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Background: Ketamine is a highly effective antidepressant for patients with treatment-resistant major depressive disorder (MDD). Resting-state functional magnetic resonance imaging studies show disruptions of functional connectivity (FC) between limbic regions and resting-state networks (RSNs) in MDD, including the default mode network, central executive network (CEN), and salience network (SN). Here, we investigated whether serial ketamine treatments change FC between limbic structures and RSNs., Methods: Patients with MDD (n = 44) were scanned at baseline (time 1 [T1]) and 24 hours after the first (T2) and fourth (T3) infusions of ketamine. Healthy control subjects (n = 50) were scanned at baseline, with a subgroup (n = 17) being rescanned at 2 weeks. Limbic regions included the amygdala and hippocampus, and RSNs included the default mode network, CEN, and SN., Results: Ketamine increased right amygdala FC to the right CEN (p = .05), decreased amygdala FC to the left CEN (p = .005) at T2 versus T1 (p = .015), which then increased at T3 versus T2 (p = .002), and decreased left amygdala FC to the SN (p = .016). Decreased left amygdala to SN FC at T2 predicted improvements in anxiety at T3 (p = .006). Ketamine increased right hippocampus FC to the left CEN (p = .001), and this change at T2 predicted decreased anhedonia at T3 (p = .005)., Conclusions: Ketamine modulates FC between limbic regions and RSNs implicated in MDD. Increases in FC between limbic regions and the CEN suggest that ketamine may be involved in restoring top-down control of emotion processing. FC decreases between the left amygdala and SN suggest that ketamine may ameliorate MDD-related dysconnectivity in these circuits. Early FC changes between limbic regions and RSNs may be predictive of clinical improvements., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: This randomized, multisite, intent-to-treat study tested the effects of 2 levels of treatment intensity (number of hours) and 2 treatment styles on the progress of young children with autism spectrum disorder (ASD). We predicted that initial severity of developmental delay or autism symptoms would moderate the effects of intensity and style on progress in 4 domains: autism symptom severity, expressive communication, receptive language, and nonverbal ability., Method: A total of 87 children with ASD, mean age 23.4 months, were assigned to 1 of 2 intervention styles (naturalistic developmental/behavioral or discrete trial teaching), each delivered for either 15 or 25 hours per week of 1:1 intervention for 12 months by trained research staff. All caregivers received coaching twice monthly. Children were assessed at 4 timepoints. Examiners and coders were naive to treatment assignment., Results: Neither style nor intensity had main effects on the 4 outcome variables. In terms of moderating the effects of initial severity of developmental delay and of autism symptom severity, neither moderated the effects of treatment style on progress in any of the 4 domains. In terms of treatment intensity, initial severity moderated effect of treatment intensity on only 1 domain, namely, change in autism symptom severity; in a secondary analysis, this effect was found in only 1 site., Conclusion: Neither treatment style nor intensity had overall effects on child outcomes in the 4 domains examined. Initial severity did not predict better response to 1 intervention style than to another. We found very limited evidence that initial severity predicted better response to 25 vs 15 hours per week of intervention in the domains studied., Clinical Trial Registration Information: Intervention Effects of Intensity and Delivery Style for Toddlers With Autism: https://clinicaltrials.gov/; NCT02272192., (Copyright © 2020 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Many persons with serious mental illness (SMI) who have experienced homelessness struggle to sustain stable and independent housing. We know little about determinants of this population's housing status. This study aimed to identify person-level determinants of housing status among homeless-experienced veterans with SMI, focused primarily on cognition. Method: We administered cross-sectional surveys and detailed cognitive assessments on a convenience sample of homeless-experienced veterans with SMI ( n = 90); we also reviewed these participants' medical records. We captured person-level potential predictors of housing status (demographics, cognition, diagnoses, symptoms, and service utilization) and 2 years of retrospective housing history. Participants' housing status was conceptualized as the setting (stable housing, other sheltered settings, and streets) they lived in for >50% of the past 2 years. We used the chi-square test and analysis of variance to determine how potential predictors differed by housing status. We used recursive partitioning to identify the combination of potential predictors and corresponding scores that best-differentiated participants by housing status. Results: No between-groups differences (p < .05) in cognition, symptoms, or other person-level factors were found among participants grouped by housing status. Recursive partitioning did not yield a stable model to predict housing status from the potential predictor variables. Conclusions and Implications for Practice: These data suggest that clinical interventions addressing studied person-level factors (e.g., cognitive rehabilitation) may not affect housing status for homeless-experienced veterans. As housing is highly influenced by social determinants of health, policies, and practices that affect contextual factors (e.g., affordable housing supply) may be more likely to improve housing status. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Individuals with psychiatric disorders are vulnerable to adverse mental health outcomes following physical illness. This longitudinal cohort study defined risk profiles for readmission for suicidal behavior and self-harm after general hospitalization of adults with serious mental illness. Structured electronic health record data were analyzed from 15,644 general non-psychiatric index hospitalizations of individuals with depression, bipolar, and psychotic disorders admitted to an urban health system in the southwestern United States between 2006 and 2017. Using data from one-year prior to and including index hospitalization, supervised machine learning was implemented to predict risk of readmission for suicide attempt and self-harm in the following year. The Classification and Regression Tree algorithm produced a classification prediction with an area under the receiver operating curve (AUC) of 0.86 (95% confidence interval (CI) 0.74-0.97). Incidence of suicide-related behavior was highest after general non-psychiatric hospitalizations of individuals with prior suicide attempt or self-harm (18%; 69 cases/389 hospitalizations) and lowest after hospitalizations associated with very high medical morbidity burden (0 cases/3090 hospitalizations). Predictor combinations, rather than single risk factors, explained the majority of risk, including concomitant alcohol use disorder with moderate medical morbidity, and age ≤55-years-old with low medical morbidity. Findings suggest that applying an efficient and highly interpretable machine learning algorithm to electronic health record data may inform general hospital clinical decision support, resource allocation, and preventative interventions for medically ill adults with serious mental illness., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Eating disorder and body dysmorphic disorder symptoms overlap and frequently co-occur clinically, yet whether they represent one or more underlying constructs in the general population is unknown. We examined relationships between these symptoms on underlying factor structures and dimensional distributions in a young adult sample of 328 students using the Eating Disorder Examination-Questionnaire (EDE-Q 6.0) and the Dysmorphic Concern Questionnaire (DCQ). We performed factor and hierarchical cluster analyses on pooled items and Gaussian mixture modeling on score distributions. EDE-Q 6.0 and DCQ total scores were correlated ( r = 0.53, p < .001). Pooled items demonstrated a three-factor solution; DCQ items separating from two EDE-Q 6.0 factors. Hierarchical clustering yielded a two-cluster solution that separated the two scales. Mixture modeling demonstrated that more than one underlying distribution best fit the data for each scale. These results suggest that the EDE-Q 6.0 and DCQ measure different sets of psychopathological features, despite their tendency to track together. Moreover, eating disorder and body dysmorphic phenotypes each show nonuniform variation from normal to abnormal. This argues against using linear dimensional applications of these scales to assess individuals ranging from mild to severe in symptom severity. Separate scales may be necessary to characterize lower and higher ranges of clinical severity.

Inflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n = 46; female, n = 17) received open label infusion of ketamine (0.5 mg/kg over 40 min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status × sex interaction: p = 0.096), in which lower baseline levels of IL-8 in females (p = 0.095) but not males (p = 0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as ≥50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status × sex × time interaction: F(1,42)=6.68, p = 0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (β = -0.63, p = 0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p = 0.08) whereas the inverse was found in males (p = 0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-α, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.

