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Objective: Schizophrenia is associated with high mortality, somatic comorbidity and reduced life expectancy. The general practitioner (GP) plays a key role in the treatment of mental and physical multimorbidity. Nevertheless, it is unclear how much individuals with schizophrenia use primary healthcare. This study aims to investigate the yearly numbers of consultations in general practice for individuals with schizophrenia. Design and Setting: We performed a population-based matched cohort study of 21,757 individuals with schizophrenia and 435,140 age- and gender-matched references from Danish National Registers. Monthly general practice consultations were analysed using a generalized linear model with log link and assuming negative binomial distribution. Main outcome measures: Consultation rates in general practice up to17 years after index diagnosis. Results: Individuals with schizophrenia attended their GP more than references throughout the study period. The cases had 82% (95% CI: 78-87) and 76% (95% CI: 71-80) more consultations in primary care after 1 year and 5 years, respectively. Individuals with both schizophrenia and comorbid somatic illness attended even more. Conclusion: Individuals with schizophrenia are in regular contact with their GP, especially if they have comorbid illnesses. Whether an average of six consultations per year for individuals with schizophrenia is sufficient is up for debate. The study demonstrates a potential for an increased prevention and treatment of individuals with schizophrenia in general practice. Schizophrenia is associated with high mortality, somatic comorbidity and reduced life expectancy. Little is known about the attendance pattern in primary care for individuals with schizophrenia. •We found high attendance rates in primary care for individuals diagnosed with schizophrenia from index diagnosis and at least 17 years after diagnosis, which suggests opportunities for earlier intervention to improve their somatic health. •We found an association between high illness comorbidity and increased risk of not attending the general practitioner. The most severely somatically and mentally ill individuals may thus be difficult to reach and support in the current healthcare system. [ABSTRACT FROM AUTHOR]

Objective: Mechanical restraint (MR) is used to prevent patients from harming themselves or others during inpatient treatment. The objective of this study was to investigate whether incident MR occurring in the first 3 days following admission could be predicted based on analysis of electronic health data available after the first hour of admission. Methods: The dataset consisted of clinical notes from electronic health records from the Central Denmark Region and data from the Danish Health Registers from patients admitted to a psychiatric department in the period from 2011 to 2015. Supervised machine learning algorithms were trained on a randomly selected subset of the data and validated using an independent test dataset. Results: A total of 5050 patients with 8869 admissions were included in the study. One hundred patients were mechanically restrained in the period between one hour and 3 days after the admission. A Random Forest algorithm predicted MR with an area under the curve of 0.87 (95% CI 0.79–0.93). At 94% specificity, the sensitivity was 56%. Among the ten strongest predictors, nine were derived from the clinical notes. Conclusions: These findings open for the development of an early warning system that may guide interventions to reduce the use of MR. [ABSTRACT FROM AUTHOR]

Objective: The home environment provided by the caregivers of a child is an influential single factor for development and well‐being. We aimed to compare the quality of the home environment of children at familial high risk of schizophrenia or bipolar disorder with population‐based controls. Methods: Danish nationwide registers were used to retrieve a cohort of 522 7‐year‐old children of parents diagnosed with schizophrenia (N = 202), bipolar disorder (N = 120) or none of these diagnoses (N = 200). The home environment was assessed using the Middle Childhood‐Home Observation for Measurement of the Environment Inventory (MC‐HOME Inventory). Results: The proportion of children living in home environments that were evaluated not to meet the needs of a 7‐year‐old child was significantly larger in the two familial high‐risk groups. This was true for 21% of the children with familial predisposition for schizophrenia and 7% of children with familial disposition for bipolar disorder. Conclusion: Children born to parents diagnosed with schizophrenia and to a lesser extent bipolar disorder are at an increased risk of growing up in a home environment with an insufficient level of stimulation and support. Identifying families with inadequate home environments is a necessary step towards specialized help and support to at‐risk families. [ABSTRACT FROM AUTHOR]

