Resting-state functional connectivity in anxiety disorders: a multicenter fMRI study.

Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. It remains uncertain how much these signatures overlap across different phenotypes due to a lack of well-powered cross-disorder comparisons. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in functional connectivity (FC) in a cross-disorder sample of AD patients and healthy controls (HC). Before treatment, 439 patients from two German multicenter clinical trials at eight different sites fulfilling a primary diagnosis of panic disorder and/or agoraphobia (PD/AG, N = 154), social anxiety disorder (SAD, N = 95), or specific phobia (SP, N = 190) and 105 HC underwent an 8 min rsfMRI assessment. We performed categorical and dimensional regions of interest (ROI)-to-ROI analyses focusing on connectivity between regions of the defensive system and prefrontal regulation areas. AD patients showed increased connectivity between the insula and the thalamus compared to controls. This was mainly driven by PD/AG patients who showed increased (insula/hippocampus/amygdala-thalamus) and decreased (dorsomedial prefrontal cortex/periaqueductal gray-anterior cingulate cortex) positive connectivity between subcortical and cortical areas. In contrast, SAD patients showed decreased negative connectivity exclusively in cortical areas (insula-orbitofrontal cortex), whereas no differences were found in SP patients. State anxiety associated with the scanner environment did not explain the FC between these regions. Only PD/AG patients showed pronounced connectivity changes along a widespread subcortical-cortical network, including the midbrain. Dimensional analyses yielded no significant results. The results highlighting categorical differences between ADs at a systems neuroscience level are discussed within the context of personalized neuroscience-informed treatments. PROTECT-AD's registration at NIMH Protocol Registration System: 01EE1402A and German Register of Clinical Studies: DRKS00008743. SpiderVR's registration at ClinicalTrials.gov: NCT03208400.

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Epigenome-Wide DNA Methylation in Unipolar Depression - Predictive Biomarker of Antidepressant Treatment Response?

BACKGROUND: Despite the well-documented efficacy of antidepressant agents for the treatment of major depressive disorder (MDD), initial treatment non-response rates are high. Recent years have seen an increase in research into predictive biomarkers towards improving diagnosis and individualized treatment. Among those, epigenetic mechanisms such as DNA methylation constitute promising candidate markers in predicting antidepressant treatment response in MDD. The present study sought to address epigenome-wide DNA methylation as a predictor of antidepressant treatment response in the so far largest sample of patients with MDD. METHODS: Epigenome-wide DNA methylation was analyzed using the Infinium MethylationEPIC BeadChip in peripheral blood of N=230 Caucasian patients with MDD receiving six-week antidepressant treatment in a naturalistic in-patient setting as well as in a subsample of N=107 patients primarily receiving continuous treatment with SSRIs or SNRIs. Treatment response was assessed by means of the Hamilton Depression Scale (HAM-D). RESULTS: No genome-wide significant hits were observed. Suggestive (p<1E-5) epigenome-wide evidence was discerned for altered DNA methylation at six CpG sites (LOC102724467, LOC100506023, RSPO2, SAG, IL16, PRKCI) to predict response to naturalistic antidepressant treatment. In patients treated with SSRIs or SNRIs, differential DNA methylation at 11 CpGs, e.g. mapping to the TIMP2, VDAC1 or SORL1 genes, was suggestively associated with treatment response. CONCLUSIONS: The present results provide preliminary evidence for altered DNA methylation patterns to be associated with antidepressant treatment response in MDD. Provided significant replication in independent and larger samples, the present findings might in the future aid in clinical decision making towards more individualized and thus more efficacious treatments of MDD.

Association of rheumatological markers with neuronal antibodies, cerebrospinal fluid, electroencephalography, and magnetic resonance imaging findings in 224 patients with psychotic syndromes.