Objective: Innovative approaches are needed for assessing treatment preferences of individuals with schizophrenia. Conjoint analysis methods may help to identify preferences, but the usability and validity of these methods for individuals with schizophrenia remain unclear. This study examined computerized conjoint analysis for persons with schizophrenia and whether preferences for weight management programs predict service use., Methods: A computerized, patient-facing conjoint analysis system was developed through iterative consultation with 35 individuals with schizophrenia enrolled at a community mental health clinic. An additional 35 overweight participants with schizophrenia then used the system to choose among psychosocial weight management programs varying in four attributes: location (community or clinic), delivery mode (Internet or in person), leader (clinician or layperson), and training mode (individual or group). A multilevel logit model with partial preference data determined contributions of each attribute to groupwide preferences. Associations were studied between preferences and use of a psychosocial weight management group., Results: Conjoint analysis system usability was rated highly. Groupwide preferences were significantly influenced by location (p<0.001; clinic was preferred), leader (p=0.02; clinician was preferred), and training mode (p<0.001; group was preferred) but not delivery mode (p=0.68). Preferences did not correlate with age, gender, body mass index, illness severity, or subsequent program use. Participants described barriers to program attendance, including transportation, scheduling, privacy, psychiatric illness, and lack of motivation., Conclusions: Computerized conjoint analysis can produce valid assessments of treatment preferences of persons with schizophrenia and inform treatment development and implementation. Although preferences may affect treatment use, they are one of multiple factors.

Recent clinical trials of transcranial direct current stimulation (tDCS) in depression have shown contrasting results. Consequently, we used in-vivo neuroimaging to confirm targeting and modulation of depression-relevant neural circuitry by tDCS. Depressed participants (N = 66, Baseline Hamilton Depression Rating Scale (HDRS) 17-item scores ≥14 and <24) were randomized into Active/Sham and High-definition (HD)/Conventional (Conv) tDCS groups using a double-blind, parallel design, and received tDCS individually targeted at the left dorsolateral prefrontal cortex (DLPFC). In accordance with Ampere's Law, tDCS currents were hypothesized to induce magnetic fields at the stimulation-target, measured in real-time using dual-echo echo-planar-imaging (DE-EPI) MRI. Additionally, the tDCS treatment trial (consisting of 12 daily 20-min sessions) was hypothesized to induce cerebral blood flow (CBF) changes post-treatment at the DLPFC target and in the reciprocally connected anterior cingulate cortex (ACC), measured using pseudo-continuous arterial spin labeling (pCASL) MRI. Significant tDCS current-induced magnetic fields were observed at the left DLPFC target for both active stimulation montages (Brodmann's area (BA) 46: p HD  = 0.048, Cohen's d HD  = 0.73; p Conv  = 0.018, d Conv  = 0.86; BA 9: p HD  = 0.011, d HD  = 0.92; p Conv  = 0.022, d Conv  = 0.83). Significant longitudinal CBF increases were observed (a) at the left DLPFC stimulation-target for both active montages (p HD  = 3.5E-3, d HD  = 0.98; p Conv  = 2.8E-3, d Conv  = 1.08), and (b) at ACC for the HD-montage only (p HD  = 2.4E-3, d HD  = 1.06; p Conv  = 0.075, d Conv  = 0.64). These results confirm that tDCS-treatment (a) engages the stimulation-target, and (b) modulates depression-relevant neural circuitry in depressed participants, with stronger network-modulations induced by the HD-montage. Although not primary outcomes, active HD-tDCS showed significant improvements of anhedonia relative to sham, though HDRS scores did not differ significantly between montages post-treatment.

Objective: To date, no one-on-one psychotherapy protocol for elementary and middle school-aged children with autism spectrum disorder (ASD) has been found to be efficacious for treating autism-related symptoms such as failure to initiate social interactions. This study compared modular cognitive behavioral therapy (CBT) with enhanced standard community treatment (ESCT) in terms of impact on the severity of autism-related symptoms., Method: Children with ASD (N = 107; aged 6-13 years) were randomly assigned to a treatment condition (CBT or ESCT). Both treatments provided 32 therapy sessions. The CBT condition utilized a modular design, matching specific evidence-based treatment elements to each child's clinical needs (e.g., social-communication symptoms). The ESCT condition provided social skills training and cognitive behavioral training in a structured and linear group therapy format. The primary outcome measure was independent evaluator ratings of peer engagement during school recess using a structured and validated observation system. Parents also made session-by-session ratings on personalized autism-related symptom profiles throughout treatment., Results: CBT outperformed ESCT on the primary outcome measure (p < .001; d = .50; 95% CI [.06, .93]) and the secondary outcome measure (p = .003; d = .87; 95% CI [.45, 1.27])., Conclusions: The modular one-on-one CBT program evaluated in this study may be beneficial for reducing the severity of autism-related symptoms in some children with ASD. Further research is needed to clarify the extent of the treatment effect and the feasibility of implementation for therapists in the community. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Patients with major depressive disorder (MDD) exhibit impaired control of cognitive and emotional systems, including deficient response selection and inhibition. Though these deficits are typically attributed to abnormal communication between macro-scale cortical networks, altered communication with the cerebellum also plays an important role. Yet, how the circuitry between the cerebellum and large-scale functional networks impact treatment outcome in MDD is not understood. We thus examined how ketamine, which elicits rapid therapeutic effects in MDD, modulates cerebro-cerebellar circuitry during response-inhibition using a functional imaging NoGo/Go task in MDD patients (N = 46, mean age: 39.2, 38.1% female) receiving four ketamine infusions, and healthy controls (N = 32, mean age:35.2, 71.4% female). We fitted psychophysiological-interaction (PPI) models for a functionally-derived cerebellar-seed and extracted average PPI in three target functional networks, frontoparietal (FPN), sensory-motor (SMN) and salience (SN) networks. Time and remission status were then evaluated for each of the networks and their network-nodes. Follow-up tests examined whether PPI-connectivity differed between patient remitter/non-remitters and controls. Results showed significant decreases in PPI-connectivity after ketamine between the cerebellum and FPN (p < 0.001) and SMN networks (p = 0.008) in remitters only (N = 20). However, ketamine-related changes in PPI-connectivity between the cerebellum and the SN (p = 0.003) did not vary with remitter status. Cerebellar-FPN, -SN PPI values at baseline were also associated with treatment outcome. Using novel methodology to quantify the functional coupling of cerebro-cerebellar circuitry during response-inhibition, our findings highlight that these loops play distinct roles in treatment response and could potentially serve as novel biomarkers for fast-acting antidepressant therapies in MDD., (Copyright © 2021. Published by Elsevier Inc.)

Background: Subcallosal cingulate (SCC) activity is associated with treatment response in major depressive disorder (MDD). Using electroconvulsive therapy (ECT) as a treatment model in this exploratory study, we addressed whether pretreatment SCC structural connectivity with corticolimbic-striatal circuitry relates to therapeutic outcome and whether these connectivity patterns change with treatment., Methods: Diffusion magnetic resonance imaging scans were acquired in 43 patients with MDD (mean [SD] age = 41 [13] years; men/women: 18/25) before and within 1 week of completing an ECT index series and in 31 healthy control subjects scanned twice (mean [SD] age = 38 [11] years; men/women: 17/18). Probabilistic tractography from subject-specific anatomically defined SCC seed regions to the ventral striatum (VS), anterior cingulate cortex (ACC), and bilateral medial prefrontal cortex (mPFC) was used to estimate structural connectivity in the target network., Results: SCC-mPFC connectivity was lower in responders (>50% symptom improvement) than nonresponders both before (p < .014) (difference 37%-96% left and right hemispheres) and after (p = .023) (difference 100% right hemisphere) treatment. SCC-mPFC connectivity in responders was also decreased compared with control subjects both at baseline (p = .012) and after ECT (p = .006), whereas nonresponders had SCC-right mPFC connectivity similar to that of control subjects. Subjects with MDD also showed decreased SCC-ACC connectivity compared with control subjects (baseline: p < .003, after ECT: p = .001), although SCC-ACC connectivity did not distinguish responders from nonresponders. Bilateral SCC-VS connectivity decreased (11%) with ECT (p = .021) regardless of treatment response., Conclusions: While SCC-ACC connectivity may be a hallmark of MDD compared with control subjects, lower pretreatment SCC-mPFC connectivity in ECT responders (compared with nonresponders and control subjects) suggests that connectivity in this pathway may serve as a potential biomarker of therapeutic outcome and be relevant for treatment selection., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