Background: No study has gathered evidence from all randomized clinical trials (RCTs) with anti‐inflammatory drugs measuring antidepressant effects including a detailed assessment of side‐effects and bias. Methods: We performed a systematic review identifying RCTs published prior to January 1, 2018, studying antidepressant treatment effects and side‐effects of pharmacological anti‐inflammatory intervention in adults with major depressive disorder (MDD) or depressive symptoms. Outcomes were depression scores after treatment, remission, response, and side‐effects. Pooled standard mean differences (SMD) and risk ratios (RR) including 95% confidence intervals (95%‐CI) were calculated. Results: We identified 36 RCTs, whereof 13 investigated NSAIDs (N = 4214), 9 cytokine inhibitors (N = 3345), seven statins (N = 1576), 3 minocycline (N = 151), 2 pioglitazone (N = 77), and 2 glucocorticoids (N = 59). Anti‐inflammatory agents improved depressive symptoms compared to placebo as add‐on in patients with MDD (SMD = −0.64; 95%‐CI = −0.88, −0.40; I2 = 51%; N = 597) and as monotherapy (SMD = −0.41; 95%‐CI = −0.60, −0.22; I2 = 93%, N = 8825). Anti‐inflammatory add‐on improved response (RR = 1.76; 95%‐CI = 1.44–2.16; I2 = 16%; N = 341) and remission (RR = 2.14; 95%‐CI = 1.03–4.48; I2 = 57%; N = 270). We found a trend toward an increased risk for infections, and all studies showed high risk of bias. Conclusion: Anti‐inflammatory agents improved antidepressant treatment effects. Future RCTs need to include longer follow‐up, identify optimal doses and subgroups of patients that can benefit from anti‐inflammatory intervention. [ABSTRACT FROM AUTHOR]

Objective: To test the validity and sensitivity of the six‐item version (PANSS‐6) of the 30‐item Positive and Negative Syndrome Scale (PANSS‐30) in treatment‐resistant schizophrenia (TRS). Method: Using data from the clozapine phase (2E) of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, we investigated the following: (i) The scalability of PANSS‐6 and PANSS‐30; (ii) The correlation between PANSS‐6 and PANSS‐30 total scores; (iii) Whether PANSS‐6 could identify cross‐sectional symptom remission; and (iv) The efficacy of clozapine, olanzapine, risperidone and quetiapine in TRS using the 'speed of change' on PANSS‐6 and PANSS‐30 (change in total score per week) as outcome measures. Results: We found that (i) only PANSS‐6 and not PANSS‐30 was scalable; (ii) The correlation between PANSS‐6 and PANSS‐30 total scores was high (Spearman coefficient: 0.85), (iii) PANSS‐6 accurately identified cross‐sectional symptom remission as defined by the Andreasen et al. criteria; and (iv) The only antipsychotic that caused improvement (speed of change significantly lower than 0 during the first three months of treatment) was clozapine, both when using PANSS‐6 (speed of change: −0.50 points/week; 95%CI: −0.84, −0.17) and PANSS‐30 (speed of change: −1.41 points/week; 95%CI: −2.80, −0.02) as outcome measures. Conclusion: PANSS‐6 validly measures severity, remission and antipsychotic efficacy in TRS. [ABSTRACT FROM AUTHOR]

Background. Studies have indicated that the association of urbanicity at birth and during upbringing with schizophrenia may be driven by familial factors such as genetic liability. We used a population-based nested case-control study to assess whether polygenic risk score (PRS) for schizophrenia was associated with urbanicity at birth and at age 15, and to assess whether PRS and parental history of mental disorder together explained the association between urbanicity and schizophrenia. Methods. Data were drawn from Danish population registries. Cases born since 1981 and diagnosed with schizophrenia between 1994 and 2009 were matched to controls with the same sex and birthdate (1549 pairs). Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of a separate, large meta-analysis. Results. Those with higher PRS were more likely reside in the capital compared with rural areas at age 15 [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], but not at birth (OR 1.09, 95% CI 0.95-1.26). Adjustment for PRS produced almost no change in relative risks of schizophrenia associated with urbanicity at birth, but slightly attenuated those for urban residence at age 15. Additional adjustment for parental history led to slight attenuation of relative risks for urbanicity at birth [incidence rate ratio (IRR) for birth in capital = 1.54, 95% CI 1.18-2.02; overall p = 0.016] and further attenuation of relative risks for urbanicity at age 15 (IRR for residence in capital = 1.32, 95% CI 0.97-1.78; overall p = 0.148). Conclusions. While results regarding urbanicity during upbringing were somewhat equivocal, genetic liability as measured here does not appear to explain the association between urbanicity at birth and schizophrenia. [ABSTRACT FROM AUTHOR]

