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Background and Hypothesis Impaired insight into the illness and its consequences is associated with poor outcomes in schizophrenia. While transcranial direct current stimulation (tDCS) may represent a potentially effective treatment strategy to relieve various symptoms of schizophrenia, its impact on insight remains unclear. To investigate whether tDCS would modulate insight in patients with schizophrenia, we undertook a meta-analysis based on results from previous RCTs that investigated the clinical efficacy of tDCS. We hypothesize that repeated sessions of tDCS will be associated with insight improvement among patients. Study Design PubMed and ScienceDirect databases were systematically searched to identify RCTs that delivered at least 10 tDCS sessions in patients with schizophrenia. The primary outcome was the change in insight score, assessed by the Positive and Negative Syndrome Scale (PANSS) item G12 following active tDCS sessions as opposed to sham stimulation. Effect sizes were calculated for all studies and pooled using a random-effects model. Meta-regression and subgroup analyses were conducted. Study Results Thirteen studies (587 patients with schizophrenia) were included. A significant pooled effect size (g) of −0.46 (95% CI [−0.78; −0.14]) in favor of active tDCS was observed. Age and G12 score at baseline were identified as significant moderators, while change in total PANSS score was not significant. Conclusions Ten sessions of active tDCS with either frontotemporoparietal or bifrontal montage may improve insight into the illness in patients with schizophrenia. The effect of this treatment could contribute to the beneficial outcomes observed in patients following stimulation.

Schizophrenia is associated with an elevated risk for impulsive aggression for which there are few psychosocial treatment options. Neurocognitive and social cognitive deficits have been associated with aggression with social cognitive deficits seemingly a more proximal contributor. The current study examined the effects of combining cognitive and social cognition treatment on impulsive aggression among inpatients with chronic schizophrenia and schizoaffective disorder and a history of aggression compared to cognitive remediation treatment alone.The two-center study randomized 130 participants to receive 36 sessions of either a combination of cognitive remediation and social cognition treatment or cognitive remediation plus a computer-based control. Participants had at least one aggressive incident within the past year or a Life History of Aggression (LHA) score of 5 or more. Participants completed measures of neurocognition, social cognition, symptom severity, and aggression at baseline and endpoint.Study participants were mostly male (84.5 %), had a mean age 34.9 years, and 11.5 years of education. Both Cognitive Remediation Training (CRT) plus Social Cognition Training (SCT) and CRT plus control groups were associated with significant reductions in aggression measures with no group differences except on a block of the Taylor Aggression Paradigm (TAP), a behavioral task of aggression which favored the CRT plus SCT group. Both groups showed significant improvements in neurocognition and social cognition measures with CRT plus SCT being associated with greater improvements.CRT proved to be an effective non-pharmacological treatment in reducing impulsive aggression in schizophrenia inpatient participants with a history of aggressive episodes. The addition of social cognitive training did not enhance this anti-aggression treatment effect but did augment the CRT effect on cognitive functions, on emotion recognition and on mentalizing capacity of our participants.

OBJECTIVE: Most assessments of suicidal ideation and behavior (SIB) are limited by reliance on a single assessor, typically a clinician or patient, with scant detail on patient-related drivers of SIB and inability to detect rapid change in SIB. Furthermore, many techniques do not include a semistructured interview, increasing rater variability. The Suicide Ideation and Behavior Assessment Tool (SIBAT) addresses these limitations. DESIGN: More than 30 experts in scale development, statistics, and clinical management of suicidal patients collaborated over a greater than four-year period to develop the SIBAT. Input for content and validity was received from patients, clinicians, and regulatory authorities in the United States (US) and Europe. Psychometric properties of the SIBAT were evaluated in validation studies. RESULTS: The SIBAT is organized into eight independent patient- or clinician-rated modules with branching logic and scoring algorithms, which necessitates computerization. Patient-reported information is first captured in Modules 1 to 5. Thereafter, an experienced clinician reviews the patient’s report, conducts a semistructured interview (Module 6), and assesses the patient’s suicide risk (Module 7) and optimal antisuicide management (Module 8). Input from cognitive interviews of diverse adult, adolescent, and clinician participants was incorporated into the final version of the SIBAT. Psychometric testing demonstrated good inter-rater reliability (intraclass coefficient range: 0.68–0.82), intra-rater reliability (weighted-kappa range: 0.64–0.76), and concurrent validity with other instruments for assessing SIB. CONCLUSION: Patient- and clinician-based assessments and the psychometric studies summarized in this report support the validity and reliability of the SIBAT for capturing critical information related to assessment of SIB in adolescents and adults at risk for suicide.

Jeffrey M Cochran,1 Hui Fang,1 John G Sonnenberg,2,3 Elan A Cohen,4 Jean-Pierre Lindenmayer,5 J Corey Reuteman-Fowler1 1Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA; 2Uptown Research Institute, Chicago, IL, USA; 3Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 4Hassman Research Institute, Marlton, NJ, USA; 5Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USACorrespondence: Jeffrey M Cochran, Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA, Tel +1 609 535 9035, Email Jeffrey.Cochran@otsuka-us.comPurpose: Schizophrenia is a severe, chronic condition accounting for disproportionate healthcare utilization. Antipsychotics can reduce relapse rates, but the characteristics of schizophrenia may hinder medication adherence. A phase 3b open-label clinical trial used aripiprazole tablets with sensor (AS; includes pills with ingestible event-marker, wearable sensor patches and smartphone application) in adults with schizophrenia. This post hoc analysis explored how healthcare providers’ (HCPs) usage of a dashboard that provided medication ingestion information impacted treatment decisions and clinical assessments.Patients and Methods: Participants used AS for 3– 6 months. HCPs were instructed to check the dashboard regularly, identify features used, and report impact on treatment decisions. After stratifying HCPs by frequency of dashboard checks and resulting treatment decisions, changes from baseline were calculated for Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI)–Severity of Illness and CGI-Improvement (CGI-I), and Personal and Social Performance (PSP), and compared using Mann–Whitney U-tests and rank-biserial correlation coefficient (r) effect sizes.Results: To ensure sufficient opportunity for AS engagement, 113 participants who completed ≥ 3 months on study were analyzed. HCPs most often accessed dashboard data regarding medication ingestion and missed doses. HCPs recommended adherence counseling and participant education most often. Participants whose HCPs used the dashboard more and recommended adherence counseling and participant education (n=61) improved significantly more than participants with less dashboard-active HCPs (n=49) in CGI-I mean score (2.9 versus 3.4 [p=0.004]), total PANSS (mean change: − 9.2 versus − 3.1 [p=0.0002]), PANSS positive subscale (− 3.2 versus − 1.5 [p=0.003]), PANSS general subscale (− 4.3 versus − 1.2 [p=0.02]), and Marder factor for negative symptoms (− 1.9 versus 0.0 [p=0.03]). Most HCPs found the dashboard easy to use (74%) and helpful for improving conversations with participants about their treatment plan and progress (78%).Conclusion: This provider dashboard may facilitate discussions with patients about regular medication-taking, which can improve patient outcomes.Keywords: digital medicine system, clinical decision-making, clinical decision support, patient–provider communication, schizophrenia

BackgroundValbenazine is a once-daily VMAT2 inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics, antiemetics, and other dopamine receptor blocking agents. The efficacy, safety, and tolerability of valbenazine has been established in several phase 3 trials, including a long-term study (KINECT 4 [NCT02405091]) in which participants received open-label valbenazine (40 or 80 mg) for 48 weeks. Post hoc analyses of KINECT 4 data were conducted to assess patterns of treatment response.MethodsData from KINECT 4 treatment completers (participants who reached the Week 48 visit and had the longest duration of treatment) were analyzed post hoc. TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7, as rated by the study investigator), the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and the Patient Global Impression of Change (PGIC). Analyses were conducted at Week 8 (first study visit after the valbenazine dose-optimization period) and Week 48 using the following definitions of response: ≥50% and ≥70% improvement from baseline in AIMS total score; rating of “much improved” or “very much improved” (score ≤2) on the CGI-TD and PGIC.ResultsOf the 167 participants who entered KINECT 4, 103 (62%) were treatment completers and included for analysis. Of these 103 participants, 39% and 86% met the ≥50% AIMS response threshold at Weeks 8 and 48, respectively. The percentages of participants who met the highly rigorous AIMS ≥70% response threshold at Weeks 8 and 48 were 17% and 52%, respectively. Of the 40 participants with AIMS ≥50% total score improvement at Week 8, 95% also met this threshold at Week 48 (“sustained response”). Of the 63 participants with ConclusionsPost hoc analyses of data from a 48-week, open-label study of once-daily valbenazine showed that the proportion of participants meeting rigorous treatment response thresholds increased over time. By the end of treatment at Week 48, >80% of participants demonstrated robust improvements in TD, as assessed using the AIMS (≥50% improvement), CGI-TD (score ≤2), and PGIC (score ≤2).FundingNeurocrine Biosciences, Inc.

