Search

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are associated with motor impairments, with some children holding a comorbid diagnosis of Developmental Coordination Disorder (DCD). However, DCD is underdiagnosed in these populations and the volume abnormalities that contribute to explaining these motor impairments are poorly understood. In this study, motor abilities as measured by the Developmental Coordination Disorder Questionnaire (DCDQ) were compared between children with ADHD, children with ASD and typically developing (TD) children, aged 8-12 years old. Additionally, the association between the DCDQ scores (general coordination, fine motor/handwriting, control during movement, total) and regional volume abnormalities were explored in 6 regions of interest (pre-central gyrus, post-central gyrus, inferior parietal cortex, superior frontal gyrus, middle frontal gyrus, medial frontal gyrus), within each group and across all participants. Children with ASD and children with ADHD showed impaired motor abilities in all the DCDQ-derived scores compared to TD children. Additionally, most children with ASD or ADHD had an indication or suspicion of DCD. Within the ASD group, coordination abilities were associated with the volume of the right medial frontal gyrus, and within the ADHD group, the total DCDQ score was associated with the volume of the right superior frontal gyrus. This study underlines the importance of routinely checking motor abilities in populations with ASD or ADHD in clinical practise and contributes to the understanding of structural abnormalities subtending motor impairments in these disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Albajara Sáenz, Villemonteix, Van Schuerbeek, Baijot, Septier, Defresne, Delvenne, Passeri, Raeymaekers, Victoor, Willaye, Peigneux, Deconinck and Massat.)

Background: Impairing irritability is highly prevalent in children with attention deficit/hyperactivity disorder (ADHD), although manifestations of irritability are not necessarily present in all settings (home, school, with peers). At the moment, little is known about the relative prevalence, stability, and etiologies of contextual versus cross-situational manifestations of irritability in ADHD. In this study, levels of dysfunctional parenting practices and sleep problems were compared in irritable versus nonirritable children with ADHD, in cases of family-restricted versus cross-situational irritability, and examined as predictors of irritability levels over a one-year interval. Stability of irritability manifestations over time was investigated, and prevalence of cross-situational disruptive mood dysregulation disorder (DMDD) versus 'family-restricted' DMDD was compared., Method: One hundred and seventy children with ADHD (age 6-11) were examined. Parents completed a semi-structured interview and questionnaire to assess irritability, and parent-report questionnaires were used to evaluate parenting practices and sleep problems. Questionnaires were completed for a second time after a one-year interval., Results: Parenting practices were more dysfunctional in the irritable group compared to the nonirritable group, while sleep problems did not differ between these two groups. Levels of parenting practices and sleep problems did not predict later irritability after correction for multiple comparison nor did they differ between the family-restricted and cross-situational irritable groups. Finally, family-restricted irritability was as prevalent and as stable over time as cross-situational irritability and family-restricted DMDD as prevalent as cross-situational DMDD., Conclusions: Factors associated with contextual versus cross-situational manifestations of irritability in ADHD remain elusive. More subtle measures of parenting practices should be considered, including psychological control or accommodation, and other constructs such as social inhibition. Despite not being captured by current nosography, severe forms of family-restricted irritability may be as prevalent as severe forms of cross-situational irritability., (© 2020 Association for Child and Adolescent Mental Health.)

The overlap/distinctiveness between Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) has been increasingly investigated in recent years, particularly since the DSM-5 allows the dual diagnosis of ASD and ADHD, but the underlying brain mechanisms remain unclear. Although both disorders are associated with brain volumetric abnormalities, it is necessary to unfold the shared and specific volume abnormalities that could contribute to explain the similarities and differences in the clinical and neurocognitive profiles between ADHD and ASD. In this voxel-based morphometry (VBM) study, regional grey matter volumes (GMV) were compared between 22 children with ADHD, 18 children with ASD and 17 typically developing (TD) children aged 8 to 12 years old, controlling for age and total intracranial volume. When compared to TD children or children with ASD, children with ADHD had a larger left precuneus, and a smaller right thalamus, suggesting that these brain abnormalities are specific to ADHD relative to ASD. Overall, this study contributes to the delineation of disorder-specific structural abnormalities in ADHD and ASD., Competing Interests: Isabelle Massat received an investigator-initiated research grant from Shire Pharmaceutical Development Limited, a member of the Takeda group of companies (Study ID: IST-BEL- 00520). This does not alter our adherence to PLOS ONE policies on sharing data and materials. Ariadna Albajara Sáenz is supported by a grant from the Belgian Kids’ Fund (www.belgiankidsfund.be), the David et Alice Van Buuren Fund and by the Fondation Jaumotte-Demoulin. Isabelle Massat and Ariadna Albajara Sáenz are supported by the Fonds National de la Recherche Scientifique (FNRS)-Belgium and the Fonds Erasme. The funders had no role in the study design, the data collection and analysis, the decision to publish, or the preparation of the manuscript.

Objective: Using Diffusion Tensor Imaging (DTI), to investigate microstructural white matter differences between ADHD and typically developing children (TDC), and their association with inhibition and working memory performance usually impaired in ADHD. Method: Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in 36 noncomorbid children with a Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR ) diagnosis of combined type ADHD and 20 TDC. Correlations between FA/MD and Stop Signal Task and N-Back performance parameters were computed. Results: Working memory performance was significantly associated with MD in the superior longitudinal fasciculus (SLF) and the cingulum in the ADHD group. No between-group differences in FA/MD reached significance, after controlling for between-group head motion differences. Conclusion: The association between white matter integrity in the cingulum and the SLF and working memory performance confirms previous studies. Our results also show that when critical conditions are controlled (age, comorbidity, head motion), no ADHD-related structural abnormality (FA/MD) are observed, in line with prior suggestions.

