Spectrum Of Psychiatric Disorders Research Articles

Genetic architecture distinguishes tinnitus from hearing loss

Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries. GWAS in 596,905 Million Veteran Program subjects identified 39 tinnitus loci, and identified genes related to neuronal synapses and cochlear structural support. Applying state-of-the-art analytic tools, we confirm a large number of shared variants, but also a distinct genetic architecture of tinnitus, with higher polygenicity and large proportion of variants not shared with hearing difficulty. Tissue-expression analysis for tinnitus infers broad enrichment across most brain tissues, in contrast to hearing difficulty. Finally, tinnitus is not only correlated with hearing loss, but also with a spectrum of psychiatric disorders, providing potential new avenues for treatment. This study establishes tinnitus as a distinct disorder separate from hearing difficulties.

The developmental interplay between the p-factor of psychopathology and the g-factor of intelligence from age 7 through 16 years.

Intelligence and mental health are the core pillars of individual adaptation, growth, and opportunity. Here, we charted across childhood and adolescence the developmental interplay between the p-factor of psychopathology, which captures the experience of symptoms across the spectrum of psychiatric disorders, and the g-factor of general intelligence that describes the ability to think, reason, and learn.Our preregistered analyses included 7,433 twin pairs from the Twins Early Development Study (TEDS), who were born 1994 to 1996 in England and Wales. At the ages 7, 9, 12, and 16 years, the twins completed two to four intelligence tests, and multi-informant measures (i.e., self-, parent- and teacher-rated) of psychopathology were collected.Independent of their cross-sectional correlations, p- and g-factors were linked by consistent, bidirectional, and negative cross-lagged paths across childhood and adolescence (from -.07 to -.13 with 95% CIs from -.03 to -.15). The cross-lagged paths from intelligence to psychopathology were largely due to genetic influences, but the paths from psychopathology to intelligence were driven by environmental factors, and increasingly so with age.Our findings suggest that intelligence and psychopathology are developmentally intertwined due to fluctuating etiological processes. Understanding the interplay of g- and p-factors is key for improving children's developmental outcomes.

Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders

Prenatal antiseizure medication (ASM) exposure has been associated with adverse early neurodevelopment, but associations with a wider range of psychiatric end points have not been studied. To examine the association between prenatal exposure to ASM with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy. This prospective, population-based register study assessed 4 546 605 singleton children born alive in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Of the 4 546 605 children, 54 953 with chromosomal disorders or uncertain birth characteristics were excluded, and 38 661 children of mothers with epilepsy were identified. Data analysis was performed from August 2021 to January 2023. Prenatal exposure to ASM was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth. The main outcome measure was diagnosis of psychiatric disorders (a combined end point and 13 individual disorders). Estimated adjusted hazard ratios (aHRs) using Cox proportional hazards regression and cumulative incidences with 95% CIs are reported. Among the 38 661 children of mothers with epilepsy (16 458 [42.6%] exposed to ASM; 19 582 [51.3%] male; mean [SD] age at the end of study, 7.5 [4.6] years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric end point (aHR, 1.80 [95% CI, 1.60-2.03]; cumulative risk at 18 years in ASM-exposed children, 42.1% [95% CI, 38.2%-45.8%]; cumulative risk at 18 years in unexposed children, 31.3% [95% CI, 28.9%-33.6%]), which was driven mainly by disorders within the neurodevelopmental spectrum. Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders, whereas associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38; 95% CI, 1.40-4.06) and exposure to levetiracetam with anxiety (aHR, 2.17; 95% CI, 1.26-3.72) and attention-deficit/hyperactivity disorder (aHR, 1.78; 95% CI, 1.03-3.07). Findings from this explorative study strengthen the evidence for the warning against the use of valproate in pregnancy and raise concern of risks of specific psychiatric disorders associated with topiramate and levetiracetam. This study provides reassuring evidence that lamotrigine, carbamazepine, and oxcarbazepine are not associated with long-term behavioral or developmental disorders but cannot rule out risks with higher doses.

