Off-label higher doses of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: Safety and tolerability.

OBJECTIVE: To examine the long-term safety and tolerability of off-label high-dose serotonin reuptake inhibitors (OLHD-SRIs) in the treatment of obsessive-compulsive disorder (OCD). METHODS: A retrospective longitudinal study was performed on 105 randomly selected outpatients diagnosed with OCD and were treated with OLHD-SRIs for at least 6 months. Patients received sertraline >200 mg/day, escitalopram >20 mg/day, fluvoxamine >300 mg/day, and fluoxetine >60 mg/day, combined with exposure and response prevention therapy. Patients were divided into three dosing groups: sertraline equivalent dose (SED) ≤ 200 mg/day (n = 26, 24.7%), 201-400 mg/day (n = 51, 48.5%) and 401-650 mg/day (n = 28, 26.6%). Safety and tolerability were assessed with an electrocardiogram, blood biochemistry, complete blood count, and side-effects monitoring. RESULTS: SED ranged from 100 to 650 mg/day and the mean duration of OLHD-SRI treatment was 20.8 months. The most common side-effects reported were sexual dysfunction (n = 36, 34%), weight gain (n = 28, 27%), sedation (n = 27, 26%), hyperhidrosis (n = 20, 19%), and tremor (n = 11, 10%). Abnormal ECG was documented in one patient, and another patient experienced a first-time seizure, whereas elevated liver enzymes were seen in 4.8% of the sample (n = 5). None of the patients had serotonin syndrome or drug-induced liver injury. Side-effects did not differ among the three dosing groups. CONCLUSION: OLHD-SRIs appear to be safe and well tolerated in OCD patients in SED ≤ 650 mg/day doses and the side-effects did not differ between the three dosing groups.

Real-Time Real-World Digital Monitoring of Adolescent Suicide Risk During the Six Months Following Emergency Department Discharge: Protocol for an Intensive Longitudinal Study.

BACKGROUND: Suicide is the second leading cause of death in adolescents, and self-harm is one of the strongest predictors of death by suicide. The rates of adolescents presenting to emergency departments (EDs) for suicidal thoughts and behaviors (STBs) have increased. Still, existing follow-up after ED discharge is inadequate, leaving a high-risk period for reattempts and suicide. There is a need for innovative evaluation of imminent suicide risk factors in these patients, focusing on continuous real-time evaluations with low assessment burden and minimal reliance on patient disclosure of suicidal intent. OBJECTIVE: This study examines prospective longitudinal associations between observed real-time mobile passive sensing, including communication and activity patterns, and clinical and self-reported assessments of STB over 6 months. METHODS: This study will include 90 adolescents recruited on their first outpatient clinic visit following their discharge from the ED due to a recent STB. Participants will complete brief weekly assessments and be monitored continuously for their mobile app usage, including mobility, activity, and communication patterns, over 6 months using the iFeel research app. Participants will complete 4 in-person visits for clinical assessment at baseline and at the 1-, 3-, and 6-month follow-ups. The digital data will be processed, involving feature extraction, scaling, selection, and dimensionality reduction. Passive monitoring data will be analyzed using both classical machine learning models and deep learning models to identify proximal associations between real-time observed communication, activity patterns, and STB. The data will be split into a training and validation data set, and predictions will be matched against the clinical evaluations and self-reported STB events (ie, labels). To use both labeled and unlabeled digital data (ie, passively collected), we will use semisupervised methods in conjunction with a novel method that is based on anomaly detection notions. RESULTS: Participant recruitment and follow-up started in February 2021 and are expected to be completed by 2024. We expect to find prospective proximal associations between mobile sensor communication, activity data, and STB outcomes. We will test predictive models for suicidal behaviors among high-risk adolescents. CONCLUSIONS: Developing digital markers of STB in a real-world sample of high-risk adolescents presenting to ED can inform different interventions and provide an objective means to assess the risk of suicidal behaviors. The results of this study will be the first step toward large-scale validation that may lead to suicide risk measures that aid psychiatric follow-up, decision-making, and targeted treatments. This novel assessment could facilitate timely identification and intervention to save young people's lives. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46464.