Attention-deficit/hyperactivity (ADHD) and autism spectrum (ASD) disorders often co-occur. In both cases, response inhibition deficits and inhibition-related atypical brain activation have been reported, although less consistently in ASD. Research exploring the overlap/distinctiveness between ADHD and ASD has significantly increased in recent years, but direct comparison of the inhibition-related neuronal correlates between these disorders are scarce in the literature. This study aimed at disentangling the shared and specific inhibitory brain dysfunctions in ASD and ADHD. Using functional magnetic resonance imaging (fMRI), brain activity was compared between children with ADHD, ASD and typically developing (TD) children aged 8-12 years during an inhibition stop-signal task, using stringent inclusion criteria. At the behavioural level, only children with ADHD exhibited inhibition deficits when compared with the TD group. Distinct patterns of brain activity were observed during successful inhibition. In children with ADHD, motor inhibition was associated with right inferior parietal activation, whereas right frontal regions were activated in children with ASD. Between-group comparisons disclosed higher middle frontal activation in the ASD group compared with the ADHD and the TD groups. Our results evidence different patterns of activation during inhibition in these two disorders, recruiting different regions of the fronto-parietal network associated to inhibition. Besides brain activity differences, behavioural inhibition deficits found only in children with ADHD further suggest that reactive inhibition is one of the core deficits in ADHD, but not in ASD. Our findings provide further evidence contributing to disentangle the shared and specific inhibitory dysfunctions in ASD and ADHD.

Dopamine active transporter gene (DAT1) is a candidate gene associated with attention-deficit/hyperactivity disorder (ADHD). The DAT1 variable number tandem repeat (VNTR)-3' polymorphism is functional and 9R carriers have been shown to produce more DAT than 10R homozygotes. We used functional magnetic resonance imaging (fMRI) to investigate the effects of this polymorphism on the neural substrates of working memory (WM) in a small but selected population of children with ADHD, naïve of any psychotropic treatment and without comorbidity. MRI and genotype data were obtained for 36 children (mean age: 10,36 +/- 1,49 years) with combined-type ADHD (9R n = 15) and 25 typically developing children (TDC) (mean age: 9,55 +/- 1,25 years) (9R n = 12). WM performance was similar between conditions. We found a cross-over interaction effect between gene (9R vs. 10R) and diagnosis (TDC vs. ADHD) in the orbito-frontal gyrus, cerebellum and inferior temporal lobe. In these areas, WM-related activity was higher for 9R carriers in ADHD subjects and lower in TDC. In ADHD children only, 10R homozygotes exhibited higher WM-related activity than 9R carriers in a network encompassing the parietal and the temporal lobes, the ventral visual cortex, the orbito-frontal gyrus and the head of the caudate nucleus. There was no significant results in TDC group. Our preliminary findings suggest that DAT1 VNTR polymorphism can modulate WM-related brain activity ADHD children., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Over the last decade, there has been a dramatic increase in the number of neuroimaging studies in attention-deficit/hyperactivity disorder (ADHD). In terms of brain structure, magnetic resonance imaging (MRI), and diffusion tensor imaging studies have evidenced differences in volume, surface-based measures (cortical thickness, surface area, and gyrification), and white matter integrity in different cerebral regions, in children and adults with ADHD compared to population norms. Abnormalities in the basal ganglia, prefrontal structures, and the corpus callosum have been the most consistently reported findings across studies. Hemodynamic (functional MRI, functional near-infrared spectroscopy, positron emission tomography, single-photon emission computed tomography) and magnetoencephalography measurements have also shown differences in neural activity during the execution of neuropsychological tasks and during rest, in widespread regions of the brain. Importantly, multimodal studies combining structural and functional methods have shown an intercorrelation between structural and functional abnormalities in ADHD. Further longitudinal studies are needed to clarify the effects of age and medication on brain structure and function in individuals with ADHD. WHAT THIS PAPER ADDS: In attention-deficit/hyperactivity disorder (ADHD), the brain is characterized by abnormal neural network interplay. Structural and functional cerebral abnormalities in ADHD are intercorrelated. Currently there is no neural biomarker that can be used in diagnosis. Longitudinal studies have shed light on the brain correlates of ADHD over the lifespan. The effects of stimulant intake on the brain correlates of ADHD remain unclear., (© 2018 Mac Keith Press.)

Objectives: Hypo/reduced activity in motor response inhibition (RI) cerebral networks was recently proposed as a promising specific neurobiological marker of attention deficit-hyperactivity disorder (ADHD). Before adopting such a pattern as a key diagnosis tool, we aim to replicate in an independent study the mechanisms underlying reduced RI-related activity in ADHD, after controlling for potentially confounding effects., Methods: In this fMRI study, we investigated the neural networks mediating successful and failed motor RI in children with ADHD and typically developing children (TDC) using the stop-signal task (SST) paradigm., Results: In contrast to hypofrontality predictions, children with ADHD exhibit increased neural activity during successful response inhibition in an RI-related brain network encompassing the indirect and/or hyperdirect pathways between the basal ganglia and cortex. Voxel-based morphometry analyses have further evidenced reduced grey matter volume in the left caudate in children with ADHD, which paralleled higher functional responses. Finally, connectivity analyses disclosed tighter coupling between a set of cortical regions and the right caudate as well as the right IFG, networks involved in successful RI., Conclusions: Hypo/reduced activity in RI cerebral networks in children with ADHD cannot at this time be considered as a systematic biomarker for ADHD.

