Pathophysiology Of Obsessive-compulsive Disorder Research Articles

Nucleus accumbens high-frequency stimulation selectively impacts nigrostriatal dopaminergic neurons

High-frequency stimulation of the nucleus accumbens, also known as deep brain stimulation (DBS), is currently used to alleviate obsessive compulsive symptoms when pharmacotherapy is ineffective. However, the mechanism by which DBS achieves its therapeutic actions is not understood. Imaging studies and the actions of dopaminergic drugs in untreated patients suggest that the dopamine (DA) system likely plays a role in the pathophysiology of obsessive compulsive disorder. Therefore, we examined whether DBS would impact the DA system as a potential component of its therapeutic actions. The activity of DA neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were recorded in anesthetized rats under high-frequency stimulation. DA neuron activity was measured in terms of number of neurons firing, average firing rate and firing pattern. DBS of the nucleus accumbens core did not significantly affect VTA activity or discharge pattern. On the other hand, DBS caused a potent decrease in the number of SNc DA neurons firing spontaneously. Such an effect could contribute to the disruption of pathological habit formation in the SNc-dorsal striatal projection system that may have therapeutic implications for the treatment of obsessive compulsive disorder.

Default network connectivity as a vulnerability marker for obsessive compulsive disorder

Aberrant functional connectivity within the default network is generally assumed to be involved in the pathophysiology of obsessive compulsive disorder (OCD); however, the genetic risk of default network connectivity in OCD remains largely unknown. Here, we systematically investigated default network connectivity in 15 OCD patients, 15 paired unaffected siblings and 28 healthy controls. We sought to examine the profiles of default network connectivity in OCD patients and their siblings, exploring the correlation between abnormal default network connectivity and genetic risk for this population. Compared with healthy controls, OCD patients exhibited reduced strength of default network functional connectivity with the posterior cingulate cortex (PCC), and increased functional connectivity in the right inferior frontal lobe, insula, superior parietal cortex and superior temporal cortex, while their unaffected first-degree siblings only showed reduced local connectivity in the PCC. These findings suggest that the disruptions of default network functional connectivity might be associated with family history of OCD. The decreased default network connectivity in both OCD patients and their unaffected siblings may serve as a potential marker of OCD.

Inhibitory deficit in semantic conflict in obsessive–compulsive disorder: An event-related potential study

The present study examines the inhibitory function of patients with obsessive–compulsive disorder (OCD) involved in semantic conflict using event-related potentials (ERPs). EPRs were recorded in a group of 18 medicine-free OCD patients and 18 normal controls using a modified Stroop paradigm in which the participants were asked to make a judgment of congruent or incongruent stimuli. The reaction time to color-word incongruent stimuli in the OCD group was significantly longer than the reaction time to congruent stimuli. In the OCD group, a significant negativity shift was discovered in P350 amplitude and N450 amplitude in response to incongruent stimuli, a shift not present in the control group. The amplitude of difference waveform was significantly higher for OCD than for control subjects. The findings probably revealed an inhibitory deficit in patients with OCD when performing semantic conflict tasks. The results suggest that this type of inhibitory deficit may be the cause of increased Stroop effects in patients with OCD, and one of contributors to the pathophysiology of OCD.

Abnormal Spontaneous Neural Activity in Obsessive-Compulsive Disorder: A Resting-State Functional Magnetic Resonance Imaging Study

