL) and self-reports in response to the stress task. Repeated measures ANOVAs were conducted to examine treatment effects on these stress response variables during the course of VR-TSST. RESULTS: The response of salivary cortisol to the VR-TSST was significantly blunted in participants pre-treated with alprazolam but was not affected by etifoxine. While levels of allopregnanolone, epinephrine and norepinephrine increased in response to stress, TSPO expression decreased. None of those endocrine stress markers was affected by the active treatments, whereas TSPO expression increased after etifoxine administration over all study days. There were no effects of the two anxiolytics on HR, SCL or any self-report measurement. CONCLUSION: The current study confirmed the attenuating effects of benzodiazepines on stress-induced HPA axis activity but did not reveal a comparable effect of the TSPO ligand etifoxine. The long-term consequences of a pharmacologically blunted response of the HPA axis to an acute stressor should be further elucidated. Due to the missing effects of etifoxine on stress-related parameters in our sample of healthy subjects, it might be concluded that the therapeutic effects of this TSPO ligand are restricted to stronger or pathological stress responses, respectively.