Background: Numerous studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders, including suicidal behavior, although with conflicting results., Methods: A total of 250 major depressive disorder patients were collected in the context of a European multicenter resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and Hamilton Rating Scale for Depression, and treatment response using the HAM-D. Genotyping was performed for the functional Val66Met polymorphism (rs6265) and 7 additional tagging single nucleotide polymorphisms within the BDNF gene., Results: Neither BDNF single markers nor haplotypes were found to be associated with suicide risk and lifetime history of suicide attempts. Gender-specific analyses revealed nonsignificant single marker (rs908867) and haplotypic association with suicide risk in males after multiple testing correction. Analyzing treatment response phenotypes, the functional Val66Met polymorphism as well as rs10501087 showed significant genotypic and haplotypic association with suicide risk in remitters (n=34, 13.6%)., Conclusions: Considering the sample size, the present findings need to be replicated in larger samples to confirm or refute a role of BDNF in the investigated suicidal behavior phenotypes., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Objectives: Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes., Methods: This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing., Results: A large, new body of evidence on genetics of schizophrenia has accumulated over recent years. Many new robustly associated genetic loci have been detected. Furthermore, there is consensus that at least a dozen microdeletions and microduplications contribute to the disease. Genetic overlap between schizophrenia, other psychiatric disorders, and neurodevelopmental syndromes raised new questions regarding the current classification of psychiatric and neurodevelopmental diseases., Conclusions: Future studies will address especially the functional characterisation of genetic variants. This will hopefully open the doors to our understanding of the pathophysiology of schizophrenia and other related diseases. Complementary, integrated systems biology approaches to genomics, transcriptomics, proteomics and metabolomics may also play crucial roles in enabling a precision medicine approach to the treatment of individual patients.

Emotional interference control refers to the ability to remain focused on goal-oriented processes when confronted with disrupting but irrelevant emotional stimuli, a process that may be impaired in children and adults with attention deficit/hyperactivity disorder (ADHD). However, emotional interference levels are known to be associated with trait anxiety, and patients with ADHD often display elevated levels of trait anxiety, such as these may have confounded previous findings of decreased emotional interference control in this population. In the present study, male and female 8-13 years old (mean =11.0 years) children with ADHD (n=33) and typically developing (TD) children (n=24) performed a visual emotional working memory (n-back) task with 2 memory loads and three different background pictures (neutral/positive/negative), and trait anxiety measures were obtained. Children with ADHD performed less well, and displayed increased emotional interference in the presence of aversive distractors when compared with TD children. Contrary to our expectations, trait anxiety did not mediate the association between diagnostic group membership and the degree of emotional interference control; however, co-morbid ODD was associated with decreased levels of emotional interference in ADHD. Future research should aim at characterizing the mechanisms subtending decreased emotional interference control in the ADHD population., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.

Attention deficit/hyperactivity disorder (ADHD) in children has been associated with attentional and executive problems, but also with socioemotional difficulties possibly associated with deficits in Theory of Mind (ToM). Socioemotional problems in ADHD are associated with more negative prognoses, notably interpersonal, educational problems, and an increased risk of developing other psychiatric disorders that emphasize the need to clarify the nature of their ToM deficits. In this study, we hypothesized that ToM dysfunction in children with ADHD is largely attributable to their attentional and/or executive deficits. Thirty-one children with ADHD (8-12 years, IQ > 85) and 31 typically developing (TD) children were assessed using executive functions (inhibition, planning, and flexibility) and attentional tasks, as well as two advanced ToM tasks (Reading the Mind in the Eyes and Faux Pas) involving different levels of executive control. Children with ADHD performed more poorly than TD children in attentional, executive function, and ToM tasks. Linear regression analyses conducted in the ADHD group indicated that inhibition scores predicted performance on the "Faux Pas" task the best, while attention scores were the best for predicting performance on the Reading the Mind in the Eyes task. When controlled for inhibition and attentional variables, ToM performance in children with ADHD was actually similar to TD children. Contrarily, controlling for ToM scores did not normalize performance for inhibition and attentional tasks in children with ADHD. This unidirectional relationship suggests that deficits in the EF and attentional domains are responsible for ToM deficits in ADHD, which therefore may contribute to their socioemotional difficulties.

So far, associations between serotonergic neurotransmission pathways and suicidality have been reported. The aim of our study was to investigate the role of genetic polymorphisms and gene-gene interactions of the 5-HTR1A and the 5-HTR2A gene on suicide risk and/or a personal history of suicide attempts. A total of 374 major depressive disorder patients, adequately treated with antidepressants for at least 4 weeks, were collected in the context of a European multicentre study on treatment-resistant depression. We assessed suicidality using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of adequate antidepressant treatment. The 5-HTR1A rs6295 (C-1019G) single nucleotide polymorphism (SNP) and the 5-HTR2A rs7997012, rs6313, rs643627 and rs17288723 SNPs were selected for genotyping. Using logistic regression analyses, no association (P<0.05) could be found between any SNP and neither suicide risk nor personal history of suicide attempts. Interactions between 5HTR1A rs6295 and 5HTR2A rs6313 in suicide risk, and 5HTR1A rs6295 and 5HTR2A rs643627 in a personal history of suicide attempts have been reported (P=0.027 and 0.036, respectively); however, the results did not survive multiple testing correction. In conclusion, our study shows no association between 5HTR1A or 5HTR2A gene polymorphisms and both current suicide risk and personal history of suicide attempts. In addition, epistatic effects of 5HTR1A and 5HTR2A genes on suicidal behaviour were not significant, although sample size limitations do not allow definitive conclusions.

