24 results
Efficacy and Safety of Iclepertin (BI 425809) in Patients With Schizophrenia: CONNEX, A Phase III Randomized Controlled Trial Program
- Glen Wunderlich, Zuzana Blahova, Sanjay Hake, Satoru Ikezawa, Stephen Marder, Peter Falkai, John H. Krystal
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 229
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Introduction
Cognitive impairment is a major determinant of poor functional outcome in schizophrenia and there are currently no available pharmacotherapies. Deficits in glutamatergic signaling play a key role in the neuropathology of cognitive symptoms. Iclepertin (BI 425809), an inhibitor of glycine transporter-1, enhances glutamatergic signaling by increasing synaptic levels of the N-methyl-D-aspartate receptor co-agonist, glycine. A 12-week, Phase II trial (NCT02832037) in 509 patients with schizophrenia demonstrated that iclepertin was well tolerated and significantly improved cognition. The Phase III CONNEX program aims to confirm the efficacy, safety, and tolerability of iclepertin in improving cognition and functioning in a larger cohort of patients.
MethodsCONNEX consists of three replicate randomized, double-blind, placebo-controlled parallel-group trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830) currently stable on antipsychotic treatment. Each trial aims to recruit ~586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 weeks on current drug; ≥35 days on current dose prior to treatment), who have functional impairment in day-to-day activities, and interact ≥1 hour per week with a designated study partner. Patients with cognitive impairment due to developmental, neurological, or other disorders, or receiving cognitive remediation therapy within 12 weeks prior to screening, will be excluded. Patients will be recruited from multiple centers across 32 countries in Asia, North and South America, and Europe, and randomized 1:1 to receive either oral iclepertin 10 mg (n=293), or placebo (n=293) once daily over 26 weeks. The primary efficacy endpoint is change from baseline (CfB) in the MATRICS Consensus Cognitive Battery overall composite T-score. Key secondary efficacy endpoints are CfB in Schizophrenia Cognition Rating Scale total score and CfB in the adjusted total time in the Virtual Reality Functional Capacity Assessment Tool. Long-term safety and tolerability data will be collected in an open-label safety extension study (CONNEX-X).
ResultsThe studies are currently recruiting (first patients enrolled Aug–Sept 2021), with completion expected in Q2 2024. Here we present an overview of the current study status, including any information relating to screening failures, and the experience of collecting these data as part of a large multi-country, multi-center study.
ConclusionTo date, most large, industry-sponsored studies testing various compounds to address cognitive function have failed to show proof-of-clinical concept. Demonstration of efficacy of iclepertin in improving cognition in this Phase III program would provide important insight into the role of glutamate in cognitive symptoms that may also have relevance for other cognitive disorders. Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia.
FundingBoehringer Ingelheim International GmbH (1346-0011, NCT04846868; 1346-0012, NCT04846881; 1346-0013, NCT04860830)
Antipsychotic discontinuation and recovery: chicken or egg?
- Joseph M. Pierre, Michael F. Zito, Yvonne S. Yang, Stephen R. Marder
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- Journal:
- Psychological Medicine / Volume 53 / Issue 3 / February 2023
- Published online by Cambridge University Press:
- 24 June 2021, pp. 1134-1135
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Onset and Resolution of Key Adverse Events in Valbenazine-Treated Patients with Tardive Dyskinesia: Pooled Analyses from Two Long-Term Clinical Trials
- Stephen R. Marder, Jean-Pierre Lindenmayer, Chirag Shah, Tara Carmack, Angel S. Angelov, Leslie Lundt
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, p. 151
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Objective
Tardive 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 <10% of participants, with somnolence (9.6%), suicidal behavior/ideation (6.4%), and dizziness (5.7%) being the most common AEs. Mean time to first occurrence ranged from 36 days (akathisia [n=9]) to 224 days (parkinsonism [n=2]). By end of study (or last study visit), resolution of AEs was as follows: 100% (suicidal ideation/behavior, parkinsonism); >85% (somnolence/sedation, dizziness); >70% (akathisia, balance disorder, tremor).
ConclusionsIn long-term clinical trials, the incidence of AEs of potential clinical interest was low (<10%) and most were resolved by end of treatment (>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.