Neuroimaging studies of obsessive-compulsive disorder have found abnormalities in orbitofronto-striato-thalamic circuitry, including the orbitofrontal cortex, anterior cingulate cortex, caudate, and thalamus, but few studies have explored abnormal intrinsic or spontaneous brain activity in the resting state. We investigated both intra- and inter-regional synchronized activity in twenty patients with obsessive-compulsive disorder and 20 healthy controls using resting-state functional magnetic resonance imaging. Regional homogeneity (ReHo) and functional connectivity methods were used to analyze the intra- and inter-regional synchronized activity, respectively. Compared with healthy controls, patients with obsessive-compulsive disorder showed significantly increased ReHo in the orbitofrontal cortex, cerebellum, and insula, and decreased ReHo in the ventral anterior cingulate cortex, caudate, and inferior occipital cortex. Based on ReHo results, we determined functional connectivity differences between the orbitofrontal cortex and other brain regions in both patients with obsessive-compulsive disorder and controls. We found abnormal functional connectivity between the orbitofrontal cortex and ventral anterior cingulate cortex in patients with obsessive-compulsive disorder compared with healthy controls. Moreover, ReHo in the orbitofrontal cortex was correlated with the duration of obsessive-compulsive disorder. These findings suggest that increased intra- and inter-regional synchronized activity in the orbitofrontal cortex may have a key role in the pathology of obsessive-compulsive disorder. In addition to orbitofronto-striato-thalamic circuitry, brain regions such as the insula and cerebellum may also be involved in the pathophysiology of obsessive-compulsive disorder.

Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine's effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (≥35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.

Widespread decreased grey and white matter in paediatric obsessive-compulsive disorder (OCD): A voxel-based morphometric MRI study

Obsessive-compulsive disorder (OCD) is a chronic, relapsing anxiety disorder. To date, neuroimaging investigations of OCD have been variable and few studies have examined paediatric populations. Eight children with OCD and 12 typically developing children matched for age, gender, handedness and performance IQ underwent a high resolution T1-weighted structural magnetic resonance imaging (MRI) scan. A voxel-based morphometry (VBM) protocol (using DARTEL) compared the brains of the paediatric OCD children with those of typically developing children. Overall, children with OCD demonstrated significantly lower intra-cranial volume (ICV) and grey- and white-matter volumes. ICV was significantly reduced (∼9%) in the OCD group compared with the typically developing group. The VBM analysis demonstrated lower volumes in widespread grey matter in bilateral frontal, cingulate, temporal–parietal, occipital–frontal and right precuneus regions for OCD. Lower white matter volume was found bilaterally in the cingulate and occipital cortex, right frontal and parietal and left temporal regions, and the corpus callosum. In summary, this study provides further evidence of brain dysmorphology in paediatric OCD patients. In addition to fronto–striatal–thalamic neural networks, abnormalities in other brain regions, such as the parietal lobe and corpus callosum, were demonstrated. These brain regions may play an additional role in the pathophysiology of OCD.

The role of the cholinergic system in the signal attenuation rat model of obsessive-compulsive disorder

In comparison to studies of the involvement of the serotonergic, dopaminergic, and glutamatergic systems in the pathophysiology of obsessive-compulsive disorder (OCD), research on the involvement of the cholinergic system in this disorder has remained sparse. The aim of this study was to test the role of the cholinergic system in compulsive behavior using the signal attenuation rat model of OCD. In this model, "compulsive" behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. The acetylcholinesterase inhibitor physostigmine (0.05, 0.10, and 0.15mg/kg), the nicotinic agonist nicotine (0.03, 0.06, 0.10, 0.30, 0.60, and 1.00mg/kg), the nicotinic antagonist mecamylamine (1, 3, 5, and 8mg/kg), the muscarinic agonist oxotremorine (0.0075, 0.0150, and 0.0300mg/kg), and the muscarinic antagonist scopolamine (0.15, 0.50, 1.00, and 1.50mg/kg) were acutely administered to rats just before assessing their lever-press responding following signal attenuation (experiments 1, 3, 5, 7, and 9, respectively). Because the effects of signal attenuation are assessed under extinction conditions, drug doses that were effective in the above experiments were also tested in an extinction session of lever-press responding that was not preceded by signal attenuation (experiments 2, 4, 6, 8, and 10). Acute systemic administration of the cholinergic agents did not exert a selective anti- or pro-compulsive effect in the signal attenuation model. Acetylcholine does not seem to play a role in the signal attenuation rat model of OCD.

Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive–compulsive symptoms

Clinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive-compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology. This study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms. A total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y-BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped. Trends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene-gene interaction model (p = 0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score (F 6, 137 = 7.650, p < 0.001), and individuals with AA/TT genotypes had a significantly higher mean Y-BOCS score than those with other genotypes, except AG/TT. These results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine.

