The capacity of cognitive tests to detect generalized anxiety disorder (GAD): A pilot study.

Cognitive impairment remains understudied in generalized anxiety disorder (GAD), despite the high prevalence and substantial burden associated with this disorder. We aimed to assess cognitive impairment in patients with GAD and evaluate the ability of cognitive tests to detect this disorder. Because of its high rate of comorbidity, we also examined how other anxiety disorders and current major depressive episodes affected our results. We tested 263 consecutive general practice outpatients. We used the GAD-7 and the Mini International Neuropsychiatric Interview (MINI) to detect anxiety and mood disorders. We assessed cognitive performance with the Stroop test, a facial emotion recognition test, and the trail-making test (TMT). Compared to patients without GAD, patients with GAD were significantly slower to complete the TMT(B-A) and faster to recognize emotions, especially negative ones such as disgust and anger. When controlling for other anxiety disorders and current major depressive episode, GAD retained a significant effect on the TMT(B-A), but not on the emotion recognition test. The TMT(B-A) could detect GAD with good accuracy (area under the curve (AUC) = 0.83, maximal Youden's index = 0.56), which was by no means comparable to the GAD-7 (AUC = 0.97, Youden's index = 0.81). While it is not efficient enough to replace the GAD-7 as a diagnostic tool, the capacity of the TMT(B-A) to detect GAD emphasizes the importance of cognitive flexibility impairment in GAD.

iPSC-derived models for anorexia nervosa research.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder with genetic and epigenetic components that results in reduced food intake combined with alterations in the reward-processing network. While studies of patient cohorts and mouse models have uncovered genes and epigenetic changes associated with the disease, neuronal networks and brain areas preferentially activated and metabolic changes associated with reduced food intake, the underlying molecular and cellular mechanisms remain unknown. The use of both 2D in vitro cultures and 3D models, namely organoids and spheroids, derived from either human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), would allow identification of cell type-specific changes associated with AN and comorbid diseases, to study preferential connections between brain areas and organs, and the development of therapeutic strategies.

The value of plasma cell-free DNA levels as biomarker in patients with eating disorders: A preliminary study.

OBJECTIVE: Circulating cell-free DNA (cfDNA) holds promise as a rapid and convenient biomarker for identifying individuals with eating disorders. To investigate this hypothesis, we measured plasma cfDNA in patients with different eating disorders. METHODS: In this study, 110 participants (98 patients with eating disorders divided into 30 patients with bulimia nervosa, 33 patients with anorexia nervosa (AN) Restricting subtype, 35 patients with AN Binge-eating/purging subtype and 12 controls) were enrolled. We measured both cell-free nuclear DNA (cf-nDNA) and cell-free mitochondrial DNA (cf-mtDNA) from plasma using two specific droplet digital PCR assays each, referring to two amplicon sizes. RESULTS: Levels of plasma cf-nDNA and cf-mtDNA showed no significant differences between control participants and those with eating disorders. However, we observed a higher proportion of long cf-nDNA fragments in patients with eating disorders, suggesting its potential as a biomarker for eating disorders. CONCLUSION: This is the first study of cfDNA in patients with eating disorders. Our findings highlight the potential for qualitative exploration of cfDNA, although not of quantitative interest. Full characterization of cfDNA may serve as a valuable biomarker for eating disorders and provide some insights into the hidden mechanisms underlying the chronic development of these conditions. Future studies are needed to confirm or refute this hypothesis.

SNPs-Panel Polymorphism Variations in GHRL and GHSR Genes Are Not Associated with Prostate Cancer.

