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Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with exposure to antipsychotics and other dopamine receptor blocking agents. Effective and comprehensive treatment of TD requires reducing patients’ abnormal involuntary movements without disrupting their psychiatric stability. This can be especially challenging when patients have complex psychiatric conditions (e.g., >1 psychiatric diagnosis) and are taking multiple medications. Valbenazine, a highly potent and selective vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved for the once-daily treatment of TD. This post hoc analysis of two long-term studies (KINECT 3, KINECT 4) was conducted to evaluate changes in psychiatric status and clinician- and patient-reported treatment success in study participants who received valbenazine (40 or 80 mg) for 48 weeks.
Data from KINECT 3 and KINECT 4 were pooled and analyzed in participants categorized by their primary psychiatric diagnosis: schizophrenia/schizoaffective disorder (“SCHZ”) or mood disorder (“MD”). Concomitant medications needed for managing these and other psychiatric or medical conditions were allowed. Treatment success was defined as achieving a rating of “much improved” or “very much improved” at Week 48, as assessed using the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) and Patient Global Impression of Change (PGIC). Psychiatric stability was monitored using the following scales: Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) in the SCHZ subgroup; Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) in the MD subgroup. Suicidal ideation/behavior was monitored using the Columbia-Suicide Severity Rating Scale.
More than 75% of study participants in the SCHZ subgroup achieved treatment success with valbenazine, based on clinician assessment (CGI-TD, 79.7%) and patient self-report (PGIC, 78.0%). Mean changes from baseline to Week 48 for PANSS scores (positive symptoms [-0.7], negative symptoms [‑0.6], general psychopathology [-1.9], total [-3.2]) and CDSS total score (-0.5) indicated maintenance of psychiatric stability in the SCHZ subgroup. Similar treatment success rates were found in the MD subgroup for both CGI-TD (77.6%) and PGIC (84.5%), with mean changes from baseline in YMRS total score (-1.0) and MADRS total score (+0.3) indicating psychiatric stability was maintained. No emergence of suicidal ideation/behavior was observed during the studies.
Pooled analyses from two 48-week studies indicate that long-term treatment of TD with once-daily valbenazine resulted in substantial clinician- and patient-reported global improvements in TD, while psychiatric stability was maintained regardless of primary psychiatric condition.
MIND-TD is a collaboration of healthcare professionals (HCPs) who are committed to raising awareness of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. The MIND-TD questionnaire was developed to help HCPs screen for TD and facilitate discussion with patients.
In August 2020, an expert panel of 13 HCPs (4 psychiatrists, 6 neurologists/movement disorder specialists [MDSs], and 3 advanced practice providers [APPs]) met virtually to discuss potential screening questions for TD. This work was continued by 4 panelists (1 psychiatrist, 2 neurologists/MDSs, and 1 APP) who tested the questions in clinical practice for revision and refinement. The same group also worked with the sponsor to develop 2 additional sections that could be used to elicit more information from patients. The panel recognized the need for a tool that could facilitate telehealth screening for TD, including audio-only interactions. Therefore, practices from speech-language pathologists (eg, diadochokinetics) were used to refine the questionnaire.
Part 1 of the MIND-TD questionnaire includes a yes-or-no question for each of the 4 following topics: presence of extra or unwanted movements (Movement); feelings of embarrassment or self-consciousness (Impact); if anyone else has noticed the movements (Notice); and if movements interfere with everyday routines (Daily Activities). Part 1 can be administered by any trained medical staff, either in person or via telehealth (with video or audio-only). Routine administration is suggested in all patients who meet any of the following criteria: current or prior use of any first- or second-generation antipsychotic; use of an anticholinergic medication in conjunction with a current or past antipsychotic; or current diagnosis of TD. Part 2 of the MIND-TD questionnaire has 2 sections. The first (Thorough Interview) includes 9 items related to physical/functional difficulties (eg, eating, speaking, walking, and gripping objects) and 3 simple instructions for speech difficulties. The second section (Differentiate) includes checklists of characteristic movements for TD and drug-induced parkinsonism, along with an item related to akathisia and suggestions for observing abnormal or involuntary movements. Part 2 should be administered by the treating HCP in patients who have abnormal movements that may be related to TD. Part 2 requires visual observation of the patient, whether in-person or via video.
