Is glutamate associated with fear extinction and cognitive behavior therapy outcome in OCD? A pilot study.

Cognitive behavioral therapy (CBT) including exposure and response prevention is a well-established treatment for obsessive-compulsive disorder (OCD) and is based on the principles of fear extinction. Fear extinction is linked to structural and functional variability in the ventromedial prefrontal cortex (vmPFC) and has been consistently associated with glutamate neurotransmission. The relationship between vmPFC glutamate and fear extinction and its effects on CBT outcome have not yet been explored in adults with OCD. We assessed glutamate levels in the vmPFC using 3T magnetic resonance spectroscopy, and fear extinction (learning and recall) using skin conductance responses during a 2-day experimental paradigm in OCD patients (n = 17) and in healthy controls (HC; n = 13). Obsessive-compulsive patients (n = 12) then received manualized CBT. Glutamate in the vmPFC was negatively associated with fear extinction recall and positively associated with CBT outcome (with higher glutamate levels predicting a better outcome) in OCD patients. Glutamate levels in the vmPFC in OCD patients were not significantly different from those in HC, and were not associated with OCD severity. Our results suggest that glutamate in the vmPFC is associated with fear extinction recall and CBT outcome in adult OCD patients.

Patient characteristics driving clinical utility in psychiatric pharmacogenetics: a reanalysis from the AB-GEN multicentric trial.

Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode.Trial registration ClinicalTrials.gov NCT02529462.

Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder.

BACKGROUND: Pathological worry is a hallmark feature of generalised anxiety disorder (GAD), associated with dysfunctional emotional processing. The ventromedial prefrontal cortex (vmPFC) is involved in the regulation of such processes, but the link between vmPFC emotional responses and pathological v. adaptive worry has not yet been examined.AimsTo study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals. METHOD: In total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging. RESULTS: Compared to HC, the GAD group demonstrated reduced vmPFC activation to safety signals and no safety-threat processing differentiation. This response was positively correlated with worry severity in GAD, whereas the same variables showed a negative and weak correlation in HC. CONCLUSIONS: Poor vmPFC safety-threat differentiation might characterise GAD, and its distinctive association with GAD worries suggests a neural-based qualitative difference between healthy and pathological worries.Declaration of interestNone.

Altered functional connectivity of the subthalamus and the bed nucleus of the stria terminalis in obsessive-compulsive disorder.

BACKGROUND: The assessment of inter-regional functional connectivity (FC) has allowed for the description of the putative mechanism of action of treatments such as deep brain stimulation (DBS) of the nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Nevertheless, the possible FC alterations of other clinically-effective DBS targets have not been explored. Here we evaluated the FC patterns of the subthalamic nucleus (STN) and the bed nucleus of the stria terminalis (BNST) in patients with OCD, as well as their association with symptom severity. METHODS: Eighty-six patients with OCD and 104 healthy participants were recruited. A resting-state image was acquired for each participant and a seed-based analysis focused on our two regions of interest was performed using statistical parametric mapping software (SPM8). Between-group differences in FC patterns were assessed with two-sample t test models, while the association between symptom severity and FC patterns was assessed with multiple regression analyses. RESULTS: In comparison with controls, patients with OCD showed: (1) increased FC between the left STN and the right pre-motor cortex, (2) decreased FC between the right STN and the lenticular nuclei, and (3) increased FC between the left BNST and the right frontopolar cortex. Multiple regression analyses revealed a negative association between clinical severity and FC between the right STN and lenticular nucleus. CONCLUSIONS: This study provides a neurobiological framework to understand the mechanism of action of DBS on the STN and the BNST, which seems to involve brain circuits related with motor response inhibition and anxiety control, respectively.

Rate and characteristics of urgent hospitalisation in persons with profound intellectual disabilities compared with general population.

