Severity Of Tardive Dyskinesia Research Articles

Analysis of schizophrenia-associated genetic markers in the HLA region as risk factors for tardive dyskinesia.

The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p=0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.

Associations between Catechol-O-methyltransferase (COMT) polymorphisms and cognitive impairments, psychiatric symptoms and tardive dyskinesia in schizophrenia

IntroductionCatechol-O-methyltransferase (COMT) is a crucial enzyme involved in dopamine metabolism and has been implicated in the etiology of tardive dyskinesia (TD). We aimed to investigate the associations between COMT gene polymorphisms and the occurrence and severity of TD in a Chinese population, as well as the impact on the psychiatric symptoms and cognitive impairments observed in TD patients. MethodsA total of 216 chronic schizophrenia patients, including 59 TD patients and 157 NTD patients, were recruited for this study. Three SNPs of the COMT gene (rs4680, rs165599 and rs4818) were selected and genotyped using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). TD severity, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. ResultsIn TD patients, total AIMs scores were higher in carriers of the rs4680 AA genotype than in carriers of the AG and GG genotypes (p = 0.01, 0.006), carriers of the rs4818 GC and CC genotypes had higher orofacial scores than in GG genotypes (p = 0.032, 0.002). In male TD patients, carriers of the rs165599 GA genotype scored lower in the extremities and trunk scores than AA genotype carriers (p = 0.015). Moreover, in male TD patients, COMT rs4818 was associated with cognition, since the C allele carriers had significantly higher immediate memory (p = 0.043) and verbal function (p = 0.040) scores than the G allele carriers. In addition, rs165599 genotype interacted with TD diagnosis on depressed factor (p = 0.031). ConclusionWithin the Chinese population, COMT gene polymorphisms could potentially serve as biomarkers for the symptoms and prognosis of TD patients.

Genetic Susceptibility to Tardive Dyskinesia and Cognitive Impairments in Chinese Han Schizophrenia: Role of Oxidative Stress-Related and Adenosine Receptor Genes.

Tardive dyskinesia (TD) is a severe rhythmic movement disorder caused by long-term antipsychotic medication in chronic patients with schizophrenia (SCZ). We aimed to investigate the association between polymorphisms in oxidative stress-related genes (GSTM1, SOD2, NOS1, and NOS3) and adenosine receptor gene (ADORA2A), as well as their interactions, with the occurrence and severity of TD, and cognitive impairments in a Chinese Han population of SCZ patients. Two hundred and sixteen SCZ patients were recruited and divided into TD group (n=157) and non-TD group (n=59). DNA extraction was performed by a high-salt method, followed by SNP genotyping using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The severity of TD, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. The combination of GSTM1-rs738491, NOS1-rs738409 and ADORA2A-rs229883 was identified as the best three-point model to predict TD occurrence (p=0.01). Additionally, GSTM-rs738491 CC or NOS3-rs1800779 AG genotypes may be protective factors for psychiatric symptoms in TD patients. TD patients carrying the NOS1-rs738409 AG or ADORA2A-rs229883 TT genotypes exhibited poorer cognitive performance. Our findings suggest that the interaction of oxidative stress-related genes and adenosine receptor gene may play a role in the susceptibility and severity of TD in Chinese Han SCZ patient. Furthermore, these genes may also affect the psychiatric symptoms and cognitive function of TD patients.

Regional Homogeneity in schizophrenia patients with tardive dyskinesia: a resting-state fMRI study

Neuronal degeneration and apoptosis may play an important role in the pathogenesis of tardive dyskinesia (TD). Previous studies suggested brain structural and functional abnormalities in patients with TD. We investigated changes in cerebral regional homogeneity (ReHo) in patients with TD using resting-state functional magnetic resonance imaging (rs-fMRI). Imaging data were collected from schizophrenia patients with TD (TD group, n=58) and without TD (non-TD group, n=66) and healthy controls (HC group, n=67), processed with SPM, and evaluated at a corrected threshold. Psychopathology and severity of TD were assessed with the Positive and Negative Syndrome Scale (PANSS) and Abnormal Involuntary Movement Scale (AIMS), respectively. Results: TD vs. non-TD group showed significantly higher ReHo in the Left Inferior Semilunar Lobule and Right Fusiform Gyrus and lower ReHo in Left Supramarginal Gyrus, Right Inferior Tempotal Gyrus, and Left Medial Frontal Gyrus. The ReHo value in the Left Inferior Semilunar Lobule was negatively correlated with AIMS upper limbs scores. Conclusions: The findings suggest altered regional neural connectivities in association with TD and may inform research of the etiology and monitor the course of TD in patients with schizophrenia and potentially other psychotic disorders.

