Abnormal Involuntary Movement Scale Research Articles

P.3.a.014 - Gene polymorphism of dopaminergic, serotoninergic and glutamatergic receptors and tardive dyskinesia in schizophrenia

Introduction: For over six decades, antipsychotic drugs have remained the mainstay of schizophrenia treatment. Tardive dyskinesia (TD) is a potentially irreversible antipsychotic-induced. movement disorder with a prevalence of about 20-30% in psychiatric patients chronically exposed to antipsychotics. TD can be dissected into two distinct subsyndromes: orofaciolingual (TDof, involves movements of mouth and face) and limb-truncal dyskinesias (TDlt, involves purposeless choreiform movements of trunk and/or limbs) which probably have different genetic liability [1]. TD in schizophrenic patients is associated with poor outcome and TD patients may suffer from more physical or psychological problems. The genetic basis of pathogenesis of TD is thought to be primarily related to dopamine dysregulation. Genes of other neurotransmitter systems are less investigated [2,3]. Aim: Study the association between antipsychotic-induced TD and a set of 43 tag single nucleotide polymorphisms (SNPs) from dopaminergic, serotoninergic and glutamatergic receptors genes GRIN2A, GRIN2B, DRD3, DRD4, and HTR2C in schizophrenic patients in Russian population. Methods: 431 Russian patients with schizophrenia were investigated. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale (AIMS). TD of and TDlt were assessed with AIMS items 1-4 and 5-7, respectively. The DNA extraction and genotyping of 43 polymorphisms of GRIN2A, GRIN2B, DRD3, DRD4, and HTR2C genes were conducted using Veracode Assay according to standard protocols. All calculations were performed in the R statistical environment with the SNPassoc package and basic R functions. Results and Discussion: Significant associations were found between five SNPs encoding three receptors: GRIN2B (rs220599, P = 0.04451), GRIN2A (rs11646587, P = 0.04652; rs7206256, P = 0.03570); rs1345423, P = 0.01043)), DRD3 (rs167770, P = 0.01751) and TDof. Also significant associations were found between six SNPs of two receptors GRIN2A (rs1345423, P = 0.02504; rs7190619, P = 0.04292; rs9788936, P = 0.04020; rs11644461, P = 0.03875), DRD3 (rs963468, P = 0.01533; rs167770, P = 0.012236) and TDlt. Moreover, significant associations were found in four specific SNPs encoding three receptors GRIN2B (rs2192970, P = 0.005411), GRIN2A (rs1345423, P = 0.015210) and DRD3 (rs324035, P = 0.03211; rs167770, P = 0.02197). Only rs1345423 in GRIN2A was significantly associated with overall TD in studied group of schizophrenic patients. No associations between polymorphism of receptors genes DRD4 and HTR2C were revealed. It is thought that TD is primarily related to DA dysregulation. Antipsychotic treatment with both serotoninergic HTR2A and HTR2C antagonists resulted in a lower annual incidence of TD [4]. This finding led to the hypothesis that HTR2A and HTR2C activate GABAergic interneurons [5], within the cerebral cortex, basal ganglia and mesencephalic areas, resulting in decreased dopaminergic activity. Hence, HTR2A and HTR2C antagonism increases dopamine release. Our results do not differ much from those found in relevant meta-analyses, which led us to propose that genetically determined variations of dopamine type 2 receptors and/or dopamine type 2 receptor signaling are unlikely to affect the sensitivity to TD. Conclusion: We suggest that mechanism other than HTR2- induced augmentation of dopamine release is responsible for explaining the lower incidence of TD after treatment with atypical antipsychotics.

P.5.d.005 - CYP2D6 and catechol-O-methyltransferase gene polymorphisms in Parkinson patients with levodopa-induced dyskinesias

