Shared deficits of education, marital and occupational functioning in unaffected siblings of multiple affected families with major psychiatric illness.

BACKGROUND: Major psychiatric illnesses often cluster in families, and their impact on affected and unaffected members within families may reflect the consequence of both genetic and social liability. METHODS: Data was derived from 202 families with multiple affected individuals. Affected individuals (N = 259) had a diagnosis of schizophrenia, bipolar disorder, obsessive-compulsive disorder or substance use disorder. For comparison, we used the unaffected siblings from the same families (N = 229) and a matched random subset of healthy control (HC) data (N = 229) from India's National Mental Health Survey, 2016 (NMHS). We compared the three groups' educational attainment, functional marital status, and occupational status. RESULTS: The highest educational attainment was significantly different between the groups. The affected and unaffected siblings had poorer educational attainment compared to HC. Similarly, the affected and unaffected siblings more often remained single, in contrast to HC. Moreover, employment rates were significantly higher in the unaffected siblings, especially female siblings. Overall, females had spent fewer years at school, were primarily married, and were majority homemakers across the three groups compared to males. DISCUSSION: Affected and unaffected siblings had lower education and marriage rates than HC. The unaffected siblings were more likely to be employed than HC. Whether the poor educational attainment and lower marriage rates in unaffected siblings is a biological marker of shared endophenotype or the effect of the social burden of having an affected family member requires further systematic evaluation.

Cognitive Training in Obsessive-Compulsive Disorder: A Systematic Review.

Background: Cognitive training (CT) for illness-linked neuropsychological deficits has been attempted in psychiatric disorders and, more recently, in obsessive-compulsive disorder (OCD). However, studies are few and far between, with a limited understanding of factors contributing to efficacy. This article aims to provide a comprehensive critical review of studies employing CT in OCD. Methods: This systematic review follows the Preferred Reporting of Items for Systematic Review and Meta-Analyses Protocols. Empirical studies that used any form of CT/remediation in individuals with OCD were included. Results: Eight articles met the criteria for inclusion, of which five were randomized controlled trials, two were case series, and one was an open-label trial. The studies have predominantly demonstrated improved trained cognitive functions, with only two showing generalization to untrained domains like clinical symptoms and socio-occupational functioning. Conclusion: There are few controlled trials of CT in OCD, which limits conclusions of efficacy. Given the sparse research in the area, the review summarizes the current status of research and examines important methodological considerations that may inform future studies.

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.

Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression.

BACKGROUND: Antidepressants are used to treat acute depression in patients with bipolar I disorder, but their effect as maintenance treatment after the remission of depression has not been well studied. METHODS: We conducted a multisite, double-blind, randomized, placebo-controlled trial of maintenance of treatment with adjunctive escitalopram or bupropion XL as compared with discontinuation of antidepressant therapy in patients with bipolar I disorder who had recently had remission of a depressive episode. Patients were randomly assigned in a 1:1 ratio to continue treatment with antidepressants for 52 weeks after remission or to switch to placebo at 8 weeks. The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide. Key secondary outcomes included the time to an episode of mania or hypomania or depression. RESULTS: Of 209 patients with bipolar I disorder who participated in an open-label treatment phase, 150 who had remission of depression were enrolled in the double-blind phase in addition to 27 patients who were enrolled directly. A total of 90 patients were assigned to continue treatment with the prescribed antidepressant for 52 weeks (52-week group) and 87 were assigned to switch to placebo at 8 weeks (8-week group). The trial was stopped before full recruitment was reached owing to slow recruitment and funding limitations. At 52 weeks, 28 of the patients in the 52-week group (31%) and 40 in the 8-week group (46%) had a primary-outcome event. The hazard ratio for time to any mood episode in the 52-week group relative to the 8-week group was 0.68 (95% confidence interval [CI], 0.43 to 1.10; P = 0.12 by log-rank test). A total of 11 patients in the 52-week group (12%) as compared with 5 patients in the 8-week group (6%) had mania or hypomania (hazard ratio, 2.28; 95% CI, 0.86 to 6.08), and 15 patients (17%) as compared with 35 patients (40%) had recurrence of depression (hazard ratio, 0.43; 95% CI, 0.25 to 0.75). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In a trial involving patients with bipolar I disorder and a recently remitted depressive episode, adjunctive treatment with escitalopram or bupropion XL that continued for 52 weeks did not show a significant benefit as compared with treatment for 8 weeks in preventing relapse of any mood episode. The trial was stopped early owing to slow recruitment and funding limitations. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00958633.).

