European Neuropsychopharmacology (v.27, #6)

Contents (OBC).

Anxious temperament (AT) is an early life disposition that markedly increases the risk to develop stress related psychopathology such as anxiety and depressive disorders. Since anxiety and depression are common, and frequently have their onset early in life, a better understanding of the factors related to their childhood onset will facilitate the development of new more effective neurally informed interventions. A nonhuman primate (NHP) developmental model of childhood AT has been established, which has provided an understanding of the neural systems and molecular mechanisms mediating the development of AT. Multimodal neuroimaging studies reveal altered brain metabolism across prefrontal, limbic (e.g. central nucleus of the amygdala (Ce) and anterior hippocampus), and brainstem regions, as well as altered functional connectivity involving the Ce. Heritability studies demonstrate that individual variation in AT is heritable, and genetic correlational analyses demonstrate that metabolism in the posterior orbital frontal cortex, the bed nucleus of the stria terminalis, and the periaqueductal gray share a genetic substrate with AT. On a molecular level, the finding of reduced expression of Ce neuroplasticity genes provides the basis for a neurodevelopmental hypothesis focused on the Ce. Viral vector methods for altering gene expression in the Ce of young NHPs are currently being used as a prelude to conceptualizing novel molecularly targeted early life interventions.

Studies over the last 20 years have demonstrated that increased inflammation and hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis are two of the most consistent biological findings in major depression and are often associated: but the molecular and clinical mechanisms underlying these abnormalities are still unclear. These findings are particularly enigmatic, especially considering the accepted notion that high levels of cortisol have an anti-inflammatory action, and therefore the coexistence of inflammation and hypercortisolemia in the same diagnostic group appears counter-intuitive. To celebrate the 2015 Anna-Monika Foundation Award to our laboratory, this review will discuss our own 20 years of research on the clinical and molecular evidence underlying the increased inflammation in depression, especially in the context of a hyperactive HPA axis, and discuss its implications for the pathogenesis and treatment of this disorder.
Keywords: HPA; Glucocorticoid receptor; Childhood trauma; Antidepressants; mRNA; Immunopsychiatry; Psychoneuroimmunology.;

Telomere length in bipolar disorder and lithium response by Alessio Squassina; Claudia Pisanu; Nathan Corbett; Martin Alda (560-567).
Telomeres consist of exanucleotide tandem repeats and proteins complexes at the end of chromosome ends. Telomeres shorten at each cell division, and as such telomere length is a marker of cellular age. Accelerated telomere shortening and cell senescence have been associated with a number of chronic medical conditions, including psychiatric disorders, where increased prevalence of age-related disorders and shorter telomere length have been reported. Shorter telomeres in psychiatric patients are thought to be the consequence of allostatic load, consisting in the overactivation of allostatic systems due to chronic exposure to severe medical conditions and failure to adapt to chronic stressful stimuli. Most of the studies on telomere length in psychiatry have focused on major depressive disorder, but recent findings have shown shorter leukocyte telomere length in bipolar disorder patients and suggested that lithium may counteract telomeres shortening. These findings provided new insights into the pathophysiology of bipolar disorder and the mechanism of action of lithium. In this review we will present findings from the literature on telomere length in bipolar disorder, with a specific focus on lithium. We will also discuss advances and limitations of published work as well as methodological issues and potential confounding factors that should be taken into account when designing research protocols to study telomere length.
Keywords: Leukocyte telomere length; Bipolar disorder; Lithium; Telomerase;

Cognitive impairment, or decline, is not only a feature of Alzheimer׳s disease and other forms of dementia but also normal ageing. Abundant evidence from epidemiological studies points towards perturbed inflammatory mechanisms in aged individuals, though the cause–effect nature of this apparent relationship is difficult to establish. Genetic association studies focusing on polymorphism in and around inflammatory genes represent a viable approach to establish whether inflammatory mechanisms might play a causal role in cognitive decline, whilst also enabling the identification of specific genes potentially influencing specific cognitive facets. Thus, here we provide a review of published genetic association studies investigating inflammatory genes in the context of cognitive decline in elderly, non-demented, samples. Numerous candidate gene association studies have been performed to date, focusing almost exclusively on genes encoding major cytokines. Some of these studies report significant cognitive domain-specific associations implicating Interleukin 1β (IL1β) (rs16944), Tumour Necrosis Factor α (TNFα) (rs1800629) and C-reactive protein (CRP) in various domains of cognitive function. However, the majority of these studies are lacking in statistical power and have other methodological limitations, suggesting some of them may have yielded false positive results. Genome-wide association studies have implicated less direct and less obvious regulators of inflammatory processes (i.e., PDE7A, HS3ST4, SPOCK3), indicating that a shift away from the major cytokine-encoding genes in future studies will be important. Furthermore, better cohesion across studies with regards to the cognitive test batteries administered to participants along with the continued application of longitudinal designs will be vital.
Keywords: Inflammation; Cognitive ageing; Genetics; GWAS; Candidate genes;

