bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenetics to Personalize Dosing of Tricyclic Antidepressants in Major Depressive Disorder: A Randomized Clinical Trial (PITA study)
Authors: Ter Hark S. , Vos N. 
Published: August 2023

IntroductionTricyclic antidepressants (TCAs) have an important role in pharmacotherapy of Major Depressive Disorder (MDD). TCA dosing is aimed at achieving a concentration in the therapeutic window. Due to inter-individual differences in activity of Cytochrome P450 (CYP) 2D6 and 2C19, (enzymes involved in TCA metabolism) patients require an individualized dose. Currently, finding of a suitable dosage is a process of trial-and-error, including multiple drug concentration measurements and dose adjustments. A starting dose based on a patient CYP2D6 and CYP2C19 metabolizer phenotype may contribute to achieving a therapeutic concentration more quickly, possibly resulting in higher treatment efficacy and the occurrence of fewer adverse effects.ObjectivesWe aimed to study whether genotype-informed dosing in TCAs leads to faster attainment of therapeutic plasma concentrations, a higher reduction of depression severity symptoms and less adverse effects.MethodsWe conducted a double-blind randomized clinical trial, in which patients (18-65 years) diagnosed with severe MDD and eligible for treatment with a TCA were randomized in two treatment arms: The intervention arm (Pharmacogenetics Informed Treatment; PIT) and standard treatment (Treatment As Usual; TAU). Patients were treated with nortriptyline, clomipramine or imipramine for seven weeks and depressive symptom severity and adverse effects were monitored weekly. The primary outcome measure, time needed to attain a therapeutic drug concentration, was analyzed using Kaplan-Meier analyses. The secondary outcome measures, reduction in depressive symptoms and adverse effects, were analyzed with mixed model linear regression.ResultsIn total, we randomized 111 patients. The PIT group (n=56) reached a therapeutic plasma concentration significantly faster (Kaplan Meier, X2 (1) = 4.3, p=0.039) compared to TAU (n=55), especially for patients treated with nortriptyline. On average depressive symptoms decreased relatively more in PIT than in TAU, although this was not significantly different: F(6) = 0.45, p = 0.84. The severity of adverse events during the study period differed significantly between PIT and TAU (F(6)=3.10, p=0.008). PIT experienced fewer adverse effects than TAU, especially in the last two weeks of the study.ConclusionsGenotype-informed dosing leads to faster attainment of therapeutic TCA concentrations and does not lead to more adverse effects. Although we were not able to demonstrate that genotype-informed dosing leads to a significantly better response, we conclude that pharmacogenetics can contribute to the optimization of pharmacological treatment. Future research may focus on subgroups for which pharmacogenetics may be of great value, such as specific antidepressants or patients with an abnormal pharmacogenetic profile.Disclosure of InterestNone Declared
Do children with ADHD symptoms become socially isolated? Longitudinal within-person associations in a nationally-representative cohort
Authors: Thompson K. N. , Agnew-Blais J. C. , Allegrini A. G. , Bryan B. T. , Danese A. , Odgers C. L. , Matthews T. , Arseneault L. 
Published: August 2023