Promoter methylation of the glucocorticoid receptor following trauma may be associated with subsequent development of PTSD.

OBJECTIVES: The ability to identify persons at elevated risk for post-traumatic stress disorder (PTSD) soon after exposure to trauma, could aid clinical decision-making and treatment. In this study, we explored whether cytosine methylation of the 1 F promoter of the NR3C1 (glucocorticoid receptor [GR]) gene obtained immediately following a trauma could predict PTSD. METHODS: Our sample comprised 52 trauma survivors (28 women, 24 men), presenting to the Emergency Department (ED) within six hours of a traumatic event and followed for 13 months. Blood samples were taken at intake (n = 42) and again at the end of the study (13 months later, n = 27) to determine NR3C1-1F promoter methylation as well as plasma levels of cortisol, adrenocorticotropic-hormone (ACTH), and neuropeptide-Y (NPY). RESULTS: At the 13-month follow-up, participants who met the PTSD criteria (n = 4) showed significantly lower NR3C1-1F promoter sum percent methylation compared to the non-PTSD group (n = 38). Further, NR3C1-1F methylation at ED intake was inversely correlated with PTSD severity 13 months later, indicating that lower NR3C1-1F promoter methylation in the immediate aftermath of trauma was associated with the development of PTSD. CONCLUSION: To the extent that reduced promoter methylation is associated with greater GR expression and responsivity, this finding is consistent with the hypothalamic-pituitary-adrenal dysregulation previously described for PTSD.

The European General Data Protection Regulation (GDPR) in mHealth: Theoretical and practical aspects for practitioners' use.

The extensive use of smart technology (smartphones and wearables) and the vast amount of information they contain have positioned remote devices and technology as a massive database resource. Harnessing these big data into the clinical and research fields has introduced a new horizon of possibilities along with significant privacy issues. A significant evolution in this respect has been the introduction of the new European Union (EU) General Data Protection Regulation (GDPR). The GDPR acknowledges that information related to individuals (i.e. personal data), as well as data flow, and thus databases, are of high political, clinical, and economic value. Hence, the Regulation aims to protect personal data and, consequentially, privacy. Nevertheless, the GDPR is a legal document with legal language. The purpose of this paper is to serve as a - practical guidance as well as a theoretical framework - for clinicians (and non-clinicians) who integrates digital tools in their clinical and research work.

Saliva metabolome alterations after acute stress.

Major stress has systemic effects on the body that can have adverse consequences for physical and mental health. However, the molecular basis of these damaging effects remains incompletely understood. Here we use a longitudinal approach to characterise the acute systemic impact of major psychological stress in a pig model. We perform untargeted metabolomics on non-invasively obtained saliva samples from pigs before and 24 h after transfer to the novel physical and social environment of a slaughterhouse. The main molecular changes occurring include decreases in amino acids, B-vitamins, and amino acid-derived metabolites synthesized in B-vitamin-dependent reactions, as well as yet-unidentified metabolite features. Decreased levels of several of the identified metabolites are implicated in the pathology of human psychological disorders and neurodegenerative disease, suggesting a possible neuroprotective function. Our results provide a fingerprint of the acute effect of psychological stress on the metabolome and suggest candidate biomarkers with potential roles in stress-related disorders.

Advances in problematic usage of the internet research - A narrative review by experts from the European network for problematic usage of the internet.