INTRODUCTION: Psychotic syndromes can have autoimmune-mediated causes in some patients. Thus, this retrospective work aims to investigate the role of rheumatological markers in the development of psychosis. PATIENTS AND METHODS: In total, 224 patients with psychotic syndromes receiving a "rheumatological laboratory screening" (including C-reactive protein [CRP], immunofixation, complement factors, rheumatoid factor [RF], antiphospholipid antibodies [APAs], antineutrophil cytoplasmic antibodies [ANCAs], and antinuclear antibodies [ANAs]) were analyzed. A further diagnostic work-up included investigations of neuronal antibodies and cerebrospinal fluid (CSF), as well as electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain. ANA testing was routinely performed in all patients using serum on human epithelioma-2 (Hep2) cells, and a subset of patients (N = 73) also underwent tissue-based assays from serum and CSF. The number of cases with autoimmune psychotic syndromes was descriptively collected, and ANA-positive and -negative patients were compared in detail. RESULTS: CRP was elevated in 9 % of patients, immunofixation identified alterations in 8 %, complement factor C3 was decreased in 14 %, RF was elevated in 1 %, APAs were elevated in 7 %, ANCAs were not clearly positive, and ANAs were positive in 19 % (extractable nuclear antigen [ENA] differentiation resulted in positive findings in 14 patients). From the 73 patient samples additionally investigated using tissue-based assays, there were 26 positive results for some kind of ANA (36 %), and overall using both methods, 54 patients (24 %) were considered positive for ANAs. A neuropsychiatric evaluation revealed a possible autoimmune psychotic syndrome in seven patients (3 %) and a probable autoimmune psychotic syndrome in two patients (1 %). ANA-positive patients were more frequently treated with antidepressants (p = 0.040) and had a higher number of somatic comorbidities (p < 0.001). In addition, (chronic) inflammatory MRI lesions (p = 0.008) and focal atrophies (p = 0.012) were found more frequently in ANA-positive than ANA-negative patients. DISCUSSION: Rheumatological screening led to suspicion of a possible or probable autoimmune psychotic syndrome in 4%. ANAs were associated with MRI pathologies. Therefore, rheumatological processes may contribute to the development of psychotic syndromes in rare cases.

Cerebrospinal fluid findings in patients with obsessive-compulsive disorder, Tourette syndrome, and PANDAS: A systematic literature review.

BACKGROUND: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are related mental disorders that share genetic, neurobiological, and phenomenological features. Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is a neuropsychiatric autoimmune disorder with symptoms of OCD and/or TS associated with streptococcal infections. Therefore, PANDAS represents a strong link between OCD, TS, and autoimmunity. Notably, cerebrospinal fluid (CSF) analyses can provide insight into the central nervous processes in OCD, TS, and PANDAS. METHODS: A systematic literature search according to the PRISMA criteria was conducted to collect all CSF studies in patients with OCD, TS, and PANDAS. The total number of cases and the heterogeneity of the low number of studies were not sufficient for a meta-analysis to provide a high level of evidence. Nevertheless, meta-analytical statistics could be performed for glutamate, 5-hydroxyindoleacetic acid (degradation product of serotonin), homovanillic acid (degradation product of dopamine), 3-methoxy-4-hydroxyphenylglycol (major metabolite of noradrenaline), and corticotropin-releasing hormone (CRH) in OCD. A risk-of-bias assessment was implemented using the Cochrane ROBINS-E tool. RESULTS: Meta-analytical testing identified elevated glutamate levels in the CSF of OCD patients compared with healthy controls, while no significant differences were found in other neurotransmitters or CRH. Single studies detected novel neuronal antibodies in OCD patients and elevated oligoclonal bands in TS patients. For TS and PANDAS groups, there was a dearth of data. Risk of bias assessment indicated a substantial risk of bias in most of the included studies. CONCLUSIONS: This systematic review of available CSF data shows that too few studies are currently available for conclusions with good evidence. The existing data indicates glutamate alterations in OCD and possible immunological abnormalities in OCD and TS. More CSF studies avoiding sources of bias are needed.

Obsessive-compulsive symptoms and brain lesions compatible with multiple sclerosis.

