Clinical characteristics of transformation obsessions in obsessive-compulsive disorder: A psychopathological study.

BACKGROUND: The obsession of turning into another person (transformation obsessions [TO]), and its related compulsions have been initially conceptualised as a form of mental contamination. Nevertheless, it has remained understudied in the current obsessive-compulsive disorder (OCD) literature. In parallel, disturbances of the self have been identified as markers of prodromal psychosis in patients with schizophrenia. Based on the later association, this study aimed to investigate the sociodemographic and clinical correlates of TO. METHODS: In all, 1001 OCD outpatients from the Brazilian OCD Research Consortium were included in this study. Several semi-structured and structured instruments were used to compare 48 OCD patients with TO with 953 OCD patients without TO. A repression model investigated the relationships between the presence of current TO and statistically significant univariate test outcomes. RESULTS: Participants with TO presented an overall younger age, a longer period of time between the onset of the OCD symptoms and an OCD diagnosis, greater severity of the sexual/religious dimension and increased suicidality symptoms. CONCLUSIONS: These results indicate that TO may be better conceptualised as a form of forbidden/taboo thoughts rather than contamination. While no significant associations with psychotic features (e.g. decreased insight) were observed, TO patients displayed increased suicidality, overall younger age and a significantly larger disparity between seeking treatment and OCD diagnosis. This demonstrates that further clinical awareness and research into TO as an OCD symptom is most needed.

Obsessional slowness in obsessive-compulsive disorder: identifying characteristics and comorbidities in a clinical sample.

BACKGROUND: Obsessional slowness (OS) is characterised by debilitating motor slowness during initiation and completion of daily tasks such as washing, dressing, eating or walking. Yet, the clinical features of OS are still poorly understood. METHODS: This study aimed to delineate demographics, comorbid disorders and obsessive-compulsive symptoms (OCS) associated with OS. Cross sectional data from 667 OCD outpatients aged 9-82 years (M = 37.86, SD = 12.78) who underwent comprehensive standardised assessments administered by trained clinicians were analysed. Participants with (n = 189) and without (n = 478) OS were compared and contrasted. RESULTS: Logistic regression revealed that being single, having tics and displaying higher severity of aggression, contamination, symmetry and hoarding symptoms significantly predicted participants having OS. CONCLUSIONS: This is the largest-scale descriptive study of OS, which also provides preliminary evidence that OS may be a more severe form of OCD. Further empirical validation of these findings is required, and future research should focus on developing OS assessment.Key PointsThis was the first large-scale descriptive study of obsessional slowness (OS), that provided preliminary evidence for an OS phenotype within obsessive-compulsive disorderOS is associated with increased severity of aggression, contamination, symmetry and hoarding obsessive-compulsive symptomsIndividuals with OS are more likely to have comorbid tics, suggesting that there may be underlying motor factors contributing to this conditionFuture research would benefit from collecting both qualitative and quantitative data when assessing OS.

Predicting marriage and divorce in obsessive-compulsive disorder.

Single (N = 472, 51.7%), married or living in stable cohabitation (N = 375, 41.1%) and divorced or separated (N = 66, 7.2%) patients with obsessive-compulsive disorder (OCD) were compared in terms of their sociodemographic features, OCD phenotypes, and comorbidity profile. Using single status as a reference group, a multinominal regression analysis found increased age, lower severity of hoarding, increased rates of panic disorder without agoraphobia, and lower rates of dysthymic disorder to be associated with married or stable cohabitation status. Concomitantly, increased age, higher severity of symmetry symptoms, and increased rates of skin picking disorder were found to be associated with divorced status. These findings suggest that there is a relationship between marital status and different OCD phenotypes.

The rates of co-occurring behavioural addictions in treatment-seeking individuals with obsessive-compulsive disorder: a preliminary report.