Global concern about problematic usage of the internet (PUI), and its public health and societal costs, continues to grow, sharpened in focus under the privations of the COVID-19 pandemic. This narrative review reports the expert opinions of members of the largest international network of researchers on PUI in the framework of the European Cooperation in Science and Technology (COST) Action (CA 16207), on the scientific progress made and the critical knowledge gaps remaining to be filled as the term of the Action reaches its conclusion. A key advance has been achieving consensus on the clinical definition of various forms of PUI. Based on the overarching public health principles of protecting individuals and the public from harm and promoting the highest attainable standard of health, the World Health Organisation has introduced several new structured diagnoses into the ICD-11, including gambling disorder, gaming disorder, compulsive sexual behaviour disorder, and other unspecified or specified disorders due to addictive behaviours, alongside naming online activity as a diagnostic specifier. These definitions provide for the first time a sound platform for developing systematic networked research into various forms of PUI at global scale. Progress has also been made in areas such as refining and simplifying some of the available assessment instruments, clarifying the underpinning brain-based and social determinants, and building more empirically based etiological models, as a basis for therapeutic intervention, alongside public engagement initiatives. However, important gaps in our knowledge remain to be tackled. Principal among these include a better understanding of the course and evolution of the PUI-related problems, across different age groups, genders and other specific vulnerable groups, reliable methods for early identification of individuals at risk (before PUI becomes disordered), efficacious preventative and therapeutic interventions and ethical health and social policy changes that adequately safeguard human digital rights. The paper concludes with recommendations for achievable research goals, based on longitudinal analysis of a large multinational cohort co-designed with public stakeholders.

Hydrocortisone in the emergency department: a prospective, double-blind, randomized, controlled posttraumatic stress disorder study. Hydrocortisone during golden hours.

OBJECTIVES: A blunted response of the hypothalamic-pituitary-adrenal axis immediately after exposure to traumatic events has been proposed as a risk factor for posttraumatic stress disorder (PTSD). Accordingly, administration of hydrocortisone in the aftermath of a traumatic event is indicated. This study consisted of a randomized, placebo-controlled, double-blind trial investigating whether a single intravenous dose of hydrocortisone administered within 6 hours after exposure to trauma would reduce the incidence of PTSD at the 13-month follow-up. METHODS: A total of 118 consented patients with acute stress symptoms were administered a single intravenous bolus of hydrocortisone/placebo within 6 hours of the traumatic event. Blood samples were taken before hydrocortisone administration. RESULTS: At 13 months, the hydrocortisone group did not differ from the placebo group regarding PTSD prevalence or symptom severity. However, a significant interaction between time of the trauma (ie, night, when cortisol's level is low) and treatment was found. Specifically, a lower prevalence of PTSD was found at the 13-month follow-up in the hydrocortisone night group. CONCLUSIONS: Administration of hydrocortisone within 6 hours of the traumatic event was not effective in preventing PTSD compared to placebo. However, nocturnal administration (when cortisol levels are low) may suggest a new venue for research.

Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial.

(Appeared originally in American Journal of Psychiatry 2019; 176:931-938) Reprinted with permission from American Psychiatric Association Publishing.

MDMA treatment paired with a trauma-cue promotes adaptive stress responses in a translational model of PTSD in rats.

MDMA (3,4-methylenedioxymethamphetamine), a synthetic ring-substituted amphetamine, combined with psychotherapy has demonstrated efficacy for the treatment of chronic posttraumatic stress disorder (PTSD) patients. This controlled prospective study aimed to assess the bio-behavioral underpinnings of MDMA in a translational model of PTSD. Rats exposed to predator-scent stress (PSS) were subjected to a trauma-cue at day 7 shortly after single-dose MDMA injection (5 mg/kg). The elevated plus maze and acoustic startle response tests were assessed on day 14 and served for classification into behavioral response groups. Freezing response to a further trauma-reminder was assessed on Day 15. The morphological characteristics of the dentate gyrus (DG) and basolateral amygdala (BLA) were subsequently examined. Hypothalamic-pituitary-adrenal axis and 5-hydroxytryptamine involvement were evaluated using: (1) corticosterone measurements at 2 h and 4 h after MDMA treatment, (2) Lewis strain rats with blunted HPA-response and (3) pharmacological receptor-blockade. MDMA treatment was effective in attenuating stress behavioral responses only when paired with memory reactivation by a trauma-cue. The effects of the treatment on behavior were associated with a commensurate normalization of the dendritic cytoarchitecture of DG and BLA neurons. Pretreatment with RU486, Ketanserin, or Pindolol prevented the above improvement in anxiety-like behavioral responses. MDMA treatment paired with memory reactivation reduced the prevalence rate of PTSD-phenotype 14 days later and normalized the cytoarchitecture changes induced by PSS (in dendritic complexities) compared to saline control. MDMA treatment paired with a trauma-cue may modify or update the original traumatic memory trace through reconsolidation processes. These anxiolytic-like effects seem to involve the HPA axis and 5-HT systems.