IntroductionSocial isolation in childhood can be detrimental to physical and mental health. Children with neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD), may be particularly at risk for becoming socially isolated. Similarly, isolated children have limited opportunities to observe, model, and learn age-appropriate interpersonal interactions with other children which could increase ADHD behaviours.ObjectivesThis study examined longitudinal associations between ADHD symptoms and social isolation across childhood. We tested the direction of this association across time, while accounting for pre-existing characteristics, and assessed whether this association varied by ADHD presentation, informant, sex, and socioeconomic status.MethodsParticipants included 2,232 children from the Environmental Risk (E-Risk) Longitudinal Twin Study. ADHD symptoms and social isolation were measured at ages 5, 7, 10, and 12. We used random-intercept cross-lagged panel models to assess the directionality of the association across childhood.ResultsChildren with increased ADHD symptoms were consistently at increased risk of becoming socially isolated later in childhood, over and above stable characteristics (β=0.05-0.08). These longitudinal associations were not bidirectional; isolated children were not at risk of worsening ADHD symptoms later on. Children with a hyperactive ADHD presentation were more likely to become isolated, compared to an inattentive presentation. This was evident in the school setting, as observed by teachers, but not by mothers at home.ConclusionsOur findings highlight the importance of enhancing peer social support and inclusion for children with ADHD, particularly in school settings. We add explanatory value over and above traditional longitudinal methods as our results represent how individual children change over time, relative to their own pre-existing characteristics.Disclosure of InterestNone Declared
Impact of selected single nucleotide polymorphisms in OXTR and AVPR1a genes on their expression in persons with ASD.
Authors: Wilczyński K. M. , Auguściak-Duma A. , Stasik A. , Cichoń L. , Sieroń A. , Janas-Kozik M. 
Published: August 2023

IntroductionAutism spectrum disorder is a heterogeneous group of disorders that affects virtually every population, regardless of their ethnic or socioeconomic origin. In recent years, the attention of researchers has been drawn to the participation of the oxytocinergic and vasopressinergic systems in the development of autism spectrum disorders. A relatively large number of studies have investigated the association of SNPs in these genes with the development of ASD, however, there is a lack of studies in the literature focusing on their actual effect on expression and on the effect of their expression on the risk of ASD.ObjectivesThe aim of this study was to assess the levels of expression of OXTR and AVPR1a genes and evaluate their links with both risk of ASD and genotypes of the most studied polymorphisms.MethodsThe study included 132 people, 77.5% of whom were male (n = 100). 113 participants (85.6%) were diagnosed with autism spectrum disorders confirmed by the ADOS-2 test conducted by a certified diagnostician. In this group, men constituted 76.1% of the population (n = 77). The remaining 28 people did not have a diagnosis of autism spectrum disorders, and in the ADOS-2 study they obtained the result below the cut-off level. The mean age in the whole group was 14.4 years (95% CI: 13.92-14.93).ResultsSignificant decrease in expression of the OXTR gene was found in case of rs53576 where presence of the alternative allele (G) was linked to the 20% decrease in expression (2^(-ΔΔCt) = 0.8). In case of AVPR1a alternative allele (T) of SNP rs10877969 was linked to the 20% increase in the gene expression(2^(-ΔΔCt) = 1.197). SNPs rs2254298 (2^(-ΔΔCt) = 0.97) and rs7294536 (2^(-ΔΔCt) = 0.97) did not influence expression of the appropriate genes in significant way. In comparison between the test and control group in participants with confirmed diagnosis of ASD 13% lower expression of AVPR1a was found (2^(-ΔΔCt) = 0.87).ConclusionsGenotype of SNPs rs53576 and rs10877969 significantly influenced the levels of expression of the genes OXTR and AVPR1a respectively. In case of rs2254298 and rs7294536 observed effects were negligible. Presence of ASD diagnosis was linked to the 13% lower expression of AVPR1a. Abnormalities in AVPR1a expression seem to be more important for the development of autistic traits than the more attention-grabbing gene abnormalities for the oxytocinergic system.Disclosure of InterestNone Declared
Cytomegalovirus infection associated with smaller cerebellum in severe mental illness
Authors: Andreou D. , Jørgensen K. N. , Nerland S. , Andreassen O. A. , Yolken R. H. , Agartz I. 
Published: August 2023