Purpose of review To provide an update of recent studies describing the effects of transcranial direct current stimulation (tDCS) on patients with schizophrenia, with particular focus on auditory verbal hallucinations (AVH), cognitive deficits, and negative symptoms. Recent findings As a low-cost, easy-to-use neuromodulation technique, tDCS may have clinical implications for those suffering from treatment-persistent AVH, negative symptoms, and cognitive symptoms in schizophrenia. Over the past decade, tDCS has shown no effects for negative symptoms, except when used at a high frequency of sessions, and inconclusive results for AVH and cognitive symptoms. The treatment has little to no adverse effects. Summary The studies reviewed here support the need for further investigation and empirical data regarding the use of tDCS. The underlying mechanisms of tDCS as well as the most effective stimulation parameters must be better understood. Findings support the need for increased duration and frequency of tDCS sessions. One of the next steps is the investigation of effects of concomitant nonpharmacological treatments with tDCS.

Individuals with serious mental illness are at increased risk of severe COVID-19 infection. Several psychotropic medications have been identified as potential therapeutic agents to prevent or treat COVID-19 but have not been systematically examined in this population.To evaluate the associations between the use of psychotropic medications and the risk of COVID-19 infection among adults with serious mental illness receiving long-term inpatient psychiatric treatment.This retrospective cohort study assessed adults with serious mental illness hospitalized in a statewide psychiatric hospital system in New York between March 8 and July 1, 2020. The final date of follow-up was December 1, 2020. The study included 1958 consecutive adult inpatients with serious mental illness (affective or nonaffective psychoses) who received testing for SARS-CoV-2 by reverse transcriptase-polymerase chain reaction or antinucleocapsid antibodies and were continuously hospitalized from March 8 until medical discharge or July 1, 2020.Psychotropic medications prescribed prior to COVID-19 testing.COVID-19 infection was the primary outcome, defined by a positive SARS-CoV-2 reverse transcriptase-polymerase chain reaction or antibody test result. The secondary outcome was COVID-19-related death among patients with laboratory-confirmed infection.Of the 2087 adult inpatients with serious mental illness continuously hospitalized during the study period, 1958 (93.8%) underwent testing and were included in the study; 1442 (73.6%) were men, and the mean (SD) age was 51.4 (14.3) years. A total of 969 patients (49.5%) had laboratory-confirmed COVID-19 infection that occurred while they were hospitalized; of those, 38 (3.9%) died. The use of second-generation antipsychotic medications, as a class, was associated with decreased odds of infection (odds ratio [OR], 0.62; 95% CI, 0.45-0.86), whereas the use of mood stabilizers was associated with increased odds of infection (OR, 1.23; 95% CI, 1.03-1.47). In a multivariable model of individual medications, the use of paliperidone was associated with decreased odds of infection (OR, 0.59; 95% CI, 0.41-0.84), and the use of valproic acid was associated with increased odds of infection (OR, 1.39; 95% CI, 1.10-1.76). Clozapine use was associated with reduced odds of mortality in unadjusted analyses (unadjusted OR, 0.25; 95% CI, 0.10-0.62; fully adjusted OR, 0.43; 95% CI, 0.17-1.12).In this cohort study of adults hospitalized with serious mental illness, the use of second-generation antipsychotic medications was associated with decreased risk of COVID-19 infection, whereas the use of valproic acid was associated with increased risk. Further research is needed to assess the mechanisms that underlie these findings.

Background Clinician-administered measures of negative symptoms may not capture patients' subjective experiences. The Self-Evaluation of Negative Symptoms (SNS) has shown good psychometric properties when used in outpatients with higher-level functioning schizophrenia. We aimed to evaluate the psychometric properties of the SNS in low functioning participants with treatment-resistant schizophrenia (TRS). Methods Participants were assessed using the following measures at two time-points; time-point 1: SNS, Wide Range Achievement Test, 4th Edition Reading Subtest (WRAT-4), and Brief Assessment of Cognition in Schizophrenia (BACS). Time-point 2 (within a week of time-point 1): SNS, Negative Symptom Assessment 16 items (NSA-16), Scale to Assess Unawareness in Mental Disorder-Abbreviated (SUMD-A), Clinical Global Impression Severity Scale (CGI-S), Simpson Angus Scale (SAS), Calgary Depression Scale for Schizophrenia (CDSS), and the Patient Feasibility Questionnaire. Results Fifty participants with TRS were enrolled, a mean age of 43.8 years (SD = 11.19, min = 25, max = 64), a mean IQ of 80.62 (SD = 17.12, min = 65, max = 110), and a mean BACS Composite T-Score of 14.08 (SD = 17.16, min = −27, max = 49). Participants responded to SNS prompts with moderate consistency across two time-points. There were no significant correlations between the SNS and the NSA-16 Global Symptom score (Pearson r = 0.207, p = .150, Spearman r = 0.101, p = .483), NSA-16 Global Functioning score (Pearson r = 0.209, p = .145, Spearman r = 0.126, p = .384), nor the NSA-16 total score (Pearson r = 0.149, p = .302, Spearman r = 0.116, p = .421). However, when participants were stratified by BACS Composite T-score, there was a significant positive correlation between the SNS total and the NSA-16 Global Functioning score (Pearson r = 0.500, p = .048, Spearman r = 0.546, p = .029) among participants who demonstrated higher cognitive functioning. Conclusion Participants with TRS and low functioning were able to respond to questions on the SNS regarding their subjective assessment of negative symptoms. However, self-reported and clinician-rated negative symptoms were not equivalent, except in a subgroup with higher cognitive functioning. This discrepant self-reporting appeared to relate to their low levels of insight and cognitive impairments.

Purpose/background One of the major challenges in the treatment of schizophrenia is nonadherence, defined as the failure to take medications as prescribed. Nonadherence is a strong predictor of symptom relapse, hospital readmission, and poorer long-term outcome. Although long-acting injectable antipsychotics (LAIs) have been found to be superior to their oral analogs at reducing relapse in large-scale meta-analyses, their prevalence seldom exceeds 30% even in populations with a history of nonadherence. We review multiple barriers to the use of LAI utilization and suggest strategies to address them. Methods/procedures We searched for the following terms: long-acting injectable/depot antipsychotics, schizophrenia, barriers, and attitude/perception in both the PubMed search index and Google scholar from 1995 to 2018. A total of 329 studies were selected, of which data from 13 were reviewed for this article. Only peer-reviewed studies, randomized controlled trials, systematic reviews, and meta-analyses that describe barriers to using LAIs were included. Findings/results Several barriers to using LAIs were identified. These are organized into 3 overarching categories: those related to the clinician; those related to the patient; and systems barriers. Clinician factors include the perception of LAIs as coercive, fears of not being able to control the dose, as well as current practice patterns and guidelines. Patient factors include perception of the injection as painful or intrusive, general lack of knowledge, and a sense of coerciveness. For each identified barrier, we propose potential solutions. Implications/conclusions We identified multiple barriers to using LAIs in patients with schizophrenia. Specific strategies are suggested for overcoming each of these barriers.

BackgroundIndividuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine.MethodsParticipants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs).ResultsAt study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4).ConclusionsValbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.

