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Randomized trial of transcranial alternating current stimulation for treatment of auditory hallucinations in schizophrenia
- Juliann M. Mellin, Sankaraleengam Alagapan, Caroline Lustenberger, Courtney E. Lugo, Morgan L. Alexander, John H. Gilmore, L. Fredrik Jarskog, Flavio Fröhlich
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- Journal:
- European Psychiatry / Volume 51 / June 2018
- Published online by Cambridge University Press:
- 01 January 2020, pp. 25-33
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Background:
Approximately 30% of patients with schizophrenia experience auditory hallucinations that are refractory to antipsychotic medications. Here, we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) that we hypothesized would improve auditory hallucination symptoms by enhancing synchronization between the frontal and temporo-parietal areas of the left hemisphere.
Method:22 participants were randomized to one of three arms and received twice daily, 20 min sessions of sham, 10 Hz 2 mA peak-to-peak tACS, or 2 mA tDCS over the course of 5 consecutive days. Symptom improvement was assessed using the Auditory Hallucination Rating Scale (AHRS) as the primary outcome measure. The Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS) were secondary outcomes.
Results:Primary and secondary behavioral outcomes were not significantly different between the three arms. However, effect size analyses show that tACS had the greatest effect based on the auditory hallucinations scale for the week of stimulation (1.31 for tACS; 1.06 and 0.17, for sham and tDCS, respectively). Effect size analysis for the secondary outcomes revealed heterogeneous results across measures and stimulation conditions.
Conclusions:To our knowledge, this is the first clinical trial of tACS for the treatment of symptoms of a psychiatric condition. Further studies with larger sample sizes are needed to better understand the effect of tACS on auditory hallucinations.
34 Long-Term Deutetrabenazine Treatment Response in Tardive Dyskinesia by Concomitant Dopamine-Receptor Antagonists and Baseline Comorbidities
- Karen E. Anderson, David Stamler, Mat D. Davis, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, Joseph McEvoy, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 193
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Background
Tardive dyskinesia (TD) results from exposure to dopamine-receptor antagonists (DRAs), such as typical and atypical antipsychotics. Clinicians commonly manage TD by reducing the dose of or stopping the causative agent; however, this may cause psychiatric relapse and worsen quality of life. In the 12-week ARM-TD and AIM-TD trials, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores versus placebo and was generally well tolerated, regardless of baseline DRA use or comorbidities.
Study ObjectiveTo evaluate the impact of underlying disease and current DRA use on efficacy and safety of long-term therapy of deutetrabenazine in patients with TD.
MethodPatients with TD who completed ARM-TD or AIM-TD were eligible to enter this open-label, single-arm, long-term extension after completing the 1-week washout period and final evaluation in the blinded portion of the trial. Change in AIMS scores from baseline to Week 54 and patients “Much Improved” or “Very Much Improved” (treatment success) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) at Week 54 were analyzed by baseline psychiatric illness type, including mood disorders (bipolar disorder/depression/other) or psychotic disorders (schizophrenia/schizoaffective disorder), and presence or absence of current DRA use.
ResultsAt Week 54, meaningful improvements from baseline in mean (standard error) AIMS scores were observed for patients with baseline mood disorders (–5.2[0.93]) and psychotic disorders (–5.0[0.63]), and in patients currently using DRAs (–4.6[0.54]) or not using DRAs (–6.4[1.27]). Most patients with mood disorders (73%) and psychotic disorders (71%) were “Much Improved” or “Very Much Improved” on CGIC at Week 54, similar to patients currently using (71%) or not using (74%) DRAs. The majority of patients with mood disorders (62%) and psychotic disorders (57%), as well as patients currently using (58%) or not using (63%) DRAs, were also “Much Improved” or “Very Much Improved” on PGIC at Week 54. Prior treatment in ARM-TD and AIM-TD did not impact the long-term treatment response. Underlying psychiatric disorder and concomitant DRA use did not impact the occurrence of adverse events (AEs). The frequencies of dose reductions, dose suspensions, and withdrawals due to AEs were low, regardless of baseline psychiatric comorbidities and DRAuse.
ConclusionsLong-term deutetrabenazine treatment demonstrated meaningful improvements in abnormal movements in TD patients, which were recognized by clinicians and patients, regardless of underlying psychiatric illness or DRAuse.
Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
45 Long-term Treatment with Deutetrabenazine Is Associated with Continued Improvement in Tardive Dyskinesia: Results from an Open-label Extension Study
- Robert A. Hauser, Hubert H. Fernandez, David Stamler, Mat D. Davis, Stewart A. Factor, Joohi Jimenez-Shahed, William G. Ondo, L. Fredrik Jarskog, Scott W. Woods, Mark S. LeDoux, David R. Shprecher, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 200-201
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Study Objective
To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.
BackgroundIn the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.
MethodPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.
Results343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.