Sex difference in association between tardive dyskinesia and cognitive deficits in patients with chronic schizophrenia.

Tardive dyskinesia (TD), a side effect due to long-term use of antipsychotic medication, is associated with cognitive impairment. Several studies have found sex differences in cognitive impairment in schizophrenia patients, while whether there are sex differences in cognitive performance in schizophrenia patients with TD has not been reported. A total of 496 schizophrenia inpatients and 362 healthy controls were recruited for this study. We used the Positive and Negative Syndrome Scale (PANSS) to assess patients' psychopathological symptoms and the Abnormal Involuntary Movement Scale (AIMS) to assess the severity of TD. Cognitive function was measured in 313 of these inpatients and 310 of healthy controls using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Patients with schizophrenia performed worse in all cognitive domains than healthy controls(all p<0.001). Compared to patients without TD, patients with TD had higher PANSS total, PANSS negative symptom subscale and AIMS scores (all p<0.001), while RBANS total, visuospatial/constructional and attention subscale scores were significantly lower (all p<0.05). In addition, the visuospatial/constructional and attention indices remained significantly lower in male patients with TD than those without TD (both p<0.05), but these results were not observed in female patients. Moreover, visuospatial/constructional and attention indices were negatively correlated with total AIMS scores only in male patients (both p<0.05). Our results suggest that there may be sex differences in cognitive impairment in schizophrenia patients with comorbid TD, indicating that female gender may have a protective effect on cognitive impairment in schizophrenia patients caused by TD.

Prevalence and Associated factors of Tardive Dyskinesia among patients with schizophrenia taking Antipsychotics

1.1. Objective: Tardive dyskinesia (TD) is one of incapacitating side effect of neuroleptics. It has been implicated in the morbidity, functional impairment, stigma and overall poor prognosis of patients with schizophrenia. However, there is little information from Ethiopia. Therefore, we conducted a cross-sectional study among 161 schizophrenia patients who were admitted and on follow up at two public hospitals in Addis Ababa. We assessed TD using the Abnormal Involuntary Movement Scale. Associated factors Were also analyzed. 1.2. Results: Out of the total study participants, 41(25.5%) have TD. Clinical characteristics variables such as depot antipsychotics, combination of antipsychotics, Chlorpromazine equivalent dose of 400 mg or more and substance use were significantly associated with TD (P – value &lt; 0.05). Nearly half of those with TD had moderate to severe TD which has significant negative impact on their day-to-day activities. 1.3. Conclusion: Prevalence of TD among schizophrenia patients taking antipsychotics is high. Root of administration and higher dose of antipsychotic medication and substance use were found to be factors associated. Rational use of antipsychotics and regular screening for TD for patients who takes antipsychotics is recommended.

Dysfunctional monocytic toll-like receptor 4 signaling pathway and cognitive deficits in chronic schizophrenia patients with tardive dyskinesia

BackgroundMounting evidence suggests that the innate immune system is disrupted in schizophrenia patients with tardive dyskinesia (TD); however, the role of the toll-like receptor 4 (TLR4) signaling pathway remains unclear. MethodsIn this study, we quantified the expression of the monocytic TLR4 signaling pathway using flow cytometry, before and after lipopolysaccharide (LPS) stimulation, in chronic schizophrenia patients with (n = 61) and without TD (NTD, n = 61) and healthy controls (HCs, n = 74). Psychopathological symptoms, the severity of TD, and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and MATRICS Consensus Cognitive Battery (MCCB), respectively. Results1) Both TD and NTD patients showed higher TLR4 signaling pathway activity at baseline than that in HCs, but their responses to LPS were weaker than those in HCs; 2) the alteration of the TLR4 signaling pathway was less severe in TD patients than in NTD patients; 3) TLR4 levels and MCCB scores were negatively correlated at baseline but positively correlated after LPS stimulation in TD patients; 4) there was no correlation between the TLR4 signals and PANSS or AIMS scores. ConclusionsOur findings suggested the TLR4 signaling pathway disturbance might be related to cognitive deficits in schizophrenia patients with TD.

