Pathophysiology Of Obsessive-compulsive Disorder Research Articles

N-acetylcysteine: An Innovative Approach to Obsessive-Compulsive Disorder Treatment: A Narrative Review

Abstract Obsessive-compulsive disorder (OCD) is a chronic mental illness defined by recurrent, intrusive thoughts (called obsessions) and repetitive actions or ideas (called compulsions). Selective serotonin reuptake inhibitors and cognitive-behavioural therapy are currently the first-line treatments. Alternative therapeutic approaches must be developed because many patients still resist conventional medicines. There is increasing evidence that glutamate, rather than serotonin, is an essential factor in the pathophysiology of OCD. N-acetylcysteine (NAC) is a supplement that targets the glutamatergic system and is derived from the amino acids. Numerous preclinical and clinical trials suggest that NAC improves OCD sufferers. Numerous suggested processes, such as the control of various neurotransmitters, oxidative equilibrium and inflammatory mediators, have been brought up to explain the therapeutic benefits of NAC. This narrative review focuses on the effect of NAC, a glutamate-modulating agent, as an augmentation in the treatment of OCD. This article reviews the clinical trials, case reports and case series exploring using NAC for OCD. We thoroughly searched PubMed, Scopus and Google Search engines to identify the relevant trials published until December 2024. Critical words for searching included (‘N acetylcysteine’ OR NAC OR ‘Glutamatergic agents’) AND (‘Obsessive-compulsive disorder’ OR OCD). NAC’s clinical effectiveness has not been identified despite pre-clinical research suggesting that it improves the animal models of OCD. Although NAC is still a promising adjunct treatment option for OCD, more research with larger sample sizes is needed to confirm these results and develop conclusions about how effectively NAC works to improve the OCD symptoms.

Functional MRI-Specific Alternations in default mode network in obsessive-compulsive disorder: A voxel-based meta-analysis.

Obsessive-compulsive disorder (OCD) is a common and debilitating mental disorder. Neuroimaging studies have highlighted that the dysfunctional default mode network (DMN) plays a key role in the pathophysiology mechanisms of OCD. However, the findings of impaired DMN regions have been inconsistent. We employed meta-analysis to identify the fMRI-specific abnormalities of the DMN in OCD. PubMed, Web of science and Embase were searched to screen resting-state functional magnetic resonance imaging (rs-fMRI) studies on the amplitude of low-frequency fluctuation/fractional amplitude of low-frequency fluctuation (ALFF/fALFF) and regional homogeneity (ReHo) of the DMN in OCD patients. Based on the activation likelihood estimation (ALE) algorithm, we compared all patients with OCD and control group in a primary meta-analysis, and analyzed the unmedicated OCD without comorbidities in secondary meta-analyses. A total of 26 eligible studies with 1219 OCD patients (707men) and 1238 healthy controls (684 men) were included in the primary meta-analysis. We concluded specific changes in brain regions of DMN, mainly in the left medial frontal gurus (MFG), bilateral superior temporal gyrus (STG), bilateral inferior parietal lobule (IPL), bilateral precuneus (PCUN), bilateral posterior cingulate cortex (PCC), and right parahippocampal gyrus (PHG). OCD patients showed dysfunction in the DMN, including impaired local important nodal brain regions. The PCC/PCUN appear to be the most affected regions within the DMN, providing valuable insights into understanding the potential pathophysiology of OCD and targets for clinical interventions.

Reduced pineal gland volume in patients with obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) can have hyperactivity of the hypothalamic-pituitary-adrenal axis and may have increased secretion of adrenocorticotropic hormone and cortisol and reduced secretion of melatonin. Examination of pineal gland volumes in patients with OCD compared to healthy controls, thus, is an important consideration and the focus of this study. A total of 20 patients with OCD and 20 healthy controls were enrolled. Demographic and clinical characteristics of participants were assessed, and structural magnetic resonance imaging was performed. Patients with OCD had a statistically significant smaller pineal gland volumes compared to healthy controls. In this initial small study, patients with OCD exhibited smaller pineal gland volumes compared to healthy control subjects. While this finding suggests a potential link between the pineal gland and OCD pathophysiology, further research with larger sample sizes and measurement of hormonal changes are necessary.