Autoimmune-mediated obsessive-compulsive disorder (OCD) can occur in multiple sclerosis (MS). Here, a well-studied case study of a patient with OCD and MS-compatible diagnostic findings is presented. The 42-year-old female patient had displayed OCD symptoms for 6 years. Magnetic resonance imaging (MRI) identified several periventricular and one brainstem lesion suggestive of demyelination. Cerebrospinal fluid (CSF) analyses detected an increased white blood cell count, intrathecal immunoglobulin (Ig) G and IgM synthesis, CSF-specific oligoclonal bands, and a positive MRZ reaction. Neopterin was increased, but sarcoidosis was excluded. In the absence of neurological attacks and clues for MRI-based dissemination in time, a radiologically isolated syndrome, the pre-disease stage of MS, was diagnosed. Neurotransmitter measurements of CSF detected reduced serotonin levels. In the absence of visible strategic demyelinating lesions within the cortico-striato-thalamo-cortical circuits, OCD symptoms may relate to reduced intrathecal serotonin levels and mild neuroinflammatory processes. Serotonin abnormalities in MS should be studied further, as they could potentially explain the association between neuroinflammation and mental illnesses.

Chronic insomnia, REM sleep instability and emotional dysregulation: A pathway to anxiety and depression?

The world-wide prevalence of insomnia disorder reaches up to 10% of the adult population. Women are more often afflicted than men, and insomnia disorder is a risk factor for somatic and mental illness, especially depression and anxiety disorders. Persistent hyperarousals at the cognitive, emotional, cortical and/or physiological levels are central to most theories regarding the pathophysiology of insomnia. Of the defining features of insomnia disorder, the discrepancy between minor objective polysomnographic alterations of sleep continuity and substantive subjective impairment in insomnia disorder remains enigmatic. Microstructural alterations, especially in rapid eye movement sleep ("rapid eye movement sleep instability"), might explain this mismatch between subjective and objective findings. As rapid eye movement sleep represents the most highly aroused brain state during sleep, it might be particularly prone to fragmentation in individuals with persistent hyperarousal. In consequence, mentation during rapid eye movement sleep may be toned more as conscious-like wake experience, reflecting pre-sleep concerns. It is suggested that this instability of rapid eye movement sleep is involved in the mismatch between subjective and objective measures of sleep in insomnia disorder. Furthermore, as rapid eye movement sleep has been linked in previous works to emotional processing, rapid eye movement sleep instability could play a central role in the close association between insomnia and depressive and anxiety disorders.

Digital cognitive behavioural therapy for insomnia reduces insomnia in nurses suffering from shift work disorder: A randomised-controlled pilot trial.

Insomnia is a primary symptom of shift work disorder, yet it remains undertreated. This randomised-controlled pilot trial examined the efficacy of a digital, guided cognitive behavioural therapy for insomnia adapted to shift work (SleepCare) in nurses with shift work disorder. The hypothesis was that SleepCare reduces insomnia severity compared with a waitlist control condition. A total of 46 unmedicated nurses suffering from shift work disorder with insomnia (age: 39.7 ± 12.1 years; 80.4% female) were randomised to the SleepCare group or the waitlist control group. The primary outcome measure was the Insomnia Severity Index. Other questionnaires on sleep, mental health and occupational functioning, sleep diary data and actigraphy data were analysed as secondary outcomes. Assessments were conducted before (T0), after the intervention/waitlist period (T1), and 6 months after treatment completion (T2). The SleepCare group showed a significant reduction in insomnia severity from T0 to T1 compared with the control condition (ß = -4.73, SE = 1.12, p < 0.001). Significant improvements were observed in sleepiness, dysfunctional beliefs about sleep, pre-sleep arousal, sleep effort, self-reported sleep efficiency and sleep onset latency. No significant effect was found in actigraphy data. Depressive and anxiety symptoms, cognitive irritation and work ability improved significantly. Overall, satisfaction and engagement with the intervention was high. SleepCare improved insomnia severity, sleep, mental health and occupational functioning. This is the first randomised-controlled trial investigating the efficacy of digital cognitive behavioural therapy for insomnia in a population suffering from shift work disorder with insomnia. Future research should further explore these effects with larger sample sizes and active control conditions.

Differential Psychological Treatment Effects in Patients With Late-Life Depression and a History of Childhood Maltreatment.