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). Use of this drug, however, is severely limited by the development of side effect. Levodopa-induced dyskinesias (LID) are involuntary muscle movements that occur as a consequence of chronic levodopa (L-DOPA) treatment. LID are a substantial barrier to effective symptomatic management of Parkinson's disease (PD), 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 evidence suggest a relationship between LID and specific genetic changes, such as changes 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 contribution of polymorphic variants of CYP2D6 and COMT genes in the development of LID in PD patients. Methods: 212 patients with Parkinson's disease on levodopa therapy were investigated. Dyskinesias were estimated with use of Abnormal Involuntary Movement Scale (AIMS). DNA extraction and fluorogenic 5'-exonuclease TaqMan genotyping assays were conducted according to standard protocols and blind to the clinical status of the subjects. Genotyping was carried out on 2 SNPs of CYP2D6 (CYP2D6∗3, rs35742686; CYP2D6∗4, rs3892097) and 7 SNPs of COMT genes (rs4680, rs6269, rs4633, rs4818, rs769224, rs165774, rs174696). The SPSS software was used for statistical analysis. 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. Dyskinesias were reported in 57 (26.9%) patients. The distribution of genotypes of studied genes corresponded to the Hardy-Weinberg equilibrium. Association of polymorphisms in CYP2D6 gene with side effects was not revealed. We found that rs4680 polymorphism in COMT gene is significantly associated with LID (χ2 = 6.048, p = 0.049). Odds ratio for carriers of the genotype AA is 2.14 [95% CI: 1.11- 4.11], which indicates the predisposing effect of this genotype on the development of dyskinesias. Rs4680 is a functional SNP in genes encoding the catechol-O-methyltransferase enzyme, which catabolizes dopamine. A valine to methionine substitution at codon 158 of the COMT gene produces a Met variant that catabolizes dopamine up to four times slower than its Val counterpart. Conclusions: Polymorphisms in the COMT gene play significant role in the therapy response to L-DOPA as well as in various adverse effects. COMT is an extracellular enzyme which inactive variants increase the extracellular concentration of dopamine. This may increase the uptake of dopamine by indirect pathway MSN and therefore increase oxidative stress. We hypothesized that functional single nucleotide polymorphism rs4680 in COMT gene may result in a clinical phenotype contributing to an increased risk of LID. Thus, the polymorphism of gene possessing predisposing effects in development of levodopa induced dyskinesia in PD has been revealed that would allow predicting risk of development of movement disorders.

Uzun süreli ve yatırılarak izlenen şizofreni hastalarında tardiv diskinezi

Objective: Tardive dyskinesia (TD) is a group of delayed-onset iatrogenic movement disorders caused by dopamine receptor-blocking agents. TD prevalence is estimated as 20-50% of all patients treated with neuroleptics. This study aimed to investigate the prevalence rate of TD in long-term hospitalized patients with schizophrenia. Method: We recorded age, gender, duration and type (first/second generation or mixed) of medication both at the time of interview and over preceding years. Dyskinesia was assessed by using the Abnormal Involuntary Movements Scale (AIMS). We also used the Simpson–Angus Scale for tardive parkinsonism. Akathisia was measured using the Barnes Akathisia Rating Scale (BARS). Results: Mean duration of the longest used antipsychotic was 206.63 months. Probable TD was found in 18 (22.5%) of patients. None of the patients had tardive akathisia. Relation between type of the longest used treatment and prevalence of TD was not statistically significant. Relationship between type of ongoing treatment and prevalence of TD was not determined statistically significant either. There was a statistically significant relationship between the mean age and TD. Discussion: Despite very long duration of antipsychotic use, 22.5% rate of prevalence is still lower than expected. This can be explained that these patients are under direct and close follow-up of healthcare providers and in hospital conditions, so that risky conditions can be intervened rapidly. Another noteworthy finding of our study is that there is no statistically significant difference betwen first and second generation antipsychotic use and TD prevalence.

Efficacy and Tolerability of Paliperidone Extended-release in the Treatment of First-episode Psychosis: An Eight-week, Open-label, Multicenter Trial.

ObjectiveWe investigated the efficacy and tolerability of paliperidone extended-release (ER) tablets in patients with first-episode psychosis (n=75).MethodsThis was an 8-week, open-label, multicenter trial. The primary outcome variable was scores on the Positive and Negative Syndrome Scale (PANSS); secondary measures included the Scale for the Assessment of Negative Symptoms (SANS), the Cognitive Assessment Interview (CAI), and the Global Assessment of Functioning (GAF). To assess safety, we measured drug-related adverse events, weight, lipid-related variables, and prolactin and administered the Simpson–Angus Rating Scale (SARS), the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale (BAS), the Arizona Sexual Experiences Scale (ASEX), and the Udvalg for Kliniske Undersogelser side effect rating scale (UKU).ResultsThe administration of paliperidone ER resulted in significant improvement in the PANSS, SANS, CAI, and GAF scores (p<0.001) over time. This improvement was evident as early as 1 week. The most frequent adverse events were akathisia, somnolence, anxiety, and sedation, which were well tolerated. Modest increases in weight and lipid profiles were also noted. Prolactin levels were substantially increased at the endpoint in both male and female patients.ConclusionThese results indicate that paliperidone ER is effective and is characterized by good tolerability in the treatment of positive and negative symptoms and cognitive functioning in first-episode psychosis.

Efficacy of Quetiapine Monotherapy in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial.