Metaanalysis of Repetitive Transcranial Magnetic Stimulation (rTMS) Efficacy for OCD Treatment: The Impact of Stimulation Parameters, Symptom Subtype and rTMS-Induced Electrical Field.

Background: Repetitive transcranial magnetic stimulation (rTMS) has recently demonstrated significant potential in treating obsessive-compulsive disorder (OCD). However, its effectiveness depends on various parameters, including stimulation parameters, OCD subtypes and electrical fields (EFs) induced by rTMS in targeted brain regions that are less studied. Methods: Using the PRISMA approach, we examined 27 randomized control trials (RCTs) conducted from 1985 to 2024 using rTMS for the treatment of OCD and conducted several meta-analyses to investigate the role of rTMS parameters, including the EFs induced by each rTMS protocol, and OCD subtypes on treatment efficacy. Results: A significant, medium effect size was found, favoring active rTMS (gPPC = 0.59, p < 0.0001), which was larger for the obsession subscale. Both supplementary motor area (SMA) rTMS (gPPC = 0.82, p = 0.048) and bilateral dorsolateral prefrontal cortex (DLPFC) rTMS (gPPC = 1.14, p = 0.04) demonstrated large effect sizes, while the right DLPFC showed a significant moderate effect size for reducing OCD severity (gPPC = 0.63, p = 0.012). These protocols induced the largest EFs in dorsal cognitive, ventral cognitive and sensorimotor circuits. rTMS protocols targeting DLPFC produced the strongest electrical fields in cognitive circuits, while pre-supplementary motor area (pre-SMA) and orbitofrontal cortex (OFC) rTMS protocols induced larger fields in regions linked to emotional and affective processing in addition to cognitive circuits. The pre-SMA rTMS modulated more circuits involved in OCD pathophysiology-sensorimotor, cognitive, affective, and frontolimbic-with larger electrical fields than the other protocols. Conclusions: While rTMS shows moderate overall clinical efficacy, protocols targeting ventral and dorsal cognitive and sensorimotor circuits demonstrate the highest potential. The pre-SMA rTMS appears to induce electrical fields in more circuits relevant to OCD pathophysiology.

Exploring functional connectivity in large-scale brain networks in obsessive-compulsive disorder: a systematic review of EEG and fMRI studies.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric condition that is difficult to treat due to our limited understanding of its pathophysiology. Functional connectivity in brain networks, as evaluated through neuroimaging studies, plays a pivotal role in understanding OCD. While both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have been extensively employed in OCD research, few have fully synthesized their findings. To bridge this gap, we reviewed 166 studies (10 EEG, 156 fMRI) published up to December 2023. In EEG studies, OCD exhibited lower connectivity in delta and alpha bands, with inconsistent findings in other frequency bands. Resting-state fMRI studies reported conflicting connectivity patterns within the default mode network (DMN) and sensorimotor cortico-striato-thalamo-cortical (CSTC) circuitry. Many studies observed decreased resting-state connectivity between the DMN and salience network (SN), implicating the 'triple network model' in OCD. Task-related hyperconnectivity within the DMN-SN and hypoconnectivity between the SN and frontoparietal network suggest OCD-related cognitive inflexibility, potentially due to triple network dysfunction. In conclusion, our review highlights diverse connectivity differences in OCD, revealing complex brain network interplay that contributes to symptom manifestation. However, the presence of conflicting findings underscores the necessity for targeted research to achieve a comprehensive understanding of the pathophysiology of OCD.

Prospects for using N-acetylcysteine in the treatment of obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) primarily has its clinical manifestations due to dysfunction in the glutamatergic system and modulation of inflammatory cytokines. Dysregulation of the glutamatergic system, the primary excitatory neurotransmitter system in the human brain, is directly related to the pathophysiology of OCD. Indeed, this system is critical for neuroplasticity, learning and memory, and recent studies have identified glutamatergic abnormalities in people with OCD. The worldwide prevalence of OCD is estimated at 2-3%, and this figure may be underestimated due to frequent misdiagnosis. Current first-line treatments include selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT). However, a significant proportion of patients remain refractory to these treatments, necessitating the search for alternative therapeutic strategies. This article examines the potential use of N-acetylcysteine (NAC) as an alternative treatment for obsessive-compulsive disorder.

