Faculty Bibliography

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.

Introduction: Older adults have an increased risk of developing tardive dyskinesia (TD), a persistent and often debilitating movement disorder that is associated with antipsychotic treatment. Valbenazine is currently approved to treat TD in adults of all ages, with no dose adjustment required for older patients. Valbenazine has been evaluated in 2 long-term Phase III studies (KINECT 3, KINECT 4) in which adults with TD (18 to 85 years) received once-daily treatment (40 or 80 mg) for up to 48 weeks. Completers from these studies were eligible to enter a long-term, open-label rollover study (NCT02736955) in which global improvements and patient satisfaction were assessed. Data from the rollover study were analyzed post hoc to further investigate the long-term effects of valbenazine in participants categorized by age (<55 years, >=55 years). Method(s): Completers from KINECT 3 or KINECT 4 were re-initiated at 40 mg following washout of prior valbenazine treatment. Dose was escalated after 4 weeks to 80 mg based on tolerability and clinical assessment of TD. Reduction to 40 mg was allowed if 80 mg was not tolerated; participants unable to tolerate 40 mg were discontinued from the study. The study was designed to include 72 weeks of treatment, but few participants reach Week 60 and none reach Week 72 because valbenazine became commercially available. Both doses of valbenazine (40 and 80 mg) were pooled. Analyses were conducted at Week 48 and end-of-treatment (EOT), based on the last available post-baseline value. 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]). All outcomes were analyzed descriptively in age subgroups (younger, <55 years; older, >=55 years). Result(s): The study included 51 younger participants (mean age, 47.9 years; range, 34-54 years) and 109 older participants (mean age, 62.5 years; range, 55-83 years). A total of 56 participants reached the Week 48 visit (<55y, n=18; >=55y, n=38); 156 were included in EOT analyses (<55y, n=47; >=55y, n=109). Mean decreases (improvements) from baseline in CGIS-TD score were similar in the younger and older subgroups at Week 48 (<55y, -1.7; >=55y, -1.8) and greater in the older subgroup at EOT (<55y, -1.5; >=55y, -1.9). In both subgroups, the percentage of participants with CGIS-TD score <=2 (normal/not at all ill or borderline ill) increased from baseline (before restarting valbenazine) (<55y, 14.0%;>=55y, 14.7%) to Week 48 (<55y, 50.0%; >=55y, 71.1%) and EOT (<55y, 61.7%; >=55y, 72.5%). At baseline, almost all participants (<55y, 100%; >=55y, 98.2%) were somewhat or very satisfied with their prior valbenazine experience (PSQ score <=2). Participants continued to express satisfaction with valbenazine with PSQ scores <=2 at Week 48 (<55y, 100%; >=55y, 97.4%) and EOT (<55y, 93.6%; >=55y, 98.1%). Conclusion(s): A clinician-based global assessment indicated ongoing, meaningful TD improvements with once-daily valbenazine in both younger and older adults. Patient satisfaction rates remained high, even in patients treated for >1 year. These results, along with the safety results presented separately at this meeting, indicate that valbenazine is an effective long-term treatment for TD. This research was funded by: This research was fully funded 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.

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.

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/OBJECTIVE: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/CONCLUSIONS: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/OBJECTIVE: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.

BACKGROUND: Valbenazine (VBZ), a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treating tardive dyskinesia (TD) in adults, has been evaluated in 2 long-term studies (KINECT 3, KINECT 4) in which participants received VBZ (40 or 80 mg) for up to 48 weeks. This long-term rollover study (NCT02736955) was the first to include a Patient Satisfaction Questionnaire (PSQ) that evaluated VBZ as a TD treatment. OBJECTIVE: To assess global improvement and patient satisfaction in adults with TD who received long-term treatment 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 < 50; no significant risk of active suicidal ideation or behavior. Following washout of prior VBZ treatment, participants were re-initiated at 40 mg (4 weeks) and escalated to 80 mg based on tolerability and clinical assessment of TD; dose was reduced to 40 mg if 80 mg was not tolerated (80/40 mg). Participants received open-label VBZ for up to 72 weeks or until commercial availability. Assessments included Clinical Global Impression of Severity-TD (CGIS-TD: range, 1 ["normal, not at all ill"] to 7 ["among the most extremely ill patient"]) and PSQ (range, 1 ["very satisfied"] to 5 ["very dissatisfied"]). RESULTS: 160 participants with available data were included in analyses (40 mg = 35; 80 mg = 117; 80/40 mg = 8); 138 were receiving treatment when VBZ became commercially available. The percentages of participants who completed visits at Wks 12, 24, 36, and 48 were 96.3%, 78.1%, 56.9% and 35.0%, respectively. Few reached Wk 60 (n = 4) or Wk 72 (n = 0) due to commercial availability. The percentage of participants with CGIS-TD score <= 2 ("normal, not at all ill" or "borderline ill") increased from baseline (before restarting VBZ; 40mg, 5.7%; 80mg, 18.1%) to Wk 48 (40 mg, 41.7%; 80 mg, 74.4%). At baseline, almost all participants rated their prior VBZ experience with a PSQ score <= 2 ("very satisfied" or "somewhat satisfied"; 40 mg, 100%, 80 mg, 99.1%). Similar results were seen at the Wk 48 visit, with most participants continuing to express satisfaction with VBZ (40 mg, 100%; 80 mg, 97.4%). CONCLUSIONS: A clinician-based global assessment indicated ongoing, meaningful TD improvements in adults who received once-daily VBZ in the current study. Patient satisfaction rates with VBZ were high, even in patients treated for up to 2 years

OBJECTIVE:Evaluate the effect of paliperidone palmitate once-monthly (PP1M) injectable on the specific functioning domains of the Personal and Social Performance (PSP) scale in patients with schizoaffective disorder (SCA) participating in a long-term study. METHODS:This study (NCT01193153) included both in- and outpatient subjects with SCA experiencing an acute exacerbation of psychotic and mood symptoms. Subjects were treated with PP1M either as monotherapy or in combination with antidepressants or mood stabilizers during a 25-week open-label (OL) phase. Stabilized subjects were randomly assigned 1:1 (PP1M or placebo) into a 15-month double-blind (DB) relapse-prevention period. Functioning of the randomized subjects during OL and DB phases was evaluated using the PSP scale (four domains: socially useful activities, personal/social relationships, self-care, and disturbing/aggressive behaviors). Three statistical approaches were utilized to analyze PSP scores to assess robustness and consistency of findings. No adjustments were made for multiplicity. RESULTS:334 of 667 enrolled subjects were stabilized with PP1M, randomly assigned to PP1M (n=164) or placebo (n=170) in the DB phase, and included in this analysis. Improvements in all PSP domain scores were observed during the OL phase and were maintained during the DB phase with PP1M, but decreased with placebo. Differences compared to placebo were significant in all four PSP domains during the DB phase (P≤0.008). CONCLUSION/CONCLUSIONS:The analysis in this study showed that PP1M improves functioning, as measured by the four PSP domain scores, in symptomatic subjects with SCA. Functioning was maintained compared with placebo.