ConclusionsPatients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
46 Confirmed Safety of Deutetrabenazine for Tardive Dyskinesia in a 2-Year Open-label Extension Study
- Hubert H. Fernandez, David Stamler, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, Joohi Jimenez-Shahed, William G. Ondo, L. Fredrik Jarskog, Scott W. Woods, Mark S. LeDoux, David R. Shprecher, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 201
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Study Objective
To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
BackgroundIn the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.
MethodPatients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).
Results343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.
ConclusionsThese results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel
35 Long-term Improvements in Site-Rated Outcomes with Deutetrabenazine Treatment in Patients with Tardive Dyskinesia
- Karen E. Anderson, David Stamler, Mat D. Davis, Nicholas Gross, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, Joseph McEvoy, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 193-194
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Background
Tardive dyskinesia (TD) is an often-irreversible movement disorder that may intensify the stigma of patients with psychiatric disorders and worsen quality of life. In two randomized, double-blind, placebo (PBO)-controlled, 12-week trials, ARM-TD and AIM-TD (‘parent studies’), deutetrabenazine (DTB) demonstrated statistically significant improvements in centrally read Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with PBO and was generally well tolerated.
Study ObjectiveTo evaluate the long-term efficacy of DTB in an open-label safety study following double-blind treatment using site-rated efficacy measures: AIMS, the Clinical Global Impression of Change (CGIC) and the Patient Global Impression of Change (PGIC), which may be used in real-world clinical practice settings.
MethodPatients with TD who completed the parent studies were eligible to enter this open-label, long-term extension (OLE) after completing the 1-week washout period and final evaluation in the blinded portion of the trial. This extension comprised a 6-week titration period followed by a long-term maintenance phase. Patients began DTB at 12mg/day, titrating up to a maximum total dose of 48mg/day based on dyskinesia control and tolerability. Efficacy endpoints included in this analysis are the change in site-rated AIMS score (items 1–7) from parent study baseline, and the proportion of patients who were “Much Improved” or “Very Much Improved” (treatment success) on the CGIC and PGIC from OLE baseline.
ResultsAt the end of the parent studies (Week 12), patients treated with DTB had experienced greater mean (standard error) improvements in site-rated AIMS score (–5.0[0.40]) than patients given PBO (–3.2[0.47]). With long-term DTB treatment, both groups experienced improvements in site-rated AIMS scores (prior DTB, –7.9[0.62]; prior placebo, –6.6[0.64]) compared with parent study baseline. Similarly, at the end of the parent studies, a greater proportion of patients treated with DTB had treatment success on the CGIC (DTB, 51%; PBO, 32%) and the PGIC (DTB, 46%; PBO: 33%); whereas at Week 54 of the OLE study, treatment success on CGIC and PGIC were similar in both the CGIC (prior DTB: 66%; prior PBO: 68%) and PGIC (prior DTB: 62%; prior PBO: 62%) groups. DTB was generally well tolerated.
ConclusionsPatients treated with DTB showed improvements in abnormal movements, as measured by site-rated AIMS, CGIC, and PGIC scores, which may be used in real-world clinical practice settings. These results corroborate the previously reported efficacy of DTB as observed in the 12-week, double-blind ARM-TD and AIM-TD trials, in which central raters were used to evaluate AIMS scores.
Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
158 Long-Term Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia: Results From an Open-Label, Long-Term Study
- Karen E. Anderson, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, William G. Ondo, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, p. 97
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Introduction
In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.
ObjectiveTo evaluate the long-term safety/tolerability and efficacy of deutetrabenazine in patients with TD. Week 54 open-labelresults are reported in this interim analysis.
MethodsPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safetymeasures included incidence of adverse events (AEs), serious AEs (SAEs), drug-related AEs, and AEs leading to withdrawal, dose reduction, or dose suspension. This analysis reports results up to Week 54.
Results304 patients enrolled in the extension study. There were 215 patient-years of exposure in this analysis, and exposure-adjusted incidence rates (EAIRs) of AEs (incidence/patient-years) were comparable to or lower than those observed with short-term deutetrabenazine treatment and placebo. The frequency of SAEs (EAIR 0.14) was similar to rates observed with short-termplacebo (EAIR 0.33) and deutetrabenazine (EAIR range 0.06–0.33) treatment. AEs leading to study discontinuation (EAIR 0.08), dose reduction (EAIR 0.17), and dose suspension (EAIR 0.09) were uncommon.
ConclusionsLong-term treatment with deutetrabenazine was generally safe and well tolerated in patients with TD, and did not result in cumulative toxicity.
Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.
Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
149 Deutetrabenazine for the Treatment of Tardive Dyskinesia: Results From an Open-Label, Long-Term Study
- Karen E. Anderson, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, FRCPC, Stanislaw Ochudlo, William G. Ondo, Hubert H. Fernandez
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- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, pp. 92-93
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Introduction
Tardive dyskinesia (TD) is an involuntary movement disorder resulting from exposure to dopamine-receptor antagonists. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.
ObjectiveTo evaluate the efficacy and safety of long-term deutetrabenazine therapy in patients with TD.