Prostate cancer (PCa) is a major public health problem worldwide. Recent studies have suggested that ghrelin and its receptor could be involved in the susceptibility to several cancers such as PCa, leading to their use as an important predictive way for the clinical progression and prognosis of cancer. However, conflicting results of single nucleotide polymorphisms (SNPs) with ghrelin (GHRL) and its receptor (GHSR) genes were demonstrated in different studies. Thus, the present case-control study was undertaken to investigate the association of GHRL and GHSR polymorphisms with the susceptibility to sporadic PCa. A cohort of 120 PCa patients and 95 healthy subjects were enrolled in this study. Genotyping of six SNPs was performed: three tag SNPs in GHRL (rs696217, rs4684677, rs3491141) and three tag SNPs in the GHSR (rs2922126, rs572169, rs2948694) using TaqMan. The allele and genotype distribution, as well as haplotypes frequencies and linked disequilibrium (LD), were established. Multifactor dimensionality reduction (MDR) analysis was used to study gene-gene interactions between the six SNPs. Our results showed no significant association of the target polymorphisms with PCa (p > 0.05). Nevertheless, SNPs are often just markers that help identify or delimit specific genomic regions that may harbour functional variants rather than the variants causing the disease. Furthermore, we found that one GHSR rs2922126, namely the TT genotype, was significantly more frequent in PCa patients than in controls (p = 0.040). These data suggest that this genotype could be a PCa susceptibility genotype. MDR analyses revealed that the rs2922126 and rs572169 combination was the best model, with 81.08% accuracy (p = 0.0001) for predicting susceptibility to PCa. The results also showed a precision of 98.1% (p < 0.0001) and a PR-AUC of 1.00. Our findings provide new insights into the influence of GHRL and GHSR polymorphisms and significant evidence for gene-gene interactions in PCa susceptibility, and they may guide clinical decision-making to prevent overtreatment and enhance patients' quality of life.

The role of dysregulated ghrelin/LEAP-2 balance in anorexia nervosa.

LEAP-2 is a ghrelin antagonist with an anorexigenic drive. This study investigates the evolution of plasma ghrelin and LEAP-2 concentrations in 29 patients with anorexia nervosa (AN) before and after refeeding and compares it to physiological adaptations during fasting in healthy controls or to mouse model of chronic food restriction and refeeding. Acute and chronic food restriction decrease LEAP-2 and increase ghrelin concentrations in both humans and mice, while patients with AN displayed higher ghrelin and LEAP-2 concentrations before than after refeeding (p = 0.043). After 6 months follow-up, patients with unstable weight gain (n = 17) had significantly decreased LEAP-2 concentrations after refeeding (p = 0.044), in contrast to patients with stable weight gain (n = 12). We provide evidence that the ghrelin/LEAP-2 system is not regulated according to the nutritional status in AN, in contrast to what is physiologically expected when coping with food restriction.

BDNF CpG methylation and serum levels covary during alcohol withdrawal in patients with alcohol use disorder: A pilot study.

OBJECTIVES: Brain-derived neurotrophic factor (BDNF) levels vary in various conditions including alcohol use disorder (AUD). We aimed to identify drivers of these variations. METHODS: Twelve patients with AUD were assessed at hospitalisation for alcohol withdrawal and four months later. We looked for associations between the change in serum BDNF levels and (1) length of abstinence, (2) anxiety (Hamilton Anxiety Scale) and depression (Beck-Depression Inventory), (3) one functional BDNF genotype (rs6265) and (4) methylation levels of 12 CpG sites within the BDNF gene (located in exons I, IV and IX). RESULTS: While abstinence remained, serum BDNF level increased. This increase correlated with the variation of methylation levels of the BDNF gene, and more specifically of exon I. We found no significant effect of length of abstinence, rs6265, depression or anxiety on serum BDNF level. CONCLUSIONS: Epigenetic regulation of the BDNF gene may be involved in variations of BDNF blood level associated with alcohol abstinence.

Chronic food restriction in mice and increased systemic ghrelin induce preference for running wheel activity.

