Abnormal Involuntary Movement Scale Research Articles

F45. THE EFFICACY AND SAFETY OF BLONASERIN AFTER SWITCHING FROM OTHER ATYPICAL ANTIPSYCHOTICS IN SCHIZOPHRENIC INPATIENTS: AN OPEN-LABEL, MULTI-CENTER TRIAL

BackgroundThe aim of this study was to investigate the efficacy and safety of blonanserin treatment after switching from other atypical antipsychotics in schizophrenic inpatients who showed inadequate efficacy and poor tolerability.MethodsA total of 63 schizophrenic inpatients (inadequate response group=45 and poor tolerability group=18) were included in this study. They were already treated with atypical antipsychotics except blonanserin and not favored due to inadequate responses or intolerable adverse effects. Blonanserin was administered during 12 weeks after switching from their previous antispsychotics. Treatment response was evaluated with Brief Psychiatric Rating Scale (BPRS) and CGI-S, and safety profile were measured with Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Extrapyramidal Side effects Scale (SAR)S and Barnes Akathisia Rating Scale (BARS). Drug Attitude Inventory (DAI-10) and Subjective Well-being Under Neuroleptic Treatment (SWN) were used for subjective estimates. Assessments were done at baseline, 1, 2, 4, 8 and 12 weeks after blonanserin treatment. Repeated measures of ANOVA were done to analyze the group (inadequate vs. intolerable group) and time effects.ResultsCGI and BPRS were showed significant treatment responses after switching to Blonaserin. Time effects were significant at 2, 4, 8, 12 weeks after switching and group by time effect were also significant at that time. Mean changes of AIMS, SARS and BARS scores were not significant throughout test trial. Although SWN was significantly improved after switching to Blonaserin, it was not found significant group by time effect.DiscussionThe results suggest that blonanserin may be effective and well tolerable in schizophrenic patients who showed inadequate treatment response or poor tolerability.

T7. PHARMACOGENETIC OF TARDIVE DYSKINESIA -- A FOLLOW-UP ON THE VALBENAZINE TARGET VMAT2/SLC18A2

BackgroundTardive dyskinesia (TD) is a motor side effect that may arise after long-term treatment of antipsychotic drugs. Its etiology is not well understood, but a number of risk factors have been associated with TD. TD occurrence appears to be familial, thus suggesting a genetic component. We previously reported on an association between the SLC18A2 gene that codes for the vesicular monoamine transporter 2 (VMAT2) that packages monoamines including dopamine from the cytoplasm into synaptic vesicles (Zai et al, 2013). In the present study, we examined the dopamine transporter gene SLC6A3 by itself and in conjunction with SLC18A2 for possible association with TD.MethodsWe genotyped and analyzed the variable-number tandem repeat (VNTR) polymorphism in the 3’ untranslated region of the SLC6A3 gene in our European sample of 187 schizophrenia/schizoaffective disorder patients assessed for TD occurrence based on the Abnormal Involuntary Movement Scale (AIMS). We also explored the interaction between the VNTR and the TD-associated SLC18A2 marker rs363224.ResultsOur preliminary analysis did not show the SLC6A3 VNTR to be associated with TD occurrence or severity. There also appeared to be no significant interaction between SLC6A3 VNTR and SLC18A2 rs363224 in TD occurrence or severity (p>0.05).DiscussionOur findings did not support a major role of the dopamine transporter gene in TD risk or severity, but we will examine additional putative functional markers in this gene.