A prospective clinical cohort-based study of the prevalence of OCD, obsessive compulsive and related disorders, and tics in families of patients with OCD.

BACKGROUND: The lifetime prevalence of obsessive - compulsive disorder (OCD) is currently estimated at 2 - 3% and the prevalence in first-degree family members is estimated to range between 10 and 11%. Separating OCD from other anxiety disorders and including it into the new "obsessive - compulsive and related disorders" (OCRDs) category has had a dramatic impact on the diagnosis, while also contributing to the better understanding of the genetics of these disorders. Indeed, grouping OCD with body dysmorphic disorder (BDD), and body-focused repetitive behaviors such as trichotillomania (hair pulling), onychophagia (nail biting), and excoriation (skin picking) into the same diagnostic family has resulted in a much greater lifetime prevalence (> 9%). These diagnostic changes necessitate an updated epidemiological study, thus motivating this investigation. METHODS: The study sample comprised of 457 patient's cases from an Israeli and an Australian OCD center. Interviews were completed as a part of the intake or during treatment in each of the centers. Prevalence of OCD, OCRDs, tics, and other psychiatric comorbidities in first- and second-degree relatives was assessed by interviewing the OCD patients. Interviews were conducted by at least two researchers (LC, OBA, JZ) and only family information on which the interviewers have reached consensus was considered. RESULTS: Initial analyses revealed an increase of OCD and OCRD prevalence in first- and second-degree family members as compared to the current literature due to reclassification of these disorders in DSM-5. CONCLUSION: The new category of OCRD has changed the landscape of epidemiological studies in OCD. Further and broader studies are needed in order to better understand the lifetime prevalence of OCRD in first- and second-degrees family member.

Manifesto for an ECNP Neuromodulation Thematic Working Group (TWG): Non-invasive brain stimulation as a new Super-subspecialty.

Non-Invasive Brain Stimulation (NIBS) techniques and in particular, repetitive Transcranial Magnetic Stimulation (rTMS), are developing beyond mere clinical application. Although originally purposed for the treatment of resistant neuropsychiatric disorders, NIBS is also contributing to a deeper understanding of psychiatric disorders. rTMS is also changing the model of the disorder itself, from "mental" to one of neural connectivity. TMS allows the assessment of brain circuit excitability and eventually, of plastic changes affecting these circuits. While a clinical translational approach is, at the present time, the most adequate to meet the dimensional-circuit base model of the disorder, it refines the standard categorical classification of psychiatric disorders. The discovery of the fundamental importance of the balance between neuroplasticity and inflammation is also now explored through neuro-modulation findings consistently with the evidence of anti-inflammatory actions of the magnetic pulses. rTMS may activate, inhibit, or otherwise interfere with the activity of neuronal cortical networks, depending on stimulus frequency and intensity of brain-induced electric field. Of particular interest, yet still unclear, is how the relatively unspecific nature of TMS stimulation may lead to specific neuronal reorganization, as well as a definition of the TMS-triggered reorganization of functional brain modules, raising attention on the importance of the active participation of the patient to the treatment.. Configuration and state of consciousness of the subject have made subjective experience under treatment regain importance in the neuro-scientific Psychiatry based on the requirement of United States National Institute of Health (NIH) and the substantial importance of the consciousness state in the efficacy of the TMS treatment. By focusing on the subjective experience, a renaissance of the phenomenology offers Psychiatry an opportunity to become proficient and to distinguish itself from other disciplines. For all these reasons, TMS should be included in the cluster of the sub-specialties as a new "Super-Specialty" and an appropriate training course has to be inaugurated. Psychiatrists are nowadays multi-specialists, moving from a specialty to another, vs super-specialist. The cultivation of a properly trained cohort of TMS psychiatrists will better meet the challenges of treatment-resistant psychiatric conditions (disorders of connectivity), through appropriate and ethical practice, meanwhile facilitating an informed development and integration of additional emerging neuro-modulation techniques. The aim of this consensus paper is to underline the interdisciplinary nature of NIBS, that also encompasses the subjective experience and to point out the necessity of a neuroscience-applied approach to NIBS in the context of the European College of Neuro-psychopharmacology (ECNP).