Exploring the role of interleukin-1β and interleukin-6 in the pathophysiology of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder. Recently, there has been a growing interest in investigating the association between pro-inflammatory cytokines and the pathogenesis of OCD. However, studies targeting interleukin-1β (IL-1β) and interleukin-6 (IL-6) in OCD are limited. Therefore, the present study aimed to explore the potential role of pro-inflammatory cytokines IL-1β and IL-6 in the pathophysiology and development of OCD. This study recruited 58 OCD patients and 30 age-sex-matched healthy controls (HCs). A qualified psychiatrist diagnosed OCD patients and assessed HCs based on the Diagnostic and Statistical Manual for Mental Health Disorders, 5th edition (DSM-5) criteria. We measured the severity of OCD using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Serum IL-1β and IL-6 levels were measured using ELISA kits following the appropriate methods. The results showed that serum IL-1β levels were significantly elevated in OCD patients compared to HCs (23.68±1.65 pg/ml vs. 15.75±1.02 pg/ml; p = 0.002). Similarly, OCD patients exhibited significantly higher serum IL-6 levels than HCs (44.97±0.73 pg/ml vs. 37.04±0.35 pg/ml; p<0.001). We observed both cytokines were positively correlated with the Y-BOCS scores in OCD patients (IL-1β: r = 0.380, p = 0.015; IL-6: r = 0.324, p = 0.026) which indicates their role in disease pathophysiology. These results suggest that serum IL-1β and IL-6 levels may be associated with the pathophysiology of OCD. Also, these cytokines levels in blood samples can serve as early risk assessment tools for the development of OCD. We recommend further studies in a large and homogeneous population to support these findings.

Executive Functions’ Alterations In Obsessive-Compulsive Disorder: A Systematic Literature Review

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder characterized by persistent obsessive and compulsive symptoms. Dysfunctions in two inhibitory systems related to cognitive and behavioral processes are believed to be associated with the pathophysiology of OCD. These dysfunctions can affect not only the cognitive and behavioral symptoms, but also the neuropsychological deficits observed in this disorder, such as attention, memory, planning, and decision-making. This study presents a systematic literature review aiming to investigate alterations in executive functions in individuals with OCD. The search was conducted in the Scopus and Scielo databases, resulting in a final sample of 13 articles that met the inclusion criteria. The results indicated deficiencies in executive functions and non-verbal memory in patients with OCD when compared to healthy control groups. However, there were inconsistencies in the results across studies, possibly due to the variety of tests used and the complexity of the disorder. Therefore, it is important to consider factors such as cultural differences, medication use, and socioeconomic factors when interpreting the results, as these aspects can influence the study outcomes. Additionally, there are still gaps in understanding the alterations in executive functions in patients with OCD, requiring further research for a better comprehension of this relationship.

Increases in functional connectivity between the default mode network and sensorimotor network correlate with symptomatic improvement after transcranial direct current stimulation for obsessive-compulsive disorder