Motivational and cognitive factors linked to community integration in homeless veterans: study 1 – individuals with psychotic disorders
- Michael F. Green, Jonathan K. Wynn, Sonya Gabrielian, Gerhard Hellemann, William P. Horan, Robert S. Kern, Junghee Lee, Stephen R. Marder, Catherine A. Sugar
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- Psychological Medicine / Volume 52 / Issue 1 / January 2022
- Published online by Cambridge University Press:
- 10 June 2020, pp. 169-177
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Background
Little is known about the determinants of community integration (i.e. recovery) for individuals with a history of homelessness, yet such information is essential to develop targeted interventions.
MethodsWe recruited homeless Veterans with a history of psychotic disorders and evaluated four domains of correlates of community integration: perception, non-social cognition, social cognition, and motivation. Baseline assessments occurred after participants were engaged in supported housing services but before they received housing, and again after 12 months. Ninety-five homeless Veterans with a history of psychosis were assessed at baseline and 53 returned after 12 months. We examined both cross-sectional and longitudinal relationships with 12-month community integration.
ResultsThe strongest longitudinal association was between a baseline motivational measure and social integration at 12 months. We also observed cross-sectional associations at baseline between motivational measures and community integration, including social, work, and independent living. Cross-lagged panel analyses did not suggest causal associations for the motivational measures. Correlations with perception and non-social cognition were weak. One social cognition measure showed a significant longitudinal correlation with independent living at 12 months that was significant for cross-lagged analysis, consistent with a causal relationship and potential treatment target.
ConclusionsThe relatively selective associations for motivational measures differ from what is typically seen in psychosis, in which all domains are associated with community integration. These findings are presented along with a partner paper (Study 2) to compare findings from this study to an independent sample without a history of psychotic disorders to evaluate the consistency in findings regarding community integration across projects.
Motivational and cognitive factors linked to community integration in homeless veterans: Study 2 – clinically diverse sample
- Jonathan K. Wynn, Sonya Gabrielian, Gerhard Hellemann, William P. Horan, Robert S. Kern, Junghee Lee, Stephen R. Marder, Catherine A. Sugar, Michael F. Green
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- Journal:
- Psychological Medicine / Volume 51 / Issue 16 / December 2021
- Published online by Cambridge University Press:
- 29 May 2020, pp. 2915-2922
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Background
In an initial study (Study 1), we found that motivation predicted community integration (i.e. functional recovery) 12 months after receiving housing in formerly homeless Veterans with a psychotic disorder. The current study examined whether the same pattern would be found in a broader, more clinically diverse, homeless Veteran sample without psychosis.
MethodsWe examined four categories of variables as potential predictors of community integration in non-psychotic Veterans: perception, non-social cognition, social cognition, and motivation at baseline (after participants were engaged in a permanent supported housing program but before receiving housing) and a 12-month follow-up. A total of 82 Veterans had a baseline assessment and 41 returned for testing after 12 months.
ResultsThe strongest longitudinal association was between an interview-based measure of motivation (the motivation and pleasure subscale from the Clinical Assessment Interview for Negative Symptoms) at baseline and measures of social integration at 12 months. In addition, cross-lagged panel analyses were consistent with a causal influence of general psychiatric symptoms at baseline driving social integration at 12 months, and reduced expressiveness at baseline driving independent living at 12 months, but there were no significant causal associations with measures of motivation.
ConclusionsThe findings from this study complement and reinforce those in Veterans with psychosis. Across these two studies, our findings suggest that motivational factors are associated at baseline and at 12 months and are particularly important for understanding and improving community integration in recently-housed Veterans across psychiatric diagnoses.
A long-term, open-label study of valbenazine for tardive dyskinesia
- Jean-Pierre Lindenmayer, Cherian Verghese, Stephen R. Marder, Joshua Burke, Roland Jimenez, Scott Siegert, Grace S. Liang, Christopher F. O’Brien
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- Journal:
- CNS Spectrums / Volume 26 / Issue 4 / August 2021
- Published online by Cambridge University Press:
- 18 May 2020, pp. 345-353
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Background
Individuals 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.
139 Early Response with Valbenazine and Long-Term Symptom Reduction in Patients with Tardive Dyskinesia: Post Hoc Analysis of the KINECT 3 Study
- Stanley N. Caroff, Jean-Pierre Lindenmayer, Stephen R. Marder, Stewart A. Factor, Khodayar Farahmand, Leslie Lundt
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 288-289
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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.
