Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: a systematic review and meta-analysis.

Background: Ketamine and esketamine offer a novel approach in the pharmacological treatment of major depressive disorder (MDD). This meta-analysis aimed to investigate the placebo response in double-blind, randomized controlled studies (RCTs) on patients with MDD receiving ketamine or esketamine. Methods: For this systematic review and meta-analysis Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo and Embase databases were systematically searched for citations published up to March 17, 2023. A total number of 5017 abstracts was identified. Quality of the included trials was assessed with the Cochrane risk-of-bias tool. The meta-analysis was performed using a restricted maximum likelihood model. This study is registered with PROSPERO, number CRD42022377591. Results: A total number of 14 studies and 1100 participants (593 in the medication group and 507 in the placebo group) meeting the inclusion criteria were selected. We estimated the pooled effect sizes of the overall placebo (d pl = -1.85 [CI 95%: -2.9 to -0.79] and overall treatment (dtr = -2.57; [CI 95% -3.36 to -1.78]) response. The overall placebo response accounts for up to 72% of the overall treatment response. Furthermore, we performed subgroup analysis of 8 studies for the for the 7 days post-intervention timepoint. Seven days post-intervention the placebo response (d pl 7d = -1.98 [CI 95%: -3.26 to -0.69]) accounts for 66% of the treatment response (d tr 7d = - 3.01 [CI 95%, -4.28 to -1.74]). Conclusion: Ketamine and esketamine show large antidepressant effects. However, our findings suggest that the placebo response plays a significant role in the antidepressant response and should be used for the benefit of the patients in clinical practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022377591.

Prediction of estimated risk for bipolar disorder using machine learning and structural MRI features.

BACKGROUND: Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features. METHODS: Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites (N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPIbipolar). RESULTS: For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11-0.361) and a balanced accuracy of 63.1% (95% CI 55.9-70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI -0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6-67.8). BARS and EPIbipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance. CONCLUSIONS: Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features.

Young people at risk for developing bipolar disorder: Two-year findings from the multicenter prospective, naturalistic Early-BipoLife study.

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long­term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk.

Study protocol: combined N-of-1 trials to assess open-label placebo treatment for antidepressant discontinuation symptoms [FAB-study].

BACKGROUND: Antidepressant discontinuation is associated with a broad range of adverse effects. Debilitating discontinuation symptoms can impede the discontinuation process and contribute to unnecessary long-term use of antidepressants. Antidepressant trials reveal large placebo effects, indicating a potential use of open-label placebo (OLP) treatment to facilitate the discontinuation process. We aim to determine the effect of OLP treatment in reducing antidepressant discontinuation symptoms using a series of N-of-1 trials. METHODS: A series of randomized, single-blinded N-of-1 trials will be conducted in 20 patients with fully remitted DSM-V major depressive disorder, experiencing moderate to severe discontinuation symptoms following antidepressant discontinuation. Each N-of-1 trial consists of two cycles, each comprising two-week alternating periods of OLP treatment and of no treatment in a random order, for a total of eight weeks. Our primary outcome will be self-reported discontinuation symptoms rated twice daily via the smartphone application 'StudyU'. Secondary outcomes include expectations about discontinuation symptoms and (depressed) mood. Statistical analyses will be based on a Bayesian multi-level random effects model, reporting posterior estimates of the overall and individual treatment effects. DISCUSSION: Results of this trial will provide insight into the clinical application of OLP in treating antidepressant discontinuation symptoms, potentially offering a new cost-effective therapeutic tool. This trial will also determine the feasibility and applicability of a series of N-of-1 trials in a clinical discontinuation trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05051995, first registered September 20, 2021.