MIND-TD is a screening questionnaire that can facilitate a dialogue between HCPs and patients about the risks, symptoms, and impact of TD. The MIND questions can stand alone and be administered during in-person visits or telehealth visits (video or audio-only). The TD section can be used to gather more information about a patient’s abnormal movements.
Older patients taking a dopamine receptor blocking agent (eg, first- or second-generation antipsychotic) have an increased risk for tardive dyskinesia (TD), a persistent and potentially disabling movement disorder. Valbenazine, a selective and potent vesicular monoamine transporter 2 inhibitor, is approved for once-daily treatment of TD with no dosing adjustments required for older patients. This analysis of valbenazine clinical trial data, which is the first to evaluate an approved TD medication in a population ≥65 years, was conducted to better understand treatment outcomes in older patients.
Data from two 48-week long-term studies (KINECT 3-extension, KINECT 4) were pooled and analyzed in older (≥65 years) and younger (<65 years) participants. Analyses based on the Abnormal Involuntary Movement Scale (AIMS) total score included: mean change from baseline (BL); clinically meaningful response (≥30% improvement from BL [AIMS-30%]); and protocol-defined response (≥50% improvement from BL [AIMS-50%]). Additional analyses included response thresholds for Clinical Global Improvement-Tardive Dyskinesia and Patient Global Impression of Change as follows: rating of “minimally improved” or better (score ≤3) at week 48 (CGI-TD≤3, PGIC≤3); rating of “much improved” or “very much improved” (score ≤2) at week 48 (CGI-TD≤2, PGIC≤2).
AIMS outcomes in the older subgroup were generally comparable to (or better than) outcomes in the younger subgroup and overall study populations. In participants ≥65 years, pooled AIMS results indicated substantial improvements in TD movements with valbenazine 40 mg (n = 8) and 80 mg (n = 20): mean change from BL (−6.4 and −9.8 [for 40 and 80 mg, respectively]); AIMS-30% (75% and 95%); AIMS-50% (75% and 85%). CGI-TD and PGIC response rates indicated that clinician- and patient-reported global improvements were also substantial in the older subgroup: CGI-TD = 3 (88% and 100% [for 40 and 80 mg, respectively]); CGI-TD = 2 (88% and 95%); PGIC = 3 (88% and 100%); PGIC = 2 (75% and 90%).
These analyses, which are the first to evaluate long-term valbenazine effects in patients ≥65 years, indicate that older study participants had clinically meaningful and substantial improvements in TD that were comparable to (or better than) those in younger participants.
This study sought to understand the evolving continuing medical education (CME) needs of physicians managing patients with tardive dyskinesia (TD). A case-based survey was developed, and later updated, to assess current practice, knowledge, and attitudes of neurologists and psychiatrists in the management of patients with TD. The original and updated survey were fielded in May 2018 and March 2020, respectively, to US-practicing psychiatrists and neurologists. Results were obtained from 213 psychiatrists and 187 neurologists in 2018 and from 125 psychiatrists and 128 neurologists in 2020. Less than half of physicians in both 2018 and 2020 were able to correctly identify the prevalence of TD in patients on maintenance antipsychotics, with many underestimating reported prevalence. Respondents reported moderate familiarity with VMAT2 inhibitor therapies for TD, with self-reported familiarity increasing more among neurologists than psychiatrists since the 2018 study. Psychiatrists are more likely than neurologists to take responsibility for medical management of TD symptoms and antipsychotic medication adjustment. Despite recommendations from APA guidelines and AAN reviews, 15% of physicians would use an anticholinergic to manage TD symptoms and only about half would opt for a VMAT2 inhibitor. There was a larger increase in VMAT inhibitor use between 2018 and 2020 among neurologists as compared to psychiatrists. The findings support the need for CME on TD focused toward specific provider groups. While both types of specialists would benefit from CME on the topic of TD epidemiology, there is an increased need for CME that includes treatment updates among psychiatrists.