BackgroundFew studies have evaluated the development in the use of antipsychotic medication and psychotic symptoms in patients with first-episode psychosis on a long-term basis. Our objective was to investigate how psychotic symptoms and the use of antipsychotic medication changed over a 10-year period in a cohort of patients with first-episode psychosis.MethodThe study is a longitudinal prospective cohort study over 10 years with follow-ups at years 1, 2, 5 and 10. A total of 496 patients with first-episode psychosis were included in a multi-centre study initiated between 1998 and 2000 in Copenhagen and Aarhus, Denmark.ResultsAt all follow-ups, a large proportion (20–30%) of patients had remission of psychotic symptoms without use of antipsychotic medication at the time of the follow-up. Patients who were in this group at the 5-year follow-up had an 87% [95% confidence interval (CI) 77–96%] chance of being in the same group at the 10-year follow-up. This stability was also the case for patients who had psychotic symptoms and were treated with antipsychotic medication at year 5, where there was a 67% (95% CI 56–78%) probability of being in this group at the consecutive follow-up.ConclusionsA large group of patients with psychotic illness were in remission without the use of antipsychotic medication, peaking at year 10. Overall there was a large degree of stability in disease courses over the 10-year period. These results suggest that the long-term outcome of psychotic illness is heterogeneous and further investigation on a more individualized approach to long-term treatment is needed. [ABSTRACT FROM PUBLISHER]

Objective Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity ( CA) on schizophrenia risk. Activity of catechol-O-methyltransferase ( COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase ( MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR. Methods We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios ( IRRs). Results Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T allele ( P = 0.005) consequent upon CA exposure. After inclusion of the significant ( P = 0.03) COMT × MTHFR × CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant. Conclusion MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia. [ABSTRACT FROM AUTHOR]

Background. Maternal smoking has consistently been associated with multiple adverse childhood outcomes including externalizing disorders. In contrast the association between maternal smoking during pregnancy (MSDP) and internalizing (anxiety and depressive) disorders in offspring has received less investigation. Method. We conducted a nationwide cohort study including 957635 individuals born in Denmark between 1991 and 2007. Data on MSDP and diagnoses of depression or anxiety disorders were derived from national registers and patients were followed up from the age of 5 years to the end of 2012. Hazard rate ratios (HRRs) were estimated using stratified Cox regression models. Sibling data were used to disentangle individual- and familial-level effects of MSDP and to control for unmeasured familial confounding. Results. At the population level, offspring exposed to MSDP were at increased risk for both severe depression [HRR 1.29, 95% confidence interval (CI) 1.22-1.36] and severe anxiety disorders (HRR 1.26, 95% CI 1.20-1.32) even when controlling for maternal and paternal traits. However, there was no association between MSDP and internalizing disorders when controlling for the mother's propensity for MSDP (depression: HRR 1.11, 95% CI 0.94-1.30; anxiety disorders: HRR 0.94, 95% CI 0.80-1.11) or comparing differentially exposed siblings (depression: HRR 1.18, 95% CI 0.75-1.89; anxiety disorders: HRR 0.87, 95% CI 0.55-1.36). Conclusions. The results suggest that familial background factors account for the association between MSDP and severe internalizing disorders not the specific exposure to MSDP. [ABSTRACT FROM AUTHOR]

Objective Severe infections are associated with increased risks of mental disorders; however, this is the first large-scale study investigating whether infections treated with anti-infective agents in the primary care setting increase the risks of schizophrenia and affective disorders. Method We identified all individuals born in Denmark 1985-2002 ( N = 1 015 447) and studied the association between infections treated with anti-infective agents and the subsequent risk of schizophrenia and affective disorders during 1995-2013. Cox regression analyses were adjusted for important confounders. Results Infections treated with anti-infective agents were associated with increased risks of schizophrenia by a hazard rate ratio ( HRR) of 1.37 (95%- CI = 1.20-1.57) and affective disorders by a HRR of 1.64 (95%- CI = 1.48-1.82), fitting a dose-response and temporal relationship ( P < 0.001). The excess risk was primarily driven by infections treated with antibiotics, whereas infections treated with antivirals, antimycotics, and antiparasitic agents were not significant after mutual adjustment. Individuals with infections requiring hospitalization had the highest risks for schizophrenia ( HRR = 2.05; 95%- CI = 1.77-2.38) and affective disorders ( HRR = 2.59; 95%- CI = 2.31-2.89). Conclusion Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors. [ABSTRACT FROM AUTHOR]