BackgroundNon-invasive neuromodulation is a promising intervention for obsessive-compulsive disorder (OCD), although its neurobiological mechanisms of action are still poorly understood. Recent evidence suggests that abnormalities in the connectivity of the default mode network (DMN) and the supplementary motor area (SMA) with other brain regions and networks are involved in OCD pathophysiology. We examined if transcranial direct current stimulation (tDCS) alters these connectivity patterns and if they correlate with symptom improvement in treatment-resistant OCD. MethodsIn 23 patients from a larger clinical trial (comparing active tDCS to sham) who underwent pre- and post-treatment MRI scans, we assessed resting-state functional MRI (rs-fMRI) data. The treatment involved 30-minute daily tDCS sessions for four weeks (weekdays only), with the cathode over the SMA and the anode over the left deltoid. We conducted whole-brain connectivity analysis comparing active tDCS-treated to sham-treated patients. ResultsWe found that active tDCS, but not sham, led to connectivity increasing between the DMN and the bilateral pre/postcentral gyri (p = 0.004, FDR corrected) and temporal-auditory areas plus the SMA (p = 0.028, FDR corrected). Also, symptom improvement was directly associated with connectivity increasing between the left lateral sensorimotor network and the left precuneus (r = 0.589, p = 0.034). LimitationsLimited sample size (23 participants with resting-state neuroimaging), inability to analyze specific OCD symptom dimensions (e.g., harm, sexual/religious, symmetry/checking, cleaning/contamination). ConclusionsThese data offer novel information concerning functional connectivity changes associated with non-invasive neuromodulation interventions in OCD and can guide new brain stimulation interventions in the framework of personalized interventions.

Heart rate and heart rate variability in obsessive-compulsive disorder: Evidence from patients and unaffected first-degree relatives

Altered heart rate (HR) and heart rate variability (HRV) are common observations in psychiatric disorders. Yet, few studies have examined these cardiac measures in obsessive-compulsive disorder (OCD). The current study aimed to investigate HR and HRV, indexed by the root mean square of successive differences (RMSSD) and further time domain indices, as putative biological characteristics of OCD. Electrocardiogram was recorded during a five-minute resting state. Group differences between patients with OCD (n = 96), healthy participants (n = 112), and unaffected first-degree relatives of patients with OCD (n = 47) were analyzed. As potential moderators of group differences, we examined the influence of age and medication, respectively. As results indicated, patients with OCD showed higher HR and lower HRV compared to healthy participants. These group differences were not moderated by age. Importantly, subgroup analyses showed that only medicated patients displayed lower HRV compared to healthy individuals, while HR alterations were evident in unmedicated patients. Regarding unaffected first-degree relatives, group differences in HRV remained at trend level. Further, an age-moderated group differentiation showed that higher HRV distinguished relatives from healthy individuals in young adulthood, whereas at higher age lower HRV was indicative of relatives. Both the role of familial risk and medication in HRV alterations need further elucidation. Pending future studies, alterations in HR and potentially HRV might serve as useful indices to characterize the pathophysiology of OCD.

Selective alterations of endocannabinoid system genes expression in obsessive compulsive disorder

Obsessive Compulsive Disorder (OCD) is listed as one of the top 10 most disabling neuropsychiatric conditions in the world. The neurobiology of OCD has not been completely understood and efforts are needed in order to develop new treatments. Beside the classical neurotransmitter systems and signalling pathways implicated in OCD, the possible involvement of the endocannabinoid system (ECS) has emerged in pathophysiology of OCD. We report here selective downregulation of the genes coding for enzymes allowing the synthesis of the endocannabinoids. We found reduced DAGLα and NAPE-PLD in blood samples of individuals with OCD (when compared to healthy controls) as well as in the amygdala complex and prefrontal cortex of dopamine transporter (DAT) heterozygous rats, manifesting compulsive behaviours. Also mRNA levels of the genes coding for cannabinoid receptors type 1 and type 2 resulted downregulated, respectively in the rat amygdala and in human blood. Moreover, NAPE-PLD changes in gene expression resulted to be associated with an increase in DNA methylation at gene promoter, and the modulation of this gene in OCD appears to be correlated to the progression of the disease. Finally, the alterations observed in ECS genes expression appears to be correlated with the modulation in oxytocin receptor gene expression, consistently with what recently reported. Overall, we confirm here a role for ECS in OCD at both preclinical and clinical level. Many potential biomarkers are suggested among its components, in particular NAPE-PLD, that might be of help for a prompt and clear diagnosis.

