The effects of a psychiatric clerkship on stigmatizing attitudes toward mental disorders as held by German medical students.

Background: According to the United Nations, access to medical care is a fundamental human right. However, there is widespread stigmatization of severe mental illnesses and this appears to seriously hamper the quality of healthcare in people with psychiatric co-morbidity. Thus, interventions that help reduce stigma among healthcare providers are urgently needed. Purpose: The objective of the current study was to investigate the effects of a psychiatric clerkship on stigmatizing attitudes toward mental disorders held by medical students. Methods: Between 2018 and 2019, a total of 256 third- and fourth-year students from Marburg University Medical School (Germany) completed two surveys-one before and one after a 2 week clerkship program that was designed to prioritize direct interaction with the patients. For measuring stigma, the questionnaires contained questions about students' attitudes toward psychiatry (ATP), including the Opening Minds Scale for Healthcare Providers (OMS-HC), Community Attitudes Toward the Mentally Ill (CAMI), and measurements according to the Stereotype-Content Model (SCM). We conducted pre-vs.-post comparisons using the Wilcoxon signed rank test with continuity correction or paired t-test and employed the Spearman method for correlational analysis. We considered p < 0.05 significant and adjusted all p-values reported here using the Benjamini-Hochberg procedure to account for family-wise error. Results: After the clerkship, a significantly reduced stigma was found, as assessed with ATP (mean p < 0.001), OMS-HC (sum and subscale "attitudes" p < 0.001; subscale "disclosure" p = 0.002), and both SCM subscales (p < 0.001). Moreover, we observed significant associations between stigma expression (e.g., OMS-HC sum) and the willingness of students to choose psychiatric residency after finishing medical school (before clerkship: p < 0.001; ρ = -0.35; change after clerkship: p = 0.004; ρ = -0.2). Conclusion: Our findings indicate that a psychiatric clerkship that involves students in direct interaction with patients may effectively reduce stigma. Therefore, we advocate the incorporation of components of direct interaction in medical education to combat stigma and unequal treatment, as this could improve outcomes in patients with severe mental illnesses.

[Recommendations for the Diagnosis and Therapy of Psychotic Disorders in the Elderly]. / Empfehlungen für die Diagnostik und Therapie psychotischer Erkrankungen im Alter.

Recommendations for the Diagnosis and Therapy of Psychotic Disorders in the Elderly Abstract. Psychotic disorders in the elderly cover a wide range of causes and manifestations. They often occur as part of a depression, dementia, substance abuse or delirium. While psychosis can occur with a first manifestation in advanced age, many patients with chronic psychotic disorders reach a high age. Many elderly individuals are also affected by cognitive impairment and somatic conditions, making a third-party history most relevant. The associated changes in life and the complexity of the individual situation needs to be integrated into the diagnosis and treatment. The presented recommendations have been developed under the lead of the Swiss Society of Old Age Psychiatry (SGAP) in collaboration with the Swiss Association of Nurses (SBK) and the subcommittees for gerontological and psychiatric nursing of the association of nursing science (VFP) as well as further professional societies. We aim to make current knowledge concerning diagnosis and treatment available to the interprofessional teams working in in- and outpatients' settings.

Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia.

PET of ß-Amyloid plaques (Aß) using [18F]florbetaben ([18F]FBB) and [18F]fluorodeoxyglucose ([18F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer's disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [18F]FBB, [18F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aß peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB); (3) [18F]FBB and [18F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aß+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aß-) subjects. Moreover, the [18F]FDG and [18F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [18F]FBB combined with [18F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [18F]FBB combined with [18F]FDG PET is a helpful tool for differential diagnosis, and supports the patients' management as well as treatment.

Ventricular volume, white matter alterations and outcome of major depression and their relationship to endocrine parameters - A pilot study.