123 Long-Term Outcomes with Valbenazine 40 mg/day in Adults With Tardive Dyskinesia
- Craig Chepke, Stephen R. Marder, Cynthia L. Comella, Carlos Singer, Khodayar Farahmand, Leslie Lundt
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- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 279-280
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Study Objective:
Tardive dyskinesia (TD), a persistent and potentially disabling movement disorder, is associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Valbenazine (VBZ) is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of TD in adults. Using data from two long-term phase 3 studies (KINECT 3 [K3], NCT02274558; KINECT 4 [K4], NCT02405091) and a rollover study (1506, NCT02736955), the long-term outcomes of once-daily VBZ on TD were examined in participants who received 40mg or had a dose reduction from 80 to 40mg.
Methods:The effects of VBZ 40mg (as well as VBZ 80mg) were evaluated in the following studies: the pivotal K3 study (6 weeks double-blind, placebo controlled), the extension phase of K3 (42 additional weeks of VBZ, 4 week discontinuation), and the open-label K4 study (48 weeks of VBZ, 4 week discontinuation). Completers from K3 extension and K4 were invited to participate in 1506 (up to 72 additional weeks of VBZ or until commercial availability of VBZ). Few participants reached Week 60 (n=4) or Week 72 (n=0) in the 1506 study before termination. Analyses focused on VBZ 40mg in two populations: pooled K3/K4 (participants who received VBZ 40mg throughout K3 or K4 or who had a dose reduction [80/40mg] during K3 or K4); and 1506 (participants who received VBZ 40mg from beginning of K3 or K4 to last visit in 1506 or who had a dose reduction [80/40mg] at any time). Outcomes for the K3/K4 population included mean change from baseline (CFB) in Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7) and AIMS response (≥50% total score improvement from baseline) at Week 48 of K3 or K4. Outcomes for the 1506 population included a Clinical Global Impression of Severity-Tardive Dyskinesia (CGIS-TD) score ≤2 (“normal, not at all ill” or “borderline ill”).
Results:In the K3/K4 population, AIMS CFB to Week 48 indicated mean TD improvements in participants who received 40mg continuously (40mg, -5.7 [n=54]) and in those who had a dose reduction to 40mg (80/40mg, -6.2 [n=13]). In addition, a majority of these participants had an AIMS response after 48 weeks of treatment (40mg, 53.7%; 80/40mg, 53.8%). In the 1506 population, the percentage of participants who had a CGIS-TD score ≤2 (rating of “normal, not at all ill” or “borderline ill”) at Week 12 was 63.6% (7/11) in the 40mg group and 30.8% (4/13) in the 80/40mg group. Data from Weeks 24 to 60 of 1506 were limited by the small sample sizes (<10 participants each in 40mg or 80/40mg group at each of these visits).
Conclusions:Based on these analyses and results from published studies, VBZ 40mg may be an effective long-term option for some TD patients. Dose reductions from 80 to 40mg, if necessary, did not appear to compromise long-term benefit.
Funding Acknowledgements:This study was sponsored by Neurocrine Biosciences, Inc.
140 Effects of Long-Term Valbenazine on Tardive Dyskinesia in KINECT 4: Post Hoc Response and Shift Analyses
- Stephen R. Marder, Cynthia L. Comella, Carlos Singer, Khodayar Farahmand, Roland Jimenez
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- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, p. 289
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Study Objective:
Valbenazine (VBZ) is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged antipsychotic exposure. Post hoc response and shift analyses were conducted using Abnormal Involuntary Movement Scale (AIMS) data from KINECT 4 (NCT02405091), a long-term open-label study in which participants received up to 48 weeks of open-label treatment with once-daily VBZ (40 or 80 mg).
Methods:KINECT 4 included participants who met the following criteria: ages 18 to 85 years; DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or mood disorder; neuroleptic-induced TD for ≥3 months prior to screening; stable psychiatric status (Brief Psychiatric Rating Scale score <50); no high risk of active suicidal ideation or behavior. Stable doses of concomitant medications to treat psychiatric and medical disorders were allowed. VBZ dosing was initiated at 40 mg, with escalation to 80 mg at Week 4 based on clinical assessment of TD and tolerability; a dose reduction to 40 mg was allowed if 80 mg was not tolerated. AIMS responses, ranging from ≥10% to 100% improvement from baseline in AIMS total score (sum of items 1-7), were analyzed at Week 48 based on scoring by site investigators. AIMS shift, conducted for each item (representing 7 different body regions), was defined as an improvement from a score ≥3 (moderate/severe) at baseline to a score ≤2 (none/minimal/mild) at Week 48.