Female participants have been underrepresented in previous structural magnetic resonance imaging reports on attention-deficit/hyperactivity disorder (ADHD). In this study, we used optimized voxel-based morphometry to examine grey matter volumes in a sample of 33 never-medicated children with combined-type ADHD and 27 typically developing (TD) children. We found a gender-by-diagnosis interaction effect in the ventral anterior cingulate cortex (ACC), whereby boys with ADHD exhibited reduced volumes compared with TD boys, while girls with ADHD showed increased volumes when compared with TD girls. Considering the key role played by the ventral ACC in emotional regulation, we discuss the potential contribution of these alterations to gender-specific symptoms' profiles in ADHD., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Psychostimulants are the first-line treatment in attention deficit/hyperactivity disorder (ADHD), but their effects on brain development remain poorly understood. In particular, previous structural magnetic resonance imaging (sMRI) studies only investigated treatment effects on grey matter (GM) volumes in selected regions of interest (ROIs). In this study, voxel-based morphometry (VBM) was used to assess medication-related GM volume differences across the entire brain. Automated tracing measurements of selected ROIs were also obtained. Three groups (77 participants aged 7-to-13 year old) underwent MRI scans and were compared: never-medicated children with ADHD (n=33), medicated (methylphenidate) children with ADHD (n=20) and typically developing children (TD; n=24). Optimised VBM was used to investigate regional GM volumes, controlling for age and gender. Automated tracing procedures were also used to assess the average volume of the caudate nucleus, the amygdala and the nucleus accumbens. When compared to both medicated children with ADHD and TD children, never-medicated children with ADHD exhibited decreased GM volume in the insula and in the middle temporal gyrus. When compared to TD children, medicated children with ADHD had decreased GM volume in the middle frontal gyrus and in the precentral gyrus. Finally, ROI analyses revealed a significant association between duration of treatment and GM volume of the left nucleus accumbens in medicated children with ADHD. In conclusion, this study documents potential methylphenidate-related GM volume normalization and deviation in previously unexplored brain structures, and reports a positive association between treatment history and GM volume in the nucleus accumbens, a key region for reward-processing., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Purpose: Mood disorders are present in more than 90% of suicides, and a genetic vulnerability to suicidality is well established. Numerous lines of evidence relate the transcription factor Cyclic adenosine monophosphate Response Element Binding protein (CREB1) to suicide, and to the aetiology of major depressive disorder (MDD). Our aim was to test for association between CREB1 single nucleotide polymorphisms (SNPs) and both suicide risk (SR) and a personal history of suicide attempt (SA) in MDD patients., Materials and Methods: A sample of 250 MDD patients collected in the context of a European multicenter resistant depression study and treated with antidepressants over a period of at least 4 weeks were genotyped for five CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). To assess suicidality, the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D) were applied., Results: Neither single-marker nor haplotypic association were found between SR and/or a personal history of SA with any of the investigated SNPs after multiple testing correction. For females, an association between rs2709376 and a personal history of SA was found (p = 0.016), however not resisting multiple testing correction., Conclusions: Although we found significant CREB1 single marker association with a personal history of SA in female MDD patients, this finding could not be confirmed in haplotypic analyses after multiple testing correction. Larger well-defined cohorts are required to confirm or refute a possible association of CREB1 and SA in female MDD patients.

Objectives: The Val158-allele of the catechol-O-methyltransferase (COMT) Val158Met (rs4680) functional polymorphism has been identified as a risk factor for antisocial behaviour in attention-deficit/hyperactivity disorder (ADHD). Here, we used voxel-based morphometry to investigate the effects of Val158Met polymorphism on grey matter (GM) volumes in a sample of 7-13-year-old children., Methods: MRI and genotype data were obtained for 38 children with combined-type ADHD and 24 typically developing (TD) children. Four regions of interest were identified: striatum, cerebellum, temporal lobe and inferior frontal gyrus (IFG)., Results: When compared to TD children, those with ADHD had a significant decrease of GM volume in the IFG. Volume in this region was negatively correlated with ratings of hyperactivity/impulsivity symptoms. Furthermore, the smaller GM volume in the IFG was attributed to the presence of the Met158-allele, as only children with ADHD carrying a Met158-allele exhibited such decrease in the IFG. Children with ADHD homozygotes for the Val158-allele presented increased GM volume in the caudate nucleus when compared with TD children., Conclusions: This study provides the first evidence of a modulation of ADHD-related GM volume alterations by Val158Met in two key regions, possibly mediating the relationship between Val158Met polymorphism and antisocial behaviour in children with ADHD.

