Brexpiprazole Augmentation in Treatment Resistant OCD: Safety and Efficacy in an Italian Sample.

Obsessive-compulsive disorder (OCD) is a common and debilitating psychiatric disorder with an approximate incidence of 2.5% in the general population. Serotonin reuptake inhibitors (SRIs) are considered the first line of pharmacological treatment but up to 50% of patients fail to achieve clinical remission or response. Atypical antipsychotics are one of the most common augmentation strategies in OCD treatment resistant patients. Brexpiprazole, a novel atypical antipsychotic with dopamine partial agonism action, has never been studied in addition to SRIs treatment in OCD resistant patients. This study retrospectively investigated the safety and efficacy of a 12 week brexpiprazole augmentation trial in 34 OCD resistant patients. SRI treatment resistance was defined as failing to improve the YBOCS total score by more than 25% from the beginning of the SRI trial. Brexpiprazole augmentation response was defined as at least a 25% improvement in the YBOCS total score. At the end of the study, 17 patients (50.0%) met the response criteria of ≥25% improvement in YBOCS total score vs. baseline. No safety issues were raised throughout the observation period. A total of 19 patients (55.9%) reported adverse experiences, generally mild and not requiring medical intervention. This is the first study to examine the safety and efficacy of brexpiprazole augmentation in resistant OCD patients. Our findings show that brexpiprazole may be a promising and well-tolerated augmentation strategy for SRI-resistant OCD patients. However, further research in larger populations is needed to confirm these results and investigate the long-term safety and tolerability of brexpiprazole in OCD patients.

IVIG response in pediatric acute-onset neuropsychiatric syndrome correlates with reduction in pro-inflammatory monocytes and neuropsychiatric measures.

Introduction: Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterized by abrupt onset of obsessive-compulsive disorder or eating restriction along with the abrupt onset of other co-occurring symptoms (tics, behavioral and cognitive regression, etc.). PANS is thought to be a post-infectious immunopsychiatric disorder, although as with most post-infectious disorders, it is challenging to establish a causal relationship with proposed infectious triggers. Intravenous immunoglobulin (IVIG) can modulate inflammation and support the elimination of infection and has been used for treatment of many post-infectious inflammatory disorders and autoimmune conditions. The aim of the study is to explore the pro-inflammatory state in PANS before and after administration of IVIG. Methods: Children with moderate-to-severe PANS received six infusions of IVIG (Octagam 5%, Octapharma) every 3 weeks with post treatment follow-up. Blood samples and psychiatric measures were obtained at Visits 1 (pre-treatment), 7 and 8 (4 and 11 weeks after last infusion, respectively). Myeloid cell activation was assessed via flow cytometry. Results: All ten patients included in the study were male, White, with mean age 12.4 years (range 6-16). Statistically significant improvements following IVIG treatment were demonstrated in all psychometric assessments and parent questionnaires including CY-BOCS (obsessive compulsive scale), YGTSS (tic scale) and a parent PANS rating scale (for all scales p<0.001). The fraction of pro-inflammatory monocytes and dendritic cells decreased from pre-IVIG treatment levels. The proportional reductions were not compensated by increases in total white blood cells; pro-inflammatory monocytes post-IVIG were decreased as a proportion of CD14+ myeloid cells and in absolute number. Conclusions: The results of this study suggest that active PANS is associated with a pro-inflammatory state. This pro-inflammatory profile and psychometric scores improved following IVIG treatment. Future work will aim to further elucidate the roles of innate and adaptive immune responses in PANS and the regulatory mechanism(s) of IVIG in PANS treatment.

The minimal important difference in obsessive-compulsive disorder: An analysis of double-blind SSRI trials in adults.