OBJECTIVES: In eating disorders, particularly anorexia nervosa (AN), patients exhibit intense physical activity which is inappropriate regarding food restriction and chronic undernutrition, and exacerbates weight loss and energy deprivation. Rodent models of food restriction exhibit increased running wheel activity in the food anticipation period, also known as Food Anticipatory Activity (FAA). FAA probably has various physiological and/or neurobiological origins. Plasma concentrations of the orexigenic hormone ghrelin are, for example, increased during FAA. We hypothesize that the drive for physical activity in chronic food restriction is triggered by metabolic factors but also relies on motivational aspects that we aim to decipher in this study. METHODS: Young female C57Bl6/J mice were exposed to a paradigm based on a progressive 50% quantitative food restriction alone (FR) or associated with running wheel activity (Food Restriction Wheel: FRW) in their home-cage during 15 days. We measured preference for running wheel in a three-chamber apparatus in which animals could choose to explore either a known running wheel or a novel object. Testing took place either during resting or during FAA. We calculated the time spent in each compartment and the activity in running wheels. After progressive refeeding over 10 days, mice were tested again when refed. Plasma levels of both ghrelin isoforms were measured with selective immunoassays. RESULTS: When tested during FAA period, food restricted mice displayed increased preference for the running wheel compared to ad libitum fed controls. Both FR and FRW mice exhibited increased running time and distance in the wheel and running distance was correlated with ghrelin levels. Similar preference and behavior were found when testing took place during the resting period. Animals housed without an active wheel also exhibited active running. Progressive refeeding resulted in body weight restoration, a decrease in FAA and completely abolished preference for the running wheel. Refed animals displayed similar behavior as ad libitum fed controls. CONCLUSIONS: These data provide evidence that food restriction-induced physical activity is closely correlated with metabolic adaptations to nutritional status implicating ghrelin in the quantity of physical activity.

A systematic literature review and meta-analysis of circulating nucleic acids as biomarkers in psychiatry.

Common mental disorders (CMDs) such as depression, anxiety and post-traumatic stress disorders account for 40% of the global burden of disease. In most psychiatric disorders, both diagnosis and monitoring can be challenging, frequently requiring long-term investigation and follow-up. The discovery of better methods to facilitate accurate and fast diagnosis and monitoring of psychiatric disorders is therefore crucial. Circulating nucleic acids (CNAs) are among these new tools. CNAs (DNA or RNA) can be found circulating in body biofluids, and can be isolated from biological samples such as plasma. They can serve as biomarkers for diagnosis and prognoses. They appear to be promising for disorders (such as psychiatric disorders) that involve organs or structures that are difficult to assess. This review presents an accurate assessment of the current literature about the use of plasma and serum cell-free DNA (cfDNA) as biomarkers for several aspects of psychiatric disorders: diagnosis, prognosis, treatment response, and monitor disease progression. For each psychiatric disorder, we examine the effect sizes to give insights on the efficacy of CNAs as biomarkers. The global effect size for plasma nuclear and mitochondrial cfDNA studies was generally moderate for psychiatric disorders. In addition, we discuss future applications of CNAs and particularly cfDNA as non-invasive biomarkers for these diseases.

Associated and intermediate factors between genetic variants of the dopaminergic D2 receptor gene and harmful alcohol use in young adults.

Dopamine receptor D2 (DRD2) and ankyrin repeat and kinase domain-containing protein 1 (ANKK1) genes have received considerable attention for their involvement in alcohol use disorder (AUD), but many questions remain on their exact role. We conducted a population-based case-control and genetic association study in a large sample of young adults. Our aim was to assess the association between DRD2 and ANKK1 single nucleotide polymorphisms (SNPs) and harmful alcohol use, disentangling associated and possible intermediate factors. A total of 1841 college students from the French region Champagne-Ardennes, aged between 18 and 21 years and who reported at least one lifetime alcohol consumption, were included in this study. Allele frequencies were analysed according to harmful alcohol use (assessed through the Alcohol Use Disorder Identification Test [AUDIT] questionnaire). Different substance use disorders, including nicotine and cannabis dependences, were also assessed through questionnaires, as was a list of potential associated factors (e.g., major depressive episode, conduct disorder, attention-deficit/hyperactivity disorder [ADHD], school failure, sugar consumption, sexual trauma, parents' use of alcohol, tobacco or cannabis). We found that DRD2 rs1800498 was associated with harmful alcohol use. Many factors were detected, but a global path analysis revealed that DRD2 rs1800498 had a significant direct effect on harmful alcohol use and that early age at first alcohol consumption and depressive symptoms moderated this effect. This study suggests an interplay between harmful alcohol use, DRD2 genotypes and other risk factors that, with a full understanding, could be useful for preventive purposes.

