UNASSIGNED: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis.
UNASSIGNED: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants.
UNASSIGNED: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives.
UNASSIGNED: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

The Research Domain Criteria (RDoC) approach seeks to understand mental functioning in continuous valid dimensions ranging from functional to pathological. Reward processing is a transdiagnostic functioning domain of the RDoC. Due to prototypical abnormalities, addictions are especially applicable for the investigation of reward processing. Subjective reward processing is challenging to determine and differs between genotypes of the catechol-O-methyltransferase gene (COMT) Val158Met polymorphism for incomparable daily life experiences. Thus, we implemented the monetary incentive delay (MID) task with comparable reward cues and visual analog scales (VAS) to assess subjective reward processing in male abstinent cannabis-dependent individuals (N = 13) and a control group of nicotine smokers (N = 13). COMT Val158Met genotypes were nominally associated with differences in cigarettes smoked per day and motivation in the MID Task (p = 0.028; p = 0.017). For feedback gain, activation of the right insula was increased in controls, and activation correlated with gain expectancy and satisfaction about gain. Subjective value is not detached from reward parameters, but is modulated from expectancy and reward by the insula. The underlying neural mechanisms are a fundamental target point for treatments, interventions, and cognitive behavioral therapy.

Autism Spectrum Disorder (ASD) is a common pediatric neurobiological disorder with up to 80% of genetic etiologies. Systems biology approaches may make it possible to test novel therapeutic strategies targeting molecular pathways to alleviate ASD symptoms. A clinical database of autism subjects was queried for individuals with a copy number variation (CNV) on microarray, Vineland, and Parent Concern Questionnaire scores. Pathway analyses of genes from pathogenic CNVs yielded 659 genes whose protein-protein interactions and mRNA expression mapped 121 genes with maximal antenatal expression in 12 brain regions. A Research Domain Criteria (RDoC)-derived neural circuits map revealed significant differences in anxiety, motor, and activities of daily living skills scores between altered CNV genes and normal microarrays subjects, involving Positive Valence (reward), Cognition (IQ), and Social Processes. Vascular signaling was identified as a biological process that may influence these neural circuits. Neuroinflammation, microglial activation, iNOS and 3-nitrotyrosine increase in the brain of Semaphorin 3F- Neuropilin 2 (Sema 3F-NRP2) KO, an ASD mouse model, agree with previous reports in the brain of ASD individuals. Signs of platelet deposition, activation, release of serotonin, and albumin leakage in ASD-relevant brain regions suggest possible blood brain barrier (BBB) deficits. Disruption of neurovascular signaling and BBB with neuroinflammation may mediate causative pathophysiology in some ASD subgroups. Although preliminary, these data demonstrate the potential for developing novel therapeutic strategies based on clinically derived data, genomics, cognitive neuroscience, and basic neuroscience methods.

BACKGROUND: Suicide has emerged as a serious concern for public health; however, only few studies have revealed the differences between major psychiatric disorders and suicide. Recent studies have attempted to quantify research domain criteria (RDoC) into numeric scores to systematically use them in computerized methods. The RDoC scores were used to reveal the characteristics of suicide and its association with major psychiatric disorders.
OBJECTIVE: We intended to investigate the differences in the dimensional psychopathology among hospitalized suicidal patients and the association between the dimensional psychopathology of psychiatric disorders and length of hospital stay.
METHODS: This retrospective study enrolled hospitalized suicidal patients diagnosed with major psychiatric disorders (depression, schizophrenia, and bipolar disorder) between January 2010 and December 2020 at a tertiary hospital in South Korea. The RDoC scores were calculated using the patients\' admission notes. To measure the differences between psychiatric disorder cohorts, analysis of variance and the Cochran Q test were conducted and post hoc analysis for RDoC domains was performed with the independent two-sample t test. A linear regression model was used to analyze the association between the RDoC scores and sociodemographic features and comorbidity index. To estimate the association between the RDoC scores and length of hospital stay, multiple logistic regression models were applied to each psychiatric disorder group.
RESULTS: We retrieved 732 admissions for 571 patients (465 with depression, 73 with schizophrenia, and 33 with bipolar disorder). We found significant differences in the dimensional psychopathology according to the psychiatric disorders. The patient group with depression showed the highest negative RDoC domain scores. In the cognitive and social RDoC domains, the groups with schizophrenia and bipolar disorder scored higher than the group with depression. In the arousal RDoC domain, the depression and bipolar disorder groups scored higher than the group with schizophrenia. We identified significant associations between the RDoC scores and length of stay for the depression and bipolar disorder groups. The odds ratios (ORs) of the length of stay were increased because of the higher negative RDoC domain scores in the group with depression (OR 1.058, 95% CI 1.006-1.114) and decreased by higher arousal RDoC domain scores in the group with bipolar disorder (OR 0.537, 95% CI 0.285-0.815).
CONCLUSIONS: This study showed the association between the dimensional psychopathology of major psychiatric disorders related to suicide and the length of hospital stay and identified differences in the dimensional psychopathology of major psychiatric disorders. This may provide new perspectives for understanding suicidal patients.

