Temporal controls over inter-areal cortical projection neuron fate diversity.

Interconnectivity between neocortical areas is critical for sensory integration and sensorimotor transformations1-6. These functions are mediated by heterogeneous inter-areal cortical projection neurons (ICPN), which send axon branches across cortical areas as well as to subcortical targets7-9. Although ICPN are anatomically diverse10-14, they are molecularly homogeneous15, and how the diversity of their anatomical and functional features emerge during development remains largely unknown. Here we address this question by linking the connectome and transcriptome in developing single ICPN of the mouse neocortex using a combination of multiplexed analysis of projections by sequencing16,17 (MAPseq, to identify single-neuron axonal projections) and single-cell RNA sequencing (to identify corresponding gene expression). Focusing on neurons of the primary somatosensory cortex (S1), we reveal a protracted unfolding of the molecular and functional differentiation of motor cortex-projecting ([Formula: see text]) ICPN compared with secondary somatosensory cortex-projecting ([Formula: see text]) ICPN. We identify SOX11 as a temporally differentially expressed transcription factor in [Formula: see text] versus [Formula: see text] ICPN. Postnatal manipulation of SOX11 expression in S1 impaired sensorimotor connectivity and disrupted selective exploratory behaviours in mice. Together, our results reveal that within a single cortical area, different subtypes of ICPN have distinct postnatal paces of molecular differentiation, which are subsequently reflected in distinct circuit connectivities and functions. Dynamic differences in the expression levels of a largely generic set of genes, rather than fundamental differences in the identity of developmental genetic programs, may thus account for the emergence of intra-type diversity in cortical neurons.

Developmental emergence of cortical neurogliaform cell diversity.

GABAergic interneurons are key regulators of cortical circuit function. Among the dozens of reported transcriptionally distinct subtypes of cortical interneurons, neurogliaform cells (NGCs) are unique: they are recruited by long-range excitatory inputs, are a source of slow cortical inhibition and are able to modulate the activity of large neuronal populations. Despite their functional relevance, the developmental emergence and diversity of NGCs remains unclear. Here, by combining single-cell transcriptomics, genetic fate mapping, and electrophysiological and morphological characterization, we reveal that discrete molecular subtypes of NGCs, with distinctive anatomical and molecular profiles, populate the mouse neocortex. Furthermore, we show that NGC subtypes emerge gradually through development, as incipient discriminant molecular signatures are apparent in preoptic area (POA)-born NGC precursors. By identifying NGC developmentally conserved transcriptional programs, we report that the transcription factor Tox2 constitutes an identity hallmark across NGC subtypes. Using CRISPR-Cas9-mediated genetic loss of function, we show that Tox2 is essential for NGC development: POA-born cells lacking Tox2 fail to differentiate into NGCs. Together, these results reveal that NGCs are born from a spatially restricted pool of Tox2+ POA precursors, after which intra-type diverging molecular programs are gradually acquired post-mitotically and result in functionally and molecularly discrete NGC cortical subtypes.

Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach.

BACKGROUND: Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. AIMS: To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. METHOD: This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. RESULTS: The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. CONCLUSIONS: Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