Meta‐analysis of association between obsessive‐compulsive disorder and the 3′ region of neuronal glutamate transporter gene SLC1A1

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

Quantitative morphology of the corpus callosum in obsessive–compulsive disorder

Neuroimaging studies have implicated the corpus callosum (CC) in the pathophysiology of obsessive–compulsive disorder (OCD). Putative dysfunctions in prefrontal cortical regions suggest anomalies in anterior segments of the CC. However, recent studies have also implicated the middle and posterior CC. The present study soughts to examine the CC using parcellation scheme informed by diffusion tensor imaging. Anatomic brain magnetic resonance scans were obtained from 21 OCD subjects (mean age=26.9±9.93) and 42 healthy age- and sex-matched controls (mean age=26.6±9.46) between the ages of 14 and 49. Area and volume measures of five subregions of the CC were obtained via manual tracings. A multivariate analysis of variance (after correcting for multiple comparisons) identified smaller area and volume in the mid-anterior region of the CC in OCD patients relative to controls. These findings implicate medio-frontal regions of the cortex in the pathophysiology of OCD.

Increased error-related brain activity in youth with obsessive-compulsive disorder and other anxiety disorders

The error-related negativity (ERN) is a negative deflection in the event-related potential after an incorrect response that is thought to reflect activity in the anterior cingulate cortex (ACC) and is often increased in patients with anxiety disorders. This study measured the ERN and correct response negativity (CRN) during an Eriksen flanker task to assess performance monitoring in 26 youth with obsessive-compulsive disorder (OCD), 13 youth with a non-OCD anxiety disorder consisting of either generalized anxiety disorder or separation anxiety disorder, and 27 age-matched healthy controls ranging in age from 8 to 16 years. Compared to healthy controls, ERN amplitude was significantly increased in patients with either OCD or a non-OCD anxiety disorder. There were no significant group differences in CRN amplitude. Treatment with a serotonergic antidepressant or cognitive-behavior therapy had no effect on the ERN in patients. Scores from the Child Behavior Checklist DSM-oriented anxiety problems scale had a significant correlation with ERN amplitude in all subjects. The results provide further evidence that the pathophysiology of OCD and some non-OCD anxiety disorders involves increased ACC activity and that the ERN may serve as a quantitative phenotype in genetic and longitudinal studies of these complex traits.

Deep brain stimulation for obsessive–compulsive disorder is associated with cortisol changes

Deep brain stimulation (DBS) is an effective treatment for obsessive-compulsive disorder (OCD), but its mechanism of action is largely unknown. Since DBS may induce rapid symptomatic changes and the pathophysiology of OCD has been linked to the hypothalamic-pituitary-adrenal (HPA) axis, we set out to study whether DBS affects the HPA axis in OCD patients. We compared a stimulation ON and OFF condition with a one-week interval in 16 therapy-refractory OCD patients, treated with DBS for at least one year, targeted at the nucleus accumbens (NAc). We measured changes in 24-h urinary excretion of free cortisol (UFC), adrenaline and noradrenaline and changes in obsessive-compulsive (Y-BOCS), depressive (HAM-D) and anxiety (HAM-A) symptom scores. Median UFC levels increased with 53% in the OFF condition (from 93 to 143nmol/24h, p=0.12). There were no changes in urinary adrenaline or noradrenaline excretion. The increase in Y-BOCS (39%), and HAM-D (78%) scores correlated strongly with increased UFC levels in the OFF condition. Our findings indicate that symptom changes following DBS for OCD patients are associated with changes in UFC levels.