Genetic evidence for a role of the SREBP transcription system and lipid biosynthesis in schizophrenia and antipsychotic treatment by Vidar M. Steen; Silje Skrede; Tatiana Polushina; Miguel López; Ole A. Andreassen; Johan Fernø; Stephanie Le Hellard (589-598).
Schizophrenia is a serious psychotic disorder, with disabling symptoms and markedly reduced life expectancy. The onset is usually in late adolescence or early adulthood, which in time overlaps with the maturation of the brain including the myelination process. Interestingly, there seems to be a link between myelin abnormalities and schizophrenia. The oligodendrocyte-derived myelin membranes in the CNS are highly enriched for lipids (cholesterol, phospholipids and glycosphingolipids), thereby pointing at lipid homeostasis as a relevant target for studying the genetics and pathophysiology of schizophrenia. The biosynthesis of fatty acids and cholesterol is regulated by the sterol regulatory element binding protein (SREBP) transcription factors SREBP1 and SREBP2, which are encoded by the SREBF1 and SREBF2 genes on chromosome 17p11.2 and 22q13.2, respectively. Here we review the evidence for the involvement of SREBF1 and SREBF2 as genetic risk factors in schizophrenia and discuss the role of myelination and SREBP-mediated lipid biosynthesis in the etiology, pathophysiology and drug treatment of schizophrenia.
Keywords: Psychosis; Cholesterol; SREBF1; SREBF2; Myelin; Antipsychotics;

Pharmacogenomic aspects of bipolar disorder: An update by M. Budde; D. Degner; J. Brockmöller; T.G. Schulze (599-609).
The hopes for readily implementable precision medicine are high. For many complex disorders, such as bipolar disorder, these hopes critically hinge on tangible successes in pharmacogenetics of treatment response or susceptibility to adverse events. In this article, we review the current state of pharmacogenomics of bipolar disorder including latest results from candidate genes and genome-wide association studies. The majority of studies focus on response to lithium treatment. Although a host of genes has been studied, hardly any replicated findings have emerged so far. Very small samples sizes and heterogeneous phenotype definition may be considered the major impediments to success in this field. Drawing from current experiences and successes in studies on diagnostic psychiatric phenotypes, we suggest several approaches for our way forward.
Keywords: Manic-depressive illness; Personalized medicine; Mood disorders; Mood stabilizers; Lithium; Genetics;

CHILDHOOD, ADOLESCENT AND ADULT AGE AT ONSET AND RELATED CLINICAL CORRELATES IN OBSESSIVE-COMPULSIVE DISORDER: A REPORT FROM THE INTERNATIONAL COLLEGE OF OBSESSIVE-COMPULSIVE DISORDERS (ICOCS) by Bernardo Dell׳Osso; Beatrice Benatti; Humberto Nicolini; Nuria Lanzagorta; M. Carlotta Palazzo; Donatella Marazziti; Eric Hollander; Naomi Fineberg; Dan J. Stein; Stefano Pallanti; Michael Van Ameringen; Christine Lochner; Georgi Hranov; Oguz Karamustafalioglu; Luchezar Hranov; Jose M Menchon; Joseph Zohar; Damiaan Denys (610-611).
Many studies suggest that age at onset of obsessive-compulsive disorder (OCD) is an important factor in subtyping OCD (1). In fact, significant differences in clinical profile and comorbidity patterns have been observed between "juvenile-onset" and "adult-onset" OCD (2). Aim of the present study was to compare the prevalence and the socio-demographic and clinical patterns of OCD patients with "childhood-onset" (≤12 years), "adolescent-onset" (12-18 years), and "adult-onset" (≥18 years) in a large international sample.The sample included 431 OCD out-patients of either gender and any age attending to different psychiatric departments worldwide participating to the “international college of obsessive-compulsive spectrum disorders” (ICOCS) network. The records of patients diagnosed with OCD and followed in the Psychiatric departments of the ICOCS network were collected and included in a common web-database and their main demographic and clinical variables were analyzed and Chi-squared and ANOVA analysis were performed to compare the three subgroups.Twenty-one percent (n=92) of the sample was represented by patients with childhood onset, while 36% (n=155) of the sample showed an adolescent onset and 43% (n=184) showed an adult onset. Patients with adult onset showed a significant female prevalence compared to the other two subgroups (χ2=10.92, p<0.05; 28% of females in the adult onset subgroup vs 11% in childhood onset and 18% in adolescent onset subgroup) and showed a significantly lower prevalence of patients receiving cognitive behavioural therapy (CBT) compared to the other two subgroups (χ2=14.5, p<0.01; 28% in adult onset subgroup were not under CBT vs 10% of the childhood onset and 19% of the adolescent onset subgroup). No significant differences among the three onset subgroups were found in terms of Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores nor in terms of psychopharmacological treatments and presence of comorbidity patterns.Present naturalistic study suggests that more than 50% of the sample showed an onset during childhood or adolescence. Furthermore, there was a female prevalence in the subgroup of OCD patients with adult onset, as previously shown in recent studies (2) and a less frequent use of CBT in the same subgroup. Further research is required to better understand the clinical features of OCD with different age at onset.