Underlying Mechanisms Involved in Gambling Disorder Severity: A Pathway Analysis Considering Genetic, Psychosocial, and Clinical Variables.

Gambling Disorder (GD) has a complex etiology that involves biological and environmental aspects. From a genetic perspective, neurotrophic factors (NTFs) polymorphisms have been associated with the risk of developing GD. The aim of this study was to assess the underlying mechanisms implicated in GD severity by considering the direct and mediational relationship between different variables including genetic, psychological, socio-demographic, and clinical factors. To do so, we used genetic variants that were significantly associated with an increased risk for GD and evaluated its relationship with GD severity through pathway analysis. We found that the interaction between these genetic variants and other different biopsychological features predicted a higher severity of GD. On the one hand, the presence of haplotype block 2, interrelated with haplotype block 3, was linked to a more dysfunctional personality profile and a worse psychopathological state, which, in turn, had a direct link with GD severity. On the other hand, having rs3763614 predicted higher general psychopathology and therefore, higher GD severity. The current study described the presence of complex interactions between biopsychosocial variables previously associated with the etiopathogenesis and severity of GD, while also supporting the involvement of genetic variants from the NTF family.

Is decision-making impairment an endophenotype of anorexia nervosa?

BACKGROUND: Patients with anorexia nervosa (AN) show impaired decision-making ability, but it is still unclear if this is a trait marker (i.e., being associated with AN at any stage of the disease) or a state parameter of the disease (i.e., being present only in acutely ill patients), and if it has endophenotypic characteristics. The aim of this study was to determine the endophenotypic, and state- or trait-associated nature of decision-making impairment in AN. METHODS: Ninety-one patients with acute AN (A-AN), 90 unaffected relatives (UR), 23 patients remitted from AN (R-AN), and 204 healthy controls (HC) carried out the Iowa gambling task (IGT). Prospective valence learning (PVL) model was employed to distinguish the cognitive dimensions underlying the decision-making process, that is, learning, consistency, feedback sensitivity, and loss aversion. IGT performance and decision-making dimensions were compared among groups to assess whether they had endophenotypic (i.e., being present in A-AN, UR, and R-AN, but not in HC) and/or trait-associated features (i.e., present in A-AN and R-AN but not in HC). RESULTS: Patients with A-AN had lower performance at the IGT (p < 0.01), while UR, R-AN, and HC had comparable results. PVL-feedback sensitivity was lower in patients with R-AN and A-AN than in HC (p < 0.01). CONCLUSIONS: Alteration of decision-making ability did not show endophenotypic features. Impaired decision-making seems a state-associated characteristic of AN, resulting from the interplay between trait-associated low feedback sensitivity and state-associated features of the disease.

The role of neurotrophin genes involved in the vulnerability to gambling disorder.

Evidence about the involvement of genetic factors in the development of gambling disorder (GD) has been assessed. Among studies assessing heritability and biological vulnerability for GD, neurotrophin (NTF) genes have emerged as promising targets, since a growing literature showed a possible link between NTF and addiction-related disorders. Thus, we aimed to explore the role of NTF genes and GD with the hypothesis that some NTF gene polymorphisms could constitute biological risk factors. The sample included 166 patients with GD and 191 healthy controls. 36 single nucleotide polymorphisms (SNPs) from NTFs (NGF, NGFR, NTRK1, BDNF, NTRK2, NTF3, NTRK3, NTF4, CNTF and CNTFR) were selected and genotyped. Linkage disequilibrium (LD) and haplotype constructions were analyzed, in relationship with the presence of GD. Finally, regulatory elements overlapping the identified SNPs variants associated with GD were searched. The between groups comparisons of allele frequencies indicated that 6 SNPs were potentially associated with GD. Single and multiple-marker analyses showed a strong association between both NTF3 and NTRK2 genes, and GD. The present study supports the involvement of the NTF family in the aetiopathogenesis of GD. An altered cross-regulation of different NTF members signalling pathways might be considered as a biological vulnerability factor for GD.