Objectives: To assess the rates of co-occurring putative 'behavioural addictions' in patients with obsessive-compulsive disorder (OCD).Methods: Twenty-three international centres specialising in the treatment of OCD were invited to participate in a survey of the rates of behavioural addictions and other relevant comorbidity within their samples.Results: Sixteen of 23 (69.6%) invited centres from 13 countries had sufficient data to participate in the survey. The use of validated diagnostic tools was discrepant, with most centres relying on a 'clinical diagnosis' to diagnose behavioural addictions. The final sample comprised of 6916 patients with a primary diagnosis of OCD. The reported rates of behavioural addictions were as follows: 8.7% for problematic internet use, 6.8% for compulsive sexual behaviour disorder, 6.4% for compulsive buying, 4.1% for gambling disorder and 3.4% for internet gaming disorder.Conclusions: Behavioural addictions should be better assessed for patients with OCD. The absence of diagnostic scales developed specifically for behavioural addictions and overlapping obsessive-compulsive phenomena such as compulsive checking of information on the internet may explain the relatively high rate of problematic internet use in this sample. The study encourages better efforts to assess and to conceptualise the relatedness of behavioural addictions to obsessive-compulsive 'spectrum' disorders.

The impact of attention deficit hyperactivity disorder in obsessive-compulsive disorder subjects.

BACKGROUND: Recent findings suggest an association between attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Thus, we evaluated the clinical associated features of ADHD in a large sample of adult OCD patients. METHODS: A cross-sectional study including 955 adult patients with OCD from the Brazilian Research Consortium of Obsessive-Compulsive Spectrum Disorders (C-TOC). Clinical characteristics in adult OCD patients with and without comorbid ADHD were compared using Fisher's exact test, t-tests or Mann-Whitney tests. Bivariate analyses were followed by logistic regression analysis to identify clinical characteristics independently associated with ADHD comorbidity. RESULTS: The lifetime prevalence of ADHD in adult OCD patients was 13.7%. The current results indicate that OCD + ADHD patients were more severe, had an earlier onset of the obsessive-compulsive symptoms, a higher history of rheumatic fever, with higher frequencies of sensory phenomena and comorbidity with Tourette syndrome. They also had an increased risk for academic impairment and suicide attempts. CONCLUSION: Adult OCD patients with ADHD present some specific clinical features and may represent a special subgroup of adult OCD. Future studies should focus on the development of interventions more tailored to the phenotype of this subgroup of patients.

Psychopathology and friendship in children and adolescents: disentangling the role of co-occurring symptom domains with serial mediation models.

The consolidation of social friendship groups is a vital part of human development. The objective of this study is to understand the direct and indirect influences of three major symptomatic domains-emotional, hyperkinetic, and conduct-on friendship. Specifically, we aim to study if the associations of one domain with friendship may be mediated by co-occurring symptoms from another domain. A total of 2512 subjects aged 6-14 years participated in this study. Friendship was evaluated by the Development and Well-Being Assessment's friendship section. We evaluated two main constructs as outcomes: (1) social isolation and (2) friendship latent construct. Emotional, hyperkinetic, and conduct symptomatic domains were evaluated with the Strengths and Difficulties Questionnaire (SDQ). All SDQ domains were positively associated with social isolation and negatively associated with friendship latent construct in univariate analysis. However, serial mediation models showed that the association between conduct domains with social isolation was mediated by emotion and hyperkinetic domains. Moreover, the associations between emotional and hyperkinetic domains with friendship latent construct in non-isolated children were mediated by the conduct domain. Emotion and hyperkinetic domains were directly and indirectly associated with social isolation, whereas conduct was directly and indirectly associated with overall friendship in non-isolated children. Results suggest that interventions aimed to improve social life in childhood and adolescence may have stronger effects if directed towards the treatment of emotion and hyperkinetic symptoms in socially isolated children and directed towards the treatment of conduct symptoms in children with fragile social connections.

International prescribing practices in obsessive-compulsive disorder (OCD).