Jeffrey M Cochran,1 Hui Fang,2 Christophe Le Gallo,3 Timothy Peters-Strickland,4 Jean-Pierre Lindenmayer,5 J Corey Reuteman-Fowler6 1Medical & Real World Data Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 2Biostatistics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 3Clinical Programming, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 4PPD, Inc., Wilmington, NC, USA; 5Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA; 6Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USACorrespondence: Jeffrey M Cochran, Medical & Real World Data Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., 508 Carnegie Center, Princeton, NJ, 08540, USA, Tel +1 609 535 9035, Email Jeffrey.Cochran@otsuka-us.comPurpose: A recent, phase 3b, mirror-image clinical trial of outpatients with schizophrenia found that use of aripiprazole tablets with sensor (AS; Abilify MyCite®, comprising an ingestible event-marker sensor embedded in aripiprazole tablets, wearable sensor patches, and a smartphone application) reduced the incidence of psychiatric hospitalizations relative to oral standard-of-care antipsychotics. This analysis explored the relationship between AS engagement by participants and changes in participant performance and symptom-severity measures assessed by clinical raters.Participants and Methods: This post hoc analysis used prospectively collected clinical data from a phase 3b clinical trial (NCT03892889). Outpatients had schizophrenia, were aged 18– 65 years, and had ≥ 1 psychiatric hospitalization in the previous 48 months. Participants were grouped by study completion status and a k-means clustering algorithm based on AS utilization, resulting in 3 groups: discontinued (discontinued AS before month 3 of the study); moderate engagement (completed 3 months, used AS intermittently); and high engagement (completed 3 months, used AS regularly). Baseline to end-of-study differences for the Clinical Global Impression Scale (Severity of Illness and Improvement of Illness scales), Personal and Social Performance Scale, and Positive and Negative Syndrome Scale were calculated.Results: A total of 277 outpatients were enrolled (discontinued, n = 164; moderate engagement, n = 63; high engagement, n = 50). All groups experienced symptom improvement from baseline to end-of-study, with significant changes in the more-engaged groups. Highly engaged participants showed significant improvement for all clinical scores and subscores (all P < 0.05) and demonstrated significantly more improvement in symptoms than participants with less engagement.Conclusion: Participants who completed 3 months of the study and had higher AS engagement experienced significantly greater improvement in their end-of-study clinical assessments versus participants who did not complete 3 months. Improvement may be related to more-consistent medication intake and better engagement with a digital health system.Keywords: digital medicine, medication ingestion, treatment utilization, Positive and Negative Syndrome Scale

ObjectiveTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Long-term safety of the approved TD medication, valbenazine, was demonstrated in 2 clinical trials (KINECT 3 [NCT02274558], KINECT 4 [NCT02405091]). Data from these trials were analyzed post hoc to evaluate the onset and resolution of adverse events (AEs).MethodsParticipants in KINECT 3 and KINECT 4 received up to 48 weeks of once-daily valbenazine (40 or 80 mg). Data from these studies were pooled and analyzed to assess the incidence, time to first occurrence, and resolution for the following AEs of potential clinical interest: akathisia, balance disorder, dizziness, parkinsonism, somnolence/sedation, suicidal behavior/ideation, and tremor.ResultsIn the pooled population (N=314), all AEs of potential clinical interest occurred in 85% (somnolence/sedation, dizziness); >70% (akathisia, balance disorder, tremor).ConclusionsIn long-term clinical trials, the incidence of AEs of potential clinical interest was low (70–100%). All patients taking valbenazine should be routinely monitored for AEs, particularly those that may exacerbate the motor symptoms associated with TD.FundingNeurocrine Biosciences, Inc.

IMPORTANCE: Schizophrenia is associated with cognitive dysfunction and cardiovascular risk factors, including metabolic syndrome (MetS) and its constituent criteria. Cognitive dysfunction and cardiovascular risk factors can worsen cognition in the general population and may contribute to cognitive impairment in schizophrenia. OBJECTIVE: To study the association between cognitive dysfunction and cardiovascular risk factors and cognitive impairment in individuals with schizophrenia. DATA SOURCES: A search was conducted of Embase, Scopus, MEDLINE, PubMed, and Cochrane databases from inception to February 25, 2020, using terms that included synonyms of schizophrenia AND metabolic adversities AND cognitive function. Conference proceedings, clinical trial registries, and reference lists of relevant publications were also searched. STUDY SELECTION: Studies were included that (1) examined cognitive functioning in patients with schizophrenia or schizoaffective disorder; (2) investigated the association of cardiovascular disease risk factors, including MetS, diabetes, obesity, overweight, obesity or overweight, hypertension, dyslipidemia, and insulin resistance with outcomes; and (3) compared cognitive performance of patients with schizophrenia/schizoaffective disorder between those with vs without cardiovascular disease risk factors. DATA EXTRACTION AND SYNTHESIS: Extraction of data was conducted by 2 to 3 independent reviewers per article. Data were meta-analyzed using a random-effects model. MAIN OUTCOMES AND MEASURES: The primary outcome was global cognition, defined as a test score using clinically validated measures of overall cognitive functioning. RESULTS: Twenty-seven studies involving 10 174 individuals with schizophrenia were included. Significantly greater global cognitive deficits were present in patients with schizophrenia who had MetS (13 studies; n = 2800; effect size [ES] = 0.31; 95% CI, 0.13-0.50; P = .001), diabetes (8 studies; n = 2976; ES = 0.32; 95% CI, 0.23-0.42; P

Treatment-resistant schizophrenia (TRS), the persistence of positive symptoms despite ≥2 trials of adequate dose and duration of antipsychotic medication with documented adherence, is a serious clinical problem with heterogeneous presentations. TRS can vary in its onset (at the first episode of psychosis or upon relapse), in its severity, and in the response to subsequent therapeutic interventions (i.e., clozapine, electroconvulsive therapy). The heterogeneity of TRS indicates that the underlying neurobiology of TRS may differ not only from treatment-responsive schizophrenia but also among patients with TRS. Several hypotheses have been proposed for the neurobiological mechanisms underlying TRS, including dopamine supersensitivity, hyperdopaminergic and normodopaminergic subtypes, glutamate dysregulation, inflammation and oxidative stress, and serotonin dysregulation. Research supporting these hypotheses is limited in part by variations in the criteria used to define TRS, as well as by the biological and clinical heterogeneity of TRS. Clinical trial designs for new treatments should be informed by this heterogeneity, and further clinical research is needed to more clearly understand the underlying neurobiology of TRS and to optimize treatment for patients with TRS.

Diagnostic classification systems of schizophrenia have changed over time, pointing to their potential lack of reliability and scientific validity. A particular challenge is comorbid presentations, which have made the delineation of clear boundaries difficult and challenging for research applications. There is a need for a new symptom domain approach that is free of traditional diagnostic “attachments.” The National Institute of Mental Health (NIMH) introduced such as system with the Research Domain Criteria (RDoC) initiative in 2013. The system relies on five behavioral dimensions. We present the potential advantage of using the RDoC in the study of behavioral domains within schizophrenia and specifically for comorbid manifestations. Using the RDoC matrix allows researchers to align information from genetic, molecular, cellular, circuit, physiological, behavioral, and self-report levels of a comorbid disorder. Overall, the NIMH RDoc criteria will not displace the International Statistical Classification of Diseases and Related health Problems/Diagnostic and Statistical Manual of Mental Disorders diagnostic systems, but they may be very useful for investigators who want to focus on the systematic underlying molecular, genetic, cellular, and neurophysiological underpinnings for the study of comorbid disorders. [ Psychiatr Ann. 2018;48(12):547–551.]

Cognitive deficits are a prominent feature of many psychiatric disorders and are predictors of decreased functioning, quality of life, and treatment response. Cognitive remediation focuses on improving cognitive skills through repeated practice and strategy learning. In people with schizophrenia, cognitive remediation is associated with improvements in cognition and psychosocial functions. This article provides an overview of cognitive remediation and some considerations for developing a cognitive remediation service in a treatment setting.