Drug-induced movement disorders (DIMDs) may occur in patients treated with antipsychotics. The CommonGround Program supports the recovery and healing of psychiatric outpatients through tools which facilitate better patient-doctor communication regarding psychiatric symptoms, DIMDs, and the effectiveness of treatment.
Patients responses to CommonGround’s web-based waiting-room questionnaire were analyzed in patients who responded yes to having concerns about developing DIMDs (MD-YES) and those who responded no to this question (MD-NO). These groups were compared descriptively to assess the potential effects of DIMD concerns on self-reported functioning and beliefs about prescribed psychiatric medications.
Of 7874 responding patients, 312 (4.0%) and 7562 (96.0%) were in the MD-YES and MD-NO subgroups, respectively. A higher percentage of MD-YES patients reported poor / not so good ability to keep up with daily responsibilities (21.2% vs 15.2% vs MD-NO), along with low energy levels (37.1% vs 26.3% for MD-NO), bothersome thoughts/beliefs/fears (30.5% vs 16.0%), and nervousness/anxiety (35.3% vs 27.5%) all / most of the time. MD-YES patients were also more likely to wonder about stopping their medications (9.3% vs 0.6% for MD-NO) and were concerned about side effects such as sleepiness (31.4% vs 3.9%) and weight gain (37.2% vs 5.7%).
Patients from community mental health centers who were concerned about developing DIMDs tended to express problems with daily functioning and concerns about their psychiatric medications. For these patients, recognizing their fears and concerns may help clinicians discuss treatment options for DIMDs, which could increase patient confidence, encourage adherence to current psychiatric medications, and potentially improve outcomes.
Vesicular monoamine transporter 2 (VMAT2) inhibitors including valbenazine are first-line therapies for tardive dyskinesia (TD), a persistent movement disorder associated with antipsychotic exposure. This real-world study was performed to assess the association between patient awareness of TD symptoms and clinician-assessed symptom severity.
Clinicians who treated antipsychotic-induced TD with a VMAT2 inhibitor within the past 24 months were asked to extract demographic/clinical data from patients charts and complete a survey for additional data, including patient awareness of TD (yes/no) and TD symptom severity (mild/moderate/severe).
Data for 601 patients were provided by 163 clinicians (113 psychiatrists; 46 neurologists; 4 primary care physicians). Patient demographics: 50% male; mean age 50.6 years; 55% schizophrenia/schizoaffective disorder; 29% bipolar disorder; 16% other psychiatric diagnoses. Positive relationships were seen between patient awareness and clinician-assessed symptom severity. Awareness was highest in patients with severe symptoms in specific body regions: face (88% vs 78%/69% [awareness by severe vs moderate/mild symptoms]); jaw (90% vs 80%/67%); wrists (90% vs 69%/63%). In other regions, awareness was similar in patients with severe or moderate symptoms: lips (85%/86% vs 68% [severe/moderate vs mild]); tongue (81%/80% vs 73%); neck (80%/78% vs 68%); arms (67%/66% vs 62%); knees (67%/67% vs 53%).
In patients prescribed a VMAT2 inhibitor for TD, patient awareness was generally higher in those determined to have moderate-to-severe symptom severity as assessed by the clinician. More research is needed to understand how awareness and severity contribute to TD burden, and whether different treatment strategies are needed based on these factors.
The Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7) is usually the primary efficacy measure in tardive dyskinesia (TD) clinical trials. However, item 8 of the AIMS (clinician’s global impression of severity) might also be an appropriate assessment in real-life healthcare settings. To explore the potential of item 8 as a clinical measure, post hoc analyses were conducted using data from a long-term study of valbenazine, an approved TD medication.
In KINECT 4 (NCT02405091), adults with TD received once-daily valbenazine (40 or 80 mg) for 48 weeks. Analyses included two sets of AIMS item 8 scores: based on investigators ratings of item 8 using protocol-defined descriptors; and based on investigators highest scores from items 1–7 (analyzed post hoc). Shift analyses included an improvement from score =3 at baseline (moderate or severe) to score =2 at Week 48 (none to mild).