OBJECTIVES: To assess rates of psychotropic medication use in patients with obsessive-compulsive disorder (OCD) in seven different countries on five continents and to compare these with international treatment guidelines. METHODS: Researchers in the field of OCD were invited to contribute summary statistics on the characteristics of their patients with OCD and on their incidence of psychotropic use. Consistency of summary statistics across countries was evaluated. RESULTS: The data came from Brazil (n = 955), Italy (n = 750), South Africa (n = 555), Japan (n = 382), Australia (n = 213), India (n = 202) and Spain (n = 82). The majority (77.9%; n = 2445) of the total sample of 3139 participants received a psychotropic medication. Consistent with international guidelines, selective serotonin reuptake inhibitors (SSRIs) were most commonly used (73.5%, n = 1796), but their use ranged from 59% in Australia to 96% in Japan. Clomipramine use varied from 5% in Japan and South Africa to 26% in India and Italy. Atypical antipsychotic use ranged from 12% in South Africa to 50% in Japan. CONCLUSIONS: Pharmacotherapy for OCD varied significantly across sites. Prospective studies are required to determine the cultural, pharmacoeconomic and pharmacogenomic factors that may play a role in the variation in prescribing practices internationally and whether these variations influence treatment outcomes. Copyright © 2016 John Wiley & Sons, Ltd.

Obsessive-compulsive symptoms are associated with psychiatric comorbidities, behavioral and clinical problems: a population-based study of Brazilian school children.

Pediatric-onset obsessive-compulsive disorder (OCD) is underdiagnosed, and many affected children are untreated. The present study seeks to evaluate the presence and the clinical impact of OCD and obsessive-compulsive symptoms (OCS) in a large sample of school-age children. In Phase I, we performed an initial screening using the Family History Screen (FHS). In Phase II, we identified an "at-risk" sample, as well as a randomly selected group of children. A total of 2,512 children (6-12 years old) were assessed using the FHS, the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), and the Child Behavior Checklist (CBCL). Data analyses included descriptive and multivariate analytical techniques. 2,512 children (mean age: 8.86 ± 1.84 years; 55.0% male) were categorized into one of the three diagnostic groups: OCD (n = 77), OCS (n = 488), and unaffected controls (n = 1,947). There were no significant socio-demographic differences (age, gender, socioeconomic status) across groups. The OCS group resembled the OCD on overall impairment, including school problems and delinquent behaviors. However, the OCD group did have significantly higher rates of several comorbid psychiatric disorders, including separation anxiety, generalized anxiety, and major depressive disorder, than OCS or unaffected controls. Moreover, the OCD group also scored higher than the SDQ, as well as on each of CBCL items rated by the parent. Our findings suggest that there is a psychopathological continuum between OCS and OCD in school-aged children. The presence of OCS is associated with functional impairment, which needs further investigation in longitudinal studies.

Brain structural correlates of sensory phenomena in patients with obsessive-compulsive disorder.

BACKGROUND: Sensory phenomena (SP) are uncomfortable feelings, including bodily sensations, sense of inner tension, "just-right" perceptions, feelings of incompleteness, or "urge-only" phenomena, which have been described to precede, trigger or accompany repetitive behaviours in individuals with obsessive-compulsive disorder (OCD). Sensory phenomena are also observed in individuals with tic disorders, and previous research suggests that sensorimotor cortex abnormalities underpin the presence of SP in such patients. However, to our knowledge, no studies have assessed the neural correlates of SP in patients with OCD. METHODS: We assessed the presence of SP using the University of São Paulo Sensory Phenomena Scale in patients with OCD and healthy controls from specialized units in São Paulo, Brazil, and Barcelona, Spain. All participants underwent a structural magnetic resonance examination, and brain images were examined using DARTEL voxel-based morphometry. We evaluated grey matter volume differences between patients with and without SP and healthy controls within the sensorimotor and premotor cortices. RESULTS: We included 106 patients with OCD and 87 controls in our study. Patients with SP (67% of the sample) showed grey matter volume increases in the left sensorimotor cortex in comparison to patients without SP and bilateral sensorimotor cortex grey matter volume increases in comparison to controls. No differences were observed between patients without SP and controls. LIMITATIONS: Most patients were medicated. Participant recruitment and image acquisition were performed in 2 different centres. CONCLUSION: We have identified a structural correlate of SP in patients with OCD involving grey matter volume increases within the sensorimotor cortex; this finding is in agreement with those of tic disorder studies showing that abnormal activity and volume increases within this region are associated with the urges preceding tic onset.