OBJECTIVE: This is the first interventional study to assess the impact of childhood maltreatment (CM) on psychological treatment outcomes in patients with late-life depression (LLD). METHODS: This is a secondary analysis of a multicenter, randomized controlled trial with 251 participants aged ≥60 years with moderate to severe depression. Participants were randomly assigned to cognitive behavioral therapy for late life depression (LLD-CBT) or to a supportive intervention (SUI). Treatment outcomes were measured by changes in the Geriatric Depression Scale (GDS). RESULTS: In the intention-to-treat sample (n = 229), both LLD-CBT (n = 115) and SUI (n = 114) significantly reduced depressive symptoms in patients with CM, with large effects at post-treatment (d = 0.95 [95% CI: 0.65 to 1.25] in LLD-CBT; d = 0.82 [95% CI: 0.52 to 1.12] in SUI). A significant treatment group*CM interaction (F(1,201.31) = 4.71; p = .031) indicated greater depressive symptom reduction in LLD-CBT compared to SUI at week 5 and post-treatment for patients without CM, but not at 6-month follow-up. Across both treatments, higher severity of the CM subtype 'physical neglect' was associated with a smaller depressive symptom reduction (F(1,207.16) = 5.37; p = .021). CONCLUSIONS: Specific and non-specific psychotherapy effectively reduced depressive symptoms in older individuals with depression and early trauma. For patients without early trauma, LLD-CBT may be preferable over SUI. Considering early trauma subtypes may contribute to develop personalized treatment approaches.

Reduced contrast sensitivity, pattern electroretinogram ratio, and diminished a-wave amplitude in patients with major depressive disorder.

The electroretinogram (ERG), a non-invasive electrophysiological tool used in ophthalmology, is increasingly applied to investigate neural correlates of depression. The present study aimed to reconsider previous findings in major depressive disorder (MDD) reporting (1) a diminished contrast sensitivity and (2) a reduced patten ERG (PERG) amplitude ratio, and additionally, to assess (3) the photopic negative response (PhNR) from the flash ERG (fERG), with the RETeval® device, a more practical option for clinical routine use. We examined 30 patients with a MDD and 42 healthy controls (HC), assessing individual contrast sensitivity thresholds with an optotype-based contrast test. Moreover, we compared the PERG ratio, an established method for early glaucoma detection, between both groups. The handheld ERG device was used to measure amplitudes and peak times of the fERG components including a-wave, b-wave and PhNR in both MDD patients and HCs. MDD patients exhibited diminished contrast sensitivity together with a reduced PERG ratio, compared to HC. With the handheld ERG device, we found reduced a-wave amplitudes in MDD, whereas no significant differences were observed in the fERG b-wave or PhNR between patients and controls. The reduced contrast sensitivity and PERG ratio in MDD patients supports the hypothesis that depression is associated with altered visual processing. The findings underscore the PERG's potential as a possible objective marker for depression. The reduced a-wave amplitude recorded with the RETeval® system in MDD patients might open new avenues for using handheld ERG devices as simplified approaches for advancing depression research compared to the PERG.

Lasting effects of transcranial direct current stimulation on the inducibility of synaptic plasticity by paired-associative stimulation in humans.

BACKGROUND: Transcranial direct current stimulation (tDCS) is capable of eliciting changes in cortical neuroplasticity. Increasing duration or repetition of tDCS during the after-effects of a first stimulation has been hypothesized to enhance efficacy. Computational models suggest sequential stimulation patterns with changing polarities to further enhance effects. Lasting tDCS effects on neural plasticity are of great importance for clinical applications. OBJECTIVE: The study systematically examined the influence of different tDCS paradigms on long term potentiation (LTP)-like plasticity in humans, focusing on stimulation duration, repetition frequency and sequential combinations of changing polarities as the underlying characteristics. METHODS: Amplitude changes of motor evoked potentials (MEP) were measured in response to paired associative stimulation (PAS) 6 h after application of different tDCS protocols. In total, 36 healthy participants completed the study, randomised into three groups with different stimulation protocols (N = 12 each). RESULTS: tDCS was able to display lasting modulatory effects on the inducibility of LTP-like plasticity in the human motor cortex 6 h after stimulation. TDCS with the anode on primary motor cortex significantly increased MEP amplitudes following PAS induction. Further analyses highlighted single stimulation block duration to be of higher importance than repetitive protocols for efficacy of effects. CONCLUSIONS: tDCS is capable of inducing lasting changes in the brain's capability to interact with future stimuli. Especially, effects on the inducibility of LTP-like plasticity might only be detectable with specific tests such as PAS and might otherwise be overlooked. Refined tDCS protocols should focus on higher current and duration of single stimulations instead of implementing complex repetitive schedules.