This was a 12-week randomized, placebo-controlled trial to assess the efficacy of quetiapine monotherapy in the treatment of posttraumatic stress disorder (PTSD). Eighty patients were randomly assigned to treatment with either quetiapine or placebo. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Secondary efficacy measures included the CAPS subscales, the Davidson Trauma Scale, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scales for severity of Illness and improvement, the Hamilton Depression Rating Scale (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A). Safety measurements included adverse events, vital signs, the Abnormal Involuntary Movement Scale, the Barnes Akathisia Scale, the Simpson-Angus Scale, and the Arizona Sexual Experiences Scale. After a 1-week placebo run-in, quetiapine was started at a daily dosage of 25 mg and increased to a maximum of 800 mg; the average was 258 mg (range, 50-800 mg). Reductions in CAPS total, re-experiencing, and hyperarousal scores were significantly greater for the quetiapine group than for the placebo group. Greater improvements were also observed for quetiapine in scores on the Davidson Trauma Scale, CGI severity and improvement ratings, PANSS positive symptom and general psychopathology subscales, HAM-A, and HAM-D than for placebo. Adverse events were generally mild and expected based on prior studies of quetiapine in this and other patient population. There were no differences in safety measures between groups. Quetiapine monotherapy was efficacious in the treatment of PTSD. These findings suggest quetiapine as a single agent is effective in treating military PTSD.

Abnormal involuntary movements are linked to psychosis-risk in children and adolescents: Results of a population-based study

BackgroundAltered motor behavior has consistently been reported in medication-naive adult patients with schizophrenia and first episode psychosis and adults at clinical high risk for psychosis (CHR). This study is the first to evaluate the prevalence of abnormal involuntary movements in a community sample of children and adolescents with and without CHR. MethodsWe examined CHR in 102 children and adolescents aged 8–17years from the general population of the Canton Bern. Attenuated and brief intermittent psychotic symptoms, as well as basic symptoms, were assessed using the Structured Interview for Psychosis Risk Syndromes and the Schizophrenia Proneness Instrument, Child & Youth Version. Motor symptoms were assessed using the Abnormal Involuntary Movement Scale (AIMS). Additionally, psychosocial functioning, a neurocognitive test battery, and DSM-IV Axis I disorders were examined. ResultsEleven (10.8%) participants met CHR criteria, 13 (12.7%, 5 with and 8 without CHR) met criteria for increased abnormal involuntary movements (AIMS≥2). Both AIMS total scores and the percentage of children with AIMS≥2 were significantly higher in the CHR group. Psychosocial functioning was reduced in subjects with abnormal involuntary movements, and movement abnormalities were linked to deficits in attention and perception but not to the presence of non-psychotic mental disorders. ConclusionsOur findings suggest that abnormal involuntary movements are linked to psychosis risk in children and adolescents from the general population. Thus, abnormal involuntary movements might represent an additional useful and easily accessible predictor of psychosis.

Adenosine Hypothesis of Antipsychotic Drugs Revisited: Pharmacogenomics Variation in Nonacute Schizophrenia.

The existing antipsychotic therapy is based on dopamine hyperfunction and glutamate hypofunction hypotheses of schizophrenia. Adenosine receptors (ADORA) have a neuromodulatory role and can control dopaminergic and glutamatergic systems. To elucidate the effect of ADORA polymorphisms on psychopathological symptoms and adverse effects in patients with schizophrenia on long-term antipsychotic treatment, we examined 127 nonacute schizophrenia outpatients in a cross-sectional study using the Positive and Negative Symptoms Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale. All patients were genotyped for 18 polymorphisms in ADORA1, ADORA2A, and ADORA3. We found an association between ADORA1 rs3766566 and psychopathological symptoms (p = 0.006), in particular, with positive psychopathological symptoms (p = 0.010) and general psychopathological symptoms (p = 0.023), between ADORA2A rs2298383 and general psychopathological symptoms (p = 0.046), and between ADORA2A rs5751876 and akathisia (p = 0.015). Haplotype analysis showed an association between ADORA1 CTCAACG haplotype and overall psychopathological symptoms (p = 0.019), positive psychopathological symptoms (p = 0.021), and akathisia (p = 0.028). ADORA2A TCCTC haplotype was associated with parkinsonism (p = 0.014). ADORA3 CACTAC was associated with akathisia (p = 0.042), whereas CACTAT was associated with akathisia (p = 0.045) and tardive dyskinesia (p = 0.023). The results of this first comprehensive study on ADORA polymorphisms in patients with nonacute schizophrenia receiving long-term antipsychotic therapy suggest an important neuromodulatory role of ADORA receptors in both psychopathological symptoms and adverse effects of antipsychotics.