This study compares behavioral and electrophysiological (P300) responses recorded in a cued continuous performance task (CPT-AX) performed by children with attention deficit hyperactivity disorder-combined subtype (ADHD-com) and age-matched healthy controls. P300 cognitive-evoked potentials and behavioral data were recorded in eight children with ADHD (without comorbidity) and nine control children aged 8-12 years while performing a CPT-AX task. Such task enables to examine several kinds of false alarms and three different kinds of P300 responses: the "Cue P300", the "Go P300" and the "NoGo P300", respectively, associated with preparatory processing/attentional orienting, motor/response execution and motor/response inhibition. Whereas hit rates were about 95% in each group, ADHD children made significantly more false alarm responses (inattention- and inhibition-related) than control children. ADHD children had a marginally smaller Cue P300 than the control children. Behavioral and electrophysiological findings both highlighted inhibition and attention deficits in ADHD-com children in the CPT-AX task. A rarely studied kind of false alarm, the "Other" FA, seems to be a sensitive FA to take into account, even if its interpretation remains unclear.

Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions.

Treatment resistant depression (TRD) is a significant clinical and public health problem. Among others, neuroplasticity and inflammatory pathways seem to play a crucial role in the pathomechanisms of antidepressant efficacy. The primary aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within two genes implicated in neuroplasticity and inflammatory processes (the mitogen activated protein kinase 1, MAPK1 (rs3810608, rs6928, rs13515 and rs8136867), and the cyclic AMP responsive element binding protein 1, CREB1 (rs889895, rs6740584, rs2551922 and rs2254137)) was associated with antidepressant treatment resistance (according to two different definitions), in 285 Major Depressive Disorder (MDD) patients. As secondary aims, we investigated the genetic modulation of the same SNPs on response, remission and other clinical features both in MDD patients and in a larger sample including 82 Bipolar Disorder (BD) patients as well. All patients were screened in the context of a European multicenter project. No association between both the investigated genes and treatment resistance and response was found in MDD patients. However, considering remission, higher rates of CREB1 rs889895 GG genotype were reported in MDD patients. Moreover, MAPK1 rs8136867 AG genotype was found to be associated with remission in the whole sample (MDD and BD). Present results suggest that some genetic polymorphisms in both CREB1 and MAPK1 could be associated with treatment remission. Although further research is needed to draw more definitive conclusions, such results are intriguing since suggest a potential role of two genes implicated in neuroplasticity and inflammatory processes in symptom remission after antidepressant treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study. They were genotyped for COX-2 and OXTR SNPs. Treatment resistance (according to two different definitions), response and remission were recorded. We did not observe any association between the genotypes or alleles of the selected SNPs within COX-2 and OXTR genes and treatment resistance, response and remission in the whole sample. Our results are consistent with those of some studies but not with those of other ones. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, and different definitions of treatment resistance., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Many association studies have reported associations between the catechol-O-methyltransferase (COMT) gene and psychiatric disorders including major depression (MDD). The COMT gene has further been associated with suicidal behaviour, as well as with treatment response, although with conflicting results. In the present study, we further elucidate the impact of COMT in treatment response in MDD patients with suicide risk and/or a personal history of suicide attempts. Two hundred fifty MDD patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for seven SNPs (rs4680, rs2075507, rs737865, rs6269, rs4633, rs4818 and rs165599) within the COMT gene. With regard to suicide risk and personal history of suicide attempts, neither single marker nor haplotypic association was found with any SNP after multiple testing correction. In non-responders, we found significant single marker and haplotypic association with suicide risk, but not in responders. The same holds true for both remitters and non-remitters, and when testing for association with a personal history of suicide attempts and treatment response phenotypes. In conclusion, we found significant association of COMT SNPs with suicide risk in MDD patients not responding to antidepressant treatment. Larger well-defined cohorts will be required to dissect this further., (Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.)

In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies., (Copyright © 2012 S. Karger AG, Basel.)

Attention Deficit/Hyperactivity Disorder (ADHD) is a pervasive neurodevelopmental disorder characterized by 3 clusters of age-inappropriate cardinal symptoms: inattention, hyperactivity and impulsivity. These clinical/behavioural symptoms are assumed to result from disturbances within brain systems supporting executive functions including working memory (WM), which refers to the ability to transiently store and flexibly manipulate task-relevant information. Ongoing or past medications, co-morbidity and differences in task performance are potential, independent confounds in assessing the integrity of cerebral patterns in ADHD. In the present study, we recorded WM-related cerebral activity during a memory updating N-back task using functional Magnetic Resonance Imaging (fMRI) in control children and never medicated, prepubescent children with ADHD but without comorbid symptoms. Despite similar updating performance than controls, children with ADHD exhibited decreased, below baseline WM-related activation levels in a widespread cortico-subcortical network encompassing bilateral occipital and inferior parietal areas, caudate nucleus, cerebellum and functionally connected brainstem nuclei. Distinctive functional connectivity patterns were also found in the ADHD in these regions, with a tighter coupling in the updating than in the control condition with a distributed WM-related cerebral network. Especially, cerebellum showed tighter coupling with activity in an area compatible with the brainstem red nucleus. These results in children with clinical core symptoms of ADHD but without comorbid affections and never treated with medication yield evidence for a core functional neuroanatomical network subtending WM-related processes in ADHD, which may participate to the pathophysiology and expression of clinical symptoms.

