Faculty Bibliography

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.

Background/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: < 0.05). Conclusion/UNASSIGNED:Our findings suggest that CRT has benefits for negative symptoms in very low-functioning patients and that this change may be in part mediated by change in cognitive functions after CRT.

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.

BACKGROUND:Patients treated with antipsychotics, regardless of psychiatric diagnosis, are at risk for developing tardive dyskinesia (TD), a potentially debilitating drug-induced movement disorder. Valbenazine (INGREZZA; VBZ) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved to treat TD in adults. Data from KINECT 4 (NCT02405091) were analyzed to evaluate the long-term effects of VBZ in adults with schizophrenia/schizoaffective disorder (SZD) or mood disorder (MD) and moderate or severe TD. METHODS:KINECT 4 included open-label treatment (48weeks) followed by washout (4weeks). Entry requirements included: moderate or severe TD, qualitatively assessed at screening by a blinded, external reviewer; DSM diagnosis of SZD or MD; psychiatric stability (Brief Psychiatric Rating Scale score <50). Stable concomitant psychiatric medications were allowed. Dosing was initiated at 40mg, with escalation to 80mg at Wk4 if participants had a Clinical Global Impression of Change-TD score of ≥3 (minimally improved to very much worse) and tolerated 40mg. A reduction to 40mg was allowed if 80mg was not tolerated (80/40mg); participants unable to tolerate 40mg were discontinued. Safety was the primary focus, but the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7) was used to evaluate changes in TD. Mean changes from baseline (BL) in AIMS total score (rated by on-site investigators) were analyzed descriptively. Safety assessments included treatment-emergent adverse events (TEAEs) and psychiatric scales (Positive and Negative Syndrome Scale [PANSS], Calgary Depression Scale for Schizophrenia [CDSS], Montgomery-Åsberg Depression Rating Scale [MADRS], Young Mania Rating Scale [YMRS], and Columbia-Suicide Severity Rating Scale [C SSRS]). RESULTS:Of 163 participants in the analyses, 103 completed the study. Adverse events (n=26) was the most common reason for discontinuation. Analyses included 119 participants with SZD (40mg=37; 80mg=76; 80/40mg=6) and 44 with MD (40mg=8; 80mg=31; 80/40mg=5). At Wk48, mean improvements from BL in AIMS total score were: SZD (40mg, -10.1; 80mg,-10.7); MD (40mg, 10.2; 80mg: -11.6). AIMS total scores at Wk52 (end of washout) indicated a return toward BL levels. Compared to SZD, the MD subgroup had a higher incidence of any TEAE (84% vs 61% [all doses]) but fewer TEAEs leading to discontinuation (7% vs 18%). Urinary tract infection was the most common TEAE in the MD subgroup (18%); somnolence and headache were most common in the SZD subgroup (7% each). Psychiatric status remained stable from BL to Wk48: SZD (PANSS positive, -0.7, PANSS negative, -0.6; CDSS, -0.7); MD (MADRS, -0.3; YMRS, -0.3). Most participants (95%) had no change in C-SSRS score during the study. CONCLUSION/CONCLUSIONS:Sustained and clinically meaningful TD improvements were observed with VBZ, regardless of primary psychiatric diagnosis. VBZ was generally well tolerated and no notable changes in psychiatric status were observed.Funding Acknowledgements: Supported by Neurocrine Biosciences, Inc.

OBJECTIVE:Valbenazine (VBZ) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved to treat tardive dyskinesia (TD) in adults. It has been evaluated in 2 long-term studies (KINECT 3, KINECT 4) in which participants received VBZ (40 or 80mg) for up to 48weeks. This long-term rollover study (NCT02736955) was conducted to evaluate global TD improvement and patient satisfaction with once-daily VBZ. METHODS:Key eligibility criteria: age 18 to 85 years; completion of KINECT 3 or KINECT 4; maintenance medications (for schizophrenia, schizoaffective disorder, or mood disorder) at stable doses; Brief Psychiatric Rating Scale score 1 year, continued patient satisfaction rates with VBZ were high.Funding Acknowledgements: Neurocrine Biosciences, Inc.

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.

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: 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