F225. LEVODOPA AUGMENTATION OF ANTIPSYCHOTICS FOR THE TREATMENT OF NEGATIVE SYMPTOMS IN SCHIZOPHRENIA

BackgroundNegative symptoms (i.e., motivation deficits and diminished emotional expression) are prevalent in schizophrenia and consistently linked with functional impairment for affected individuals. Despite advances in psychopharmacology for schizophrenia, there remain no effective treatments for these negative symptoms. Older literature, however, suggests that levodopa in conjunction with antipsychotic treatment can have beneficial effects for patients with schizophrenia. While supporting the safety and potential efficacy of dopamine augmentation, these studies did not evaluate effects within specific symptom domains, particularly negative symptoms. This open-label pilot study was conducted to evaluate the preliminary efficacy and safety of levodopa augmentation of antipsychotics for the treatment of negative symptoms.MethodsTen stable outpatients with schizophrenia between the ages of 18 and 60 were enrolled. All were treated with stable atypical antipsychotic monotherapy for at least eight weeks, and had a minimum total score of 30 on the Scale for the Assessment of Negative Symptoms (SANS). Participants were treated with adjunctive open-label levodopa/carbidopa, with dose titration to levodopa 300mg TID over 38 days as tolerated, and dose maintenance for the remainder of the eight-week trial. Baseline assessments consisted of the SANS, Scale for the Assessment of Positive Symptoms (SAPS), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), Calgary Depression Scale for Schizophrenia (CDSS), MATRICS Consensus Cognitive Battery (MCCB), and Quality of Life Scale (QLS) for community functioning. Treatment side effects were evaluated with the Simpson Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), UKU side effect rating scale (UKU), Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), Yale-Brown Obsessive Compulsive Scale (YBOCS), and Barratt Impulsiveness Scale (BIS). Participants were reassessed on measures of psychosis and side effects weekly for the first four weeks, and every two weeks thereafter. The SANS and CGI were repeated at weeks 4 and 8, with the MCCB and QLS re-administered at week 8. Statistical analyses included the intent-to-treat sample (i.e., participants who received at least one dose of study medication) and consisted of linear mixed models for change in SANS total score (our primary outcome), and change in other clinical and side effects measures as a result of treatment.ResultsEnrolled participants (eight male and two female) had a mean age of 37.2 years. Seven participants completed the study, with three participants dropping out. The mean final dose of levodopa for study completers was 835.7 mg (SD 170.1). Levodopa augmentation resulted in a significant improvement in negative symptoms, with a mean SANS reduction for study completers of 15.3 (SD 5.7). This equated to a mean SANS improvement of 25.5% (range 17% to 57%), with 43% of study completers experiencing > 20% improvement in SANS score. Notably, significant improvement in negative symptoms emerged after the first four weeks of treatment. There was no significant change in positive symptoms, nor other clinical outcomes or side effect measures.DiscussionOur findings suggest that levodopa augmentation of antipsychotics may be an effective and well-tolerated treatment for negative symptoms in schizophrenia. These findings, however, need replication in larger randomized controlled trials. With the dearth of available treatments for negative symptoms, levodopa augmentation may represent a novel pharmacologic strategy to address this critical unmet therapeutic need for schizophrenia.

Zuklopentiksol dekanoattan paliperidon palmitata geçiş sonrasında tardiv diskinezide düzelme: Bir olgu sunumu

Long-acting injectable (LAI) antipsychotics are an effective option in schizophrenia that increase treatment adherence in potentially non-compliant patients. Tardive dyskinesia is a potentially treatment-resistant movement disorder that can be a problem after long-term antipsychotic use. Atypical antipsychotics with long-acting formulations offer a safer option for acute extrapyramidal side effects, but their effect in tardive dyskinesia is not clear. We report a case of tardive dyskinesia of the perioral area and the tongue after long-term use of zuclopenthixol decanoate, a LAI antipsychotic is a potent dopamine (D2) receptor antagonist. The patient was a 45-year-old Caucasian male with a 25-year history of schizophrenia who was using olanzapine and zuclopenthixol decanoate at the index consultation when the dyskinesia was recognized. Chlorpromazine, haloperidol, olanzapine, and quetiapine were the antipsychotics that had been used for differing periods in addition to zuclopenthixol decanoate over the last six months, before the emergence of tardive dyskinesia. The Abnormal Involuntary Movements Scale was used in scoring the oropharyngeal dyskinesia. Because of the patient’s former non-compliance with oral medication and concerns of treatment adherence, we planned to continue using LAI. After switching to paliperidone palmitate, a second generation LAI with receptor-antagonist effects for dopamine (D2), serotonin (5HT-2), and noradrenaline (NE-alpha2) receptors, we observed the improvement of the tardive dyskinesia.

Calcium channel blockers for antipsychotic-induced tardive dyskinesia.

Schizophrenia and related disorders affect a sizable proportion of any population. Antipsychotic medications are the primary treatment for these disorders. Antipsychotic medications are associated with a variety of adverse effects including tardive dyskinesia. Dyskinesia is a disfiguring movement disorder of the orofacial region that can be tardive (having a slow or belated onset). Tardive dyskinesia is difficult to treat, despite experimentation with several treatments. Calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil, flunarizine) have been among these experimental treatments. To determine the effects of calcium channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses. We searched the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information. We selected randomised controlled trials comparing calcium channel blockers with placebo, no intervention or any other intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness who remained on their antipsychotic medication. We independently extracted data and estimated risk ratios of dichotomous data or mean differences (MD) of continuous data, with 95% confidence intervals (CI). We assumed that people who left the trials early had no improvement. We also created a 'Summary of findings' table using GRADE. Previous versions of this review included no trials. From the 2015 search, we identified three cross-over trials that could be included. The 2017 search found no new studies relevant to this review. The included trials randomised 47 inpatients with chronic mental illnesses in the USA and China. Trials were published in the 1990s and were of short duration (six to 10 weeks). Overall, the risk of bias was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, and attrition and outcome data were not fully reported. Findings were sparse, no study reported on the primary outcome 'no clinically important improvement in tardive dyskinesia symptoms,' but two small studies (37 participants) found no difference on the tardive dyskinesia symptoms scale Abnormal Involuntary Movement Scale (AIMS) scores between diltiazem or flunarizine and placebo after three to four weeks' treatment (MD -0.71, 95% CI -2.68 to 1.26, very low quality evidence). Only one study randomising 20 participants reported on adverse events, and reported that there were no adverse events with flunarizine or with placebo (very low quality evidence). One study with 18 participants reported no events of deterioration in mental state with diltiazem or with placebo (very low quality evidence). No studies reported on acceptability of treatment or on social confidence, social inclusion, social networks or personalised quality of life outcomes designated important to patients. Available evidence from randomised controlled trials is extremely limited and very low quality, conclusions cannot be drawn. The effects of calcium channel blockers for antipsychotic-induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well-designed randomised trials.