Criminal behaviors and substance abuse in psychiatric patients

IntroductionPeople with mental illness are overrepresented throughout the criminal justice system. In Italy, an ongoing process of deinstitutionalization has been enacted: the Judicial Psychiatric Hospitals are now on the edge of their closure in favor of small-scale therapeutic facilities (Residenze per l’Esecuzione delle Misure di Sicurezza - REMS). Law 81/2014 prescribes that a patient cannot stay in a REMS for a period longer than a prison sentence for the same index offense. Therefore, when patients end their duty for criminal behaviors, their clinical management moves back to outpatient psychiatric centers. Elevated risks of violent behavior are not equally shared across the spectrum of psychiatric disorders. In the past several years, multiple studies in the field of forensic psychiatry confirmed a close relationship between violent offenders and comorbid substance abuse.ObjectivesIn order to broaden the research in this area, we analyzed sociodemographic, clinical and forensic variables of a group of psychiatric patients with a history of criminal behaviors, attending an outpatient psychiatric service in Milan, with a focus on substance abuse.MethodsThis is a cross-sectional single center study, conducted in 2020. Seventy-six subjects with a history of criminal behaviors aged 18 years or more and attending an outpatient psychiatric service were included. Demographic and clinical variables collected during clinical interviews with patients were retrospectively retrieved from patients’ medical records. Appropriate statistical analyses for categorical and continuous variables were conducted.ResultsData were available for 76 patients, 51,3% of them had lifetime substance abuse. Lifetime substance abuse was significantly more common in patients with long-acting injectable antipsychotics therapy, >3 psychiatric hospitalizations, history of previous crimes and economic crime (Table 1). Additionally, this last potential correlation was confirmed by logistic regression.Table 1.Lifetime substance abusers (N=39)Non-lifetime substance abusers (N=37)Proportion DifferenceP-valueN%N%Depot administrationYes11(28,9%)0(0%)28,9%0,02HospitalizationsFour or more25(64,1%)5(33,3%)30,8%0,04Economic crimeYes15(40,5%)1(6,7%)33,8%0,02Previous crimesYes17(51,4%)2(13,3%)38,1%0,02ConclusionsData emerging from this survey provide new information about offenders in an Italian mental health service with a focus on lifetime substance abuse in these patients. Our preliminary results should be confirmed in larger sample sizes.Disclosure of InterestNone Declared

Reproductive Safety of Lurasidone and Quetiapine: Update from the National Pregnancy Registry for Psychiatric Medications.

Background: Second-generation antipsychotics (SGAs), also called atypical antipsychotics, are common therapies for women with a spectrum of psychiatric disorders. No systematically ascertained human reproductive safety data are available for lurasidone, and prospective data for quetiapine are limited, making decisions regarding use of these medications during pregnancy complicated. Materials and Methods: The National Pregnancy Registry for Psychiatric Medications is a prospective cohort study designed to collect reproductive safety data relative to SGAs. Pregnant women aged 18-45 years, with psychiatric illness and prenatal psychotropic medication exposure completed three phone interviews during pregnancy and the postpartum period. Cases of presumed malformations are abstracted from medical records for adjudication by a teratologist blinded to medication exposure. Results: Of 2,293 women enrolled at the time of analysis, 134 in the lurasidone group, 264 in the quetiapine group, and 886 controls completed the postpartum interview and were therefore eligible for inclusion. Dropped or lost-to-follow-up participants (13%) and those currently pregnant were excluded. Participants were predominantly White, college-educated, and married (lurasidone = 88.1%, 76.9%, 77.6%; quetiapine = 89.8%, 71.2%, 75.0%; controls = 92.7%, 86.7%, 89.1%). Absolute risks of major malformations were 2.19% (lurasidone), 1.85% (quetiapine), and 1.77% (controls). Odds ratios comparing lurasidone and quetiapine with controls were 1.24 (95% confidence interval [CI] = 0.36-4.32) and 1.04 (95% CI = 0.38-2.85), respectively. Conclusions: No specific patterns of malformations were observed in infants exposed to the medications of interest. Lurasidone and quetiapine did not appear to be major teratogens, but further information is needed to refine risk estimates. Food and Drug Administration guidance underscores the importance of pregnancy registries. Clinical trial number: NCT01246765.

Cortical profiles of numerous psychiatric disorders and normal development share a common pattern.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Psychotic-like experiences among university female students in Qatar: A qualitative-phenomenological study.