Schizophrenia is associated with an elevated risk of aggression. Cognitive deficits have been associated with inpatient aggression and future violence. The relationship between cognitive deficits and violent behavior has however been inconsistent across studies. In addition, studies have failed to inform how cognitive deficits may contribute to aggression in schizophrenia. The current study examined the association of cognitive deficits with schizophrenia-related aggression and violent offending. It also explored the putative mediating role of negative emotionality on the impact of cognitive deficits on aggression. People with schizophrenia and schizoaffective disorder (N = 78) were recruited from a state hospital. Participants were classified based on their history of violent offending. Participants completed measures of cognition, symptoms, and aggression. Deficits in working memory, reasoning/problem-solving, and verbal learning were the most prioritized for the prediction of violent offender status. Violent offenders demonstrated greater impairments in most cognitive domains especially working memory and verbal learning. Offenders also demonstrated greater negative emotionality, excitement/agitation, and incidents of verbal and physical aggression. Negative emotionality and excitement/agitation fully transmitted the effect of cognitive deficits on impulsive aggression in meditational models. Cognitive deficits increase the risk of impulsive aggression in schizophrenia via inefficient regulation of negative affective states.

Background Studies have shown a convergence of neural systems implicated in cognitive control and social emotional functions with mechanisms involved in emotion regulation, awareness, and impulsive aggression. In a sample of patients with a history of aggression, we examined the association of cognitive and social cognitive functions with emotion regulation capacity, emotional awareness, impulse control, and aggression. Methods Participants were 78 individuals with schizophrenia or schizoaffective disorder that participated in a cognitive training study. Emotion regulation capacity was indexed by obtaining participants’ heart rate variability (HRV), respiration, and skin conductance while participants viewed pictures selected from the International Affective Picture System (IAPS). Three blocks of pictures were presented—a neutral block depicting pictures of everyday objects preceded by audio recordings of their description; an emotionally-evocative block preceded by their description, and a reappraisal block of emotionally-evocative pictures preceded by reappraisal statements. A subset of participants (N=37) completed the emotion regulation task. The MATRICS Consensus Cognitive Battery (MCCB), the Reading the Mind in the Eyes Task (Eyes Task), and the Emotion Recognition-40 (ER-40) were administered to assess cognitive functioning, mentalizing, and facial affect recognition respectively. Negative affectivity was captured using the Positive and Negative Affect Schedule (PANAS) whereas aggression was measured with the Taylor Aggression Paradigm (TAP) and the Overt Aggression Scale Modified (OAS-M). In a smaller subsample of 12 individuals, we performed analyses of activation patterns during the performance of the emotion regulation task. Regions of interest (ROI) included the dACC, DLPFC, VLPFC, vmPFC, left and right amygdala, and the subcallosal cingulate. We created a regional mask of the cognitive control and emotional appraisal regions for event-related fMRI. Results There were inverse associations between performance on the MCCB and the Eyes Task and indices of emotion regulation capacity—in particular, significant associations were obtained with Low Frequency/High Frequency HRV ratio (r=-0.324, p There were inverse associations between activation within the event-related regional mask and low frequency/high frequency heart rate variability ratio at rest (r=-0.504, p=0.095) and during the viewing of emotionally-evocative pictures (r = -0.264, p=0.36). Associations with HRV were especially remarkable for the dorsomedial, ventrolateral, and right amygdala regions. Remarkably, increased activation in the regional mask when reappraisal statements were provided with emotionally-evocative pictures was inversely correlated with the life history of aggression LHA (r=-0.32, p=0.28, n=14) and OAS (r=-0.284, p=0.34, n=14) aggression scores. This pattern was present when the dACC, right and left amygdala, DLPFC, VLPFC, and the subcallosal cingulate were set as the seed region. Discussion The results show an association between cognitive functions and emotion regulation capacity indexed by measuring physiological arousal during the performance of the picture viewing task. Emotion regulation capacity also showed significant association with aggression. Deficits in cognitive and social cognitive abilities may contribute to and be viable targets for improving emotion regulation capacity and decreasing aggression risk.

Background Many individuals with chronic or treatment resistant schizophrenia experience multiple relapses or treatment failures during the course of the illness. Some of these relapses are due to poor treatment compliance that is inherent to schizophrenia. Poor insight may be a leading cause for partial- or non-adherence to treatment as a high proportion of individuals with schizophrenia are partially or completely unaware of their mental disorder. The first two years after stabilization are thought to be key for long-term functional and clinical prognosis. In the present study, we first estimated the rate of treatment failure or relapse following clinical stability at one and two years, investigate the time to occurrence of relapse among individuals with chronic schizophrenia and the association between baseline clinical features recorded during the inpatient hospitalization and relapse at one- and two-year time points. We hypothesized that lack of insight, as measured by the PANSS item G12, would be a greater predictor of relapse than other characteristics previously suggested as possible predictors, including other symptoms from the PANSS, age, duration of illness, age at onset of illness, substance use, number of prior hospitalizations, and length of stay of the pre-discharge hospitalization. Methods A total of 138 participants diagnosed with schizophrenia or schizo-affective disorder were assessed with a comprehensive assessment at one year and two-year following discharge from a long-term psychiatric facility. Regression models were used to determine factors predicting time to relapse and other elements of functioning. Baseline factors examined included PANSS, MCCB, PSP, demographics and treatment variables. Results Relapse rates were 56.52% (n=78 of 138) by Year 1, and 69.56% (n=96 of 138) by end of Year 2. The estimated relapse-free period for all individuals at the end of the study was 8.78 months. The backward elimination (–2 log likelihood=189.59, χ2=9.01, df=2, p=.021) showed that the best predictive variables for relapse were lack of insight/judgment as assessed by PANSS item G12 at baseline (B=.20, SE=.09, df=1, p=.011, Exp[B]=1.36), lifetime years of substance use (B=.16, SE=.11, df=1, p=.029, Exp[B]=1.33), PANSS Factor baseline score on Disorganization (B=.15, SE=.12, df=1, p=.031, Exp[B]=1.56), and number of previous hospitalizations (B=.13, SE=.11, df=1, p=.048, Exp[B]=1.23). No other baseline variables were found to be significant. Discussion Poor insight is a fundamental symptom of schizophrenia that, while not entirely and uniformly expressed in all individuals, is among the most common symptoms across subjects. Our study shows that the numerous negative consequences of lack of insight should lead clinicians and researchers to make insight a high priority for allocation of clinical resources. Effective approaches to managing these predictive characteristics will allow affected individuals and their families and care providers to take part in collaborative treatment and relapse risk-management paradigms.

Study Objective:Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of TD in adults. Using data from a long-term study (KINECT 3; NCT02274558), the effects of once-daily valbenazine (40 mg, 80 mg) on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS) in participants who were early responders based on subjective measures, including patient self-report (Patient Global Impression of Change [PGIC]) or clinician judgment (Clinical Impression of Change-Tardive Dyskinesia [CGI-TD]).Methods:Data from KINECT 3 (6-week double-blind, placebo-controlled [DBPC] period; 42-week double-blind extension) were analyzed post hoc. Long-term outcomes included mean change from baseline to Week 48 in AIMS total score (sum of items 1-7) and AIMS response (≥50% total score improvement from baseline) at Week 48. These AIMS outcomes were assessed in participants who achieved early improvement, defined as a PGIC or CGI-TD score of ≤3 (“minimally improved” or better) at Week 2 (first post-baseline visit of the DBPC period). Participants who initially received placebo were not included in the analyses.Results:In participants who received only valbenazine (40 or 80 mg) during KINECT 3 and had available Week 2 assessment, 50% (72/143) had early PGIC improvement (score ≤3) and 43% (61/142) had early CGI-TD improvement (score ≤3). Baseline characteristics were generally similar between participants who achieved early PGIC or CGI-TD improvement and those who did not. Based on available assessments at Week 48, mean AIMS total score change from baseline in participants with early PGIC improvement was similar to those who did not reach the early PGIC improvement threshold (-4.1 [n=35] vs -3.5 [n=41]). Mean AIMS total score change from baseline in participants with early CGI-TD improvement was similar to those who did not achieve early CGI-TD improvement (-4.2 [n=31] vs -3.5 [n=45]). AIMS response at Week 48 was also similar in those who achieved early PGIC and CGI-TD improvement (40% and 42%, respectively) compared to those who did not achieve early PGIC and CGI-TD improvement (39% and 38%, respectively).Conclusions:Results from this long-term valbenazine trial indicate that many participants achieved at least minimal patient- and clinician-reported improvement at Week 2. AIMS outcomes at Week 48 demonstrated long-term reductions in TD severity regardless of early response. More research is needed to understand the association between early improvement and long-term treatment effects, but early non-improvement based on subjective measures may not be predictive of long-term treatment failure.Presented:International Congress of Parkinson’s Disease and Movement Disorders; September 22-26, 2019; Nice, France.Funding Acknowledgements:This study was sponsored by Neurocrine Biosciences, Inc.