Rating Scales for Motor Symptoms and Signs in Huntington's Disease: Critique and Recommendations.

Motor symptoms are a major feature of Huntington's disease (HD). The International Parkinson and Movement Disorder Society (MDS) commissioned the assessment of the clinimetric properties of motor rating scales in HD to make recommendations regarding their use, following previously established standardized criteria. After a systematic literature search, a total of 6 rating scales assessing motor symptoms and signs in HD were included for review. Performance testing (reviewed elsewhere) and quantitative motor rating methods were excluded. Only the Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) was classified as "recommended" for assessing the severity of motor signs in HD. The following scales were classified as "suggested": Abnormal Involuntary Movement Scale, the UHDRS-TMS4, the Quantified Neurological Examination, and the Marsden and Quinn Chorea Severity Scale. The committee also concluded that further assessment of existing rating scales, including the UHDRS-TMS, is necessary to determine sensitivity to change and to screening for the presence of motor signs specific to HD. There is also a need to develop a motor rating scale to be used in positive gene carriers with subtle but not definite motor signs.

A Study on Drug-Induced Tardive Dyskinesia: Orofacial Musculature Involvement and Patient’s Awareness

Schizophrenia is a psychiatric disorder that requires long-term treatment. Long-term antipsychotic treatment is often associated with the emergence of tardive dyskinesia (TD), the severity of which is measured by Abnormal Involuntary Movement Scale (AIMS). This study examined the relationship among TD, orofacial musculature activity, and patient's awareness of AIM. The knowledge would help dentists to deliver oral care for schizophrenics with TD. We identified 317 patients from a standard, data sharing initiative, of whom 38.3% exhibited AIM score of 2 to 15. The patient demographics, drug history, details of AIMS were subjected to descriptive and inferential statistical analysis using SPSS with P≤0.05 as significance. The mean of only orofacial features (n = 56) was 3.43 ± 2.68. Muscles of facial expression was involved in nine (7.9% of all TD), lip/perioral area in 27 (23.68%), jaw in 52 (45.61%), and tongue in 77 (67.54%). The patient's perception of AIM precipitated stress when involving jaw, tongue, limbs, and trunk was statistically significant (P≤0.05). The multiple regression model statistically significantly predicted TD for factors considered. Around 1% of global population is being diagnosed with schizophrenia, carry an inherent risk of developing TD. They might have orodental care requirements, including prosthodontic and restorative services. Primary physicians and dentists need to be aware of TD and its mechanism for appropriate patient management.

The Effects of Valbenazine in Participants with Tardive Dyskinesia: Results of the 1-Year KINECT 3 Extension Study.

Valbenazine, a highly selective vesicular monoamine transporter 2 inhibitor, is approved for the treatment of tardive dyskinesia. This is the first report of long-term effects in adults with tardive dyskinesia. Participants with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or a mood disorder who completed the 6-week, double-blind, placebo-controlled period of KINECT 3 were eligible to enter the 42-week valbenazine extension (VE) period and subsequent 4-week washout period. The extension phase was conducted from December 16, 2014, to August 3, 2016. Participants who received placebo and entered the VE period were re-randomized 1:1 to valbenazine 80 or 40 mg while others continued valbenazine at the KINECT 3 dose. Safety assessments included treatment-emergent adverse events (TEAEs) and scales for suicidal ideation/behavior, treatment-emergent akathisia or parkinsonism, and psychiatric symptoms. Efficacy assessments included the Abnormal Involuntary Movement Scale (AIMS) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD). 198 participants entered the VE period, 124 (62.6%) completed treatment (week 48), and 121 (61.1%) completed the follow-up visit after washout (week 52). During the VE period, 69.2% of participants had ≥ 1 TEAE, 14.6% had a serious TEAE, and 15.7% discontinued due to a TEAE. During washout, 13.1% of participants experienced a TEAE. No apparent risk for suicidal ideation or behavior was found. Long-term valbenazine treatment did not appear to induce or worsen akathisia or parkinsonism. Participants generally remained psychiatrically stable during the study. AIMS and CGI-TD measures indicated sustained tardive dyskinesia improvement, with scores returning toward baseline after 4 weeks of valbenazine washout. The long-term safety and tolerability of valbenazine were generally favorable, and maintenance of treatment effect was apparent with both doses during this long-term study. ClinicalTrials.gov identifier: NCT02274558.

Botulinum toxin A for patients with orofacial dystonia: prospective, observational, single-centre study

The objective of this study was to demonstrate the efficacy of intramuscular botulinum toxin type A (BTX-A) as a method of controlling the symptoms of focal facial dystonia. A prospective, longitudinal, observational, pre–post (case-series) single-centre study was conducted over a period of 3 months, involving 30 patients with focal dystonia. The patients were enrolled on a first-come, first-served basis. For all patients, the abnormal movements were evaluated using the Abnormal Involuntary Movement Scale (AIMS). The AIMS results were recorded immediately before BTX-A injection (primary predictor variable) and after 3 months (the toxin reaches its maximum effect 2 weeks after injection, and the effect is maintained for 3 months). An improvement in AIMS score was the primary outcome variable. Treatment efficacy was evaluated using the Pearson correlation index with a level of significance of P<0.05. The average age of the study subjects was 70.9±12.7years (20 female, 10 male). The mean dose of BTX-A used was 27.4±20.5U. The mean improvement in AIMS score after treatment was 5.2±4.2. A significant correlation was found between the dose applied and the reduction in AIMS score (P<0.05). BTX-A can be used in the treatment of focal dystonia and provides reproducible results.

