An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis.

INTRODUCTION: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. METHODS: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. RESULTS: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. CONCLUSION: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Prognosis of impulse control disorders in Parkinson's disease: a prospective controlled study.

BACKGROUND: The long-term prognosis of impulsive compulsive disorders (ICD) remains poorly studied in Parkinson's disease (PD). OBJECTIVE: Evaluating the natural history of ICD and its impact on PD symptoms including cognition and treatment adjustments. MATERIALS AND METHODS: We assessed PD patients at baseline (BL) with (BL-ICD+) or without (BL-ICD-) ICD despite dopamine agonist (DA) exposure of > 300 mg levodopa-equivalent daily dose for > 12 months at baseline and after more than two years of follow-up. ICD were assessed using the Ardouin's Scale of Behaviors in PD (ASBPD), cognition using the Mattis scale, and PD symptoms using the UPDRS score. Treatment adjustments, DA withdrawal-associated symptoms, and ICDs social consequences were recorded. RESULTS: 149 patients were included (78 cases and 71 controls), mean duration of follow-up was 4.4 ± 1 years. At baseline, psychiatric disorders were more common among BL-ICD + (42.3 vs 12.3% among BL-ICD-, p < 0.01). At follow-up, 53.8% of BL-ICD + were not ICD-free while 21.1% of BL-ICD- had developed ICD. BL-ICD + more frequently experienced akinesia (21.8 vs 8.5%, p = 0.043) and rigidity worsening (11.5 vs 1.4%, p = 0.019) following therapeutic modifications. Decision to decrease > 50% DA doses (12.8 vs 1.4%, p = 0.019) or to withdraw DA (19.2 vs 5.6%, p = 0.025) was more frequently considered among BL-ICD+ . At follow-up, the prevalence of cognitive decline was lower among BL-ICD + (19.2 vs 37.1%, p = 0.025). CONCLUSION: ICDs were associated with increased psychiatric burden at baseline and better cognitive prognosis. Most patients were still showing ICDs at the follow-up visit, suggesting ICD to be considered as a chronic, neuropsychiatric disorder.

Psilocybin-assisted therapy for severe alcohol use disorder: protocol for a double-blind, randomized, placebo-controlled, 7-month parallel-group phase II superiority trial.

BACKGROUND: A significant number of individuals with alcohol use disorder remain unresponsive to currently available treatments, which calls for the development of new alternatives. In parallel, psilocybin-assisted therapy for alcohol use disorder has recently yielded promising preliminary results. Building on extant findings, the proposed study is set to evaluate the feasibility and preliminary clinical efficacy of psilocybin-assisted therapy when incorporated as an auxiliary intervention during inpatient rehabilitation for severe alcohol use disorder. Moreover, it intends to pinpoint the modifications in the two core neurocognitive systems underscored by dual-process models of addiction. METHODS: In this double-blind, randomized, placebo-controlled, 7-month parallel-group phase II superiority trial, 62 participants aged 21-64 years will be enrolled to undergo psilocybin-assisted therapy as part of a 4-week inpatient rehabilitation for severe alcohol use disorder. The experimental group will receive a high dose of psilocybin (30 mg), whereas the control group will receive an active placebo dose of psilocybin (5 mg), both within the context of a brief standardized psychotherapeutic intervention drawing from key elements of acceptance and commitment therapy. The primary clinical outcome is the between-group difference regarding the change in percentage of heavy drinking days from baseline to four weeks posthospital discharge, while safety and feasibility metrics will also be reported as primary outcomes. Key secondary assessments include between-group differences in terms of changes in (1) drinking behavior parameters up to six months posthospital discharge, (2) symptoms of depression, anxiety, trauma, and global functioning, (3) neuroplasticity and key neurocognitive mechanisms associated with addiction, and (4) psychological processes and alcohol-related parameters. DISCUSSION: The discussion outlines issues that might arise from our design. TRIAL REGISTRATION: EudraCT 2022-002369-14 and NCT06160232.

Improvement in OCD symptoms associated with serotoninergic psychedelics: a retrospective online survey.