Factor structure of the Dimensional Yale-Brown Obsessive-Compulsive Scale in a large sample of adults with obsessive-compulsive disorder.

OBJECTIVES: Although the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a widely used instrument for assessing different obsessive-compulsive symptom dimensions, its factor structure has never been studied in a Brazilian population. Thus, we aimed to assess the goodness-of-fit indexes and factor loadings of two higher-order models of the DY-BOCS using confirmatory factor analysis (CFA) in a large obsessive-compulsive disorder (OCD) sample. METHODS: We tested two CFA models in a sample of 955 adults with OCD who had been assessed with the DY-BOCS in a cross-sectional multi-site study. The first model encompassed the symptom checklist (present or absent), whereas the second focused on items related to severity scores. RESULTS: Both models presented adequate goodness-of-fit indexes. The comparative fit index, Tucker-Lewis index, and omega were > 0.9, while the root mean square error of approximation was ≤ 0.06 for both models. Factor loadings for each item of each dimension are presented and discussed. CONCLUSION: Higher-order factor models showed adequate goodness-of-fit indexes, indicating that they appropriately measured OCD dimensions in this Brazilian population.

The impact of generalized anxiety disorder in obsessive-compulsive disorder patients.

Despite generalized anxiety disorder (GAD) being one of the most prevalent comorbidities in obsessive-compulsive disorder (OCD), few studies have researched its impact on the OCD phenotype. The present study investigated how the sociodemographic and clinical profile of people with OCD with comorbid GAD differs from people with OCD without comorbid GAD. We hypothesised that the phenotype of the comorbid group would be closely related to GAD, in that it would more likely be female, have an earlier age at onset of OCD, and show an increased severity of fear-related OCD symptoms (aggressive, sexual/religious, and contamination dimensions), more avoidant behaviours, greater suicidality, more severe anxiety symptoms, and increased rates of comorbid anxiety and mood disorders. The study included 867 participants with OCD, with GAD being comorbid in 33.56%. Mann-Whitney U tests, chi-square tests with continuity correction, and logistic regressions were performed. Results showed that comorbid GAD was uniquely associated with an increased number of avoidant behaviours, greater anxiety severity, panic disorder without agoraphobia, social phobia, specific phobia, and type II bipolar disorder. These results illustrate the clinical severity associated with this comorbidity and highlight markers that can aid diagnosis of GAD in OCD. Future studies should investigate whether this comorbidity has an impact on the treatment of OCD.

Symmetry Dimension in Obsessive-Compulsive Disorder: Prevalence, Severity and Clinical Correlates.

Background: Obsessive-compulsive disorder (OCD) is a very heterogeneous condition that frequently includes symptoms of the "symmetry dimension" (i.e., obsessions and/or compulsions of symmetry, ordering, repetition, and counting), along with aggressive, sexual/religious, contamination/cleaning, and hoarding dimensions. Methods: This cross-sectional study aimed to investigate the prevalence, severity, and demographic and clinical correlates of the symmetry dimension among 1001 outpatients from the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. The main assessment instruments used were the Dimensional Yale-Brown Obsessive-Compulsive Scale, the Yale-Brown Obsessive-Compulsive Scale, the USP-Sensory Phenomena Scale, the Beck Depression and Anxiety Inventories, the Brown Assessment of Beliefs Scale, and the Structured Clinical Interview for DSM-IV Axis I Disorders. Chi-square tests, Fisher's exact tests, Student's t-tests, and Mann-Whitney tests were used in the bivariate analyses to compare patients with and without symptoms of the symmetry dimension. Odds ratios (ORs) with confidence intervals and Cohen's D were also calculated as effect size measures. Finally, a logistic regression was performed to control for confounders. Results: The symmetry dimension was highly prevalent (86.8%) in this large clinical sample and, in the logistic regression, it remained associated with earlier onset of obsessive-compulsive symptoms, insidious onset of compulsions, more severe depressive symptoms, and presence of sensory phenomena. Conclusions: A deeper knowledge about specific OCD dimensions is essential for a better understanding and management of this complex and multifaceted disorder.