This study tested whether the effect of treatment intensity or treatment style on children's frequency and maturity of spontaneous communication varied by initial severity of disability. Eighty-seven toddlers with autism spectrum disorders were randomly assigned to either (a) 15 hrs per week of discrete trial teaching (DTT), (b) 25 hrs per week of DTT, (c) 15 hrs per week of a naturalistic developmental behavioral intervention (NDBI), or (d) 25 hrs per week of NDBI. Trained research staff implemented the 1:1 treatments in homes or educational centers over 12 months. We quantified the frequency and maturity of spontaneous communication during monthly 6-min communication samples. We quantified disability severity at Time 1 using the developmental quotient from the Mullen Scales of Early Learning and the total calibrated severity score from the Autism Diagnostic Observation Schedule-second edition. Higher levels of treatment intensity (i.e., more hours per week) benefited frequency and maturity of spontaneous communication growth rate only in children with relatively mild autism symptoms. Other results were nonsignificant. Autism Res 2020, 13: 1902-1912. © 2020 International Society for Autism Research and Wiley Periodicals LLC LAY SUMMARY: Eighty-seven toddlers with autism spectrum disorders were randomly assigned to 15 hrs per week of discrete trial teaching (DTT), 25 hrs per week of DTT, 15 hrs per week of a naturalistic developmental behavioral intervention (NDBI), or 25 hrs per week of NDBI. Trained research staff implemented the treatments in homes or educational centers over 12 months. More hours of treatment per week benefited frequency and maturity of spontaneous communication growth rate only in children with relatively mild autism symptoms. Other results were nonsignificant., (© 2020 International Society for Autism Research and Wiley Periodicals LLC.)

Females suffer from depression at twice the rate of males and have differential neural and emotional responses to inflammation. However, sex-specific evaluation of relationships between inflammation and response to depression treatments are lacking. Some data suggest that interleukin(IL)-8 predicts treatment response to antidepressants and has a relationship with depressive symptom severity. This study examines whether IL-8 predicts treatment response to electroconvulsive therapy (ECT), and whether there are sex specific effects. In 40 depressed patients (22 female), plasma levels of IL-8, as well as other markers of inflammation including IL-6, IL-10, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) were obtained prior to administration of ECT and after completion of the index treatment series. Depression treatment response was defined as ≥ 50% reduction in Hamilton Depression Rating Scale (HAM-D) Score. Baseline levels of IL-8 differed by responder status, depending on sex (group × sex interaction: β = -0.571, p = 0.04), with female responders having lower levels of IL-8 at baseline as compared to female non-responders [t(20) = 2.37, p = 0.03]. Further, IL-8 levels from baseline to end of treatment differed by responder status, depending on sex (group × sex × time interaction: [F(1,36) = 9.48, p = 0.004]), and change in IL-8 from baseline to end of treatment was negatively correlated with percentage change in HAM-D score in females (β = -0.458, p = 0.03), but not in males (β = 0.315, p = 0.20). Other inflammatory markers did not differ in relation to responder status and sex. Further evaluation of sex differences in the relationship between IL-8, depression, and treatment response, across disparate treatment modalities, may inform mechanisms of response and aid in development of personalized medicine strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Objective: Symptom heterogeneity in major depressive disorder obscures diagnostic and treatment-responsive biomarker identification. Whether symptom constellations are differentially changed by electroconvulsive therapy (ECT) remains unknown. We investigate the clustering of depressive symptoms over the ECT index and whether ECT differentially influences symptom clusters., Methods: The 17-item Hamilton Depression Rating Scale (HDRS-17) was collected from 111 patients with current depressive episode before and after ECT from 4 independent participating sites of the Global ECT-MRI Research Collaboration. Exploratory factor analysis of HDRS-17 items pre- and post-ECT treatment identified depressive symptom dimensions before and after ECT. A 2-way analysis of covariance was used to determine whether baseline symptom clusters were differentially changed by ECT between treatment remitters (defined as patients with posttreatment HDRS-17 total score ≤8) and nonremitters while controlling for pulse width, titration method, concurrent antidepressant treatment, use of benzodiazepine, and demographic variables., Results: A 3-factor solution grouped pretreatment HDRS-17 items into core mood/anhedonia, somatic, and insomnia dimensions. A 2-factor solution best described the symptoms at posttreatment despite poorer separation of items. Among remitters, core mood/anhedonia symptoms were significantly more reduced than somatic and insomnia dimensions. No differences in symptom dimension trajectories were observed among nonremitting patients., Conclusions: Electroconvulsive therapy targets the underlying source of depressive symptomatology and may confer differential degrees of improvement in certain core depressive symptoms. Our findings of differential trajectories of symptom clusters over the ECT index might help related predictive biomarker studies to refine their approaches by identifying predictors of change along each latent symptom dimension.

Background: Current diagnostic strategy for bipolar disorders relies on symptomological classification. Yet, responses to both pharmacological and psychotherapeutic treatments vary widely, suggesting that underlying neuropathological differences are not well defined by current nosology. Classifying patients with bipolar disorder based on emotion regulation network (ERN) activation may account for some of the heterogeneity within the disorder., Methods: Euthymic participants diagnosed with bipolar I disorder (n = 86) and healthy subjects (n = 80) underwent functional magnetic resonance imaging scans while engaged in emotional reappraisal of negative stimuli. After determining average regional activations in key network regions, we applied agglomerative hierarchical clustering to identify subtypes of bipolar disorder. Next, we examined relations among neural subtypes, demographic variables, and mood symptoms., Results: Analyses revealed two primary neural subtypes of euthymic bipolar I disorder participants. The first subtype, ERN cluster 1, was characterized by increased amygdala activation and slightly increased ventrolateral prefrontal and subgenual cingulate activation, whereas ERN cluster 2 was defined by decreased amygdala activation with wider-spread prefrontal activation. Cluster 1 was associated with a higher number of hospitalizations for depression (odds ratio = 1.30, 95% confidence interval = 1.02-1.64) and later onset of manic episodes (odds ratio = 1.06, 95% confidence interval = 1.00-21.13) than cluster 2. ERN clusters of healthy subjects differed from bipolar disorder clusters and were defined by differential activation of the prefrontal cortex. ERN clusters of healthy subjects, which differed from bipolar disorder clusters, were defined by differential activation of the prefrontal cortex., Conclusions: Emotion regulation circuitry can distinguish neurobiological subtypes of bipolar disorder in the euthymic state. These subtypes, which are differentially associated with indices of illness severity and subsyndromal affective symptoms, may help to inform relapse risk and more personalized treatment approaches., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD., (Copyright © 2020 McPartland, Bernier, Jeste, Dawson, Nelson, Chawarska, Earl, Faja, Johnson, Sikich, Brandt, Dziura, Rozenblit, Hellemann, Levin, Murias, Naples, Platt, Sabatos-DeVito, Shic, Senturk, Sugar, Webb and the Autism Biomarkers Consortium for Clinical Trials.)

We present a new method for constructing structural inference brain networks from functional measures of cortical features. Instead of averaging vertex-wise cortical features, we propose the use of full functions of spatial densities of measures such as thickness and use two dimensional pairwise correlations between regions to construct population networks. We show increased within group correlations for both healthy controls and toddlers with prenatal alcohol exposure compared to the existing mean-based correlation approach. Further, we also show significant differences in brain connectivity between the healthy controls and the exposed group.