BACKGROUND: Little is known about the hospitalisation rate of adults with severe/profound intellectual disability (PID) presenting at emergency services or about the appropriateness of hospital admissions in this population. Examining the possible differences in the patterns of hospitalisation between people with PID and those without intellectual disability (ID) may shed light on aspects of health and illness in these patients and may in turn make it possible to differentiate more clearly between mild-moderate ID and PID. METHODS: After an evaluation of the emergency visits made by adults with PID and by people without ID, patients in both groups requiring one or more hospitalisations were subsequently followed up for 18 months. The appropriateness of the decision to hospitalise was assessed using the ambulatory care-sensitive conditions index. RESULTS: There were no differences in the proportion of people with PID and controls admitted to hospital after their emergency visit. The median hospital stay was higher for PIDs: 7.5 vs. 4 days for controls. People with PID were admitted more than controls for respiratory reasons and somewhat less for other somatic causes unrelated to the nervous system. There were no admissions for psychiatric causes in the group with PID other than unspecified conduct disorders. There were no differences in other diagnostic groups. The rate of inappropriate admissions was similar in the two study groups. CONCLUSIONS: In contrast to previous results reported for the group with ID as a whole, patients with PID consulting the emergency service were not admitted to hospital more frequently than the general population nor did they present a higher rate of inappropriate admissions. These results support the utility of maintaining two distinct groups of people with ID: mild-moderate and severe-profound.

Pain underreporting associated with profound intellectual disability in emergency departments.

BACKGROUND: Little information is available regarding the visits made by persons with profound intellectual disability (PID) to general hospital emergency departments (ED). This study aims to know whether persons with PID who attend ED are given the same type of diagnoses as people with no such disability. METHODS: Over a period of 18 months, we gathered data from all non-scheduled visits to an ED by persons with PID to identify the reason for consultation (according to the classification used by the Spanish Society for Emergency Nursing) and the final diagnosis upon discharge. The results were compared with data obtained from a control group of people with no ID who attended an ED for any reason during the same period. RESULTS: Somatic complaints were the main reason for ED attendance among persons with PID (90% of consultations). These complaints were more often related to the central nervous system than was the case among non-ID patients (16 vs. 4.7%), whereas other kinds of non-central nervous system somatic complaint were less common among persons with PID (74 vs. 91%). A diagnosis implying physical pain was given less often to people with PID than to controls (3 vs. 20%). CONCLUSIONS: The results suggest that persons with PID are less able to conceptualise and communicate information about their symptoms, especially as regards pain, and that this influences the diagnosis they are given when attending an ED. Professionals working in this environment need to be aware of this possibility so as not to underestimate or overlook such symptoms and the illnesses related to them.

Conversion to dementia in mild cognitive impairment diagnosed with DSM-5 criteria and with Petersen's criteria.

OBJECTIVE: In a background of revision of criteria for states of increased risk for progression to dementia, we compare the conversion rate to dementia and Alzheimer's disease (AD) of mild cognitive impairment (MCI) as diagnosed using DSM-5 (DSM-5-MCI) and Petersen's (P-MCI) criteria. METHOD: A population representative cohort of 4057 dementia-free individuals 55+ years of age was followed up at 2.5 and 4.5 years in Zaragoza, Spain (ZARADEMP). Using the Geriatric Mental State- AGECAT for assessment, research psychiatrists diagnosed DSM-5-MCI and P-MCI following operationalized criteria. 'Conversion rate' (CR), 'annual conversion rate' (ACR), and incidence rate (IR) were calculated along with incidence rate ratio (IRR) to compare the performance of the intermediate cognitive definitions. RESULTS: At 4.5-year follow-up, in individuals aged 65+ years, ACRs for non-cases, P-MCI, and DSM-5-MCI were 0.8, 1.9 and 3.4, respectively, for global dementia. The IRRs were 2.9 and 5.3 for P-MCI and DSM5-MCI, respectively, being the non-cases the reference category. The corresponding values were slightly lower for AD. CONCLUSION: Conversion rate to dementia and AD was higher using DSM-5-MCI criteria than using Petersen's criteria. However, prediction of the construct still has some way to go, as most MCI individuals did not convert at 4.5-year follow-up.

Sex addiction and gambling disorder: similarities and differences.

OBJECTIVE: Recently, the DSM-5 has developed a new diagnostic category named "Substance-related and Addictive Disorders". This category includes gambling disorder (GD) as the sole behavioral addiction, but does not include sex addiction (SA). The aim of this study is to investigate whether SA should be classified more closely to other behavioral addictions, via a comparison of the personality characteristics and comorbid psychopathology of individuals with SA with those of individuals with GD, which comes under the category of addiction and related disorders. METHOD: The sample included 59 patients diagnosed with SA, who were compared to 2190 individuals diagnosed with GD and to 93 healthy controls. Assessment measures included the Diagnostic Questionnaire for Pathological Gambling, the South Oaks Gambling Screen, the Symptom CheckList-90 Items-Revised and the Temperament and Character Inventory-Revised. RESULTS: No statistically significant differences were found between the two clinical groups, except for socio-economic status. Although statistically significant differences were found between both clinical groups and controls for all scales on the SCL-90, no differences were found between the two clinical groups. The results were different for personality characteristics: logistic regression models showed that sex addictive behavior was predicted by a higher education level and by lower scores for TCI-R novelty-seeking, harm avoidance, persistence and self-transcendence. Being employed and lower scores in cooperativeness also tended to predict the presence of sex addiction. CONCLUSIONS: While SA and GD share some psychopathological and personality traits that are not present in healthy controls, there are also some diagnostic-specific characteristics that differentiate between the two clinical groups. These findings may help to increase our knowledge of phenotypes existing in behavioral addictions.