The effects of esketamine and treatment expectation in acute major depressive disorder (Expect): study protocol for a pharmacological fMRI study using a balanced placebo design.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent (8-15%), severely disabling disorder and is associated with enormous socioeconomic impact. Antidepressant medication for the treatment of MDD has proven effective in RCTs; however, placebo response is also substantial. Given the potential benefits of modulating the placebo response in patient care and pharmacological research, understanding the mechanisms underlying placebo response is of high clinical relevance. The placebo response is mediated by treatment expectation, i.e. an individual's belief about whether and how much they will improve as a consequence of their treatment. The mechanisms and moderators of treatment expectation effects in MDD are poorly understood. Initial brain imaging studies on placebo responses in MDD point towards the relevance of the lateral prefrontal cortex and the rostral anterior cingulate cortex (rACC). In this project, we will investigate the neural mechanisms underlying the antidepressant effects of treatment expectation associated with the fast-acting antidepressant esketamine in patients with MDD. Esketamine is an NMDA receptor antagonist inducing antidepressant effects within hours. METHODS: We will employ a fully balanced placebo design with the factors "treatment" (i.v. esketamine / placebo) and verbally induced "expectation" (high / low) combined with fMRI (resting state, emotion and reward processing paradigms) to investigate the psychological and neural mechanisms underlying the antidepressant effects of expectation, and how these interact with the pharmacological effects of esketamine. DISCUSSION: The insights gained by this project promise fundamental implications for clinical treatment and future drug trials. Unraveling the mechanisms underlying expectation effects on antidepressant treatment may inform (1) strategies to modulate these effects and thus improve assay sensitivity in RCTs and (2) novel treatment regiments aiming to maximize the synergistic effects of expectation and pharmacological treatment in the clinical care of patients with MDD. TRIAL REGISTRATION: This trial has been prospectively registered with the EU Clinical Trials Register: EudraCT-No.: 2020-000784-23 (November 17, 2020).

Machine Learning Prediction of Estimated Risk for Bipolar Disorders Using Hippocampal Subfield and Amygdala Nuclei Volumes.

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI (n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPIbipolar. We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

Disentangling pharmacological and expectation effects in antidepressant discontinuation among patients with fully remitted major depressive disorder: study protocol of a randomized, open-hidden discontinuation trial.

BACKGROUND: Antidepressants are established as an evidence-based, guideline-recommended treatment for Major Depressive Disorder. Prescriptions have markedly increased in past decades, with a specific surge in maintenance prescribing. Patients often remain on antidepressants longer than clinically necessary. When attempting to stop, many patients experience adverse discontinuation symptoms. Discontinuation symptoms can be debilitating and hinder successful discontinuation. While discontinuation symptoms can result from pharmacological effects, evidence on nocebo-induced side effects of antidepressant use suggests that patients' expectations may also influence occurrence. METHODS: To disentangle pharmacological and expectation effects in antidepressant discontinuation, patients with fully remitted Major Depressive Disorder who fulfill German guideline recommendations to discontinue will either remain on or discontinue their antidepressant. Participants' expectations will be manipulated by varying verbal instructions using an open-hidden paradigm. Within the open trial arms, participants will receive full information about treatment, i.e., high expectation. Within the hidden trial arms, participants will be informed about a 50% chance of discontinuing versus remaining on their antidepressant, i.e., moderate expectation. A total of N = 196 participants will be randomly assigned to either of the four experimental groups: open discontinuation (OD; n = 49), hidden discontinuation (HD; n = 49), open continuation (OC; n = 49), or hidden continuation (HC; n = 49). Discontinuation symptom load during the 13-week experimental phase will be our primary outcome measure. Secondary outcome measures include discontinuation symptom load during the subsequent 39-week clinical observation phase, recurrence during the 13-week experimental period, recurrence over the course of the complete 52-week trial evaluated in a time-to-event analysis, and stress, anxiety, and participants' attentional and emotional processing at 13 weeks post-baseline. Blood and saliva samples will be taken as objective markers of antidepressant blood serum level and stress. Optional rsfMRI measurements will be scheduled. DISCUSSION: Until today, no study has explored the interplay of pharmacological effects and patients' expectations during antidepressant discontinuation. Disentangling their effects has important implications for understanding mechanisms underlying adverse discontinuation symptoms. Results can inform strategies to manage discontinuation symptoms and optimize expectations in order to help patients and physicians discontinue antidepressants more safely and effectively. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05191277), January 13, 2022.