OBJECTIVES: Brain morphology and its relation to endocrine parameters were examined, in order to determine the link of these parameters to treatment outcome to psychopharmacological treatment in depressed patients. METHODS: We examined the potentially predictive value of Magnetic Resonance Imaging (MRI) parameters related to mineralocorticoid receptor (MR) function on the treatment outcome of depression. 16 inpatients with a major depressive episode (MDE) were studied at baseline and 14 of them approximately six weeks later. Physiological biomarkers and 3-T-structural MRI based volume measures, using FreeSurfer 6.0 software, were determined. RESULTS: Non-responders (<50% reduction of HAMD-21; n = 6) had a significantly smaller volume of the right anterior cingulate cortex, a significantly larger ventricle to brain ratio (VBR) and third ventricle volume, and smaller volumes of the central and central-anterior corpus callosum (CC) in comparison to responders (n = 7; all p ≤ 0.05). Correlational analysis (Spearman) demonstrated that larger ventricle volume was correlated to a worse treatment outcome, higher body mass index (BMI) and smaller CC segment volume, whereas the total CC volume was negatively correlated to the saliva aldosterone/cortisol concentration ratio (AC-ratio). CONCLUSION: Large ventricular volume may be a predictive marker for worse treatment response to standard antidepressant treatment, potentially via compression of white matter structures. A mediating role of the previously identified markers BMI and the AC-ratio, is suggested.

Adjunct Therapy With Glycyrrhiza Glabra Rapidly Improves Outcome in Depression-A Pilot Study to Support 11-Beta-Hydroxysteroid Dehydrogenase Type 2 Inhibition as a New Target.

Mineralocorticoid-receptor (MR) dysfunction as expressed by low systolic blood pressure and a high salivary aldosterone/cortisol ratio predicts less favorable antidepressant treatment outcome. Inhibition of peripheral 11-beta-hydroxysteroid-dehydrogenase type 2 (11betaHSD2) reverses these markers. We therefore tested the hypothesis that the 11betaHSD2 inhibitor glycyrrhizin affects treatment outcome via this mechanism. We administered Glycyrrhiza glabra (GG) extract containing 7-8 % of glycyrrhizin at a dose of 2 × 700 mg daily adjunct to standard antidepressants in hospitalized patients with major depression. These subjects were compared in an open-label fashion with patients, who did not receive GG (treatment as usual, TAU). Assessments were done at baseline and approximately 2 weeks after. Twelve subjects were treated with GG and compared to 55 subjects with TAU. At week 2, the Hamilton Depression Rating Scale (HAMD-21) change from baseline as well as the CGI-S change showed a significant time × treatment interaction (p < 0.03), indicating a possible therapeutic benefit of GG. Clinical benefit seems to be more pronounced in subjects with lower systolic blood pressure and significantly correlated with reduced sleep duration in the GG group. Our preliminary data show that treatment with the 11betaHSD2 inhibitor glycyrrhizin may possess a beneficial effect on antidepressant response, which may be specific to a defined depression subtype.

Theta-Burst Stimulation for Auditory-Verbal Hallucination in Very-Late-Onset Schizophrenia-Like Psychosis-A Functional Magnetic Resonance Imaging Case Study.

BACKGROUND: Treating very-late-onset (>60 years) schizophrenia-like psychosis (VLOSLP) is challenging. Age-related factors in elderly individuals (e.g., metabolism, medication side effects, drug-interaction, somatic morbidity) may adversely affect treatment. Novel therapeutic approaches are needed to ensure the favorable therapeutic outcome in geriatric patients. Previously, theta-burst stimulation (TBS), a novel form of repetitive transcranial magnetic stimulation, was reported being beneficial in the treatment for auditory-verbal hallucination (AVH) in young and middle-aged schizophrenia (SZ) patients. CASE PRESENTATION: Here we present a case of a male patient aged 73. His first psychotic episode manifested with paranoid delusions, auditory-verbal and tactile hallucinations at the age of 66, and first remitted following a second-generation antipsychotics (SGA). Years later, after a relapse the AVH did not respond to previously effective olanzapine, whereas its augmentation with an inhibitory TBS over the left temporal lobe led to a stable remission. During his second relapse, TBS was again capable of facilitating therapeutic action of SGA in the same patient. Extending to our clinical observation, a series of functional MRI scans employing a tonal activation paradigm depicted altered auditory processing during AVH as well as brain activation change during remission. CONCLUSIONS: The current case might indicate to favorable effects of combining conventional medicament therapy and non-invasive brain stimulation techniques for elderly patients. Also, we speculate that despite obviously distinct etiologies, the present functional imaging and clinical observation may also demonstrate a possible common pathophysiological pathway underlying AVH in VLOSLP and SZ.

