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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.
Neuroinflammation and brain structural abnormalities are found in bipolar disorder (BD). Elevated levels of cytokines and chemokines have been detected in the serum and cerebrospinal fluid of patients with BD. This study investigated the association between peripheral inflammatory markers and brain subregion volumes in BD patients.
Euthymic patients with bipolar I disorder (BD-I) aged 20–45 years underwent whole-brain magnetic resonance imaging. Plasma levels of monocyte chemoattractant protein-1 (MCP-1), chitinase-3-like protein 1 (also known as YKL-40), fractalkine (FKN), soluble tumour necrosis factor receptor-1 (sTNF-R1), interleukin-1β, and transforming growth factor-β1 were measured on the day of neuroimaging. Clinical data were obtained from medical records and interviewing patients and reliable others.
We recruited 31 patients with a mean age of 29.5 years. In multivariate regression analysis, plasma level YKL-40, a chemokine, was the most common inflammatory marker among these measurements displaying significantly negative association with the volume of various brain subareas across the frontal, temporal, and parietal lobes. Higher YKL-40 and sTNF-R1 levels were both significantly associated with lower volumes of the left anterior cingulum, left frontal lobe, right superior temporal gyrus, and supramarginal gyrus. A greater number of total lifetime mood episodes were also associated with smaller volumes of the right caudate nucleus and bilateral frontal lobes.
The volume of brain regions known to be relevant to BD-I may be diminished in relation to higher plasma level of YKL-40, sTNF-R1, and more lifetime mood episodes. Macrophage and macrophage-like cells may be involved in brain volume reduction among BD-I patients.
Tardive dyskinesia (TD) is an involuntary movement disorder that is more prevalent in older patients. However, there is limited information on TD treatment for this population. In two 12-week pivotal trials (ARM-TD and AIM-TD), TD patients demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) score with deutetrabenazine versus placebo.
Patients who completed ARM-TD or AIM-TD enrolled in an open-label extension (OLE) study. This post hoc analysis assessed change and percent change from baseline in AIMS score, response rates for ≥50% AIMS improvement, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety in younger (<55 years) and older (≥55 years) patients.
This analysis included 119 younger and 218 older patients enrolled in the OLE. Data presented at Week 145 (mean±SE): total deutetrabenazine dose was 39.4±1.39mg/day and 39.5±1.04mg/day in younger and older patients, respectively. Changes from baseline in AIMS score were –6.7±0.62 and –6.5±0.47, respectively (percent changes of –61.4%±4.10% and –54.6%±3.01%). The majority of younger and older patients achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%) and achieved ≥50% AIMS response (76% and 62%). Deutetrabenazine was generally well tolerated in both groups. Exposure-adjusted incidence rates (incidence/patient-years) were <0.01 and 0.02 for akathisia, 0.07 (both) for somnolence and sedation, 0.04 and 0.11 for parkinson-like events, and 0.06 and 0.09 for depression in younger and older patients, respectively.
Deutetrabenazine treatment was associated with sustained improvements in AIMS score and was well tolerated in both younger and older TD patients.
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Chronic psychotic disorders (CPDs) occur worldwide and cause significant burden. Poor medication adherence is pervasive, but has not been well studied in sub-Saharan Africa.
This cross-sectional survey of 100 poorly adherent Tanzanian patients with CPD characterised clinical features associated with poor adherence.
Descriptive statistics characterised demographic and clinical variables, including barriers to adherence, adherence behaviours and attitudes, and psychiatric symptoms. Measures included the Tablets Routine Questionnaire, Drug Attitudes Inventory, the Brief Psychiatric Rating Scale, the Clinical Global Impressions scale, the Alcohol Use Disorders Identification Test and Alcohol, Smoking and Substance Involvement Screening Test. The relationship between adherence and other clinical variables was evaluated.
Mean age was 35.7 years (s.d. 8.8), 61% were male and 80% had schizophrenia, with a mean age at onset of 22.4 (s.d. 7.6) years. Mean proportion of missed CPD medication was 64%. One in ten had alcohol dependence. Most individuals had multiple adherence barriers. Most clinical variables were not significantly associated with the Tablets Routine Questionnaire; however, in-patients with CPD were more likely to have worse adherence (P ≤ 0.01), as were individuals with worse medication attitudes (Drug Attitudes Inventory, P < 0.01), higher CPD symptom severity levels (Brief Psychiatric Rating Scale, P < 0.001) and higher-risk use of alcohol (Alcohol Use Disorders Identification Test, P < 0.001).
Poorly adherent patients had multiple barriers to adherence, including poor attitudes toward medication and treatment, high illness acuity and substance use comorbidity. Treatments need to address adherence barriers, and consider family supports and challenges from an intergenerational perspective.
Low- and middle-income countries (LMICs) experience a disproportionate burden from chronic psychotic disorders (CPDs), which are the most disabling conditions among people aged 10–24 in Sub-Saharan Africa. Poor medication adherence is seen in approximately half of individuals with CPDs in Sub-Saharan Africa, and is a major driver of relapse. A CPD treatment approach that combines the use of long-acting injectable (LAI) antipsychotic medications with a brief and practical customised adherence-enhancement behavioural intervention (CAE-L) was recently developed and tested for use in the USA.
