Risk Phenotypes, Comorbidities, Pharmacotherapy, and Electroconvulsive Therapy (ECT) in a Cohort with Difficult-to-Treat Depression in Comparison to an Unmedicated Control Group.

BACKGROUND: Approximately 15-25% of depressed patients suffer from difficult-to-treat depression (DTD). Patients with DTD require a thorough examination to avoid the oversight of treatable (psychiatric/somatic) comorbidities or (pseudo-)resistance to antidepressant drugs (ADs). Polymorphisms of the cytochrome P450 (CYP) enzymes 2D6 and 2C19, which play a major role in the metabolism of ADs, may contribute to resistance to ADs. Patients with DTD might benefit from electroconvulsive therapy (ECT). METHODS: We enrolled 109 patients with DTD and 29 untreated depressed controls (UDC). We assessed risk phenotypes, comorbidities, and treatment, including ECT. We also performed pharmacokinetic analyses of CYP2D6 and CYP2C19. RESULTS: DTD patients significantly more often suffered from comorbid psychiatric diseases, especially ICD-10: F40-F48 (DTD:40.4%, UDC:17.2%, OR 11.87, p=0.011) than UDC patients. DTD patients receiving ECT were more likely to achieve remission (37.7% vs. 11.8%, OR=3.96, p=0.023). Treatment with ADs did not differ between remitters and non-remitters. No significant differences were observed in the distribution of CYP2D6 and CYP2C19 variants between both groups. CONCLUSION: Patients with DTD appear to experience comorbid neurotic stress and somatoform disorders (ICD-10: F40 - F48) more frequently. Therefore, a comprehensive differential diagnosis is crucial when patients do not respond sufficiently to antidepressant medication. Genotyping CYP2D6 and CYP2C19 should be considered.

Improving causality perception judgments in schizophrenia spectrum disorder via transcranial direct current stimulation.

BACKGROUND: Deficient causality perception and attribution may underlie key symptoms of schizophrenia spectrum disorder (SSD), such as delusions and ideas of reference. Although transcranial direct current stimulation (tDCS) can increase the influence of spatial information on perceptual causality judgments among healthy participants, its effect among patients with SSD remains unknown. We sought to determine whether tDCS modulates the contribution of stimulus characteristics to perceptual causality judgments among patients with SSD; we predicted that right parietal tDCS would increase the influence of spatial stimulus characteristics on patients' causality perception. METHODS: Patients with SSD received frontal, parietal, frontoparietal and sham tDCS in 4 separate sessions. Pre- and post-tDCS, patients viewed video clips of ball A colliding with ball B. Spatial linearity (ball B's angle of egress) and temporal contiguity (delay between collision and ball B's movement) varied parametrically. After each launching event, patients rated perceived causality. RESULTS: Among 19 patients with SSD, we found a brain region-dependent effect of tDCS regarding sensitivity to violations of spatial linearity. After right parietal anodal tDCS, the influence of angle variations on patients' perceptual causality judgments increased, reflected by a higher probability of perceived causality for stimuli with small angles and a lower probability of perceived causality for stimuli with high angles. CONCLUSION: Transcranial direct current stimulation increased the influence of spatial stimulus characteristics on causality perception among patients with SSD. Future research should explore potential links between tDCS-induced changes in basic perceptual processes and clinical symptoms, such as delusions and ideas of reference.

DNA Methylation of POMC and NR3C1-1F and Its Implication in Major Depressive Disorder and Electroconvulsive Therapy.

INTRODUCTION: Precision medicine in psychiatry is still in its infancy. To establish patient-tailored treatment, adequate indicators predicting treatment response are required. Electroconvulsive therapy (ECT) is considered one of the most effective options for pharmacoresistant major depressive disorder (MDD), yet remission rates were reported to be below 50%. METHODS: Since epigenetics of the stress response system seem to play a role in MDD, we analyzed the DNA methylation (DNAm) of genes encoding the glucocorticoid receptor (NR3C1) and proopiomelanocortin (POMC) through Sanger Sequencing. For analysis, blood was taken before and after the first and last ECT from MDD patients (n=31), unmedicated depressed controls (UDC; n=19, baseline), and healthy controls (HC; n=20, baseline). RESULTS: Baseline DNAm in NR3C1 was significantly lower in UDCs compared to both other groups (UDC: 0.014(±0.002), ECT: 0.031(±0.001), HC: 0.024(±0.002); p<0.001), whereas regarding POMC, ECT patients had the highest DNAm levels (ECT: 0.252(±0.013), UDC: 0.156(±0.015), HC: 0.162(±0.014); p<0.001). NR3C1m and POMCm decreased after the first ECT (NR3C1: p<0.001; POMC: p=0.001), and responders were less methylated compared to non-responders in NR3C1(p<0.001). DISCUSSION: Our findings indicate that both genes might play a role in the chronification of depression and NR3C1 may be relevant for ECT response prediction.

Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).

BACKGROUND: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To assess cognitive performance and changes over time in NMOSD. METHODS: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. RESULTS: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. CONCLUSIONS: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

Neurological soft signs are increased in major depressive disorder irrespective of treatment.

The significance of neurological soft signs (NSS) in major depressive disorder (MDD) remains unclear and the stability of NSS in relation to antidepressant treatment has never been investigated. We hypothesized that NSS are relatively stable trait markers of MDD. We thus predicted that patients show more NSS than healthy controls, irrespective of illness duration and antidepressant treatment. To test this hypothesis, NSS were assessed in chronically depressed, medicated MDD patients before (n = 23) and after (n = 18) a series of electroconvulsive therapy (ECT). In addition, NSS were assessed once in acutely depressed, unmedicated MDD patients (n = 16) and healthy controls (n = 20). We found that both chronically depressed, medicated MDD patients and acutely depressed, unmedicated MDD patients showed more NSS than healthy controls. The degree of NSS in both patient groups did not differ. Importantly, we found no change in NSS after on average eleven sessions of ECT. Thus, the manifestation of NSS in MDD seems to be independent of illness duration and pharmacological and electroconvulsive antidepressant treatment. From a clinical perspective, our findings corroborate the neurological safety of ECT.

Is transcranial direct current stimulation, alone or in combination with antidepressant medications or psychotherapies, effective in treating major depressive disorder? A systematic review and meta-analysis.

BACKGROUND: Transcranial direct current stimulation (tDCS) has shown mixed results for depression treatment. The efficacies of tDCS combination therapies have not been investigated deliberately. This review aims to evaluate the clinical efficacy of tDCS as a monotherapy and in combination with medication, psychotherapy, and ECT for treating adult patients with major depressive disorder (MDD) and identified the factors influencing treatment outcome measures (i.e. depression score, dropout, response, and remission rates). METHODS: The systematic review was performed in PubMed/Medline, EMBASE, PsycINFO, Web of Sciences, and OpenGrey. Two authors performed independent literature screening and data extraction. The primary outcomes were the standardized mean difference (SMD) for continuous depression scores after treatment and odds ratio (OR) dropout rate; secondary outcomes included ORs for response and remission rates. Random effects models with 95% confidence intervals were employed in all outcomes. The overall effect of tDCS was investigated by meta-analysis. Sources of heterogeneity were explored via subgroup analyses, meta-regression, sensitivity analyses, and assessment of publication bias. RESULTS: Twelve randomised, sham-controlled trials (active group: N = 251, sham group: N = 204) were included. Overall, the integrated depression score of the active group after treatment was significantly lower than that of the sham group (g = - 0.442, p = 0.017), and further analysis showed that only tDCS + medication achieved a significant lower score (g = - 0.855, p < 0.001). Moreover, this combination achieved a significantly higher response rate than sham intervention (OR = 2.7, p = 0.006), while the response rate remained unchanged for the other three therapies. Dropout and remission rates were similar in the active and sham groups for each therapy and also for the overall intervention. The meta-regression results showed that current intensity is the only predictor for the response rate. None of publication bias was identified. CONCLUSION: The effect size of tDCS treatment was obviously larger in depression score compared with sham stimulation. The tDCS combined selective serotonin re-uptake inhibitors is the optimized therapy that is effective on depression score and response rate. tDCS monotherapy and combined psychotherapy have no significant effects. The most important parameter for optimization in future trials is treatment strategy.

Mindfulness practice for protecting mental health during the COVID-19 pandemic.

Emerging evidence shows that the coronavirus disease 2019 (COVID-19) pandemic is negatively affecting mental health around the globe. Interventions to alleviate the psychological impact of the pandemic are urgently needed. Whether mindfulness practice may protect against the harmful emotional effects of a pandemic crisis remains hitherto unknown. We investigated the influence of mindfulness training on mental health during the COVID-19 outbreak in China. We hypothesized that mindfulness practitioners might manifest less pandemic-related distress, depression, anxiety, and stress than non-practitioners and that more frequent practice would be associated with an improvement in mental health during the pandemic. Therefore, we assessed pandemic-related distress and symptoms of depression, anxiety, and stress, as well as the frequency of meditation practice at the peak of new infections (Feb 4-5; N = 673) and three weeks later (Feb 29-30; N = 521) in mindfulness practitioners via online questionnaires. Self-reported symptoms were also collected from non-practitioners at peak time only (N = 1550). We found lower scores of pandemic-related distress in mindfulness practitioners compared to non-practitioners. In general, older participants showed fewer symptoms of depression and anxiety. In younger practitioners, pandemic-related distress decreased from peak to follow-up. Importantly, increased mindfulness training during the preceding two weeks was associated with lower scores of depression and anxiety at both assessments. Likewise, practice frequency predicted individual improvement in scores of depression, anxiety, and stress at follow-up. Our results indicate that mindfulness meditation might be a viable low-cost intervention to mitigate the psychological impact of the COVID-19 crisis and future pandemics.