Intermittent theta-burst stimulation moderates interaction between increment of N-Acetyl-Aspartate in anterior cingulate and improvement of unipolar depression.

BACKGROUND: Intermittent theta-burst stimulation (iTBS), a novel repetitive transcranial magnetic stimulation (rTMS) technique, appears to have antidepressant effects when applied over left dorsolateral prefrontal cortex (DLPFC). However, its underlying neurobiological mechanisms are unclear. Proton magnetic resonance spectroscopy (1H-MRS) provides in vivo measurements of cerebral metabolites altered in major depressive disorder (MDD) like N-acetyl-aspartate (NAA) and choline-containing compounds (Cho). We used MRS to analyse effects of iTBS on the associations between the shifts in the NAA and Cho levels during therapy and MDD improvement. METHODS: In-patients with unipolar MDD (N = 57), in addition to treatment as usual, were randomized to receive 20 iTBS or sham stimulations applied over left DLPFC over four weeks. Single-voxel 1H-MRS of the anterior cingulate cortex (ACC) was performed at baseline and follow-up. Increments of concentrations, as well as MDD improvement, were defined as endpoints. We tested a moderated mediation model of effects using the PROCESS macro (an observed variable ordinary least squares and logistic regression path analysis modeling tool) for SPSS. RESULTS: Improvement of depressive symptoms was significantly associated with decrease of Cho/NAA ratio, mediated by NAA. iTBS had a significant moderating effect enhancing the relationship between NAA change and depression improvement. CONCLUSIONS: Our findings suggest a potential neurochemical pathway and mechanisms of antidepressant action of iTBS, which may moderate the improvement of metabolic markers of neuronal viability. iTBS might increase neuroplasticity, thus facilitating normalization of neuronal circuit function.

Health-related Internet use and treatment adherence: A transdiagnostic comparison of outpatients with major depressive disorder and schizophrenia.

Treatment adherence is relevant for clinical and economic outcome in affective disorders as well as psychosis. Knowledge concerning the disease and its treatment might influence patients' willingness to follow the health-care providers' recommendations and mutual decision-making. In the current study, we investigated how Internet surfing for health-related issues and attitude toward the relevance of the online information impact treatment adherence in major depressive disorder (MDD) and schizophrenia (SZ). A total of 83 outpatients (59 MDD, 24 SZ) participated in a survey. A multiple linear regression model with "exposure," "attitude," "diagnosis," and their interaction as regressors was significant predictive of medication-adherence rating scores, R2 = .179; 95% CI [0.00, 0.32]. In the MDD group only, more extended exposure to Internet surfing for health-related issues and attribution of higher personal relevance were associated with poorer medication adherence at a statistical trend level, p = .060 and p = .077, respectively. In both groups, being female as well as higher age and intelligence were associated with favorable adherence, p = .003, p = .044, and p = .039, respectively. Considering the limitations (e.g., small sample size), our findings add to previously published data contributing to a better understanding of how Internet use may impact treatment adherence in MDD and schizophrenia.

[Psychiatric polypharmacy and electroconvulsive therapy in treatment-resistant depression]. / Psychiatrische Polypharmazie und Elektrokonvulsionstherapie bei therapieresistenter Depression.

