Faculty Bibliography

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.

PURPOSE/BACKGROUND/OBJECTIVE: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/UNASSIGNED: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/UNASSIGNED:After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS/UNASSIGNED:Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.

AIM/OBJECTIVE: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/CONCLUSIONS:The MMI is a valid and reliable tool to use with individuals with schizophrenia spectrum disorders undergoing a cognitive training intervention.

Background: Tardive dyskinesia (TD) is a persistent and debilitating movement disorder associated with prolonged antipsychotic use. Valbenazine (VBZ), a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of TD in adults, has been evaluated in 2 prior long-term studies (KINECT 3 extension, KINECT 4). Participants who completed KINECT 3 or KINECT 4 were eligible to participate in the current rollover study (NCT02736955). Data from this study were analyzed to evaluate the long-term safety and effectiveness of once-daily VBZ in adults with schizophrenia or schizoaffective disorder (SCHZ subgroup).
Method(s): Key eligibility criteria included: age 18 to 85 years; completion of KINECT 3 extension or KINECT 4; maintenance medications for psychiatric disorders at stable doses; Brief Psychiatric Rating Scale score <50; and without high risk of active suicidal ideation or behavior. Following washout of prior VBZ treatment, participants were re-initiated at 40 mg for 4 weeks and escalated to 80 mg based on the investigator's assessments of safety/tolerability and clinical assessment of TD; a subsequent reduction to 40 mg was allowed if 80 mg was not tolerated (80/40 mg group). Participants received open-label VBZ for up to 72 weeks or until VBZ became commercially available. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD: range, 1 [normal/not at all ill] to 7 [extremely ill]) and Patient Satisfaction Questionnaire (PSQ: range, 1 [very satisfied] to 5 [very dissatisfied]). Treatment-emergent adverse events (TEAEs) were monitored for safety. Outcomes were analyzed descriptively in the SCHZ subgroup.
Result(s): Of 160 participants in the analyses, 104 were in the SCHZ subgroup (40 mg, n=23; 80 mg, n=75; 80/40 mg, n=6). Approximately one-third of these participants reached the Week 48 visit (n=34). Only 1 participant reached Week 60, and none reached Week 72 because VBZ became commercially available during the study. In SCHZ participants, mean CGIS-TD score changes from baseline to Week 48 indicated sustained global improvement (40 mg, -1.1; 80 mg, -1.3; 80/40 mg, -2.0). The percentage of participants with a CGIS-TD score <=2 increased from baseline (40 mg, 8.7%; 80 mg, 14.7%; 80/40 mg, 0%) to Week 48 (40 mg, 37.5%; 80 mg, 60.9%; 80/40 mg, 66.7%). At baseline, almost all SCHZ participants had a PSQ score <=2 (99.0%), indicating satisfaction with their prior VBZ experience in KINECT 3 or KINECT 4. At Week 48, this subgroup continued to express satisfaction with treatment (97.1%). During the study, 51.0% of participants in the SCHZ subgroup had >=1 TEAE; 6.7% discontinued due to a TEAE.
Discussion(s): Similar to the overall population in this study, VBZ was generally well tolerated and no new safety signals were observed, even in participants with a dose reduction. Clinician-based assessments indicated ongoing and meaningful TD improvements in participants with schizophrenia/ schizoaffective disorder who received long-term VBZ treatment (80 or 40 mg) in the current study following up to 48 weeks of treatment in previous VBZ studies. Patient satisfaction rates with VBZ remained high in this subgroup

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.
Method(s): 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).
Result(s): 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<0.001, eta2 =0.61) with a slight edge to the combined CRT+SCT group (F (1,47)=3.61, p=0.064, eta2 =0.07). The Mind in the Eyes Test showed a significant improvement between groups (p = 0.025) with the CRT + SCT group showing greater improvement at endpoint. There were no other significant differences between groups.
Discussion(s): CRT with and without SCT improved both cognitive functions and emotion recognition as well as aspects of emotion regulation in patients with significant histories of impulsive aggression. While social cognition training only added a small increment in emotion recognition, possibly facilitating better emotion regulation control and impulsivity, more direct measures of aggression and impulsivity need to be interrogated to assess the effect on aggressive behaviors

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.
Method(s): 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.
Result(s): 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(s): 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: Few studies have compared clinical evaluations of negative symptoms to those done by patients. Self-report tools may better reflect the patients' subjective experience. The Self-Evaluation of Negative Symptoms (SNS; Dollfus et al., 2015), a 20-item scale, was developed to assess the subjective experience of negative symptoms by schizophrenia patients. Dollfus et al (2015) found that the SNS had good psychometric properties and demonstrated that the patients' ratings were highly correlated with observer ratings. Patients included in the Dollfus et al (2015) study were stable outpatients with a high level of functioning. It remains to be explored whether patients with a lower level of functioning can identify their negative symptoms in a reliable fashion. Our goals were (1) to examine if chronic, low functioning patients can complete the instrument without assistance, potentially providing more immediate insight into their internal perception of negative symptoms and (2) to examine the correlation of their subjective reports with the research assessment of negative symptoms.
Method(s): Stable in- and outpatients who met DSM-5 criteria for schizophrenia spectrum disorder were included in the study. After consenting, patients self-administered the SNS assessment at two time points, separated by one week, with other rater-administered concurrent evaluations: the 16-Item Negative Symptom Assessment (NSA-16), a validated clinical assessment for negative symptoms, the CGI-S, WRAT, BACS, and CDSS.
Result(s): A total of 50 subjects with a mean age of 43.71 years (SD = 11.03), 86% male, 64.81% African American, with a mean chlorpromazine equivalency dose of 869.22 (SD = 59.69). Mean premorbid IQ was 79.71 (SD = 17.51) determined by WRAT Standard Total, and BACS Composite T Score mean was 33.56 (SD = 12.11). Cronbach's coefficient of the SNS (alpha = 0.903) showed good internal consistency. The intraclass correlation coefficients (ICCs) between SNS time point 1 and SNS time point 2 showed good inter-rater reliability (ICC = .849, 95% CI [.739, .928]. Of the 20 SNS items, significant correlations with the NSA- 16 Global Level are reported for only 2 items: "I don't take any great pleasure in talking with people" (r = 0.65, p < 0.001), and item "I am not interested in having sex, with "Sexual interest" (r = 0.58, p = 0.003). There was a significant difference in the SNS total score between Visit 1 (t(53) = 9.11, p < 0.001) and Visit 2 (t(53) = 8.23, p < 0.001). Significant correlations were also identified for SNS Item "I don't take any great pleasure in talking with people" and the SUM-D Awareness of Asociality item (r = 0.564, p = .005) and SNS Item "I am not interested in going out with friends or with a family member" and the SUM-D "Awareness of mental disorder" (r = 0.578, p = .004).
Discussion(s): This study shows that patients with negative symptoms can self-administer a patient reported outcome measure. However, the relatively low correlation between the self-reported SNS items and the research rated NSA-16, suggests that the agreement between self-rating and observer-rating of negative symptoms in patients with chronic schizophrenia is rather low, except for two items. Patients also evaluated the severity of their negative symptoms rather differently one week apart suggesting different subjective assessment levels by patients at different times. It appears that patients with chronic schizophrenia and low levels of functioning are not able to self-evaluate their negative symptoms and give variable answers on repeat self-evaluations

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.