[Treatment resistance in anxiety disorders-Definition and treatment options]. / Therapieresistenz bei Angsterkrankungen ­ Definition und Behandlungsoptionen.

Treatment resistance in anxiety disorders represents a clinical challenge, contributes to the chronicity of the diseases as well as sequential comorbidities, and is associated with a significant individual and socioeconomic burden. This narrative review presents the operational definition of treatment resistance in anxiety disorders according to international consensus criteria (< 50% reduction in the Hamilton Anxiety Scale, HAM­A, score or < 50% reduction in the Beck Anxiety Inventory, BAI, score or a clinical global impression-improvement, CGI­I, score > 2). At least two unsuccessful guideline-based treatment attempts with pharmacological monotherapy or at least one unsuccessful treatment attempt with adequately delivered cognitive behavioral therapy are required. Pharmacotherapeutically, after excluding pseudo-resistance, switching the medication within one class or to another class and augmentation strategies with other antidepressants (mirtazapine, agomelatine), antipsychotics (quetiapine) or anticonvulsants (valproate) are recommended. Psychotherapeutically, third-wave therapies, psychodynamic therapy, systemic therapy and physical exercise can be considered for therapy resistance. In cases of no response to psychotherapy or pharmacotherapy, the respective other form of therapy or a combination of both should be offered. Compounds targeting the glutamatergic and endocannabinoid systems as well as neuropeptides are being tested as potential innovative pharmaceuticals for treatment-resistant anxiety disorders. There is an urgent need for further research to identify predictive markers and mechanisms as well as to develop innovative pharmacological and psychotherapeutic interventions for treatment-resistant anxiety disorders.

[Treatment-resistant obsessive-compulsive disorders]. / Therapieresistente Zwangsstörungen.

BACKGROUND: Obsessive-compulsive disorders (OCD) are mainly treated with disorder-specific cognitive behavioral therapy using exposure and response management and/or selective serotonin reuptake inhibitors; however, a significant subgroup of patients does not sufficiently benefit from this approach. OBJECTIVE: This article provides an overview of treatment-resistant OCD. MATERIAL AND METHODS: In this narrative review the definition, causes, diagnostic and therapeutic approaches to treatment-resistant OCD are addressed. RESULTS: Treatment resistance can be assumed in the absence of clinically relevant improvement under therapy, in the sense of a reduction of < 25% on the Yale-Brown obsessive-compulsive scale and a score of 4 (no change) on the clinical global impression-improvement scale. The number of unsuccessful treatment attempts required to establish treatment resistance is defined differently. Causative factors include misdiagnosis, a high severity, comorbid disorders, substance use, specific symptom constellations, organic causes, environmental factors, and aggravating factors in psychotherapy and pharmacotherapy. Suggestions for diagnostic and therapeutic approaches based on the German S3 guideline on OCD are presented. CONCLUSION: For patients with treatment resistance to first-line therapy, useful diagnostic and therapeutic recommendations are available (psychotherapeutic, psychopharmacological and neurostimulation procedures).

[Genetic diagnostics of mental health disorders in adulthood]. / Genetische Diagnostik bei psychischen Erkrankungen im Erwachsenenalter.

This review article provides insights into the role of genetic diagnostics in adult mental health disorders. The importance of genetic factors in the development of mental illnesses, from rare genetic syndromes to common complex genetic disorders, is described. Current clinical characteristics that may warrant a genetic diagnostic work-up are highlighted, including intellectual disability, autism spectrum disorders and severe psychiatric conditions with specific comorbidities, such as organ malformations or epilepsy. The review discusses when genetic diagnostics are recommended according to current guidelines as well as situations where they might be considered even in the absence of explicit guideline recommendations. This is followed by an overview of the procedures and the currently used diagnostic methods. Current limitations and possible developments in the field of genetic diagnostics in psychiatry are discussed, including the fact that, for many mental health conditions, genetic testing is not yet part of standard clinical practice; however, in summary genetic causes should be considered more frequently in certain clinical constellations, and genetic diagnostics and counselling should be offered where appropriate.

