Executive control in schizophrenia: a preliminary study on the moderating role of COMT Val158Met for comorbid alcohol and substance use disorders

Background: A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158Met) appears to influence cognition in people with alcohol/substance use disorders (AUD/SUD) and in those with psychosis.

Methods: To explore the potential moderating effect of these factors, a cross-sectional study was conducted, randomly recruiting subjects with DSM-IV diagnosis of schizophrenia. AUD/SUD was rigorously assessed, as well as COMT Val158Met polymorphism. Executive control functioning was measured using the Intra-Extra Dimensional Set Shift (IED). The effect of a possible interaction between comorbid AUD/SUD and COMT Val158Met polymorphism on IED scores was explored.

Results: Subjects with schizophrenia, comorbid AUD/SUD, and MetMet carriers for SNP rs4680 of the COMT gene showed worse performance on IED completed stages scores, as compared with individuals with ValVal genotype. However, among subjects without AUD/SUD, those with the MetMet variant performed better than people carrying ValVal genotype.

Conclusions: This study is the first to date examining the impact of COMT on cognition in a highly representative sample of people with schizophrenia and comorbid AUD/SUD. Differential moderating effects of COMT Val/Met genotype variations may similarly influence executive functions in people with schizophrenia and comorbid AUD/SUD.     

Manic symptom severity correlates with COMT activity in the striatum: A post-mortem study

Objectives: The enzyme catechol-O-methyltransferase (COMT), which catalyses the degradation of dopamine and norepinephrine, is posited to participate in the pathophysiology of bipolar disorder (BD) and schizophrenia. In support of this notion, rich evidence has documented that the severity of various BD and schizophrenia symptoms is moderated by rs4680, a single nucleotide polymorphism of the COMT gene featuring a valine (Val)-to-methionine (Met) substitution that results in lower catalytic activity. Nevertheless, the specific relevance of COMT enzymatic activity in the pathophysiology of BD and schizophrenia dimensions remains elusive.

Methods: We measured COMT catalytic activity in post-mortem prefrontal cortices, striata and cerebella of schizophrenia and BD patients, as well as non-affected controls. These values were then correlated with rs4680 genotypes and psychopathology scores in the last week of life.

Results: No direct correlation between COMT activity and rs4680 genotypes was found; however, the severity of manic symptoms was highly correlated with COMT activity in the striatum, irrespective of the diagnostic group.

Conclusions: These results suggest that COMT striatal activity, but not rs4680 genotype, may serve as a biomarker for manic symptoms. Future studies are warranted to confirm these findings and assess the neurobiological links between COMT striatal activity and manic symptoms.     

DNA methylation of imprinted loci of autosomal chromosomes and IGF2 is not affected in Parkinson’s disease patients’ peripheral blood mononuclear cells

Objective: Genomic imprinting is an epigenetic phenomenon that results in differential expression of alleles, depending on their parental origin. The functional significance of DNA methylation in genomic imprinting has been widely investigated, and to date, approximately 100 imprinted genes have been identified in humans.

Methods: To investigate whether the methylation status of these ‘known’ imprinting genes was associated with Parkinson’s disease (PD), we analyzed the methylation profiles of all ‘known’ imprinted genes using the Illumina 450K methylation chip. Samples were derived from mononuclear blood cells of 17 male Parkinson’s disease patients vs. 21 healthy male individuals and 12 discordant MZ twin pairs.

Results: None of the annotated autosomal genes show changes in DNA methylation between PD individuals and healthy individuals. We further refined our analysis by evaluating the DNA methylation status of the maternally imprinted human gene encoding insulin-like growth factor 2 (IGF2) using bisulfite sequencing PCR (BSP) of DNA derived from 15 PD patients and 9 controls, taking into consideration different dosages of L-dopa.

Conclusion: Our results demonstrated that methylation of IGF2 in PD patients was neither influenced by the dosage of L-dopa treatment nor by the disease itself. Thus, loss or disruption of imprinting in autosomal chromosomes does not seem to be relevant for the pathogenesis of the disease.     