Frequency and correlates of tardive dyskinesia in Indian patients with type I bipolar disorder.

Patients with Bipolar Disorder (BD) may have higher risk of Tardive Dyskinesia (TD). Theories for TD include inflammatory or oxidative stress and altered iron metabolism. The current frequency and clinical and biochemical correlates of TD in BD needs exploration. To assess: (1) the frequency of TD in BD; (2) clinical correlates of TD in BD; (3) oxidative stress markers, inflammatory markers and hepcidin in TD in BD. In this cross-sectional study, 170 patients with BD were assessed for clinical characteristics using structured assessments. Inflammatory and oxidative markers like Interleukin-6 (IL-6), high sensitivity C-Reactive Protein (hsCRP), malondialdehyde (MDA), Total Antioxidant Status (TAS) and hepcidin were assessed by ELISA. Frequency of TD was 10.6% (95%C.I.=6.4%-16.2%). Compared to patients without TD, patients with TD were older (F=0.340;p=0.000), had more episodes of illness (U=962.5;p=0.044) higher rates of medical comorbidity (X2=6.924; p=0.009*), antipsychotic exposure (U=592.5;p=0.000), typical antipsychotic exposure (U=756.5;p=0.001) and cognitive deficits (F=1.129;p=0.001). The biomarkers levels did not differ between the groups. Hepcidin levels correlated with Abnormal involuntary Movements scale (AIMS) score (r=0.213;p=0.006). Patients treated with lithium were more likely to have TD, but also had greater exposure to antipsychotics than patients on valproate. About one-tenth of patients with BD-I have TD. The presence of TD is associated several clinical characteristics such as age, exposure to typical antipsychotics and chronicity of illness. Hepcidin was associated with greater severity of dyskinetic movements and needs further exploration.

Deutetrabenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

Deutetrabenazine is a deuterated formulation of tetrabenazine. The aim of this systematic review is to describe the efficacy, tolerability and safety of deutetrabenazine for the treatment of tardive dyskinesia (TD). The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'deutetrabenazine' OR 'SD-809', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information. All available clinical reports of studies were identified. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. Deutetrabenazine, a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2), received approval for the treatment of TD in adults based on a clinical trial development programme that included two 12-week parallel group, randomised and placebo-controlled studies. Deutetrabenazine dose is determined individually for each patient based on reduction of TD and tolerability. The recommended starting dose of deutetrabenazine for TD is 6mg BID, administered with food, and can be increased at weekly intervals in increments of 6mg/day to a maximum recommended daily dosage of 24mg BID. The percentage of responders in the fixed-dose Phase III acute study, as defined by a rating of "much improved" or "very much improved" on the clinical global impression of change, was 46% for deutetrabenazine (pooled dose groups 12 and 18mg BID) vs 26% for placebo, yielding a NNT of 5 (95% CI 3-19); the percentage of responders as defined by an improvement in Abnormal Involuntary Movement Scale (AIMS) severity score (sum of items 1-7) of 50% or more, was 34% for deutetrabenazine (pooled dose groups 12 and 18mg BID) vs 12% for placebo, yielding a NNT of 5 (95% CI 3-11). Pooling the data across both short-term studies, NNT for AIMS response for the therapeutic doses of deutetrabenazine vs placebo was 7 (95% CI 4-18). Discontinuation because of an adverse event occurred among 3.6% of patients randomised to deutetrabenazine (any dose) vs 3.1% for placebo, yielding a NNH of 189 (not significant). The Likelihood to be Helped or Harmed comparing success (AIMS response) vs discontinuation because of an adverse event is 27. The most common adverse reactions (that occurred in ≥4% of deutetrabenazine-treated patients with TD and greater than placebo) were nasopharyngitis and insomnia, with NNH values of 50 (not significant) and 34 (95% CI 18-725), respectively. Deutetrabenazine is the second FDA-approved agent specifically indicated for the treatment of TD. Head-to-head comparisons with other VMAT2 inhibitors among patients with TD in the "real world" are needed.

A Cross-Sectional Study on the Characteristics of Tardive Dyskinesia in Patients with Chronic Schizophrenia.