Results:103 participants had an available AIMS assessment at Week 48 (40 mg, n=20; 80 mg, n=83 [including 9 with a dose reduction]). At Week 48, 94.2% of participants had ≥30% total AIMS score improvement (40 mg, 90.0%; 80 mg, 95.2%) and 86.4% had ≥50% improvement (40 mg, 90.0%; 80 mg, 85.5%). The percentage of participants meeting the remaining AIMS response thresholds ranged from 9.7% (for 100% response) to 97.1% (for ≥10% response). In participants who had an AIMS item score ≥3 at baseline, shifts to a score ≤2 at Week 48 were as follows: 100% for lips, upper extremities, and lower extremities (VBZ 40 mg and 80 mg). Shift rates for the remaining regions were as follows (40 mg, 80 mg): face (100% [9/9], 96.9% [31/32]), jaw (100% [10/10], 97.6% [40/41]), tongue (100% [11/11], 97.9% [47/48]), trunk (87.5% [7/8], 88.9% [16/18]).
Conclusions:After 48 weeks of treatment with once-daily VBZ (40 or 80 mg), >85% of KINECT 4 participants had a clinically meaningful AIMS response (≥30% total score improvement), a robust AIMS response (≥50% total score improvement), or an AIMS shift (from item score ≥3 at baseline to score ≤2 at Week 48). These results suggest that VBZ is an appropriate long-term treatment for many adults with TD.
Funding Acknowledgements:This study was sponsored by Neurocrine Biosciences, Inc.
Post hoc analysis of a randomised, placebo-controlled, active-reference 6-week study of brexpiprazole in acute schizophrenia
- Stephen R. Marder, Hans Eriksson, Yudong Zhao, Mary Hobart
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- Acta Neuropsychiatrica / Volume 32 / Issue 3 / June 2020
- Published online by Cambridge University Press:
- 14 February 2020, pp. 153-158
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Objective:
We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint – change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome.
Methods:Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation.
Results:Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: −4.3 [95% CI (−8.0, −0.5), p = 0.0254]. OC, ANCOVA: −3.9 [95% CI (−7.3, −0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of −29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of −13.5 [95% CI (−23.1, −4.0), p = 0.0057], and those who did not had an LS mean change of −18.9 and a difference between brexpiprazole and placebo of −2.9 [95% CI (−7.2, 1.4), p = 0.1809].
Conclusion:Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.
Brain glutathione levels and age at onset of illness in chronic schizophrenia
- Yvonne S. Yang, Richard J. Maddock, Junghee Lee, Huailin Zhang, Gerhard Hellemann, Katherine L. Narr, Stephen R. Marder, Michael F. Green
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- Acta Neuropsychiatrica / Volume 31 / Issue 6 / December 2019
- Published online by Cambridge University Press:
- 27 August 2019, pp. 343-347
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Objective:
Oxidative stress is implicated in the aetiology of schizophrenia, and the antioxidant defence system (AODS) may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain and its correlates with clinical and demographic variables in schizophrenia.
Methods:GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms.
Results:We found a negative correlation between GSH levels and age at onset (r = −0.46, p = 0.015), and a trend-level positive relationship between GSH and duration of illness (r = 0.34, p = 0.076).
Conclusion:Our findings are consistent with a possible compensatory upregulation of the AODS with longer duration of illness and suggest that the AODS may play a role in schizophrenia.
77 Long-term Valbenazine Treatment in Patients with Schizophrenia/Schizoaffective Disorder or Mood Disorder and Tardive Dyskinesia
- Jean-Pierre Lindenmayer, Stephen R. Marder, Carlos Singer, Cynthia Comella, Khody Farahmand, Joshua Burke, Roland Jimenez, Scott Siegert
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 214-215
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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.
MethodsKINECT 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]).
ResultsOf 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.
ConclusionSustained 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.