Elevated mRNA expression of CASPR3 in patients with schizophrenia

Background: Recently, it was reported that antipsychotic treatment reverted Contactin Associated Protein-Like 3 (CASPR3, same as CNTNAP3) mRNA expressions in leukocytes of schizophrenia (SCZ) subjects to the same levels as healthy controls. CASPR3 was expressed in various regions of the mice brain (cortex, frontal lobes, corpus callosum, hippocampus, etc.). Thus, this study evaluated CASPR3 mRNA expression in SCZ subjects to find a new clue of schizophrenia pathogenesis.

Methods: One hundred SCZ subjects and 100 age-matched controls were compared. Levels of CASPR3 mRNA in leukocytes were analysed with a quantitative real-time PCR method using TaqMan probes.

Results: CASPR3 mRNA expression was significantly higher in leukocytes of SCZ subjects than controls. However, there were no significant correlations between expression level and any clinical parameters in 50 SCZ subjects.

Conclusion: Considering that CASPR3 is involved in building the brain neural network and autophagy in circulating leukocytes, abnormal CASPR3 expression in SCZ subjects may be associated with the pathogenesis of SCZ.     

Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia,part III: Molecular mechanisms

Objectives: Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response.

Methods: This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed.

Results: Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition.

Conclusions: Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice.     

High-throughput DNA methylation analysis in anorexia nervosa confirms TNXB hypermethylation

Objectives: Patients with anorexia nervosa (AN) are ideally suited to identify differentially methylated genes in response to starvation.

Methods: We examined high-throughput DNA methylation derived from whole blood of 47 females with AN, 47 lean females without AN and 100 population-based females to compare AN with both controls. To account for different cell type compositions, we applied two reference-free methods (FastLMM-EWASher, RefFreeEWAS) and searched for consensus CpG sites identified by both methods. We used a validation sample of five monozygotic AN-discordant twin pairs.

Results: Fifty-one consensus sites were identified in AN vs. lean and 81 in AN vs. population-based comparisons. These sites have not been reported in AN methylation analyses, but for the latter comparison 54/81 sites showed directionally consistent differential methylation effects in the AN-discordant twins. For a single nucleotide polymorphism rs923768 in CSGALNACT1 a nearby site was nominally associated with AN. At the gene level, we confirmed hypermethylated sites at TNXB. We found support for a locus at NR1H3 in the AN vs. lean control comparison, but the methylation direction was opposite to the one previously reported.

Conclusions: We confirm genes like TNXB previously described to comprise differentially methylated sites, and highlight further sites that might be specifically involved in AN starvation processes.     

Resistin as an inflammatory marker in patients with schizophrenia treated with clozapine

Background: Schizophrenia is associated with excess cardiovascular comorbidity and mortality related to lifestyle factors, such as lack of physical activity, poor diet, and smoking. The prevalence of metabolic syndrome is increased among patients with schizophrenia, with the highest rates among patients on clozapine treatment. Smoking, obesity, physical inactivity, airway inflammation and obstruction, and adipose tissue and inflammatory marker activation are related in systemic inflammation. Low-grade inflammation is also associated with schizophrenia. Adipokine resistin is a biomarker involving several acute and chronic inflammatory states. However, the inflammatory role of resistin is so far inconclusive and studies in schizophrenia are scanty.

Aims: The aim of the present study was to explore the role of serum resistin as an inflammatory marker in patients with schizophrenia on clozapine treatment.

Methods: Associations between serum levels of resistin and some other selected cytokines/adipokines (adiponectin, leptin, adipsin, IL-6, IL-1Ra, TNF-α, hs-CRP) and metabolic markers in 190 patients with schizophrenia on clozapine treatment were studied using a cross-sectional study design.

Results: Among male patients especially, smokers had higher levels of resistin than non-smokers, and among smokers resistin levels were associated with IL-1Ra and hs-CRP levels. In the whole patient group levels of resistin associated with levels of IL-1Ra, and among male patients with low HDL-cholesterol.

Conclusions: Resistin is a biomarker of systemic inflammation associated with smoking among patients with schizophrenia on clozapine treatment. Resistin might have a role as a marker of cardiovascular comorbidity.     