Daring to Feel: Emotion-Focused Psychotherapy Increases Amygdala Activation and Connectivity in Euthymic Bipolar Disorder-A Randomized Controlled Trial.

BACKGROUND: In bipolar disorder (BD), the alternation of extreme mood states indicates deficits in emotion processing, accompanied by aberrant neural function of the emotion network. The present study investigated the effects of an emotion-centered psychotherapeutic intervention on amygdala responsivity and connectivity during emotional face processing in BD. METHODS: In a randomized controlled trial within the multicentric BipoLife project, euthymic patients with BD received one of two interventions over 6 months: an unstructured, emotion-focused intervention (FEST), where patients were guided to adequately perceive and label their emotions (n = 28), or a specific, structured, cognitive behavioral intervention (SEKT) (n = 31). Before and after interventions, functional magnetic resonance imaging was conducted while patients completed an emotional face-matching paradigm (final functional magnetic resonance imaging sample of patients completing both measurements: SEKT, n = 17; FEST, n = 17). Healthy control subjects (n = 32) were scanned twice after the same interval without receiving any intervention. Given the focus of FEST on emotion processing, we expected FEST to strengthen amygdala activation and connectivity. RESULTS: Clinically, both interventions stabilized patients' euthymic states in terms of affective symptoms. At the neural level, FEST versus SEKT increased amygdala activation and amygdala-insula connectivity at postintervention relative to preintervention time point. In FEST, the increase in amygdala activation was associated with fewer depressive symptoms (r = 0.72) 6 months after intervention. CONCLUSIONS: Enhanced activation and functional connectivity of the amygdala after FEST versus SEKT may represent a neural marker of improved emotion processing, supporting the FEST intervention as an effective tool in relapse prevention in patients with BD.

Boosting the Theory of Mind Network: Specific Psychotherapy Increases Neural Correlates of Affective Theory of Mind in Euthymic Bipolar Disorder.

BACKGROUND: In bipolar disorder, impaired affective theory of mind (aToM) performance and aberrant neural activation in the ToM brain network partly explain social functioning impairments. However, it is not yet known whether psychotherapy of bipolar disorder influences neuroimaging markers of aToM. METHODS: In this study, conducted within the multicentric randomized controlled trial of the BipoLife consortium, patients with euthymic bipolar disorder underwent 2 group interventions over 6 months (mean = 28.45 weeks): 1) a specific, cognitive behavioral intervention (specific psychotherapeutic intervention [SEKT]) (n = 31) targeting impulse regulation, ToM, and social skills and 2) an emotion-focused intervention (FEST) (n = 28). To compare the effect of SEKT and FEST on neural correlates of aToM, patients performed an aToM task during functional magnetic resonance imaging before and after interventions (final functional magnetic resonance imaging sample of pre- and postcompleters, SEKT: n = 16; FEST: n = 17). Healthy control subjects (n = 32) were scanned twice with the same time interval. Because ToM was trained in SEKT, we expected an increased ToM network activation in SEKT relative to FEST postintervention. RESULTS: Both treatments effectively stabilized patients' euthymic state in terms of affective symptoms, life satisfaction, and global functioning. Confirming our expectations, SEKT patients showed increased neural activation within regions of the ToM network, bilateral temporoparietal junction, posterior cingulate cortex, and precuneus, whereas FEST patients did not. CONCLUSIONS: The stabilizing effect of SEKT on clinical outcomes went along with increased neural activation of the ToM network, while FEST possibly exerted its positive effect by other, yet unexplored routes.

Parent-Child Play and the Emergence of Externalizing and Internalizing Behavior Problems in Childhood: A Systematic Review.