Tardive dyskinesia in mentally retarded patients under long-term antipsychotic treatment

Objective: Tardive dyskinesia (TD) is an iatrogenic movement disorder, developing due to prolonged use of dopamine receptor blocking agents, that may affect various parts of the body. In a number of studies, prevalence rates between 5 and 30% have been reported. This study aims to research TD in patients with mental retardation who have been hospitalized for a long time and medicated regularly. Method: Included in this study were 40 patients with a diagnosis of mental retardation comorbid with schzophrenia or other psychotic disorders according to DSM-IV TR that had been hospitalized in the chronic patients’ ward of Bakirkoy Training and Research Hospital for Psychiatry, Neurology and Neurosurgery for a long period. Duration and type of antipsychotics both at the time of interview and over the preceding years were recorded. Dyskinesia was assessed using the Abnormal Involuntary Movements Scale (AIMS). We also used the Simpson–Angus Rating Scale (SAS) for Parkinsonism. Akathisia was measured using the Barnes Akathisia Rating Scale (BARS). Results: According to AIMS scores, 9 participants (22.5%) received a diagnosis of TD. There was no significant correlation between the type and duration of ongoing or the longest used treatment and the prevalence of TD. There was a statistically significant correlation between the participants’ age and TD (p=0.009). There were no gender differences for TD Conclusion: We found that long-term use of antipsychotics is unrelated with TD, while age is an important risk factor for TD. It can be said that switching from first generation to second generation antipsychotics does not reduce the prevalence of TD.

Intercultural adaptation of the AIMS in German language: A scale for abnormal involuntary movements

Dyskinesias are abnormal involuntary movements and occur across many movement disorders. In Parkinson's disease dyskinesias can be troublesome and are a determinant of the quality of life throughout the course of the disease. Assessment and rating of dyskinesias is thus important for clinical assessment of patients, as well as for academic studies and clinical trials. The abnormal involuntary movement scale (AIMS) is an English language standardised, reliable and validated scale to evaluate dyskinesias. In this article we present a linguistically validated German version of AIMS. The intercultural adaptation of the German translation was performed following an internationally accepted procedure. Firstly, two neurologists independently translated the original into German. Taking both versions into account, a consensus version was agreed on by both translators and was tested on 10 patients. This preliminary German version was then independently translated back into the original language by two different neurologists, and again, a consensus version was agreed on. All translators then compared this English version to the original. Subsequently, the German version was linguistically modified until it resulted in a final German version, which was agreed on by all translators, deemed linguistically acceptable, and the translation back into English was considered to be as unambiguous as possible. This final German version of AIMS was applied to 50 patients in two different hospitals for diagnostic purposes and tested for feasibility and comprehension. In this paper, we present an intercultural adaptation of a linguistically validated German version of AIMS.

Extract of Ginkgo biloba for Tardive Dyskinesia: Meta-analysis of Randomized Controlled Trials.

Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). We conducted this meta-analysis to systematically examine the efficacy of extract of Ginkgo biloba (EGb), a potent antioxidant possessing free radical-scavenging properties, as a treatment for TD in schizophrenia using randomized controlled trial (RCT) data. Drawn from English and Chinese databases, 3 RCTs of EGb augmentation of antipsychotics (APs) vs. AP plus placebo or AP monotherapy were identified. 2 evaluators extracted data. The primary outcome measure was the severity of TD symptoms assessed by the Abnormal Involuntary Movement Scale (AIMS). Weighted mean difference (WMD) and risk ratio (RR) ±95% confidence intervals (CI) were calculated. Statistical analyses were performed using Review Manager (version 5.1.7.0) and STATA (version 12.0). The 3 RCTs (n=299) from China, of 12 weeks duration, involved schizophrenia patients with TD of 55.9±13.4 years old. EGb (240 mg/day) outperformed the control group in reducing the severity of TD and clinical symptoms as measured by the AIMS (trials=3, n=299, WMD: -2.30 (95%CI: - 3.04, -1.55), P<0.00001) and the adverse drug reactions as assessed by the Treatment Emergent Symptom Scale (TESS) (trials=2, n=142, WMD: -2.38 (95%CI: -4.01, -0.74), P=0.004). Both the Positive and Negative Syndrome Scale (PANSS) total score (trials=2, n=239, P=0.87) and all-cause discontinuation (trials=3, n=299, P=0.21) were similar between the EGb and control group. This meta-analysis suggests that adjunctive EGb appeared to be an effective and safe option for improving TD in the treatment of schizophrenia patients. However, better RCTs are needed to demonstrate its efficacy and safety especially on cognitive function in TD. CRD42015024930.