Obsessive Compulsive Disorder Networks: Positron Emission Tomography and Neuropsychology Provide New Insights

BackgroundDeep brain stimulation has shed new light on the central role of the prefrontal cortex (PFC) in obsessive compulsive disorder (OCD). We explored this structure from a functional perspective, synchronizing neuroimaging and cognitive measures.Methods and FindingsThis case-control cross-sectional study compared 15 OCD patients without comorbidities and not currently on serotonin reuptake inhibitors or cognitive behavioural therapy with 15 healthy controls (matched for age, sex and education level) on resting-state 18FDG-PET scans and a neuropsychological battery assessing executive functions. We looked for correlations between metabolic modifications and impaired neuropsychological scores. Modifications in glucose metabolism were found in frontal regions (orbitofrontal cortex and dorsolateral cortices), the cingulate gyrus, insula and parietal gyrus. Neuropsychological differences between patients and controls, which were subtle, were correlated with the metabolism of the prefrontal, parietal, and temporal cortices.ConclusionAs expected, we confirmed previous reports of a PFC dysfunction in OCD patients, and established a correlation with cognitive deficits. Other regions outside the prefrontal cortex, including the dorsoparietal cortex and the insula, also appeared to be implicated in the pathophysiology of OCD, providing fresh insights on the complexity of OCD syndromes.

706 – 110 years after first report of obsessive compulsive disorder in childhood - where do we stand?

Introduction First case report of paediatric obsessive compulsive disorder (OCD) was presented by Janet in 1903. Since then many more reports of OCD in children and adolescents have been published. OCD in adult patients has been studied in the last decades but studies for pediatric OCD only began in the last 20 years. Objectives To review the most recent knowledge on the characteristics, epidemiology, pathophysiology and treatment of pediatric OCD. Methods Review literature published on MEDLINE/Pubmed database in English language using “obsessive compulsive disorder in childhood”, “obsessive compulsive disorder in children and adolescents”, “OCD in childhood”, “OCD in children and adolescents” and “pediatric OCD” as key-words. Results OCD is common among children and adolescents, with prevalence of 1-3% that often becomes a chronic condition. OCD onset has a bimodal age distribution with one peak at age 11 and other peak in early adulthood. There is a male preponderance in affected children, high comorbidity with psychiatric disorders mainly with tic disorders and attention deficit hyperactivity disorder, higher familiality and higher rates of aggressive/harm obsessions and religious obsessions. The current etiologic model most commonly accepted points to a dysfunction of cortico-striato-thalamic loops. Cognitive behavioural therapy (CBT) and a combination of CBT with a selective serotonin reuptake inhibitor are the treatments of choice for pediatric OCD. Conclusions Pediatric OCD seems to be an OCD subtype with similarities but also with important differences from adultonset OCD. Further research is still needed to better elucidate the genetics and the exact pathophysiology of pediatric OCD.

Reduced dorsolateral prefrontal cortical hemodynamic response in adult obsessive-compulsive disorder as measured by near-infrared spectroscopy during the verbal fluency task

BackgroundNear-infrared spectroscopy has helped our understanding of the neurobiological mechanisms of psychiatric disorders and has advantages including noninvasiveness, lower cost, and ease of use compared with other imaging techniques, like functional magnetic resonance imaging. The verbal fluency task is the most common and well established task used to assess cognitive activation during near-infrared spectroscopy. Recent functional neuroimaging studies have shown that the orbitofrontal cortex and other brain regions, including the dorsolateral prefrontal cortex, may play important roles in the pathophysiology of obsessive-compulsive disorder (OCD). This study aimed to evaluate hemodynamic responses in the dorsolateral prefrontal cortex in patients with OCD using near-infrared spectroscopy during the verbal fluency task and to compare these with dorsolateral prefrontal cortex responses in healthy controls.MethodsTwenty patients with OCD and 20 controls matched for age, gender, handedness, and estimated intelligence quotient participated in this study. The verbal fluency task was used to elicit near-infrared spectroscopic activation and consisted of a 30-second pre-task, followed by three repetitions of a 20-second verbal fluency task (total 60 seconds), followed by a 70-second post-task period. The near-infrared spectroscopy experiment was conducted on the same day as surveys of obsessive-compulsive symptoms, depression, and anxiety. Z-scores for changes in the concentration of oxygenated hemoglobin were compared between the OCD patients and controls in 14 channels set over the left and right dorsolateral prefrontal cortex and frontopolar areas.ResultsDuring the verbal fluency task, significant task-related activation was detected in both the OCD group and the controls. Changes in oxygenated hemoglobin concentration in the right dorsolateral prefrontal cortex were significantly smaller in the OCD group than in the controls, but were not statistically significant after correction for multiple comparisons.ConclusionPatients with OCD have reduced prefrontal, especially right dorsolateral prefrontal, cortical hemodynamic responses as measured by near-infrared spectroscopy during the verbal fluency task. These results support the hypothesis that the dorsolateral prefrontal cortex plays a role in the pathophysiology of OCD.