Association between schizophrenia symptoms and neurocognition on mobility in older adults with schizophrenia

Objectives: Older persons with schizophrenia develop problems associated with aging, such as poor mobility, at more rapid rates than people without serious mental illness. Decrements in mobility contribute to poor health outcomes. Impaired neurocognitive function and psychiatric symptoms are central aspects of schizophrenia. The purpose of this study was to determine the association between neurocognitive impairment and schizophrenia symptoms to mobility in older adults with schizophrenia.

Methods: A cross-sectional study with 46 older adults with schizophrenia. Participants were assessed on neurocognitive function (MATRICS Consensus Cognitive Battery), psychiatric symptoms (Positive and Negative Syndrome Scale or PANSS), and mobility (Timed Get Up and Go or TGUG test). Pearson's bivariate correlations (two-tailed) and a simultaneous regression model were used.

Results: Lower severity of negative symptoms and faster speed of processing tests were associated with faster TGUG time in bivariate correlations and multivariate regression analyses (p < .05).

Conclusion: Our data suggest that lower negative symptoms and faster speed of processing positively impact mobility in older patients with schizophrenia. Mobility interventions for this population need to target neurocognitive impairment and schizophrenia symptoms for optimal results.     

Chemokine gene variants in schizophrenia

Background Chemokines are known to play a major role in driving inflammation and immune responses in several neuroinflammatory diseases, including multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Inflammation has also been implicated in the pathogenesis of schizophrenia.

Aim We aimed to investigate a potential link between chemokines and schizophrenia and analyze the role of MCP-1-A2518G, SDF-1-3’A, CCR5-delta32, CCR5-A55029G, CXCR4-C138T and CCR2-V64I gene polymorphisms in the Turkish population.

Methods Genotyping was conducted by PCR-RFLP based on 140 patients and 123 unrelated healthy controls to show the relation between chemokine gene variants and schizophrenia risk.

Results Frequencies of CCR5-A55029G A genotypes and CCR5-A55029G AG genotypes were found higher in patients than the controls and even also CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes significantly associated according to Bonferroni correction. However, no significant association was found for any of the other polymorphisms with the risk of schizophrenia.

Conclusions Our findings suggest that CCR5-A55029G polymorphisms and CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes might have association with schizophrenia pathogenesis.     

Obsessive–compulsive symptoms in schizophrenia: prevalence and associated factors in a Nigerian population

Objectives: The objectives of this study were to determine the prevalence of obsessive–compulsive symptoms (OCS) among subjects with schizophrenia and also to determine their associated factors.

Methods: A cross-sectional study involving 232 patients with schizophrenia were recruited from a teaching hospital in Nigeria. Socio-demographic questionnaire, Obsessive–Compulsive Inventory, Positive and Negative Syndrome Scale and Suicidality module of the MINI International Neuropsychiatric Inventory were administered.

Results: The prevalence of OCS was 54.3% among patients with schizophrenia, and washing symptom was the most common (51.7%). Patients with schizophrenia that had OCS had more severe psychopathologies and higher levels of suicidality. OCS among patients with schizophrenia were also associated with the use of second-generation antipsychotic medications.

Conclusions: OCS are common in schizophrenia. Hence, there is a need for routine screening of patients with schizophrenia for OCS and then, manage them appropriately.     

Seasonality and BDNF polymorphism influences depression outcome in patients with atopic dermatitis and psoriasis

Objectives: To examine the effect of seasonality and rs6265 genotype on depression outcome and brain-derived neurotrophic factor (BDNF) level with dermatitis patients from onset through remission.

Methods: Atopic dermatitis (AD, 56) and psoriasis (PS, 33) patients and healthy controls (HC, 49) were recruited over the 2014 calendar year. Patients were subdivided by immunoglobulin E (IgE) sensitivity (AD only), season and rs6265 genotype. Assessments were performed at onset and week 10 (Hamilton Depression Rating Scale [HAM-D], SCORAD/PASI, IgE, BDNF). Patients received standard corticosteroid and antihistamine interventions.