BACKGROUND: The change in symptoms necessary to be clinically relevant in obsessive-compulsive disorder (OCD) is currently unknown. In this study, we aimed to create an empirically validated threshold for clinical significance or minimal important difference (MID). METHODS: We analyzed individual participant data from short-term, double-blind, placebo-controlled registration trials of selective serotonin reuptake inhibitors in adult OCD patients. Data were collected from baseline to week 12. We used equipercentile linking to equate changes in the Clinical Global Impression (CGI) scale to changes in the Yale-Brown Obsessive-Compulsive Scale (YBOCS). We defined the MID as the YBOCS change linked to a CGI improvement of 3 (defined as "minimal improvement"). RESULTS: We included 7 trials with a total of 1216 patients. The CGI-scores and YBOCS were moderately to highly correlated. The MID corresponded to 4.9 YBOCS points (95% CI 4.4-5.4) for the full sample, or a 24% YBOCS-decrease compared to baseline. The MID varied with baseline severity, being lower in the group with mild symptoms and higher in the group with severe symptoms. CONCLUSIONS: By linking the YBOCS to the CGI-I, this is the first study to propose an MID in OCD trials. Having a clearly defined MID can guide future clinical research and help interpretation of efficacy of existing interventions. Our results are clinician-based; however, there is further need for patient-reported outcomes as anchor to the YBOCS.

Psilocybin in pharmacotherapy of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic mental disease that affects approximately 2% of the population. Obsessions and compulsions are troublesome for patients and may disturb their everyday activities. The pathogenesis of this disease is still not fully elucidated, but dysfunctions of serotonin-, dopamine- and glutamate-mediated neurotransmission together with early maladaptive schemas seem of importance. Pharmacological treatment includes drugs affecting the serotoninergic, dopaminergic, and glutamatergic systems, such as selective serotonin reuptake inhibitors (SSRIs). Providing that up to 40% of patients with OCD are resistant to the currently available medications, there is a need for novel and effective therapies. Recent discoveries suggest that psilocybin, a non-physically addictive psychoactive substance, may ameliorate disease symptoms. When used in appropriate doses and under strict clinical control, psilocybin appears as a valuable treatment for OCD. This narrative article provides a thorough overview of OCD's etiology, current treatment options, and the emerging evidence supporting psilocybin's efficacy in managing OCD symptoms.

New horizons for obsessive-compulsive disorder drug discovery: is targeting glutamate receptors the answer?

INTRODUCTION: Over the past decade, glutamate has emerged as a prominent focus in the field of obsessive-compulsive disorder (OCD) pathophysiology. A convergence of evidence from genetic, preclinical, and clinical studies points to glutamatergic dysfunction as a key feature of this condition. In light of these findings, there has been a growing interest in exploring the potential of glutamatergic agents in the treatment of OCD. AREAS COVERED: This paper reviews the literature on glutamate transmission in OCD. In addition, the authors examine the results of clinical trials investigating the efficacy of glutamatergic agents in the treatment of OCD patients. EXPERT OPINION: Along with the recognition of neuroinflammation in the brain in OCD, the evidence of glutamate dysfunction represents one of the most promising recent discoveries for understanding the mechanisms involved in OCD. The importance of this discovery lies primarily in its pharmacological implications and has led to intense research activity in the field of glutamatergic agents. While this research has not yet had a substantial clinical impact, targeting glutamate receptors remains a promising horizon for the successful treatment of OCD patients.

Cerebellar functional connectivity and its associated genes: A longitudinal study in drug-naive patients with obsessive-compulsive disorder.