Background and aimsPsychotic-like experiences (PLEs) are hallucinatory or delusional experiences that fall below the threshold of a diagnosable psychotic disorder. Although PLEs are common across the spectrum of psychiatric disorders, they also have been commonly reported in the general population. In this study, we aimed to describe the types of PLEs experienced by university students in Qatar. Furthermore, we aimed to examine how students frame, explain, and deal with these experiences as well as understand how culture and religion may shape the way students attribute and respond to these experiences.MethodThis study used a qualitative phenomenological approach. For collecting the data, we conducted semi-structured interviews using the Questionnaire for Psychotic Experiences (QPE). The QPE is a valid and reliable tool to assess the phenomenology of psychotic-like experiences. The questionnaire was translated into Arabic and tested and validated in Qatar (a fast-developing Muslim country in the Arabian Peninsula). We conducted interviews in Arabic with 12 undergraduate female students at Qatar University (the only national university in Qatar). The interviewees were of different Arab nationalities. Interviews were transcribed verbatim and two authors conducted the content-thematic analysis separately, as a strategy to validate the findings. The study was part of a larger nationally funded project that was approved by the Qatar University Institutional Review Board. The approvals were granted before any interview was conducted.ResultsThe PLEs were prevalent in our non-clinical sample. The content-thematic analysis revealed the following main themes about these experiences: type, impact on daily function, frequency, immediate reaction, attribution style, assumptions about the root cause of these experiences, other associations, and religious links to experiences. The results also highlighted that religion and culture play a role in shaping the types of hallucinations and some delusions.ConclusionOur findings support the importance of culture and religion in relation to the types and explanations that students provided when describing PLEs. Notably, it was common among those who reported having these experiences to normalize and link PLEs to real-life events. This may be a defense mechanism to protect the self against the stigma of mental illness and from being labeled as “abnormal”.

Web-Based Graphic Representation of the Life Course of Mental Health: Cross-Sectional Study Across the Spectrum of Mood, Anxiety, Eating, and Substance Use Disorders

BackgroundAlthough patient history is essential for informing mental health assessment, diagnosis, and prognosis, there is a dearth of standardized instruments measuring time-dependent factors relevant to psychiatric disorders. Previous research has demonstrated the potential utility of graphical representations, termed life charts, for depicting the complexity of the course of mental illness. However, the implementation of these assessments is limited by the exclusive focus on specific mental illnesses (ie, bipolar disorder) and the lack of intuitive graphical interfaces for data collection and visualization.ObjectiveThis study aimed to develop and test the utility of the Tulsa Life Chart (TLC) as a Web-based, structured approach for obtaining and graphically representing historical information on psychosocial and mental health events relevant across a spectrum of psychiatric disorders.MethodsThe TLC interview was completed at baseline by 499 participants of the Tulsa 1000, a longitudinal study of individuals with depressive, anxiety, substance use, or eating disorders and healthy comparisons (HCs). All data were entered electronically, and a 1-page electronic and interactive graphical representation was developed using the Google Visualization Application Programming Interface. For 8 distinct life epochs (periods of approximately 5-10 years), the TLC assessed the following factors: school attendance, hobbies, jobs, social support, substance use, mental health treatment, family structure changes, negative and positive events, and epoch and event-related mood ratings. We used generalized linear mixed models (GLMMs) to evaluate trajectories of each domain over time and by sex, age, and diagnosis, using case examples and Web-based interactive graphs to visualize data.ResultsGLMM analyses revealed main or interaction effects of epoch and diagnosis for all domains. Epoch by diagnosis interactions were identified for mood ratings and the number of negative-versus-positive events (all P values <.001), with all psychiatric groups reporting worse mood and greater negative-versus-positive events than HCs. These differences were most robust at different epochs, depending on diagnosis. There were also diagnosis and epoch main effects for substance use, mental health treatment received, social support, and hobbies (P<.001). User experience ratings (each on a 1-5 scale) revealed that participants found the TLC pleasant to complete (mean 3.07, SD 1.26) and useful for understanding their mental health (mean 3.07, SD 1.26), and that they were likely to recommend it to others (mean 3.42, SD 0.85).ConclusionsThe TLC provides a structured, Web-based transdiagnostic assessment of psychosocial history relevant for the diagnosis and treatment of psychiatric disorders. Interactive, 1-page graphical representations of the TLC allow for the efficient communication of historical life information that would be useful for clinicians, patients, and family members.