The objective of the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is to evaluate a set of lab-based behavioral video tracking (VT), electroencephalography (EEG), and eye tracking (ET) measures for use in clinical trials with children with autism spectrum disorder (ASD). Within the larger organizational structure of the ABC-CT, the Data Acquisition and Analytic Core (DAAC) oversees the standardization of VT, EEG, and ET data acquisition, data processing, and data analysis. This includes designing and documenting data acquisition and analytic protocols and manuals; facilitating site training in acquisition; data acquisition quality control (QC); derivation and validation of dependent variables (DVs); and analytic deliverables including preparation of data for submission to the National Database for Autism Research (NDAR). To oversee consistent application of scientific standards and methodological rigor for data acquisition, processing, and analytics, we developed standard operating procedures that reflect the logistical needs of multi-site research, and the need for well-articulated, transparent processes that can be implemented in future clinical trials. This report details the methodology of the ABC-CT related to acquisition and QC in our Feasibility and Main Study phases. Based on our acquisition metrics from a preplanned interim analysis, we report high levels of acquisition success utilizing VT, EEG, and ET experiments in a relatively large sample of children with ASD and typical development (TD), with data acquired across multiple sites and use of a manualized training and acquisition protocol., (Copyright © 2020 Webb, Shic, Murias, Sugar, Naples, Barney, Borland, Hellemann, Johnson, Kim, Levin, Sabatos-DeVito, Santhosh, Senturk, Dziura, Bernier, Chawarska, Dawson, Faja, Jeste, McPartland and the Autism Biomarkers Consortium for Clinical Trials.)

Objective: Oxidative stress is implicated in the aetiology of schizophrenia, and the antioxidant defence system (AODS) may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain and its correlates with clinical and demographic variables in schizophrenia., Methods: GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms., Results: We found a negative correlation between GSH levels and age at onset (r = -0.46, p = 0.015), and a trend-level positive relationship between GSH and duration of illness (r = 0.34, p = 0.076)., Conclusion: Our findings are consistent with a possible compensatory upregulation of the AODS with longer duration of illness and suggest that the AODS may play a role in schizophrenia.

Background: Individuals with co-existing serious mental illness and non-psychiatric medical illness are at high risk of acute care utilization. Mining of electronic health record data can help identify and categorize predictors of psychiatric hospital readmission in this population., Objective: This study aimed to identify modifiable predictors of psychiatric readmission among individuals with comorbid bipolar disorder and medical illness. This goal was accomplished by applying objective variable selection via machine learning techniques., Method: This was a retrospective analysis of electronic health record data derived from 77,296 episodes of care from 2006 to 2016 within the University of California Health Care System. Data included 1,250 episodes of care involving patients with bipolar disorder and serious comorbid medical illnesses (defined by transfer between medicine and psychiatry services or concomitant primary medical and psychiatric admission diagnoses). Machine learning (classification trees) was used to identify potential predictors of 30-day psychiatric readmission across hospital encounters. Predictors included demographics, medical and psychiatric diagnoses, medication regimen, and disposition. The algorithm was internally validated using 10-fold cross-validation., Results: The model predicted 30-day readmission with high accuracy (98% unbalanced model, 88% balanced model). Modifiable predictors of readmission were length of stay, transfers between medical and psychiatric services, discharge disposition to home, and all-cause acute health service utilization in the year before the index hospitalization., Conclusion: Among bipolar disorder patients with comorbid medical conditions, characteristics of the index hospitalization (e.g., duration, transfer, and disposition) emerged as more predictive than static properties of the patient (e.g., sociodemographic factors and psychiatric comorbidity burden). Findings identified phenotypes of patients at high risk for rehospitalization and suggest potential ways of modifying the risk of early readmission., (Copyright © 2019 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

We present a method for multimodal brain data registration that aligns shapes of nodal network configurations in an invertible manner. We use ideas from shape analysis to represent an individual subject data configuration as an element on a hypersphere, where geodesics have closed form solutions. The method not only performs inter-subject data registration, but also allows for the construction of a population data template to which all subject data configurations can be registered. Results show compression of data measures and significant reduction in variance after registration. We also observe increased predictive power of regions of interest (ROI) node identification, significant increases in pairwise network connectivity measures, as well as significant increases in canonical correlations with age after registration.

Objective: Resilience is broadly defined as the ability to respond adaptively to challenges or adversity. It is unclear which clinical and cognitive factors are most closely related to resilience. Also, the dimensions that comprise resilience may differ among different groups, such as those who are homeless. The purpose of this study was to understand the relationships between resilience and clinical, cognitive, and functional variables among homeless veterans and to determine independent predictors of resilience., Method: One hundred homeless veterans completed measures of resilience, defeatist beliefs, negative symptoms, psychotic and mood symptoms, social and nonsocial cognition, and community functioning. We examined associations between resilience and clinical, cognitive, and functional measures. We performed regression analyses to determine independent contributions of the variables to resilience., Results: Resilience was correlated with negative symptoms, defeatist beliefs, depression/anxiety symptoms, and social cognition. There were no significant correlations with nonsocial cognition or psychotic symptoms. Stepwise multiple linear regression showed that defeatist beliefs, motivational negative symptoms, expressive negative symptoms, and depression/anxiety symptoms made independent contributions. Resilience was correlated with community functioning in the domains of work, independent living, and social and family relationships. History of psychosis moderated the relationship between resilience and defeatist beliefs, which was stronger in those who had experienced psychosis., Conclusions and Implications for Practice: These findings suggest that resilience is an important construct to consider in homeless veterans, is related to other clinical factors such as defeatist beliefs and negative symptoms, and could be a valuable treatment target with the goal of improving functioning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objective: This single-blind, randomized, multisite, intent-to-treat study was designed to replicate and extend Dawson et al.'s (Pediatrics. 2010;125: e17-e23) randomized controlled trial testing the effects of the Early Start Denver Model (ESDM), an intensive play- and routines-based intervention delivered in natural settings., Method: A randomized controlled trial was conducted at 3 universities. One hundred eighteen children 14 to 24 months old with autism spectrum disorder were enrolled and randomly assigned to ESDM or community interventions for 27 months. Eighty-one children completed the full treatment course and all assessments; data from all 118 children were used in analyses. Children assigned to the ESDM intervention received 3 months of weekly parent coaching followed by 24 months of 15 hour per week (on average) 1:1 treatment weekly on average in homes or daycare settings from supervised therapy assistants while parents received coaching 4 hours monthly from a certified ESDM therapist., Results: For the primary analyses, there were time-by-group and time-by-group-by-site interactions for language outcome. In the significant 3-way interaction involving site, 2 sites showed a significant ESDM advantage and the third site showed no significant group differences. In the planned 2-way analysis that pooled data across all 3 sites, there was a significant advantage found for the ESDM group. For the secondary analyses, there were no significant differences between the ESDM and community groups involving developmental quotient, autism severity, or adaptive behavior. The treatment effect of group on language outcomes was not moderated by baseline developmental quotient, autism severity, or language., Conclusion: Results of the primary analysis provide a partial replication of Dawson et al.'s 2010 language findings., Clinical Trial Registration Information: Intensive Intervention for Toddlers with Autism; https://clinicaltrials.gov/; NCT00698997., (Copyright © 2019 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: This study examines barriers to participation and retention in 2 modalities (web-based and in-person) of a weight-management intervention tailored for individuals with serious mental illness (SMI)., Method: Using a mixed-methods approach, we explored the barriers veterans with SMI face when participating in a web-based (WebMOVE) or in-person (MOVE-SMI) version of the same SMI-adapted MOVE weight-management program. Participants in the randomized controlled trial (n = 277) were recruited from specialty mental health clinics at a Veterans Affairs medical center. Barriers were analyzed across treatment condition and program attendance (engagement) at baseline and follow-up using a generalized lineal model. Post hoc analyses assessed whether changes in the trajectory of barriers over time were associated with engagement. A subsample of participants (n = 48) from the WebMOVE and MOVE-SMI treatment conditions completed a qualitative interview, and 2 coders used open coding to analyze the data., Results: Although barriers specific to treatment modality existed, most barriers cut across intervention modality, including financial hardship, lack of reliable housing and transportation, comorbid physical and mental health issues, and competing demands on personal time. Results of post hoc analyses found the association between engagement and emotional and motivational factors to be statistically significant., Conclusions: This study is the 1st to identify barriers in a web-based intervention for SMI. Similar barriers persisted across treatment modalities. Known barriers, particularly socioeconomic barriers, should be addressed to improve engagement and retention of individuals in weight-management interventions adapted for SMI, irrespective of modality. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Smoking-induced relief of craving and withdrawal promotes continued cigarette use. Understanding how relief is produced and the role of nicotine in this process may facilitate development of new smoking-cessation therapies. As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief also can inform policy. We assessed effects of nicotine using resting state functional magnetic resonance imaging (MRI) and behavioral assessments of craving and negative affect. Twenty-one young (18-25 years old) daily smokers underwent overnight abstinence on 4 days. On each of the following mornings, they self-rated their cigarette craving and negative affect and underwent resting-state functional MRI (fMRI) before and after smoking a cigarette that delivered 0.027, 0.110, 0.231, or 0.763 mg of nicotine. Functional connectivity between the anterior insula and anterior cingulate cortex (ACC) and between the nucleus accumbens and orbitofrontal cortex (OFC) was assessed. Smoking reduced craving, negative affect, and nucleus accumbens-OFC connectivity irrespective of nicotine dose, with positive correlations of the effects on behavioral and connectivity measures. Only the highest nicotine dose (0.763 mg) reduced right anterior insula-ACC connectivity; this reduction was positively correlated with the behavioral effects of the 0.763-mg dose only. While nicotine-based therapies may act on right anterior insula-ACC functional circuits to facilitate smoking cessation, non-nicotine (eg, the conditioned and sensorimotor) aspects of smoking may promote cessation by reducing OFC-accumbens connectivity to alleviate withdrawal., (© 2018 Society for the Study of Addiction.)