Increased Reactivity of the Mesolimbic Reward System after Ketamine Injection in Patients with Treatment-resistant Major Depressive Disorder.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: The antidepressant effect of ketamine is associated with increased activity in the reward circuitry of the brain and a suppression of circuitry that mediates perceptual processing of negative emotions. The duration of ketamine effect on these brain structures remains to be defined. WHAT THIS ARTICLE TELLS US THAT IS NEW: As expected, ketamine administration led to an improvement in mood and global vigilance. The improvement in mood was accompanied by an increased recruitment of the orbitofrontal cortex, ventral striatum, medial substantial nigra and ventral tegmental area, structures that are part of the reward circuitry.Responses in the mesolimbic structures (amygdala, medial substantial nigra and ventral tegmental area, orbitofrontal cortex) to negative stimuli were decreased after ketamine administration.The data are consistent with the premise that ketamine induces sustained changes in the mesolimbic neural circuits to reset pathological reward and emotional processing. BACKGROUND: Ketamine rapidly improves maladaptive mood states in major depressive disorder, and some of the neural substrates underlying this therapeutic effect have been identified. This study aimed to identify functional changes within neural networks that may underlie the impact of ketamine on both reward and emotional processing in patients with treatment-resistant major depression. METHODS: Ten adult patients with a Montgomery-Åsberg Depression Rating Scale score above 25 were enrolled to receive a single intravenous administration of ketamine (0.5 mg/kg). Patients' performance along with related neural network activations were analyzed in a game-like reward task and in an emotional judgment task using functional magnetic resonance imaging 1 day before and 1 and 7 days after ketamine administration. RESULTS: A significant correlation (R = 0.46, P = 0.03) between the improvement of depression scores and the enhanced reaction time for positive items was found in the game-like reward task 1 day after ketamine administration. This enhanced sensitivity for rewarded items was accompanied by increased activity of reward-related brain regions, including the orbitofrontal cortex, ventral striatum, and the ventral tegmental area, an effect that persisted up to 1 week after ketamine injection. In the emotional judgment task, it was found that ketamine rapidly modified local brain activities in response to emotionally negative, positive, or neutral stimuli in the amygdala, insula, anterior cingulate cortex, and in the ventral tegmental area. CONCLUSIONS: Single bolus ketamine administration rapidly triggers lasting changes in mesolimbic neural networks to improve pathologic reward and emotional processing in patients with major depressive disorder.

Psychiatric disorders among offspring of patients with Bipolar and Borderline Personality Disorder.

OBJECTIVE: As part of a larger study investigating biological risk factors for bipolar disorder (BD) and borderline personality disorder (BPD), we investigated the prevalence of psychiatric diagnoses presented by young BD or BPD offspring. With respect to the scarcity of studies interested in psychiatric disorders among BPD offspring, we have chosen to report these results despite the small sample size for a prevalence study. METHOD: We recruited 21 BD and 22 BPD offspring and 23 control subjects. All subjects were assessed with a structured interview. RESULTS: Our main finding suggests that BPD offspring present a higher rate of psychiatric disorders compared to BD offspring. Attention deficit and hyperactivity disorder was the most prevalent disorder. CONCLUSION: Our results contribute to the evidence that offspring of patients with BPD, are at high risk with regard to their mental health and deserve both more research and special attention at the clinical level.

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Efficacy and Safety of a Rapid Intravenous Injection of Ketamine 0.5 mg/kg in Treatment-Resistant Major Depression: An Open 4-Week Longitudinal Study.

BACKGROUND: Ketamine has been documented for its rapid antidepressant effects. However, optimal dose and delivery route have not yet been thoroughly investigated. The objectives of this study were to document the safety and test the antidepressant and antisuicidal effects of a single rapid 1-minute injection of ketamine 0.5 mg/kg in treatment-resistant depression (TRD). METHODS: Ten patients with TRD were included in an open, noncontrolled 4-week study and received a rapid intravenous dose of ketamine 0.5 mg/kg. Main outcome measure was the Montgomery-Åsberg Depression Rating Scale and suicidality was assessed using the Scale for Suicide Ideation. RESULTS: Rapid injection of ketamine elicited transient increase of blood pressure and altered states of consciousness in all patients and mild psychotomimetic effects in 4 patients, which all resolved without any intervention. Decrease of depression severity was observed from 40-minute postinjection until day 15. Eight patients became responders within 1 day and all were nonresponders after 4 weeks. The decrease of suicidal ideation was significant until day 7. Analysis indicated that higher severity of depression and anxiety at baseline predicted a larger Montgomery-Åsberg Depression Rating Scale decrease after 4 weeks. CONCLUSIONS: This study suggests that in well-controlled medical settings with adequate monitoring, a single rapid 1-minute injection of ketamine 0.5 mg/kg can be well tolerated and is efficacious in rapidly reducing depression symptoms and suicidal thoughts in outpatients with TRD. These findings are relevant to the practice of general clinical psychiatry and emergency departments were ketamine can have a place in acute management of TRD. Larger studies are necessary to confirm these results.