A renewed interest in the use of psychedelics for treating obsessive compulsive disorder (OCD) has emerged in the last 20 years. But pre-clinical and clinical evidence remain scarce, and little is known about the factor determining the magnitude and persistence of the therapeutic effect. We therefore designed a retrospective online survey to explore, in the general population using psychoactive drugs, their impact on OCD symptoms. We also assessed the attitude of the participants towards the substance in term of frequency of intakes. In a sample of 174 participants, classic psychedelics were reported as the only substances effective at reducing OCD symptoms. In classic psychedelics users, symptoms reduction was associated with the intensity of acute effects, itself correlated to the dose. Reports on the persistence of the therapeutic effect varied from weeks to months, but we could not find any predicting factor. Finally, the occurrence and frequency of subsequent intakes, which seemed to be limited in our sample, were predicted by the magnitude and persistence of the therapeutic effect, respectively. Our observations support the hypothesis of classic psychedelics efficacy in reducing OCD symptoms but a careful evaluation of the persistence of this effect is still needed.

Psilocybin-assisted therapy for depression: A systematic review and dose-response meta-analysis of human studies.

Psilocybin is increasingly studied for its antidepressant effect, but its optimal dosage for depression remains unclear. We conducted a systematic review and a dose-response meta-analysis to find the optimal dosage of psilocybin to reduce depression scores. Following our protocol (CRD 42022220190) multiple electronic databases were searched from their inception until February 2023, to identify double-blind randomized placebo-controlled (RCTs) fixed-dose trials evaluating the use of psilocybin for adult patients with primary or secondary depression. A one-stage dose-response meta-analysis with restricted cubic splines was used. Cochrane risk of bias was used to assess risk of bias. Our analysis included seven studies with a total of 489 participants. Among these, four studies focused on primary depression (N = 366), including one study with patients suffering from treatment-resistant depression. The remaining three studies examined secondary depression (N = 123). The determined 95% effective doses per day (ED95) were 8.92, 24.68, and 36.08 mg/70 kg for patients with secondary depression, primary depression, and both subgroups, respectively. We observed significant dose-response associations for all curves, each plateauing at different levels, except for the bell-shaped curve observed in the case of secondary depression. Additionally, we found significant dose-response associations for various side effects, including physical discomfort, blood pressure increase, nausea/vomiting, headache/migraine, and the risk of prolonged psychosis. In conclusion, we discovered specific ED95 values for different populations, indicating higher ED95 values for treatment-resistant depression, primary depression, and secondary depression groups. Further RCTs are necessary for each population to determine the optimal dosage, allowing for maximum efficacy while minimizing side effects.

A century of research on neuromodulation interventions: A scientometric analysis of trends and knowledge maps.

Interest in neurostimulation interventions has significantly grown in recent decades, yet a scientometric analysis objectively mapping scientific knowledge and recent trends remains unpublished. Using relevant keywords, we conducted a search in the Web of Science Core Collection on September 23, 2022, retrieving a total of 47,681 documents with 987,979 references. We identified two prominent research trends: 'noninvasive brain stimulation' and 'invasive brain stimulation.' These methods have interconnected over time, forming a cluster focused on evidence synthesis. Noteworthy emerging research trends encompassed 'transcutaneous auricular vagus nerve stimulation,' 'DBS/epilepsy in the pediatric population,' 'spinal cord stimulation,' and 'brain-machine interface.' While progress has been made for various neurostimulation interventions, their approval as adjuvant treatments remains limited, and optimal stimulation parameters lack consensus. Enhancing communication between experts of both neurostimulation types and encouraging novel translational research could foster further development. These findings offer valuable insights for funding agencies and research groups, guiding future directions in the field.

A single case report of STN-DBS for severe crack-cocaine dependence: double-blind ON vs. SHAM randomized controlled assessment.