MILD WHITE MATTER CHANGES IN UN-MEDICATED OBSESSIVE-COMPULSIVE DISORDER PATIENTS AND THEIR UNAFFECTED SIBLINGS by Siyan Fan; Odile A. van den Heuvel; Danielle C. Cath; Ysbrand D. van der Werf; Stella J. de Wit; Froukje E. de Vries; Dick J. Veltman; Petra J.W. Pouwels (611).
Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with moderate genetic influences and white matter (WM) abnormalities in frontal-striatal and limbic regions. Inconsistencies in reported WM results from diffusion tensor imaging (DTI) studies can be explained, at least partly, by medication use and between-group differences in disease profile and stage. We used a family design aiming to establish whether WM abnormalities, if present in un-medicated OCD patients, also exist in their unaffected siblings.Forty-four un-medicated OCD patients, 15 of their unaffected siblings and 37 healthy controls (HC) underwent DTI using a 3-Tesla MRI-scanner. Data analysis was done using tract-based spatial statistics (TBSS). Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) values were compared within seven skeletonised regions of interest (ROIs), i.e., corpus callosum (CC), bilateral cingulum bundle (CB), bilateral inferior longitudinal fasciculus/frontal-occipital fasciculus (ILF/FOF) and bilateral superior longitudinal fasciculus (SLF).Un-medicated OCD patients, compared with HC, had significantly lower FA in the left CB. FA was trend-significantly lower in all other ROIs, except for the CC. Significant three-group differences in FA (and in RD at trend-significant level) were observed in the left CB, with the unaffected siblings representing an intermediate group between OCD patients and HC.OCD patients showed lower FA in the left CB, partly driven by trend-significantly higher values in RD. Since the unaffected siblings were found to be an intermediate group between OCD patients and HC, this WM alteration may be considered an endophenotype for OCD.

ATOMOXETINE FOR HOARDING DISORDER: A PRECLINICAL AND CLINICAL INVESTIGATION by Giacomo Grassi; Laura Micheli; Lorenzo Di Cesare Mannelli; Elisa Compagno; Carla Ghelardini; Stefano Pallanti (612-613).
Hoarding disorder is a mental disorder that has been newly included in the DSM-5 into the obsessive-compulsive and related disorders chapter. To date only two open studies investigated the pharmacological management of hoarding disorder and its management remains controversial. Despite some studies suggested that childhood attention-deficit hyperactivity disorder (ADHD) and inattention symptoms may be related to hoarding [1], only a small case series study investigated the effectiveness of ADHD medications (metilphenidate) in hoarding disorder [2]. The aim of the present study was to evaluate the preclinical and clinical effectiveness of atomoxetine, a noradrenaline reuptake inhibitor approved for childhood and adulthood ADHD, in an animal model of compulsive-like behaviors (marble burying test) and in two patients with a primary diagnosis of hoarding disorder.We performed a preclinical investigation assessing the effects of atomoxetine on the marble burying behavior test in mice. During the test, mice were placed individually in a clear plastic box containing 24 black marbles (1 cm diameter), evenly spaced on 5 cm sawdust. The number of marbles buried (to at least 60% of the depth of the sawdust) within 30 min in vehicle and atomoxetine treated groups was measured. Atomoxetine (10, 30 and 60 mg kg-1) was administered per os 30 min before the test. Subsequently, we conducted a clinical investigation on two patients fulfilling the DSM-5 criteria for hoarding disorder. These patients were treated with atomoxetine 40-100 mg for 12 weeks. A history of adult or childhood ADHD was excluded through the diagnostic interview DIVA 2.0. No changes of the ongoing medications or psychotherapy were allowed during the treatment period. To measure the severity of hoarding, the Saving Inventory-Revised (SI-R) and the UCLA Hoarding Severity Scale (UHSS) were administered before and after the treatment. Response was defined as a more of 30% decrease in UHSS and SI-R scores and at least “much improved” on the Clinical Global Impression/Improvement (CGI-I) scale.Atomoxetine significantly reduced the number of buried marbles in a dose dependent manner in comparison to control mice, without affecting the locomotor activity. Atomoxetine (30 and 60 mg kg-1) significantly reduced the number of buried marbles in a dose dependent manner (12.3 ± 1.0 and 10.0 ± 1.8, respectively) in comparison to control mice (19.3 ± 1.0), without affecting the locomotor activity. Atomoxetine 10 mg kg-1 was not effective (21.3 ± 0.9). Atomoxetine-treated patients were both classified as treatment responders after 12 weeks of treatment. Atomoxetine was well tolerated during all the treatment period. Furthermore, both patients as were still classified responders at the 6 months follow-up visits.These preclinical and clinical data suggest that atomoxetine may be considered as a potentially effective compound for hoarding disorder. Therefore, atomoxetine should be considered for future controlled trials in hoarding disorder.