Objective: The management of treatment-resistant depression is a much debated issue. In particular, the evidence supporting the commonly suggested sequential use of antidepressants from 2 different pharmacological classes is weak. This retrospective study was undertaken to investigate whether there is a better response in nonresponders switched to a different class of antidepressants (across-class) compared with nonresponders switched to an antidepressant from the same class (within-class)., Methods: Three hundred forty patients with primary major depressive disorder were recruited in the context of a European multicenter project. Subjects whose current depressive episode had failed to respond to a first antidepressant trial of adequate dose and duration were included., Results: There was no significant difference in response or remission rates between the across-class and within-class groups after controlling for possible confounders., Conclusions: In depressed nonresponders to a previous antidepressant treatment, switching to a different class of antidepressants was not associated with a better response or remission rate.

OBJECTIVES. Evidence in favour of switching between selective serotonin reuptake inhibitor (SSRI) and tricyclic (TCA) antidepressants in treatment resistant depression has been tested in a few studies only, consequently a prospective study was undertaken to evaluate the impact of switching strategies. METHODS. One hundred eighty-nine patients who failed to respond to a previous antidepressant were randomised to four arms: firstly they received citalopram or desipramine for a 4-week period; secondly, those who failed to respond were treated for a further 4-week period with the same antidepressant (citalopram-citalopram and desipramine-desipramine arms) or switched to the alternate one (citalopram-desipramine and desipramine-citalopram arms). RESULTS. There was no difference in the first 4-week phase between patients receiving citalopram versus desipramine in Hamilton Rating Scale for Depression (HRSD), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression (CGI) scores. In the second 4-week phase remitter rates were higher among non-switched patients (P = 0.04). Moreover, considering HRSD and MADRS, switched patients reported significantly higher scores (P ≤ 0.02 for both scales at each time-point). CONCLUSIONS. This study supports the thesis that switching from an SSRI to a TCA (and vice versa) in non-responders to a 4-week trial of an SSRI/TCA is not associated with improved response. The result goes in the opposite direction to that predicted by current guidelines.

Our study aims at replicating our previous finding of an association between COMT rs4680 G/A polymorphism and early onset major depression (MD). We included 462 MD, 147 bipolar disorders (BD) subjects and 295 healthy controls. We could partially replicate previous findings. In particular, rs4680 GG+AG genotypes were more represented in the subgroup of early onset MD patients (p=0.04). Additionally, we observed an association between rs737865 alleles and early onset MD (p=0.04). Rs4680 genotype was associated with early onset BD as well (p=0.01). In conclusion, we partially replicated our previous findings confirming a possible influence of COMT variants in MD and BD, particularly in early onset subjects, though not with the same risk genotypes., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In the present study, aimed at investigating whether a set of single nucleotide polymorphisms (SNPs) within PTGS2 gene (rs4648276, rs2066826 and rs689466) could be associated with antidepressant response, remission and treatment resistance in a sample of major depression patients, we did not find evidence supporting any of such associations., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has pivotal roles in neuronal survival, proliferation, and synaptic plasticity in the brain. Both clinical and pharmacological studies have implicated the common single nucleotide polymorphism (SNP) at position 196, Val66Met in the pathophysiology of major depressive disorder (MDD), and antidepressant response. However, inconsistent results were found between Val66Met (rs6265) polymorphism and treatment response phenotypes in genetic association studies. The functional Val66Met polymorphism and seven other tagging SNP markers selected to capture the major allelic variations across BDNF locus were analyzed in depressed patients, treated with antidepressants, and 76 control patients. Two hundred and six patients with Diagnostic and Statistical Manual of Mental Disorders-IV MDD were recruited for this study and genotyped for eight BDNF tagging SNPs (rs11030096, rs925946, rs10501087,rs6265, rs12273363, rs908867, rs1491850, and rs1491851)to investigate the functional impact of genotypes/haplotypes in the susceptibility of depression and on treatment response. None of the eight SNPs, including the rs6265, were significantly associated with MDD after permutation correction. However, we found an association for rs10501087, rs6265 with nonresponse to antidepressant treatment (corrected permutation P:0.03599; 0.0399 and power: 0.1420; 0.1492, respectively).Analysis of each two-marker, three-marker, and four-marker sliding window haplotypes showed significance in haplotype combinations. Especially rs10501087 (C), rs6265 (A), and rs149,1850 (C) together or with the other SNP haplotypes showed a similar pattern in all treatment response phenotypes. Despite the limited power of analysis, our results suggest that these three SNPs may play a role in antidepressant treatment response phenotypes in MDD.

Background: The transcription factor Cyclic adenosine monophosphate Response Element Binding (CREB) protein has been repeatedly involved in the aetiology and pharmacotherapy of major depression (MD). The aim of this study was to investigate the potential association of a set of single nucleotide polymorphisms (SNPs) in CREB1 gene and both MD and response, remission and treatment resistance to antidepressants., Methods: One hundred-ninety MD patients collected in the context of a resistant depression study and treated with antidepressants for at least 4weeks were genotyped for 5 CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). Response, remission and treatment resistance were recorded., Results: An allele of rs7569963 as well as rs2253206-rs7569963 A-A and rs7569963-rs4675690 A-C haplotypes were associated with the status of treatment resistance. Additionally, rs7569963 GG genotype was positively associated with remission. No further significant associations were observed., Limitations: Limitations of the present study include a relatively small sample size and the incomplete ascertainment of data which could influence the outcome., Conclusions: Our results preliminary suggest that some genetic polymorphisms in CREB1 could be associated to treatment resistance. Although such finding needs to be replicated in larger samples, it increases current knowledge about the genetic predictors of response to antidepressants that will probably lead to enhance treatment outcomes by addressing each individual to the most appropriate treatment strategy in the early stages of treatment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objectives: Dystrobrevin binding protein 1 (Dysbindin) is a plausible candidate gene for major depressive disorders (MDD) due to its involvement in synaptic signaling, plasticity and localization in the brain., Methods: Two intronic SNPs of DTNBP1; rs760761 (P1320) and rs2619522 (P1763) were analyzed in 206 patients with DSM-IV MDD to investigate the functional impact of genotypes on susceptibility for depression and some clinical phenotypes. The Sequenom iPLEX assay (Sequenom, Cambridge, MA) was used for genotyping., Results and Conclusions: Despite the limited power of analysis, our results showed that these two SNPs in DTNPB1 gene were not related to clinical phenotypes such as melancholia, age at onset, suicidality and co-morbid anxiety disorders, as well as to treatment response phenotypes.