Crack-cocaine dependence is a severe condition with a high mortality rate. This single case study report details the first deep brain stimulation (DBS) trial targeting the sub-thalamic nucleus (STN) for crack-cocaine dependence. The investigation aimed to assess the effects of STN-DBS on cocaine craving and cocaine use, as well as STN-DBS safety and tolerance in this indication. In this pilot study, we performed double blind cross-over trials, with "ON-DBS" vs. "SHAM-DBS" for 1-month periods. STN-DBS failed to reduce cocaine craving and use. An episode of DBS-induced hypomania occurred after several weeks of cocaine intake at stimulation parameters previously well tolerated. Future research on cocaine dependence should be conducted after a prolonged abstinence period and/or explore novel types of stimulation patterns.

Psychiatric consequences and issues of long COVID on patients with prior psychiatric comorbidities: a scoping review.

SARS-CoV-2 is a growing field of research and mental health in long COVID is one of its interesting domains. This scoping review aims at studying the outcomes of mental health in patients already known for psychiatric illness. This was done by researching the literature in two databases (Embase and PubMed) for articles studying mental health consequences of long COVID in patients already known for psychiatric history. Eleven studies were included. 6/11 studies found an effect of long COVID, with varying severity of outcomes studied, with either a worsening in length or severity. 4/11 did not find any correlation between worsening symptoms and psychiatric history. The methods for assessing which psychiatric symptoms to include and how to determine prior history were heterogeneous, making direct comparison sometimes difficult. The data seem to show worse effects of long COVID on mental health of patients with prior mental illness, with limitations regarding the heterogeneity of the studies' designs and focuses. It also highlights how neglected this population of patients is in the current state of research.

Therapies for obsessive-compulsive disorder: Current state of the art and perspectives for approaching treatment-resistant patients.

Even though obsessive compulsive disorder (OCD) is one of the ten most disabling diseases according to the WHO, only 30-40% of patients suffering from OCD seek specialized treatment. The currently available psychotherapeutic and pharmacological approaches, when properly applied, prove ineffective in about 10% of cases. The use of neuromodulation techniques, especially Deep Brain Stimulation, is highly promising for these clinical pictures and knowledge in this domain is constantly evolving. The aim of this paper is to provide a summary of the current knowledge about OCD treatment, while also discussing the more recent proposals for defining resistance.

No effect of subthalamic deep brain stimulation on metacognition in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a powerful treatment in Parkinson's disease (PD), which provides a positive effect on motor symptoms although the way it operates on high cognitive processes such as metacognition remains unclear. To address this issue, we recorded electroencephalogram (EEG) of PD patients treated with STN-DBS that performed a reversal learning (RL) paradigm endowed with metacognitive self-assessment. We considered two stimulation conditions, namely DBS-ON (stimulation on) and DBS-OFF (stimulation off), and focused our EEG-analysis on the frontal brain region due to its involvement on high cognitive processes. We found a trend towards a significant difference in RL ability between stimulation conditions. STN-DBS showed no effect on metacognition, although a significant association between accuracy and decision confidence level held for DBS OFF, but not in the case of DBS ON. In summary, our study revealed no significant effect of STN-DBS on RL or metacognition.

The Sapap3-/- mouse reconsidered as a comorbid model expressing a spectrum of pathological repetitive behaviours.

Symptom comorbidity is present amongst neuropsychiatric disorders with repetitive behaviours, complicating clinical diagnosis and impeding appropriate treatments. This is of particular importance for obsessive-compulsive disorder (OCD) and Tourette syndrome. Here, we meticulously analysed the behaviour of Sapap3 knockout mice, the recent rodent model predominantly used to study compulsive-like behaviours, and found that its behaviour is more complex than originally and persistently described. Indeed, we detected previously unreported elements of distinct pathologically repetitive behaviours, which do not form part of rodent syntactic cephalo-caudal self-grooming. These repetitive behaviours include sudden, rapid body and head/body twitches, resembling tic-like movements. We also observed that another type of repetitive behaviour, aberrant hindpaw scratching, might be responsible for the flagship-like skin lesions of this mouse model. In order to characterise the symptomatological nature of observed repetitive behaviours, we pharmacologically challenged these phenotypes by systemic aripiprazole administration, a first-line treatment for tic-like symptoms in Tourette syndrome and trichotillomania. A single treatment of aripiprazole significantly reduced the number of head/body twitches, scratching, and single-phase grooming, but not syntactic grooming events. These observations are in line with the high comorbidity of tic- and compulsive-like symptoms in Tourette, OCD and trichotillomania patients.