Early Detection and Prevention of Schizophrenic Psychosis-A Review.

Psychotic disorders often run a chronic course and are associated with a considerable emotional and social impact for patients and their relatives. Therefore, early recognition, combined with the possibility of preventive intervention, is urgently warranted since the duration of untreated psychosis (DUP) significantly determines the further course of the disease. In addition to established diagnostic tools, neurobiological factors in the development of schizophrenic psychoses are increasingly being investigated. It is shown that numerous molecular alterations already exist before the clinical onset of the disease. As schizophrenic psychoses are not elicited by a single mutation in the deoxyribonucleic acid (DNA) sequence, epigenetics likely constitute the missing link between environmental influences and disease development and could potentially serve as a biomarker. The results from transcriptomic and proteomic studies point to a dysregulated immune system, likely evoked by epigenetic alterations. Despite the increasing knowledge of the neurobiological mechanisms involved in the development of psychotic disorders, further research efforts with large population-based study designs are needed to identify suitable biomarkers. In conclusion, a combination of blood examinations, functional imaging techniques, electroencephalography (EEG) investigations and polygenic risk scores should be considered as the basis for predicting how subjects will transition into manifest psychosis.

Transcranial direct current stimulation improves action-outcome monitoring in schizophrenia spectrum disorder.

Patients with schizophrenia spectrum disorder often demonstrate impairments in action-outcome monitoring. Passivity phenomena and hallucinations, in particular, have been related to impairments of efference copy-based predictions which are relevant for the monitoring of outcomes produced by voluntary action. Frontal transcranial direct current stimulation has been shown to improve action-outcome monitoring in healthy subjects. However, whether transcranial direct current stimulation can improve action monitoring in patients with schizophrenia spectrum disorder remains unknown. We investigated whether transcranial direct current stimulation can improve the detection of temporal action-outcome discrepancies in patients with schizophrenia spectrum disorder. On 4 separate days, we applied sham or left cathodal/right anodal transcranial direct current stimulation in a randomized order to frontal (F3/F4), parietal (CP3/CP4) and frontoparietal (F3/CP4) areas of 19 patients with schizophrenia spectrum disorder and 26 healthy control subjects. Action-outcome monitoring was assessed subsequent to 10 min of sham/transcranial direct current stimulation (1.5 mA). After a self-generated (active) or externally generated (passive) key press, subjects were presented with a visual outcome (a dot on the screen), which was presented after various delays (0-417 ms). Participants had to detect delays between the key press and the visual consequence. Symptom subgroups were explored based on the presence or absence of symptoms related to a paranoid-hallucinatory syndrome. In general, delay-detection performance was impaired in the schizophrenia spectrum disorder compared to the healthy control group. Interaction analyses showed group-specific (schizophrenia spectrum disorder versus healthy control group) and symptom-specific (with/without relevant paranoid-hallucinatory symptoms) transcranial direct current stimulation effects. Post hoc tests revealed that frontal transcranial direct current stimulation improved the detection of long delays in active conditions and reduced the proportion of false alarms in undelayed trials of the passive condition in patients. The patients with no or few paranoid-hallucinatory symptoms benefited especially from frontal transcranial direct current stimulation in active conditions, while improvement in the patients with paranoid-hallucinatory symptoms was predominantly reflected in reduced false alarm rates in passive conditions. These data provide some first evidence for the potential utility of transcranial direct current stimulation in improving efference copy mechanisms and action-outcome monitoring in schizophrenia spectrum disorder. Current data indicate that improving efference copy-related processes can be especially effective in patients with no or few positive symptoms, while intersensory matching (i.e. task-relevant in passive conditions) could be more susceptible to improvement in patients with paranoid-hallucinatory symptoms.

Transcranial Direct Current Stimulation Improves Semantic Speech-Gesture Matching in Patients With Schizophrenia Spectrum Disorder.