The psychoeducational approach of Danger Ideation Reduction Therapy (DIRT) was developed and researched in Australia. There have been limited trials in other countries. Indeed, there are extremely few publications highlighting the use of DIRT outside Australia (Govender, Drummond and Menzies, 2006, Drummond and Kolb,).All patients who had a contamination fears and who were inpatients at the time of the pilot study (5th May 2015 – 19th May 2015) were asked to attend a series of 3 Psychoeducational Groups. The groups were weekly and covered the following topics:These groups were prepared and delivered by the Ward-based junior doctor with the assistance of medical students attached to the Ward. All patients continued to receive appropriate psychopharmacological treatment as well as treatment involving Graded Exposure and self-imposed Response Prevention alongside those groups.At the end of the pilot patients were asked for their feedback. The qualitative data obtained from the patients were analyzed.Feedback from the participating patients revealed the following qualitative data:Provision of relevant, practical information on various health issues, relevant to people having OCD fears regarding possibility of catching various infectionProvision of factual information was useful.It was an eye opener to know about the statistics and to realise how slim the chances of contamination are.Facts were provided in relation to the actual risks of acquiring various diseases rather than the risk/ fears in this regard or perceived by various OCD sufferersUnderstood about the digestive system, how it works, what faeces is made of (mainly water) Learnt that getting HIV off people is very rare.Acquired a good understanding about the natural defence mechanisms of the body.The study is small and is a pilot study. However it demonstrates that the Psychoeducational component of DIRT delivered in group format to a group of profound refractory OCD patients is generally well received and appreciated. Full studies need to continue to examine the efficacy of this approach.The feedback of the pilot study has showed that it was well received and appreciated. Sample size being small and data being qualitative nature has been the two main limitations. A further study of a larger sample with more structured monitoring of progress in profound refractory OCD will be worth exploring.

TOLERATING UNCERTAINTY IN OCD, DO PATIENTS REQUIRE MORE INFORMATION TO MAKE DECISIONS? by Sharon Morein-Zamir; Sonia Shahper; Julia Gasull Camos; Alice Deruix; Yulia Worbe; Naomi A. Fineberg; Trevor W. Robbins (613-614).

AUTISTIC SPECTRUM DISORDER IN ADULTS WITH OBSESSIVE COMPULSIVE DISORDER: RESULTS FROM A UK SURVEY by S Kaur; M Wikramanayake; S Kolli; S Shahper; K Jefferies-Sewell; J Reid; S Osman; W Mandy; NA. Fineberg (614-615).
To study the frequency and clinical impact of co-morbid autistic traits and Autistic Spectrum Disorder (ASD) on patients with Obsessive Compulsive Disorder (OCD), using the Autism Quotient (AQ) as the primary measure of autistic traits.Repetitive compulsive acts represent key symptoms in OCD and ASD. Existing data suggest that as many as one in five treatment-seeking individuals with OCD show autistic traits.Patients attending a UK specialist OCD clinic were screened using the AQ. A score of 26/50 on AQ was chosen as a cut-off to determine the likelihood of ASD. Those scoring 26 or above on the AQ then participated in a semi-structured diagnostic interview, the Clinical Autism Structured Assessment (CASA). Participants were rated with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for OCD severity, the Compulsive Personality Assessment Scale for obsessive-compulsive personality disorder (OCPD) and the Brown Assessment of Beliefs Scale for insight.73 patients consented to participate in the study. Out of these 34 (46%) scored ≥26/50 on the AQ and 21/34 (28%) were diagnosed with an ASD. Almost all cases were previously undiagnosed. No significant differences were observed between the high AQ-scoring and low-AQ scoring groups in terms of gender ratio, age of onset of OCD or total Y-BOCS score, suggesting that co-morbid ASD does not simply represent a more severe form of OCD. The presence of autistic traits was associated with OCPD and poor insight.The autistic trait most strongly associated with OCD was impaired attention shifting, suggesting overlap with OCD. However, other autistic traits not usually associated with OCD were also frequently endorsed in the comorbid group, including poor social, communication and imaginative skills.We found a high prevalence of a broad spectrum of clinically relevant autistic traits and ASD (altogether around one third) in the treatment-seeking OCD population.Our findings carry implications for the clinical assessment and management of OCD.

NEURO-HEMODYNAMIC ENDOPHENOTYPES OF EMOTIONAL INTERFERENCE IN OCD: FMRI STUDY USING EMOTION COUNTING STROOP TASK by Janardhanan C. Narayanaswamy; Dania Jose; Sri Mahavir Agarwal; Sunil V. Kalmady; Upasana Baruah; Venkataram Shivakumar; Chandrajit Prasad; Biju Viswanath; Naren P. Rao; Ganesan Venkatasubramanian; Y.C. Janardhan Reddy (614).
Patients with obsessive compulsive disorder (OCD) have bias toward threat-related information as evidenced through emotional interference tasks, for which fronto-striatal and fronto-limbic regions have been proposed as substrates. In this study, we sought to examine the endophenotype pattern of neuro-hemodynamic substrates of emotion counting stroop (ecStroop) paradigm in patients with OCD, their unaffected siblings [first degree relatives-FDR] and healthy controls.OCD patients (medication naïve)[N=16], their unaffected siblings(FDR)[N=16] and healthy controls [N=24] were compared using an established ecStroop paradigm in a 3-Tesla fMRI. The relative BOLD signals corresponding to the three types of conditions (neural words-N, words with negative emotional salience-E and words with salience for OCD-O) were examined in the apriori hypothesized brain regions with age, sex and years of education as covariates. The regions with uncorrected p<0.005 [Bonferroni corrected for 10 masks with spatial extent of minimum 10 voxels and 10mm sphere small volume correction (SVC)] were considered significant.Both in O minus N contrast (F=10.9) and O minus E contrast (F=10.5), the groups demonstrated significant differential activation of right insula (BA 13,p=0.02). The post-hoc analyses showed in patients and FDRs relative to HC the following: significant hyperactivation of insula in O minus E contrast; significant hyperactivation of right insula and right DLPFC (BA 9) in O minus N contrast.The neuro-hemodynamic responses corresponding to the obsessive words in insula and DLPFC could be potential endophenotypes. “Threat relatedness” might thus have a vulnerability meaning in the pathogenesis and neurobiological basis of OCD.

