Animal models of obsessive-compulsive disorder: utility and limitations

Obsessive-compulsive disorder (OCD) is a disabling and common neuropsychiatric condition of poorly known etiology. Many attempts have been made in the last few years to develop animal models of OCD with the aim of clarifying the genetic, neurochemical, and neuroanatomical basis of the disorder, as well as of developing novel pharmacological and neurosurgical treatments that may help to improve the prognosis of the illness. The latter goal is particularly important given that around 40% of patients with OCD do not respond to currently available therapies. This article summarizes strengths and limitations of the leading animal models of OCD including genetic, pharmacologically induced, behavioral manipulation-based, and neurodevelopmental models according to their face, construct, and predictive validity. On the basis of this evaluation, we discuss that currently labeled 'animal models of OCD' should be regarded not as models of OCD but, rather, as animal models of different psychopathological processes, such as compulsivity, stereotypy, or perseverance, that are present not only in OCD but also in other psychiatric or neurological disorders. Animal models might constitute a challenging approach to study the neural and genetic mechanism of these phenomena from a trans-diagnostic perspective. Animal models are also of particular interest as tools for developing new therapeutic options for OCD, with the greatest convergence focusing on the glutamatergic system, the role of ovarian and related hormones, and the exploration of new potential targets for deep brain stimulation. Finally, future research on neurocognitive deficits associated with OCD through the use of analogous animal tasks could also provide a genuine opportunity to disentangle the complex etiology of the disorder

Factors Associated with Long-Term Sickness Absence Due to Mental Disorders: a Cohort Study of 7.112 Patients during the Spanish Economic Crisis

Background: Mental health problems are very common and often lead to prolonged sickness absence, having serious economic repercussions for most European countries. Periods of economic crisis are important social phenomena that are assumed to increase sickness absence due to mental disorders, although research on this topic remains scarce. The aim of this study was to gather data on long-term sickness absence (and relapse) due to mental disorders in Spain during a period of considerable socio-economic crisis. Methods: Relationships were analyzed (using chi-squared tests and multivariate modelling via binary logistic regression) between clinical, social/employment-related and demographic factors associated and long-term sickness absence (>60 consecutive days) due to mental disorders in a cohort of 7112 Spanish patients during the period 2008-2012. Results: Older age, severe mental disorders, being self-employed, having a non-permanent contract, and working in the real estate and construction sector were associated with an increased probability of long-term sickness absence (gender had a mediating role with respect to some of these variables). Relapses were associated with short-term sick leave (return to work due to 'improvement') and with working in the transport sector and public administration. Conclusions: Aside from medical factors, other social/employment-related and demographic factors have a significant influence on the duration of sickness absence due to mental disorders

Long-term comparative effectiveness of deep brain stimulation in severe obsessive-compulsive disorder

Background: Twenty years after the first use of Deep Brain Stimulation (DBS) in obsessive-compulsive disorder (OCD), our knowledge of the long-term effects of this therapeutic option remains very limited. Objective: Our study aims to assess the long-term effectiveness and tolerability of DBS in OCD patients and to look for possible predictors of long-term response to this treatment. Methods: We studied the course of 25 patients with severe refractory OCD treated with DBS over an average follow-up period of 6.4 years (+/- 3.2) and compared them with a control group of 25 patients with severe OCD who refused DBS and maintained their usual treatment. DBS was implanted at the ventral anterior limb of the internal capsule and nucleus accumbens (vALIC-Nacc) in the first six patients and later at the bed nucleus of stria terminalis (BNST) in the rest of patients. Main outcome was change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score between the two groups assessed using mixed models. Secondary effectiveness outcomes included Hamilton Depression Rating Scale (HDRS) and Global Assessment of Functioning (GAF) scores. Results: Obsessive symptoms fell by 42.5% (Y-BOCS score) in patients treated with DBS and by 4.8% in the control group. Fifty-six per cent of DBS-treated patients could be considered responders at the end of follow-up and 28% partial responders. Two patients among those who rejected DBS were partial re-sponders (8%), but none of the non-DBS group achieved criteria for complete response. HDRS and GAF scores improved significantly in 39.2% and 43.6% among DBS-treated patients, while did not significantly change in those who rejected DBS (improvement limited to 6.2% in HDRS and 4.2% in GAF scores). No statistically significant predictors of response were found. Mixed models presented very large compar-ative effect sizes for DBS (4.29 for Y-BOCS, 1.15 for HDRS and 2.54 for GAF). Few patients experienced adverse effects and most of these effects were mild and transitory. Conclusions: The long-term comparative effectiveness and safety of DBS confirm it as a valid option for the treatment of severe refractory OCD. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Looking into the genetic bases of OCD dimensions: a pilot genome-wide association study