Community integration is recognized as a meaningful goal that is highly relevant to the long-term success of supportive housing programs. Research to date highlights concerns that some individuals in permanent supportive housing remain socially isolated and have limited success in other domains of community integration. However, we know little about what factors impact formerly homeless veterans' ability to achieve community integration. To identify factors associated with community integration among homeless veterans housed through the Department of Veterans Affairs' (VA's) Supportive Housing program (HUD-VASH), we performed secondary database analyses of Veterans ( n = 560) housed via HUD-VASH in the VA Greater Los Angeles Healthcare System from 10/1/14-9/30/15. We conducted ordinal and logit regressions to examine associations between baseline HUD-VASH participant characteristics, supportive housing voucher type, health service utilization in the year post-housing, and three types of community integration outcomes (i.e., change in community adjustment, status of housing stability, and change in employment). Data were obtained from HOMES (VA's homeless registry) and Corporate Data Warehouse (CDW) (VA's a national administrative dataset of VA inpatient and outpatient care). Mental health service utilization was negatively associated with community adjustment, housing stability, and employment. Employment at baseline was positively associated with housing stability and employment. Also, substance use disorder visits was positively associated with employment, and combined medical and substance use disorder diagnoses was positively associated with change in community adjustment. We considered 29 variables and found relatively few were associated with community integration. Consistent with previous research, our study highlights the importance of mental health needs, and suggests that utilization of mental health services is an important indicator of improvements in community adjustment, housing stability, and employment.

Introduction: Supported housing-which offers permanent, community-based housing and supportive services-effectively addresses homelessness. Yet, many persons with serious mental illness (SMI) struggle to retain housing in these programs. Social skills-which facilitate social interactions and instrumental tasks-predict premature exits from supported housing. Though social skills training effectively improves social skills and functioning for persons with SMI, this intervention is essentially absent from supported housing initiatives., Methods: This study will use literature review, key informant interviews and an expert panel to adapt social skills training for supported housing, aiming to improve housing retention among SMI persons in these programs. In the Department of Housing and Urban Development-VA Supported Housing program (HUD-VASH) at VA Greater Los Angeles, we will conduct an effectiveness-implementation hybrid type I trial of the adapted intervention. Baseline and 6-month assessments (measuring social skills, mental health status, healthcare utilization, social networks, money management, and housing outcomes) will be conducted with intervention participants (n = 30) and a usual care control group (n = 20). We will use the generalized linear mixed model (GLMM) to compare change over 6 months between groups, capturing the intervention's effectiveness on factors strongly associated with housing retention. Qualitative data and surveys with staff, leadership, and participants will gather data on factors relevant to the intervention's future implementation in routine care., Discussion: Few effective psychosocial interventions for persons with SMI have been adapted or studied in supported housing initiatives. To our knowledge, this is the first study to adapt and study the effectiveness and implementation of social skills training in supported housing programs.

Efforts to replicate results from both basic and clinical models have highlighted problems with reproducibility in science. In psychiatry, reproducibility issues are compounded because the complex behavioral syndromes make many disorders challenging to model. We develop translatable tasks that quantitatively measure psychiatry-relevant behaviors across species. The behavioral pattern monitor (BPM) was designed to analyze exploratory behaviors, which are altered in patients with bipolar disorder (BD), especially during mania episodes. We have repeatedly assessed the behavioral effects of reduced dopamine transporter (DAT) expression in the BPM using a DAT knockdown (KD) mouse line (~10% normal expression). DAT KD mice exhibit a profile in the BPM consistent with acutely manic BD patients in the human version of the task-hyperactivity, increased exploratory behavior, and reduced spatial d (Perry et al., 2009). We collected data from multiple DAT KD BPM experiments in our laboratory to assess the reproducibility of behavioral outcomes across experiments. The four outcomes analyzed were: 1) transitions (amount of locomotor activity); 2) rearings (exploratory activity); 3) holepokes (exploratory activity); and 4) spatial d (geometrical pattern of locomotor activity). By comparing DAT KD mice to wildtype (WT) littermates in every experiment, we calculated effect sizes for each of the four outcomes and then calculated a mean effect size using a random effects model. DAT KD mice exhibited robust, reproducible changes in each of the four outcomes, including increased transitions, rearings, and holepokes, and reduced spatial d, vs. WT littermates. Our results demonstrate that the DAT KD mouse line in the BPM is a consistent, reproducible model of mania-relevant behaviors. More work must be done to assess reproducibility of behavioral outcomes across experiments in order to advance the field of psychiatry and develop more effective therapeutics for patients., (Copyright © 2017. Published by Elsevier Inc.)