Background The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is an “applied” game-based assessment that uses a multi-level functional task to assess instrumental activities of daily living (iADL). This study examines the feasibility, convergent validity, and predictive ability of the VRFCAT in a sample of inpatients with chronic schizophrenia. Methods Inpatients with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder, completed the VRFCAT prior to discharge. The UPSA-B, SLOF, and PSP were administered, both at baseline and after four-weeks in the community. VRFCAT performance scores were compared to published data from the VRFCAT validation study. Results All 62 participants completed the VRFCAT. Compared to the performance of stable outpatients, participants performed 1.50 SDs below the VRFCAT mean adjusted total time (ATT) (Validation study: Mean T Score = 32.5, SD = 16.59) with more errors. The VRFCAT ATT T-score was significantly correlated with baseline UPSA-B total score (p = 0.005) and PSP Global score (p = 0.010). 34 participants completed the follow-up period (55%), and 28 were lost to follow-up. There were no statistically significant differences in VRFCAT scores between these two groups (all p > 0.29). The VRFCAT composite score at baseline was significantly associated with the UPSA-B total score (p = 0.010) and the PSP total score (p = 0.008) at four-weeks, as was the PSP Socially Useful Activities subscale score (p = 0.006). Conclusion The VRFCAT is a valid measure of iADLs in inpatients with chronic schizophrenia. The VRFCAT predicted instrumental functioning four-weeks post-discharge. Future studies should examine other moderators of measures of functional capacity pre-discharge, predicting function later in the community.

PURPOSE/BACKGROUND Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS After week 4

Cognitive remediation is now widely recognized as an effective treatment for cognitive deficits in schizophrenia. Its effects are meaningful, durable, and related to improvements in everyday functional outcomes. As with many therapies, the evolution of cognitive remediation has resulted in treatment programs that use a variety of specific techniques, yet share common core principles. This paper is the product of a cognitive remediation expert working group consensus meeting to identify core features of the treatment and produce recommendations for its design, conduct, reporting, and implementation. Four techniques were identified as core features of cognitive remediation: facilitation by a therapist, cognitive exercise, procedures to develop problem-solving strategies, and procedures to facilitate transfer to real world functioning. Treatment techniques within each of these core features are presented to facilitate decisions for clinical trials and implementation in clinical settings.

Objective A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence. Participants A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate. Evidence A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included. Consensus process Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with 75% agreement (unless feedback suggested further investigation). Conclusions Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.

BACKGROUND: Clinical trials for schizophrenia are increasingly using electronic methods to collect patient-reported outcomes (ePRO). Hence, several ePROs have been developed to better understand patients’ experience with their own illness. Lack of insight into illness is a core feature of schizophrenia that is multidimensional,and related to poor compliance with treatment and relapse. Assessing insight into illness via an ePRO, and attaining patient perception may provide supplemental information to the clinician as data is collected in real-time to facilitate functional and risk assessment. Core questions are whether it is feasible for patients with schizophrenia to complete an ePRO on their smartphone, and will the results obtained from patient’s perception of insight compare to clinician assessed insight, and passive digital biomarkers of psychiatric morbidity. The aim is to (1) develop a short, multidimensional self-report measure of insight (Awareness of Insight Scale, AIS), (2) assess validity and reliability, and (3) evaluate feasibility in schizophrenia study context. METHODS: A Delphi method was used to facilitate expert participation and ensure face and content validity for development of the AIS. The SUMD and SCI-PANSS G12 Lack of Insight were used as a reference for scale development. A new scale with 8 items incorporating David’s (1990) dimensions of insight was developed consisting of: (1) awareness of having a mental illness, 2) relabel unusual mental events as pathological, and 3) adherence to treatment. The scale was presented as a smartphone app for 6 months via a parent study assessing passive digital biomarkers of psychiatric morbidity (Mindstrong Health). Feasibility was assessed based on the rate of completion of the ePRO. Internal consistency, test-retest reliability and validity were assessed by comparing with PANSS: G12 and Disorganization Factor in a sample of 16 outpatients. The ePRO was designed with push messages suggesting patients complete the scale once per week. RESULTS: The 8 items selected for inclusion in the AIS assessed awareness of psychiatric illness, need to take medications, attributing being sad or upset to unusual experiences, and belief that s/he is always correct. Of the 22 subjects enrolled, data is presented for 16 subjects, as the remaining 6 subjects were not active on their smartphones. Of the 16 subjects, all completed at least 2 weeks of AIS assessments on their smartphone with 68.75% completing all weekly assessments since enrollment with an average of 3.66 minutes to complete. Internal Consistency was high (α = 0.79). Preliminary findings show scores on AIS correlated with PANSS G12 (r = 0.51, p = 0.03) and with the PANSS Disorganization Factor (r = 0.39, p = 0.04). Test-retest reliability are moderate with ICCs = 0.72. DISCUSSION: Preliminary findings show the AIS is a short, reliable and valid measure of insight in schizophrenia. Findings support its feasibility in a small sample of outpatients with chronic and treatment resistant schizophrenia with multiple relapses.

BACKGROUND: A patient’s readiness for discharge can be assessed from the perspectives of the clinician, patient, and family. Criterion-based assessment by the clinician is the most commonly reported method, but there is no ecologically valid method available to assess readiness for discharge while in the hospital. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a novel game-based program, that provides a sequence of objectives related to activities involved in a multi-level shopping task. The aim of the present study was (1) to examine the feasibility of administering the VRFCAT in a population of very low functioning patients with chronic schizophrenia, (2) to relate the performance of the study patients to standardized VRFCAT performance data of higher functioning patients (Keefe et al. 2016), (3) to assess the concurrent validity of the VRFCAT in this population, and (4) to correlate the performance measures to measures of community adjustment 4 weeks after hospital discharge. METHODS: The VRFCAT was administered after informed consent to inpatients with DSM 5 diagnosis of chronic schizophrenia, who were eligible for discharge from a long-term inpatient psychiatric facility. Independent variables included the VRFCAT time to completion (adjusted total time), number of errors on 12 VRFCAT objectives, and the number of times that an individual failed to complete a task (forced progression). The SLOF, the UPSA-B and the PSP were completed for concurrent validity. Patients were followed for one month after their discharge to assess the level of their community adjustment as measured by the SLOF, the UPSA-B and the PSP. RESULTS: Of the 80 subjects enrolled, a total of 72 subjects had evaluable data with a mean age of 41.23 years (SD = 10.11). 55.56% of subjects also had an axis I substance use diagnosis. The mean level of education was 9.89 (SD = 2.69) and 56.94% of patients had a history of incarceration. When compared to higher functioning patients’, participants performed 2.5 standard deviations below the mean for the adjusted total time (Mean T Score = 24.89, SD = 16.56), total errors (T = 24.11, SD = 22.69), and 2 SDs below the mean for total forced progressions (T = 29.56, SD = 14.311). VRFCAT test-retest reliability showed unchanged mean T scores: total time (T Score = 23.11, SD = 16.23), total errors (T = 23.56, SD = 22.00). Pearson correlations at baseline for 4 of 12 VRFCAT objectives with concurrent SLOF Activities (Pay for the Bus, Shop for Groceries, Pay for Groceries), and Work Skills (Shop for Groceries, Pay for Groceries) domain scores were statistically significant (p < 0.001). At 4-week follow-up, significant correlation was found with the change in PSP Domain A of socially useful activities and change in VRFCAT Adjusted Total Time [r = 0.586, p = 0.044]. There were no significant correlations between the SLOF and VRFCAT for change from baseline. There was no difference in VRFCAT scores between the subjects who were re-hospitalized and those who missed clinic appointments. Non-relapsing participants had a higher score on adjusted total time, which indicates worst functional outcomes. DISCUSSION: Results indicate that the VRFCAT is feasible in schizophrenia patients with low levels of functioning and delivers meaningful functional concurrent data. Both concurrent and test-retest validity were good. The VRFCAT performance level was not useful for measurement of readiness for discharge for clinical purposes.