Drug-induced tardive dyskinesia: A case report

IntroductionTardive dyskinesia (TD) is a serious medical condition that affects a significant proportion of patients treated with antipsychotic agents.ObjectiveTo report a patient who developed tardive dyskinesia after initiation of antipsychotic and antidepressant treatment.Case reportMiss H. is 24-year-old Tunisian woman who had been diagnosed with bipolar disorder 6 years ago. She received various drugs: olanzapine, haloperidol, amisulpride, sertraline, paroxetine, etc. On November 2013, she first complained of hand tremor and then developed severe dystonia of the trunk and chorea. A series of laboratory tests was performed after the onset of these involuntary movements. It included complete blood count, liver, renal, and thyroid function tests, blood prolactin level, blood glucose level, blood copper level and ceruloplasmin level. A brain MRI was also performed. These examinations showed no specific findings. The diagnosis of TD was presumed. The patient was first treated with amisulpride, lorazepam, avlocardyl and piracetam until May 2014. Then, amisulpride was substituted by olanzapine until August 2015. The luck of improvement led to her admission. We stopped antipsychotic treatments and prescribed her vitamin E (900 mg/day), clonazepam (6 mg/day) and vitamin B6. The follow-up led to the decline of the Abnormal Involuntary Movement Scale (AIMS) score of 7 points over 6 weeks.ConclusionTD remains a serious side effect that worsens the prognosis and affects the quality of life of patients. Cluster randomised trial should be done in order to develop practice recommendations for prevention and management of TD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The validity of observer-based scales in the measure of drug-induced motor symptoms in a spanish sample of patients with severe mental disorders

BackgroundAntipsychotic drugs are effective in schizophrenic disorders, but they are also used to treat other psychiatric conditions. Typical antipsychotics cause important extrapyramidal symptoms (EPS), which frequently result in non-compliance with antipsychotic medication. It has been stated that the second-generation antipsychotics (atypical) provoke EPS side effects less frequently than typical antipsychotics. However, there is some controversy around this statement, especially because of inefficient measures of EPS. Clinical assess of EPS normally relies upon observer-based ratings, but their reliability and validity has not been consistently established.ObjectiveIn the present work, we have explored the convergent and discriminant validity of the Abnormal Involuntary Movement Scale (AIMS) and the Simpson-Angus Scale (SEE), in a Spanish sample of patients with severe mental disorders. Patients could be under typical or atypical antipsychotics, antidepressants, benzodiacepines, or a combination of these.MethodSixty-one patients with severe mental disorders from the Mental Health Day Hospital of St. Agustín (Linares, Spain) participated in the study. Inclusion criteria were DSM-V diagnosis of schizophrenia or schizophrenic disorder, bipolar, or borderline personality disorders, and age between 18-61. In order to explore the discrimination capacity of each rating scale, Receiver Operator Characteristic (ROC) analyses were conducted.ResultsROC curves indicated a suitable construct validity of the scales in the measurement of drug-induced motor symptoms. However, the scales were not sensitive to the number of years under treatment.ConclusionsIn line with previous research, our results question the use of rating scales as the only measure in the evaluation of EPS symptoms.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder, Part 3: Clinical Trial Data.

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients who develop abnormal movements during treatment with antipsychotics. The first column in the series presented a patient who developed abnormal movements while being treated with aripiprazole as an augmentation strategy for major depressive disorder (MDD) and reviewed data concerning the historical background, incidence, prevalence, and risk factors for tardive and spontaneous dyskinesias, the clinical presentations of which closely resemble each other. The second column in the series reviewed the unique mechanism of action of aripiprazole and preclinical studies and an early-phase human translational study that suggest a low, if not absent, risk of TD with aripiprazole. This column reviews clinical trial data to assess whether those data support the conclusion that aripiprazole has a low to absent risk of causing TD when used as an augmentation strategy to treat MDD. To date, no randomized, placebo-controlled trials have established a definitive link between exposure to aripiprazole and TD in patients with MDD. One long-term, open-label, safety trial examined aripiprazole as an augmentation strategy in individuals with MDD and found a rare occurrence (4/987, 0.4%, the confidence interval of which overlaps with zero) of an adverse event termed TD. In all 4 cases, the observed movements resolved within weeks of aripiprazole discontinuation, suggesting that they were either amenable to treatment or represented an acute syndrome rather than TD. No cases of TD were reported in the registration trials for the MDD indication for aripiprazole. These data were presented in a pooled analysis of three, 14-week studies involving 1088 subjects, 409 of whom were elderly like the 76-year-old individual presented in the case in the first column of this series. Finally, 3 short-term studies evaluated the use of aripiprazole in patients with psychosis associated with Alzheimer disease, a population who would be considered a relatively higher risk group for developing TD when exposed to antipsychotics and that also closely matches the patient in the case presented at the beginning of this series in terms of age. No incidence of TD was reported in this sample and mean scores on the Abnormal Involuntary Movement Scale decreased in individuals exposed to aripiprazole compared with those on placebo. On the basis of results of this review and data from registration trials of aripiprazole for all indications, the potential (or raw) incidence of what was termed TD occurred at rates ranging from 0.004 (4/987) based on long-term safety data from the program investigating aripiprazole augmentation treatment in MDD, to 0.0016 (19/11,897) based on the total safety database from aripiprazole registration trials for all indications, to 0 in trials in elderly individuals with Alzheimer disease. The confidence intervals for all of these potential incidence rates overlap with zero. The next column in this 5-part series reviews 37 case reports that reported TD in association with aripiprazole treatment and 27 case reports that suggested an improvement in preexisting TD with aripiprazole treatment. The fifth and final column in this series will discuss the types of prohibitively expensive and logistically difficult studies that would be needed to determine whether a definitive causal relationship between aripiprazole and TD exists.