The Research Domain Criteria seeks to bridge knowledge from neuroscience with clinical practice by promoting research into valid neurocognitive phenotypes and dimensions, irrespective of symptoms and diagnoses as currently conceptualized. While the Research Domain Criteria offers a vision of future research and practice, its 39 functional constructs need refinement to better target new phenotyping efforts. This study aimed to determine which Research Domain Criteria constructs are most relevant to understanding obsessive-compulsive and related disorders, based on a consensus between experts in the field of obsessive-compulsive and related disorders.
Based on a modified Delphi method, 46 experts were recruited from Australia, Africa, Asia, Europe and the Americas. Over three rounds, experts had the opportunity to review their opinion in light of feedback from the previous round, which included how their response compared to other experts and a summary of comments given.
Thirty-four experts completed round one, of whom 28 (82%) completed round two and 24 (71%) completed round three. At the final round, four constructs were endorsed by ⩾75% of experts as \'primary constructs\' and therefore central to understanding obsessive-compulsive and related disorders. Of these constructs, one came from the Positive Valence System (Habit), two from the Cognitive Control System (Response Selection/Inhibition and Performance Monitoring) and the final construct was an additional item suggested by experts (Compulsivity).
This study identified four Research Domain Criteria constructs that, according to experts, cut across different obsessive-compulsive and related disorders. These constructs represent key areas for future investigation, and may have potential implications for clinical practice in terms of diagnostic processes and therapeutic management of obsessive-compulsive and related disorders.

Preventing dementia, or modifying disease course, requires identification of presymptomatic or minimally symptomatic high-risk individuals.
We used longitudinal electronic health records from two large academic medical centers and applied a validated natural language processing tool to estimate cognitive symptomatology. We used survival analysis to examine the association of cognitive symptoms with incident dementia diagnosis during up to 8 years of follow-up.
Among 267,855 hospitalized patients with 1,251,858 patient years of follow-up data, 6516 (2.4%) received a new diagnosis of dementia. In competing risk regression, an increasing cognitive symptom score was associated with earlier dementia diagnosis (HR 1.63; 1.54-1.72). Similar results were observed in the second hospital system and in subgroup analysis of younger and older patients.
A cognitive symptom measure identified in discharge notes facilitated stratification of risk for dementia up to 8 years before diagnosis.

Sluggish cognitive tempo (SCT) is separable from attention-deficit/hyperactivity disorder (ADHD) and other psychopathologies, and growing evidence demonstrates SCT to be associated with impairment in both children and adults. However, it remains unclear how SCT should optimally be conceptualized. In this article, we argue that multiple models of psychopathology should be leveraged to make substantive advances to our understanding of SCT. Both categorical and dimensional approaches should be used, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology, the Research Domain Criteria (RDoC) initiative, and hierarchical models of psychopathology. Studies are needed to determine whether individuals categorized with SCT can be reliably identified and differentiated from individuals without SCT in pathophysiological, neuropsychological, behavioral, and daily life functioning. Studies are also needed to evaluate the validity and utility of SCT as a transdiagnostic and dimensional construct. In considering SCT as a dimensional and potentially transdiagnostic construct, we describe ways in which SCT might be examined within the RDoC framework, including negative valence systems, cognitive systems, and arousal/regulatory systems, as well as within hierarchical models of psychopathology. Conceptualizing SCT within both categorical and dimensional models of psychopathology will help to better understand the causes, developmental pathways, and clinical implications of SCT, both as a construct in its own right and also in relation to other psychopathologies.

The clinical presentation of pediatric obsessive-compulsive disorder (OCD) is heterogeneous, which is a stumbling block to understanding pathophysiology and to developing new treatments. A major shift in psychiatry, embodied in the Research Domain Criteria (RDoC) initiative of National Institute of Mental Health, recognizes the pitfalls of categorizing mental illnesses using diagnostic criteria. Instead, RDoC encourages researchers to use a dimensional approach, focusing on narrower domains of psychopathology to characterize brain-behavior relationships. Our aim in this multidisciplinary pilot study was to use computer vision tools to record OCD behaviors and to cross-validate these behavioral markers with standard clinical measures.
Eighteen youths with OCD and 21 healthy controls completed tasks in an innovation laboratory (free arrangement of objects, hand washing, arrangement of objects on contrasting carpets). Tasks were video-recorded. Videos were coded by blind raters for OCD-related behaviors. Children\'s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and other scales were administered. We compared video-recorded measures of behavior in OCD versus healthy controls and correlated video measures and clinical measures of OCD.
Behavioral measures on the videos were significantly correlated with specific CY-BOCS dimension scores. During the free arrangement task, more time spent ordering objects and more moves of objects were both significantly associated with higher CY-BOCS ordering/repeating dimension scores. Longer duration of hand washing was significantly correlated with higher scores on CY-BOCS ordering/repeating and forbidden thoughts dimensions. During arrangement of objects on contrasting carpets, more moves and more adjustment of objects were significantly associated with higher CY-BOCS ordering/repeating dimension scores.
Preliminary data suggest that measurement of behavior using video recording is a valid approach for quantifying OCD psychopathology. This methodology could serve as a new tool for investigating OCD using an RDoC approach. This objective, novel behavioral measurement technique may benefit both researchers and clinicians in assessing pediatric OCD and in identifying new behavioral markers of OCD. Clinical Trial Registry: Development of an Instrument That Monitors Behaviors Associated With OCD. NCT02866422. http://clinicaltrials.gov.

The Research Domain Criteria (RDoC) initiative put forth by the National Institute of Mental Health represents an exciting new framework in which to study psychopathology. The article by Hamm et al. (2016) is an interesting application of an \"RDoC lens\" toward a program of research on panic disorder. This commentary highlights the many strengths of the Hamm et al. (2016) study-most notably the article\'s application of a well-studied animal model of anxiety (Fanselow\'s, , threat imminence model) to humans, utilization of an interesting behavioral paradigm (as an analog for avoidance behaviors in panic disorder), and using RDoC to examine predictors of treatment response. This commentary also discusses several questions about RDoC that arise out of Hamm et al. For example, (a) How should participants be selected for RDoC studies? (b) Are RDoC constructs risk factors (and risk factors for what)? (c) Besides Hamm et al.\'s, approach, how else can RDoC be used in treatment studies? In sum, Hamm et al. is a very good example of an RDoC study, and in this early phase of the initiative, more examples for how the approach plays out are needed.