Brain regions related to fear extinction in obsessive-compulsive disorder and its relation to exposure therapy outcome: a morphometric study.

BACKGROUND: The size of particular sub-regions within the ventromedial prefrontal cortex (vmPFC) has been associated with fear extinction in humans. Exposure therapy is a form of extinction learning widely used in the treatment of obsessive-compulsive disorder (OCD). Here we investigated the relationship between morphometric measurements of different sub-regions of the vmPFC and exposure therapy outcome in OCD. METHOD: A total of 74 OCD patients and 86 healthy controls underwent magnetic resonance imaging (MRI). Cortical thickness and volumetric measurements were obtained for the rostral anterior cingulate cortex (rACC), the medial orbital frontal cortex and the subcallosal cortex. After MRI acquisition, patients were enrolled in an exposure therapy protocol, and we assessed the relationship between MRI-derived measurements and treatment outcome. Baseline between-group differences for such measurements were also assessed. RESULTS: Compared with healthy controls, OCD patients showed a thinner left rACC (p = 0.008). Also, left rACC thickness was inversely associated with exposure therapy outcome (r - 0.32, p = 0.008), and this region was significantly thinner in OCD patients who responded to exposure therapy than in those who did not (p = 0.006). Analyses based on regional volumetry did not yield any significant results. CONCLUSIONS: OCD patients showed cortical thickness reductions in the left rACC, and these alterations were related to exposure therapy outcome. The precise characterization of neuroimaging predictors of treatment response derived from the study of the brain areas involved in fear extinction may optimize exposure therapy planning in OCD and other anxiety disorders.

Late onset eating disorders in Spain: clinical characteristics and therapeutic implications.

OBJECTIVE: The literature on later age of onset (LAO) in women with eating disorders is scarce. We compared the severity of eating disorders, eating disorder subtype, and personality profiles in a clinical sample of consecutively assessed women with eating disorders with later age of onset (LAO, > = 25 years) to women with typical age of onset (TAO, <25 years). METHOD: All eating disorder patients met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria and were admitted to the Eating Disorder Unit of the University Hospital of Bellvitge in Barcelona, Spain. Ninety-six patients were classified as LAO and 759 as TAO. ASSESSMENT: Measures included the Eating Attitude Test-40 (EAT-40), Eating Disorders Inventory-2 (EDI-2), Bulimic Investigatory Test Edinburgh (BITE), Symptom Checklist Revised (SCL-90-R), and the Temperament and Character Inventory-Revised (TCI-R), as well as other clinical and psychopathological indices. RESULTS: LAO individuals reported significantly fewer weekly vomiting episodes, fewer self-harming behaviours, less drug abuse, and lower scores on the BITE symptoms, the EDI-2 drive for thinness, and the TCI-R harm avoidance scales than TAO individuals. Conversely, the LAO group reported more current and premorbid obesity than the TAO group. CONCLUSION: LAO eating disorder patients in this sample presented with milder symptomatology and less extreme personality traits. Premorbid obesity may be more relevant to LAO than TAO eating disorders and should be routinely assessed and considered when planning treatment.

Cognitive and clinical predictors of a long-term course in obsessive compulsive disorder: A machine learning approach in a prospective cohort study.