Aberrant resting-state functional networks in depression

Numerous resting-state functional magnetic resonance imaging studies have revealed that major depressive disorder (MDD) is associated with abnormal functional connectivity (FC) within and between large-scale functional networks such as the default mode network (DMN), cognitive control network (CCN) and affective network (AN). Compared with healthy controls, individuals with MDD usually show (i) increased FC within the anterior DMN and decreased FC within the posterior DMN, (ii) decreased FC within the CCN and (iii) increased FC within limbic system and decreased FC in the reward system in the AN. Depression related interactive changes between networks have also been reported: (i) decreased FC between DMN and CCN, (ii) increased FC between DMN and AN, and (iii) decreased FC between CCN and AN. These findings on network interaction may represent impaired resource allocation and information integration in MDD. Major weakness in the present rfMRI studies of depression resides in small sample and lack of multidimensional features. Meanwhile, as several brain disorders may show commonly disrupted functional architectures, depression-related specific alterations are typically lacking. We suggest that future studies may advance by combining multidimensional big data and individualized characterization, as well as examining shared and distinct functional network mechanisms of MDD in the spectrum of psychiatric disorders.

The 5th Summit on Chinese Psychiatric Genetics: Multi–Omics and Spectrum of Psychiatric Disorders

The 5th Summit on Chinese Psychiatric Genetics: Multi–Omics and Spectrum of Psychiatric Disorders

The role of DSCAM in the regulation of synaptic plasticity: possible involvement in neuropsychiatric disorders

Synaptic plasticity simply put, is the activity‑dependent modification of the strength or efficacy of synaptic transmission in the network of synapses in the brain. The role of synaptic plasticity in disease is an active area of research. Changes in plasticity translate to the release of neurotransmitters at the synapse and subsequently, the way humans see the world. It is known that neuropsychiatric disorders such as depression, posttraumatic stress disorder (PTSD), and Alzheimer's disease (AD) are related to pathological changes in dynamic processes in synapses, dialogue between neurons, and finally, changes in overall plasticity. To find a cure for these plasticity related diseases, it is imperative that we understand the precise mechanisms that perturb the homeostatic balance leading to the disease state. The aim of this review is to present what is currently known about DSCAM (Down Syndrome Cell Adhesion Molecule) a protein that is directly connected to pathological changes in synaptic plasticity. The review will present information on DSCAM and how it is connected to glutamate (Glu) and γ‑Aminobutyric acid (GABA) neurotransmission pathways. Finally, the review throws some light on the possible involvement of DSCAM in a spectrum of psychiatric disorders apart from Down syndrome (DS).

The Development and Well-Being Assessment (DAWBA) Screening for Psychiatric Comorbidity in Urban Siberian Adolescents with Functional Gastrointestinal Disorders

Introduction: The Development and Well-Being Assessment (DAWBA) diagnostic tool was developed by R. Goodman et al. [1] as comprehensive semistructured interview for the diagnosis of psychiatric disorders and has been found to been an effective diagnostic tool in clinical and epidemiological settings. Data regarding the DAWBA estimated psychiatric symptoms in Russian adolescents with functional gastrointestinal disorders (FGIDs) are limited. Methods: T69 urban Siberian (Krasnoyarsk, Russia) adolescents aged 12-18 attending a tertiary medical center with recurrent abdominal pain were tested with Questionnaire on Pediatric Gastrointestinal Symptoms Rome III Version (QPGS-RIII) questionnaire. The rates of FGIDs in accordance to QPGS-RIII scoring instructions were as follows: functional dyspepsia (FD) - 15, irritable bowel syndrome (IBS) - 34, abdominal migraine - 8, functional abdominal pain - 12. All of them and 95 healthy matched controls (adolescents without recurrent abdominal pain and headache) completed computer-assisted DAWBA package of interviews. Each of psychiatric disorders was coded on a computer-generated 5-point probability scale. Data are shown as Mean (Mean-SE-Mean+SE) of computer-predicted probability. The Mann-Whitney U test is used to compare differences between groups. Results: Significant positive associations were detected between all FGIDs subgroups and obsessivecompulsive disorder with maximal diagnosis probability in abdominal migraine subgroup (Table 1). At the same time, adolescents with abdominal migraine are more prone to have specific phobia. Posttraumatic stress disorder and generalized anxiety disorder were more characteristic for adolescents with IBS, whereas depressive disorder was more typical for FD subgroup.Table 1: Computer-predicted probability of psychiatric disorder generated by the DAWBA in adolescents with with functional gastrointestinal disordersConclusion: Urban Siberian adolescents with FGIDs have a significantly high prevalence of psychiatric comorbidity. Spectrum of psychiatric disorders may be different in FGIDs subtypes that should be taken into account when evaluating the adolescent's mental health status.