Background Early diagnosis is important for the course of schizophrenia. Aim To investigate whether prodromal symptoms of schizophrenia lead to increased use of primary care. Method A register-based cohort study of 21 894 cases with incident schizophrenia and 437 880 matched controls. Results Cases used daytime primary care 43% more than controls during the 6 years before diagnosis ( IRR = 1.43; 95% CI: 1.39; 1.48) and 132% more during the last 2 months ( IRR = 2.32; 95% CI: 2.27; 2.37), and 34% ( IRR = 1.34; 95% CI: 1.23; 1.48) vs. 374% more for out-of-hours services ( IRR = 3.74; 95% CI: 3.52; 3.98). Six years before index diagnosis, 30% of cases had at least one psychiatric contact without being diagnosed with schizophrenia, increasing to 75% 1 month before diagnosis. Conclusion Increased help-seeking behaviour was seen at least 6 years before index diagnosis, suggesting a 'window' for earlier diagnosis of prodromal schizophrenia. [ABSTRACT FROM AUTHOR]

Objective The 30-item Positive and Negative Syndrome Scale ( PANSS-30) is the most widely used rating scale in schizophrenia, but too long for clinical use. Shorter PANSS versions have been proposed, including the PANSS-14 and PANSS-8. However, none of these PANSS versions has been validated using the parametric Rasch rating scale model, which evaluates 'scalability'. Scalability means that each item in a rating scale provides unique information regarding syndrome severity and is a statistical prerequisite for using the total score as a measure of overall severity. Method Based on data from two randomized placebo-controlled trials in schizophrenia, we tested the scalability of PANSS-30, PANSS-14 and PANSS-8 by means of the parametric Rasch rating scale model. Furthermore, we tested whether a scalable PANSS version could separate efficacy of haloperidol and sertindole from placebo. Results Neither PANSS-30, PANSS-14 nor PANSS-8 was scalable. However, PANSS-6, consisting of the items: P1-Delusions, P2-Conceptual disorganization, P3-Hallucinations, N1-Blunted Affect, N4-Social withdrawal, N6-Lack of spontaneity and flow of conversation, was scalable. Furthermore, PANSS-6 captured superior symptom reduction and higher remission rates during treatment with haloperidol and sertindole vs. placebo. Conclusion PANSS-6 is a short schizophrenia severity rating scale that adequately separates antipsychotic efficacy from that of placebo. [ABSTRACT FROM AUTHOR]

BackgroundStrategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).MethodFor investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.ResultsSignificant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.ConclusionsAAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses. [ABSTRACT FROM PUBLISHER]

BackgroundThe post-pubertal association of female gender with emotional disorder is a robust finding. However, studies exploring the association of gender and emotional disorders before puberty are few and present diverging results. The aim of this study was to present gender-specific incidence rates of emotional disorders throughout childhood.MethodThis is a population-based cohort study of 907 806 Danish 3- to 18-year-olds. The outcome was assignment of an emotional disorder diagnosis based on in-patient and out-patient data from The Danish Psychiatric Central Register. Outcome measures were incidence rates and cumulative incidences for unipolar depressive disorder (ICD-10: F32–F33), anxiety disorders (ICD-10: F40–F42), and emotional disorders with onset specific to childhood (ICD-10: F93).ResultsPre-pubertal incidence rates for depressive and anxiety disorders were higher for boys than girls. At age 12 years the pattern reversed. The cumulative incidence for any emotional disorder (F32–F33, F40–F42, F93) on the 11th birthday was 0.52% (95% CI 0.50–0.55) for boys and 0.31% (95% CI 0.29–0.33) for girls. On the 19th birthday cumulative incidence was 2.33% (95% CI 2.24–2.43) for boys and 3.77% (95% CI 3.64–3.90) for girls. The pre-pubertal male preponderance was also significant for depressive disorders (F32–F33, p = 0.00144) and anxiety disorders (F40–F42, F93, p < 0.00001) separately.ConclusionsEmotional disorders seem to display a male preponderance before the age of 12 years and a female preponderance thereafter. Studies exploring this gender–age interaction are needed. Still, the results question the general assumption that females throughout the lifespan are more at risk for emotional disorders than males. [ABSTRACT FROM AUTHOR]