39 Long-term Safety and Tolerability of Once-Daily Valbenazine in Patients with Tardive Dyskinesia
- Stephen R. Marder, Martha Sajatovic, Dan Michel, Joshua Burke, Khody Farahmand, Scott Siegert
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 196
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Objective
To evaluate the long-term safety and tolerability of once-dailyvalbenazine in adults with tardive dyskinesia(TD).
MethodsData were pooled from KINECT 3 (NCT02274558: 6-week double-blind placebo-controlled period, followed by a 42-week double-blind extension and 4-week drug-free washout) and KINECT 4 (NCT02405091: 48-week open-label treatment period and 4-week drug-free washout). KINECT 3/4 study completers could enroll in a subsequent rollover study (NCT02736955: up to 72weeks of open-label treatment or until valbenazine became commercial available); data from this study were described separately for this analysis. Valbenazine dose groups (40 and 80mg) were pooled for analysis. Safety assessments included treatment-emergent adverse events (TEAEs) and the Columbia-Suicide Severity Rating Scale (C-SSRS). Psychiatric status was assessed in KINECT 3 and KINECT 4 using the following measures: Positive and Negative Syndrome Scale (PANSS) total score and Calgary Depression Scale for Schizophrenia (CDSS) in participants with schizophrenia/schizoaffective disorder; Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in participants with a mood disorder.
ResultsAnalyses included 304 KINECT 3/4 participants and 160 rollover participants. In KINECT 3/4, the summary of TEAEs was as follows: any TEAE (71.7%), serious TEAE (16.8%), and discontinuation due to TEAE (15.5%). TEAEs reported in ≥5% of all KINECT 3/4 participants were headache (8.9%), urinary tract infection (8.9%), somnolence (7.9%), fatigue (6.3%), dizziness (5.9%), and suicidal ideation (5.6%). The summary of TEAEs from the rollover study was as follows: any TEAE (53.1%), serious TEAE (10.0%), and discontinuation due to TEAE (5.6%). The most common TEAEs in the rollover study were back pain and urinary tract infection (4.4%, each); no TEAE was reported in ≥5% of participants. Minimal changes in psychiatric status were observed in KINECT 3/4, as indicated by mean score changes from baseline to Week 48 in participants with schizophrenia/schizoaffective disorder (PANSS total, –3.2; CDSS total, –0.5) or a mood disorder (MADRS total, 0.3; YMRS total, –1.0). Over one-third of study participants had a lifetime history of suicidal ideation or behavior (KINECT 3/4, 41%; rollover, 38%). Most participants had no C-SSRS suicidal ideation at study baseline; of these, >90% had no emergence of suicidal ideation at any time during the study (KINECT 3/4, 93% [276/296]; rollover, 98% [153/156]).
ConclusionsValbenazine was well tolerated and no unexpected safety signals were found in adults who received >1 year of once-daily treatment. Psychiatric stability was maintained, and few participants experienced any emergence of suicidal ideation during the studies despite 35–40% having a lifetime history of suicidality. These results indicate that once-daily valbenazine may be an appropriate treatment for the long-term management of TD.
Funding Acknowledgements: Neurocrine Biosciences, Inc.
38 Global Improvement and Patient Satisfaction: Results from a Long-term, Open-label, Rollover Study of Valbenazine in Tardive Dyskinesia
- Cherian Verghese, Jean-Pierre Lindenmayer, Stephen R. Marder, Joshua Burke, Roland Jimenez, Chuck Yonan, Khody Farahmand, Scott Siegert
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 195-196
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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.
MethodsKey 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 (Weeks 48 to 52 of KINECT 3 and KINECT 4), participants were re-initiated at 40mg (4weeks) and escalated to 80mg based on tolerability and clinical assessment of TD; dose was reduced to 40mg if 80mg was not tolerated (80/40mg). If unable to tolerate the 40mg dose, the participant was discontinued. Participants received open-label VBZ for up to 72weeks 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 Patient Satisfaction Questionnaire (PSQ: range, 1[“very satisfied”] to 5[“very dissatisfied”]).
Results160 participants with available data were included in analyses (40mg =35; 80mg =117; 80/40mg =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 (40mg , 41.7%; 80mg , 74.4%). At baseline, almost all participants rated their prior VBZ experience with a PSQ score ≤2 (“very satisfied” or “somewhat satisfied”) (40mg , 100%, 80mg , 99.1%). Similar results were seen at the Wk 48 visit, with most participants continuing to express satisfaction with VBZ (40mg , 100%; 80mg , 97.4%).