BACKGROUND: Obsessive compulsive disorder (OCD) is a disabling illness with a chronic course, yet data on long-term outcomes are scarce. This study aimed to examine the long-term course of OCD in patients treated with different approaches (drugs, psychotherapy, and psychosurgery) and to identify predictors of clinical outcome by machine learning. METHOD: We included outpatients with OCD treated at our referral unit. Demographic and neuropsychological data were collected at baseline using standardized instruments. Clinical data were collected at baseline, 12 weeks after starting pharmacological treatment prescribed at study inclusion, and after follow-up. RESULTS: Of the 60 outpatients included, with follow-up data available for 5-17 years (mean = 10.6 years), 40 (67.7 %) were considered non-responders to adequate treatment at the end of the study. The best machine learning model achieved a correlation of 0.63 for predicting the long-term Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score by adding clinical response (to the first pharmacological treatment) to the baseline clinical and neuropsychological characteristics. LIMITATIONS: Our main limitations were the sample size, modest in the context of traditional ML studies, and the sample composition, more representative of rather severe OCD cases than of patients from the general community. CONCLUSIONS: Many patients with OCD showed persistent and disabling symptoms at the end of follow-up despite comprehensive treatment that could include medication, psychotherapy, and psychosurgery. Machine learning algorithms can predict the long-term course of OCD using clinical and cognitive information to optimize treatment options.

Interaction of SLC1A1 gene variants and life stress on pharmacological resistance in obsessive-compulsive disorder.

Genetic and environmental factors seem to interact and influence both the onset and the course of obsessive-compulsive disorder (OCD), but the role of glutamate transporter variants (SLC1A1) in pharmacological resistance is not known. We aimed to assess whether genetic variants in SLC1A1 and life stress at onset of the disorder interact and modulate pharmacological resistance in OCD. A single-marker association study of several single-nucleotide polymorphisms in the SLC1A1 genomic region was performed in a sample of 238 OCD patients. For the most strongly associated SNP (rs3087879), one copy of the risk allele increased the probability of higher treatment resistance (odds ratio=2.42; 95% confidence interval=1.39-4.21; P=0.0018), but only in OCD patients without life stress at onset of the disorder. These results suggest a gene-by-environment interaction effect on treatment resistance in OCD and strengthen the existing evidence of the role of the glutamatergic system in the phenomenology of OCD.

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

BACKGROUND: 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.

Eating-related environmental factors in underweight eating disorders and obesity: are there common vulnerabilities during childhood and early adolescence?

OBJECTIVE: This study aimed to examine whether there is an association between individual, social and family influences and dysfunctional eating patterns early in life and the likelihood of developing a subsequent underweight eating disorder (ED) or obesity. METHOD: The total sample comprised 152 individuals (underweight ED, n = 45; obese patients, n = 65; healthy controls; n = 42) from Barcelona, Spain. The Cross-Cultural Questionnaire (CCQ) was used to assess early eating influences as well as individual and family eating patterns and attitudes towards food. RESULTS: Even though a few shared eating influences emerged for both groups, unique factors were also observed. Whereas relationship with friends, teasing about eating habits by family members and the mass media were of specific relevance to the underweight ED group, the patient's own physical appearance, body dissatisfaction, teasing about eating habits by friends, teasing about body shape by family members and dysfunctional eating patterns were unique to obesity. CONCLUSIONS: Overlapping environmental risk factors provide evidence for integral prevention and intervention approaches that simultaneously tackle a range of weight-related problems. The unique factors might be important for targeting high-risk individuals.

The genomics of visuospatial neurocognition in obsessive-compulsive disorder: A preliminary GWAS.

BACKGROUND: The study of Obsessive-Compulsive Disorder (OCD) genomics has primarily been tackled by Genome-wide association studies (GWAS), which have encountered troubles in identifying replicable single nucleotide polymorphisms (SNPs). Endophenotypes have emerged as a promising avenue of study in trying to elucidate the genomic bases of complex traits such as OCD. METHODS: We analyzed the association of SNPs across the whole genome with the construction of visuospatial information and executive performance through four neurocognitive variables assessed by the Rey-Osterrieth Complex Figure Test (ROCFT) in a sample of 133 OCD probands. Analyses were performed at SNP- and gene-level. RESULTS: No SNP reached genome-wide significance, although there was one SNP almost reaching significant association with copy organization (rs60360940; P = 9.98E-08). Suggestive signals were found for the four variables at both SNP- (P < 1E-05) and gene-levels (P < 1E-04). Most of the suggestive signals pointed to genes and genomic regions previously associated with neurological function and neuropsychological traits. LIMITATIONS: Our main limitations were the sample size, which was limited to identify associated signals at a genome-wide level, and the composition of the sample, more representative of rather severe OCD cases than a population-based OCD sample with a broad severity spectrum. CONCLUSIONS: Our results suggest that studying neurocognitive variables in GWAS would be more informative on the genetic basis of OCD than the classical case/control GWAS, facilitating the genetic characterization of OCD and its different clinical profiles, the development of individualized treatment approaches, and the improvement of prognosis and treatment response.