Background: Electroconvulsive therapy (ECT) is an effective treatment for severe depression and is shown to increase hippocampal volume and modulate hippocampal functional connectivity. Whether variations in hippocampal structural connectivity occur with ECT and relate to clinical response is unknown., Methods: Patients with major depression (n = 36, 20 women, age 41.49 ± 13.57 years) underwent diffusion magnetic resonance imaging at baseline and after ECT. Control subjects (n = 32, 17 women, age 39.34 ± 12.27 years) underwent scanning twice. Functionally defined seeds in the left and right anterior hippocampus and probabilistic tractography were used to extract tract volume and diffusion metrics (fractional anisotropy and axial, radial, and mean diffusivity). Statistical analyses determined effects of ECT and time-by-response group interactions (>50% change in symptoms before and after ECT defined response). Differences between baseline measures across diagnostic groups and in association with treatment outcome were also examined., Results: Significant effects of ECT (all p < .01) and time-by-response group interactions (all p < .04) were observed for axial, radial, and mean diffusivity for right, but not left, hippocampal pathways. Follow-up analyses showed that ECT-related changes occurred in responders only (all p < .01) as well as in relation to change in mood examined continuously (all p < .004). Baseline measures did not relate to symptom change or differ between patients and control subjects. All measures remained stable across time in control subjects. No significant effects were observed for fractional anisotropy and volume., Conclusions: Structural connectivity of hippocampal neural circuits changed with ECT and distinguished treatment responders. The findings suggested neurotrophic, glial, or inflammatory response mechanisms affecting axonal integrity., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Rationale: Attentional bias toward drug-related stimuli is a feature of drug addiction that is linked to craving and drug-seeking behavior., Objectives/method: An attentional bias modification (ABM) program was tested in 42 methamphetamine-dependent clients (DSM-IV criteria) receiving residential treatment for their drug use. Participants were randomly assigned to one of two groups (N = 21 each), receiving 12 sessions of either computerized ABM training (designed to train attention away from methamphetamine stimuli 100% of the time) or an attentional control condition (designed to train attention away from methamphetamine stimuli 50% of the time). Outcome measures included attentional bias to methamphetamine-related stimuli on a probe detection task, self-reported craving, and preferences to view methamphetamine-related images on a Simulated Drug Choice Task. A subset of participants (N = 17) also underwent fMRI in a cue-induced craving paradigm., Results: Poor split-half reliability was observed for the probe detection task. Using this task, attentional bias toward methamphetamine-related stimuli was greater after training than at baseline, irrespective of group (p = 0.037). Spontaneous and cue-induced methamphetamine craving diminished with time (ps < 0.01), but ABM training did not influence these effects (group by time interactions, ps > 0.05). ABM training did not influence selection of methamphetamine-related pictures in the Simulated Drug Choice task (p > 0.05). In the fMRI assessment, cue-induced activation in the ventromedial prefrontal cortex was reduced over time, without an effect of ABM training., Conclusions: ABM training did not improve several clinically relevant variables in treatment-seeking methamphetamine users. Additional research is needed to improve the measurement of attentional bias.

The development of effective cognitive training (CT) interventions is critical for improving the daily lives of people with schizophrenia. At this point, it is unclear whether a so-called "bottom-up" or "top-down" CT approach is more beneficial for inducing cognitive gains and generalization in this population. The aims of this randomized controlled trial were to: 1) Compare the effects of these two types of training approaches on performance-based (MATRICS Consensus Cognitive Battery, MCCB) and neurophysiological (mismatch negativity, MMN) measures of cognition, and 2) Evaluate MMN as a potential predictor of treatment response. Ninety-nine patients with persistent schizophrenia (mean age of 51 and illness duration of 30 years) were randomly assigned in a 2:2:1 ratio to a "bottom-up" intervention that selectively targets basic auditory processing and verbal learning (Brain Fitness), a "top-down" intervention that targets a broad range of higher-order cognitive functions (COGPACK), or a control condition consisting of commercial computer games (Sporcle). Participants completed on average 30 h of training over 12 weeks. Despite demonstrated improvement on training tasks, we found no significant treatment effects on measures of neurocognition (MCCB), MMN, or functional capacity from either intervention. Interestingly, there was an association between an enhanced MMN response at 6 weeks and improved reasoning/problem solving at 12 weeks in the COGPACK group. Although this study had several methodological strengths, the results were mainly negative. It suggests that CT trials in schizophrenia should try to better understand mediators and moderators of treatment response to develop more personalized interventions., (Published by Elsevier Ltd.)

Recent interest has focused on oxytocin (OT), a neurotransmitter that promotes social processing, to improve social functioning in people with schizophrenia. However, little information is available regarding the doses of OT that are effective for influencing social processing in the brain (i.e., target engagement). In this study, we conducted a double-blind, placebo-controlled, cross-over dose ranging study of OT. In total 47 patients with schizophrenia were randomly assigned to one of eight doses of OT (8, 12, 24, 36, 48, 60, 72, or 84 IU). Patients completed two social processing tasks: one electroencephalography (EEG) task, a biological motion Mu-suppression task (i.e., identifying the gender, emotion, or direction of walking of point-light animations of human movement); and one pupillometry task, pupil dilation in response to viewing affective faces. Participants completed these tasks twice, one week apart, and were randomly administered drug or placebo intranasally 30 min prior to each session. Mu-suppression, i.e., suppression of oscillations in the 8-12 Hz range over central electrodes in response to social stimuli, was significantly enhanced at doses of 36 and 48 IU in comparison to placebo, but not at other doses. Significant pupil dilation was observed in response to faces vs. non-face stimuli, though there were no drug effects at any dose. Results suggest that OT affects central measures of social information processing in patients with schizophrenia and is optimal at a mid-range dose (36-48 IU). These results provide dosing guidance for future studies of OT to be used to enhance social processing in people with schizophrenia.

The United States Department of Housing and Urban Development (HUD)-Veteran Administration Supportive Housing (VASH) program uses project- and tenant-based vouchers to provide permanent supportive housing for homeless Veterans. We compared Veteran characteristics, health service utilization, and neighborhood characteristics between HUD-VASH participants with project-based (n=114) vs. tenant-based (n=978) vouchers. We found that project-based voucher holders were older and more ill than tenant-based voucher holders. Project-based vouchers were also associated with higher-quality neighborhoods and higher rates of health service utilization than tenant-based vouchers. With the limited availability of project-based vouchers, juxtaposed with the increased service use and better neighborhood quality with this voucher type, our findings suggest a need to think strategically about how best to allocate housing vouchers to meet homeless Veteran's needs.

"Enhancing QUality of Care In Psychosis" (EQUIP) was an eight-site clustered controlled trial of the implementation and effectiveness of patient-reported outcomes to support evidence-based practice and improve care for schizophrenia. Implementation sites chose to improve care for weight. Implementation included monitoring patient-reported outcomes using kiosks, patient and staff education, quality improvement teams, and phone care management. Qualitative and quantitative methods compared implementation and effectiveness between sites for 13 months. Eighty percent of 801 randomly selected patients were overweight. Two hundred one clinicians varied in competency. Baseline use of behavioral weight services was low. At implementation sites, patients became 2.3 times more likely to use weight services compared with control sites (95% CI, 1.5-3.6; χ 2  = 14.4; p < 0.01). There was no effect on the weight gain liability of medications prescribed. Controlling for baseline, patients' final weight at control sites was 5.9 ± 2.7 kg heavier than at implementation sites (F = 4.8, p = 0.03). Patient-reported outcomes can inform implementation of evidence-based practice and improvement in outcomes.

Impairments in social cognition are key determinants of poor functioning in psychosis and an important new target for treatment development. Initial studies support the feasibility and efficacy of training interventions for social cognition, but have been small and have had substantial methodological limitations. This report describes the largest rigorously controlled study of a social cognitive treatment to date. We evaluated the efficacy of a refined version of the 24-session Social Cognitive Skills Training (SCST) program, and whether adding in vivo training sessions in community settings would enhance generalization to functional improvements. One hundred thirty-nine outpatients with psychotic disorders were randomly assigned to one of 3 time- and format-matched conditions: (1) SCST plus in vivo community-based training, (2) SCST plus clinic-based training, or (3) Illness management control condition. SCST targeted the domains of emotion processing, social perception, attributional bias, empathy, and mentalizing. Assessments of social cognition, nonsocial cognition, symptoms, and functioning were completed at baseline, mid-treatment, posttreatment, and 3-month follow-up. On the primary social cognitive outcome measures, there was significant, durable SCST-related improvement in facial emotion identification. There was also a significant SCST benefit for emotional intelligence and an in vivo training effect for empathy, though these improvements were not durable. Further, there were no overall or in vivo-related changes in functioning. This study bolsters and extends support for the efficacy of SCST in a relatively large and rigorously controlled trial, although our effort to enhance generalization to functional improvements through in vivo community-based training was not successful.