The multidimensional nature of obsessive-compulsive disorder (OCD) has been consistently reported. Clinical and biological characteristics have been associated with OCD dimensions in different ways. Studies suggest the existence of specific genetic bases for the different OCD dimensions. In this study, we analyze the genomic markers, genes, gene ontology and biological pathways associated with the presence of aggressive/checking, symmetry/order, contamination/cleaning, hoarding, and sexual/religious symptoms, as assessed via the Dimensional Yale-Brown Obsessive Compulsive Scale (DY-BOCS) in 399 probands. Logistic regression analyses were performed at the single-nucleotide polymorphism (SNP) level. Gene-based and enrichment analyses were carried out for common (SNPs) and rare variants. No SNP was associated with any dimension at a genome-wide level (p < 5 × 10−8). Gene-based analyses showed one gene to be associated with hoarding (SETD3, p = 1.89 × 10−08); a gene highly expressed in the brain and which plays a role in apoptotic processes and transcriptomic changes, and another gene associated with aggressive symptoms (CPE; p = 4.42 × 10−6), which is involved in neurotrophic functions and the synthesis of peptide hormones and neurotransmitters. Different pathways or biological processes were represented by genes associated with aggressive (zinc ion response and lipid metabolism), order (lipid metabolism), sexual/religious (G protein-mediated processes) and hoarding (metabolic processes and anion transport) symptoms after FDR correction; while no pathway was associated with contamination. Specific genomic bases were found for each dimension assessed, especially in the enrichment analyses. Further research with larger samples and different techniques, such as next-generation sequencing, are needed to better understand the differential genetics of OCD dimensions

Removing and reimplanting deep brain stimulation therapy devices in resistant OCD (when the patient does not respond): case report

Background: Deep brain stimulation (DBS) is emerging as a promising tool in the treatment of refractory obsessive-compulsive disorder (OCD) but the search for the best target still continues. This issue is especially relevant when particularly resistant profiles are observed in some patients, which have been ascribed to individual responses to DBS according to differential patterns of connectivity. As patients have been implanted, new dilemmas have emerged, such as what to do when the patient does not respond to surgery. Case presentation: Here we describe a 22-year-old male with extremely severe OCD who did not respond to treatment with DBS in the nucleus accumbens, but who did respond after explanting and reimplanting leads targeting the ventral capsule-ventral striatum region. Information regarding the position of the electrodes for both surgeries is provided and possible brain structures affected during stimulation are reviewed. To our knowledge this case is the first in the literature reporting the removal and reimplantation of DBS leads for therapeutical benefits in a patient affected by a mental disorder. Conclusion: The capability for explantation and reimplantation of leads should be considered as part of the DBS therapy reversibility profile in resistant mental disorders, as it allows application in cases of non-response to the first surgery

Memory and strategic processing in first-degree relatives of obsessive compulsive patients

Background: the same executive dysfunctions and alterations in neuroimaging tests (both functional and structural) have been found in obsessive-compulsive patients and their first-degree relatives. These neurobiological findings are considered to be intermediate markers of the disease. The aim of our study was to assess verbal and non-verbal memory in unaffected first-degree relatives, in order to determine whether these neuropsychological functions constitute a new cognitive marker for obsessive-compulsive disorder (OCD). Method: recall and use of organizational strategies in verbal and non-verbal memory tasks were measured in 25 obsessive-compulsive patients, 25 unaffected first-degree relatives and 25 healthy volunteers. Results: first-degree relatives and healthy volunteers did not show differences on most measures of verbal memory. However, during the recall and processing of non-verbal information, deficits were found in first-degree relatives and patients compared with healthy volunteers. Conclusions: the presence of the same deficits in the execution of non-verbal memory tasks in OCD patients and unaffected first-degree relatives suggests the influence of certain genetic and/or familial factors on this cognitive function in OCD and supports the hypothesis that deficits in non-verbal memory tasks could be considered as cognitive markers of the disorder