ConclusionsA clinician-based global assessment indicated ongoing, meaningful TD improvements in adults who received once-daily VBZ in the current study. In participants treated for >1 year, continued patient satisfaction rates with VBZ were high.
Funding Acknowledgements: Neurocrine Biosciences, Inc.
Parsing components of auditory predictive coding in schizophrenia using a roving standard mismatch negativity paradigm
- Amanda McCleery, Daniel H. Mathalon, Jonathan K. Wynn, Brian J. Roach, Gerhard S. Hellemann, Stephen R. Marder, Michael F. Green
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- Journal:
- Psychological Medicine / Volume 49 / Issue 7 / May 2019
- Published online by Cambridge University Press:
- 15 January 2019, pp. 1195-1206
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Background
Mismatch negativity (MMN) is an event-related potential (ERP) component reflecting auditory predictive coding. Repeated standard tones evoke increasing positivity (‘repetition positivity’; RP), reflecting strengthening of the standard's memory trace and the prediction it will recur. Likewise, deviant tones preceded by more standard repetitions evoke greater negativity (‘deviant negativity’; DN), reflecting stronger prediction error signaling. These memory trace effects are also evident in MMN difference wave. Here, we assess group differences and test-retest reliability of these indices in schizophrenia patients (SZ) and healthy controls (HC).
MethodsElectroencephalography was recorded twice, 2 weeks apart, from 43 SZ and 30 HC, during a roving standard paradigm. We examined ERPs to the third, eighth, and 33rd standards (RP), immediately subsequent deviants (DN), and the corresponding MMN. Memory trace effects were assessed by comparing amplitudes associated with the three standard repetition trains.
ResultsCompared with controls, SZ showed reduced MMNs and DNs, but normal RPs. Both groups showed memory trace effects for RP, MMN, and DN, with a trend for attenuated DNs in SZ. Intraclass correlations obtained via this paradigm indicated good-to-moderate reliabilities for overall MMN, DN and RP, but moderate to poor reliabilities for components associated with short, intermediate, and long standard trains, and poor reliability of their memory trace effects.
ConclusionMMN deficits in SZ reflected attenuated prediction error signaling (DN), with relatively intact predictive code formation (RP) and memory trace effects. This roving standard MMN paradigm requires additional development/validation to obtain suitable levels of reliability for use in clinical trials.
Brexpiprazole in patients with schizophrenia: overview of short- and long-term phase 3 controlled studies
- Stephen R. Marder, Mika Juhani Hakala, Mette Krog Josiassen, Peter Zhang, John Ouyang, Emmanuelle Weiller, Catherine Weiss, Mary Hobart
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- Journal:
- Acta Neuropsychiatrica / Volume 29 / Issue 5 / October 2017
- Published online by Cambridge University Press:
- 16 November 2016, pp. 278-290
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Objective
Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies.
MethodsPatients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2–4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1–4 mg), 52-week, placebo-controlled maintenance study.
ResultsThe efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of −20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs.
ConclusionsOverall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.
Chapter 15 - Population pharmacokinetics of antipsychotics
- Edited by T. Scott Stroup, Columbia University, New York, Jeffrey A. Lieberman, Columbia University, New York
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- Antipsychotic Trials in Schizophrenia
- Published online:
- 03 May 2010
- Print publication:
- 01 April 2010, pp 267-280
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Summary
Research has shown that up to 83% of friends and family members of people diagnosed with schizophrenia experience financial, emotional, and practical burdens. In their pioneering study of family psychoeducation, Falloon and colleagues found that reductions in family burden associated with family psychoeducation were associated with improvements in patient clinical status and reductions in relapse over time. The design of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) permits investigation of the impact of random assignment to the first-generation antipsychotic perphenazine and four second-generation drugs on family outcomes over an 18-month study period. In addition, family members frequently take an active role in helping patients manage their medication and in other aspects of preventing relapse and promoting recovery. The findings of the CATIE study underscore the importance of involving family caregivers in treatment planning for their relatives with schizophrenia.