Clozapine in Gambling Disorder by Armando Piccinni; Michela Giorgi Mariani; Antonello Veltri; Anna Ciberti; Donatella Marazziti (615).

The National Inpatient service for Obsessive-Compulsive Disorder (OCD) And Body Dysmorphic Disorders (BDD), funded by NHS England, is the only 24-hour staffed dedicated inpatient facility for profound, refractory OCD in the UK.Although OCD is a common and frequently disabling condition, often responds well to treatment with either Cognitive Behavioural Therapy or SRI. Pharmacological strategies utilized in SRI non-responders include, amongst the others, the use of first or second-generation antipsychotics. David Veale et al (2014) highlighted in A recent Meta-analysis that two studies found Aripiprazole to be effective in the short term.The aim of this study was to look at the use of Aripiprazole compared to other antipsychotics in the National OCD Service for all the patients admitted between March 2006 and September were gathered from case records, electronic records system. We used the Yale Brown Obsessive-Compulsive Rating Scale (YBOCS) to measure severity.our sample consisted of 89 patients (45 males and 44 females) with an initial YBOCS average score of 23.5± 2.9 SD, indicating profound OCD. Overall, the highest number of patients (n=30) patients were treated with Aripiprazole when discharged from the National Service. Patients whose treatment was augmented with Aripiprazole, displayed an average YBOCS reduction of 14.Aripiprazole was widely used in our population of inpatients with profound, treatment-refractory OCD, producing a reduction in the YBOCS scores

COMT VAL/158/MET POLYMORPHISM AND IOWA-TYPE-TEST PERFORMANCE IN EARLY ONSET OCD PATIENTS by Humberto Nicolini; Julio C. Flóres-Lázaro; Nuria Lanzagorta; Alma D. Genis; Mirna Morales; Esther Mancera-Damy; Aurora García; Fernando López-Armenta; Daniel Santana (616-617).

DIRT IS NOT DANGEROUS by Lidewij H. Wolters; Elske Salemink; Else de Haan; Vivian op de Beek (617).

NEUROIMAGING OF SUBCORTICAL BRAIN VOLUME ALTERATIONS IN PEADIATRIC AND ADULT OBSESSIVE-COMPULSIVE DISORDER: Preliminary findings from the ENIGMA Obsessive-Compulsive Disorder working group by Premika S.W. Boedhoe; Lianne Schmaal; J.C. Janardhan Reddy; Jun Soo Kwon; Yuqi Cheng; Takashi Nakamae; Gianfranco Spalletta; Jan-Carl Beucke; Carles Soriano-Mas; Luisa Lazaro; Kate Fitzgerald; Kathrin Koch; Marcello Q. Hoexter; Francesco Benedetti; Tomohiro Nakao; Zhen Wang; David Mataix-Cols; H. Blair Simpson; Susanne Walitza; David Tolin; Paul Arnold; Chaim Huyser; Damiaan Denys; Noam Soreni; Patricia Guner; Paul M. Thompson; Derrek P. Hibar; Neda Jahanshad; Dan J. Stein; Odile A. van den Heuvel (617-619).
Structural MRI studies investigating the neural correlates of OCD have been numerous. Nevertheless, results of these studies have not always been consistent. Variability in study results may partially be explained by small sample sizes resulting in limited statistical power, clinical heterogeneity between patient samples, and methodological differences between studies. In this context, we initiated the ENIGMA-OCD working group. Our aim is to identify robust imaging markers of OCD using coordinated standardized image processing and statistical analysis protocols. Here, we perform the largest study to date of subcortical brain volumes in OCD patients and healthy controls using an individual participant data (IPD) based meta-analysis approach.Structural T1-weightred MRI scans from 3722 subjects (361 paediatric OCD patients, 1574 adult OCD patients, 314 paediatric controls and 1473 adult controls) from 25 research sites worldwide were analysed using FreeSurfer 5.3. Segmentations of subcortical regions, lateral ventricles and total intracranial volumes (ICV) were visually inspected for accuracy and compared between patients and controls using regression models controlling for age, sex, and ICV. Each site followed standardized protocols designed to facilitate harmonized image analysis across multiple sites. Separate stratified analyses assessing effects of age of onset, disease duration, symptom dimensions, and symptom severity were performed. Results were combined in random-effects meta-analysis models. Meta-regression analyses were used to test whether mean age of each sample and field strength of MR images explained a significant proportion of the variance in effect seizes across sites in the meta-analysis. Results were considered significant if they exceeded a Bonferroni corrected P-value threshold (p=0.05/9 regions = 5.6x10-3).Adult patients, compared to adult controls, had significantly smaller hippocampal volumes (Cohen’s d= -0.15, p= 7.4x10-4) and bigger pallidum volumes (d= 0.16, p=1.8x10-3). This effect was notably stronger in medicated patients versus controls (d= -0.29, p=2.8x10-6 and d= 0.24, p=2.5x10-4, respectively). The hippocampus effect seemed to be driven by patients with comorbid depression d= 0.29, p=4.8x10-5). Also, symptom severity was associated with a smaller hippocampus (R= -0.08, p=4.9x10-3). Sample characteristics such as mean age and field strength did not moderate brain volume alterations.None of the subcortical structures, neither ICV nor lateral ventricles were significantly different between paediatric OCD cases and controls after Bonferroni correction. However, unmedicated paediatric patients show bigger thalamus volumes (d= 0.40, p=9.0x10-4) relative to control children. Additionally, longer disease duration and ad trend-significant level, younger age of onset was associated with bigger thalamus volume in paediatric OCD (d= 0.18, p=5.1x10-3 and d= -0.17, p=5.7x10-3, respectively).Results of this subcortical meta-analysis indicate a key role of the pallidum in the pathophysiology of OCD. Different ENIGMA disease working groups, such as MDD, schizophrenia, and bipolar disorder also observed hippocampal abnormalities, which suggests that our findings regarding hippocampal abnormalities are aspecific for OCD. In addition, we showed that unmedicated paediatric OCD patients have significantly enlarged thalamus volumes. Moreover, our findings suggest a different pattern of subcortical abnormalities in paediatric OCD patients and adult OCD patients in line with the developmental nature of the disease.