BackgroundThe post-pubertal association of female gender with emotional disorder is a robust finding. However, studies exploring the association of gender and emotional disorders before puberty are few and present diverging results. The aim of this study was to present gender-specific incidence rates of emotional disorders throughout childhood.MethodThis is a population-based cohort study of 907 806 Danish 3- to 18-year-olds. The outcome was assignment of an emotional disorder diagnosis based on in-patient and out-patient data from The Danish Psychiatric Central Register. Outcome measures were incidence rates and cumulative incidences for unipolar depressive disorder (ICD-10: F32–F33), anxiety disorders (ICD-10: F40–F42), and emotional disorders with onset specific to childhood (ICD-10: F93).ResultsPre-pubertal incidence rates for depressive and anxiety disorders were higher for boys than girls. At age 12 years the pattern reversed. The cumulative incidence for any emotional disorder (F32–F33, F40–F42, F93) on the 11th birthday was 0.52% (95% CI 0.50–0.55) for boys and 0.31% (95% CI 0.29–0.33) for girls. On the 19th birthday cumulative incidence was 2.33% (95% CI 2.24–2.43) for boys and 3.77% (95% CI 3.64–3.90) for girls. The pre-pubertal male preponderance was also significant for depressive disorders (F32–F33, p = 0.00144) and anxiety disorders (F40–F42, F93, p < 0.00001) separately.ConclusionsEmotional disorders seem to display a male preponderance before the age of 12 years and a female preponderance thereafter. Studies exploring this gender–age interaction are needed. Still, the results question the general assumption that females throughout the lifespan are more at risk for emotional disorders than males. [ABSTRACT FROM PUBLISHER]

It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant. [ABSTRACT FROM AUTHOR]

Introduction: The six-item Positive And Negative Syndrome Scale (PANSS-6) is short psychometric valid scale quantifying the severity of core schizophrenia symptoms. Using PANSS-6 to guide treatment decision-making requires that staff members' ratings are valid and reliable. Objectives: The objective of the study was to evaluate whether such valid and reliable PANSS-6 ratings can be obtained through a video-based training program. Methods: One-hundred-and-four staff members from Aarhus University Hospital - Psychiatry, Denmark participated in the training. Participants conducted baseline PANSS-6 ratings based on a video of a patient being interviewed using the Simplified Positive And Negative Symptoms interview (SNAPSI). Subsequently, a theoretical introduction video was displayed followed by five SNAPSI patient interviews. After each SNAPSI video, individual ratings were performed before a video providing the gold standard scores was displayed. The validity of ratings was estimated by calculating the proportion of participants not deviating from the gold standard scores with >2 points on individual items or >6 points on the PANSS-6 total score. Reliability was evaluated after each step in the training by means of Gwet's Agreement Coefficient (Gwet). Results: By the end of the training, 72% of the participants rated within the acceptable deviations of the gold standard, ranging from 60% (nurses) to 91% (medical doctors/psychologists). The reliability improved (Gwet baseline vs. endpoint) for all PANSS-6 items, except for Blunted affect. Conclusions: The majority of the staff members conducted valid PANSS-6 ratings after a brief standardized training program, supporting the implementation of PANSS-6 in clinical settings to facilitate measurement-based care. [ABSTRACT FROM AUTHOR]

BackgroundAlthough usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies.MethodWe examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings.ResultsA significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This ‘heritability’ was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10−8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R2 = 0.08 in SLEs (p = 0.03).ConclusionsThese results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality. [ABSTRACT FROM AUTHOR]

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 × 10−6, odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13-1.37)) and to screened controls (P=5.6 × 10−4, OR=1.52 (95% CI 1.20-1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression. [ABSTRACT FROM AUTHOR]

Background. It has been proposed that non-steroidal anti-inflammatory drugs (NSAIDs) may interfere with the efficacy of antidepressants and contribute to treatment resistance in major depressive disorder (MDD). This effect requires replication and a test of whether it is specific to serotonin-reuptake inhibiting (SRI) antidepressants. Method. We tested the effect of concomitant medication with NSAIDs on the efficacy of escitalopram, a SRI antidepressant, and nortriptyline, a tricyclic antidepressant, among 811 subjects with MDD treated for up to 12 weeks in the GENDEP study. Effects of NSAIDs on improvement of depressive symptoms were tested in mixed-effect linear models. Effects on remission were tested in logistic regression. Age, sex, baseline severity and centre of recruitment were considered as potential confounding factors. Results. Ten percent (n = 78) of subjects were taking NSAIDs during the antidepressant treatment. Older subjects were significantly more likely to take NSAIDs. After controlling for age, sex, centre of recruitment and baseline severity, concomitant medication with NSAIDs did not significantly influence the efficacy of escitalopram [β=0.035, 95% confidence interval (CI) -0.145 to 0.215, p=0.704] or nortriptyline (β=0.075, 95% CI -0.131 to 0.281, p=0.476). Although slightly fewer subjects who took NSAIDs reached remission [odds ratio (OR) 0.80, 95% CI 0.49-1.31, p=0.383], this non-significant effect was reversed after controlling for age, sex, baseline severity and recruitment centre effects (OR 1.04, 95% CI 0.61-1.77, p=0.882). Conclusions. NSAIDs are unlikely to affect the efficacy of SRI or other antidepressants. Concurrent use of NSAIDs and antidepressants does not need to be avoided. [ABSTRACT FROM AUTHOR]