Do patients with late-stage Parkinson's disease still respond to levodopa?

BackgroundLate-stage Parkinson’ disease (PD) is dominated by loss of autonomy due to motor and non-motor symptoms which can be marginally corrected by medications adjustments. However, controversy exists on the mechanisms underlying the apparent decrease of benefit from levodopa. ObjectiveTo study the response to levodopa in late-stage PD (LSPD). Methods20 LSPD patients (Schwab and England ADL Scale <50 or Hoehn Yahr Stage >3 in MED ON) and 22 PD patients treated with subthalamic deep brain stimulation (DBS) underwent an acute levodopa challenge test. MDS-UPDRS-III and the modified Abnormal Involuntary Movement Scale were evaluated in off and after administration of a supra-maximal levodopa dose. ResultsLSPD patients had a median age of 78.8 (IQR: 73.5–82) and median disease duration of 14 years (IQR: 10-19.75). DBS patients had a median age of 66 (IQR: 61-72) and median disease duration of 18 years (IQR: 15-22). LSPD and DBS patients' MDS-UPDRS-III score improved 11.3% and 37% after levodopa, respectively. Rest tremor showed the largest improvement, while axial signs did not improve in LSPD. However, the magnitude of levodopa response significantly correlated with dyskinesias severity in LSPD patients. One third of LSPD and 9% of DBS patients reported moderate drowsiness. ConclusionsLSPD patients show a slight response to a supra-maximal levodopa dose, which is greater if dyskinesia are present, but it is frequently associated with adverse effects. A decrease in levodopa response is a potential marker of disease progression in LSPD.

Long-term efficacy and tolerability of bilateral pallidal stimulation to treat tardive dyskinesia.

To confirm the efficacy and safety of deep brain stimulation (DBS) of the internal part of the globus pallidus in improving severe tardive dyskinesia (TD). Nineteen patients with severe pharmacoresistant TD were included. All were assessed at baseline and at 3, 6 (main outcome measure), and 12 months, and in the long term (6-11 years) for 14 patients, after bilateral pallidal DBS, using motor scales (Extrapyramidal Symptoms Rating Scale [ESRS], Abnormal Involuntary Movement Scale [AIMS]), cognitive scales, and a psychiatric assessment. At 6 months, a double-blind ESRS evaluation was performed in the stimulation "on" and stimulation "off" conditions. At 6 months, all patients had a decrease of more than 40% on the ESRS. The efficacy of the procedure was confirmed by a double-blind evaluation. This improvement was maintained at 12 months (ESRS: decrease of 58% [21%-81%]; decrease of 50% [7%-77%]) and in the long term (ESRS: decrease of 60% [22%-90%]; decrease of 63% [14%-94%], n = 14). All the subscores of the ESRS (parkinsonism, dystonia, and chorea) and of the AIMS (facial, oral, extremities, and trunk movements) improved. Despite psychiatric comorbidities at baseline, cognitive and psychiatric tolerability of the procedure was excellent. No cognitive decline was observed and mood was improved in most of the patients. Pallidal DBS procedure should be considered as a therapeutic option in disabling TD refractory to medical treatment. This study provides Class II evidence that in patients with severe pharmacoresistant TD with implanted pallidal leads, the stimulation "on" condition significantly improved ESRS scores compared to the stimulation "off" condition.