Obsessive Compulsive Disorder During Coronavirus Disease 2019 (COVID-19): 2- and 6-Month Follow-Ups in a Clinical Trial.

BACKGROUND: Psychiatric patients are perceived to be especially vulnerable during a pandemic, as it increases stress and uncertainty. Several current publications have considered obsessive-compulsive disorder (OCD) patients to be particularly vulnerable during the coronavirus disease 2019 (COVID-19), and clinicians were advised to adjust treatments accordingly. The purpose of this study was to evaluate the 2- and 6-month impacts of COVID-19 on the symptom severity of OCD patients. METHODS: A cohort of OCD patients actively treated with Exposure and Response Prevention (ERP) combined with pharmacological treatment was evaluated as part of their regular psychiatric assessment twice: 113 patients were evaluated at their 2-month follow-up and 90 patients (from that cohort) were evaluated at their 6-month follow up. RESULTS: Obsessive-compulsive symptom deterioration was not present in 84% of the patients at the 2-month follow-up and 96% of the patients at the 6-month follow-up. The results were also replicated in the OCD subgroup that included patients with contamination (washers) and illness obsessions, who were believed to be particularly vulnerable considering their obsessional content. CONCLUSIONS: OCD patients (including those with obsessions related to contamination and health) who were under active ERP and pharmacological treatment did not experience exacerbated symptoms during COVID-19 at their 2- and 6-month follow-ups.

Expert appraisal of criteria for assessing gaming disorder: an international Delphi study.

BACKGROUND AND AIMS: Following the recognition of 'internet gaming disorder' (IGD) as a condition requiring further study by the DSM-5, 'gaming disorder' (GD) was officially included as a diagnostic entity by the World Health Organization (WHO) in the 11th revision of the International Classification of Diseases (ICD-11). However, the proposed diagnostic criteria for gaming disorder remain the subject of debate, and there has been no systematic attempt to integrate the views of different groups of experts. To achieve a more systematic agreement on this new disorder, this study employed the Delphi expert consensus method to obtain expert agreement on the diagnostic validity, clinical utility and prognostic value of the DSM-5 criteria and ICD-11 clinical guidelines for GD. METHODS: A total of 29 international experts with clinical and/or research experience in GD completed three iterative rounds of a Delphi survey. Experts rated proposed criteria in progressive rounds until a pre-determined level of agreement was achieved. RESULTS: For DSM-5 IGD criteria, there was an agreement both that a subset had high diagnostic validity, clinical utility and prognostic value and that some (e.g. tolerance, deception) had low diagnostic validity, clinical utility and prognostic value. Crucially, some DSM-5 criteria (e.g. escapism/mood regulation, tolerance) were regarded as incapable of distinguishing between problematic and non-problematic gaming. In contrast, ICD-11 diagnostic guidelines for GD (except for the criterion relating to diminished non-gaming interests) were judged as presenting high diagnostic validity, clinical utility and prognostic value. CONCLUSIONS: This Delphi survey provides a foundation for identifying the most diagnostically valid and clinically useful criteria for GD. There was expert agreement that some DSM-5 criteria were not clinically relevant and may pathologize non-problematic patterns of gaming, whereas ICD-11 diagnostic guidelines are likely to diagnose GD adequately and avoid pathologizing.

From checking the door to checking the app: assessment and treatment implications for obsessive-compulsive disorder in the digital era.