Prevalence, clinical correlates and risk factors associated with Tardive Dyskinesia in Chinese patients with schizophrenia.

Tardive Dyskinesia (TD) is a serious, nonrhythmic and iatrogenic movement disorder, and is a common comorbidity in patients with schizophrenia (SZ). The main goal of this study was to investigate the prevalence, clinical correlates, and risk factors of TD in Chinese patients with chronic SZ, which has not been fully studied. This study adopted a cross-sectional design. A total of 901 Chinese inpatients with SZ were recruited between 2008 and 2011. We used the Abnormal Involuntary Movement Scale (AIMS) to measure the severity of TD, and the Positive and Negative Syndrome Scale (PANSS) was used to measure the psychopathological symptoms of SZ. Blood samples were also collected for routine blood tests, including the levels of triglyceride (TG), cholesterol (CHO), HDL-cholesterol (HDL-CHO), LDL-cholesterol (LDL-CHO), Apolipoprotein A1 (ApoA1), and Apolipoprotein B (ApoB). Overall, 36% of patients with SZ had TD. Compared with the non-TD patients, the TD patients were more likely to be men, had older age, lower education level, higher smoking rate, higher hospitalization frequency, and longer duration of illness (DOI). Further, compared with the non-TD patients, the TD patients had higher PANSS total, PANSS negative subscale, and cognitive subscale scores, but had lower depressive subscale scores and lower mean levels of metabolic biomarkers, including TG, CHO, HDL-CHO, LDL-CHO, ApoA1 and ApoB. Moreover, binary regression analysis showed that antipsychotic type, BMI, gender, age, HDL-CHO, and ApoB were associated with TD. Our findings indicate that TD is a common movement disorder in patients with chronic SZ, with certain demographic and clinical variables being risk factors for the development of TD.

Sudden Cognitive Decline in Bipolar Mood Disorder Patient with Underlying Severe Tardive Dyskinesia After the Failure of His Deep Brain Stimulation Device Battery

Bipolar disorder (BD) is a chronic mood disorder associated with multiple comorbidities. Structural and functional abnormalities in these subjects’ brains have been related to cognitive deficits correlated with the severity of the mood symptoms. These deficits are also present in euthymic states, indicating a trait characteristic. Bipolar subjects would risk developing tardive dyskinesia due to being exposed to long periods of antipsychotic treatment. Unfortunately, the presence of tardive dyskinesia is also associated with worsening cognition. One treatment option for severe tardive dyskinesia is deep brain stimulation that has also been implicated with cognitive decline. We present a case of Bipolar disorder with underlying cognitive impairment, who had a deep brain stimulation device inserted for severe tardive dyskinesia. He was admitted to a depressive phase and was noted to have a sudden worsening of cognitive impairment following his deep brain stimulation device battery running low. Possible explanations discussed for this unexpected observation are attributed to a further deterioration of his tardive dyskinesia following the device failure and depressive episode, which causes added pseudo-cognitive deficit signs.

Abnormal functional connectivity of motor circuit in the schizophrenic patients with tardive dyskinesia: A resting-state fMRI study

BackgroundAnimal and neuroimaging studies suggest that the volume of the motor-circuit region decreases in tardive dyskinesia (TD). This study examined the differences in functional connectivity within the motor circuit of patients with schizophrenia with and without TD to further clarify how the dysfunction is related to the pathogenesis of TD. MethodsFunctional magnetic resonance images were taken of 56 schizophrenic patients with TD (TD group), 64 without TD (non-TD group), and 68 healthy controls (HC group). The motor-circuit area was selected as the seed region for a whole brain resting-state functional connectivity (rsFC) analysis. Psychopathological symptoms and TD severity were assessed with the Positive and Negative Syndrome Scale (PANSS) and Abnormal Involuntary Movement Scale (AIMS), respectively. Group differences and correlations among 18 brain regions of interest (e.g., the global strength of connectivity between two regions) were analyzed. ResultsThe analysis of variance results were as follows: The three groups exhibited rsFC losses in the left primary motor cortex, bilateral parietal cortices, right postcentral gyrus, right putamen, right superior parietal lobule, right supplementary motor area and bilateral thalami (false discovery rate,p < 0.05). The TD group showed a significant rsFC loss between the right postcentral gyrus and the inferior frontal gyrus of the left triangular part when compared with the non-TD group (AlphaSim, p < 0.001), which was negatively correlated with the AIMS total score (r=-0.259, p = 0.03). ConclusionsThese findings may suggest dysfunction of the postcentral and inferior frontal gyri of the triangular part in patients with schizophrenia and TD.