Targeting the prefrontal-supplementary motor network in obsessive-compulsive disorder with intensified electrical stimulation in two dosages: a randomized, controlled trial

Obsessive-compulsive disorder (OCD) is associated with a high disease burden, and treatment options are limited. We used intensified electrical stimulation in two dosages to target a main circuitry associated with the pathophysiology of OCD, left dorsolateral prefrontal cortex (l-DLPFC), and pre-supplementary motor area (pre-SMA) and assessed clinical outcomes, neuropsychological performance, and brain physiology. In a double-blind, randomized controlled trial, thirty-nine patients with OCD were randomly assigned to three groups of sham, 2-mA, or 1-mA transcranial direct current stimulation (tDCS) targeting the l-DLPFC (F3) and pre-SMA (FC2) with anodal and cathodal stimulation respectively. The treatment included 10 sessions of 20-minute stimulation delivered twice per day with 20-min between-session intervals. Outcome measures were reduction in OCD symptoms, anxiety, and depressive states, performance on a neuropsychological test battery (response inhibition, working memory, attention), oscillatory brain activities, and functional connectivity. All outcome measures except EEG were examined at pre-intervention, post-intervention, and 1-month follow-up times. The 2-mA protocol significantly reduced OCD symptoms, anxiety, and depression states and improved quality of life after the intervention up to 1-month follow-up compared to the sham group, while the 1-mA protocol reduced OCD symptoms only in the follow-up and depressive state immediately after and 1-month following the intervention. Both protocols partially improved response inhibition, and the 2-mA protocol reduced attention bias to OCD-related stimuli and improved reaction time in working memory performance. Both protocols increased alpha oscillatory power, and the 2-mA protocol decreased delta power as well. Both protocols increased connectivity in higher frequency bands at frontal-central areas compared to the sham. Modulation of the prefrontal-supplementary motor network with intensified tDCS ameliorates OCD clinical symptoms and results in beneficial cognitive effects. The 2-mA intensified stimulation resulted in larger symptom reduction and improved more converging outcome variables related to therapeutic efficacy. These results support applying the intensified prefrontal-SMA tDCS in larger trials.

Human microbiota from drug-naive patients with obsessive-compulsive disorder drives behavioral symptoms and neuroinflammation via succinic acid in mice.

Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive-compulsive disorder (OCD). Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice and showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16 S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota-brain-immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice. We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.

Age of onset of obsessive-compulsive disorder differentially affects white matter microstructure

Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges by harmonizing data collection to identify consistent brain signatures of OCD that are reproducible and generalizable. Single-shell diffusion measures (e.g., fractional anisotropy), multi-shell Neurite Orientation Dispersion and Density Imaging (NODDI) and fixel-based measures, were extracted from skeletonized white matter tracts in 260 medication-free adults with OCD and 252 healthy controls. We additionally performed structural connectome analysis. We compared cases with controls and cases with early (<18) versus late (18+) OCD onset using mixed-model and Bayesian multilevel analysis. Compared with healthy controls, adult OCD individuals showed higher fiber density in the sagittal stratum (B[SE] = 0.10[0.05], P = 0.04) and credible evidence for higher fiber density in several other tracts. When comparing early (n = 145) and late-onset (n = 114) cases, converging evidence showed lower integrity of the posterior thalamic radiation —particularly radial diffusivity (B[SE] = 0.28[0.12], P = 0.03)—and lower global efficiency of the structural connectome (B[SE] = 15.3[6.6], P = 0.03) in late-onset cases. Post-hoc analyses indicated divergent direction of effects of the two OCD groups compared to healthy controls. Age of OCD onset differentially affects the integrity of thalamo-parietal/occipital tracts and the efficiency of the structural brain network. These results lend further support for the role of the thalamus and its afferent fibers and visual attentional processes in the pathophysiology of OCD.

Esketamine Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: A Retrospective Chart Review.