Characterization of Depressive Symptoms Trajectories After Breast Cancer Diagnosis in Women in France.

Importance: Breast cancer (BC) diagnosis and treatment expose patients to a 5-fold higher risk of depression compared with the general population, with an estimated prevalence of 10% to 25%. A depressive episode in patients with BC has implications for the tolerance of and adherence to treatment, impairing quality of life and reducing life expectancy. Objective: To identify and characterize distinct longitudinal patterns of depressive symptoms in patients with BC from diagnosis to 3 years after treatment. Design, Settings, and Participants: The CANTO-DEePRESS (Deeper in the Understanding and Prevention of Depression in Breast Cancer Patients) cohort study included women in the French multicenter CANTO (CANcer TOxicities) cohort study (conducted between March 20, 2012 and December 11, 2018), who were 18 years or older with invasive stage I to III BC and no previous BC treatment. The study aimed to characterize toxicities over a 5-year period following stage I to III primary BC treatment. Assessments of depressive symptoms were performed on a subset of patients with available data at diagnosis and at least 2 other time points. All data were extracted from the CANTO database on October 1, 2020. Main Outcomes and Measures: The primary outcome was the level of depressive symptoms at each assessment time point measured with the Hospital Anxiety and Depression Scale and depression subscale at BC diagnosis and at 3 to 6, 12, and 36 months after the end of treatment. The group-based trajectory modeling was used to identify trajectory groups, and multinomial logistic regression models were used to characterize the following factors associated with trajectory group affiliation: demographic, socioeconomic, clinical, lifestyle, and quality-of-life data. Results: A total of 4803 women (mean [SD] age, 56.2 [11.2] years; 2441 patients [50.8%] with stage I BC) were included in the study. Six trajectory groups that described the heterogeneity in the expression of depressive symptoms were identified: noncases with no expression of symptoms (n = 2634 [54.8%]), intermediate worsening (1076 [22.4%]), intermediate improvement (480 [10.0%]), remission (261 [5.4%]), delayed occurrence (200 [4.2%]), and stable depression (152 [3.2%]). HADS-D scores at diagnosis were consistently associated with the 5 depressive trajectory group affiliations, with an estimated higher probability per point increase of experiencing subthreshold or clinically significant depressive symptoms between diagnosis and the 3 years after the end of BC treatment. The higher probabilities ranged from 1.49 (95% CI, 1.43-1.54) for the intermediate worsening group to 10.53 (95% CI, 8.84-12.55) for the stable depression group. Trajectory groups with depressive symptoms differed from the noncases group without symptoms by demographic and clinical factors, such as having dependent children, lower household income, cancer stage, family history of BC, previous psychiatric hospitalizations, obesity, smoking status, higher levels of fatigue, and depression at diagnosis. Conclusions and Relevance: In this cohort study, nearly a third of patients with BC experienced temporary or lasting significant depressive symptoms during and after treatment. Improving early identification of women at risk of developing long-term or delayed depression is therefore critical to increase quality of life and overall survival. Subjected to validation, this study is an important first step toward personalized care of patients with BC at risk of depression.

Association Between the A118G Polymorphism of the OPRM1 Gene and Suicidal Depression in a Large Cohort of Outpatients with Depression.