Liver enzyme CYP2D6 gene and tardive dyskinesia.

Background: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. Materials & methods: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n =198, of which 82 had TD). Results: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. Conclusion: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

Schizophrenia-associated gene dysbindin-1 and tardive dyskinesia.

Tardive dyskinesia (TD) is a potentially irreversible movement disorder observed following long-term antipsychotic exposure. Its cause is unknown; however, a genetic component has been supported by studies of affected families. Dysbindin-1, encoded by the dystrobrevin-binding protein 1 DTNBP1 gene, has been associated with schizophrenia and is potentially involved in dopamine neurotransmission through its regulation of dopamine release and dopamine D2 receptor recycling, making it a candidate for investigation in TD. We investigated common variants across the DTNBP1 gene in our schizophrenia/patients with schizoaffective disorder of European ancestry. We found a number of DTNBP1 three-marker haplotypes to be associated with TD occurrence and TD severity (p< 0.05). These preliminary findings, if replicated in larger independent samples, would suggest that drugs targeting dysbindin-1 may be an option in the prevention and treatment of TD.

Association Study of the Complement Component C4 Gene in Tardive Dyskinesia.

Tardive dyskinesia (TD) is a movement disorder that may develop in schizophrenia patients being treated long-term with antipsychotic medication. TD interferes with voluntary movements and leads to stigma, and can be associated with treatment non-adherence. The etiology of TD is unclear, but it appears to have a genetic component. There is emerging evidence of immune dysregulation in TD. In the current study, we set out to investigate the complex schizophrenia-associated complement component 4 (C4) gene for possible association with TD occurrence and TD severity as assessed by the Abnormal Involuntary Movement Scale (AIMS) in a sample of 129 schizophrenia patients of European ancestry. We have genotyped the copy numbers of long and short forms of C4A and C4B gene variants in 129 European ancestry patients with schizophrenia or schizoaffective disorder. We did not find predicted C4A or C4B expression to be nominally associated with TD risk or severity. However, we found the number of copies of C4BL to be nominally associated with TD severity (p = 0.020).

Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia.

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

New insights into tardive dyskinesia genetics: Implementation of whole-exome sequencing approach

Tardive dyskinesia (TD) is an adverse movement disorder induced by chronic treatment with antipsychotics drugs. The contribution of common genetic variants to TD susceptibility has been investigated in recent years, but with limited success. The aim of the current study was to investigate the potential contribution of rare variants to TD vulnerability.In order to identify TD risk genes, we performed whole-exome sequencing (WES) and gene-based collapsing analysis focusing on rare (allele frequency < 1%) and putatively deleterious variants (qualifying variants). 82 Jewish schizophrenia patients chronically treated with antipsychotics were included and classified as having severe TD or lack of any abnormal movements based on a rigorous definition of the TD phenotype. First, we performed a case-control, exome-wide collapsing analysis comparing 39 schizophrenia patients with severe TD to 3118 unrelated population controls. Then, we checked the potential top candidate genes among 43 patients without any TD manifestations. All the genes that were found to harbor one or more qualifying variants in patients without any TD features were excluded from the final list of candidate genes.Only one gene, regulating synaptic membrane exocytosis 2 (RIMS2), showed significant enrichment of qualifying variants in TD patients compared with unrelated population controls after correcting for multiple testing (Fisher's exact test p = 5.32E−08, logistic regression p = 2.50E−08). Enrichment was caused by a single variant (rs567070433) due to a frameshift in an alternative transcript of RIMS2. None of the TD negative patients had qualifying variants in this gene. In a validation cohort of 140 schizophrenia patients assessed for TD, the variant was also not detected in any individual. Some potentially suggestive TD genes were detected in the TD cohort and warrant follow-up in future studies. No significant enrichment in previously reported TD candidate genes was identified.To the best of our knowledge, this is the first WES study of TD, demonstrating the potential role of rare loss-of-function variant enrichment in this pharmacogenetic phenotype.