Outbreak of hepatitis B and hepatitis C virus infections associated with a cardiology clinic, West Virginia, 2012-2014.

OBJECTIVE: To stop transmission of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in association with myocardial perfusion imaging (MPI) at a cardiology clinic. DESIGN: Outbreak investigation and quasispecies analysis of HCV hypervariable region 1 genome. SETTING: Outpatient cardiology clinic. PATIENTS: Patients undergoing MPI. METHODS: Case patients met definitions for HBV or HCV infection. Cases were identified through surveillance registry cross-matching against clinic records and serological screening. Observations of clinic practices were performed. RESULTS: During 2012-2014, 7 cases of HCV and 4 cases of HBV occurred in 4 distinct clusters among patients at a cardiology clinic. Among 3 case patients with HCV infection who had MPI on June 25, 2014, 2 had 98.48% genetic identity of HCV RNA. Among 4 case patients with HCV infection who had MPI on March 13, 2014, 3 had 96.96%-99.24% molecular identity of HCV RNA. Also, 2 clusters of 2 patients each with HBV infection had MPI on March 7, 2012, and December 4, 2014. Clinic staff reused saline vials for >1 patient. No infection control breaches were identified at the compounding pharmacy that supplied the clinic. Patients seen in clinic through March 27, 2015, were encouraged to seek testing for HBV, HCV, and human immunodeficiency virus. The clinic switched to all single-dose medications and single-use intravenous flushes on March 27, 2015, and no further cases were identified. CONCLUSIONS: This prolonged healthcare-associated outbreak of HBV and HCV was most likely related to breaches in injection safety. Providers should follow injection safety guidelines in all practice settings.

An epidemiological study of childhood development in an urban setting in Brazil.

OBJECTIVE: Mental illness is an important public health concern, often starting early in life and particularly impacting children from low-and middle-income countries. Our aims were to 1) determine, in a representative sample of public preschool 4- to 5-year old children in Brazil, the prevalence of internalizing and externalizing disorders and socioemotional development delays; and 2) to identify modifiable risk factors associated with mental, behavioral, or developmental disorders (MBDD), such as microsystem (i.e., parent-child relationship), mesosystem (social support), and macrosystem contextual factors (neighborhood disadvantage). METHODS: A random sample of public preschool children was recruited in the city of Embu das Artes (São Paulo metropolitan area) (n=1,292 from 30 public preschools). Six-month prevalence of MBDD was measured using the Child Behavior Checklist (CBCL) and the Ages and Stages Questionnaires: Social-Emotional (ASQ:SE). RESULTS: Six-month prevalence estimates were 25.4% for internalizing disorders, 12.1% for externalizing disorders, and 30.3% for socioemotional development delays. MBDD prevalence estimates were higher in families with stressful relationships and parental depression or anxiety, and in families with lower social capital. CONCLUSION: At least 25% of preschool children living in an urban area in Brazil presented a mental health disorder. These mental disorder were associated with modifiable factors such as stressful family relationships and lower social capital. Prevention and intervention measures such as family therapy are needed to decrease such high prevalence.

Perfectionism and sensory phenomena: phenotypic components of obsessive-compulsive disorder.