In the last 20 years, technology is increasingly integrated into daily life. Daily interactions with smart devices have become routine with much of our lives taking place in a digital environment. It is therefore not surprising that the manifestations of psychiatric disorders including Obsessive-Compulsive Disorder have changed in recent years reflecting this reality. Clinicians should be aware of the potential impact of such changes when considering symptom presentation and diagnosis.

Deep transcranial magnetic stimulation for obsessive-compulsive disorder is efficacious even in patients who failed multiple medications and CBT.

OCD is a chronic and disabling disease with a lifetime prevalence of 2%-3%. About 40-60% of these patients do not adequately respond to pharmacotherapy and CBT. Deep transcranial magnetic stimulation (dTMS) was shown to be safe and effective as a treatment alternative for OCD and recently received regulatory approvals. Yet it is unclear whether patients who failed numerous medications and/or CBT can still benefit from dTMS. Here, we analyzed recent data from a double-blind multicenter dTMS study and found efficacy of this novel treatment even in OCD patient cohorts who previously failed to respond to multiple medications and CBT.

Clinical advances in obsessive-compulsive disorder: a position statement by the International College of Obsessive-Compulsive Spectrum Disorders.

In this position statement, developed by The International College of Obsessive-Compulsive Spectrum Disorders, a group of international experts responds to recent developments in the evidence-based management of obsessive-compulsive disorder (OCD). The article presents those selected therapeutic advances judged to be of utmost relevance to the treatment of OCD, based on new and emerging evidence from clinical and translational science. Areas covered include refinement in the methods of clinical assessment, the importance of early intervention based on new staging models and the need to provide sustained well-being involving effective relapse prevention. The relative benefits of psychological, pharmacological and somatic treatments are reviewed and novel treatment strategies for difficult to treat OCD, including neurostimulation, as well as new areas for research such as problematic internet use, novel digital interventions, immunological therapies, pharmacogenetics and novel forms of psychotherapy are discussed.

Effects of agomelatine on behaviour, circadian expression of period 1 and period 2 clock genes and neuroplastic markers in the predator scent stress rat model of PTSD.

Objectives: The therapeutic value of the antidepressant agomelatine in the aftermath of traumatic experience and early post-reminder has been questioned. Herein, agomelatine, its vehicle or melatonin agonist were administered either acutely 1 h post-stressor or repeatedly (7 days) after early post-reminder in a post-traumatic stress rat model (PSS) using the scent of predator urine.Methods: Behavioural responses, and brain molecular and morphological changes were evaluated after each treatment procedure in PSS-exposed and unexposed rats.Results: When administered immediately after PSS, agomelatine induced a significant reduction of anxiety-like behaviour as assessed in the elevated-plus-maze and acoustic startle response at 8 days post-administration. Concomitantly, agomelatine significantly decreased Per1/Per2 expression in the CA1/CA3 areas, suprachiasmatic nucleus and basolateral amygdala, thereby partially restoring genes expression overregulated by PSS. Agomelatine further significantly increased cell growth and facilitated dendritic growth and arbour in dentate gyrus (DG) granule and apical CA1 cells and upregulated brain-derived neurotrophic factor protein in the DG and cortex III versus vehicle. When administered early post-reminder over 7 days before testing, agomelatine was ineffective on behavioural responses pattern, molecular and morphological changes induced by PSS.Conclusions: These findings suggest that agomelatine may be a potential agent in the acute aftermath of traumatic stress exposure.

Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic and disabling condition that often responds unsatisfactorily to pharmacological and psychological treatments. Converging evidence suggests a dysfunction of the cortical-striatal-thalamic-cortical circuit in OCD, and a previous feasibility study indicated beneficial effects of deep transcranial magnetic stimulation (dTMS) targeting the medial prefrontal cortex and the anterior cingulate cortex. The authors examined the therapeutic effect of dTMS in a multicenter double-blind sham-controlled study. METHODS: At 11 centers, 99 OCD patients were randomly allocated to treatment with either high-frequency (20 Hz) or sham dTMS and received daily treatments following individualized symptom provocation, for 6 weeks. Clinical response to treatment was determined using the Yale-Brown Obsessive Compulsive Scale (YBOCS), and the primary efficacy endpoint was the change in score from baseline to posttreatment assessment. Additional measures were response rates (defined as a reduction of ≥30% in YBOCS score) at the posttreatment assessment and after another month of follow-up. RESULTS: Eighty-nine percent of the active treatment group and 96% of the sham treatment group completed the study. The reduction in YBOCS score among patients who received active dTMS treatment was significantly greater than among patients who received sham treatment (reductions of 6.0 points and 3.3 points, respectively), with response rates of 38.1% and 11.1%, respectively. At the 1-month follow-up, the response rates were 45.2% in the active treatment group and 17.8% in the sham treatment group. Significant differences between the groups were maintained at follow-up. CONCLUSIONS: High-frequency dTMS over the medial prefrontal cortex and anterior cingulate cortex significantly improved OCD symptoms and may be considered as a potential intervention for patients who do not respond adequately to pharmacological and psychological interventions.

Early intervention for obsessive compulsive disorder: An expert consensus statement.

Obsessive-compulsive disorder (OCD) is common, emerges early in life and tends to run a chronic, impairing course. Despite the availability of effective treatments, the duration of untreated illness (DUI) is high (up to around 10 years in adults) and is associated with considerable suffering for the individual and their families. This consensus statement represents the views of an international group of expert clinicians, including child and adult psychiatrists, psychologists and neuroscientists, working both in high and low and middle income countries, as well as those with the experience of living with OCD. The statement draws together evidence from epidemiological, clinical, health economic and brain imaging studies documenting the negative impact associated with treatment delay on clinical outcomes, and supporting the importance of early clinical intervention. It draws parallels between OCD and other disorders for which early intervention is recognized as beneficial, such as psychotic disorders and impulsive-compulsive disorders associated with problematic usage of the Internet, for which early intervention may prevent the development of later addictive disorders. It also generates new heuristics for exploring the brain-based mechanisms moderating the 'toxic' effect of an extended DUI in OCD. The statement concludes that there is a global unmet need for early intervention services for OC related disorders to reduce the unnecessary suffering and costly disability associated with under-treatment. New clinical staging models for OCD that may be used to facilitate primary, secondary and tertiary prevention within this context are proposed.

Clinical and electrophysiological outcomes of deep TMS over the medial prefrontal and anterior cingulate cortices in OCD patients.

BACKGROUND: Obsessive Compulsive Disorder (OCD) is a chronic and disabling disorder with poor response to pharmacological treatments. Converging evidences suggest that OCD patients suffer from dysfunction of the cortico-striato-thalamo-cortical (CSTC) circuit, including in the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC). OBJECTIVE: To examine whether modulation of mPFC-ACC activity by deep transcranial magnetic stimulation (DTMS) affects OCD symptoms. METHODS: Treatment resistant OCD participants were treated with either high-frequency (HF; 20 Hz), low-frequency (LF; 1 Hz), or sham DTMS of the mPFC and ACC for five weeks, in a double-blinded manner. All treatments were administered following symptoms provocation, and EEG measurements during a Stroop task were acquired to examine changes in error-related activity. Clinical response to treatment was determined using the Yale-Brown-Obsessive-Compulsive Scale (YBOCS). RESULTS: Interim analysis revealed that YBOCS scores were significantly improved following HF (n = 7), but not LF stimulation (n = 8), compared to sham (n = 8), and thus recruitment for the LF group was terminated. Following completion of the study, the response rate in the HF group (n = 18) was significantly higher than that of the sham group (n = 15) for at least one month following the end of the treatment. Notably, the clinical response in the HF group correlated with increased Error Related Negativity (ERN) in the Stroop task, an electrophysiological component that is attributed to ACC activity. CONCLUSION: HF DTMS over the mPFC-ACC alleviates OCD symptoms and may be used as a novel therapeutic intervention. Notwithstanding alternative explanations, this may stem from DTMS ability to directly modify ACC activity.