Results: All patients responded to corticosteroid treatment. Seasonally differential outcomes were observed in all groups. HAM-D was elevated at onset and improved over 10 weeks: AD cohort 1 (autumn/winter, AD-1) patients improved and AD cohort 2 (spring/summer, AD-2) patients remained elevated. BDNF levels were elevated in AD and seasonal differential: AD-2 declined at 10 weeks, whereas AD-1 remained high (intrinsic AD) or elevated further (extrinsic AD). PS cohort 2 declined to below control at 10 weeks. AD Val/Val had persistently elevated HAM-D and AD Val/Met were either normal (AD-1) or persistently elevated (AD-2).

Conclusions: Findings presented here suggest a strong influence of seasonality on depression outcome and BDNF expression in AD and PS and likely reflect separate patient populations which differentially respond to environment-based stressors.     

An interleukin 12 B single nucleotide polymorphism increases IL-12p40 production and is associated with increased disease susceptibility in patients with relapsing-remitting multiple sclerosis

Background: Through mounting genetic investigations, it has been established that IL12B and IL23R gene single nucleotide polymorphisms have significant associations with autoimmune diseases including inflammatory bowel disease, psoriasis, and ankylosing spondylitis. IL-12/IL-23 pathway plays a pivotal role in etiopathogenesis of multiple sclerosis (MS), suggested by studies both in patients and animal models.

Methods: In a case-control study, 145 MS patients and 200 healthy subjects were genotyped for polymorphisms in IL12B and IL23R genes using Real-Time PCR allelic discrimination approach. Additionally, quantitative analysis of mRNA expression of IL12B in Peripheral Blood Mononuclear Cells from patients and controls was conducted through Real-Time PCR using the TaqMan Gene Expression Assay.

Results: The rs6887695 single-nucleotide polymorphism (SNP) in IL12B gene showed an association with susceptibility to MS. GG genotype of this variation was more frequent in patients. mRNA expression of IL12B was upregulated in patients. Expression of IL12B mRNA in both MS patients collectively and those with GG genotype for rs6887695 SNP correlated negatively with onset age of MS patients.

Conclusions: The GG genotype of rs6887695 SNP in IL12B gene plays a role in etiopathogenesis of MS.     

High neutrophil-lymphocyte ratio in schizophrenia independent of infectious and metabolic parameters

Background: Immunological and inflammatory mechanisms play an important role in schizophrenia. In the literature, there are studies investigating neutrophil-lymphocyte ratio (NLR) association with schizophrenia.

Aims: The purpose of this study was to compare NLR values between patients with schizophrenia and healthy controls. In addition, the study aimed to investigate the relationship between NLR and disease severity and some metabolic/inflammatory parameters.

Methods: Fifty-two patients diagnosed with schzophrenia and 53 healthy controls were included in the study. A socio-demographic information form was filled out by the clinician. Height, body weight, waist and hip circumference and blood pressure values of each patient were measured. Severity of disease was assessed by positive and negative syndrome scale (PANSS) and clinical global impression-severity scale (CGI-S). Complete blood count was performed to both patient and control groups. Fasting blood glucose, insulin, HbA1c, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride, total cholesterol and C-reactive protein (CRP) were measured.

Results: The number of leukocytes, neutrophils, monocytes and NLR values in patients with schizophrenia was significantly higher than in the control group. There was no significant relationship between NLR values and the number of hospitalisation, duration of ilness or disease severity in patients. There was no correlation between other laboratory findings and NLR values.

Conclusion: NLR levels are high in schizophrenia independent of metabolic parameters according to the results. So, it can be considered that inflammatory processes may play a role in the etiology of the disease.     

Multiple physical healthcare needs among outpatients with schizophrenia: findings from a health examination study

Background: Despite the abundant literature on physical comorbidity, the full range of the concurrent somatic healthcare needs among individuals with schizophrenia has rarely been studied.

Aims: This observational study aimed to assess the distressing somatic symptoms and needs for physical health interventions in outpatients with schizophrenia, and factors predicting those needs.