Markedly raised risk of attempted suicide in female immigrants and violent criminality in male immigrants in Denmark

ABSTRACT FROM: Webb RT, Antonsen S, Mok PL, et al . National Cohort Study of Suicidality and Violent Criminality among Danish Immigrants. PLoS ONE 2015;10:e0131915. Immigrant populations in the European...

Mental health among adolescent girls - An effort to know the association of mental disorders with socio-demographic variables

Background: Adolescents constituting 21% of India’s population (Census, 2011) form the major chunk of adolescents in the world. Most mental disorders begin during youth (12–24 years), though they are often first detected later in life. Less described in the literature is the association between common life stressors and a wide range of psychopathology in adolescents especially among late adolescent girls and henceforth this study was conducted to know the extent and spectrum of psychiatric disorders and its association with sociodemographic variables. Objective: (1)To determine the prevalence of mental health disorders among adolescent girls. (2) To determine the association of mental disorders with various sociodemographic variables. Materials and Methods: It was a cross-sectional study conducted in pre-university and Degree Colleges belonging to JSS Mahavidyapeeta in Mysore city. Sample size was estimated to be 683. Adolescent girls between 16 and 19 years were included. The study was conducted from June 2013 to November 2013. Mini International Neuropsychiatric Interview, Version 6.0 was used to diagnose psychiatric morbidity. Data collected were analyzed using SPSS V. 22. Proportions were calculated using Chi-square analysis and regression model was used. Results: Among the 664 adolescent girls, the overall prevalence of mental health disorders was found to be 15.5% with major depressive disorder being the most common disorder amounting to 37% followed by dysthymia (12.3%), panic disorder and social phobia (15.7%), posttraumatic stress disorder (10%), obsessive compulsive disorder (7.8%), and generalized anxiety disorder (6.7%). Age, place of residence, birth order, education of father, education of mother, and socioeconomic status were significantly associated with mental disorders (p < 0.05). Conclusion: High prevalence of mental disorders among adolescent girls necessitates life skill–based education (LSBE) in the regular curriculum, counseling services , mentorship program, and health education at colleges.

Clinical and Demographic Profile of Patients Using a Liaison-Psychiatry Service in a General Hospital Setting in Abeokuta, Nigeria

Objective: A significant proportion of patients seen at the general hospital setting for physical illnesses also suffer from psychiatric disorders. Failure to treat these underlying psychiatric disorders may affect the quality of health care given to such patients.This study was designed to assess the clinical and socio- demographic profile of patients using a consultation liaison- psychiatry service at Sacred Heart Hospital, a general hospital setting in Abeokuta. Method: We conducted a retrospective review of records of all new referral patients who were entered into Aro liaison–psychiatry register for a two year period (January 2009 to December 2010 inclusive). Descriptive statistics was used to report the socio-demographic characteristics of the patients. Chi-square statistics was used to assess association between categorical variables and Independent student- t-test to compare the difference in the means of quantitative variables. P-values of significance were set at p ≤ 0.05. Results: Two hundred and ninety eight patients with complete entries into the register were analyzed. There were 129 (43.3%) males. The mean (SD) age of the patients was 40.6 (15.8) years. A majority of the patients was unemployed (52.7%), and 40.6% were of lower educational status .The proportion of patients who were of unskilled labour was 44.0% and 38.9% were not married. A broad spectrum of psychiatric disorders was represented with depression (23.8%) being the commonest. Among the physical co-morbidities, neurological and cardiovascular conditions were the most reported (28.8%). Conclusion: An adult population with wide spectrum of clinical diagnoses were referred to the consultation liaison psychiatry service during the period under review. There is need for a more integrated, comprehensive and holistic medical care in our health facilities. Future research on the dynamics of this consultation liaison psychiatry service is highly indicated.