Transient Cell-intrinsic Activity Regulates the Migration and Laminar Positioning of Cortical Projection Neurons.

Neocortical microcircuits are built during development and require the coordinated assembly of excitatory glutamatergic projection neurons (PNs) into functional networks. Neuronal migration is an essential step in this process. In addition to cell-intrinsic mechanisms, external cues including neurotransmitters regulate cortical neuron migration, suggesting that early activity could influence this process. Here, we aimed to investigate the role of cell-intrinsic activity in migrating PNs in vivo using a designer receptor exclusively activated by a designer drug (DREADD) chemogenetic approach. In utero electroporation was used to specifically express the human M3 muscarinic cholinergic Gq-coupled receptor (hM3Dq) in PNs and calcium activity, migratory dynamics, gene expression, and laminar positioning of PNs were assessed following embryonic DREADD activation. We found that transient embryonic DREADD activation induced premature branching and transcriptional changes in migrating PNs leading to a persistent laminar mispositioning of superficial layer PNs into deep cortical layers without affecting expression of layer-specific molecular identity markers. In addition, live imaging approaches indicated that embryonic DREADD activation increased calcium transients in migrating PNs and altered their migratory dynamics by increasing their pausing time. Taken together, these results support the idea that increased cell-intrinsic activity during migration acts as a stop signal for migrating cortical PNs.

Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism.

The formation of a laminar structure such as the mammalian neocortex relies on the coordinated migration of different subtypes of excitatory pyramidal neurons in specific layers. Cyclin-dependent kinase 5 (Cdk5) is a master regulator of pyramidal neuron migration. Recently, we have shown that Cdk5 binds to the serotonin 6 receptor (5-HT6R), a G protein-coupled receptor (GPCR). Here, we investigated the role of 5-HT6R in the positioning and migration of pyramidal neurons during mouse corticogenesis. We report that constitutive expression of 5-HT6R controls pyramidal neuron migration through an agonist-independent mechanism that requires Cdk5 activity. These data provide the first in vivo evidence of a role for constitutive activity at a GPCR in neocortical radial migration.

Effects of interpersonal violence-related post-traumatic stress disorder (PTSD) on mother and child diurnal cortisol rhythm and cortisol reactivity to a laboratory stressor involving separation.

Women who have experienced interpersonal violence (IPV) are at a higher risk to develop posttraumatic stress disorder (PTSD), with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired social behavior. Previously, we had reported impaired maternal sensitivity and increased difficulty in identifying emotions (i.e. alexithymia) among IPV-PTSD mothers. One of the aims of the present study was to examine maternal IPV-PTSD salivary cortisol levels diurnally and reactive to their child's distress in relation to maternal alexithymia. Given that mother-child interaction during infancy and early childhood has important long-term consequences on the stress response system, toddlers' cortisol levels were assessed during the day and in response to a laboratory stressor. Mothers collected their own and their 12-48month-old toddlers' salivary samples at home three times: 30min after waking up, between 2-3pm and at bedtime. Moreover, mother-child dyads participated in a 120-min laboratory session, consisting of 3 phases: baseline, stress situation (involving mother-child separation and exposure to novelty) and a 60-min regulation phase. Compared to non-PTSD controls, IPV-PTSD mothers - but not their toddlers, had lower morning cortisol and higher bedtime cortisol levels. As expected, IPV-PTSD mothers and their children showed blunted cortisol reactivity to the laboratory stressor. Maternal cortisol levels were negatively correlated to difficulty in identifying emotions. Our data highlights PTSD-IPV-related alterations in the HPA system and its relevance to maternal behavior. Toddlers of IPV-PTSD mothers also showed an altered pattern of cortisol reactivity to stress that potentially may predispose them to later psychological disorders.