Effect of MAOA DNA Methylation on Human in Vivo Protein Expression Measured by [11C]harmine Positron Emission Tomography.

BACKGROUND: Epigenetic modifications like DNA methylation are understood as an intermediary between environmental factors and neurobiology. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the MAOA gene, particularly in the promoter/exon I/intron I region. An effect of MAOA methylation on peripheral protein expression was shown, but the extent to which methylation affects brain MAO-A levels is not fully understood. METHODS: Here, the influence of MAOA promoter/exon I/intron I region DNA methylation on global MAO-A distribution volume (VT), an index of MAO-A density, was assessed via [11C]harmine positron emission tomography in 22 patients (14 females) suffering from seasonal affective disorder and 30 healthy controls (17 females). RESULTS: No significant influence of MAOA DNA methylation on global MAO-A VT was found, despite correction for health status, sex, season, and MAOA variable number of tandem repeat genotype. However, season affected average methylation in women, with higher levels in spring and summer (Puncorr = .03). We thus did not find evidence for an effect of MAOA DNA methylation on brain MAO-A VT. CONCLUSIONS: In contrast to a previous study demonstrating an effect of methylation of a MAOA promoter region located further 5' on brain MAO-A, MAOA methylation of the region assessed here appears to affect brain protein levels to a limited extent at most. The observed effect of season on methylation levels is in accordance with extensive evidence for seasonal effects within the serotonergic system. CLINICALTRIALS.GOV IDENTIFIER: NCT02582398 (https://clinicaltrials.gov/ct2/show/NCT02582398).

Clinical manifestations and immunomodulatory treatment experiences in psychiatric patients with suspected autoimmune encephalitis: a case series of 91 patients from Germany.

Autoimmune encephalitis (AE) can rarely manifest as a predominantly psychiatric syndrome without overt neurological symptoms. This study's aim was to characterize psychiatric patients with AE; therefore, anonymized data on patients with suspected AE with predominantly or isolated psychiatric syndromes were retrospectively collected. Patients with readily detectable neurological symptoms suggestive of AE (e.g., epileptic seizures) were excluded. Patients were classified as "probable psychiatric AE (pAE)," if well-characterized neuronal IgG autoantibodies were detected or "possible pAE" (e.g., with detection of nonclassical neuronal autoantibodies or compatible cerebrospinal fluid (CSF) changes). Of the 91 patients included, 21 (23%) fulfilled our criteria for probable (autoantibody-defined) pAE and 70 (77%) those for possible pAE. Among patients with probable pAE, 90% had anti-NMDA receptor (NMDA-R) autoantibodies. Overall, most patients suffered from paranoid-hallucinatory syndromes (53%). Patients with probable pAE suffered more often from disorientation (p < 0.001) and impaired memory (p = 0.001) than patients with possible pAE. Immunotherapies were performed in 69% of all cases, mostly with high-dose corticosteroids. Altogether, 93% of the patients with probable pAE and 80% of patients with possible pAE reportedly benefited from immunotherapies (p = 0.251). In summary, this explorative, cross-sectional evaluation confirms that autoantibody-associated AE syndromes can predominantly manifest as psychiatric syndromes, especially in anti-NMDA-R encephalitis. However, in three out of four patients, diagnosis of possible pAE was based on nonspecific findings (e.g., slight CSF pleocytosis), and well-characterized neuronal autoantibodies were absent. As such, the spectrum of psychiatric syndromes potentially responding to immunotherapies seems not to be limited to currently known autoantibody-associated AE. Further trials are needed.

Rare copy number variation in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.

Deep phenotyping as a contribution to personalized depression therapy: the GEParD and DaCFail protocols.