Background: Hippocampal enlargements are commonly reported after electroconvulsive therapy (ECT). To clarify mechanisms, we examined if ECT-induced hippocampal volume change relates to dose (number of ECT sessions and electrode placement) and acts as a biomarker of clinical outcome., Methods: Longitudinal neuroimaging and clinical data from 10 independent sites participating in the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) were obtained for mega-analysis. Hippocampal volumes were extracted from structural magnetic resonance images, acquired before and after patients (n = 281) experiencing a major depressive episode completed an ECT treatment series using right unilateral and bilateral stimulation. Untreated nondepressed control subjects (n = 95) were scanned twice., Results: The linear component of hippocampal volume change was 0.28% (SE 0.08) per ECT session (p < .001). Volume change varied by electrode placement in the left hippocampus (bilateral, 3.3 ± 2.2%, d = 1.5; right unilateral, 1.6 ± 2.1%, d = 0.8; p < .0001) but not the right hippocampus (bilateral, 3.0 ± 1.7%, d = 1.8; right unilateral, 2.7 ± 2.0%, d = 1.4; p = .36). Volume change for electrode placement per ECT session varied similarly by hemisphere. Individuals with greater treatment-related volume increases had poorer outcomes (Montgomery-Åsberg Depression Rating Scale change -1.0 [SE 0.35], per 1% volume increase, p = .005), although the effects were not significant after controlling for ECT number (slope -0.69 [SE 0.38], p = .069)., Conclusions: The number of ECT sessions and electrode placement impacts the extent and laterality of hippocampal enlargement, but volume change is not positively associated with clinical outcome. The results suggest that the high efficacy of ECT is not explained by hippocampal enlargement, which alone might not serve as a viable biomarker for treatment outcome., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Although nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies., Methods: Functional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16-21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18-25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers., Results: Connectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal., Conclusions: Relief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking.

Individuals with cognitive problems may be predisposed to develop substance use disorders; therefore, differences in cognitive function between methamphetamine users and control participants may be attributable to premorbid factors rather than methamphetamine use. The goal of this study was to clarify the extent to which this is the case. Childhood academic transcripts were obtained for 37 methamphetamine-dependent adults and 41 control participants of similar educational level and premorbid IQ. Each participant completed a comprehensive cognitive battery and received a structural magnetic resonance imaging scan. Data from control participants and linear regression were used to develop a normative model to describe the relationship between childhood academic performance and scores on the cognitive battery. Using this model, cognitive performance of methamphetamine users was predicted from their premorbid academic scores. Results indicated that methamphetamine users' childhood grade point average was significantly lower than that of the control group (p < 0.05). Further, methamphetamine users' overall cognitive performance was lower than was predicted from their grade point average prior to methamphetamine use (p = 0.001), with specific deficits in attention/concentration and memory (ps < 0.01). Memory deficits were associated with lower whole-brain cortical thickness (p < 0.05). Thus, in addition to having an apparent premorbid weakness in cognition, methamphetamine users exhibit subsequent cognitive function that is significantly lower than premorbid estimates would predict. The results support the view that chronic methamphetamine use causes a decline in cognition and/or a failure to develop normative cognitive abilities, although aside from methamphetamine use per se, other drug use and unidentified factors likely contribute to the observed effects.

Objectives: A high incidence of Axis II personality disorders is described in patients with bipolar disorder; however, their relationship to mood state remains uncertain., Methods: A total of 966 outpatients with bipolar disorder gave informed consent and filled out the Personality Disorder Questionnaire, 4th edition (PDQ4) and a questionnaire on demographics and course of illness prior to Bipolar Treatment Outcome Network entry at average age 41 years. Patients were rated at each visit for depression on the Inventory of Depressive Symptoms-Clinician version (IDS-C) and for mania on the Young Mania Rating Scale (YMRS). In a subgroup, the PDQ4 was retaken during periods of depression and euthymia., Results: Patients met criteria for most personality disorders at a much higher rate when they took the PDQ4 while depressed compared to while euthymic, and scores were significantly related to the severity of depression (IDS) and of mania (YMRS) assessed within 2 weeks of taking the PDQ. Even when euthymic, more than quarter to half of the patients met criteria for a cluster A, B or C personality disorder., Conclusions: A wide range of personality disorders occur in bipolar patients, but are highly dependent on filling out the form while depressed compared to while euthymic. How this relates to having a personality disorder assessed using a structured clinical interview remains to be tested. However, higher PDQ4 scores are related to an earlier age of onset of bipolar disorder and other factors portending a more difficult course of bipolar disorder, and the optimal treatment of these patients remains to be illuminated., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The relationship of personality disorder (PD) psychopathology to the course of bipolar disorder remains inadequately described. After giving informed consent, more than 782 outpatients with bipolar disorder rated themselves on the 99-item Personality Disorder Questionnaire, Version 4 (PDQ4) when depressed or euthymic. They also rated six poor prognosis factors (PPFs). The relationships of the PPFs to the total PDQ4 score were examined by a linear regression. Even after correcting for the higher PDQ4 scores observed when patients were suffering depression, the PDQ4 was significantly related to a history of child abuse, early age of onset, an anxiety disorder comorbidity, rapid cycling, and 20 or more previous episodes, but not substance abuse. The data suggest close relationships between the total burden of PD psychopathology and correlates of an adverse outcome of bipolar disorder. The nature of this of association and approaches to treatment of comorbid PD remain to be further explored.

Introduction: Working Memory and Task-Switching are essential components of cognitive control, which underlies many symptoms evident across multiple neuropsychiatric disorders, including psychotic and mood disorders. Vulnerability to these disorders has a substantial genetic component, suggesting that clinically unaffected first-degree relatives may carry some vulnerability-related traits. Converging evidence from animal and human studies demonstrates that dopamine transmission, striatal and frontal brain regions, and attention and switching behaviors are essential components of a multilevel circuit involved in salience, and disruptions in that circuit may lead to features of psychosis. Yet, it is possible that unaffected relatives may also possess characteristics that protect against development of illness. We hypothesized that reduced switch cost in a cued task-switching task, may be a behavioral expression of this "resilience" phenotype that will be observable in unaffected relatives., Methods: We tested a large community sample (n = 536) via the web, to assess different subcomponents of cognitive control, including task-switching and working memory, as well as risk-taking, among individuals who report having an affected relative with a psychotic or mood disorder., Results: Healthy individuals with suspected genetic risk due to a self-reported familial history of a psychotic disorder demonstrated better task-switching performance compared to healthy people without a psychiatrically ill relative and those with a relative with a mood disorder. This result was specific to illness status and task domain, in that individuals with a personal history of depression or anxiety did not show improved task-switching performance, and this improvement was selective to task-switching and not seen in other putative cognitive control domains (working memory or risk taking)., Conclusions: Although this study has limitations and independent replication is needed, these preliminary findings suggest a potential avenue for understanding susceptibility to these disorders by highlighting possible protective as well as vulnerability-related aspects of risk phenotypes., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Over the last decades, the treatment of schizophrenia has shifted fundamentally from a focus on symptom reduction to a focus on recovery and improving aspects of functioning. In this study, we examined the effect of transcranial direct current stimulation (tDCS) on social cognitive and nonsocial neurocognitive functions, as well as on electroencephalogram (EEG) measures, in individuals with schizophrenia. Thirty-seven individuals with schizophrenia were administered one of three different tDCS conditions (cathodal, anodal, and sham) per visit over the course of three visits, with approximately one week between each visit. Order of conditions was randomized and counterbalanced across subjects. For the active conditions, the electrode was placed over the left dorsolateral prefrontal cortex with the reference electrode over right supraorbital cortex. Current intensity was 2 mA and was maintained for two 20-minute sessions, with a one hour break between the sessions. Assessments were conducted immediately following each session, in a counterbalanced order of administration. No systematic effects were found across the social and nonsocial cognitive domains, and no significant effects were detected on event-related potentials (ERPs). The very small effect sizes, further validated by post-hoc power analyses (large Critical Ns), demonstrated that these findings were not due to lack of statistical power. Except for mild local discomfort, no significant side effects were reported. Findings demonstrate the safety and ease of administration of this procedure, but suggest that a single dose of tDCS over these areas does not yield a therapeutic effect on cognition in schizophrenia., Trial Registration: ClinicalTrials.gov NCT02539797.