The role of cerebellar-cerebral functional connectivity (CC-FC) in obsessive-compulsive disorder (OCD), its trajectory post-pharmacotherapy, and its potential as a prognostic biomarker and genetic mechanism remain uncertain. To address these gaps, this study included 37 drug-naive OCD patients and 37 healthy controls (HCs). Participants underwent baseline functional magnetic resonance imaging (fMRI), followed by four weeks of paroxetine treatment for patients with OCD, and another fMRI scan post-treatment. We examined seed-based CC-FC differences between the patients and HCs, and pre- and post-treatment patients. Support vector regression (SVR) based on CC-FC was performed to predict treatment response. Correlation analysis explored associations between CC-FC and clinical features, as well as gene profiles. Compared to HCs, drug-naive OCD patients exhibited reduced CC-FC in executive, affective-limbic, and sensorimotor networks, with specific genetic profiles associated with altered CC-FC. Gene enrichment analyses highlighted the involvement of these genes in various biological processes, molecular functions, and pathways. Post-treatment, the patients showed partial clinical improvement and partial restoration of the previously decreased CC-FC. Abnormal CC-FC at baseline correlated negatively with compulsions severity and social functional impairment, while changes in CC-FC correlated with cognitive function changes post-treatment. CC-FC emerged as a potential predictor of symptom severity in patients following paroxetine treatment. This longitudinal resting-state fMRI study underscores the crucial role of CC-FC in the neuropsychological mechanisms of OCD and its pharmacological treatment. Transcriptome-neuroimaging spatial correlation analyses provide insight into the neurobiological mechanisms underlying OCD pathology. Furthermore, SVR analyses hold promise for advancing precision medicine approaches in treating patients with OCD.

Pediatric Treatment-Resistant Obsessive Compulsive Disorder: Treatment Options and Challenges.

Pediatric obsessive-compulsive disorder (OCD) is a chronic, potentially debilitating psychiatric condition. Although effective treatments exist, at least 10% of youth do not achieve remission despite receiving first-line treatments. This article reviews the extant, albeit limited, evidence supporting treatment approaches for youth with treatment-resistant OCD. A literature search for articles addressing pediatric treatment-resistant OCD was conducted through April 11, 2024. These results were augmented by searching for treatment-resistant OCD in adults; treatment strategies discovered for the adult population were then searched in the context of children and adolescents. In general, intensive treatment programs and antipsychotic augmentation of an antidepressant had the most substantial and consistent evidence base for treatment-resistant youth with OCD, although studies were limited and of relatively poor methodological quality (i.e., open trials, naturalistic studies). Several pharmacological approaches (clomipramine, antipsychotics [e.g., aripiprazole, risperidone], riluzole, ketamine, D-cycloserine, memantine, topiramate, N-acetylcysteine, ondansetron), largely based on supporting data among adults, have received varying levels of investigation and support. There is nascent support for how to treat pediatric treatment-resistant OCD. Future treatment studies need to consider how to manage the significant minority of youth who fail to benefit from first-line treatment approaches.

Effects of antidepressants on brain structure and function in patients with obsessive-compulsive disorder: A review of neuroimaging studies.

Obsessive-compulsive disorder (OCD) affects 2-3% of people worldwide. Although antidepressants are the standard pharmachological treatment of OCD, their effect on the brain of individuals with OCD has not yet been fully clarified. We conducted a systematic search on PubMed, Scopus, Embase, and Web of Science to explore the effects of antidepressants on neuroimaging findings in OCD. Thirteen neuroimaging investigations were included. After antidepressant treatment, structural magnetic resonance imaging studies suggested thalamic, amygdala, and pituitary volume changes in patients. In addition, the use of antidepressants was associated with alterations in diffusion tensor imaging metrics in the left striatum, the right midbrain, and the posterior thalamic radiation in the right parietal lobe. Finally, functional magnetic resonance imaging highlighted possible changes in the ventral striatum, frontal, and prefrontal cortex. The small number of included studies and sample sizes, short durations of follow-up, different antidepressants, variable regions of interest, and heterogeneous samples limit the robustness of the findings of the present review. In conclusion, our review suggests that antidepressant treatment is associated with brain changes in individuals with OCD, and these results may help to deepen our knowledge of the pathophysiology of OCD and the brain mechanisms underlying the effects of antidepressants.

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.

Crocin (bioactive compound of Crocus sativus L.) potently restores REM sleep deprivation-induced manic- and obsessive-compulsive-like behaviors in female rats.