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity. [ABSTRACT FROM AUTHOR]

BackgroundSymptom dimensions have not yet been comprehensively tested as predictors of the substantial heterogeneity in outcomes of antidepressant treatment in major depressive disorder.MethodWe tested nine symptom dimensions derived from a previously published factor analysis of depression rating scales as predictors of outcome in 811 adults with moderate to severe depression treated with flexibly dosed escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP). The effects of symptom dimensions were tested in mixed-effect regression models that controlled for overall initial depression severity, age, sex and recruitment centre. Significant results were tested for replicability in 3637 adult out-patients with non-psychotic major depression treated with citalopram in level I of Sequenced Treatment Alternatives to Relieve Depression (STAR*D).ResultsThe interest-activity symptom dimension (reflecting low interest, reduced activity, indecisiveness and lack of enjoyment) at baseline strongly predicted poor treatment outcome in GENDEP, irrespective of overall depression severity, antidepressant type and outcome measure used. The prediction of poor treatment outcome by the interest-activity dimension was robustly replicated in STAR*D, independent of a comprehensive list of baseline covariates.ConclusionsLoss of interest, diminished activity and inability to make decisions predict poor outcome of antidepressant treatment even after adjustment for overall depression severity and other clinical covariates. The prominence of such symptoms may require additional treatment strategies and should be accounted for in future investigations of antidepressant response. [ABSTRACT FROM PUBLISHER]

Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10−7) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted. [ABSTRACT FROM AUTHOR]

Objective To explore the empirical support for a reclassification of the eating disorders NOS (EDNOS) category. Methods In a cross-sectional design eight specific subgroups of EDNOS were compared to anorexia nervosa (AN) and bulimia nervosa (BN) on interview-based data and questionnaire measures. The sample consisted of 965 patients in the age 13-54 years admitted to treatment for an eating disorder. Results According to the DSM-IV 176(18%) presented with AN, 290(30%) with BN and 499(52%) with EDNOS. Of all EDNOS cases 34% could be reclassified as AN or BN. Three specific subgroups emerged as separate diagnostic entities. A heterogeneous subgroup of 122 patients (13% of all) was proposed as 'true' EDNOS. Implications of the results on the DSM-V are discussed. Conclusions The results support a broader definition of AN and BN and suggest subgroups of EDNOS as separate diagnostic entities. This results in a substantial reduction of the heterogeneous EDNOS group. Copyright © 2010 John Wiley & Sons, Ltd and Eating Disorders Association. [ABSTRACT FROM AUTHOR]

Panic disorder (PD) is an anxiety disorder characterized by recurrent panic attacks with a lifetime prevalence of 4.7%. Genetic factors are known to contribute to the development of the disorder. Several lines of evidence point towards a major role of the norepinephrine system in the pathogenesis of PD. The SLC6A2 gene is located on chromosome 16q12.2 and encodes the norepinephrine transporter ( NET), responsible for the reuptake of norepinephrine into presynaptic nerve terminals. The aim of the present study was to analyze genetic variants located within the NET gene for association with PD. The case-control sample consisted of 449 patients with PD and 279 ethnically matched controls. All cases fulfilled the ICD-10 diagnostic criteria for PD. Genotyping was performed using the Sequenom platform (Sequenom, Inc, San Diego, USA). To test for allelic and haplotypic association, the PLINK software was used, and COMBASSOC was applied to test for gene-wise association. After quality control 29 single nucleotide polymorphisms (SNPs) spanning the gene-region were successfully analyzed. Seven SNPs located within the 5′ end of the gene were significantly associated with PD. Furthermore, the NET gene showed overall evidence for association with the disease ( P = 0.000035). In conclusion, the present study indicates that NET could be a susceptibility gene for PD. [ABSTRACT FROM AUTHOR]