This study is the first investigation to identify clinical factors associated with treatment resistance in bipolar depression (TRBD). TRBD is defined as failure to respond to at least two consecutive adequate antidepressant trials. The primary objective of this European Multicenter Study was to identify specific clinical and demographic factors associated with TRBD in a sample of bipolar patients treated for a major depressive episode. A total of 261 bipolar patients with major depressive episode were included in the analysis. Among them, 162 patients were considered as responders to treatment and the remaining 99 patients were considered as treatment resistant with a 17-item Hamilton Rating Scale for Depression Score remaining superior or equal to 17 after two consecutive adequate antidepressant trials. Cox regression analysis was used to examine the association between individual clinical variables and TRBD. We found four clinical variables to be significantly associated with TRBD: melancholia [P=0.01, odds ratio (OR)=2.4], comorbidity with social phobia (P=0.02, OR=2.3), current suicidal risk (P=0.02, OR=1.8) and severe intensity of current depressive episode (P=0.01, OR=1.8). Our findings identify four clinical variables associated with TRBD, which could be further investigated in controlled prospective trials.

Catechol-O-methyltransferase (COMT) has been suggested to be involved in the pathogenesis and pharmacological treatment of affective disorders. The nonsynonymous single nucleotide polymorphism (SNP) in exon 4 (Val108/158Met; rs4680) influences the COMT enzyme activity. Inconsistent results were found between Val158Met polymorphism (rs4680) and treatment response phenotypes in genetic association studies. However, the haplotype combinations of alleles at the Val108/158Met SNP with the other synonymous SNPs in the COMT gene region have shown association between enzyme activity/amount and COMT-dependent phenotypes. We carried out this study to define the functional impact of COMT genotypes/haplotypes on susceptibility and on treatment response phenotypes of major depressive disorder (MDD). Three hundred and ninety-six patients with MDD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [(DSM)-IV] and 295 healthy controls were recruited for this study and genotyped for the seven COMT SNPs (rs2075507, rs737865, rs6269, rs4633, rs4818, rs4680, and rs165599). This is the first study with all these SNPs to investigate for MDD and treatment response phenotypes. Our results show that none of the seven SNPs, including the rs4680, was significantly associated with MDD after permutation correction in single SNP analyses. Although several haplotype combinations showed significance, the combinations of G-T-G-G haplotype for rs6269, rs4633, rs4818 and rs4680 were only present in the MDD group (G-T 4.5%, corrected sim P=0.0001; G-T-G 3.87%, corrected sim P=0.001; G-T-G-G 3.3% corrected sim P=0.0025). In the treatment response phenotypes, the GG genotype of the rs2075507 SNP (located in the promoter region of MB-COMT) was less common in resistant patients in a single SNP analysis with low corrected sim P=0.052 and power=0.086. However, in the haplotype analysis, the haplotypes of exonic SNPs, rs4633, rs4818, and rs4680, were related to the treatment response phenotypes investigated, especially the phenotype of the response to antidepressant treatment. The C-C-A haplotype of these SNPs was overrepresented (almost four-and eight-fold) in the responders compared with the nonresponders and controls, respectively, after Bonferroni correction (corrected sim P=0.048, 0.0001, respectively). Both nonsynonymous and synonymous SNPs within haplotypes may be more relevant than the single SNP in conferring MDD susceptibility and treatment response phenotypes. Despite the limited power of our analysis, this finding suggests that the polymorphic COMT gene that influences catecholaminergic neurotransmission may play a role in the individual response to antidepressants.

The 5HT2A (5HTR2A) and 5HT1A receptor (5HTR1A) genes are plausible candidate genes for major depressive disorders. Two single nucleotide polymorphisms, the rs7997012 in 5HTR2A and the -1019C/G in 5HTR1A, were analyzed in 206 patients with Diagnostic and Statistical Manual of Mental Disorders, fourth edition major depressive disorder. Patients were retrospectively characterized for clinical response to antidepressant treatment. We found a significant difference in the rs7997012 allele frequency between resistant and nonresistant patients. However, following the Bonferroni correction we could not find any association between this single nucleotide polymorphism and treatment resistance phenotype. Nevertheless, given the limited power of our analysis, we are not able to conclude that these results reflect a lack of association. Additional studies are needed to confirm or to disprove our result.