It has widely been accepted that play has a major role in human development. The play situation is considered a save and controlled space in which children can learn to express their problems and to regulate their emotions, thus promoting emotional and behavioral adjustment. In early childhood, this process is thought to emerge in close interaction with caregivers. Parent-child play is thus viewed as an ideal window for parents to connect with their children and to support them in their social-emotional development. In this preregistered systematic review, we sought to integrate evidence from developmental and clinical psychology to shed more light on the role of parents in the relationship between parent-child play and children's behavioral adjustment as expressed in internalizing or externalizing behavior. Our review revealed that increased harsh control during play interactions as well as a lack of parental responsiveness, warmth and sensitivity were found to be associated with increased behavioral problems. Yet, no protective effect of warmth or responsiveness could be found in the context of risk groups. Moreover, the included studies indicated that positive affect expressed by parents during parent-child play was associated with fewer behavior problems in children, while negative affect was associated with more behavior problems. In general, this review revealed that quality and quantity of playful parent-child interactions were reduced in children with behavioral problems of both domains compared to children without behavioral problems. These findings illustrate the important role of parental characteristics during play interactions and their possible impact on children's behavioral adjustment.

The German research consortium for the study of bipolar disorder (BipoLife): a magnetic resonance imaging study protocol.

BACKGROUND: Bipolar disorder is one of the most severe mental disorders. Its chronic course is associated with high rates of morbidity and mortality, a high risk of suicide and poor social and occupational outcomes. Despite the great advances over the last decades in understanding mental disorders, the mechanisms underlying bipolar disorder at the neural network level still remain elusive. This has severe consequences for clinical practice, for instance by inadequate diagnoses or delayed treatments. The German research consortium BipoLife aims to shed light on the mechanisms underlying bipolar disorders. It was established in 2015 and incorporates ten university hospitals across Germany. Its research projects focus in particular on individuals at high risk of bipolar disorder, young patients in the early stages of the disease and patients with an unstable highly relapsing course and/or with acute suicidal ideation. METHODS: Functional and structural magnetic resonance imaging (MRI) data was acquired across nine sites within three different studies. Obtaining neuroimaging data in a multicenter setting requires among others the harmonization of the acquisition protocol, the standardization of paradigms and the implementation of regular quality control procedures. The present article outlines the MRI imaging protocols, the acquisition parameters, the imaging paradigms, the neuroimaging quality assessment procedures and the number of recruited subjects. DISCUSSION: The careful implementation of a MRI study protocol as well as the adherence to well-defined quality assessment procedures is one key benchmark in the evaluation of the overall quality of large-scale multicenter imaging studies. This article contributes to the BipoLife project by outlining the rationale and the design of the MRI study protocol. It helps to set the necessary standards for follow-up analyses and provides the technical details for an in-depth understanding of follow-up publications.

Individuals at increased risk for development of bipolar disorder display structural alterations similar to people with manifest disease.

In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen's d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.

Humor in Psychiatry: Lessons From Neuroscience, Psychopathology, and Treatment Research.

Humor is a ubiquitous human characteristic that is socially motivated at its core and has a broad range of significant positive effects on emotional well-being and interpersonal relationships. Simultaneously, however, impairments in humor abilities have often been described in close association with the occurrence and course of neuropsychiatric disorders, such as schizophrenia, social anxiety, or depression. In the past decade, research in the neuroimaging and psychiatric domain has substantially progressed to (i) characterize impaired humor as an element of psychopathology, and (ii) shed light on the neurobiological mechanisms underlying the role of humor in neuropsychiatric diseases. However, (iii) targeted interventions using concepts of positive psychology have revealed first evidence that a systematic training and/or a potential reactivation of humor-related skills can improve rehabilitative outcome in neuropsychiatric patient groups. Here, we sought to integrate evidence from neuroscience, as well as from psychopathology and treatment research to shed more light on the role of humor in psychiatry. Based on these considerations, we provide directions for future research and application in mental health services, focusing on the question of how our scientific understanding of humor can provide the basis for psychological interventions that foster positive attitudes and well-being.

Antagonism between brain regions relevant for cognitive control and emotional memory facilitates the generation of humorous ideas.