Converging evidence supports the role of the glutamate, an excitatory amino acid neurotransmitter, in the pathophysiology of obsessive-compulsive disorder (OCD). Ketamine and esketamine, both noncompetitive N -methyl- d -aspartate antagonists, have emerged as a promising medication for this psychiatric disorder, given its possible efficacy with faster onset and good tolerability. The purpose of this retrospective chart review is to evaluate whether unbiased clinical documentation supports formal clinical trials of esketamine for an OCD indication. A retrospective chart review of patients with treatment-resistant OCD receiving a single dose of esketamine (0.5mg/kg) added to standard therapy was conducted. The Yale-Brown Obsessive-Compulsive Scale and the Montgomery-Åsberg Depression Rating Scale were used to evaluate OCD and depressive symptoms respectively at baseline, 24 hours, and 7 days after esketamine administration. Descriptive statistics were used to analyze the data. Eight subjects were identified in this retrospective chart review: esketamine was administered subcutaneously in 7 and intravenously in 1. One week after infusion, 25% of the sample met criteria for treatment response and 50% for partial response. Major depressive disorder was a comorbid diagnosis in 75% of the sample and 2 of these subjects showed a positive antidepressant response. Our findings provide preliminary evidence that esketamine may reduce obsessive-compulsive symptoms in a subset of treatment-resistant OCD patients.

Drug repurposing for obsessive-compulsive disorder using deep learning-based binding affinity prediction models.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disease in which patients suffer from obsessions compelling them to engage in specific rituals as a temporary measure to alleviate stress. In this study, deep learning-based methods were used to build three models which predict the likelihood of a molecule interacting with three biological targets relevant to OCD, SERT, D2, and NMDA. Then, an ensemble model based on those models was created which underwent external validation on a large drug database using random sampling. Finally, case studies of molecules exhibiting high scores underwent bibliographic validation showcasing that good performance in the ensemble model can indicate connection with OCD pathophysiology, suggesting that it can be used to screen molecule databases for drug-repurposing purposes.

Potential biomarkers and therapeutic targets for obsessive compulsive disorder: Evidences from clinical studies.

Obsessive compulsive disorder (OCD) is a prevalent behavioral disorder with a complex etiology. However, the underlying pathogenic molecular pathways and the associated risk factors are largely obscure. This has hindered both the identification of relevant prognostic biomarkers and the development of effective treatment strategies. Because of the diverse range of clinical manifestations, not all patients benefit from therapies currently practiced in the clinical setting. Nevertheless, several lines of evidence indicate that neurotrophic, neurotransmitter, and oxidative signaling are involved in the pathophysiology of OCD. Based upon evidences from clinical (and pre-clinical studies), the present review paper sets out to decipher the utilities of three parameters (i.e. brain-derived neurotrophic factor; BDNF, noradrenalin-synthesizing enzyme dopamine beta-hydroxylase; DBH; and oxidative damage marker malondialdehyde; MDA) as diagnostic peripheral biomarkers as well as bio-targets for therapeutic strategies. While the data indicates promising results, there is necessitation for future studies to further confirm and establish these. Further, based again on the available clinical data, we investigated the possibilities of exploiting the etiological links between disruptions in the sleep-wake cycle and insulin signaling, and OCD for the identification of potential anti-OCD ameliorative agents with the ability to elicit multimodal effects, including attenuation of the alterations in BDNF, noradrenergic and redox pathways. In this respect, agomelatine and metformin may represent particularly interesting candidates; however, further clinical studies are warranted to establish these as singular or complementary medications in OCD subjects.

Identifying risk loci for obsessive-compulsive disorder and shared genetic component with schizophrenia: A large-scale multi-trait association analysis with summary statistics

Due to limited samples, no genetic loci have been identified for obsessive-compulsive disorder (OCD) in genome-wide association studies. Additionally, although co-morbidities between OCD and schizophrenia (SCZ) were observed, their common genetic etiology was not completely known. Here, we conducted a comprehensive investigation regarding the genetic architecture of OCD and the common genetic foundation shared by OCD and SCZ using summary statistics data (2688 cases and 7037 controls for OCD; 53,386 cases and 77,258 controls for SCZ). We discovered significant genetic correlation between OCD and SCZ (r̂g=0.296, P = 2.82 × 10−11). We then performed two multi-trait association analyses to detect OCD-associated loci and colocalization analysis to detect causal variants. Parallel gene-level analyses were also implemented. We identified 323 OCD-relevant variants located within 12 loci, with four loci shared the same causal variants between OCD and SCZ. Further, the gene-level analyses discovered 8 OCD-associated genes. Finally, multiple functional analyses at both SNP and gene levels showed that these genetic association signals had significant enrichments in the regions of left ventricle and anterior cingulate cortex, and suggested an important role of pathways involving regulation of telomere maintenance, histone phosphorylation, and GnRH secretion. Overall, this study identified new genetic loci for OCD and provided substantial evidence supporting common genetic foundation underlying OCD and SCZ. The findings advanced our understanding of genetic architecture and pathophysiology of OCD as well as shedding light on shared genetic etiology of the two disorders.