PND84 FACTORS THAT IMPACT HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH TARDIVE DYSKINESIA: REGRESSION ANALYSES OF DATA FROM THE REAL-WORLD RE-KINECT STUDY

RE-KINECT, an ongoing study of tardive dyskinesia (TD) in antipsychotic-treated outpatients, includes 2 cohorts: patients with visible uncontrollable movements that are clinician-confirmed as possible TD (C2); and patients with no visible movements or with non-TD movements (C1). Data from the EuroQoL 5-Dimension 5-Level (EQ-5D-5L) questionnaire, administered before cohort assignment, were analyzed to assess health-related quality of life (HRQoL) in C2 vs. C1 and the effects of possible TD on HRQoL (C2 only). To eliminate non-TD as a confounding factor, patients who presented with (or reported having) any uncontrollable movements not confirmed as TD were excluded from C1. A linear regression model (adjusted for confounding factors: age, gender, overall health, psychiatric severity, functional status, psychiatric diagnosis) was used to analyze the difference in EQ-5D-5L utility score (0=health state equivalent to death; 1=perfect health) between C2 (n=204) and C1 (n=450). Analyses were also conducted based on C2 patients who rated themselves as having “a lot” of overall TD severity (n=53) or “a lot” of TD impact on daily activities (n=41). In C2, the effects of TD severity (patient-rated, clinician-rated) and TD impact (patient-rated) on EQ-5D-5L utility were analyzed. The difference (±SE) between C2 and C1 was significant for EQ-5D-5L utility (-0.04±0.02, P<0.05). Larger significant differences were found when the model was limited to C2 patients with “a lot” of TD severity (-0.09±0.03; P<0.001) or TD impact (-0.15±0.03, P<0.001). EQ-5D-5L utility was most strongly associated with patient-rated TD impact (-0.021, P<0.001), followed by patient-rated TD severity (-0.028, P<0.05]). No significant association was found between EQ-5D-5L utility and clinician-rated TD severity (-0.007, P>0.05), which was significantly lower (less severe) than patient-rated severity (difference±SE: -0.28±0.12, P<0.05). TD is associated with measurably worse HRQoL, especially from the perspective of patients versus clinicians and particularly in patients who self-reported greater TD severity/TD impact.

RE-KINECT, A REAL-WORLD, PROSPECTIVE TARDIVE DYSKINESIA SCREENING STUDY: AN EVALUATION OF BASELINE CHARACTERISTICS IN OLDER PATIENTS

Introduction Older age is a risk factor for developing tardive dyskinesia (TD), a persistent movement disorder associated with prolonged exposure to antipsychotics. In older patients, TD symptoms may appear after shorter antipsychotic treatment. RE-KINECT (NCT03062033), a real-world study of outpatients prescribed antipsychotics, was designed to identify the presence of drug-induced involuntary movements consistent with TD (i.e., “possible TD”) and to characterize the impact of these movements on health-related quality of life. Baseline data from RE-KINECT were analyzed to explore the patient experience of possible TD and how it affects functioning in older adults (≥55 years). Methods Adults with ≥3 months of lifetime exposure to antipsychotics and ≥1 psychiatric disorder were recruited. The presence of possible TD was based on clinicians’ observation and assessment of involuntary movements in 4 body regions (head/face, trunk/neck, upper extremities, and lower extremities). Patients were categorized into Cohort 1 (without visible movements or possible TD) or Cohort 2 (with visible movements and confirmed by clinician as consistent with possible TD). Baseline outcomes for all patients included demographics, clinical history, patient-reported health status (score range, 0 [“no health problems”] to 10 [“health as bad as you can imagine”]), and the patient-reported EuroQoL 5-Dimensional 5-Level questionnaire (EQ-5D-5L; domain score range, 1 [no problems or symptoms] to 5 [extreme problems or symptoms]). Clinicians also assessed the location and severity (ratings, “none”, “some”, or “a lot”) of abnormal movements in Cohort 2 patients. Exploratory statistical testing was conducted between older adults (≥55 years) in Cohorts 1 and 2. Results Of the 738 patients enrolled in the study, the results of those ≥55 years (N=300, 41%) are presented here. Within this subgroup, 114 (38%) had clinician-confirmed possible TD (Cohort 2) and 186 (62%) had no visible movements or had movements that were inconsistent with TD (Cohort 1). In Cohort 2 patients, the highest frequencies of severe abnormal movements (severity rating: “a lot”) were observed in the head/face (25%) and upper extremities (14%). Cohort 2 patients were less likely to be married, more likely to live in care homes, and were more likely to have longer lifetime exposure to antipsychotics than Cohort 1 patients (Table). More patients in Cohort 2 had schizophrenia or schizoaffective disorder, while those in Cohort 1 were more likely to have a mood disorder. Patients in Cohort 2 also had slightly higher mean EQ-5D-5L scores at baseline in four EQ-5D-5L domains, suggesting a somewhat greater impact on health-related quality of life, particularly in the domain of self-care. Conclusions Results from this real-world sample of older psychiatric outpatients suggest that the greater risk and severity of TD in this population may be associated with more limited support systems and reduced quality of life, which are separate from the effects of age itself. This research was funded by This research was fully funded by Neurocrine Biosciences, Inc.