The ability to generate humor gives rise to positive emotions and thus facilitate the successful resolution of adversity. Although there is consensus that inhibitory processes might be related to broaden the way of thinking, the neural underpinnings of these mechanisms are largely unknown. Here, we use functional Magnetic Resonance Imaging, a humorous alternative uses task and a stroop task, to investigate the brain mechanisms underlying the emergence of humorous ideas in 24 subjects. Neuroimaging results indicate that greater cognitive control abilities are associated with increased activation in the amygdala, the hippocampus and the superior and medial frontal gyrus during the generation of humorous ideas. Examining the neural mechanisms more closely shows that the hypoactivation of frontal brain regions is associated with an hyperactivation in the amygdala and vice versa. This antagonistic connectivity is concurrently linked with an increased number of humorous ideas and enhanced amygdala responses during the task. Our data therefore suggests that a neural antagonism previously related to the emergence and regulation of negative affective responses, is linked with the generation of emotionally positive ideas and may represent an important neural pathway supporting mental health.

The Relationship Between Different Aspects of Theory of Mind and Symptom Clusters in Psychotic Disorders: Deconstructing Theory of Mind Into Cognitive, Affective, and Hyper Theory of Mind.

Background: Several meta-analyses highlight pronounced problems in general Theory of Mind (ToM), the ability to infer other persons' mental states, in patients with psychosis in comparison to non-clinical controls. In addition, first studies suggest associations between Hyper-ToM, an exaggerated inference of mental states to others, and delusions. Research on different ToM subtypes (Cognitive ToM, Affective ToM, and Hyper-ToM) and symptom clusters of psychosis (positive, negative, and disorganized symptoms) have gathered conflicting findings. Thus, the present study examined group differences between patients with psychosis and non-clinical controls concerning Cognitive ToM/Affective ToM and Hyper-ToM. Further, the association between ToM subtypes and symptom clusters (positive, negative, and disorganized symptoms) were examined. Methods: Patients with psychotic disorders (n = 64, 1/3 with present delusions indicated by a minimum score of four in the PANSS P1 item) and non-clinical controls (n = 21) were examined with assessments of Cognitive ToM and Affective ToM abilities and Hyper-ToM errors using the Frith-Happé animations. Psychopathology was assessed using the Positive and Negative Syndrome Scale. Results: Patients with psychosis presented more pronounced problems in Cognitive and Affective ToM in comparison to non-clinical controls, whereas there were no group differences with regard to Hyper-ToM errors. Furthermore, deficits in Cognitive ToM were associated with general delusions, whereas problems in Affective ToM were associated with negative and disorganized symptoms. In addition, there was no association between Hyper-ToM errors and any symptoms when controlling for years of education. Conclusions: Our findings suggest that deficits in ToM subtypes might not be directly related to delusions and positive symptoms and are in line with more recently developed cognitive models of delusions. In addition, our results support the well-established finding of associations between ToM alterations and negative or disorganized symptoms. Our results shed light on the role of different dimensions of ToM in specific symptoms of psychosis.

Characterizing the theory of mind network in schizophrenia reveals a sparser network structure.

Impaired social functioning is a hallmark of schizophrenia and altered functional integration between distant brain regions are expected to account for signs and symptoms of the disorder. The functional neuroarchitecture of a network relevant for social functioning, the mentalizing network, is however poorly understood. In this study we examined dysfunctions of the mentalizing network in patients with schizophrenia compared to healthy controls via dynamic causal modelling and an interactive social decision-making game. Network characteristics were analyzed on a single subject basis whereas graph theoretic metrics such as in-degree, out-degree and edge-connectivity per network node were compared between the groups. The results point to a sparser network structure in patients with schizophrenia and highlight the dorsomedial prefrontal cortex as a disconnected network hub receiving significantly less input from other brain regions in the network. Further analyses suggest that integrating pathways from the right and the left temporo-parietal junction into the dorsomedial prefrontal cortex were less frequently found in patients with schizophrenia. Brain and behavior analyses further suggest that the connectivity-intactness within the entire network is associated with functional interpersonal behavior during the task. Thus, the neurobiological alterations within the mentalizing network in patients with schizophrenia point to a specific integration deficit between core brain regions underlying the generation of higher-order representations and thereby provide a potential treatment target.

Cortical Complexity in People at Ultra-High-Risk for Psychosis Moderated by Childhood Trauma.