To use a qualitative cross-sectional analysis to gather information on potentially modifiable barriers to management of CPDs, and assess attitudes about LAIs from community participants in Tanzania. Findings were intended to refine the CAE-L curriculum for use in Tanzania.
In-depth interviews and focus groups were conducted with 44 participants (patients with CPD, caregivers, mental healthcare providers). All interviews and focus groups were audiotaped, translated, transcribed and analysed using content analysis, with an emphasis on dominant themes.
Findings indicated that promoting medication adherence and management of CPDs in the Tanzanian setting needs to consider the individual with CPD, the family, the healthcare setting and the broader community context.
Qualitative findings enabled the study team to better understand the real-time barriers to medication adherence, LAI use and management of CPDs more broadly. Refinement of the CAE-L is expected to pave the way for an intervention trial for individuals with CPDs that is culturally and linguistically appropriate to the Tanzanian setting.
Older-age bipolar disorder (OABD), which has been defined as the occurrence of bipolar disorder in individuals who are aged 60 years or older  represents as much as one-quarter of the population with bipolar disorder. In spite of the early mortality that is known to occur among individuals with bipolar disorder , the absolute numbers of individuals with mental health conditions such as OABD are expected to increase in upcoming years. Given these global demographic changes and emerging evidence base, there has been growing interest in OABD. However, complicating the study and characterisation of OABD, there is substantial variability in clinical expression, such as early-onset versus late-onset illness with a potentially different pathogenesis, clinical course and care needs. A hierarchical terminology for OABD that considers age of onset and course of illness has been proposed by the International Society for Bipolar Disorders Task Force on Older-Age Bipolar Disorder .
To evaluate the long-term safety and tolerability of once-dailyvalbenazine in adults with tardive dyskinesia(TD).
Data 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.
Analyses 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]).
Valbenazine 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.
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 efficacy of valbenazine (INGREZZA) in tardive dyskinesia (TD) was demonstrated in placebo-controlled clinical trials, based on the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7). In these trials, mean changes in the AIMS total score were significantly greater with valbenazine 80 mg than with placebo. Currently, no minimal clinically important difference (MCID) has been established for the AIMS total score in patients with TD. Using valbenazine trial data, analyses were conducted to establish a MCID for AIMS total score in TD.
Data were pooled from three 6-week trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), KINECT 3 (NCT02274558). Using the Clinical Global Impression ofChange (CGI-TD) as an anchor comparison, AIMS total score changes from baseline to Week 6 were summarized for all study participants (pooled valbenazine and placebo groups) with a “minimal” CGI-TD score of ≤3 (minimally improved or better) or “robust” ≤2 (much improved or better) at Week 6.
In the pooled population (N=373), 72% and 29% of all participants had CGI-TD scores of ≤3 and ≤2, respectively. The median (maximum, minimum) change from baseline in AIMS total score at Week 6 was -2 (-13, 8) in participants with CGI-TD score ≤3 and -3 ( 13, 8) in participants with a score ≤2.
Pooled data from 3 randomized, double-blind, placebo-controlled trials suggest that a 2 point decrease in AIMS total score may represent the minimal clinically meaningful improvement. Larger AIMS score improvements were associated with “much improved” or “very much improved” CGI TD assessments.
This study was funded by Neurocrine Biosciences, Inc.
This discussion will focus on medical comorbidity and recovery in individuals with bipolar disorder. The complexity of care will be discussed in the context of a case study, with particular focus on the medical burden of mania, aging and bipolar disorder, and treatment approaches that promote functional recovery.
To describe the training and participant experience of patients with both severe mental illness (SMI) and diabetes (DM) who were enrolled in a Peer Educator Training Program adapted to a primary health care setting.
The mortality of patients with both SMI and DM is high. Illness self-management includes medications, psychosocial treatments, and healthy behaviors, yet treatment engagement is often sub-optimal with adherence rates of 52% for diabetic medications and 62% for antipsychotic medications among the SMI. To address this problem, a new behavioral intervention study targeting SMI and DM self-management used trained peer educators (PEs) with the same chronic conditions to enhance program effectiveness. A manual facilitated training on intervention topics such as SMI and DM therapies, stress management, and stigma reduction as well as training in group intervention techniques, telephone skills, and crisis management.
We assessed PE attitudes and input using in-depth face-to-face interviews. Interviews were audio-taped, transcribed, coded, and analyzed using the classic method of content analysis emphasizing dominant themes. A member check-in was conducted where participants commented on analysis results.
Six relevant descriptive themes emerged: (1) positive group experience; (2) success with learning manual content; (3) increased knowledge about SMI and DM; (4) improved self-management skills; (5) increased self-confidence and self-efficacy in becoming a PE; and being (6) united in purpose to help others self-manage their SMI and DM. Qualitative evidence supports structured training for SMI-DM PEs. Key components include written educational materials and the power of the group process to increase knowledge, self-management skills, confidence, and self-efficacy. Recommendations are offered to support further endeavors to mobilize peers with SMI to help other patients with complex comorbidities better manage their own health.
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