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

Measurement fidelity of clinical assessment methods in a global study on identifying reproducible brain signatures of obsessive-compulsive disorder.

OBJECTIVE: To describe the steps of ensuring measurement fidelity of core clinical measures in a five-country study on brain signatures of obsessive-compulsive disorder (OCD). METHOD: We collected data using standardized instruments, which included the Yale-Brown Obsessive-Compulsive Scale (YBOCS), the Dimensional YBOCS (DYBOCS), the Brown Assessment of Beliefs Scale (BABS), the 17-item Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale (HAM-A), and the Structured Clinical Interview for DSM-5 (SCID). Steps to ensure measurement fidelity included translating instruments, developing a clinical decision manual, and continuing reliability training with 11-13 transcripts of each instrument by 13 independent evaluators across sites over 4 years. We use multigroup confirmatory factor analysis (MGCFA) to report interrater reliability (IRR) among the evaluators and factor structure for each scale in 206 participants with OCD. RESULTS: The overall IRR for most scales was high (ICC > 0.94) and remained good to excellent throughout the study. Consistent factor structures (configural invariance) were found for all instruments across the sites, while similarity in the factor loadings for the items (metric invariance) could be established only for the DYBOCS and the BABS. CONCLUSIONS: It is feasible to achieve measurement fidelity of clinical measures in multisite, multilinguistic global studies, despite the challenges inherent to such endeavors. Future studies should not only report IRR but also consider reporting methods of standardization of data collection and measurement invariance to identify factor structures of core clinical measures. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Efficacy of Repetitive Transcranial Magnetic Stimulation on Comorbid Anxiety and Depression Symptoms in Obsessive-Compulsive Disorder: A Meta-Analysis of Randomized Sham-Controlled Trials.

OBJECTIVE: To systematically evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in reducing comorbid anxiety and depressive symptoms in patients with obsessive-compulsive disorder (OCD). METHODS: Three electronic databases were searched for randomized, sham-controlled clinical trials evaluating rTMS for the treatment of OCD. Hedge's g was calculated as the effect size for anxiety/depression symptom severity (primary outcome) and OCD severity (secondary outcome). Subgroup analyses and meta-regression analyses were carried out to evaluate the most promising target and whether a reduction in OCD severity moderates the change in anxiety or depression scores. RESULTS: Twenty studies (n = 688) were included in the meta-analysis. rTMS had small-medium effect size on OCD (Hedge's g = 0.43; 95% confidence interval [CI]: [0.20, 0.65]; P < 0.001), anxiety (Hedge's g = 0.3; 95% CI: [0.11, 0.48]; P = 0.001) and depression (Hedge's g = 0.24; 95% CI: [0.07, 0.40]; P = 0.003) symptoms. Subgroup analysis showed that protocols targeting dorsolateral prefrontal cortex (DLPFC) were effective for 3 outcome measures. The change in anxiety, but not depression severity, was moderated by a change in OCD symptom scores. However, the findings are uncertain as a majority of the studies had some concerns or a high risk of bias. CONCLUSIONS: Active rTMS protocol targeting DLPFC is effective in reducing the comorbid anxiety/depression symptoms along with OCD severity. The antidepressant effect is not moderated by the anti-obsessive effect of rTMS.

Treatment strategies for serotonin reuptake inhibitor-resistant obsessive-compulsive disorder: A network meta-analysis of randomised controlled trials.

OBJECTIVES: Treatment-resistant obsessive-compulsive disorder is a chronic debilitating illness. We conducted a network meta-analysis [NMA] to compare the efficacy of all interventions in SRI-resistant OCD from published Randomised controlled trials [RCT]. METHODS: We performed an NMA of RCTs in SRI resistant OCD from all modalities of treatments; pharmacological, psychological, neuromodulation, neurosurgery including deep brain stimulation. The design-by-treatment interaction inconsistency model within the frequentist framework was adopted with a change in Yale-Brown Obsessive-Compulsive Scale score as the primary outcome. We conducted sensitivity analyses excluding studies examining neurosurgical interventions, deep brain stimulation, studies in the paediatric population, and studies from a single geographical region. We also conducted analyses of interventions categorised into treatment groups. RESULTS: 55 RCTs examining 19 treatments or placebo involving 2011 participants were included in the NMA. Ondansetron [Standardised mean difference -2.01 (95% CI: -3.19, -0.83)], deep TMS [- 1.95 (-3.25, -0.65)], therapist administered Cognitive Behavioural Therapy [CBT-TA] [-1.46 (-2.93, 0.01)] and aripiprazole [-1.36 (-2.56, -0.17)] were ranked as the best four treatments on using the Surface Under the Cumulative Ranking [SUCRA] percentage values (85.4%, 83.2%, 80.3%, 67.9% respectively). While all four interventions had large effect sizes, CBT[TA] narrowly missed statistical significance in our analysis. In sensitivity analyses, deep TMS was ranked as the best treatment strategy for SRI-resistant OCD. The small number of subjects in individual studies, higher confidence interval limits, and wider prediction interval for most agents warrant a cautious interpretation. CONCLUSIONS: Considering the principal analysis and sensitivity analyses together, deep TMS, ondansetron, CBT[TA], and aripiprazole may be considered a first-line intervention for SRI-resistant OCD in adults. OTHER: This work was not funded. The NMA has been registered with PROSPERO, [Registration number: CRD42020173589].