BackgroundTardive dyskinesia (TD) is an abnormal involuntary movement disorder caused by patients’ long-term use of antipsychotic medication. It diminishes the social functioning of patients with mental disorders, thereby affecting their compliance with antipsychotic medication. The cause and nosogenesis of TD remains unclear; furthermore, because the presentation differs greatly among individuals it often goes undiagnosed or can be easily misdiagnosed. The present study aims to evaluate the abnormal movement patterns in patients with TD, and analyze the differences among different TD patterns, in order to seek effective methods of preventing, diagnosing and treating TD.AimsTo describe the movement patterns of patients with chronic schizophrenia with TD, and analyze their clinical characteristics and risk factors.MethodsA cross-sectional study was carried out on a psychiatric unit of the Xuhui Mental Health Center with inpatients who had chronic schizophrenia as participants. Abnormal Involuntary Movement Scale (AIMS) was employed to screen for patients with schizophrenia who also had TD. These patients’ movement disorders were evaluated, and they were divided into groups based on their movement patterns. Positive and Negative Syndrome Scale (PANSS) was used to assess the psychotic symptoms of patients, collect clinical information, compare the differences between the two groups and analyze the clinical characteristics and risk factors of TD.Results(1) A total of 448 patients met the inclusion criteria for chronic schizophrenia with 46 in the TD group and 402 in the control group. After the TD group and the control group was compared, significant differences were seen between the two groups in gender, age, total duration of illness, age of onset, dosage of antipsychotic medication (daily chlorpromazine equivalent), factor scores of negative symptoms on PANSS and PANSS total scores. (2) It was possible that age, factor scores of negative symptoms in PANSS, the amount of antipsychotic medication used (daily chlorpromazine equivalent) and gender are correlated with the occurrence of TD. (3) There were significant differences among the number of TD patients with movement disorders in facial and oral areas (67.4%), limbs (58.7%) and torso (37%). The AIMS scores corresponding with movement disorders in different parts of the body were also significantly different. (4) Comparing TD patients with single affected area and those with multiple affected areas, we found that they had significant differences in gender, age of onset, AIMS total scores, severity scores of abnormal movements and loss of range due to abnormal movements.Conclusion(1) Compared to the control group, the TD group had more men, was older, had a longer duration of illness, later age of onset, generally took a higher dosage of antipsychotic medication and presented with more severe negative symptoms. It is possible that age, factor scores of negative symptoms on PANSS, dosage of antipsychotic medication (daily chlorpromazine equivalent) and gender are correlated with the occurrence of TD. (2) The occurrence of movement disorders in facial and oral areas for patients with chronic schizophrenia with TD was the most frequent, and the symptoms were the most severe. (3) Compared to TD patients with a single affected area, TD patients with multiple affected areas may have an earlier age of onset, more severe movement disorders, and more setbacks in their movement and functioning.

P.5.d.009 - Predictive genetic model for levodopa-induced dyskinesia in patients with Parkinson’s disease

Predictive genetic model for levodopa-induced dyskinesia in patients with Parkinson's disease S.A. Ivanova(1), V.M. Alifirova(2), M.B. Freidin(3), I.V. Pozhidaev(4), O.Y. Fedorenko(4), N.A. Bokhan(4), I.A. Zhukova(5), N.G. Zhukova(5), B. Wilffert(6), A.J.M. Loonen(6) (1)Mental Health Research Institute, Molecular Genetics and Biochemistry Laboratory, Tomsk, Russia (2)Siberian State Medical University, Department of Neurology and Neurosurgery, Tomk, Russia (3)Tomsk National Research Medical Center of the Russian Academy of Sciences, Research Institute of Medical Genetics, Tomsk, Russia (4)Tomsk National Research Medical Center of the Russian Academy of Sciences, Mental Health Research Institute, Tomsk, Russia (5)Siberian State Medical University, Department of Neurology and Neurosurgery, Tomsk, Russia (6)University of Groningen, Groningen Research Institute of Pharmacy, Groningen, The Netherlands Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with levodopa (L-DOPA). The use of this drug, however, is severely limited by adverse effects. Levodopa-induced dyskinesia (LID) is one of these and characterized by involuntary muscle movements that occur as a consequence of chronic levodopa treatment. LID is a substantial barrier to effective symptomatic management of PD as up to 45% of L-DOPA users develop LID within 5 years [1]. Clinical heterogeneity of LID suggests a significant role of endogenous factors in determining their prevalence. Some evidences suggest a relationship between LID and specific genetic variants, such as polymorphisms in the genes controlling enzymes responsible for drug and monoamine metabolism, neurotransmitter receptors and proteins involved in oxidative stress or antioxidant function [2–4]. Objective: To investigate a contribution of polymorphic variants of neurotransmitter receptors and cytochrome genes in the development of LID in PD patients. Methods: A total of 212 PD patients who received L-DOPA therapy were studied. Dyskinesia was assessed by using the Abnormal Involuntary Movement Scale (AIMS). DNA extraction and genotyping were conducted according to standard protocols and blind to the clinical status of the subjects. Genotyping was carried out for 72 SNPs of DRD1, DRD2, DRD2/ANKK1, DRD3, DRD4, HTR2C, HTR3A, HTR3B, HTR6, HTR2A, HTR1A, HTR1B, CYP1A2*1F, CYP2D6*3, CYP2D6*4, CYP2C19*3, CYP2C19*17, CYP2C19*2, and GSTP1 genes using MassARRAY® Analyzer 4 (Agena Bioscience™) and the set SEQUENOM Consumables iPLEX Gold 384. Discriminant analysis and receiver operating curve (ROC)-analysis were carried out to build a genetic predictive model for dyskinesia. Results: Group of PD patients consists of 149 females and 83 males (age ranging from 40 to 86 years, average age 68.7 ± 7.6 years). The mean age of onset is 60.04 ± 9.46 years, average disease duration is 9.79 ± 5.57 years. Dyskinesia was reported in 57 (26.9%) patients. The best discriminant model was obtained with the following predictors: rs11721264, rs165774, rs3758653, rs4245147, rs6313, rs1364043, rs2734849, rs324035, rs6311, rs11246226 and rs4244285. These polymorphisms are localized in the following genes: DRD3 (rs11721264, rs324035), DRD4 (rs3758653, rs11246226), DRD2 (rs4245147, rs2734849), HTR2A (rs6313, rs6311), HTR1A (rs1364043). The discriminant model using this set of SNPs gives the error of classification about 13% and the AUC 0.795. Depending on the anticipated frequency of LID, positive and negative predictor values varied between 0.745–0.834 and 0.864–0.916, respectively. We hypothesized in our previous studies that the pathological basis of LID might be degeneration of indirect pathway medium spiny neurons [5]. These indirect pathway medium spiny neurons carry type 2 family dopamine receptors (DRD2, DRD3, DRD4), and HTR2A receptors. Moreover, dopamine release may be promoted by inhibiting serotonergic neurotransmission. Hence, the current findings are well in line with this hypothesis. Conclusion: The resulting panel of 11 SNPs provides a sufficiently high accuracy of LID prediction. The use of this panel in a prospective study will clarify the prospects for its application in clinical practice for predicting risk of LID in patients with PD.