IntroductionPostnatal cytomegalovirus (CMV) infection of immunocompetent hosts is usually inapparent but typically results in lifelong latency. Congenital CMV infections as well as CMV infections in patients with immunodeficiencies have been linked to major cerebellar pathology. Patients with severe mental illness have been repeatedly found to have smaller cerebellum, and they may be particularly susceptible to CMV infections. Finally, both animal and human studies have shown a differential male and female immune response to CMV.ObjectivesWe evaluated whole cerebellar grey matter volumes (CGMV) in CMV immunoglobulin G (IgG) seropositive (CMV+) and seronegative (CMV-) patients with severe mental illness and healthy controls (HC). We hypothesized that CMV seropositivity, reflecting previous infection and current latency, is associated with smaller CGMV in patients but not in HC, and that such a putative association may be sex-dependent.MethodsWe included 529 adult patients with severe mental illness (CMV+ 57%, women 48%), i.e., 324 patients with schizophrenia spectrum disorders and 205 patients with bipolar spectrum disorders, and 494 HC (CMV+ 56%, women 45%). MRI scans were obtained with a 1.5T Siemens scanner (n=596) and two 3.0T General Electric scanners (n=427), and processed with FreeSurfer v6.0. Circulating CMV IgG concentrations were measured with immunoassays. In age-, scanner- and estimated total intracranial volume-adjusted analyses of covariance (ANCOVAs), we investigated main and interaction effects of CMV status and sex on CGMV in patients and HC.ResultsCMV+ patients had smaller CGMV than CMV- patients (p=0.042). There was no CGMV difference between CMV+ and CMV- HC (p=0.858). The adjusted CGMV means in CMV+ patients and CMV- patients were 115078 mm3 and 116725 mm3, respectively (p=0.042); the adjusted CGMV means in CMV+ and CMV- HC were 117980 mm3 and 117840 mm3, respectively (p=0.858) (Image). Among patients, a trend towards CMV-by-sex interaction (p=0.073) was found. Post-hoc analyses showed a significant CMV-CGMV association in the female patient group (p=0.005), with no association among male patients (p=0.840).Image:ConclusionsCMV IgG seropositivity is associated with smaller cerebellum in severe mental illness, an effect driven by the female patients, but not among HC. This may indicate a CMV-related deleterious impact on cerebellum restricted to patients.Disclosure of InterestNone Declared
Applying the Surgical Checklist Approach for Psychiatric Trainees to a Busy, Time Sensitive Psychiatric Crisis Environment
Authors: Celentano L. , Sadeghpour A. , Durand D. 
Published: August 2023

IntroductionThe Jackson Hospital Crisis (Psychiatric ED) Center serves the entirety of Miami-Dade County in Florida and is considered one of the top three busiest and per capita of clinical staff likely the busiest nationally across the United States. Simultaneously, the management of mental health emergencies has ascended near the top of international priorities driven by multiple trends (e.g., growing social isolation associated with the pandemic, de-stigmatization). The crisis environment presents a uniquely difficult challenge in applying high quality medical care: frequent suicidal gestures, impulsive often intoxicated or psychotic patients, unprecedented demand, diminishing staff capacity, and requirements to consistently apply specific medical and psychiatric protocols. These challenges are specifically difficult for new trainees who are not yet accustoms to the high acuity situations found in psychiatry. Moreover, academic, institutional, and governmental policies change on a monthly, or even weekly basis, often with the objective of improving care. Nevertheless, such constant shifts in workflow result in opportunities for errors that impact patient trajectories.ObjectivesAs such we endeavored to apply an evidence-based approach to improving the likelihood of success. One such vetted approach, the use of checklists, benefits from 10+ years of peer-reviewed research in “operational” medical specialties (e.g., surgery, ED, ICU) where work is segmented around interventions or time-shifts which share commonalities with the Psychiatric ED model. Yet the difficulty in implementing such models is typically not in the “hard” aspects of defining the checklist, but in the “soft” implementation dimensions of syndication, distribution, and enablement in the context of the individual unique settings.MethodsWe developed a checklist that will be implemented on the Jackson Crisis emergency department, with the aim of having first year trainees complete the check list on each individual patient. Surveys were administered before implementation of checklist and will be distributed on a quarterly basis to trainees to evaluate for changes in resident confidence and clinical care.ResultsOver six months, we launched this initiative with drivers of adoption focused on accelerating and easing new resident training, safety incident targeting, and in the balancing of “push” top/down and “pull” bottom/up dynamics. Initial learnings include rapidly improving resident satisfaction as well as various other impacts currently being observed throughout the institution.ConclusionsOverall reception to the checklist has been positive from attendings and new trainees alike, further evidence will be analyzed and presented as the checklist is utilized throughout the psychiatric ED.Disclosure of InterestNone Declared
Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model
Authors: Péricat D. , Leon-Icaza S. A. , Sánchez-Rico M. , Mühle C. , Zoicas I. , Schumacher F. , Planès R. , Mazars R. , Gros G. , Carpinteiro A. , Becker K. A. , Izopet J. , Strub-Wourgaft N. , Sjö P. , Neyrolles O. , Kleuser B. , Limosin F. , Gulbins E. , Kornhuber J. , Meunier E. , Hoertel N. , Cougoule C. 
Published: August 2023