Neurocognition and its association with adverse childhood experiences and familial risk of mental illness.

Environmental factors such as adverse childhood experiences (ACEs) may affect neurocognition, an endophenotype for several mental illnesses. This study examines the effect of ACEs on neurocognitive performance in first-degree relatives (FDRs) of patients with severe mental illness to determine whether familial risk has a moderating effect on the relationship between ACEs and neurocognition. Unaffected FDRs from multiplex families with severe mental illnesses (schizophrenia, bipolar disorder, obsessive-compulsive disorder, or alcohol use disorder) (n = 324) and healthy controls (with no familial risk) (n = 188) underwent neurocognitive tests for processing speed, new learning, working memory and Theory of Mind. ACEs were measured using the WHO ACE-International Questionnaire (ACE-IQ). Regression models were done to predict each neurocognitive domain by the effect of familial risk, ACE-IQ Score and their interaction (familial risk*ACE-IQ score). The main effect of familial risk predicted poor performance in all domains of neurocognition (p < 0.01), and the interaction had a negative association with global neurocognition (ß = -0.093, p = 0.009), processing speed (ß = -0.109, p = 0.003) and working memory (ß = -0.092, p = 0.01). Among the ACEs sub-domains, only maltreatment (specifically the main effect of physical neglect and the interaction effect of sexual abuse with familial risk) predicted poorer neurocognition. In FDRs of schizophrenia and bipolar disorder, only the main effects of familial risk were significantly associated with poorer neurocognition. We conclude that there is a relationship between ACEs (especially maltreatment) and neurocognitive functioning, which is moderated by the familial risk of mental illnesses. Genetic/familial vulnerability may have a stronger association with neurocognition in schizophrenia and bipolar disorder.

Determinants of family functioning in caregivers of persons with obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is known to cause significant burden to patients and their caregivers. However, there is limited data on its impact on family functioning, especially from families with an adult member having OCD. METHODS: Four hundred subjects, which included treatment-seeking adult OCD patients (n = 200) and their caregivers (n = 200) were recruited. Patients were evaluated using the Mini International Neuropsychiatric Interview (MINI) and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Caregivers were evaluated using the MINI, the Caregiver Strain Index (CSI), the Hamilton Anxiety Rating Scale (HAM-A), the Hamilton Depression Rating Scale (HAM-D), the Socio-Occupational Functioning Assessment Scale (SOFAS), the Family Accommodation Scale (FAS) and the Connor-David Resilience scale (CD-RISC) in a cross-sectional interview. Family functioning was measured using the OCD Family Functioning (OFF) Scale. Structural equation modeling (SEM) was carried out to evaluate the relationships between the patient and caregiver variables to predict family functioning. RESULTS: From the best-fitting path model, we ascertained that OCD symptoms did not have a direct relationship with family dysfunction. Their effects were in turn was mediated by family accommodation, anxiety, caregiver stress/burden and depression. "Contamination & washing" was the only significant symptom dimension within the model. Caregiver resilience was found to predict only their individual functioning, and not family functioning. LIMITATIONS: Study sample included patients from a tertiary care OCD service, only one caregiver from each patient's family was interviewed. CONCLUSIONS: Evaluating family functioning, addressing it as part of interventional modules for patients and caregivers may help improving treatment outcomes.

Prediction of Obsessive-Compulsive Disorder: Importance of Neurobiology-Aided Feature Design and Cross-Diagnosis Transfer Learning.