BACKGROUND: Growing evidences suggest that depression with suicidal ideation (SI) could be a specific phenotype with its own characteristics. Moreover, opioid system deregulation might be implicated in suicidal behaviour (SB). The aim of this study was to determine whether the A118G polymorphism (rs1799971) in ORPM1 (the gene encoding opioid receptor mu 1) is associated with suicidal depression (ie, moderate to severe depression with SI) in a large cohort of outpatients with depression. METHODS: GENESE is a large, prospective, naturalistic cohort of French adult outpatients with depression (DSM-IV criteria), treated and followed for 6 weeks. Depression severity was assessed with the Hospital Anxiety and Depression Scale (HADS), and SI with the suicidal item of the Montgomery-Åsberg Depression Rating Scale (MADRS-SI). From this cohort, patients with moderate or severe depression (HADS-D subscale score >11) were selected and classified as without SI (MADRS-SI < 2), or with SI (MADRS-SI ≥ 2). RESULTS: The AA/AG genotypes of the A118G polymorphism were significantly associated with suicidal depression in the non-adjusted (OR = 2.32, 95% CI = [1.28; 4.18]; p-value = 0.005) and in the adjusted models (OR = 2.54, 95% CI = [1.35; 4.78]; p-value = 0.004). CONCLUSION: Outpatients with depression harbouring the A allele are at higher risk of SI (and possibly SB) than those carrying the G allele. More studies are needed to better understand the link between this polymorphism and SB.

Auto-qPCR; a python-based web app for automated and reproducible analysis of qPCR data.

Quantifying changes in DNA and RNA levels is essential in numerous molecular biology protocols. Quantitative real time PCR (qPCR) techniques have evolved to become commonplace, however, data analysis includes many time-consuming and cumbersome steps, which can lead to mistakes and misinterpretation of data. To address these bottlenecks, we have developed an open-source Python software to automate processing of result spreadsheets from qPCR machines, employing calculations usually performed manually. Auto-qPCR is a tool that saves time when computing qPCR data, helping to ensure reproducibility of qPCR experiment analyses. Our web-based app ( https://auto-q-pcr.com/ ) is easy to use and does not require programming knowledge or software installation. Using Auto-qPCR, we provide examples of data treatment, display and statistical analyses for four different data processing modes within one program: (1) DNA quantification to identify genomic deletion or duplication events; (2) assessment of gene expression levels using an absolute model, and relative quantification (3) with or (4) without a reference sample. Our open access Auto-qPCR software saves the time of manual data analysis and provides a more systematic workflow, minimizing the risk of errors. Our program constitutes a new tool that can be incorporated into bioinformatic and molecular biology pipelines in clinical and research labs.

Is there a hypothalamic basis for anorexia nervosa?

The hypothalamus has long been known to control food intake and energy metabolism through a complex network of primary and secondary neurons and glial cells. Anorexia nervosa being a complex disorder characterized by abnormal feeding behavior and food aversion, it is thus quite surprising that not much is known concerning potential hypothalamic modifications in this disorder. In this chapter, we review the recent advances in the fields of genetics, epigenetics, structural and functional imaging, and brain connectivity, as well as neuroendocrine findings and emerging animal models, which have begun to unravel the importance of hypothalamic adaptive processes to our understanding of the pathology of eating disorders.

Self-consciousness impairments in schizophrenia with and without first rank symptoms using the moving rubber hand illusion.

INTRODUCTION: The moving rubber hand illusion allows the evaluation both the sense of body ownership and agency using visuo-motor stimulations. METHODS: We used the moving rubber hand illusion in anatomic congruence with explicit measures to compare active asynchronous and passive synchronous movements in patients diagnosed with schizophrenia with first rank symptoms (FRS) (n = 31) versus without FRS (n = 25). RESULTS: Patients with FRS are characterized by a lack of agency in active asynchronous condition. The two groups had no sense of ownership in synchronous passive condition. Using a multivariate regression model, we found an association between agency and body ownership measures in the active asynchronous condition in two groups (OR: 1.825, p < 0.001). In the passive condition, this association was only present in the group with first rank symptoms (OR: 2.04, p < 0.001). CONCLUSION: Temporal proximity and sensorimotor information are essential in the understanding of self-consciousness disorders in schizophrenia.