Rapid-eye movement (REM) sleep deprivation (SD) can induce manic-like behaviors including hyperlocomotion. On the other hand, crocin (one of the main compounds of Crocus sativus L. or Saffron) may be beneficial in the improvement of mental and cognitive dysfunctions. Also, crocin can restore the deleterious effects of SD on mental and cognitive processes. In this study, we investigated the effect of REM SD on female rats' behaviors including depression- and anxiety-like behaviors, locomotion, pain perception, and obsessive-compulsive-like behavior, and also, the potential effect of crocin on REM SD effects. We used female rats because evidence on the role of REM SD in modulating psychological and behavioral functions of female (but not male) rats is limited. REM SD was induced for 14 days (6h/day), and crocin (25, 50, and 75 mg/kg) was injected intraperitoneally. Open field test, forced swim test, hot plate test, and marble burying test were used to assess rats' behaviors. The results showed REM SD-induced manic-like behavior (hyperlocomotion). Also, REM SD rats showed decreased anxiety- and depression-like behavior, pain subthreshold (the duration it takes for the rat to feel pain), and showed obsessive compulsive-like behavior. However, crocin at all doses partially or fully reversed REM SD-induced behavioral changes. In conclusion, our results suggested the possible comorbidity of OCD and REM SD-induced manic-like behavior in female rats or the potential role of REM SD in the etiology of OCD, although more studies are needed. In contrast, crocin can be a possible therapeutic choice for decreasing manic-like behaviors.

Mechanisms of therapeutic change after psychedelic treatment in OCD.

Novel treatments are required for the 30-50% of individuals with obsessive-compulsive disorder (OCD) who remain resistant to first-line pharmacological and psychotherapeutic treatments. Recent pilot data suggest benefit from psilocybin-assisted psychotherapy (PAP) and from imagery rescripting (ImRs). We explore psychological mechanisms of change underpinning both interventions that appear to allow for reprocessing of negative emotions and core beliefs associated with past aversive events. A next critical step in PAP is the development of psychotherapeutic frameworks grounded in theory. We propose that basing PAP on an ImRs framework may provide synergistic benefits in symptom reduction, modification of core beliefs, and value-based living.

The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia: longitudinal observational study.

BACKGROUND: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. AIMS: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS). METHOD: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample. RESULTS: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04-0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = -0.28, 95% CI -0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction. CONCLUSIONS: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions.

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.

New horizons for the study of saffron (Crocus sativus L.) and its active ingredients in the management of neurological and psychiatric disorders: A systematic review of clinical evidence and mechanisms.

Saffron (Crocus sativus), as an herbal medicine, has been extensively investigated for treating neurological and psychiatric disorders. This systematic review aimed to assess the overall effects of saffron on cognition, depression, anxiety, sleep disorders, attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD). Relevant randomized controlled trials (RCTs) were identified by searching PubMed/Medline, Web of Science, and Clinical Trials databases up to June 2023 according to search terms and inclusion criteria. The participants were either healthy or suffering from some diseases, including neurological and psychiatric disorders, and consumed saffron or its extracts as an intervention. The risk of bias was assessed according to the Cochrane guidelines, and the PRISMA statement was followed. The meta-analysis was performed using RevMan and STATA software. A random-effects or fixed-effects model was used to calculate the pooled effect sizes. Forty-six RCTs were enrolled, and the duration of these trials ranged from 4 to 48 weeks with saffron or its extracts, both alone or in combination with conventional drugs. Saffron was more effective than placebo in improving cognition, depression with an overall effect size of -4.26 (95% CI: -5.76, -2.77), anxiety of -3.75 (95% CI: -5.83, -1.67), and sleep disorders of -1.91 (95% CI: -2.88, -0.93). Saffron was non-inferior to conventional drugs for treating cognitive disorders, depression, anxiety, ADHD, and OCD, and it exhibited good tolerance with few side effects. Saffron may exert protective roles for neurological and psychiatric disorders and represents a relatively favorable and safe treatment.