BACKGROUND: Despite its relevant medical risks, polypharmacy is common particularly among difficult to treat conditions, e.g. treatment refractory depression (TRD). According to numerous guidelines, electroconvulsive therapy (ECT) is the treatment of choice in severe and treatment-resistant major depression due to the high effectiveness; however, to date limited data are available concerning the effects of ECT on the concomitant prescription of psychiatric medication. METHODS: For a retrospective explorative analysis of psychiatric polypharmacy (MED) in TRD, data from 58 inpatient treatments were collected. Due to depressive episodes, all patients received psychopharmacological treatment and cognitive behavioral therapy (MED group). Of the patients 29 also underwent ECT (ECT group). Using a modified drug burden index (mod-DBI), the psychiatric medication was quantified at admission (TP0), start (TP1) and termination of ECT (TP2) and discharge in the ECT group or in comparable periods in the MED group (TP3). Differences in distribution were tested with the t-test and alterations in measurements were tested by means of variance analysis (F-test). RESULTS: Patients treated with ECT showed higher mod-DBI values at TP0, mainly due to more frequent prescription of benzodiazepines (BZD), mood stabilizers (MS) and antipsychotic drugs (AP). At the beginning of the inpatient treatment (TP0-TP1) there was an increase in BZD use (in both groups); in the ECT group MS were reduced and AP increased. In the time interval TP1-TP3, BZD (in both groups) and AP (ECT group) were again less frequently prescribed and MS (ECT and MED group) were increased again. Excluding BZD, there was a significant increase in mod-DBI in both groups, whereas the mod-DBI no longer showed significant differences at TP2 and TP3. CONCLUSION: The data possibly indicate that patients with TRD who receive ECT during inpatient treatment already have a more extensive psychiatric medication at admission. Also, psychiatric medication appears to be increased less prominently when ECT is performed. These findings and the possibly associated long-term benefits should be addressed in future research.

Electroconvulsive therapy induced gray matter increase is not necessarily correlated with clinical data in depressed patients.

BACKGROUND: Electroconvulsive therapy (ECT) and depression have been associated with brain volume changes, especially in the hippocampus and the amygdala. METHODS: In this retrospective study we collected data from individual pre-post ECT whole brain magnetic resonance imaging scans of depressed patients from six German university hospitals. Gray matter volume (GMV) changes were quantified via voxel-based morphometry in a total sample of 92 patients with major depressive episodes (MDE). Additionally, 43 healthy controls were scanned twice within a similar time interval. RESULTS: Most prominently longitudinal GMV increases occurred in temporal lobe regions. Within specific region of interests we detected significant increases of GMV in the hippocampus and the amygdala. These results were more pronounced in the right hemisphere. Decreases in GMV were not observed. GMV changes did not correlate with psychopathology, age, gender or number of ECT sessions. We ruled out white matter reductions as a possible indirect cause of the detected GMV increase. CONCLUSION: The present findings support the notion of hippocampus and amygdala modulation following an acute ECT series in patients with MDE. These results corroborate the hypothesis that ECT enables primarily unspecific and regionally dependent neuroplasticity effects to the brain.

Low left amygdala volume is associated with a longer duration of unipolar depression.

The amygdala plays a crucial role in the pathogenesis of major depressive disorder (MDD). While robust findings support a negative impact of illness duration on hippocampal volume in MDD, morphometric studies of the amygdala have yielded inhomogeneous results. Considering the methodical problems of automatic segmentation methods, a standardized segmentation protocol with proven inter- and intra-rater reliability was employed using high-resolution magnetic resonance imaging. To identify the effect of MDD on amygdala morphometry, 23 unipolar depressed patients who responded to antidepressant medication and 30 age-matched healthy controls (HC) were enrolled. First, gray matter volumes (GMV) of the bilateral amygdala were delineated manually in 3D by three blinded experts using the MultiTracer. The whole brain GMV was determined by using voxel-based morphometry. Second, the differences of the whole brain and the bilateral amygdala GMV values between MDD and HC were calculated with t-statistics. The GMV of the whole brain and the amygdala did not differ between HC and MDD patients. Third, MDD characteristics were correlated with amygdala GMV. Within the normal range, the left amygdala GMV was larger in patients with later onset and smaller in cases of prolonged depression. In line with prior reports of depressed patients responding to antidepressant treatment, amygdala GMV was negatively related to illness duration, suggesting volume loss with disease progression. It remains unclear as to whether the association between illness duration and GMV reduced left amygdala volume indicates a neurotoxic effect of prolonged MDD or is rather a negative predictor of chronic depression.