BACKGROUND: One of the key risk factors for relapse in schizophrenia is poor insight. Genetic influences on poor insight have not yet been studied despite growing evidence to the extent of genetic contributions in schizophrenia. There is evidence of genetic associations for psychopathology symptom domains (Arnedo et al., 2015) and these domains are strongly associated with insight. Dysfunction of the catechol-O-methyltransferase (COMT) gene is shown to confer susceptibility to schizophrenia because of its catalytic activity for dopamine degradation. COMT Val allele more rapidly inactivates released dopamine than the Met allele, and is shown to be associated with cognitive performance such as working memory and attention, and influences ToM functioning by modulating the dopamine pathways. Since the role of COMT in schizophrenia remains questionable, we determined whether any association exists between COMT genotypes and clinical symptomatology (Lack of Insight and Judgment) in a large cohort of schizophrenia subjects. METHODS: 145 subjects with DSM-IV-TR schizophrenia or schizoaffective disorder were genotyped via saliva sampling. Subjects were evaluated on clinical symptoms (PANSS). Genotyping of the COMT Val158Met polymorphism was evaluated compared to PANSS Marder factors, including PANSS items Lack of Insight and Judgment. RESULTS: Of 145 subjects, data from 138 subjects were usable. Distribution of COMT genotype: Met/Met: 28 (20.29%), Val/Met: 61 (44.20%), and Val/Val: 49 (35.51%). There was no significant difference between mean PANSS total score Met/Met: 76.053 (SD 13.011), Met/Val: 78.001 (SD 12.489), Val/Val: 79.596 (SD 11.286). Patients with the COMT Val/Val genotype had significantly higher total score on the PANSS Item Lack of Insight than those with the Val/Met or Met/Met genotypes (p = 0.041). Patients with the COMT Val/Val genotype also had significantly higher scores on the PANSS Disorganized Factor than those with the COMT Val/Met genotype (p = 0.043). As an exploratory analysis, COMT Val/Met showed significant association with Blunted Affect (p = 0.039), but no other items of the negative symptom factor. DISCUSSION: Our findings support hypotheses regarding associations between COMT polymorphisms and lack of insight and judgment in schizophrenia. It is important that the exact mechanisms of genetic contribution to insight are delineated to aid the development of effective treatments and to identify prevention strategies.

BACKGROUND: The association between schizophrenia and violence is an important issue in psychiatry. The impact of several factors (social cognition, neurocognition, alexithymia, emotion regulation capacity, and the therapeutic milieu) on aggression in schizophrenia creates an opportunity for the development and evaluation of novel treatments for aggression. Previous studies show that cognitive remediation training (CRT) and social cognitive training (SCT) help to decrease hostility. The parent study examined whether cognitive training leads to improvements in cognition emotion regulation capacity, and impulse control in participants with a history of impulsive aggression. The current study examined the effectiveness of CRT alone versus a combination of CRT and SCT in terms of emotion recognition and cognitive improvement. METHODS: The study recruited participants with schizophrenia or schizoaffective disorder with a past year history of at least one or more violent acts or a significant lifetime history of aggression as indicated by a score of 5 or more on the Life History of Aggression (LHA) interview from two inpatient sites (Manhattan Psychiatric Center and New York Hospital, Westchester Division). Participants were randomized to two groups of 36 one-hour sessions. Participants in the control group had 24 sessions of CRT (BrainHQ) and 12 sessions of Encyclopedia readings. Participants in the treatment group had 24 sessions of CRT (BrainHQ) and 12 sessions of computerized SCT (MindReading). To assess neurocognition, mentalizing, and facial affect recognition abilities, participants were administered the MATRICS Consensus Cognitive Battery (MCCB), Reading the Mind in the Eyes Task (Eyes Task), and the Emotion Recognition-40 (ER-40) respectively. Negative emotionality was captured using the Positive and Negative Affect Schedule (PANAS). RESULTS: The study data included 49 completers and 5 intent-to-treat samples, with 24 and 25 per group, respectively (CRT+ SCT and CRT alone). Results indicated no significant differences between groups at baseline. Significant overall improvements were observed in the ER-40 for all subjects across time (Mean Time 1 = 25.06 (SD = 25.023), Time 2 Mean = 30.86 (SD = 6.849), p < 0.001), the Mind in the Eyes Test - Revised (Time 1 Mean = 19.70 (SD = 7.407), Time 2 Mean = 26.15 (SD = 7.830), p < 0.001), and the PANAS Negative affect Score (Time 1 Mean = 29.40 (SD = 11.836), Time 2 Mean = 18.47 (SD = 2.688), p < 0.001). Both cognitive groups showed improvements from baseline on the composite cognition score of the MCCB composite (F (1,47)=74.51, p

Treatment-resistant schizophrenia (TRS) occurs in approximately 30% of individuals diagnosed with schizophrenia. The identification and management of TRS in clinical practice are inconsistent and not evidence based. No established clinically relevant criteria for defining and treating TRS exist, although guidelines have been promulgated for clozapine use among TRS patients. This report summarizes the consensus from a roundtable that focused on defining and identifying TRS, pathways to treatment resistance, current treatments, unmet needs, and disease burden. Nine clinical experts in schizophrenia and TRS participated in a closed meeting on June 23, 2017, sponsored by Lundbeck, at which published literature in key areas of TRS research was reviewed. The findings from published studies were synthesized by experts in each area and presented to the group for review and discussion. It was agreed that inadequate response to 2 different antipsychotics, each taken with adequate dose and duration, is required to establish TRS. This recommendation is consistent with guidelines for clozapine use. For each trial, objective symptom measures should be used to assess treatment response, with medication adherence ensured. Once nonresponse is established (after ≥ 12 weeks for positive symptoms [2 trials of ≥ 6 weeks]), the treatment plan should be reevaluated and alternative pharmacologic or nonpharmacologic treatments considered. With increased awareness, those involved in the care of patients with schizophrenia will be able to identify TRS earlier in its course, thus supporting more informed treatment decisions by clinicians, patients, and caregivers to reduce the overall disease burden.