Neurohemodynamic Correlates of Washing Symptoms in Obsessive-compulsive Disorder: A Pilot fMRI Study Using Symptom Provocation Paradigm

Background:Obsessive-compulsive disorder (OCD) is increasingly being viewed as a multidimensional heterogeneous disorder caused due to the dysfunction of several closely related, overlapping frontostriatal circuits. A study investigating the dimensional construct in treatment naïve, co-morbidity free patients with identical handedness is likely to provide the necessary homogeneity and power to elicit neural correlates of the various symptom dimensions, and overcome the limitations of previous studies.Materials and Methods:Nine DSM-IV OCD patients with predominant contamination-related obsessive-compulsive symptoms (age=29.8±7.1 years; five males: four females; years-of-education=13.9±1.6, YBOCS total score=28.8±4.7, DYBOCS Contamination dimension score=10.7±1.8) and nine healthy controls matched one to one with the patients for age, sex, and years of education (age=27.8±5.4, five males: four females; years-of-education=14.9±3.0), were examined during symptom provocation task performance in 3TMRI. Paired samples t test of brain activation differences (contamination relevant pictures – neutral pictures), limited to apriori regions of interest was done using SPM8 (uncorrected P<0.005).Results:Patients found significantly more pictures to be anxiety provoking in comparison to healthy controls. Patients were found to have deficient activation in the following areas in comparison with healthy controls: bilateral anterior prefrontal, dorsolateral prefrontal, orbitofrontal, anterior cingulate, insular and parietal cortices, precuneus, and caudate.Conclusions:Results underscore the importance of frontal, striatal, parietal, and occipital areas in the pathophysiology of OCD. Divergence of findings from previous studies might be attributed to the absence of confounding factors in the current study and may be due to production of intense anxiety in patients.

Abnormal corticostriatal-limbic functional connectivity in obsessive–compulsive disorder during reward processing and resting-state

Compulsive behaviors in obsessive–compulsive disorder (OCD) may be related to deficits in reward processing mediated by corticostriatal circuitry, a brain network implicated in the pathophysiology of OCD. Performing compulsive actions can be perceived as a reward to OCD patients because it temporarily reduces the anxiety provoked by obsessions. Although most OCD literature provides evidence of altered regional activity in these corticostriatal circuits, very little is known about the connectivity between individual regions of the corticostriatal-limbic circuits, including the cognitive and affective neural circuitry associated with OCD. Thus, this study investigated the differences in functional connectivity (FC) patterns in this network during resting-state and incentive processing. Nineteen patients with OCD and 18 well-matched healthy controls were scanned during resting-state and a monetary incentive delay task (task state). FC was assessed using both voxel-wise and region-of-interest (ROI)-wise analyses. Voxel-wise FC analysis with the nucleus accumbens seed revealed that patients with OCD exhibited increased FC between the nucleus accumbens and the lateral orbitofrontal cortex during resting-state. Additionally, these patients showed decreased FC between the nucleus accumbens and limbic areas such as the amygdala during incentive processing. Exploratory ROI-wise FC analysis revealed that OCD patients demonstrated enhanced FC between the nucleus accumbens and the lateral orbitofrontal cortex and increased total connectivity of the lateral orbitofrontal cortex during resting-state. Additionally, patients showed alterations in FC between resting and task state. This study provides evidence that patients with OCD have altered FC in the corticostriatal-limbic network, particularly in striatal-amygdala and striatal-orbitofrontal circuitry, during incentive processing and resting-state. These findings also emphasize that functional connections in the network are modulated by affective/motivational states and further suggest that OCD patients may have abnormalities of such modulation in this network.