S -ketamine compared to etomidate during electroconvulsive therapy in major depression.

Objective of the study was to compare two commonly used anesthetic drugs, S-ketamine and etomidate, regarding their influence on seizure characteristics, safety aspects, and outcome of electroconvulsive therapy (ECT) in major depression. Treatment data of 60 patients who underwent a total number of 13 ECTs (median) because of the severe or treatment-resistant major depressive disorder (DSM-IV) were analyzed. Etomidate, mean dosage (SD) = 0.25 (0.04) mg/kg, was used for anesthesia in 29 participants; 31 patients received S-ketamine, mean dosage (SD) = 0.96 (0.26) mg/kg. Right unilateral brief pulse ECTs were performed. The number of ECTs was individually adjusted to clinical needs, mean (SD) = 13.0 (4.3). Seizure characteristics, adverse events, and the clinical global impression (CGI) scores were compared between the both groups during ECT series. In the S-ketamine group, a lower initial seizure threshold (p = 0.014), stimulation charge (p < 0.001), higher postictal suppression (p < 0.001), EEG ictal amplitude (p = 0.04), EEG coherence (p < 0.001) and maximum heart rate (p = 0.015) were measured. Etomidate was associated with more frequent abortive seizures (p = 0.02) and restimulations (p = 0.01). The CGI scores, the number of sessions within an ECT series, and the incidence of adverse events did not differ between groups. Due to its lower initial seizure threshold, S-ketamine might hold a potential to become a clinically favorable anesthetic agent during ECT. However, the current findings should be interpreted with caution, and further prospective randomized clinical trials are required. Also, specific adverse effects profile of S-ketamine, especially with regard to the cardiovascular risk, needs to be taken into account.

Prediction of Individual Response to Electroconvulsive Therapy via Machine Learning on Structural Magnetic Resonance Imaging Data.

IMPORTANCE: Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, biomarkers that accurately predict a response to ECT remain unidentified. OBJECTIVE: To investigate whether certain factors identified by structural magnetic resonance imaging (MRI) techniques are able to predict ECT response. DESIGN, SETTING, AND PARTICIPANTS: In this nonrandomized prospective study, gray matter structure was assessed twice at approximately 6 weeks apart using 3-T MRI and voxel-based morphometry. Patients were recruited through the inpatient service of the Department of Psychiatry, University of Muenster, from March 11, 2010, to March 27, 2015. Two patient groups with acute major depressive disorder were included. One group received an ECT series in addition to antidepressants (n = 24); a comparison sample was treated solely with antidepressants (n = 23). Both groups were compared with a sample of healthy control participants (n = 21). MAIN OUTCOMES AND MEASURES: Binary pattern classification was used to predict ECT response by structural MRI that was performed before treatment. In addition, univariate analysis was conducted to predict reduction of the Hamilton Depression Rating Scale score by pretreatment gray matter volumes and to investigate ECT-related structural changes. RESULTS: One participant in the ECT sample was excluded from the analysis, leaving 67 participants (27 men and 40 women; mean [SD] age, 43.7 [10.6] years). The binary pattern classification yielded a successful prediction of ECT response, with accuracy rates of 78.3% (18 of 23 patients in the ECT sample) and sensitivity rates of 100% (13 of 13 who responded to ECT). Furthermore, a support vector regression yielded a significant prediction of relative reduction in the Hamilton Depression Rating Scale score. The principal findings of the univariate model indicated a positive association between pretreatment subgenual cingulate volume and individual ECT response (Montreal Neurological Institute [MNI] coordinates x = 8, y = 21, z = -18; Z score, 4.00; P < .001; peak voxel r = 0.73). Furthermore, the analysis of treatment effects revealed a increase in hippocampal volume in the ECT sample (MNI coordinates x = -28, y = -9, z = -18; Z score, 7.81; P < .001) that was missing in the medication-only sample. CONCLUSIONS AND RELEVANCE: A relatively small degree of structural impairment in the subgenual cingulate cortex before therapy seems to be associated with successful treatment with ECT. In the future, neuroimaging techniques could prove to be promising tools for predicting the individual therapeutic effectiveness of ECT.