P.1.a.025 - Dopamine receptors genes polymorphisms in Parkinson patients with levodopa-induced dyskinesia

Dopamine receptors genes polymorphisms in Parkinson patients with levodopa-induced dyskinesia I. Pozhidaev(1), V.M. Alifirova(2), M.B. Freidin(3), I.A. Zhukova(2), O.Y. Fedorenko(1), D.Z. Osmanova(1), Y.S. Mironova(2), B. Wilffert(4), S.A. Ivanova(1), A.J.M. Loonen(5) (1)Mental Health Research Institute, Molecular Genetics and Biochemistry, Tomsk, Russia (2)Siberian State Medical University, Neurology and Neurosurgery, Tomsk, Russia (3)Research Institute for Medical Genetics, Laboratory of Population Genetics, Tomsk, Russia (4)Groningen Research Institute of Pharmacy, Pharmacotherapy and Clinical Pharmacology, Groningen, The Netherlands (5)Groningen Research Institute of Pharmacy, Pharmacotherapy in Psychiatric Patients, Groningen, The Netherlands Introduction: Long-term levodopa treatment of Parkinson's disease (PD) is frequently complicated by spontaneously occurring involuntary muscle movements called levodopa-induced dyskinesia (LID). LID are a substantial barrier to effective symptomatic management of Parkinson's disease (PD), as up to 45% of L-DOPA users develop LID within 5 years [1]. The exact pathological mechanism of this complication has not yet been elucidated. A lot of studies nowadays which approved complex genetic nature of LID. And these genes are involved not only for oxidative stress, but in drug metabolism too [2–4]. Objective: This study aimed to investigate a possible contribution of polymorphic variants of DRD1, DRD2, DRD2/ANKK1, DRD3, DRD4 genes in the development of LID in PD patients. Methods: 212 patients with Parkinson's disease on levodopa therapy were investigated. Dyskinesia was measured by using Abnormal Involuntary Movement Scale (AIMS). DNA extraction and fluorogenic 5′-exonuclease TaqMan genotyping assays were conducted according to standard protocols and blind to clinical status of the subjects. Genotyping was carried out on 28 SNPs of dopamine receptors (rs4532, rs936461, rs6275, rs1801028, rs4245147, rs134655, rs6277, rs1076560, rs2283265, rs179997, rs6279, rs1076562, rs2734842, rs2734849, rs11721264, rs167770, rs3773678, rs963468, rs7633291, rs2134655, rs9817063, rs324035, rs1800828, rs167771, rs6280, rs1587756, rs3758653, rs11246226) on the MassARRAY® Analyzer 4 (Agena Bioscience™) using the set SEQUENOM Consumables iPLEX Gold 384. SPSS software was used for statistical analysis. Statistical significance of the association testing was established using permutations. P-value <0.05 after permutations was considered statistically significant. Results: Patients in our cohort demonstrated typical PD demographics, with a mean age of onset of 60.04 ± 9.46 years, a mean disease duration of 9.79 ± 5.57 years. Dyskinesia was reported in 57 (26.9%) patients. The distribution of genotypes of studied genes corresponded to the Hardy-Weinberg equilibrium. We found that 5 polymorphisms (rs4245147, rs6275, rs2734842, rs6279, rs1076562) are significantly associated with LID. All these polymorphisms are located in DRD2 gene. In logistic regression models adjusted for the covariates, such as age, gender and duration of disease only one of the studied markers was associated with LID (rs4245147). Odds ratio for carriers of the genotype TT is 1.73 [95% CI: 1.12–2.70], which indicates the predisposing effect of this genotype on the development of dyskinesia. Polymorphisms in the dopamine receptors genes play significant role in the therapy response to L-DOPA as well as in various of its adverse effects. We hypothesized that single nucleotide polymorphisms in DR genes may result in a clinical phenotype contributing to an increased risk of LID. This appears to be especially true for rs4245147 of the DRD2 gene. Hence, this gene polymorphism is a good candidate for studying (genetic) biomarkers predicting the risk of developing this movement disorder. Conclusion: Rs4245147 polymorphism of the DRD2 gene is a putative component of a set of biomarkers predicting the vulnerability to develop dyskinesia.