Neuropsychological performance and predictors of pharmacological treatment response in obsessive compulsive disorder.

BACKGROUND: Obsessive Compulsive Disorder (OCD) is characterized by the presence of executive dysfunctions. As organizational strategies may play an important role as a possible endophenotype of the disorder, we decided to investigate non-verbal memory and organizational abilities in OCD. We also investigated how organization and non-verbal memory differ between responder and non-responder patients to pharmacological treatment, to test whether cognitive functions can predict the response to pharmacological treatment. METHODS: In Study 1, executive and clinical functioning measures were applied to 162 OCD and 95 controls. In Study 2, clinical, intelligence and executive functioning measures were applied to 72 OCD responders and 63 OCD non-responder patients. RESULTS: OCD patients and controls from Study 1 differed in copy organization (p < 0.01) and delayed recall (p = 0.048). In Study 2, the OCD responders displayed better copy organization (p = 0.013) and lower depressive, anxious and OCD symptoms (p < 0.01 in the three cases). Scores in the following instruments were found to predict the response to pharmacological treatment: HDRS, Y-BOCS, Raven progressive matrices, and Direct digit subtest from the Wechsler's scale (p < 0.01 in all four cases). LIMITATIONS: In Study 1, the imbalance of the sample can be considered a limitation, whilst in Study 2, some of the levels of pharmacological resistance were not represented. CONCLUSIONS: In this study, non-verbal memory and organization was affected in OCD. Responder patients also displayed better executive functioning and fluid intelligence. Organizational ability is a predictor of pharmacological response to SSRI monotherapy in a predictive model controlling for anxious symptoms.

How is COVID-19 affecting patients with obsessive-compulsive disorder? A longitudinal study on the initial phase of the pandemic in a Spanish cohort.

BACKGROUND: Although the consequences of the COVID-19 pandemic on emotional health are evident, little is known about its impact on patients with obsessive-compulsive disorder (OCD). METHODS: One hundred and twenty-seven patients with OCD who attended a specialist OCD Clinic in Barcelona, Spain, were assessed by phone from April 27 to May 25, 2020, during the early phase of the pandemic, using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a structured interview that collected clinical and sociodemographic information. Results were compared with those for 237 healthy controls from the same geographic area who completed an online survey. RESULTS: Although 65.3% of the patients with OCD described a worsening of their symptoms, only 31.4% had Y-BOCS scores that increased >25%. The risk of getting infected by SARS-CoV2 was reported as a new obsession by 44.8%, but this only became the main obsessive concern in approximately 10% of the patients. Suicide-related thoughts were more frequent among the OCD cohort than among healthy controls. The presence of prepandemic depression, higher Y-BOCS scores, contamination/washing symptoms, and lower perceived social support all predicted a significantly increased risk of OCD worsening. CONCLUSIONS: Most patients with OCD appear to be capable of coping with the emotional stress of the COVID-19 outbreak and its consequences during the initial phase of the pandemic. Nevertheless, the current crisis constitutes a risk factor for a significant worsening of symptoms and suicidal ideation. Action is needed to ensure effective and individualized follow-up care for patients with OCD in the COVID-19 era.

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.

Executive functioning among female pathological gambling and bulimia nervosa patients: preliminary findings.

Shared vulnerabilities have been described across disorders of impulse control, including pathological gambling (PG) and bulimia nervosa (BN). Our aim was to compare the executive functioning of PG and BN females in order to confirm their similarity at a neurocognitive level. A total of 15 BN females, 15 PG females, and 15 healthy control (HC) females were administered the Wisconsin Card Sorting Test (WCST) and the Stroop Color and Word Test. Analysis of covariance adjusted for age and education was conducted to compare groups. PG showed the greatest impairment, that is, the highest percentage of WCST perseverative errors (p = .023), the lowest percentage of conceptual-level responses (p = .034), and the highest number of total trials administered (p = .021), while BN showed the highest percentage of WCST nonperseverative errors (p = .003). Both BN and PG females demonstrated executive dysfunction relative to HCs but different specific correlates (i.e., greater vulnerability to distraction in BN, but more cognitive inflexibility in PG).