Effect of tricyclic antidepressants on L-DOPA-induced dyskinesia and motor improvement in hemi-parkinsonian rats

Although dopamine replacement therapy with L-DOPA in Parkinson's disease initially reduces motor symptoms, its chronic use often leads to the development of abnormal involuntary movements known as L-DOPA-induced dyskinesia. Increasingly, research has indicated that non-dopaminergic neurons gain function in the parkinsonian brain, taking up and converting L-DOPA to dopamine and releasing it as a “false neurotransmitter”. Although less explored, promiscuity between monoamine transporters may also modulate these processes. Therefore, in order to examine the differential roles of monoamine transporters in L-DOPA's behavioral effects, three tricyclic antidepressants (TCA) with graded affinity for serotonin (SERT) vs. norepinephrine (NET) transporters were tested in hemi-parkinsonian rats: clomipramine (SERT>NET), amitriptyline (SERT=NET), and desipramine (SERT<NET). Rats received 6-hydroxydopamine lesions and were primed with L-DOPA (12mg/kg, s.c.) to develop stable dyskinesia (N=19 of 26). In a series of studies, rats were administered TCAs (0, 7.5, 15 or 30mg/kg, i.p.) followed by L-DOPA (6mg/kg, s.c.) and were measured for dyskinesia using the abnormal involuntary movements scale as well as motor performance and activity using the forepaw adjusting steps test and locomotor chambers, respectively. Clomipramine, the compound with the highest affinity for SERT was most effective in attenuating L-DOPA-induced dyskinesia without altering L-DOPA's stimulatory effects. In contrast, desipramine, the TCA with the highest NET affinity deferred L-DOPA's effects to later time points in testing. The current results indicate divergent roles for non-dopaminergic neuronal transporters in L-DOPA's mechanisms of action and point to novel targets for improving Parkinson's disease treatment.

Effects of soybean ingestion on pharmacokinetics of levodopa and motor symptoms of Parkinson's disease — In relation to the effects of Mucuna pruriens

Mucuna pruriens is a levodopa-containing legume and its favorable effects on motor complications in Parkinson disease patients have been reported. The aim of this study was to investigate the effects of another legume, soybeans, on the pharmacokinetics and metabolism of levodopa. Seven parkinsonian patients with the wearing-off phenomenon and dyskinesia and five healthy volunteers participated in this study. We conducted a crossover study of the clinical effects on the participants before and after taking either levodopa (100mg)/carbidopa (10mg) only (LD/CD) or levodopa/carbidopa with 11g of ground soybeans (LD/CD/soy). Parkinsonism and dyskinesia before and after ingestion of these substances were evaluated using UPDRS partIII, the modified Abnormal Involuntary Movement Scale (mAIMS) and a self-rating scale. The concentrations of plasma levodopa and its major metabolites were measured by high-performance liquid chromatography. Clinical assessment and blood sampling were conducted before and three hours after the ingestion of ground soybeans. When the patients took LD/CD/soy, they had a significantly longer on-period (p=0.028) and a lower mAIMS score (p<0.001). From the comparison of the results of pharmacokinetic study before and after taking LD/CD or LD/CD/soy, the estimated marginal mean (EMM) of HVA after LD/CD/soy increased in the PD group. EMMs of 3-OMD after LD/CD/soy significantly decreased both in PD patients and healthy controls. These results indicate that soy partly increased the bioavailability of levodopa and suppressed levodopa degradation through COMT. Soybeans may have favorable effects on the motor complications occurring under current levodopa therapy. Further investigation to clarify the mechanism underlying such effects is required.

Divalproex sodium leading to sustained significant improvement in tardive dyskinesia in a patient with bipolar disorder.