Research documents bidirectional associations between parental overcontrol (OC) and children's anxiety; OC may place children at risk for anxiety and also may occur in response to children's requests for help. However, to date no studies have examined children's or parents' in-the-moment emotional responses to OC. Using a community sample of mothers and school-age children, we examine the individual and interactive influences of maternal OC, maternal anxiety, children's help-seeking, and children's anxiety in predicting physiological reactivity in response to a stressor faced by children and observed by mothers, predicting that for children of higher anxiety mothers, higher OC will be associated with increases in reactivity (decreases in respiratory sinus arrhythmia [RSA]), whereas for higher anxiety mothers themselves, engaging in OC will be associated with reductions in physiological reactivity (decreases in heart rate). Multilevel modeling suggested that for children of higher anxiety mothers, greater peak OC is associated with greater reductions in RSA (increases in reactivity) after the onset of OC. In contrast, for higher anxiety mothers themselves, greater peak OC was linked with attenuations in heart rate. Effects held when controlling for children's anxiety and help-seeking, and no pattern of effects was observed with analyses in which children's help-seeking was the predictor or children's anxiety was the moderator, suggesting that in this case, physiological reactivity is uniquely associated with the interaction between maternal OC and anxiety. Among mothers with higher anxiety, OC may serve a regulatory function, reducing physiological reactivity, while exacerbating children's reactivity. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Background: Electroconvulsive therapy (ECT) is arguably the most effective available treatment for severe depression. Recent studies have used MRI data to predict clinical outcome to ECT and other antidepressant therapies. One challenge facing such studies is selecting from among the many available metrics, which characterize complementary and sometimes non-overlapping aspects of brain function and connectomics. Here, we assessed the ability of aggregated, functional MRI metrics of basal brain activity and connectivity to predict antidepressant response to ECT using machine learning., Methods: A radial support vector machine was trained using arterial spin labeling (ASL) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) metrics from n = 46 (26 female, mean age 42) depressed patients prior to ECT (majority right-unilateral stimulation). Image preprocessing was applied using standard procedures, and metrics included cerebral blood flow in ASL, and regional homogeneity, fractional amplitude of low-frequency modulations, and graph theory metrics (strength, local efficiency, and clustering) in BOLD data. A 5-repeated 5-fold cross-validation procedure with nested feature-selection validated model performance. Linear regressions were applied post hoc to aid interpretation of discriminative features., Results: The range of balanced accuracy in models performing statistically above chance was 58-68%. Here, prediction of non-responders was slightly higher than for responders (maximum performance 74 and 64%, respectively). Several features were consistently selected across cross-validation folds, mostly within frontal and temporal regions. Among these were connectivity strength among: a fronto-parietal network [including left dorsolateral prefrontal cortex (DLPFC)], motor and temporal networks (near ECT electrodes), and/or subgenual anterior cingulate cortex (sgACC)., Conclusion: Our data indicate that pattern classification of multimodal fMRI metrics can successfully predict ECT outcome, particularly for individuals who will not respond to treatment. Notably, connectivity with networks highly relevant to ECT and depression were consistently selected as important predictive features. These included the left DLPFC and the sgACC, which are both targets of other neurostimulation therapies for depression, as well as connectivity between motor and right temporal cortices near electrode sites. Future studies that probe additional functional and structural MRI metrics and other patient characteristics may further improve the predictive power of these and similar models.

Relapse of depression following treatment is high. Biomarkers predictive of an individual's relapse risk could provide earlier opportunities for prevention. Since electroconvulsive therapy (ECT) elicits robust and rapidly acting antidepressant effects, but has a >50% relapse rate, ECT presents a valuable model for determining predictors of relapse-risk. Although previous studies have associated ECT-induced changes in brain morphometry with clinical response, longer-term outcomes have not been addressed. Using structural imaging data from 42 ECT-responsive patients obtained prior to and directly following an ECT treatment index series at two independent sites (UCLA: n = 17, age = 45.41±12.34 years; UNM: n = 25; age = 65.00±8.44), here we test relapse prediction within 6-months post-ECT. Random forests were used to predict subsequent relapse using singular and ratios of intra and inter-hemispheric structural imaging measures and clinical variables from pre-, post-, and pre-to-post ECT. Relapse risk was determined as a function of feature variation. Relapse was well-predicted both within site and when cohorts were pooled where top-performing models yielded balanced accuracies of 71-78%. Top predictors included cingulate isthmus asymmetry, pallidal asymmetry, the ratio of the paracentral to precentral cortical thickness and the ratio of lateral occipital to pericalcarine cortical thickness. Pooling cohorts and predicting relapse from post-treatment measures provided the best classification performances. However, classifiers trained on each age-disparate cohort were less informative for prediction in the held-out cohort. Post-treatment structural neuroimaging measures and the ratios of connected regions commonly implicated in depression pathophysiology are informative of relapse risk. Structural imaging measures may have utility for devising more personalized preventative medicine approaches.

Objectives: The risk of cognitive impairment is a concern for patients with major depressive disorder receiving electroconvulsive therapy (ECT). Here, we evaluate the acute, short-term and long-term effects of ECT on tests of processing speed, executive function, memory, and attention., Methods: Forty-four patients with major depressive disorder receiving ECT (61% right unilateral, 39% mixed right unilateral-bitemporal, left unilateral, and/or bitemporal lead placement) underwent a cognitive battery prior to ECT (T1), after 2 sessions (T2), and at the end of the index (T3). Thirty-two patients returned for a 6-month follow-up (T4). Thirty-three control subjects were assessed at 2 times approximately 4 weeks apart (C1 and C2)., Results: At baseline, patients showed deficits in processing speed, executive function, and memory compared with control subjects. Including depression severity and lead placement covariates, linear mixed-model analysis showed significant improvement in only processing speed between T1 and T3 and between T1 and T4 in patients. An acute decline in attention and verbal memory was observed at T2, but performance returned to baseline levels at T3. Longitudinal cognitive outcomes did not differ in patients defined as ECT responders/nonresponders., Limitations: Episodic memory was not measured, and medications were not controlled between T3 and T4. Control subjects also showed improvements in processing speed, suggesting practice effects for some measures., Conclusions: In this naturalistic ECT treatment study, results show that the initiation of ECT may transiently affect memory and executive function, but cognition is largely unaffected during and after ECT. Whereas some functions might improve, others will at least remain stable up to 6 months following the ECT index.

We sought to explore clinical factors associated with successful transition from Assertive Community Treatment to less intensive clinical services. Mixed-method observational follow up study of veterans discharged from three VA-affiliated ACT teams to less intensive clinical services. Of the 240 veterans in ACT, 9% (n = 21) were discharged during the study period. Among the 11 of 21 discharged veterans who enrolled in the follow up study, reason for discharge, designated by the veteran's primary clinician at the time of discharge, predicted outcomes (p = 0.02) at 9 months, with "disengagement" as a reason for discharge predicting poorer outcomes. Six of 11 veterans experienced poor outcomes at 9 months, including incarceration and substance use relapse. ACT clinicians rarely discharge clients. Many clients may experience negative clinical events following ACT discharge, and clients may be difficult to follow post-discharge. Client disengagement from ACT may indicate higher likelihood of poor outcomes following discharge to less intensive clinical services.

Transcranial direct current stimulation (tDCS) was applied bilaterally over the auditory cortex in 12 schizophrenia patients to modulate early auditory processing. Performance on a tone discrimination task (tone-matching task-TMT) and auditory mismatch negativity were assessed after counterbalanced anodal, cathodal, and sham tDCS. Cathodal stimulation improved TMT performance (p < 0.03) compared to sham condition. Post-hoc analyses revealed a stimulation condition by negative symptom interaction in which greater negative symptoms were associated with a better TMT performance after anodal tDCS.