Poor medication adherence contributes to negative treatment response, symptom relapse, and hospitalizations in schizophrenia. Many health plans use claims-based measures like medication possession ratios or proportion of days covered (PDC) to measure patient adherence to antipsychotics. Classifying patients solely on the basis of a single average PDC measure, however, may mask clinically meaningful variations over time in how patients arrive at an average PDC level.To model patterns of medication adherence evolving over time for patients with schizophrenia who initiated treatment with an oral atypical antipsychotic and, based on these patterns, to identify groups of patients with different adherence behaviors.We analyzed health insurance claims for patients aged ≥ 18 years with schizophrenia and newly prescribed oral atypical antipsychotics in 2007-2013 from 3 U.S. insurance claims databases: Truven MarketScan (Medicaid and commercial) and Humana (Medicare). Group-based trajectory modeling (GBTM) was used to stratify patients into groups with distinct trends in adherence and to estimate trends for each group. The response variable was the probability of adherence (defined as PDC ≥ 80%) in each 30-day period after the patient initiated antipsychotic therapy. GBTM proceeds from the premise that there are multiple distinct adherence groups. Patient demographics, health status characteristics, and health care resource use metrics were used to identify differences in patient populations across adherence trajectory groups.Among the 29,607 patients who met the inclusion criteria, 6 distinct adherence trajectory groups emerged from the data: adherent (33%); gradual discontinuation after 3 months (15%), 6 months (7%), and 9 months (5%); stop-start after 6 months (15%); and immediate discontinuation (25%). Compared to patients 18-24 years of age in the adherent group, patients displaying a stop-start pattern after 6 months had greater odds of having a history of drug abuse (OR = 1.46; 95% CI = 1.26-1.66; P0.001), alcohol abuse (OR = 1.34; 95% CI = 1.14-1.53; P0.001), and a codiagnosis of major depressive disorder (OR = 1.24; 95% CI = 1.05-1.44; P0.001) and were less likely to be aged 35-54 years (OR = 0.66; 95% CI = 0.46-0.85; P0.001).Longitudinal medication adherence patterns can be expressed as distinct trajectories associated with specific patient characteristics and health care utilization patterns. We found 6 distinct patterns of adherence to antipsychotics over 12 months. Patients in different groups may warrant different types of clinical interventions to prevent hospitalizations, longer hospital stays, and increased clinical complexity. For example, clinicians may consider regular home visits, assertive community treatment, and other related interventions for patients at high risk of immediate discontinuation. Health plans should consider supplementing claims-based adherence measures with new technologies that are able to track patient adherence patterns over time.Otsuka Pharmaceutical DevelopmentCommercialization provided support for this research. MacEwan and Shafrin are employees of Precision Health Economics, which was contracted by Otsuka Pharmaceutical DevelopmentCommercialization to conduct this study. Lakdawalla is the Chief Scientific Officer and a founding partner of Precision Health Economics. Forma is an employee of Otsuka Pharmaceutical DevelopmentCommercialization. Hatch is a former employee of Otsuka Pharmaceutical DevelopmentCommercialization and is a current employee of ODH, Inc. Lindenmayer has received grant/research support from Janssen, Lilly, AstraZeneca, JohnsonJohnson, Pfizer, BMS, Otsuka, Dainippon, and Roche and is a consultant for Janssen, Lilly, Merck, Shire, and Lundbeck. Portions of this study were presented as a poster at the American Society of Clinical Psychopharmacology Annual Meeting in Miami Beach, Florida; June 23, 2015; and at the 28th Annual U.S. Psychiatric and Mental Health Congress; San Diego, California; September 12, 2015. Study concept and design were contributed by Forma, Ladkawalla, MacEwan, and Shafrin, along with Hatch and Lindenmayer. MacEwan, Shafrin, Forma, and Lakdawalla collected the data, along with Hatch and Lindenmayer. Data interpretation was performed by Hatch, Lindenmayer, MacEwan, and Shafrin, assisted by Forma and Lakdawalla. The manuscript was written and revised by MacEwan, Forma, and Shafrin, along with Hatch Lakdawalla, and Lindenmayer.

Schizoaffective disorder (SAD) is an incapacitating illness that presents clinicians with challenges in terms of both its diagnosis and its psychopharmacological management. Most studies conducted on the psychopharmacological treatment of SAD also include patients with schizophrenia or other psychotic illnesses, thereby providing an unspecific view to the clinician as to the best way of treating patients with SAD. The objective of this article is to review studies on evidence-based treatment of patients with SAD. We conducted a systematic literature search in MEDLINE/PubMed for full-text studies in the English language using the terms 'Schizoaffective and treatment' or 'antipsychotic schizoaffective'. Our review found relatively few studies with either an active comparator or placebo that examined the efficacy of antipsychotics for patients with SAD without an admixture of patients with schizophrenia. Only oral paliperidone extended release (ER), paliperidone long-acting injection (LAI), and risperidone have been shown to be effective and safe in reducing psychotic as well as affective components in acutely ill SAD patients in controlled studies. Paliperidone ER and LAI have also been shown to be efficacious in the maintenance treatment phase of SAD patients. While no supportive data exist, it is possible that other atypical antipsychotics may have similar efficacy to the two mentioned above. We conclude with a number of research recommendations for the study of treatment options for patients with SAD. First, there is a need for studies with patients specifically diagnosed with SAD for both the acute and the maintenance phase. The sample size needs to be adequate to allow a primary analysis of efficacy and to allow for analysis of the SAD subtypes: depressed and bipolar. Another recommendation is the need for studies of patients with SAD stratified into patients with and without mood stabilizers or antidepressants to allow the examination of the adjunctive role of these psychotropic medications. A third recommendation is to focus on specific co-morbid aspects of patients with SAD, such as suicidality and substance use disorders. Data from such studies will fill the gap of evidence-based treatment approaches and help clinicians in making important treatment decisions for patients with this complex condition.

Background An individual’s mental health is best captured by considering the overall associations of biological, behavioral, and social functions that comprise the framework of individual experience. As such, accessing data on various health indicators concurrently can influence prediction of disease progression or change in response to treatment. Data generated passively by smartphones to measure human behavior has generated significant research interest and has increasingly been utilized in psychiatric disorders. In schizophrenia, passive and continuous assessment of how an individual uses their mobile device may give rise to clinically useful markers that can be used to improve treatment processes, adapt treatment choices, identify early risk for relapse to initiate clinical intervention, and develop new clinical models. A promising approach is to leverage current advances in mobile technology, data analytics and machine learning to enable automated and fast phenotyping of digital data. . In this context, the workflow for phenotyping (passive data collection → data storage and curation → trait extraction → machine learning/classification → models/apps for decision support) has to be carefully designed and efficiently executed to minimize resource usage and maximize utility. Digital phenotyping can be used in conjunction with standard care to reduce time to recognition and acknowledgement that worsening of a symptom needs to be addressed, to reduce time to receiving appropriate level of care, to increase ability to analyze and collect data from a variety of sources to improve mental health needs assessment and delivery of services, and to advance outcome measurement through comparison of passive and active data sets. Aim The aim of this pilot study is to test whether a smartphone digital phenotyping application can help detect early signs of treatment failure or response in individuals with chronic schizophrenia after discharge from hospital. Methods 17 individuals with DSM-5 schizophrenia were provided with a smartphone and digital phenotyping app, MindStrong Health app, following discharge from an inpatient psychiatric facility. The participants were followed for 6 months with monthly rater administered evaluations assessing neurocognition (Brief Assessment of Cognition in Schizophrenia (BACS)), symptomatology (PANSS; CGI-S/I), quality of life (SF-36), healthcare utilization, alcohol/drug use, level of clinical insight and depression (Calgary Depression Rating Scale, CDSS). Digital phenotyping data included gestures (swipes, taps, other), orientation (the way the phone is pointing), acceleration (sudden movements of the phone), keystroke patterns with characters encoded, number of calls made, number of emails sent, number of text messages sent, and location information from the GPS. Predictive models were built using multiple machine learning techniques - random forest plots, linear regression and gradient boosting, to predict the target scores based on phone usage patterns. Results Of the 17 enrolled participants, 10 provided analyzable data (i.e., had at least 22 target days with data). There was a gradual reduction of passive data generation due to either non-use of the smart phone or due to non-recharging of the device. The mean PANSS score was 80.12 (14.56). BACS scores corresponding to motor speed (token motor task), verbal fluency (category instances, letter fluency), and attention and processing speed (symbol coding) were found to be highly correlated with a composite digital phenotyping marker while scores on the PANSS or CDSS were not. Discussion The study provides a basis for using smartphone-base mobile apps to use as an augmentation within clinical practice to gather further information on patients outside the clinic setting, focusing on their behavior in the ‘real world.’ In particular, the cognitive data derived from the digital device correlated well with rater administered traditional cognitive ratings. Collecting digital data can provide a much needed window into the lives of patients in between normally scheduled visits, while minimizing costs and inconvenience to the patient. Studies with larger sample sizes are required to assess relationships with relapse, rehospitalizations and treatment failure.