Insomnia in adult attention-deficit/hyperactivity disorder: A comparison with borderline personality disorder population in a clinical setting and control participants.

OBJECTIVES: Many adults with attention-deficit/hyperactivity disorder (ADHD) report sleeping difficulties. The relationship between sleep and ADHD is poorly understood, and shows discrepancies between subjective and objective measures. In order to determine the specificity of sleep-associated symptoms in ADHD, subjective sleep assessments among ADHD adult patients were compared with control subjects and with individuals suffering from borderline personality disorder (BPD). METHODS: 129 outpatients with ADHD, 70 with BPD (including 17 patients with BPD and ADHD comorbidity), and 65 control participants were assessed for sleep quality, insomnia, and sleepiness, using the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), and the Epworth Sleepiness Scale (ESS). RESULTS: ADHD- and BPD-sufferers achieved higher insomnia and lower sleep quality scores than control subjects. Clinical groups did not differ in terms of sleep quality, although insomnia was more severe among BPD patients. Depression scores explained most of sleep symptoms, but even when controlling for depression, ADHD sufferers showed higher sleep latency. Inattentive symptoms were associated with somnolence, while hyperactive/impulsive symptoms were associated with insomnia and lower sleep efficiency. CONCLUSION: Sleep-related symptoms associated with ADHD were partly explained by non-specific factors, especially depression symptoms. In a dimensional perspective, hyperactive and inattentive symptoms were associated with specific sleep symptoms.

METHYLATION OF SEROTONIN RECEPTOR 3A IN ADHD, BORDERLINE PERSONALITY, AND BIPOLAR DISORDERS: LINK WITH SEVERITY OF THE DISORDERS AND CHILDHOOD MALTREATMENT.

BACKGROUND: Serotonin 3A receptor (5-HT3A R) is associated at the genetic and epigenetic levels with a variety of psychiatric disorders and interacts with early-life stress such as childhood maltreatment. We studied the impact of childhood maltreatment on the methylation status of the 5-HT3A R and its association with clinical severity outcomes in relation with a functional genetic polymorphism. METHODS: Clinical severity indexes of 346 bipolar, borderline personality, and adult attention deficit hyperactivity disorders patients were tested for association with the DNA methylation status of eight 5-HT3A R gene CpGs. Relationship between the functional variant rs1062613 (C > T) and methylation status on severity of the disorders were also assessed. RESULTS: Childhood maltreatment was associated with higher severity of the disease (higher number of mood episodes, history of suicide attempts, hospitalization, and younger age at onset) across disorders and within each individual disorder. This effect was mediated by two 5-HT3A R CpGs. Compared to T allele carriers, CC carriers had higher methylation status at one CpG located 1 bp upstream of this variant. CONCLUSIONS: This study shows that epigenetic modification of the 5-HT3A R is involved in the mechanism underlying the relationship between maltreatment in childhood and the severity of several psychiatric disorders in adulthood.