THE ENDOPHENOTYPE OF EMOTIONAL REGULATION IN OBSESSIVE-COMPULSIVE DISORDER (OCD) by Anders Lillevik Thorsen; Stella J. de Wit; Froukje E. de Vries; Danielle C. Cath; Dick J. Veltman; Ysbrand D. van der Werf; Bjarne Hansen; Gerd Kvale; Odile A. van den Heuvel (619).
OCD symptoms have been associated with task-dependent alterations in brain activity implying dysregulation in limbic (e.g. the amygdala) and frontal-striatal circuits. Emerging evidence shows that there are functional neural endophenotypes in executive processing suggesting compensatory hyperactivation of fronto-parietal executive control networks and fronto-limbic dysregulation in OCD patients and first-degree relatives (de Wit et al., 2012; van Velzen et al., 2015). There are however few studies on emotional processing using a family-study design. We recently showed altered frontal-parietal and limbic functioning in OCD patients during emotion processing and emotion regulation (de Wit et al., 2015), but it remains unclear if these changes are also present in first-degree relatives.Forty-three unmedicated adult OCD patients, 19 of their unaffected siblings and 38 healthy controls underwent functional magnetic resonance imaging (MRI) during an emotion regulation task including neutral, fear and OCD-related visual stimuli. Stimuli were processed during natural appraisal (‘attend’ instruction) and during cognitive reappraisal (‘regulate’ instruction). Self-report distress ratings were collected from each picture. The neural correlates of emotion regulation were assessed using SPM12.Fear and OCD symptom provocation resulted in higher self-report distress ratings in patients compared with both siblings and healthy controls. Functional MRI analyses showed that specifically during OCD-related provocation, compared with controls, BOLD activation amplitude and timing was altered in the left hippocampus, right caudate nucleus and amygdala (for both patients and siblings), and bilateral thalamus (for siblings only). During fear regulation we previously found fronto-parietal hypoactivation in OCD patients, but fronto-parietal activation was not significantly different in siblings from patients or controls. During regulation of OCD-related stimuli siblings were more similar to patients (i.e. showing hyperactivation of the dorsomedial PFC (dmPFC) compared with controls). Compared with both patients and controls, hyperactivation in siblings was more extensive (including the supplementary motor area and parietal regions), and siblings showed increased dmPFC-connectivity with the middle cingulate, superior temporal, and superior frontal cortices during OCD-related emotion regulation. The diminished dmPFC-amygdala connectivity we previously reported in OCD patients during fear-regulation was not present in the sibling group.Unaffected siblings of OCD patients were similar to controls on the behavioral response to emotional provocation, but showed dissimilar neural responses during OCD-related emotion provocation and regulation compared to healthy controls, while there were fewer differences for general fear stimuli. During OCD-related emotion provocation we observed altered activation in limbic and striatal regions in both OCD patients and siblings. During OCD-related emotion regulation siblings showed few differences compared to patients, but showed increased activation in fronto-parietal and temporal areas compared to controls. Siblings also showed extensive dmPFC hyperconnectivity compared to the patients and controls, which suggests a compensatory response. These results extend previous findings of functional endophenotypes in OCD, and show dissociation between subjective distress and brain activity during emotion processing in unaffected siblings of people with OCD.