MethodsPatients with TD who completed the ARM-TD or AIM-TD studies were eligible to enter this open-label, single-arm, long-term safety study after they completed the 1-week washout period and final evaluation in the blinded portion of the trial. Efficacy endpoints included the change in AIMS score from baseline, and treatment success (defined as “much improved” or “very much improved”) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC). This analysis reports results up to Week 54.
Results304 patients enrolled in the extension study. At Week 54, the mean (standard error) change in AIMS score was –5.1 (0.52). After 6 weeks of deutetrabenazine treatment, the proportion of patients who achieved treatment success was 58% per the CGIC and 53% per the PGIC, and by Week 54 was 72% per the CGIC and 59% per the PGIC, thus demonstrating maintenance or enhancement of benefit over time. Deutetrabenazine was well tolerated for up to 54 weeks, and compared with the ARM-TD and AIM-TD studies, no new safety signals were detected.
Conclusions54 weeks of deutetrabenazine treatment was generally efficacious, safe, and well tolerated in patients with TD.
Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.
Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
134 Improvements in Clinical Global Impression of Change With Deutetrabenazine Treatment in Tardive Dyskinesia From the ARM-TD and AIM-TD Studies
- Hubert H. Fernandez, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, William G. Ondo, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, p. 84
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Introduction
Tardive dyskinesia (TD) is an involuntary movement disorder that is often irreversible, can affect any body region, and can be debilitating. In the ARM-TDand AIM-TD studies, deutetrabenazine treatment demonstrated statistically and clinically significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo (primary endpoint).
ObjectiveTo evaluate the efficacy of deutetrabenazine, as measured by the Clinical Global Impression of Change (CGIC) scale, in patients with TD from the pooled ARM-TDand AIM-TD (24 and 36 mg/day doses) data sets, as compared with the pooled placebo cohort.
MethodsARM-TD and AIM-TD were 12-week, randomized, double-blind, placebo-controlled studies that evaluated the safety and efficacy of deutetrabenazine for thetreatment of TD. The key secondary endpoint of each study was the proportion of patients “much improved” or “very much improved” (treatment success) at Week 12 on theCGIC.
ResultsAt Week 12, the odds of treatment success among patients treated with deutetrabenazine (n=152) was more than double that of patients given placebo (n=107; odds ratio: 2.12; P=0.005). In a categorical analysis of CGIC ratings, patients treated with deutetrabenazine showed greater improvement than patients given placebo (P=0.003). Patients treated with deutetrabenazine also had a significantly better treatment response than those given placebo (least-squares mean CGIC score treatment difference: –0.4; P=0.006).
ConclusionsDeutetrabenazine treatment led to statistically and clinically significant improvements in TD symptoms based on the CGIC result, suggesting that clinicians were able to recognize the benefit in patients treated with deutetrabenazine.
Presented at: The International Congress of Parkinson’s Disease and Movement Disorders; June 4–8, 2017; Vancouver, British Columbia, Canada.
Funding AcknowledgementsThese studies were funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
Neurobiology and Functional Progression in Schizophrenia
- L. Fredrik Jarskog
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- CNS Spectrums / Volume 12 / Issue S4 / 2007
- Published online by Cambridge University Press:
- 07 November 2014, pp. 9-12
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Schizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia.
In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.
20 - Neurodegenerative models of schizophrenia
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- By L. Fredrik Jarskog, University of North Carolina School of Medicine, Chapel Hill, USA, John H. Gilmore, University of North Carolina School of Medicine, Chapel Hill, USA, Jeffrey A. Lieberman, University of North Carolina School of Medicine, Chapel Hill, USA
- Edited by Matcheri S. Keshavan, University of Pittsburgh, James L. Kennedy, Clarke Institute of Psychiatry, Toronto, Robin M. Murray, Institute of Psychiatry, London
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- Neurodevelopment and Schizophrenia
- Published online:
- 04 August 2010
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- 18 November 2004, pp 373-389
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Summary
The concept of schizophrenia as a neurodegenerative disorder has a long and somewhat controversial past. The absence of a histopathological phenotype in schizophrenia has been cited as evidence against a neurodegenerative hypothesis. However, studies of schizophrenia increasingly demonstrate subtle yet consistent histopathological deficits in addition to evidence of progressive clinical and neuroimaging findings. It is believed that schizophrenia can be considered as a limited neurodegenerative disorder with neurodevelopmental antecedents. Studies from clinical, neurocognitive, neuroimaging, and neuropathological domains are reviewed in critical analysis of this hypothesis. The conclusion is increasingly supported by neuroimaging studies that find progressive neurostructural changes, especially in gray matter content and ventricle size, and studies that report limited progression of clinical symptoms and neurocognitive function. Future studies utilizing high-resolution neuroimaging and sophisticated neuropsychological testing techniques will undoubtedly provide greater insight on the timing, regionality, and degree of progression in the early stages of schizophrenia.