Mother-Child Agreement on Behavioral Ratings in Tourette Syndrome

In Tourette syndrome, motor and phonic tics are associated with a spectrum of psychiatric disorders. As proxy report instruments are commonly used to assess children with Tourette syndrome, we investigated the relationship between child and mother ratings of behavioral problems. We enrolled 28 children with Tourette syndrome (25 males; mean age, 13.9 years) and 61 gender- and age-matched healthy controls (55 males; mean age, 14.7 years). Clinicians completed measures of tic severity, and all children completed the Youth Self-Report version of the Child Behavior Checklist, while their mothers completed the Child Behavior Checklist. In the clinical group, Youth Self-Report scores were significantly lower than mothers' Child Behavior Checklist scores across the majority of subscales (especially affect and somatization). In contrast, for the control group, mother and child ratings only differed for the externalizing behavior subscales. Clinicians should be aware of these differences between self and mother ratings for specific behavioral problems in Tourette syndrome.

Tryptophan hydroxylase 2 (TPH2) in a neuronal cell line: modulation by cell differentiation and NRSF/rest activity

Serotonin (5-HT) is a neurotransmitter involved in many aspects of the neuronal function. The synthesis of 5-HT is initiated by the hydroxylation of tryptophan, catalyzed by tryptophan hydroxylase (TPH). Two isoforms of TPH (TPH1 and TPH2) have been identified, with TPH2 almost exclusively expressed in the brain. Following TPH2 discovery, it was reported that polymorphisms of both gene and non-coding regions are associated with a spectrum of psychiatric disorders. Thus, insights into the mechanisms that specifically regulate TPH2 expression and its modulation by exogenous stimuli may represent a new therapeutic approach to modify serotonergic neurotransmission. To this aim, a CNS-originated cell line expressing TPH2 endogenously represents a valid model system. In this study, we report that TPH2 transcript and protein are modulated by neuronal differentiation in the cell line A1 mes-c-myc (A1). Moreover, we show luciferase activity driven by the human TPH2 promoter region and demonstrate that upon mutation of the NRSF/REST responsive element, the promoter activity strongly increases with cell differentiation. Our data suggest that A1 cells could represent a model system, allowing an insight into the mechanisms of regulation of TPH2 and to identify novel therapeutic targets in the development of drugs for the management of psychiatric disorders.

Special Issue: circadian rhythms, clock genes and neuropsychiatry: interesting times