Impact of electroconvulsive therapy on magnetoencephalographic correlates of dysfunctional emotional processing in major depression.

In major depressive disorder (MDD), electrophysiological and imaging studies provide evidence for a reduced neural activity in parietal and dorsolateral prefrontal regions. In the present study, neural correlates and temporal dynamics of visual affective perception have been investigated in patients with unipolar depression in a pre/post treatment design using magnetoencephalography (MEG). Nineteen in-patients and 19 balanced healthy controls passed MEG measurement while passively viewing pleasant, unpleasant and neutral pictures. After a 4-week treatment with electroconvulsive therapy or 4-week waiting period without intervention respectively, 16 of these patients and their 16 corresponding controls participated in a second MEG measurement. Before treatment neural source estimations of magnetic fields evoked by the emotional scenes revealed a general bilateral parietal hypoactivation in depressed patients compared to controls predominately at early and mid-latency time intervals. Successful ECT treatment, as reflected by a decline in clinical scores (Hamilton Depression Scale; HAMD) led to a normalization of this distinct parietal hypoactivation. Effective treatment was also accompanied by relatively increased neural activation at right temporo-parietal regions. The present study indicates dysfunctional parietal information processing and attention processes towards emotional stimuli in MDD patients which can be returned to normal by ECT treatment. Since convergent neural hypoactivations and treatment effects have recently been shown in MDD patients before and after pharmacological therapy, this electrophysiological correlate might serve as a biomarker for objective treatment evaluation and thereby potentially advance treatment options and support the prediction of individual treatment responses.

Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic.

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.

Inhibitory repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex modulates early affective processing.

The dorsolateral prefrontal cortex (dlPFC) has often been suggested as a key modulator of emotional stimulus appraisal and regulation. Therefore, in clinical trials, it is one of the most frequently targeted regions for non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). In spite of various encouraging reports that demonstrate beneficial effects of rTMS in anxiety disorders, psychophysiological studies exploring the underlying neural mechanisms are sparse. Here we investigated how inhibitory rTMS influences early affective processing when applied over the right dlPFC. Before and after rTMS or sham stimulation, subjects viewed faces with fearful or neutral expressions while whole-head magnetoencephalography (MEG) was recorded. Due to the disrupted functioning of the right dlPFC, visual processing in bilateral parietal, temporal, and occipital areas was amplified starting at around 90 ms after stimulus onset. Moreover, increased fear-specific activation was found in the right TPJ area in a time-interval between 110 and 170 ms. These neurophysiological effects were reflected in slowed reaction times for fearful, but not for neutral faces in a facial expression identification task while there was no such effect on a gender discrimination control task. Our study confirms the specific and important role of the dlPFC in regulation of early emotional attention and encourages future clinical research to use minimal invasive methods such as transcranial magnetic (TMS) or direct current stimulation (tDCS).

Acute shift in glutamate concentrations following experimentally induced panic with cholecystokinin tetrapeptide--a 3T-MRS study in healthy subjects.