There is substantial inter-individual variation in response to antidepressants, and genetic variation may, in part, explain these differences. For example, there is evidence to suggest that variation in the serotonin transporter gene (SLC6A4) predicts response to selective serotonin reuptake inhibitors (SSRIs). Environmental factors such as the occurrence of stressful life events before treatment may also be important. One prior report suggests that both factors interact in predicting response to antidepressants. GENDEP, a prospective part-randomized pharmacogenomics trial, collected longitudinal data on the outcome of 811 patients with major depression undergoing treatment with either an SSRI (escitalopram) or a tricyclic antidepressant (nortriptyline). Life events experienced over 6 months preceding treatment were measured using a List of Threatening Experiences Questionnaire, and several polymorphisms in the serotonin transporter gene (SLC6A4) have been genotyped including the serotonin transporter-linked polymorphic region (5-HTTLPR). Stressful life events were shown to predict a significantly better response to escitalopram but had no effect on response to nortriptyline. Variation in the 5-HTTLPR and another polymorphism in the gene, STin4, significantly modified these effects. Gene-environment interactions including life events may therefore be important not only in the aetiology of depression, but also in predicting response to antidepressant medication. [ABSTRACT FROM AUTHOR]

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10−8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders). [ABSTRACT FROM AUTHOR]

Laegsgaard MM, Stamp AS, Hall EOC, Mors O. The perceived and predicted implications of psychiatric genetic knowledge among persons with multiple cases of depression in the family. Psychiatric genetic research raises hope regarding better treatment and prevention, but also regarding a possible de-stigmatizing effect of attributing mental illness to genetics. This study explores i) the impact on family relations of participating in a genetic study; ii) the impact of biogenetic attributions on perceptions of depression and stigma and iii) the perceived benefits and concerns regarding psychiatric genetic testing. Focus groups were conducted with 17 participants suffering from depression, with multiple cases of depression in the family, and previously participating in a genetic study. Participating in a genetic study caused more openness about depression in most families. A biogenetic explanation of depression was perceived as having the potential of diminishing self stigma. Testing of self and children was widely accepted, whereas prenatal testing raised concern. Persons suffering from depression may benefit from endorsing a biogenetic explanation, especially in relation to self-understanding and self-stigma. [ABSTRACT FROM AUTHOR]

Objective: To assess the 30-month outcome and predictors of outcome in a cohort of patients with any eating disorder (ED). Method: A naturalistic design was used to determine time to remission, predictors of remission, relapse, diagnostic cross-over and mortality of 629 patients. Results: At follow-up (FU) 312 patients attended, 42% obtained full remission and 72% partial remission. No differences were found between diagnostic groups for adolescents. Adult patients with anorexia-like eating disorder not otherwise specified-anorexia nervosa (EDNOS-AN) had the poorest outcome. Bulimia-like EDNOS was the most frequent relapse diagnosis. Bingeing/purging behaviour predicted a poorer outcome for individuals with bulimic disorders. Desired low BMI predicted a poorer outcome for individuals with anorexia. Comorbid personality disorder was a common predictor of a worse outcome. Conclusion: Adults with EDNOS-AN had the poorest prognosis. Bulimic symptoms emerged frequently during FU regardless of diagnosis. Remission rates and outcome predictors were similar to previous findings. [ABSTRACT FROM AUTHOR]

Background. Response and remission defined by cut-off values on the last observed depression severity score are commonly used as outcome criteria in clinical trials, but ignore the time course of symptomatic change and may lead to inefficient analyses. We explore alternative categorization of outcome by naturally occurring trajectories of symptom change. Method. Growth mixture models were applied to repeated measurements of depression severity in 807 participants with major depression treated for 12 weeks with escitalopram or nortriptyline in the part-randomized Genome-based Therapeutic Drugs for Depression study. Latent trajectory classes were validated as outcomes in drug efficacy comparison and pharmacogenetic analyses. Results. The final two-piece growth mixture model categorized participants into a majority (75%) following a gradual improvement trajectory and the remainder following a trajectory with rapid initial improvement. The rapid improvement trajectory was over-represented among nortriptyline-treated participants and showed an antidepressant-specific pattern of pharmacogenetic associations. In contrast, conventional response and remission favoured escitalopram and produced chance results in pharmacogenetic analyses. Controlling for drop-out reduced drug differences on response and remission but did not affect latent trajectory results. Conclusions. Latent trajectory mixture models capture heterogeneity in the development of clinical response after the initiation of antidepressants and provide an outcome that is distinct from traditional endpoint measures. It differentiates between antidepressants with different modes of action and is robust against bias due to differential discontinuation. [ABSTRACT FROM AUTHOR]

Objective: To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor ( CCKAR) gene is a risk factor in the pathogenesis of schizophrenia. Method: The variation was analysed in a case–control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay. Results: In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR. Conclusion: This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia. [ABSTRACT FROM AUTHOR]