IntroductionThe coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world’s population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19.ObjectivesThe aim of this sudy was to test the potential antiviral and anti-inflammatory activities of fluoxetine against
SARS-CoV-2 in a K18-hACE2 mouse model of infection, and against several variants of concern in vitro, and test the hypothesis of the implication of ceramides and/or their derivatives hexosylceramides.MethodsWe evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5.ResultsFluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres (Figure 1) and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10) (Figure 2). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects (Figure 3).Image:Image 2:Image 3:ConclusionsOur findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.Disclosure of InterestNone Declared
Brain correlates of perceived cognitive impairment after covid-19 infection: a multimodal MRI study.
Authors: Bettonagli V. , Paolini M. , Palladini M. , Mazza M. G. , Rovere Guerini P. , Poletti S. , Benedetti F. 
Published: August 2023

IntroductionMany different long-term neuropsychiatric sequelae of the novel Coronavirus have been described after the pandemic outbreak. One of the most common symptoms in the months following infection is related to “brain fog”. This condition includes several signs of cognitive impairment like mental slowness, deficits in attention, executive functions, processing, memory, learning, and/or psychomotor coordination, which can be perceived on a subjective level and further confirmed by objective data. Since this kind of mental status has been documented in previous viral infections, and the SARS-COV-2 has been characterized by a worldwide diffusion, investigation into this condition in post-covid individuals is warranted. Currently, several hypotheses on its pathophysiology have been put forward, mostly hypothesizing a direct effect of the virus on the central nervous system or indirect consequences of the inflammatory response.ObjectivesThe aim of our research is to analyze brain correlates of subjective cognitive complaints in Covid-19 survivors using multimodal brain imaging.MethodsWe performed a voxel-based morphometry (VBM) and a resting state functional connectivity analysis on 60 post-COVID-19 individuals recruited from the San Raffaele Hospital in Milan, that underwent a 3 tesla MRI scan. We assessed the perceived cognitive impairment both after the infection and at the time of the MRI scan through the PROMIS Cognitive Abilities scale. The difference of the two scores (delta PROMIS) was calculated as a measure of cognitive improvement over time.ResultsWe found the perceived amelioration of cognitive abilities (delta PROMIS) to be positively associated to grey matter volumes in the bilateral caudate, putamen and pallidum (pFWE: ˂0.001). Moreover, in the resting state fMRI analysis, subjective cognitive status at MRI was found to be associated with functional connectivity between the right putamen and pallidum, and two clusters belonging to the attentional (pFWE: ˂0.001) and salience (pFWE: 0.02) networks.ConclusionsThis is one of the first studies investigating brain correlates of subjective cognitive impairment after COVID-19 infection; our main finding is the convergence of structural and functional results on brain areas located within the basal ganglia, implying their possible role in the pathophysiology of the condition. Moreover, this research could be interpreted as the first step toward understanding a very complex condition, with potential implications for the development of treatment and neurorehabilitative strategies.Disclosure of InterestNone Declared
Comparison of VR-Assisted Therapy to Cognitive-Behavioral Therapy in the treatment of verbal hallucinations in patient with treatment-resistant schizophrenia
Authors: Beaudoin M. , Potvin S. , Dumais A. 
Published: August 2023