P.3.d.028 - Potential biomarkers of tardive dyskinesia: a multiplex analysis of blood serum

Potential biomarkers of tardive dyskinesia: a multiplex analysis of blood serum A.S. Boiko(1), E.G. Kornetova(2), S.A. Ivanova(1), A.J.M. Loonen(3) (1)Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Laboratory of Molecular Genetics and Biochemistry, Tomsk, Russia (2)Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Department of Endogenous Disorders, Tomsk, Russia (3)University of Groningen, Groningen Research Institute of Pharmacy, Groningen, The Netherlands Long-term antipsychotic treatment of schizophrenia is associated with the emergence of tardive dyskinesia (TD), a motor syndrome consisting of involuntary and hyperkinetic movements [1]. Pathogenesis of this drug-induced movement disorder is not yet fully established, but may be connected to oxidative stress-related indirect pathway neurotoxicity [2]. Dysregulations in immune, hormonal and neurotrophic systems have been postulated to be one of the mechanisms underlying this form of neurotoxicity [3,4]. Principle aims of translational psychiatric research are searching for biomarkers which can be used to diagnose pathological biochemical processes and to identify molecular targets for treatment as well as development of pharmacogenetic approaches to personalize this therapy. The aim is to study potential endocrine, neurotrophic and immunological markers of tardive dyskinesia in the blood serum of patients with schizophrenia with antipsychotic therapy. Methods: After obtaining approval of the study protocol by the local ethical committee, suitable participants were recruited from psychiatric hospitals. All subjects gave informed consent after proper explanation of the study. TD was assessed cross-sectionally by the use of the Abnormal Involuntary Movement Scale (AIMS) [1,5]. The concentrations of cortisol, brain-derived neurotrophic factor (BDNF), prolactin, cytokines (tumor necrosis factor (TNFa), interleukin 1 (IL-1β), interleukin 3 (IL-3), interleukin 6 (IL-6), interferon gamma (INF-γ) and S100β were measured in blood serum using the MILLIPLEX® MAP panels (Merck, Darmstadt, Germany) by the multiplex analyzer MAGPIX (Luminex, USA). Statistical analyses were performed using SPSS software for Windows. Results were expressed as median and quartile intervals (Me [Q1; Q3]) or mean and standard deviation (M ± SD). Differences were considered significant at p ≤ 0.05. Results: In total 180 patients with schizophrenia, 128 males and 52 females (age 39.2 ± 12.1 years), receiving long-term antipsychotic treatment were included. These patients were divided into two groups: 71 patients with tardive dyskinesia and 109 patients without this movement disorder. A significant (p = 0.04) decrease in BDNF concentration was observed in patients with TD (1.9 [1.01; 2.99] ng/ml) in comparison to patients without TD (2.66 [1.29; 3.89] ng/ml). An increase (p = 0.05) of the serum IL-6 level of patients with TD (5.69 [3.55; 7.4] pg/ml) was detected relative to patients without TD (4.69 [2.82; 6.13] pg/ml). In addition, a statistical trend (p = 0.06) of increased serum S100β concentration was found in TD patients (85.29 ± 5.53 ng/L) compared to patients without this side effect (75.14 ± 2.81 ng/L). No other significant differences were established concerning the other assayed biomarkers. Conclusions: The biological processes that might play a role in the development of TD are not confined to the human brain per se. Hormonal and immune systems are also involved, which may be related to these systems being closely interrelated. Furthermore, these parameters may provide information about risk factors of the movement disorder. Identifying markers that can be used as diagnostics or predictors of treatment response in people with tardive dyskinesia will be an important step towards being able to provide personalized treatment.

Prevalence and pattern of antipsychotic induced movement disorders in a tertiary care teaching hospital in India – a cross-sectional study

Objectives: To assess prevalence and pattern of movement disorders among patients taking antipsychotic medications.Methods: This cross-sectional, intensive monitoring (patient interview, case record form review and clinical examination) study was conducted in patients taking antipsychotic drugs irrespective of duration for the development of movement disorders. The psychiatrist used Modified Simpson-Angus Scale score (10-item scale), Barnes’ rating scale and Abnormal Involuntary Movement Scale to diagnose parkinsonism, akathisia and tardive dyskinesia, respectively. We assessed movement disorders for the preventability and seriousness.Results: The overall prevalence of antipsychotic induced movement disorders was 5.67% (95% CI: 4.19–7.62). The prevalence of parkinsonism, akathisia and tardive dyskinesia was 5.10% (95% CI: 3.71–6.98), 0.85% (95% CI: 0.39–1.84) and 0.57% (95% CI: 0.22–1.45), respectively. There was a trend of high proportions of movement disorders in extreme of age group, female gender, patients treated with conventional antipsychotics, on poly therapy, patients of epilepsy with psychosis, schizophrenia and bipolar mood disorder. The movement disorder was lowest with quetiapine (2.02%).Conclusions: The higher use of atypical antipsychotics had reduced the occurrence of movement disorders in our setup.