Depressive patients suffer from a complex of symptoms of varying intensity compromising their mood, emotions, self-concept, neurocognition, and somatic function. Due to a mosaic of aetiologies involved in developing depression, such as somatic, neurobiological, (epi-)genetic factors, or adverse life events, patients often experience recurrent depressive episodes. About 20-30% of these patients develop difficult-to-treat depression. Here, we describe the design of the GEParD (Genetics and Epigenetics of Pharmaco- and Psychotherapy in acute and recurrent Depression) cohort and the DaCFail (Depression-associated Cardiac Failure) case-control protocol. Both protocols intended to investigate the incremental utility of multimodal biomarkers including cardiovascular and (epi-)genetic markers, functional brain and heart imaging when evaluating the response to antidepressive therapy using comprehensive psychometry. From 2012 to 2020, 346 depressed patients (mean age 45 years) were recruited to the prospective, observational GEParD cohort protocol. Between 2016 and 2020, the DaCFail case-control protocol was initiated integrating four study subgroups to focus on heart-brain interactions and stress systems in patients > 50 years with depression and heart failure, respectively. For DaCFail, 120 depressed patients (mean age 60 years, group 1 + 2), of which 115 also completed GEParD, and 95 non-depressed controls (mean age 66 years) were recruited. The latter comprised 47 patients with heart failure (group 3) and 48 healthy subjects (group 4) of a population-based control group derived from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study. Our hypothesis-driven, exploratory study design may serve as an exemplary roadmap for a standardized, reproducible investigation of personalized antidepressant therapy in an inpatient setting with focus on heart comorbidities in future multicentre studies.

How many hours do you sleep? A comparison of subjective and objective sleep duration measures in a sample of insomnia patients and good sleepers.

Our objective was to assess the agreement and linear relationships amongst multiple measures of sleep duration in a sample of patients with insomnia disorder and good sleeper controls. We retrospectively analysed data from 123 patients with insomnia disorder and 123 age- and gender-matched good sleeper controls who completed a simple subjective habitual sleep duration question (Pittsburgh Sleep Quality Index), a sleep diary (5-14 days), 2 nights of polysomnography, and two corresponding morning subjective estimates of sleep duration. Descriptive statistics, linear regression analyses and Bland-Altman plots were used to describe the relationship and (dis)agreement between sleep duration measures. Relationships between polysomnography and the simple question as well as between polysomnography and sleep diary were weak to non-existent. Subjective measures and polysomnography did not agree. Sleep duration measured with the Pittsburgh Sleep Quality Index or sleep diary was about 2 hr above or up to 4 hr below polysomnography-measured sleep duration. Patients with insomnia disorder, on average, reported shorter sleep duration compared with polysomnography, while good sleeper controls, on average, reported longer sleep duration compared with polysomnography. The results suggest that subjective and objective measures apparently capture different aspects of sleep, even when nominally addressing the same value (sleep duration). They disagree in both patients with insomnia disorder and good sleeper controls, but in different directions. Studies assessing sleep duration should take into account both the investigated population and the assessment method when interpreting results. Future studies should continue to investigate possible psychological and physiological correlates of sleep (mis)perception.

No alterations in potential indirect markers of locus coeruleus-norepinephrine function in insomnia disorder.

The norepinephrine locus coeruleus system (LC NE) represents a promising treatment target in patients with insomnia disorder (ID) due to its well understood links to arousal and sleep regulation. However, consistent markers of LC NE activity are lacking. This study measured three potential indirect markers of LC NE activity - REM sleep, P3 amplitude during an auditory oddball paradigm (as a marker of phasic LC activation), and baseline pupil diameter (as a marker of tonic LC activation). The parameters were then combined in a statistical model and tested to compare LC NE activity between 20 subjects with insomnia disorder (13 female; age 44.2 ± 15.1 year) and 20 healthy, good sleeping controls (GSC; 11 female; age 45.4 ± 11.6 year). No group differences regarding the primary outcome parameters were detected. Specifically, insomnia disorder did not display the hypothesised changes in markers of LC NE function. While increased LC NE function remains an interesting speculative pathway for hyperarousal in insomnia disorder, the investigated markers do not appear closely related to each other and fail to discriminate between insomnia disorder and good sleeping controls in these samples.