A century of research on psychedelics: A scientometric analysis on trends and knowledge maps of hallucinogens, entactogens, entheogens and dissociative drugs.

A scientometric analysis was realized to outline clinical research on psychedelics over the last century. Web of Science Core Collection was searched up to March 18, 2022, for publications on psychedelics. Network analyses and bibliometrics were combined, to identify research themes and trends with Bibliometrix and CiteSpace. The primary aim was to measure research trends evolution over time, and the secondary aims were to identify bibliometric performance and influence networks of publications, authors, institutions, and countries. Sensitivity analyses were conducted for 2016-2022, and 2021 time periods. We included 31,687 documents (591,329 references), which aggregated into a well-structured network with credible clustering. Research productivity was split into an early less productive period mainly focusing on safety issues, and a "psychedelic renaissance" after the 1990s. Major trends were identified for hallucinogens/entheogens, entactogens, novel psychoactive substances (NPS), and on dissociative substances. There was a translational evolution from the bench to the bedside, with phase 2 and 3 trials and/or evidence synthesis in particular. The most recent trends concerned NPS, ketamine-associated brain changes, and ayahuasca-assisted psychotherapy. The USA and Canada were the most productive settings for the research overall, and more recently this geographical distribution became more prominent, reflecting legislative context/policy making. A translational evolution of psychedelics has been occurring, that has brought approval of esketamine for depression and will likely lead to approval of additional psychedelics across mental and physical conditions. Toxicology screening tools for NPS are urgently needed, which in turn might follow the same translational evolution of psychedelics in the future.

Immunological causes of obsessive-compulsive disorder: is it time for the concept of an "autoimmune OCD" subtype?

Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of "autoimmune OCD" is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for "autoimmune OCD" could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.

Joint contributions of metacognition and self-beliefs to uncertainty-guided checking behavior.

Checking behavior is a natural and adaptive strategy for resolving uncertainty in everyday situations. Here, we aimed at investigating the psychological drivers of checking and its regulation by uncertainty, in non-clinical participants and controlled experimental settings. We found that the sensitivity of participants' explicit confidence judgments to actual performance (explicit metacognition) predicted the extent to which their checking strategy was regulated by uncertainty. Yet, a more implicit measure of metacognition (derived from asking participants to opt between trials) did not contribute to the regulation of checking behavior. Meanwhile, how participants scaled on questionnaires eliciting self-beliefs such as self-confidence and self-reported obsessive-compulsive symptoms also predicted participants' uncertainty-guided checking tendencies. Altogether, these findings demonstrate that checking behavior is likely the outcome of a core explicit metacognitive process operating at the scale of single decisions, while remaining influenced by general self-beliefs. Our findings are thus consistent with two mechanisms (micro vs. macro) through which this otherwise adaptive behavior could go awry in certain psychiatric disorders such as obsessive-compulsive disorder.

Identification of biomarkers that predict response to subthalamic nucleus deep brain stimulation in resistant obsessive-compulsive disorder: protocol for an open-label follow-up study.

INTRODUCTION: Deep brain stimulation (DBS) of bilateral anteromedial subthalamic nucleus (amSTN) has been found to be helpful in a subset of patients with severe, chronic and treatment-refractory obsessive-compulsive disorder (OCD). Biomarkers may aid in patient selection and optimisation of this invasive treatment. In this trial, we intend to evaluate neurocognitive function related to STN and related biosignatures as potential biomarkers for STN DBS in OCD. METHODS AND ANALYSIS: Twenty-four subjects with treatment-refractory OCD will undergo open-label STN DBS. Structural/functional imaging, electrophysiological recording and neurocognitive assessment would be performed at baseline. The subjects would undergo a structured clinical assessment for 12 months postsurgery. A group of 24 healthy volunteers and 24 subjects with treatment-refractory OCD who receive treatment as usual would be recruited for comparison of biomarkers and treatment response, respectively. Baseline biomarkers would be evaluated as predictors of clinical response. Neuroadaptive changes would be studied through a reassessment of neurocognitive functioning, imaging and electrophysiological activity post DBS. ETHICS AND DISSEMINATION: The protocol has been approved by the National Institute of Mental Health and Neurosciences Ethics Committee. The study findings will be disseminated through peer-reviewed scientific journals and scientific meetings.