At baseline in all participants (N=163), AIMS item 8 mean scores were 3.2 (protocol) and 3.3 (post hoc). In participants with a score =3 at baseline per investigators ratings using protocol-defined descriptors, 95.9% [94/98] shifted to a score =2 by Week 48. A similar result (93.9% [93/99]) was found when item 8 was based on investigators highest scores from items 1–7.
Shift analyses using AIMS item 8 scores indicated that most participants in KINECT 4 had a clinically meaningful improvement after 48 weeks of once-daily treatment with valbenazine. AIMS item 8 may be an appropriate clinical measure for assessing changes in TD severity.
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).
Participants 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.
In 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).
In 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.
Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos. Exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics or antiemetics is associated with a spectrum of movement disorders including TD. The differential diagnosis of TD is based on history of DRBA exposure, recent discontinuation or dose reduction of a DRBA, and movement phenomenology. Common diagnostic challenges are the abnormal behaviors and dyskinesias associated with advanced age or chronic mental illness, and other movement disorders associated with DRBA therapy, such as akathisia, parkinsonian tremor, and tremor related to use of mood stabilizing agents (eg, lithium, divalproex). Duration of exposure may help rule out acute drug-induced syndromes such as acute dystonia or acute/subacute akathisia. Another important consideration is the potential for TD to present together with other drug-induced movement disorders (eg, parkinsonism, parkinsonian tremor, and postural tremor from mood stabilizers) in the same patient, which can complicate both diagnosis and management. After documentation of the phenomenology, severity, and distribution of TD movements, treatment options should be reviewed with the patient and caregivers.
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]).
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.
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).
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.
International Congress of Parkinson’s Disease and Movement Disorders; September 22-26, 2019; Nice, France.
This study was sponsored by Neurocrine Biosciences, Inc.
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.
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”).
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).
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.
This study was sponsored by Neurocrine Biosciences, Inc.
Valbenazine is approved for tardive dyskinesia (TD) in adults based on clinical trials that included patients with mood disorders (e.g., bipolar disorder, major depressive disorder). In two long-termphase 3 trials, KINECT 3 (NCT02274558) and KINECT 4 (NCT02405091), sustained TD improvements were found in participants who received once-daily treatment with valbenazine (40 or 80mg). Data from these studies were analyzed post hoc to evaluate changes in psychiatric status of patients with a primary mood disorder.
Data were pooled from participants with mood disorders in KINECT 3 (6-week double-blind, placebo-controlled period; 42-week double-blind extension period; 4-week drug-free washout) and KINECT 4 (48week open-label treatment; 4-week drug-free washout). At screening, patients must have had a Brief Psychiatric Rating Scale total score <50. Mood changes were evaluated after long-term treatment (Week 48) and washout (Week 52) using the Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS). For each scale, mean changes from baseline in the total score and individual item scores were analyzed descriptively.
Of the 95 participants with a primary mood disorder (40mg , n=32; 80mg , n=63), 59 (62.1%) were diagnosed with bipolar disorder, 32 (33.7%) with major depressive disorder, and 4 (4.2%) with another mood disorder. A majority of all mood participants received concomitant antidepressants (84.2%) and/or antipsychotics (76.8%) during treatment; other common concomitant medications included antiepileptics (47.4%), anxiolytics (38.9%), and anticholinergics (22.1%). Mean YMRS and MADRS total scores in all mood participants indicated mood symptom stability at baseline (YMRS, 2.7; MADRS, 5.9). This stability was maintained during the studies, as indicated by minimal changes from baseline in mean total scores (YMRS: Week 48, 1.0; Week 52, –1.0; MADRS: Week 48, 0.3; Week52,0.9). Changes in individual items on both scales were also small (<±0.3), indicating no clinically significant changes or worsening in specific mood symptoms or domains.
Mood symptom stability was maintained in patients with TD and a primary mood disorder who received up to 48 weeks of treatment with once-daily valbenazine in addition to their psychiatric medication(s).