Background: Negative symptoms and cognitive deficits have a substantial predictive value for functional deficits and recovery in schizophrenia. However, the relationship between negative symptoms and cognitive abnormalities is unclear possibly due to the heterogeneity of negative symptoms. This study used the model of expressive and experiential negative symptoms subfactors to decrease this heterogeneity. It examined these subfactors and cognition before and after treatment with computerized cognitive remediation training (CRT) in chronically-hospitalized individuals with psychosis and predominant negative symptoms. Methods: Seventy-eight adult participants with a DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder were enrolled in a 12-week CRT program. Assessments of demographic and illness variables, baseline and endpoint assessments of psychopathology (Positive and Negative Syndrome Scale) and cognition (MATRICS Consensus Cognitive Battery - MCCB) were conducted. Results: The baseline expressive negative subfactor was associated with Processing Speed (r = −0.352, p ≤ 0.001) and Reasoning/Problem Solving (r = −0.338, p ≤ 0.001). Following CRT, there was a significant decrease in the experiential negative subfactor (p

Background Transcranial direct-current stimulation (tDCS), a non-invasive neurostimulation treatment, has been reported in a number of sham-controlled studies to show significant improvements in treatment-resistant auditory hallucinations in schizophrenia patients, primarily in ambulatory and higher-functioning patients, but little is known of the effects of tDCS on hospitalized, low-functioning inpatients. Objective/Hypothesis The purpose of this study was to examine the efficacy and safety of tDCS for auditory hallucinations in hospitalized ultra-treatment-resistant schizophrenia (TRS) and to evaluate the effects of tDCS on cognitive functions. We hypothesized that treatment non-response reported in previous tDCS studies may have been due to the insufficient duration of direct-current stimulation. Methods Inpatient participants with DSM-V schizophrenia, long-standing treatment-resistance, and auditory verbal hallucinations (AVH) participated in this 4-week sham-controlled, randomized trial. Assessments included the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) at baseline and endpoint (at the end of Week 4), and the Auditory Hallucinations Rating Scale (AHRS) administered at baseline, endpoint, and weekly throughout the study. Participants were randomized to receive active vs. sham tDCS treatments twice daily for 4 weeks. Results Twenty-eight participants were enrolled (tDCS, n = 15; control, n = 13) and 21 participants completed all 4 weeks of the trial. Results showed a significant reduction for the auditory hallucination total score (p ≤ 0.05). We found a 21.9% decrease in AHRS Total Score for the tDCS group and a 12.6% decrease in AHRS Total Score for the control group. Significant reductions in frequency, number of voices over time, length of auditory hallucinations, and overall psychopathology were also observed for the tDCS group. When assessing cognitive functioning, only Working Memory showed improvement for the tDCS group. Conclusion Although there was only a small improvement noted in auditory hallucination scores for the tDCS group, this improvement was meaningful when compared to no standard treatment of the control group. While this makes the interpretation of clinical significance debatable, it does confirm that tDCS combined with pharmacological intervention can provide clinical gains over pharmacological intervention alone. Therefore, tDCS treatment appears to be effective not only for ambulatory, higher-functioning patients, but also for patients with ultra-treatment-resistant schizophrenia.

Objectives Cognitive remediation therapy (CRT) has shown significant improvement in cognition in schizophrenia. However, effect sizes of CRT have been reported to be modest raising the issue how to augment the effects of CRT on neurocognition and social cognition. Our aim was to examine whether the addition of computerized social cognition training would enhance the effects on neurocognition and social cognition as compared to CRT alone. Methods This is a 12-week, parallel group trial of 131 in- and out-patients with schizophrenia randomized to CRT (COGPACK or Brain Fitness) with computerized social cognition training (MRIGE), or CRT alone for 36 sessions. Participants were assessed at baseline and after 12 weeks of treatment. Assessments included neurocognition, social cognition, psychopathology, and functioning. Results The combined intervention, CRT + MRIGE, showed greater improvements in the MCCB indices of Visual Learning, Working Memory, Reasoning and Problem-Solving, and the neurocognitive composite score compared to CRT alone (Bonferroni adjusted p = 0.004, p = 0.005, p = 0.01, respectively), as did social cognition measures (Bonferroni adjusted p = 0.006, p = 0.005, respectively). Conclusions Supplementing CRT with computerized social cognition training produced greater benefits in neurocognition, including visual learning, memory, executive functions, and social cognition relative to cognitive training alone. These findings favoring the combined training may be contributed to both the greater overall amount of cognitive practice, as well as the specific cognitive functions engaged by the social cognition training.

Aim Low motivation is a core symptom of schizophrenia which significantly impacts successful engagement in and benefit from psychosocial treatments. Therefore, it is important for clinicians to design psychosocial treatments to effectively motivate and engage patients during the treatment. The MUSIC® Model of Academic Motivation Inventory (MMI) is an 18-item instrument with five scales that assess students' motivation during academic tasks. The objective of the current study was to validate the MMI for use with schizophrenia-spectrum patients undergoing cognitive training. Methods Participants included 181 people with schizophrenia spectrum disorders enrolled in cognitive training in four countries. A confirmatory factor analysis (CFA) assessed construct validity. Quality of fit was determined using the Comparative Fit Index (CFI), the Standardized Root Mean Square Residual (SRMR), and the Root Mean Square Error of Approximation (RMSEA). Pearson's correlation coefficients assessed construct validity and Cronbach's alphas assessed reliability. Furthermore, we examined factor loadings for each inventory item and assessed predictive validity by analyzing MMI scales with attendance outcomes. Results Consistent with the original MMI validation studies used in academic settings, we found CFI values indicated a good fit, as did the SRMR and RMSEA values. The scales were correlated yet distinct. Cronbach's alpha values ranged from good to excellent and factor loadings showed that all items loaded very well onto their intended factors. The MMI had a positive relationship to treatment intensity. Conclusion The MMI is a valid and reliable tool to use with individuals with schizophrenia spectrum disorders undergoing a cognitive training intervention.

The Positive and Negative Syndrome Scale (PANSS) is a well-established assessment tool for measuring symptom severity in schizophrenia. Researchers and clinicians have been interested in the development of a short version of the PANSS that could reduce the burden of its administration for patients and raters. The author presents a comprehensive overview of existing brief PANSS measures, including their strengths and limitations, and discusses some possible next steps. There are two available scales that offer a reduced number of original PANSS items: PANSS-14 and PANSS-19; and two shorter versions that include six items: Brief PANSS and PANSS-6. The PANSS-6 has been tested quite extensively in established trials and appears to demonstrate high sensitivity to change and an established cut off definition for remission. Prospective testing in new antipsychotic treatment trials is still required for these shorter versions of PANSS. In addition, they need to be supplemented with interview guides, as well as provide conversion formulas to translate total scores from the short PANSS versions to the PANSS-30. Both short versions of the PANSS are essentially designed to evaluate response to antipsychotic treatment. Future PANSS scale development needs to address specific measurement of treatment-responsive positive symptoms by including treatment-sensitive items, as well as illness-phase specific PANSS tools.

BACKGROUND: The risk of impulsive aggression is elevated in schizophrenia and reducing the risk of violent acts in patients is a critical to their overall functional recovery. Cognitive training interventions have been shown in previous studies to decrease the risk of aggression. The current study examined whether cognitive training leads to improvements in emotion regulation and impulse control, two contributors to aggression. METHODS: The study recruited participants (N=90) with schizophrenia or schizoaffective disorder with a past year history of one or more violent acts or a significant lifetime history of aggression as indicated by a score of 5 or more on the Life History of Aggression (LHA) interview. Participants were randomized into one of two cognitive training groups—a cognitive remediation training plus social cognition training (CRT+SCT) group versus CRT alone. The study primary outcome—aggression—was measured using the Overt Aggression Scale (OAS), Point Subtraction Aggression Paradigm (PSAP), and the Taylor Aggression Paradigm (TAP). Emotion Regulation Capacity was indexed by obtaining participants’ heart rate, respiration, and skin conductance while participants viewed pictures selected from the International Affective Picture System (IAPS). Negative emotionality was captured using the Positive and Negative Affect Schedule (PANAS). The Go/NoGo task was used to measure impulse control. RESULTS: Participants were 35.23 years old (SD=9.99) and had completed 11.82 (SD=1.94) years of education. Most were men (83.5%) and African-American (44.4%). All participants had a past year history of violence and an LHA score of 19.57 (SD=5.70). The study data included 49 completers and 5 intent-to-treat samples. Both cognitive training groups showed reductions in negative affectivity scores from baseline but differences were minimal between both groups. Both groups demonstrated pre-to-post reductions in their Low Frequency/High Frequency heart rate variability ratio (Cohen’s d=-0.83) and skin conductance (Cohen’s d = -0.48). Pre-to-post differences between the two training groups were minimal. Both groups demonstrated large pre-to-post reductions in misses on the No-Go trials of the Go No-Go Task (d =-1.74). Reductions were greater in the CRT+SCT than the CRT only group (d=0.27) suggesting that the CRT+SCT group show greater improvements in impulse control after cognitive training. Both groups also showed pre-to-post reductions on the TAP, the PSAP, and the OAS. Differences favored the CRT+SCT group on TAP (F(1,37)=3.99, p