Circadian rhythms are cycles in physiological, behavioural, psychological and other domains that recur approximately every 24 h. Such rhythms are driven by an endogenous circadian timekeeping system, whose molecular basis consists of the interlocking transcription and translation of a panel of ‘‘clock’’ genes, the expression of which then regulates gene expression and cellular function in a tissuespecific manner. Such rhythmic expression of clock genes is observed in most tissues, including the master circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus, other CNS sites and peripheral organs. Therefore, the circadian system exerts considerable control over physiology and behaviour, and equally dysfunction of this circadian system may result in detrimental pathophysiological and psychopathological consequences. It has been observed for many years that a number of neuropsychiatric conditions, most markedly mood disorders, are associated with circadian rhythm and sleep disturbances, with the implications that such disturbances are important in the aetiology and/or the clinical phenomenology of such conditions. In this special issue of the Journal of Neural Transmission, the contributing authors provide a comprehensive collection of reviews and original investigations that cover the field of circadian rhythm and sleep investigations across a broad range of neuropsychiatric disorders. The evidence for circadian rhythm disturbance in schizophrenia (Pritchett et al.), obsessive– compulsive disorder (Lange et al.), depression (Lall et al.), childhood and adolescent psychiatric disorders (Dueck et al.), borderline personality disorder (Fleischer et al.) and alcoholism are reviewed (Wong and Schumann), as are the links between shift work (which results in circadian disruption) and mood disorders (Braungart et al.). These reviews illustrate a notable fact that some measure of circadian rhythm disturbance is observed across a spectrum of psychiatric disorders. Genetic evidence that implicates polymorphisms in clock genes with mood disorders is also overviewed (Partonen) and such evidence may point to circadian roles in disease aetiology. Given that the circadian system is complex and pervasive, there are many potential pathways through which circadian dysfunction might ultimately affect affective and cognitive as well as psychomotor, volatile and perceptive processes. This is highlighted in a review focussing on links between the circadian and immune systems, and the implications arising for major depression (Eyre and Baune). The therapeutic opportunities offered by addressing abnormal circadian rhythm is highlighted in a review on the use of light therapy in childhood, adolescent and postpartum depression, as well as in eating disorders (Krysta et al.). Original investigations address circadian rhythmicity and sleep in those with, and those at elevated risk of, bipolar disorder (Ritter et al.), assessing skin temperature rhythms in Alzheimer’s disease (van Someren et al.), the links between sleep and diurnal preference and ADHD in adults (Voinescu et al.), changes of subjective time estimation in mentally traumatised patients (Kowalski et al.), alterations of time-dependent psychological processes in migraine patients (Kropp et al.), associations between salivary oxytocin and cortisol and sleep stage (Blagrove et al.), the role of circadian rhythms and sleep in cognitive function in healthy older adults (Cochrane et al.) and how circadian A. N. Coogan (&) National University of Ireland, Maynooth, Republic of Ireland e-mail: Andrew.Coogan@nuim.ie

DISC1: Structure, Function, and Therapeutic Potential for Major Mental Illness

Disrupted in schizophrenia 1 (DISC1) is well established as a genetic risk factor across a spectrum of psychiatric disorders, a role supported by a growing body of biological studies, making the DISC1 protein interaction network an attractive therapeutic target. By contrast, there is a relative deficit of structural information to relate to the myriad biological functions of DISC1. Here, we critically appraise the available bioinformatics and biochemical analyses on DISC1 and key interacting proteins, and integrate this with the genetic and biological data. We review, analyze, and make predictions regarding the secondary structure and propensity for disordered regions within DISC1, its protein-interaction domains, subcellular localization motifs, and the structural and functional implications of common and ultrarare DISC1 variants associated with major mental illness. We discuss signaling pathways of high pharmacological potential wherein DISC1 participates, including those involving phosphodiesterase 4 (PDE4) and glycogen synthase kinase 3 (GSK3). These predictions and priority areas can inform future research in the translational and potentially guide the therapeutic processes.

Association study of 44 candidate genes with depressive and anxiety symptoms in post-partum women

The post-partum period is a time of extreme vulnerability for a whole spectrum of psychiatric disorders. Delivery may be considered an important risk factor in genetically susceptible women. Five hundred and eight SNPs in 44 genes at candidate pathways putatively related to mood changes after delivery were genotyped in a multicenter cohort of 1804 women from Spain. Participants completed two scales at 2–3 days, 8 weeks, and 32 weeks post-partum, the Edinburgh Post-partum Depression Scale (EPDS) and the Spielberger State-Trait Anxiety Inventory (STAI). Those women who scored 9 or more on EPDS were evaluated for major depression using the Diagnostic Interview for Genetics Studies (DIGS) adapted for post-partum depression. Association with major depression was assessed using likelihood ratio tests under a codominant genotype model. Association with scale scores was tested using linear mixed models to take into account repeated measures over time. Two intronic SNPs, one at the serotonin transporter gene ( SLC6A4) and another at dopa decarboxylase ( DDC), were significantly associated to STAI anxiety scores after multiple testing correction (nominal P = 0.0000513 and 0.000097, respectively). In addition, post hoc analysis at the unphased haplotype level using nominal significant SNPs revealed an association with a combination of three SNPs at protein kinase C, beta ( PRKCB) with major depression, significant after multiple testing correction (nominal global P = 0.0001596). In conclusion, we detected a role of SLC6A4 in mood changes after stressful events, and revealed new putative associations involving DDC and PRKCB. Therefore, these genes deserve further investigation to confirm these results.