Funding Acknowledgements: Neurocrine Biosciences, Inc.
Vesicular monoamine transporter 2 (VMAT2) inhibitors are the first class of drugs approved to treat tardive dyskinesia (TD). With the recent approval of these medications, a modified Delphi process was implemented to address the need for updated clinical guidelines for TD screening, diagnosis, and treatment.
A Steering Committee of 11 TD experts met in a Nominal Group meeting format to discuss/prioritize questions to be addressed about TD and identify individuals to be invited to serve as Delphi survey panelists. Two survey rounds were conducted anonymously; responses were collected, collated, and analyzed. Respondent agreement was defined a priori by the Steering Committee as unanimous (100%), consensus (75–99%), or majority (50–74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥4 (“agree completely” or “agree”). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with <25% agreement (deemed unlikely to achieve consensus) and some questions that already achieved consensus (>75% agreement).
Online surveys were sent to 60 individuals; 29 agreed to participate as panelists (23 psychiatrists; 6 neurologists). Respondents unanimously agreed (100%) that all patients currently taking dopamine receptor blocking agents (DRBAs) should be screened for TD, and that the Abnormal Involuntary Movement Scale (AIMS) is the standard structured assessment for monitoring severity of TD. There was consensus (76%) that a semi-structured assessment could be used for more frequent routine TD screening. Respondents unanimously agreed that treatment with first generation antipsychotics, older age, and longer cumulative exposure to antipsychotics were risk factors for TD. For TD diagnosis, consensus (89%) was reached that a patient with an AIMS score >2 (mild) affecting 1 body area should be considered as having possible TD; consensus (93%) was also reached that TD was most often evident in orofacial musculature, although other body areas may be affected and should not be neglected. Consensus was not reached on minimum cumulative duration of DRBA exposure for TD diagnosis, but a majority (70%) agreed that minimum cumulative exposure of 1month may be sufficient. For TD treatment, unanimity or consensus was reached on 4 strategies to consider: discussion of treatment options with patients/caregivers (100%), modification of antipsychotic regimen (100%), treatment with VMAT2 inhibitor (100%), and modification of anticholinergic regimen (86%).
Using a Nominal Group and modified Delphi process, consensus was reached within 1−2 rounds on several key aspects of TD screening, diagnosis, and treatment. This process may offer an expedient method to identify gaps in agreement and facilitate updated management guidelines.
Funding Acknowledgements: Sponsored by Neurocrine Biosciences,Inc.
The medications used to treat narcolepsy are targeted toward alleviating symptoms such as excessive sleepiness and cataplexy. The cause of this neurological sleep disorder is still not completely clear, though a destruction of hypocretin/orexin neurons has been implicated. The destruction of these neurons is linked to inactivity of neurotransmitters including histamine, norepinephrine, acetylcholine, and serotonin, causing a disturbance in the sleep/wake cycles of narcoleptic patients. Stimulants and MAOIs have traditionally been used to counteract excessive daytime sleepiness and sleep attacks by inhibiting the breakdown of catecholamines. Newer drugs, called wake-promoting agents, have recently become first-line agents due to their better side-effect profile, efficacy, and lesser potential for abuse. These agents similarly inhibit reuptake of dopamine, but have a novel mechanism of action, as they have been found to increase neuronal activity in the tuberomamillary nucleus and in orexin neurons. Sodium oxybate, a sodium salt of gamma-hydroxybutyrate (GHB), is another class that is used to treat many symptoms of narcolepsy, and is the only U.S. Food and Drug Administration (FDA)-approved medication for cataplexy. It has a different mechanism of action than either stimulants or wake-promoting agents, as it binds to its own unique receptor. Antidepressants, like selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have also been used, as similar to stimulants, they inhibit reuptake of specific catecholamines. In this article, we seek to review the mechanisms behind these classes of drugs in relation to the proposed pathophysiology of narcolepsy. Appropriate clinical strategies will be discussed, including specific combinations of medications that have been shown to be effective.
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