BACKGROUND: Patients with schizophrenia spectrum disorders (SSD) have severe deficits in speech and gesture processing that contribute considerably to the burden of this disorder. Brain imaging shows left inferior frontal gyrus involvement for impaired processing of co-verbal gestures in patients with schizophrenia. Recently, transcranial direct current stimulation (tDCS) of the left frontal lobe has been shown to modulate processing of co-verbal gestures in healthy subjects. Although tDCS has been used to reduce symptoms of patients with SSD, the effects of tDCS on gesture processing deficits remain hitherto unexplored. OBJECTIVE: Here we tested the hypothesis that inhibitory cathodal tDCS of the left frontal lobe decreases pathological dysfunction and improves semantic processing of co-verbal gestures in patients with SSD. METHODS: We measured ratings and reaction times in a speech-gesture semantic relatedness assessment task during application of frontal, frontoparietal, parietal, and sham tDCS to 20 patients with SSD and 29 healthy controls. RESULTS: We found a specific effect of tDCS on speech-gesture relatedness ratings of patients. Frontal compared to parietal and sham stimulation significantly improved the differentiation between related and unrelated gestures. Placement of the second electrode (right frontal vs parietal) did not affect the effect of left frontal stimulation, which reduced the preexisting difference between patients and healthy controls. CONCLUSION: Here we show that left frontal tDCS can improve semantic co-verbal gesture processing in patients with SSD. tDCS could be a viable tool to normalize processing in the left frontal lobe and facilitate direct social communicative functioning in patients with SSD.

Hemispheric differences in the processing of visual consequences of active vs. passive movements: a transcranial direct current stimulation study.

Perceiving the sensory consequences of one's own actions is essential to successfully interact with the environment. Previous studies compared self- (active) and externally generated (passive) movements to investigate the processing of voluntary action-outcomes. Increased temporal binding (intentional binding) as well as increased detection of delays between action and outcome have been observed for active compared to passive movements. Using transcranial direct stimulation (tDCS) it has been shown that left hemispheric anodal stimulation decreased the intentional binding effect. However, whether the left hemisphere contributes to delay detection performance between action and outcome is unknown. We investigated polarization-dependent effects of left and right frontoparietal tDCS on detecting temporal action-outcome discrepancies. We applied anodal and cathodal stimulation to frontal (F3/F4), parietal (CP3/CP4) and frontoparietal (F3/CP4) areas. After stimulation, participants were presented with visual feedback with various delays after a key press. They had to report whether they detected a delay between the key press and the feedback. In half of the trials the key press was self-initiated, in the other half it was externally generated. A main effect of electrode location indicated highest detection performance after frontal stimulation. Furthermore, we found that the advantage for active versus passive conditions was larger for left hemispheric anodal stimulation as compared to cathodal stimulation. Whereas the frontal cortex is related to delay detection performance in general, hemispheric differences seem to support the differentiation of self-initiated versus externally generated movement consequences.

Modulating the assessment of semantic speech-gesture relatedness via transcranial direct current stimulation of the left frontal cortex.

BACKGROUND: Co-verbal gestures are crucial for communication. Neuroimaging studies suggest that the left frontal lobe may be especially important for processing metaphoric co-verbal gestures. However, so far, the specific functional relevance of the left frontal lobe in metaphoric (abstract sentence content) co-verbal gesture processing compared to iconic (concrete sentence content) co-verbal gesture processing has not been demonstrated. OBJECTIVE: We investigated the functional relevance of the left frontal lobe for processing metaphoric co-verbal gestures using transcranial direct current stimulation (tDCS). We hypothesised a polarisation dependent effect of left frontal tDCS on reaction times and ratings in a speech-gesture semantic relatedness assessment task. METHODS: We applied anodal, cathodal and sham stimulation to the frontal (F3/F4), parietal (CP3/CP4) and frontoparietal (F3/CP4) areas. During stimulation, seventeen subjects were presented with videos of an actor saying concrete or abstract sentences accompanied by related or unrelated iconic or metaphoric gestures and rated to what extent gestures were related to the sentence content. RESULTS: We found electrode localisation- and polarisation-dependent changes in reaction times and ratings for metaphoric co-verbal gestures compared to iconic gestures. Post-hoc tests revealed a specific polarisation effect for frontoparietal stimulation sites: compared to cathodal stimulation, anodal stimulation of the left frontal lobe decreased reaction times and relatedness assessments for metaphoric conditions only. CONCLUSION: Using tDCS, we demonstrated the functional relevance of the left frontal lobe for processing metaphoric co-verbal gestures. Thus, tDCS may possibly constitute an approach to facilitate metaphoric co-verbal gesture-processing in patients with specific deficits.