CBT/DBT skills training for adults with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is associated with marked impairments in familial, social, and professional functioning. Although stimulant treatments can be effective in adult ADHD, some patients will respond poorly or not at all to medication. Previous studies demonstrated that cognitive behavioural therapy- (CBT) and dialectical behavior therapy- (DBT) oriented interventions are effective in reducing the burden of the disease, which is mainly marked by depression, interpersonal difficulties, low self-esteem, and low quality of life. In order to determine the effectiveness of this intervention, we assessed the benefits of a CBT/DBT programme to reduce residual symptoms and help patients improve their quality of life. SUBJECTS AND METHODS: 49 ADHD-patients, poor responders to medication, were enrolled in a one-year programme where they received individual therapy, associated with weekly sessions of group therapy with different modules: Mindfulness, Emotion Regulation, Interpersonal Effectiveness and Distress Tolerance, Impulsivity/Hyperactivity and Attention. Each subject was assessed at baseline, at months 3 and 6, and at the end of the treatment for ADHD severity (ASRS v1.1), depression severity (BDI-II), hopelessness (BHS), mindfulness skills (KIMS), anger expression and control (STAXI), impulsivity (BIS-11), quality of life (WHOQOL-BREF), and social functioning (QFS). The 49 ADHD patients were compared with 13 ADHD subjects on a waiting list. Linear mixed models were used to measure response to treatment. RESULTS: Overall, the psychotherapeutic treatment was associated with significant improvements in almost all dimensions. The most significant changes were observed for BDI-II (b=-0.30; p<0.0001), ASRS total score (b=-0.16; p<0.0001), and KIMS AwA (b=0.21; p<0.0001), with moderate to large effect sizes. Compared with the waiting list controls, ADHD patients showed a better, albeit non-significant, pattern of response. CONCLUSIONS: Individual and structured psycho-educational DBT/CBT groups support existing data suggesting that a structured psychotherapeutic approach is useful for patients who respond partially or not at all to drug therapy.

Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder.

BACKGROUND: Early-life adversities represent risk factors for the development of bipolar affective disorder and are associated with higher severity of the disorder. This may be the consequence of a sustained alteration of the hypothalamic-pituitary-adrenal (HPA) axis resulting from epigenetic modifications of the gene coding for the glucocorticoid receptor (NR3C1). AIMS: To investigate whether severity of childhood maltreatment is associated with increased methylation of the exon 1F NR3C1 promoter in bipolar disorder. METHOD: A sample of people with bipolar disorder (n = 99) were assessed for childhood traumatic experiences. The percentage of NR3C1 methylation was measured for each participant. RESULTS: The higher the number of trauma events, the higher was the percentage of NR3C1 methylation (ß = 0.52, 95% CI 0.46-0.59, P<<0.0001). The severity of each type of maltreatment (sexual, physical and emotional) was also associated with NR3C1 methylation status. CONCLUSIONS: Early-life adversities have a sustained effect on the HPA axis through epigenetic processes and this effect may be measured in peripheral blood. This enduring biological impact of early trauma may alter the development of the brain and lead to adult psychopathological disorder.

Subjective experience of thought overactivation in mood disorders: beyond racing and crowded thoughts.

BACKGROUND: Racing thoughts, crowded thoughts and flight of ideas are frequent symptoms in mood disorders, but the underlying subjective experience of overactivation of thought processes remains poorly documented. METHODS: Qualitative analysis of audiotaped interviews explored subjective experience of thought overactivation in patients with mood disorders (sample 1, n = 45). Quantitative analysis considered the properties of a newly developed rating scale in sample 1, in an additional sample of patients with mood disorders (sample 2, n = 37) and in healthy subjects (sample 3, n = 38). RESULTS: Qualitative analysis of individual interviews revealed that 5 conceptual categories characterized thought overactivation: sequential thought flow, overstimulation, competition for resource allocation, unexpected/unexplained onset, and association with mood and emotions. A principal component analysis of the initial 16-item rating scale indicated that a single component explained 55.9% of the variance, with major and exclusive contributions from 9 items, which were retained in the final 9-item Subjective Thought Overactivation Questionnaire (STOQ; Cronbach's α = 0.95). Total score correlated significantly with activation, depression and perceived conflict subscales of the Internal State Scale (ISS; rs = 0.57-0.66, p < 0.001). It was associated with decreased well-being (ISS; rs = -0.48, p = 0.001) and increased state anxiety (State-Trait Anxiety Inventory; rs = 0.60, p < 0.001). The STOQ score was significantly higher in patients than in healthy subjects. It allowed distinguishing between ISS mood states, with the highest median score in mixed states. LIMITATIONS: Sample size, representativeness, possible bias in qualitative analysis, and quality of expert consensus. CONCLUSIONS: Qualitative analysis of clinical interviews, together with a new short rating scale, contributed to a documentation of subjective thought overactivation, an important but often undetected feature in mood disorders.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.