Subjects with ultra-high risk (UHR) states for psychosis show brain structural volume changes similar to first-episode psychosis and also elevated incidence of environmental risk factors like childhood trauma. It is unclear, however, whether early neurodevelopmental trajectories are altered in UHR. We screened a total of 12,779 first-year Chinese students to enroll 36 UHR subjects (based on clinical interviews) and 59 non-UHR healthy controls for a case-control study of markers of early neurodevelopment. Subjects underwent 3T MRI scanning and clinical characterization, including the childhood trauma questionnaire (CTQ). We then used the CAT12 toolbox to analyse structural brain scans for cortical surface complexity, a spherical harmonics-based marker of early neurodevelopmental changes. While we did not find statistically significant differences between the groups, a trend level finding for reduced cortical complexity (CC) in UHR vs. non-UHR subjects emerged in the left superior temporal cortex (and adjacent insular and transverse temporal cortices), and this trend level association was significantly moderated by childhood trauma (CTQ score). Our findings indicate that UHR subjects tend to show abnormal cortical surface morphometry, in line with recent research; more importantly, however, this association seems to be considerably modulated by early environmental impacts. Hence, our results provide an indication of environmental or gene × environment interactions on early neurodevelopment leading up to elevated psychosis risk.

Improving early recognition and intervention in people at increased risk for the development of bipolar disorder: study protocol of a prospective-longitudinal, naturalistic cohort study (Early-BipoLife).

BACKGROUND: Bipolar disorders (BD) belong to the most severe mental disorders, characterized by an early onset and recurrent, severe episodes or a chronic course with poor psychosocial functioning in a proportion of patients. Many patients with BD experience substantial symptomatology months or even years before full BD manifestation. Adequate diagnosis and treatment is often delayed, which is associated with a worse outcome. This study aims to prospectively evaluate and improve early recognition and intervention strategies for persons at-risk for BD. METHODS: Early-BipoLife is a prospective-longitudinal cohort study of 1419 participants (aged 15-35 years) with at least five waves of assessment over a period of at least 2 years (baseline, 6, 12, 18 and 24 months). A research consortium of ten university and teaching hospitals across Germany conducts this study. The following risk groups (RGs) were recruited: RG I: help-seeking youth and young adults consulting early recognition centres/facilities presenting ≥ 1 of the proposed risk factors for BD, RG II: in-/outpatients with unipolar depressive syndrome, and RG III: in-/outpatients with attention-deficit/hyperactivity disorder (ADHD). The reference cohort was selected from the German representative IMAGEN cohort. Over the study period, the natural course of risk and resilience factors, early symptoms of BD and changes of symptom severity (including conversion to manifest BD) are observed. Psychometric properties of recently developed, structured instruments on potential risk factors for conversion to BD and subsyndromal symptomatology (Bipolar Prodrome Symptom Scale, Bipolar at-risk criteria, EPIbipolar) and biomarkers that potentially improve prediction are investigated. Moreover, actual treatment recommendations are monitored in the participating specialized services and compared to recently postulated clinical categorization and treatment guidance in the field of early BD. DISCUSSION: Findings from this study will contribute to an improved knowledge about the natural course of BD, from the onset of first noticeable symptoms (precursors) to fully developed BD, and about mechanisms of conversion from subthreshold to manifest BD. Moreover, these generated data will provide information for the development of evidence-based guidelines for early-targeted detection and preventive intervention for people at risk for BD.

Negative Interpretation Biases Precede the Onset of Psychosis.

This study investigated whether a negative interpretation bias was present in people at high risk for psychosis. People with an At Risk Mental State (ARMS; n = 21), patients with First Episode Psychosis (FEP; n = 20), and healthy controls (n = 20) performed three tasks, each of which was designed to measure interpretation bias. Both ARMS and FEP participants showed an attenuated positive bias compared to controls. These findings extend previous results investigating interpretation bias in psychosis by showing that interpretative biases are present before the onset of psychosis, and could therefore contribute to its development. Biased interpretation mechanisms could be a new target for clinical intervention in the early phase of psychosis.