Cytochrome P450 genes are involved in the metabolism of antidepressants and could influence treatment response. The aim of this study was to investigate the role of allelic variations of the cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes in antidepressant treatment response and remission rates. Two hundred and seventy-eight patients affected by major depression, responders (N = 81) and nonresponders (N=197) to at least one adequate antidepressant treatment, were recruited with a multicentre design for resistant depression and genotyped for all relevant variations. None of the considered metabolic profiles (e.g. poor, intermediate, extensive and ultrarapid metabolizers) was found to be associated with either response or remission rates. In conclusion, the investigated cytochrome genes do not seem to play a major role in antidepressant response in the present sample of depressive patients. Nevertheless, methodological and sample size limitations of this study do not allow definitive conclusions.

Objectives: Very few studies have investigated clinical features associated with treatment-resistant depression (TRD) defined as failure of at least 2 consecutive antidepressant trials. The primary objective of this multicenter study was to identify specific clinical and demographic factors associated with TRD in a large sample of patients with major depressive episodes that failed to reach response or remission after at least 2 consecutive adequate antidepressant treatments., Method: A total of 702 patients with DSM-IV major depressive disorder, recruited from January 2000 to February 2004, were included in the analysis. Among them, 346 patients were considered as nonresistant. The remaining 356 patients were considered as resistant, with a 17-item Hamilton Rating Scale for Depression score remaining greater than or equal to 17 after 2 consecutive adequate antidepressant trials. Cox regression models were used to examine the association between individual clinical variables and TRD., Results: Among the clinical features investigated, 11 variables were found to be associated with TRD. We found anxiety comorbidity (p < .001, odds ratio [OR] = 2.6), comorbid panic disorder (p < .001, OR = 3.2) and social phobia (p = .008, OR = 2.1), personality disorder (p = .049, OR = 1.7), suicidal risk (p = .001, OR = 2.2), severity (p = .001, OR = 1.7), melancholia (p = .018, OR = 1.5), a number of hospitalizations > 1 (p = .003, OR = 1.6), recurrent episodes (p = .009, OR = 1.5), early age at onset (p = .009, OR = 2.0), and nonresponse to the first antidepressant received lifetime (p = .019, OR = 1.6) to be the factors associated with TRD., Conclusions: Our findings provide a set of 11 relevant clinical variables associated with treatment resistance in major depressive disorder that can be explored at the clinical level. The statistical model used in this analysis allowed for a hierarchy of these variables (based on the OR) showing that comorbid anxiety disorder is the most powerful clinical factor associated with TRD.

The possible association between phospholipase A2 gene and bipolar mood disorder was examined in 557 bipolar patients and 725 controls (all personally interviewed), recruited from seven countries (Belgium, Bulgaria, Croatia, Germany, Greece, Italy, and UK). The frequencies of the eight alleles that were identified did not differ between patients and control individuals in the whole population, while the power to detect an association based on our sample was relatively high. Some differences were noted among the various ethnic groups, but no significant trends existed, suggesting that population stratification by country may not be responsible for a type II error. On the basis of these results, mutations of the phospholipase A2 gene, at least in the region close to the polymorphism examined between exons 1 and 2, are not involved in the pathogenesis of bipolar mood disorder.

In the search of genes potentially implicated in the aetiology of affective disorders (AD), SUBSTANCE P (SP) pathway is receiving increased interest. SP receptor antagonists, such as MK-869 and L-759274, have been shown to have antidepressant effect. Results from preclinical and human studies implicate SP and its pathway in the pathophysiology of mood disorders. We investigated a possible association between 20 single nucleotide polymorphisms (SNPS) among four SP-related genes and unipolar and bipolar ad (UPAD and BPAD) in a first sample of 92 UPAD patients and 92 control individuals and in a replication sample of 92 UPAD patients and 92 control individuals. An additional sample of 113 BPAD patients has also been ascertained. Our results showed a significant association between the angiotensin-converting enzyme gene (ACE1) and UPAD in our first sample, but not in the replication sample. No significant evidence of association was found in other SP-related genes. We did not find any association in the BPAD sample. When pooling first and replication UPAD samples, an association was found between ACE1 and a subgroup of patients remaining depressed after an adequate antidepressant treatment. In conclusion, our findings do not support a major contribution of SP-related genes in UPAD and BPAD, but provides some evidence of an ace influence in treatment response to antidepressants.

Controversial evidence exists regarding the presence of the phenomenon of anticipation in affective disorder. To further evaluate this hypothesis on the unipolar pattern of the disease, we examined 21 two-generation pairs of first and second degree relatives with unipolar recurrent major depression. Biases from index-patient and from unaffected sibs were taken into consideration. A significant difference in the age at onset and episode frequency (as measure of disease severity) between parental and offspring generation was observed. The median age at onset of the parental generation was 37+/-8.2 years compared to 22+/-8.3 years in the offspring generation (p=0.001). The offspring generation also experienced an episode frequency two times greater than the parent generation (p=0.001). Anticipation was demonstrated in 95% of pairs regarding age at onset and in 84% of pairs in episode frequency. However, the observation of a birth cohort effect may possibly explain the differences in age at onset between generations in our sample.

Several lines of evidence have suggested an implication of brain-derived neurotrophic factor (BDNF) in unipolar affective disorder (UPAD). In the present study, we investigated the role of BDNF gene in UPAD in two independent samples of 92 patients/92 controls and 156 patients/197 controls. Two single nucleotide polymorphisms (SNPs) were investigated. We found no significant differences of BDNF gene SNPs distribution between UPAD patients and controls in both samples. Haplotype analyses were performed on both samples. A statistical difference was found between cases and controls in the first sample but not in the second. These results are not in favour of an implication of BDNF in UPAD but need to be replicated before final conclusion.

The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.