2148 – Agomelatine augmentation in obsessive compulsive disorder

Introduction Augmentation treatment has been the subject of several studies in treatment-resistant obsessive compulsive disorder (OCD). We hypothesized that medications with a dual action on the melatoninergic and serotoninergic systems may be of use in treatment-resistant OCD. Objectives/aims In this open label study we investigated the efficacy and safety of agomelatine augmentation in treatmentresistant OCD. Methods Twelve patients, aged 18–50, fulfilling OCD criteria, with no response to a 16-week or longer treatment with a selective serotonine reuptake inhibitor (SSRI) at the indicated dose, were assigned to receive agomelatine augmentation. Subjects were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), and were screened for treatmentemergent side effects at baseline, week 8 and week 12 of treatment. Results The overall Y-BOCS score fell during the duration of the study (all comparisons among baseline, 8 th week and 16 th week were statistically significant, p th week of the study (p th week of the study (p Conclusion Agomelatine could be efficacious and well tolerated as an augmenting agent in refractory to treatment OCD. Further controlled studies are warranted to explore the efficacy of agomelatine, as well as the potential role of circadian rhythm modulation both in the pathophysiology and treatment of OCD.

INCREASED ERROR-RELATED BRAIN ACTIVITY IN YOUTH WITH OBSESSIVE-COMPULSIVE DISORDER AND UNAFFECTED SIBLINGS

The pathophysiology of obsessive-compulsive disorder (OCD) involves increased activity in cortico-striatal circuits connecting the anterior cingulate cortex (ACC) with other brain regions. The error-related negativity (ERN) is a negative deflection in the event-related potential following an erroneous response and is thought to reflect ACC activity. This study was done to assess the ERN as a biomarker for OCD by comparing ERN amplitudes in pediatric OCD patients, unaffected siblings of pediatric OCD patients, and healthy controls. The ERN and correct response negativity (CRN) were measured during an Eriksen flanker task to assess performance monitoring in 40 youth with a lifetime diagnosis of OCD, 19 unaffected siblings of OCD patients, and 40 unrelated healthy comparison subjects ranging in age from 10 to 17 years. ERN and CRN amplitudes were compared between groups using linear regression by the generalized estimating equation method to account for correlated data. Compared to healthy controls, ERN amplitude was significantly increased in both pediatric OCD patients and unaffected siblings. There were no significant group differences in CRN amplitude. ERN amplitude in patients was unrelated to OCD symptom severity, current diagnostic status, or treatment effects. Increased error-related brain potentials were observed not only in pediatric OCD patients but also in unaffected siblings. The results provide evidence that enhanced error-related brain activity may serve as a biomarker for OCD in youth that is independent of the presence of clinical symptoms. The ERN may be a useful quantitative phenotype in genetic studies of OCD.

Translational Research in OCD: Circuitry and Mechanisms

Although the pathophysiology of obsessive-compulsive disorder (OCD) remains unknown, converging lines of evidence point to abnormalities in the orbital (OFC), ventromedial (vmPFC-subgenual cingulate and medial OFC), and dorsal anterior cingulate (dACC) cortical-basal ganglia circuits. OCD-linked patterns of activity in these PFC regions are accentuated during provocation of symptoms and can predict treatment response; they tend to normalize following successful treatment (Greenberg et al, 2010). Moreover, neurosurgical interventions (lesions or deep brain stimulation-DBS) within the ventral internal capsule (VC), ventral striatum (VS), or dACC (treatments for intractable OCD) all act on subcomponents of the vmPFC/OFC/dACC-basal ganglia network (Greenberg et al, 2010). Indeed, DBS interventions specifically affect vmPFC, OFC, and possibly dACC connections with striatum, thalamus, and/or brainstem (Figure 1) (Lehman et al, 2011). The efficacy of VC/VS DBS (or lesions) for OCD likely requires modulating the OFC/vmPFC/dACC-basal ganglia circuit. Interestingly, high frequency stimulation (HFS) in a rat homolog of the VC/VS DBS target reduces OFC activity, enhances local field potential delta band activity in OFC, and enhances synchrony between specific regions within this prefrontal network (McCracken and Grace, 2009). Thus, OCD pathophysiology likely represents dysfunctional network interactions rather than only disruption within specific structures.