Inhibition and attentional switching both play central role in theorizing about cognitive impairments in OCD. The aim of the present study was to investigate inhibition and shifting abilities within a single experimental task. A new ‘inhibition-of-switching’ task was designed with minimal memory load suitable for patients under medication. The goal of this task was to simulate a real life situation, where following consecutive successful execution of a simple algorithm, participants need to change to another algorithm in order to respond adequately to new stimuli configurations. However, a further difficulty could be if the response must be inhibited for the same stimuli configuration on the next encounter with it. We hypothesized that OCD patients along with slower switching performance, will have difficulties in inhibiting previously adequate switching responses, making more false alarm type errors.Twenty-six properly diagnosed OCD patients and twenty-six healthy adults matched in age and education undertook an inhibition-of-switching task in two conditions. 1) Single task condition: two digits appeared on a computer screen, and subjects had to press the right or the left-arrow key under the bigger number, and 2) Secondary task conditions: here the participants’ primary task was identical with the single task condition, whereas their secondary task was to press the up-arrow key if the two presented digits were identical. Furthermore, participants had an inhibition rule for the secondary task, they needed to respond only on every second time encountering with identical digits. To assess the memory performance, subjects completed the Digit Span Forward and Backward Tasks and the Prospective Retrospective Memory Questionnaire (PRMQ). Statistical analyses were performed using mixed analysis of variance and two-tailed t-tests.We found that secondary task instruction produced significantly more cost in terms of reaction time during the execution of primary task for OCD patients compared to a healthy control group. However, there was no difference in switching cost in terms of reaction time between the two groups, suggesting that OCD patients had no difficulty with changing one stimuli-based response algorithm to another one. Additionally, OCD patients made significantly more false alarm type errors in the secondary task, and there was a significant positive correlation between the number of false alarm type errors and the prospective memory subscale scores of the PRMQ in the OCD group.These results suggest that OCD patients experience difficulties during inhibition-of-switching task, and here we propose that these difficulties originate from over-monitoring of secondary task stimuli during execution of primary task and disinhibition of activated out-of-date responses. We argue that over-activated intentions go together with a response inhibition deficit, and these two factors together contribute to the higher rate of perseverative errors.

Obsessive compulsive disorder (OCD) is a syndrome characterised by obsessions and compulsions, as well as other neuropsychiatric features, and is often associated with primary psychiatric disorders and various neurologic conditions. Despite the beneficial effect of selective serotonin reuptake inhibitors (SSRIs) in OCD, up to 40% of patients remain refractory to treatment. The therapeutic limitations of standard psychopharmacological treatments of OCD warrant the investigation of other treatment strategies. One potential candidate is pregabalin, a novel analogue of the inhibitory neurotransmitter gamma amino butyric acid (GABA). Pregabalin has been shown to be efficacious in other anxiety disorders and in a recent open-label trial was found to lead to a significant improvement in clinical symptoms in treatment-resistant OCD patients . We present findings from a case series of inpatients with severe, complex, and resistant obsessive-compulsive disorder (OCD) whose treatment was augmented with pregabalin. Methods: The National Obsessive Compulsive Disorder/Body Dysmorphic Disorder (OCD/BDD) Service at South West London and St George’s Mental Health NHS Trust, affiliated with St George's University of London, is one of five nationally funded tertiary centres providing outreach across all regions in England. This case series consisted of 16 patients, 11 men and 5 women, with severe OCD, as defined by a score of 30 or more on the Yale-Crown Obsessive Compulsive Scale (YBOCS), who were treated with pregabalin during the course of their admission to the above unit in the time period December 2013-June 2015. We compared YBOCS scores at discharge against the patient’s initial severity and also examined patient notes to gather anonymised qualitative data for case vignettes to further elucidate their treatment experiences.The median age of patients was 38.5 years at the time of admission and the median duration of admission was 6 months. The median dosage of pregabalin at the time of discharge was 300mg/day, representing a median dose increase of 150mg/day from admission. Improvement in patients’ OCD symptoms was observed with a median reduction in YBOCS score of 13, reflecting a median 33% reduction in symptom severity. Case vignettes showed that adjunctive pregabalin was generally well-tolerated.In severe OCD a 30% reduction in symptom severity is seen as a reasonable aim; the improvement seen therefore represents a clinically meaningful change. To the best of our knowledge, so far only one study has been published looking at pregabalin as an adjunctive treatment in treatment-resistant OCD. Our findings were consistent with theirs, and in addition we were able to examine changes in YBOCS scores over a longer duration. There are several important limitations to this case series - namely, its small sample-size, lack of control group, the fact that participants were non-blinded, and that we were not able to control for the therapeutic effects of the hospital environment. However, given the lack of currently available data around the use of pregabalin as an adjunctive agent, this data represents a meaningful step in this burgeoning area of research. We would encourage further research that addresses the aforementioned limitations.