77 Long-term Valbenazine Treatment in Patients with Schizophrenia/Schizoaffective Disorder or Mood Disorder and Tardive Dyskinesia

AbstractBackgroundPatients 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 &lt;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.

The use of clozapine and clonazepam co-administration in the treatment of a severe tardive dyskinesia: A case report

This is a case report of a patient who was treated with clozapine and clonazepam after he developed neuroleptic-induced tardive dyskinesia following treatment for schizophrenia. There are reports of clozapine treatment itself causing tardive dyskinesia; however, more reports have shown clozapine’s benefit for patients with neuroleptic-induced tardive dyskinesia. This is a case report of a patient with neuroleptic-induced tardive dyskinesia who benefitted from clozapine treatment with adjuvant use of clonazepam – the first such case report from Ethiopia. A 43-year-old male patient developed severe involuntary abnormal body movements mainly involving the trunk after he received chlorpromazine for 8 years for the diagnosis of schizophrenia. When the movement disorder became intolerable and disabling, the diagnosis of severe neuroleptic-induced tardive dyskinesia was established and the patient was started on clozapine with adjuvant clonazepam treatment. Following such management, the patient responded well and the dyskinetic movements were fully controlled, and the patient was able to work. Patients with severe and disabling neuroleptic-induced tardive dyskinesia can be treated and be productive if they receive treatment with clozapine, with adjuvant use of clonazepam.

Characterizing Treatment Effects of Valbenazine for Tardive Dyskinesia: Additional Results From the KINECT 3 Study.

In the KINECT 3 (NCT02274558; October 2014 to September 2015) study, valbenazine efficacy in tardive dyskinesia (TD) was demonstrated based on mean changes from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7). Data from this study were analyzed further to provide a more clinically meaningful interpretation of the primary AIMS results. The study included adults who had a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or any mood disorder and also met DSM-IV criteria for neuroleptic-induced TD. Study participants received 6 weeks of double-blind treatment with valbenazine (40 or 80 mg/d) or placebo. Post hoc AIMS analyses, based on available data, included Cohen d effect sizes, response analyses with odds ratios (ORs) and numbers needed to treat (NNTs), and shift analyses. At week 6 (N = 202), medium-to-high effect sizes were found for mean improvements in AIMS total score (40 mg/d, d = 0.52; 80 mg/d, d = 0.89). For AIMS total score responses of ≥ 10% to ≥ 70% improvement from baseline, statistical significance was found for valbenazine 80 mg/d versus placebo (P ≤ .01), with ORs (range, 3.0-10.3) and NNTs (range, 3-9) indicating clinical relevance. For response per AIMS item (score ≤ 1 at week 6), significant differences between valbenazine (both doses or 80 mg/d) and placebo were found in the lips, jaw, tongue, and upper extremities. In participants who had an AIMS item score ≥ 1 at baseline, the percentage with a ≥ 1-point improvement at week 6 (shift) was significantly higher with valbenazine (40 and/or 80 mg/d) versus placebo in all 7 body regions. Consistent with primary published results for KINECT 3, these supplemental analyses indicate that participants treated with valbenazine (40 or 80 mg/d) had statistically significant and clinically relevant improvements in TD severity both overall and in specific body regions. ClinicalTrials.gov identifier: NCT02274558.