BACKGROUND: Machine learning applications using neuroimaging provide a multidimensional, data-driven approach that captures the level of complexity necessary for objectively aiding diagnosis and prognosis in psychiatry. However, models learned from small training samples often have limited generalizability, which continues to be a problem with automated diagnosis of mental illnesses such as obsessive-compulsive disorder (OCD). Earlier studies have shown that features incorporating prior neurobiological knowledge of brain function and combining brain parcellations from various sources can potentially improve the overall prediction. However, it is unknown whether such knowledge-driven methods can provide a performance that is comparable to state-of-the-art approaches based on neural networks. METHODS: In this study, we apply a transparent and explainable multiparcellation ensemble learning framework EMPaSchiz (Ensemble algorithm with Multiple Parcellations for Schizophrenia prediction) to the task of predicting OCD, based on a resting-state functional magnetic resonance imaging dataset of 350 subjects. Furthermore, we apply transfer learning using the features found effective for schizophrenia to OCD to leverage the commonality in brain alterations across these psychiatric diagnoses. RESULTS: We show that our knowledge-based approach leads to a prediction performance of 80.3% accuracy for OCD diagnosis that is better than domain-agnostic and automated feature design using neural networks. Furthermore, we show that a selection of reduced feature sets can be transferred from schizophrenia to the OCD prediction model without significant loss in prediction performance. CONCLUSIONS: This study presents a machine learning framework for OCD prediction with neurobiology-aided feature design using resting-state functional magnetic resonance imaging that is generalizable and reasonably interpretable.

An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Preschool-onset OCD: A review of literature and clinical experience.

Obsessive-compulsive disorder (OCD) has been described in preschool children as young as 2-3 years old. A preschool age onset of OCD has unique diagnostic and therapeutic challenges. In this article, the authors review published literature on preschool onset OCD and present data on preschool-onset OCD (age of onset ≤ 5 years) from clinical records at a tertiary care child and adolescent psychiatry center in India. Literature suggests that OCD that starts this early is phenomenologically similar to OCD in older individuals; however, it has very high rates of comorbidity and a family history of OCD. There is a paucity of data on course, treatment, and long-term outcome in this group. At their center, the authors found a 3% prevalence of preschool-onset OCD, with a male predominance (69%) and fairly high comorbidity rates (62%). Qualitative review highlighted delay in treatment seeking, poor follow-up rates, frequent use of pharmacological treatment, and a high remission rate in those treated adequately.

Plasma IL-6 levels in unmedicated, comorbidity free obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is increasingly being evaluated for a neuro-immune basis. Interleukin-6 (IL-6) is the most widely studied cytokine with a potential role in altering neurotransmission. The evidence for plasma IL-6 alterations in OCD has yielded mixed results. Psychotropic medications are known to modulate inflammatory processes and cytokine levels. METHODS: In this study, we recruited unmedicated, co-morbidity-free adult OCD patients (n = 49) and sex-matched healthy controls HC (n = 47) and compared their plasma IL-6 levels and their correlation with age at onset, duration of illness, and severity. RESULTS: IL-6 plasma level (ng/ml) in unmedicated OCD patients (1.31 ± 0.67) was significantly greater compared to HC (1.03 ± 0.47) [t = 2.33 (p = 0.02)]. The group differences persisted even after controlling for age and sex [F(1, 91) = 4.57, p = 0.035, η2 = 0.05]. Plasma IL-6 did not correlate significantly with any clinical variables. CONCLUSIONS: This study adds to the existing literature on immune alterations in OCD. Alterations in plasma IL-6 might have implications in the neurotransmitter alterations and stress-response in OCD. The current study results in unmedicated and comorbidity-free OCD patients give us a better understanding of the immune alterations in OCD. Future studies in such a population will probably help in reducing the heterogeneity of findings.

Cognitive-behavioral and related therapies for obsessive-compulsive and related disorders.

PURPOSE OF REVIEW: Cognitive behavioral therapy (CBT) with exposure and response prevention is the first-line treatment for obsessive-compulsive disorder (OCD) and related disorders such as body dysmorphic disorder (BDD). We review here recent developments in CBT and related therapies in treating OCD and related disorders. RECENT FINDINGS: Superiority of CBT over medications in treating OCD is being questioned by some recent meta-analyses, nonetheless CBT continues to be the mainstay of treatment. Web-based therapies have been shown to be beneficial in treating at least mild-to-moderately ill patients. Mindfulness-based CBT, intensive residential treatment and Bergen 4-day concentrated exposure are also proving to be useful in treating OCD. Large well designed studies have demonstrated the efficacy CBT over supportive therapy in treating BDD. Research on the efficacy of CBT in treating hoarding disorder is accumulating. SUMMARY: Efficacy of web-based CBT has a potential public health importance in that CBT may now become accessible to all and benefit at least mild-to-moderately ill patients who form most of the clinically ill sample. Similarly, efficacy of Bergen 4-day concentrated exposure will have a huge public health implication if the findings can be replicated in other centers across the world.