Novel Compound Shows Promise in Treating Negative Symptoms of Schizophrenia

Novel Compound Shows Promise in Treating Negative Symptoms of Schizophrenia

Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia.

The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia. The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia. A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score. MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial

Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses. We aimed to assess the efficacy, safety, and tolerability of fixed doses of deutetrabenazine-a novel vesicular monoamine transporter-2 inhibitor-in patients with tardive dyskinesia. We did this double-blind, randomised, placebo-controlled, phase 3 trial at 75 centres in the USA and Europe. Patients aged 18-80 years with tardive dyskinesia (≥3 months before screening) were randomly assigned centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomisation was stratified by baseline use of dopamine receptor antagonists. Patients were started on oral deutetrabenazine 12 mg/day, and this dose was increased through week 4 until the randomised dose was achieved, then maintained over 8 weeks. During the treatment period, patients, investigators, their site personnel, and sponsor were masked to group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to week 12 in patients with at least one post-baseline rating. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at least one post-baseline rating). The safety analysis was done in patients who received any study drug. This trial is registered with ClinicalTrials.gov, number NCT02291861. Between Oct 29, 2014, and Aug 19, 2016, we randomly assigned 298 patients to receive at least one dose of placebo (n=74), deutetrabenazine 12 mg/day (n=75), 24 mg/day (n=74), or 36 mg/day (n=75); 222 patients comprised the modified intention-to-treat population and 293 patients comprised the safety population. From baseline to week 12, the least-squares mean AIMS score improved by -3·3 points (SE 0·42) in the deutetrabenazine 36 mg/day group, -3·2 points (0·45) in the 24 mg/day group, and -2·1 points (0·42) in the 12 mg/day group, with a treatment difference of -1·9 points (SE 0·58, 95% CI -3·09 to -0·79; p=0·001), -1·8 points (0·60, -3·00 to -0·63; p=0·003), and -0·7 points (0·57, -1·84 to 0·42; p=0·217), respectively, versus -1·4 points (0·41) in the placebo group. The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 [51%]), 24 mg/day group (n=32/73 [44%]), and 12 mg/day group (n=36/74 [49%]), and those in the placebo group (n=34/72 [47%]). Serious adverse events were reported in four (5%) patients given deutetrabenazine 36 mg/day, six (8%) patients given 24 mg/day, and two (3%) patients given 12 mg/day, compared with four (6%) patients given placebo. Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor. Deutetrabenazine 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with favourable safety and tolerability. These findings suggest that dosing regimens could be individualised and tailored for patients on the basis of dyskinesia control and tolerability. Teva Pharmaceutical Industries.

Adjunctive Melatonin for Tardive Dyskinesia in Patients with Schizophrenia: A Meta-Analysis.

BackgroundTardive dyskinesia (TD) is characterized by abnormal and involuntary movements. Importantly, TD could cause considerable personal suffering and social and physical disabilities.AimsThis meta-analysis based on randomized controlled trials (RCTs) systematically assessed the therapeutic effect and tolerability of melatonin for TD in schizophrenia.MethodsA computerized and systematical search of both Chinese (Wanfang Data, Chinese National Knowledge Infrastructure (CNKI), SINOMED) and English (PubMed, PsycINFO, Embase, Cochrane Library databases) databases, from their inception until June 8, 2017, was conducted by two independent authors. The severity of TD symptoms were the primary outcome measure and analyzed using a random effects model by the Review Manager (RevMan) Version 5.3. Quality evaluation of included RCTs was conducted using the Cochrane risk of bias and Jadad scale. The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system recommendation grading method was used to assess the overall quality level of meta-analytic outcomes.ResultsFour RCTs (n=130) were identified and analyzed. Three RCTs used double blind and 1 RCT used masked assessors using the Cochrane risk of bias, and 3 RCTs were rated as high quality based on Jadad scale. Compared with the control group, adjunctive melatonin was superior in reducing the severity of TD as measured by the Abnormal Involuntary Movement Scale (AIMS) (4 RCTs, n=130, weighted mean difference (WMD): -1.52 (95% confidence intervals (CI): -3.24, 0.20), p=0.08; I2=0%) although the improvement did not reach a significant level. The overall evidence quality of the improvement of TD symptoms, according to GRADE approach, was rated as “Low”. The data on the ADRs and cognitive effect were limited.ConclusionsThis meta-analysis shows that melatonin has potential for improving TD symptoms in schizophrenia. Future higher quality and larger RCTs are warranted to confirm the findings.