Common pitfalls, and how to avoid them, in child and adolescent psychopharmacology: Part I.

As Faculty of the British Association for Psychopharmacology course on child and adolescent psychopharmacology, we present here what we deem are the most common pitfalls, and how to avoid them, in child and adolescent psychopharmacology. In this paper, we specifically addressed common pitfalls in the pharmacological treatment of attention-deficit/hyperactivity disorder, anxiety, bipolar disorder, depression, obsessive-compulsive disorder and related disorders, and tic disorder. Pitfalls in the treatment of other disorders are addressed in a separate paper (part II).

The use of antipsychotics in obsessive compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic disease with a prevalence in the general population of around 2%-3%, generally accompanied by a severe impairment of functioning and quality of life. A consistent subgroup of patients may not achieve adequate symptom remission with first-line treatments (i.e., cognitive behavioral therapy, selective serotonin reuptake inhibitors [SSRIs]). The most validated option for treatment-resistant cases relies on the augmentative use of antipsychotics to SSRIs, preferably of the 'second generation'. Indeed, dopamine appears to be crucially involved in OCD neuropathology due to its implication in systems relating to goal-directed behaviour and maladaptive habits. Nevertheless, the mechanism of action of antipsychotics in OCD symptom improvement is still unclear. Risperidone, aripiprazole, and haloperidol seem to be the most useful medications, whereas 'first generation' antipsychotics may be indicated in case of comorbidity with tics and/or Tourette Syndrome. Antipsychotic augmentation may be also related to side-effects, particularly in the long term (e.g., alteration in metabolic profile, sedation, extrapyramidal symptoms). The present mini-review sought to provide the most updated evidence on augmentative antipsychotic use in treatment-resistant patients with OCD, providing a road map for clinicians in daily practice and shedding light on avenues for further research.

Influence of study characteristics, methodological rigour and publication bias on efficacy of pharmacotherapy in obsessive-compulsive disorder: a systematic review and meta-analysis of randomised, placebo-controlled trials.

QUESTION: We examined the effect of study characteristics, risk of bias and publication bias on the efficacy of pharmacotherapy in randomised controlled trials (RCTs) for obsessive-compulsive disorder (OCD). STUDY SELECTION AND ANALYSIS: We conducted a systematic search of double-blinded, placebo-controlled, short-term RCTs with selective serotonergic reuptake inhibitors (SSRIs) or clomipramine. We performed a random-effect meta-analysis using change in the Yale-Brown Obsessive-Compulsive Scale (YBOCS) as the primary outcome. We performed meta-regression for risk of bias, intervention, sponsor status, number of trial arms, use of placebo run-in, dosing, publication year, age, severity, illness duration and gender distribution. Furthermore, we analysed publication bias using a Bayesian selection model. FINDINGS: We screened 3729 articles and included 21 studies, with 4102 participants. Meta-analysis showed an effect size of -0.59 (Hedges' G, 95% CI -0.73 to -0.46), equalling a 4.2-point reduction in the YBOCS compared with placebo. The most recent trial was performed in 2007 and most trials were at risk of bias. We found an indication for publication bias, and subsequent correction for this bias resulted in a depleted effect size. In our meta-regression, we found that high risk of bias was associated with a larger effect size. Clomipramine was more effective than SSRIs, even after correcting for risk of bias. After correction for multiple testing, other selected predictors were non-significant. CONCLUSIONS: Our findings reveal superiority of clomipramine over SSRIs, even after adjusting for risk of bias. Effect sizes may be attenuated when considering publication bias and methodological rigour, emphasising the importance of robust studies to guide clinical utility of OCD pharmacotherapy. PROSPERO REGISTRATION NUMBER: CRD42023394924.