BACKGROUND: The aim of the study was to investigate how perfectionism and sensory phenomena (SP) interact as possible phenotypic components of obsessive-compulsive disorder (OCD). METHODS: Forty-seven adult outpatients, meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for OCD, and a control group of 41 community subjects were assessed using the Frost Multidimensional Perfectionism Scale (FMPS), the University of São Paulo-Sensory Phenomena Scale, and other standard measures of OCD severity. RESULTS: Three of the FMPS subscales ("concern over mistakes," "doubts about action," and "parental criticism") were significantly different between OCD patients and control subjects. All subtypes of SP were significantly more frequent and more severe in OCD than in control subjects. The "incompleteness" subtype of SP was associated with high scores on all dimensions of the FMPS, whereas the "just-right" subtype of SP was only associated with "doubts about action," "personal standards," and "organization" subscales of the FMPS. CONCLUSIONS: Presence and severity of SP and specific elements of perfectionism clearly distinguish OCD patients from healthy control subjects. Some SP subtypes are associated with specific FPMS subscale scores, whereas others are not. These results emphasize the relevance of assessing different subtypes of perfectionism and SP in OCD patients as important subcomponents of the OCD phenotype.

Bipolar disorder comorbidity in patients with obsessive-compulsive disorder: Prevalence and predictors.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) often present with comorbidities, mainly anxiety and affective disorders, which may influence OCD course, help-seeking and treatment response. Some authors have studied bipolar disorder (BD) comorbidity in patients with OCD, but usually in small samples. The objective was to estimate the lifetime prevalence of BD in a large clinical sample of OCD patients, and to compare demographic and clinical features of patients with and without BD comorbidity. METHOD: This cross-sectional study with 955 adult OCD patients from the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders (C-TOC) used several assessment instruments, including the Yale-Brown Obsessive-Compulsive Scale, the Dimensional Yale-Brown Obsessive-Compulsive Scale, the Beck Depression and Anxiety Inventories, and the Structured Clinical Interview for DSM-IV Axis I Disorders. Descriptive and bivariate analyses were followed by logistic regression. RESULTS: The lifetime prevalence of BD was 7.75% (N = 74). The variables that were independently associated with BD comorbidity were: panic disorder with agoraphobia, impulse control disorders, and suicide attempts. LIMITATIONS: The cross-sectional design does not permit causal inferences; the external validity may be limited, as the participants were from tertiary services. Despite the large sample size, some analyses may have been underpowered due to the relatively low prevalence of the outcome and of some explanatory variables. CONCLUSIONS: Patients with OCD comorbid with BD have some clinical features indicative of greater severity, including higher suicide risk, and require a careful therapeutic approach for the appropriate treatment of both disorders.

Reaction time variability and attention-deficit/hyperactivity disorder: is increased reaction time variability specific to attention-deficit/hyperactivity disorder? Testing predictions from the default-mode interference hypothesis.

Increased reaction time variability (RTV) is one of the most replicable behavioral correlates of attention-deficit/hyperactivity disorder (ADHD). However, this may not be specific to ADHD but a more general marker of psychopathology. Here we compare RT variability in individuals with ADHD and those with other childhood internalizing and externalizing conditions both in terms of standard (i.e., the standard deviation of reaction time) and alternative indices that capture low-frequency oscillatory patterns in RT variations over time thought to mark periodic lapses of attention in ADHD. A total of 667 participants (6-12 years old) were classified into non-overlapping diagnostic groups consisting of children with fear disorders (n = 91), distress disorders (n = 56), ADHD (n = 103), oppositional defiant or conduct disorder (ODD/CD; n = 40) and typically developing controls (TDC; n = 377). We used a simple two-choice reaction time task to measure reaction time. The strength of oscillations in RTs across the session was extracted using spectral analyses. Higher RTV was present in ADHD compared to all other disorder groups, effects that were equally strong across all frequency bands. Interestingly, we found that lower RTV to characterize ODD/CD relative to TDC, a finding that was more pronounced at lower frequencies. In general, our data support RTV as a specific marker of ADHD. RT variation across time in ADHD did not show periodicity in a specific frequency band, not supporting that ADHD RTV is the product of spontaneous periodic lapses of attention. Low-frequency oscillations may be particularly useful to differentiate ODD/CD from TDC.

Population pharmacokinetic/pharmacodynamic analysis of CCR5 receptor occupancy by maraviroc in healthy subjects and HIV-positive patients.