Emerging neurobiological evidence suggests that the boundaries between compulsive symptoms in obsessive-compulsive disorder (OCD) and both addictive and habitual behaviors may not be impervious as previously though. For instance, attenuated activity in the nucleus accumbens during reward anticipation in OCD patients compared with healthy controls has been reported. 1 This effect was most pronounced in patients with contamination fears. 1 There is also evidence of an increased tendency to form both avoidance and “rewarding” habits in OCD, leading to the hypothesis that OCD compulsions are in fact overlearned habits. 2 Nevertheless, we are not aware of any phenomenological study attempting to investigate to contribution of reward and/or habit processes to compulsive behaviors in OCD and whether they are associated to any specific sociodemographic or clinical correlates.To help filling this gap, 73 OCD patients attending a university-based clinic had their most clinically significant compulsive behaviors assessed with (1) the Temporal Impulsive Compulsive Scale (TICS), a self-report instrument that measures how frequently (from 0=never to 4=always) positive (rewarding) and negative affective states are experienced before, in anticipation, during, and after the OCD patients’ compulsive behavior; and (2) the Self-Report Habit Index (SRHI) a self-report instrument that assesses perceptions of habit strength (including prior behavior, automaticity, and identity expression). Patients were also assessed with a (3) a modified version of the Yale-Brown Obsessive-Compulsive Scale (YBOCS) to measure severity of compulsive symptoms (including avoidance), and (4) the Obsessive-Compulsive Inventory-Revised (OCI-R), to provide severity of symptoms across obsessions, washing, checking, ordering, neutralization and hoarding dimensions.Additional instruments were selected on the basis of whether they were thought to measure other aspects of reward and/or punishment and fear including: (5) the Temporal Experience of Pleasure Scale (TEPS); (6) the Behavioral Inhibition/Activation Scales (BIS/BAS); (7) the Urgency, Premeditation, Perseverance, Sensation seeking, and Positive Urgency scale (UPPS-p); (8) the Obsessive Beliefs Questionnaire (OBQ-44); and (9) the Intolerance of Uncertainty Scale (IUS-12).Reward in anticipation and after the performance of OCD compulsive behaviors in the TICS correlated positively with anticipatory (r=0.25; p=0.03) and consummatory (r=0.28; p=0.02) pleasure in the TEPS, respectively. In terms of symptom content, anticipated reward (i.e., predicted positive affect prior to initiating compulsive behavior as measured on the TICS) correlated positively with severity of washing symptoms (r=0.24; p=0.04) and negatively with checking (r=-.024; p=0.04) and neutralization symptoms (r=0.25; p=0.03). In contrast, habit strength correlated positively with checking (r=0.27; p=0.02), hoarding (r=0.36; p=0.01), and ordering (r=0.29; p=0.13) and negatively with BIS scores (r=-0.26; p=0.03).Our preliminary findings suggest that the ability to experience reward in anticipation and after the performance of OCD compulsions may be partially depend on whether patients are able to experience anticipatory and consummatory pleasure in domains other than those related to OCD compulsions. We were also able to confirm the finding that OCD patients with washing symptoms experience greater reward in anticipation of their OCD compulsions. In contrast, the greater the severity of checking, hoarding and ordering, the more habitual features the OCD compulsions tend to display.

PREVALENCE OF INTERNET ADDICTION: A PILOT STUDY IN A GROUP OF ITALIAN HIGH-SCHOOL STUDENTS by Federico Mucci; Mario Campanella; Stefano Baroni; Donatella Marazziti (622-623).

EFFECTIVENESS OF RISPERIDONE AUGMENTATION IN OBSESSIVE-COMPULSIVE DISORDER – EXPERIENCE OF A SPECIALTY CLINIC IN INDIA by Aditya Hegde; B.G. Kalyani; Malvika Ravi; Aditi Singh; Shyam Sundar Arumugham; Janardhanan; C. Narayanaswamy; Y.C. Janardhan Reddy (623).
Randomized placebo-controlled trials suggest that risperidone may be efficacious as an add-on treatment to serotonin reuptake inhibitors (SRIs) in patients with obsessive compulsive disorder (OCD). Inherent limitations of these studies are the relatively small sample sizes and concern over their generalizability to real-world clinical practice. Also, factors predicting response to risperidone augmentation are unclear.To assess the effectiveness of risperidone augmentation in OCD, and to study the predictors of response, in a real-world setting.1314 consecutive patients who consulted a specialty OCD clinic between 2004 and 2014 at a large psychiatric hospital in India were evaluated with Mini International Neuropsychiatric Interview, the Yale-Brown Obsessive–Compulsive Scale, and the Clinical Global Impression scale. Patients with OCD initiated on risperidone, not having psychosis or mental retardation, without ongoing cognitive behavior therapy and who were on stable SRI medication for at least 12 preceding weeks were included for analysis. Primary outcome measure was all-cause discontinuation. Principal component analysis with Varimax rotation was conducted utilizing responses from YBOCS checklist, which yielded a 5-factor solution with the following dimensions - ‘pathological doubts/checking’, ‘need for symmetry/orderliness’, ‘forbidden thoughts’, ‘cleaning/contamination’, and ‘hoarding’. Predictors of treatment response were evaluated by logistic regression analysis (backward wald) with symptom dimensions and other relevant antecedent variables as independent variables and all-cause discontinuation as the dependent variable.104 patients were eligible for analysis. In all except 24 patients (23.08%), risperidone had been discontinued at the time of last follow-up, either due to ineffectiveness or intolerability. 26 patients (25%) were noted to have at least 25 % reduction on YBOCS. 24 patients (23.08%) were marked either as ‘much improved’ or ‘very much improved’ on CGI-I.Mean reduction in YBOCS scores for the whole sample (n=104) was 13.54% (t=5.45, p<0.001).On regression analysis, ‘forbidden thoughts’ predicted discontinuation of risperidone (p=0.021).Risperidone proved to be an effective augmenting agent in a significant sub-set of patients with OCD. The drug may be less beneficial in patients with ‘forbidden thoughts’ (sexual, religious, or aggressive obsessions).