According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p<0.0001; PSS: F(1,17)=88.03; p<0.0001) and heart rate (HR: F(1,17)=72.79; p<0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17)=15.94; p=0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11)=8.68; p=0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both APImax (r=0.598; p=0.009) and maximum heart rate (HR(max)) during challenge (r=0.519; p=0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.

Acute anxiolytic effects of quetiapine during virtual reality exposure--a double-blind placebo-controlled trial in patients with specific phobia.

Anxiety disorders are among the most frequent psychiatric disorders. With regard to pharmacological treatment, antidepressants, the calcium modulator pregabalin and benzodiazepines are recommended according to current treatment guidelines. With regard to acute states of anxiety, so far practically only benzodiazepines provide an immediate anxiolytic effect. However, the risk of tolerance and dependency limits the use of this class of medication. Therefore, there is still a need for alternative pharmacologic strategies. Increasing evidence points towards anxiety-reducing properties of atypical antipsychotics, particularly quetiapine. Therefore, we aimed to evaluate the putative acute anxiolytic effects of this compound, choosing the induction of acute anxiety in patients with specific phobia as a model for the evaluation of ad-hoc anxiolytic properties in a proof-of-concept approach. In a randomized, double-blind, placebo-controlled study, 58 patients with arachnophobia were treated with a single dose of quetiapine XR or placebo prior to a virtual reality spider challenge procedure. Treatment effects were monitored using rating scales for acute anxiety as well as measurements of heart rate and skin conductance. Overall, quetiapine showed significant anxiolytic effects compared to placebo. However, effects were not seen on the primary outcome measure (VAS Anxiety), but were limited to somatic anxiety symptoms. Additionally, a significant reduction of skin conductance was observed. Further exploratory analyses hint towards a mediating role of the (COMT) val158met genotype on treatment response. The present results thus suggest a possible suitability of quetiapine in the acute treatment of anxiety, particularly with regard to somatic symptoms.

Dopamine D3 receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression.

Dysfunction of dopamine D3 receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D3 receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D3 receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a sample of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent samples of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02-0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009; corrected p=0.045) and rs3773679 (uncorrected p=0.009; corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (sample 1: cluster-corrected p=0.002; sample 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.

Associations between cognitive performance and cortisol reaction to the DEX/CRH test in patients recovered from depression.

BACKGROUND: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in major depression (MDD) is one of the most reliably reported neurobiological characteristics of affective disorders. Whether these alterations in HPA axis regulation are limited to the acute stage of MDD or whether they persist after recovery, remains ambiguous. A relationship between hypercortisolemia and cognitive dysfunction in acutely depressed patients has been repeatedly observed and it was also demonstrated in a number of studies that a discrete cognitive impairment often persists in the remitted state of depression. In the present study we were interested, whether these subtle impairments in cognitive functioning observed in patients recovered from depression compared to healthy control subjects are associated with HPA axis feedback sensitivity. METHODS: In 20 recovered patients and 20 matched healthy controls we assessed HPA axis feedback sensitivity with the combined dexamethasone suppression/corticotropin-releasing-hormone (DEX/CRH) challenge test. Furthermore cognitive performance was investigated with respect to the following domains: verbal memory (Auditory Verbal Learning Test, VLMT), attention and executive control (Trail Making Test, TMT-A/B) as well as verbal fluency (Controlled Oral Word Association Test, COWAT). RESULTS: Recovered patients showed a significantly poorer cognitive performance compared to healthy controls (all p<.05). With regard to HPA-axis activity, no overall difference was observed in the DEX/CRH test between recovered patients and controls. In recovered patients however, a significant association was observed between cortisol response and verbal memory (main effect VLMT trial 1-5: p=.046), attention (main effect TMT-A: p=.015) and executive functioning in terms of set shifting (interaction samples*TMT-B: p=.018). Poorer test performance was related to increased cortisol levels in response to challenge. CONCLUSIONS: The present findings suggest that patients recovered from MDD are especially vulnerable toward detrimental effects of subtle HPA axis disturbances on cognitive performance.