Methods: A structured, comprehensive health examination was carried out, including a visit to a nurse and a general practitioner on 275 outpatients with schizophrenia. The required interventions were classified by type of disease. Logistic regression was used to assess the influence of sociodemographic factors, lifestyle, functional limitations, factors related to psychiatric disorder, and healthcare use on the need for interventions.

Results: In total, 44.9% of the patients (mean age 44.9 years) reported somatic symptoms affecting daily life; 87.6% needed specific interventions for a disease or condition, most commonly for cardiovascular, dermatological, dental, ophthalmological, and gastrointestinal conditions, and for altered glucose homeostasis. Smoking and obesity predicted significantly a need of any intervention, but the predictors varied in each disease category. Strikingly, use of general practitioner services during the previous year did not reduce the need for interventions.

Conclusions: Health examinations for outpatients with schizophrenia revealed numerous physical healthcare needs. The health examinations for patients with schizophrenia should contain a medical history taking and a physical examination, in addition to basic measurements and laboratory tests. Prevention and treatment of obesity and smoking should be given priority in order to diminish somatic comorbidities in schizophrenia.     

Positive mental health in schizophrenia and healthy comparison groups: relationships with overall health and biomarkers

Objective: Positive psychological factors (PPFs) have been reported to have a significant impact on health in the general population. However, little is known about the relationship of these factors with mental and physical health in schizophrenia.

Method: One hundred and thirty-five outpatients with schizophrenia and 127 healthy comparison subjects (HCs), aged 26–65 years, were evaluated with scales of resilience, optimism, happiness, and perceived stress. Measures of mental and physical health were also obtained. Regression analyses examined associations of a PPF composite with health variables.

Results: Relative to the HCs, the schizophrenia group had lower levels of PPFs. However, there was considerable heterogeneity, with over one-third of schizophrenia participants having values within the ‘normative’ range. The PPF composite was positively related to mental and physical health variables and with biomarkers of inflammation and insulin resistance. The relationship between PPFs and mental health was particularly strong for individuals with schizophrenia.

Conclusion: A sizable minority of adults with chronic schizophrenia have levels of resilience, optimism, happiness, and perceived stress similar to HCs. Psychosocial interventions to enhance PPFs should be tested in patients with serious mental illnesses, with the goal of improving their mental health (beyond controlling symptoms of psychosis) and their physical health.     

Increased serum midkine levels in autism spectrum disorder patients

Background: Midkine (MK) is a heparin binding growth factor and is involved in neurogenesis, neural development and neuroprotection. Additionally, MK may contribute to cancer development and pathogenesis of neurodegenerative disorders and schizophrenia. Considering these effects of MK, this study researched whether MK is involved in autism spectrum disorders (ASD) pathogenesis.

Methods: We evaluated serum MK levels of 38 patients with ASD and 32 healthy control group. MK levels were measured with ELISA, while ASD severity was assessed with Childhood Autism Rating Scale.

Results: Our data showed that the serum MK concentration in ASD patients (mean ± SD, 11.51 ± 8.53 pg/ml) is significantly higher than healthy controls (mean ± SD, 6.19 ± 3.94 pg/ml) (p = 0.007).

Conclusions: According to these results, MK may play a role in ASD pathogenesis.     

Clinical and cognitive insight in patients with acute-phase psychosis: Association with treatment and neuropsychological functioning

Background: The severity of psychopathology cannot fully explain deficits in the multi-dimensional construct of insight.

Aims: The aim of this study was to evaluate the correlates and associations of clinical and cognitive insight in patients in an acute phase of psychosis and to analyse the impact of acute treatment on these variables.

Methods: This study examined 47 inpatients who were recently hospitalized with acute exacerbation of schizophrenia. All subjects were assessed at both admission and discharge with the Positive and Negative Syndrome Scale (PANSS), Schedule for the Assessment of Insight-Expanded Version (SAI-E), Beck Cognitive Insight Scale (BCIS), and a neurocognition battery.

Results: Patients with schizophrenia gained clinical insight after treatment. Cognitive insight did not change significantly after treatment. Insight showed significant negative correlations with positive symptoms and general psychopathology, but not with negative symptoms. Clinical insight was not associated with neuropsychological functioning in this cohort.