IntroductionAuditory verbal hallucinations (AVH), which often present in individuals with schizophrenia, can cause great psychological distress. Although antipsychotic medication can reduce AVH, 30% of patients will be resistant. Treatment resistance could be associated with important consequences, and there are only few treatment alternatives. Unfortunately, more than 50% of patients will not respond favorably to the best available psychological therapy, cognitive-behavioral therapy (CBT). However, using virtual reality (VR), our research team has adapted a therapy whose goal is to recreate the faces and voices of the patients’ persecutory voices as avatars. By interacting with an external representation of their hallucinations, patients implement new strategies to control their voices and to regulate their emotions. A small clinical trial (proof of concept) has demonstrated the safety and validity of this therapy as well as its superiority compared to the usual treatment.Objectives(1) To verify whether VR-Assisted Therapy (VRT) is superior to CBT for the treatment of AVH; and (2) to examine the effects of VRT and CBT on the symptomatology and quality of life.MethodsFor this single-blind randomized controlled clinical trial, 136 patients will by recruited (68/intervention) The effects on psychotic symptomatology as well as on quality of life is assessed using standardized questionnaires. Patients are included if they hear persecutory voices and have not responded to at least 2 trials of antipsychotics. Both groups are randomized from an external site and begin with an initial clinical assessment prior to randomization. Participants then receive 9 weekly one-hour therapy sessions (CBT or VRT), beginning the following week. A second clinical evaluation is carried out one week after the last session. A linear mixed effects model will be used to compare the effects of the 2 interventions.ResultsResults from a pilot randomized comparative trial evaluating the short- and long-term efficacy of VRT over CBT for patients with treatment-resistant schizophrenia (N=37/group) showed that both interventions produced significant improvements in AVH severity and depressive symptoms. Although results did not show a statistically significant superiority of VRT over CBT for AVH, VRT did achieve larger effects particularly on overall AVH (d = 1.080 for VRT and d = 0.555 for CBT). The recruitment of the current clinical trial is in progress.Image:ConclusionsVRT, which is currently under clinical investigation, presents itself as an interesting complement to existing pharmacological treatments. Since VR technologies allow the recreation of scenarios that are nearly impossible to reproduce in real life, VR-assisted psychotherapy could eventually become an integral part of our clinical practices.Disclosure of InterestNone Declared
Striatal ups or downs? Neural correlates of monetary reward anticipation, cue reactivity and their interaction in gambling disorder and alcohol use disorder
Authors: Goudriaan A. 
Published: August 2023

AbstractStriatal dysfunction is a key characteristic of addictive disorders, but neuroimaging studies have reported conflicting findings. An integrative model of addiction points to the presence or absence of addiction-related cues as an explanation for striatal hypo- or hyperactivations, respectively, but has never been directly tested. Here, we developed a novel paradigm to investigate striatal activation during monetary reward anticipation in the presence versus absence of addiction-related pictures using functional MRI. Across two studies, we compared 24 gambling disorder (GD) patients with 22 matched healthy controls and 46 alcohol use disorder (AUD) patients with 30 matched healthy controls. A behavioral interaction was seen where gambling cues made participants respond faster for bigger, but slower for smaller rewards. During monetary reward anticipation, hypoactivation of the reward system was seen in AUD individuals compared to HCs. However, no striatal differences were seen between the participants with GD or AUD and their matched controls. In sum, these findings suggest that striatal dysfunction is a key but heterogeneous mechanism within both AUD and GD and indicate an important but complex role for addiction-related cues in explaining striatal dysfunction in addiction.Disclosure of InterestNone Declared