Contributors
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- By Paul Appelbaum, Robert R. Bies, Kristin L. Bigos, Stanley N. Caroff, James J. Crowley, Sonia M. Davis, Vicki G. Davis, Donald C. Goff, Richard Kaczynski, Richard S. E. Keefe, Gary G. Koch, Douglas L. Leslie, Jeffrey A. Lieberman, Joseph P. McEvoy, Stephen R. Marder, Jonathan M. Meyer, Del D. Miller, John L. Olsen, Deborah A. Perlick, Bruce G. Pollock, Fred Reimherr, Sandra G. Resnick, Robert A. Rosenheck, T. Scott Stroup, Patrick F. Sullivan, Jeffrey Swanson, Marvin S. Swartz, Richard Van Dorn
- Edited by T. Scott Stroup, Columbia University, New York, Jeffrey A. Lieberman, Columbia University, New York
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- Antipsychotic Trials in Schizophrenia
- Published online:
- 03 May 2010
- Print publication:
- 01 April 2010, pp ix-x
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26 - Psychosocial and pharmacological treatments for schizophrenia
- from Part III - Specific treatments
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- By Peter B. Jones, Department of Psychiatry Addenbrooke's Hospital Cambridge UK, Stephen R. Marder, West Los Angeles VA Healthcare Center Los Angeles, CA USA
- Edited by Peter Tyrer, Imperial College of Science, Technology and Medicine, London, Kenneth R. Silk, University of Michigan, Ann Arbor
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- Book:
- Cambridge Textbook of Effective Treatments in Psychiatry
- Published online:
- 12 May 2010
- Print publication:
- 24 January 2008, pp 469-480
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Summary
Editor's note
One of the most striking advances in psychiatry in the last 50 years has been the improvement in the outcome of those with schizophrenia. Although it is commonly assumed that the largest part of this has been due to the introduction of effective drug treatments (starting with chlorpromazine), there have been major advances in both society's attitudes to schizophrenia and its psychosocial management that have played a major, if not the most important, part in this shift in outcome and general attitudes. The advances achieved are often difficult to evaluate as many are very complex interventions, but they have been considerable. It is perhaps worth noting that both our distinguished authors are very modest in their descriptions of these, but do not be misled; many are considerable advances that have helped to humanise the problems of those who were in the past regarded as degenerate and irredeemable.
Introduction
Once seen as a separate approach to the treatment of schizophrenia, the interventions under the psycho-social umbrella are now viewed as an essential aspect of modern management. They are partners with pharmacotherapy and form part of a multidisciplinary approach outlined in the previous chapter. Psycho-social interventions are often seen as part of a complex set of interventions, delivered by the range of services outlined in Chapter 8. However, the interventions described in this chapter are, in essence, simple and can be taught to, and delivered by, many individuals in a clinical team, perhaps with supervision from an expert.
25 - Pharmacological treatments for schizophrenia
- from Part III - Specific treatments
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- By Stephen R. Marder, West Los Angeles VA Healthcare Center Los Angeles, CA USA, Peter B. Jones, Department of Psychiatry Addenbrooke's Hospital Cambridge UK
- Edited by Peter Tyrer, Imperial College of Science, Technology and Medicine, London, Kenneth R. Silk, University of Michigan, Ann Arbor
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- Book:
- Cambridge Textbook of Effective Treatments in Psychiatry
- Published online:
- 12 May 2010
- Print publication:
- 24 January 2008, pp 459-468
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Summary
Editor's note
It is interesting that the most researched and possibly most important area of therapeutics in mental illness, the drug treatment of schizophrenia, is covered in less than 4000 words in this chapter. Why is this? Is it that our two authors are so good at précis that they can summarize in 10 words information that would use 100 words in the writing of others, or is it because the information is so diffuse that no conclusions can be drawn? Or is there another reason: that the subject has such a strong evidence base that it is possible to describe it both briefly and fully? Perhaps the last option has it. Lord Moran of Manton, perhaps best known as the personal doctor of Winston Churchill, in his Harveian oration of 1945 put it this way:-
“The physician who knows what is wrong with a patient and has an effective remedy can cut the cackle. He has no need of it”. Now we are not suggesting that the other longer chapters are full of cackle, but when there is more doubt, there is more conjecture and this takes up more space. As Adams et al. (2006) states, ‘the literature on the drug treatment of schizophrenia is actually quite clear and unequivocal; the problem is that in rich countries with powerful drug companies, the constant jockeying for market position tends to confuse by setting up winners and losers on flimsy evidence.