Conclusion: Gaining clinical insight in the acute phase of illness was associated with the remission of positive symptoms, but not with neuropsychological functioning. Some significant correlations between clinical and cognitive insights were detected, which suggests that cognitive insight contributes to clinical insight but is not treatment-dependent. Long-term treatment may be required to understand the contribution of insight to the outcome of patients with schizophrenia.     

Fire-setting performed in adolescence or early adulthood predicts schizophrenia: a register-based follow-up study of pre-trial offenders

Background: Aggressive and disruptive behaviours often precede the onset of serious mental illnesses. Fire-setting is a type of crime that is associated with psychotic disorders.

Aim: The aim of this prospective follow-up study was to investigate if fire-setting performed in adolescence or early adulthood was associated with future diagnoses of schizophrenia or schizoaffective disorder.

Methods: The consecutive sample consisted of 111 Finnish 15–25-year old males with fire-setting crimes, decreed to a pre-trial forensic psychiatric examination in 1973–1998, and showing no past nor current psychosis at the time of examination. For each firesetter, four age-, gender-, and place of birth-matched controls were randomly selected from the Central Population Register. The subjects were followed until the death of the individual, until they moved abroad, or until the end of 2012.

Results: Fourteen firesetters (12.6%) and five controls (1.1%) were diagnosed with either schizophrenia or schizoaffective disorder later in life, corresponding to a hazard ratio of 12.5. The delay between the fire-setting offense and the future diagnosis was on average nearly 10 years.

Conclusions: Young male offenders undergoing a forensic psychiatric examination because of fire-setting crimes had a significant propensity for schizophrenia and schizoaffective disorder. Accurate assessments should be made both during imprisonment and later in life to detect possible psychotic signs in these individuals.     

Attitudes towards people with depression and schizophrenia among social service workers in Denmark

Background: Mental health-related stigma is a major public health issue, and is an obstacle to the possibility for successful treatment, recovery, and reintegration.

Aim: To examine attitudes towards mental illness among employees in the social services.

Methods: The study design was part of a large randomized trial, and data presented in this study are baseline data from this trial. Respondents completed a baseline questionnaire to assess the respondents’ attitudes.

Results: A significant difference was found between employees’ personal attitudes towards depression and schizophrenia. The same significant difference was found in the employees’ perceived attitudes. Furthermore, a significant difference was found between the employees’ personal and perceived attitudes. A significant difference was found between the respondents wish for social distance towards depression and schizophrenia in all cases, except regarding the willingness to provide a job at one’s own workplace.

Conclusion: Employees in the social services are comparable to the general public concerning attitudes towards mental illness.

Implications: The results indicate that the employees in social services could have great use of gaining more knowledge about mental illness and ways in which to recognize a mental illness, in order to be able to offer the right kind of help and reduce the treatment gap concerning people suffering from mental illness.     

Levodopa,placebo and rotigotine change biomarker levels for oxidative stress

Introduction: Homocysteine increase and glutathione derivative cysteinyl-glycine fall are indirect biomarkers for oxidative stress, for instance due to dopamine D₁ receptor stimulation.

Objectives: To investigate the influence of the D₁ receptor agonists levodopa and rotigotine compared with placebo on homocysteine and cysteinyl-glycine in plasma of patients with Parkinson’s disease.

Methods: Patients received 100 mg levodopa, 4 mg rotigotine or placebo. Cysteinyl-glycine and homocysteine were measured every 30 min over three hours.

Results: Homocysteine rose during levodopa- and placebo administration. Rotigotine had no effect. Cysteine-glycine only increased after placebo- but not after levodopa- or rotigotine.

Discussion: Homocysteine elevation results from hepatic and gastrointestinal methylation processes. Transdermal rotigotine circumvents these methylation locations. Turnover of segregated alkyl residuals from rotigotine serves as methyl group donors, which counteract homocysteine increment. The placebo-related cysteinyl-glycine increase results from reduced free radical exposure. Low levodopa dosing and antioxidants in the rotigotine patch matrix prevented cysteinyl-glycine fall.