Sleep disturbances in obsessive-compulsive disorder: influence of depression symptoms and trait anxiety

Background: Sleep disturbances have been reported in obsessive-compulsive disorder (OCD) patients, with heterogeneous results. The aim of our study was to assess sleep function in OCD and to investigate the relationship between sleep and the severity of obsessive-compulsive (OC) symptoms, depressive symptoms and trait anxiety. Methods: Sleep quality was measured in 61 OCD patients and 100 healthy controls (HCs) using the Pittsburgh Sleep Quality Index (PSQI). Multiple linear regression was conducted to explore the association between sleep and psychopathological measures; a mediation analysis was also performed. Results: OCD patients showed poor sleep quality and more sleep disturbances compared to HCs. The severity of depression, trait anxiety and OC symptomatology were correlated with poor sleep quality. Multiple linear regression analyses controlling for potential confounders revealed that the severity of depression and trait anxiety were independently related to poor sleep quality in OCD. A mediation analysis showed that both the severity of trait anxiety and depression mediate the relationship between the severity of OC symptoms and poor sleep quality among patients with OCD. Conclusions: Our findings support the existence of sleep disturbances in OCD. Trait anxiety and depression play a key role in sleep quality among OCD patients

First manic/hypomanic episode in obsessive-compulsive disorder patients treated with antidepressants: a systematic review

High doses of antidepressants, particularly clomipramine and selective serotonin reuptake inhibitors (SSRIs), are the well-established treatment for obsessive-compulsive disorder (OCD), but manic/hypomanic episodes are potential adverse events associated with this treatment. A systematic literature review was performed on manic/ hypomanic episodes in non-bipolar OCD patients. Clinical, sociodemographic and antidepressant characteristics during the manic/hypomanic switch were extracted using descriptive statistics. Data were obtained from 20 case reports and case series. Switching episodes mostly appeared in the first 12 weeks after antidepressant initiation and took place more frequently during SSRI use (mostly fluoxetine) in 64.3% of cases. Clomipramine and SSRI use differed non-significantly between the switching episodes that appeared during the first 12 weeks of antidepressant treatment and the episodes that appeared beyond 12 weeks. Switching episodes emerging before 12 weeks were associated with a lower defined daily dose of antidepressants than episodes emerging after 12 weeks. These findings suggest that there are two independent characteristics involved in manic/hypomanic switch in OCD: a) they appeared most frequently with SSRI use (fluoxetine) regardless of the time of it use, and b) episodes appeared in the first 12 weeks after SSRI or clomipramine initiation had a lower dose of antidepressant than episodes appeared after 12 weeks

Neurological soft signs in obsessive-compulsive disorder: two empirical studies and meta-analysis

Neurological soft signs (NSS) have been inconsistently reported in obsessive-compulsive disorder (OCD) but may make an impact on treatment response. Method: The current study examined the presence of NSS in two independent European samples of OCD patients (combined 85 patients and 88 matched healthy controls) using a standardized instrument and conducted a meta-analysis of all published studies identified in the literature with the aim to provide a more definitive answer to the question of whether OCD patients are characterized by increased NSS. Results Both empirical studies found elevated NSS scores in patients compared with matched controls. The results of the meta-analysis, which included 15 studies (combined 498 patients and 520 controls) showed large effect sizes (Hedges' g=1.27, 95% confidence interval 0.80-1.75), indicating that OCD patients have significantly higher rates of NSS than matched controls on both sides of the body and in multiple domains (motor coordination, sensory integration and primitive reflexes). The results were robust and remained largely unchanged in our reliability analyses, which controlled for possible outliers. Meta-regression was employed to examine the role of potential variables of interest including sociodemographic variables, symptom severity, medication effects and the use of different instruments, but none of these variables was clearly associated with NSS. Conclusions: As a group, OCD patients are characterized by increased rates of NSS, compared with healthy controls. However, their origins and potential clinical importance remain to be clarified. Future directions for research are discussed