Byline: Raman. Pattanayak, Deepak. Charan Sir, Not many therapeutic options are available to treat tardive dyskinesia (TD). Usual algorithm involves a reduction of antipsychotic dosage, clozapine, or tetrabenazine. [sup][1] Apart from that, available literature is scant and inconclusive. [sup][2] We report a case where divalproex sodium at a relatively higher serum concentration lead to improvement in TD. A 35-year-old married male with no family history first visited the outpatient clinic in August 2014 with irritable behavior, racing thoughts, referential ideas for 1 week. He had been a known case of bipolar affective disorder [sup][3] (four episodes between 1994 and 2009) and cannabis dependence for 6 months in 2009 (as per subjective and objective corroboration). Between 2009 and 2013, he maintained largely euthymic and occupationally functional while on unknown medications. In December 2013, patient stopped all medications, maintained well for subsequent 8 months until current presentation. He was prescribed aripiprazole 5 mg/day by the treating doctor (pending a detailed assessment), with which remission was achieved. After being on low-dose aripiprazole for 2 months, patient started to experience involuntary movements involving lips, mouth, and jaw. As a result, patient reported feeling inhibited while attending to customers at workplace. Patient presented again in November 2014 for a detailed work-up. He was euthymic. However these movements were present consistently for a month. The movements were noticeable during the interview and an impression of TD was made. On Abnormal Involuntary Movement Scale (AIMS), [sup][4] these were rated as 3 for lips and perioral area (0-4) and 3 for jaw (0-4), three for awareness (0-4) with moderate distress. During that visit, tablet valproate 1000 mg/day was added as prophylaxis for bipolar disorder. Aripiprazole was continued with a plan to stop it later. The patient was compliant to both medications. During his next visit after 10 days, patient and informants reported a significant improvement (of more than 90%) in TD. It was now barely noticeable during the interview. The AIMS rating was 1 for lips/perioral movements (0-3) and 0 for jaws (0-3), and 1 for awareness (0-3) with no accompanying distress. [sup][5] Serum valproate level (12-h postdose) was 134 [micro]g/ml. Clinically, neurological examination was within normal limits. Considering that level was on somewhat higher side, an attempt was made to reduce divalproex sodium to 750 mg/day. However, TD re-surfaced almost at previous intensity, as observed after 2 weeks. Consequently, the dosage was increased to 1000 mg/day, which was well tolerated. During the next 4 months, he continued on both divalproex sodium and aripiprazole, with no TD, and periodic review every 2-4 weeks. Aripiprazole was discontinued in early April 2015. In the same visit, he was shifted to tablet valproate sodium 1000 mg/day (free of cost at hospital's pharmacy). The urinalysis (thin layer chromatography) was negative for cannabis. He was euthymic and free of movements during his recent visit in August 2015. …

Safety and treatment adherence of commonly prescribed typical and atypical antipsychotics in schizophrenic patients in a tertiary care hospital.

Background: Schizophrenia is a chronic mental disorder characterized by delusions, hallucinations, incoherence and physical agitation. Presently available drugs in the treatment of Schizophrenia are typical and atypical antipsychotics which act on various neurotransmitters like Dopamine, Serotonin and Acetylcholine. Though both classes of drugs are effective in treatment, they differ in tolerability and treatment adherence. Hence present study has been taken to compare safety and treatment adherence of typical and atypical antipsychotics.Methods: It was a comparative study conducted on 90 patients of Schizophrenia for one year. The study subjects were randomly assigned into 3 groups of 30 patients each. Group 1 were treated with Risperidone, group 2 with Olanzapineand and group 3 with Haloperidol. Safety was measured by Abnormal involuntary movement scale, Barnes akathisia scale, Simpson angus scale and pattern of adverse effects in each group. Treatment adherence was measured by number of dropout subjects and pill count.Results: Barnes akathisia scale and Simpson angus scale showed one point improvement in Risperidone and Olanzapine group where as one point worsening in haloperidol group. Abnormal involuntary movement scale showed low scores in haloperidol group. Extra Pyramidal symptoms were more common adverse effect in Haloperidol group where as weight gain in Olanzapine and Risperidone group. Pill count was more in Olanzapine group than Risperidone and Haloperidol group.Conclusions: The adverse effect like extrapyramidal symptoms is more common among haloperidol. Weight gain was common in olanzapine treated patients than Risperidone treated patients but treatment adherence was better in Olanzapine treated patients.

Adjunctive use of interferon γ inducer for treatment of patients with schizophrenia

The present paper is devoted to evaluation of clinical and immunomodulatory effect of ultra-high dilutions of antibodies to human interferon γ, included in the complex therapy of patients with schizophrenia. Materials and methods The study was carried out at the Mental Health Research Institute, Tomsk, Russian Federation. This double-blind, placebo-controlled randomised in parallel-group study enrolled 40 patients. As a part of complex therapy, patients from the main group (n=20) received anaferon, a drug containing ultra-high dilutions of affinity-purified antibodies to human interferon γ as the active pharmaceutical ingredient; patients from the comparative group (n=20) received placebo. Duration of the therapy was 30±5 days. Assessment of severity of symptoms and changes in them were made using clinical scales: Positive and Negative Syndrome Scale, Clinical Global Impression, Abnormal Involuntary Movements Scale. Spontaneous and phytohemagglutinin-induced production of interferon γ by immunocompetent cells in supernatants of 48 h whole blood culture of patients was measured by enzyme-linked immunosorbent assay (ELISA) method. The reduction of interferon-producing potential by immunocompetent cells in comparison with reference normal value was shown in total group of patients (n=40) before combined therapy. During the treatment, increase of spontaneous interferon γ production and favourable changes in psychopathological symptoms as compared with placebo were shown in subjects receiving anaferon. It was found that favourable changes in clinical symptoms assessed using clinical scales with a high degree of confidence correlated with high level of spontaneous interferon γ production. Anaferon as a part of complex therapy of patients with schizophrenia contributes to enhancement of its efficacy acting via mechanism of psychoimmunomodulation.