Immunity and Gilles de la Tourette syndrome: A systematic review and meta-analysis of evidence for immune implications in Tourette syndrome.

BACKGROUND AND PURPOSE: The neurobiology of Gilles de la Tourette syndrome (GTS) is known to involve corticostriatal loops possibly under genetic control. Less is known about possible environmental triggers of GTS. Specifically, immune-related events following possible environmental inducers have been evoked, but important controversies still exist. In this systematic review and meta-analysis, we looked for evidence in favor of such possibilities. METHODS: We performed a systematic review and meta-analysis of all immunological data in PubMed. RESULTS: We found large discrepancies concerning immune dysfunctions in GTS, and meta-analyzing cytokines data did not allow us to conclude there is an involvement of specific cytokines in GTS neurobiology. When looking specifically at pediatric autoimmune neuropsychiatric disorder associated with streptococcus/pediatric acute onset neuropsychiatric syndrome, we found some important evidence of a possible infectious involvement but in a limited number of studies. Our meta-analysis found an increased level of anti-streptolysin O antibodies in GTS patients, but the level of anti-DNase B antibodies was not increased. CONCLUSIONS: Too many questions still exist to allow us to definitively reach the conclusion that there is an infectious and immunological etiology in GTS. Much work is still needed to elucidate the possible role of immunology in GTS neurobiology and to favor immunological treatment rather than classical treatment.

A cross-species assessment of behavioral flexibility in compulsive disorders.

Lack of behavioral flexibility has been proposed as one underlying cause of compulsions, defined as repetitive behaviors performed through rigid rituals. However, experimental evidence has proven inconsistent across human and animal models of compulsive-like behavior. In the present study, applying a similarly-designed reversal learning task in two different species, which share a common symptom of compulsivity (human OCD patients and Sapap3 KO mice), we found no consistent link between compulsive behaviors and lack of behavioral flexibility. However, we showed that a distinct subgroup of compulsive individuals of both species exhibit a behavioral flexibility deficit in reversal learning. This deficit was not due to perseverative, rigid behaviors as commonly hypothesized, but rather due to an increase in response lability. These cross-species results highlight the necessity to consider the heterogeneity of cognitive deficits in compulsive disorders and call for reconsidering the role of behavioral flexibility in the aetiology of compulsive behaviors.

Emotions Modulate Subthalamic Nucleus Activity: New Evidence in Obsessive-Compulsive Disorder and Parkinson's Disease Patients.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation alleviates obsessive-compulsive disorder (OCD) symptoms, suggesting that this basal ganglia structure may play a key role in integrating limbic and motor information. We explored the modulation of STN neural activity by visual emotional information under different motor demands. METHODS: We compared STN local field potentials acquired in 7 patients with OCD and 15 patients with Parkinson's disease off and on levodopa while patients categorized pictures as unpleasant, pleasant, or neutral and pressed a button for 1 of these 3 categories depending on the instruction. RESULTS: During image presentation, theta power increased for unpleasant compared with neutral images in both patients with OCD and patients with Parkinson's disease. Only in patients with OCD was theta power also increased in pleasant compared with neutral trials. During the button press in patients with OCD, no modification of STN activity was seen on average, but theta power increased when the image triggering the motor response was unpleasant. Conversely, in patients with Parkinson's disease, a beta decrease was observed during the button press unrelated to the valence of the stimulus. Finally, in patients with OCD, a significant positive relationship was observed between the amplitude of the emotionally related theta response and symptom severity (measured using the Yale-Brown Obsessive Compulsive Scale). CONCLUSIONS: We highlighted modulations of STN theta band activity related to emotions that were specific to OCD and correlated with OCD symptom severity. STN theta-induced activity might therefore underlie dysfunction of the limbic STN and its related network leading to OCD pathophysiology.