Disgust-reduction evaluative conditioning (DREC) and brain stimulation in patients with contamination-based obsessive-compulsive disorder: a protocol for a randomized control trial

BackgroundThe negative emotional valence of a stimulus can be altered if paired with a pleasant stimulus, a phenomenon referred to as evaluative conditioning. Disgust, as a central emotion in obsessive-compulsive disorder (OCD), particularly in the contamination subtype, may be an appropriate target for such a method. We know that disgust processing and OCD pathophysiology share in some brain areas, including the orbitofrontal cortex, as the neuromodulation techniques targeted in this area have been able to decrease OCD symptoms. We aim to conduct a randomized clinical trial to investigate the evaluative conditioning effect on disgust reduction in patients with contamination-based OCD when administered with or without neuromodulation targeted orbitofrontal cortex.MethodIn a single-blind randomized control trial (RCT), 55 patients with contamination-based OCD will be randomly assigned to four arms. In a factorial design, they will receive 10 sessions of evaluative conditioning training (either sham or real) plus cathodal transcranial direct current stimulation (tDCS) over the orbitofrontal cortex (either sham or real). The intensity of disgust experience and clinical symptoms will be investigated as primary outcomes and quantitative electroencephalogram and cognitive functions as secondary outcomes. The data will be collected at three assessment levels: baseline, after completing intervention sessions, and 2-month follow-up.DiscussionThe present RCT is the first study that applies evaluative conditioning training in the OCD clinical sample. It will clarify the effect of the evaluative conditioning method alone and with tDCS on disgust reduction in patients with contamination-based OCD. It will provide initial evidence for such an emotion modulation method in the OCD population. The effect of this emotion-focused protocol on cognitive functions and electroencephalogram components is also of interest.Trial registrationClinicalTrials.gov, NCT05907369. Registered on 16 June 2023. Retrospectively registered.

Proton magnetic resonance spectroscopy-based evaluation of metabolic abnormalities in the right dorsolateral prefrontal cortex and caudate nucleus in treatment-naïve patients with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder whose underlying pathophysiology is insufficiently understood. The pathophysiology of OCD may be related to abnormalities in the biochemistry of neurotransmitters. The aim of the present study was to measure the absolute concentration of various metabolites in the right dorsolateral prefrontal cortex (DLPFC) and caudate nucleus (CN) in treatment-naive patients with OCD and compare it with healthy controls (HCs). The present study investigated the metabolic profile of two brain regions, namely right DLPFC and CN, by using single voxel in-vivo proton magnetic resonance spectroscopy (1H MRS) in drug-naive patients with OCD (n = 17, mean age = 30.71 ± 10.104 years) and compared it with healthy controls (n = 13, mean age = 30.77 ± 5.449 years). The patients with OCD were recruited after appropriate psychometric assessments. The 1H-MRS experiments were performed using the 3 Tesla (3T) human MR scanner, and absolute concentrations of metabolites were estimated using the LC model. Significantly lower concentration of tNAA in the right DLPFC was observed in the patients with OCD compared to the controls, which may be indicative of neurodegeneration in this region. However, no significant differences were observed in the concentrations of the metabolites between the patients and controls in the CN region. The level of tNAA in DLPFC significantly correlated with the disability level (WHO-DAS) of the patients. The present study demonstrates abnormalities in the metabolic profile of an important region, DLPFC of the CSTC circuit, which is suggestive of neurodegeneration in the region in OCD patients.