BACKGROUND: Maraviroc, a noncompetitive antagonist of the CCR5 coreceptor, was recently approved in the USA as a treatment of HIV infection. For antiretroviral agents that target the virus, antiviral effect can be related to some extent to plasma drug concentrations. For CCR5 antagonists that target the host cells, receptor occupancy in vivo might be a better predictor of efficacy. AIMS To develop a population pharmacokinetic (PK)-pharmacodynamic (PD) model that describes CCR5 receptor occupancy by maraviroc after oral administration at different doses in healthy volunteers and HIV-positive patients and to assess the relevance of receptor occupancy in predicting the decrease in viral load (HIV-1 RNA copies ml(-1)) in HIV-positive patients. METHODS: Receptor occupancy data from 88 individuals enrolled in two multiple dose trials were included in the population PK-receptor binding model. Out of the 88 individuals, 25 were HIV-1-infected patients and had viral load measurements, whereas the remaining 63 were healthy volunteers. Doses ranged from 3 mg b.i.d. to 600 mg q.d. A previously published PK-PD disease model describing the effect of maraviroc on the viral load was updated by replacing its PD module by the receptor occupancy model. Simulated viral load-time profiles with the updated model were compared with the profiles observed in patients. RESULTS: The majority of measured plasma concentrations were associated with receptor occupancy > or = 50% even at the lowest dose of 3 mg b.i.d. A simple direct E(max) model appeared to describe satisfactorily the PK-receptor occupancy relationship. The estimated K(D) was around 0.0894 ng ml(-1), far below the operational in vivo antiviral IC(50) of 8 ng ml(-1). Accordingly, simulations led to marked overprediction of the decrease in viral load-time profiles. CONCLUSIONS: Maraviroc receptor occupancy close to the maximum is required to induce a significant decrease in viral load, indicating that in vivo CCR5 receptor occupancy by maraviroc is not a direct measure of drug inhibitory activity. Considering the imprecision of the measurement in the upper flat part of the maraviroc concentration vs. percent CCR5 occupancy curve, it can reasonably be concluded that routine monitoring of receptor occupancy as a biomarker for maraviroc efficacy will not be helpful. Based on this analysis, it was decided not to use receptor occupancy as a biomarker of viral load inhibition during the development of CCR5 antagonist compounds.

Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers.

AIMS: To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers. METHODS: Three double-blind, placebo-controlled, dose-escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed. RESULTS: Maraviroc is rapidly absorbed following oral administration, and plasma T(max) is achieved within 0.5-4.0 h postdose. Steady-state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3-1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10-12 l h(-1) and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose-limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. CONCLUSIONS: Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug-metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate.

Low frequency fluctuation of brain spontaneous activity and obsessive-compulsive symptoms in a large school-age sample.

BACKGROUND: The present study was designed to explore alterations in brain dynamics at rest that are associated with Obsessive Compulsive Symptoms (OCS) in childhood by measuring low frequency fluctuation of spontaneous brain activity in a large school community sample from a developing country. METHOD: Resting state functional magnetic resonance imaging data were collected in a sample of 655 children and adolescents (6-15 years old) from the brazilian 'High Risk Cohort Study for Psychiatric Disorders (HRC)'. OCS were assessed using items from the Compulsion and Obsessions section of the Development and Well-Being Assessment (DAWBA). The correlation between the fractional amplitude of low frequency fluctuations (fALFF) and the number of OCS were explored by using a general linear model, considering fALFF as response variable, OCS score as regressor and age, gender and site as nuisance variables. RESULTS: The number of OCS was positively correlated with the fALFF coefficients at the right sensorimotor cortex (pre-motor, primary motor cortex and post-central gyrus) and negatively correlated with the fALFF coefficients at the insula/superior temporal gyrus of both hemispheres. Our results were specific to OCS and not due to associations with overall psychopathology. CONCLUSIONS: Our results suggest that brain spontaneous activity at rest in the sensorimotor and insular/superior-temporal cortices may be involved in OCS in children. These findings need independent replication and future studies should determine whether brain spontaneous activity changes within these regions might be predictors of risk for obsessive-compulsive disorder latter in life.