BACKGROUND: A number of scales are used to estimate the severity of depression. However, differences between self-report and clinician rating, multi-dimensionality and different weighting of individual symptoms in summed scores may affect the validity of measurement. In this study we examined and integrated the psychometric properties of three commonly used rating scales.MethodThe 17-item Hamilton Depression Rating Scale (HAMD-17), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI) were administered to 660 adult patients with unipolar depression in a multi-centre pharmacogenetic study. Item response theory (IRT) and factor analysis were used to evaluate their psychometric properties and estimate true depression severity, as well as to group items and derive factor scores. RESULTS: The MADRS and the BDI provide internally consistent but mutually distinct estimates of depression severity. The HAMD-17 is not internally consistent and contains several items less suitable for out-patients. Factor analyses indicated a dominant depression factor. A model comprising three dimensions, namely 'observed mood and anxiety', 'cognitive' and 'neurovegetative', provided a more detailed description of depression severity. CONCLUSIONS: The MADRS and the BDI can be recommended as complementary measures of depression severity. The three factor scores are proposed for external validation. [ABSTRACT FROM AUTHOR]

BackgroundA number of scales are used to estimate the severity of depression. However, differences between self-report and clinician rating, multi-dimensionality and different weighting of individual symptoms in summed scores may affect the validity of measurement. In this study we examined and integrated the psychometric properties of three commonly used rating scales.MethodThe 17-item Hamilton Depression Rating Scale (HAMD-17), the Montgomery?Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI) were administered to 660 adult patients with unipolar depression in a multi-centre pharmacogenetic study. Item response theory (IRT) and factor analysis were used to evaluate their psychometric properties and estimate true depression severity, as well as to group items and derive factor scores.ResultsThe MADRS and the BDI provide internally consistent but mutually distinct estimates of depression severity. The HAMD-17 is not internally consistent and contains several items less suitable for out-patients. Factor analyses indicated a dominant depression factor. A model comprising three dimensions, namely ?observed mood and anxiety?, ?cognitive? and ?neurovegetative?, provided a more detailed description of depression severity.ConclusionsThe MADRS and the BDI can be recommended as complementary measures of depression severity. The three factor scores are proposed for external validation. [ABSTRACT FROM AUTHOR]

Context: Studies on postpartum mental disorders among mothers have primarily focused on either depression or psychoses and have generally not included the broader spectrum of mental disorders. A few studies have found that some men have symptoms of depression after becoming fathers, but these studies have not documented whether this exceeds the morbidity among men in general.Objectives: To estimate the risk of postpartum mental disorders necessitating hospital admission or outpatient contact for mothers as well as fathers during a 1-year postnatal follow-up period after birth of first live-born child and to investigate whether parents in general differ from nonparents in the risk of admission with a mental disorder and how this difference varies with age.Design, Setting, and Patients: Register-based cohort formed by linking information from Danish health and civil service registers. A total of 2,357,942 Danish-born persons were followed up from their 15th birthday or January 1, 1973, whichever came later, until date of onset of the disorder in question, date of death, date of emigration from Denmark, or July 1, 2005, whichever came first. From 1973 to 2005, a total of 630,373 women and 547,431 men became parents for the first time, and during the first year after childbirth, these parents contributed 1,115,639 person-years at risk.Main Outcome Measure: First-time psychiatric hospital admission or outpatient contact 0 to 12 months after becoming a parent.Results: A total of 1171 mothers and 658 fathers were admitted with a mental disorder to a psychiatric hospital during the first 12 months after parenthood, and the corresponding prevalence of severe mental disorders through the first 3 months after childbirth was 1.03 per 1000 births for mothers and 0.37 per 1000 births for fathers. Compared with women who had given birth 11 to 12 months prior, primiparous women had an increased risk of incident hospital admission with any mental disorder through the first 3 months after childbirth, with the highest risk 10 to 19 days postpartum (relative risk [RR], 7.31; 95% confidence interval [CI], 5.44-9.81). Among mothers, risk was also increased for psychiatric outpatient contacts through the first 3 months after childbirth, also with the highest risk occurring 10 to 19 days postpartum (RR, 2.67; 95% CI, 1.99-3.59). Unlike motherhood, fatherhood was not associated with any increased risk of hospital admission or outpatient contact.Conclusion: In Denmark, the risk of postpartum mental disorders among primiparous mothers is increased for several months after childbirth, but among fathers there is no excess of severe mental disorders necessitating admission or outpatient contacts. [ABSTRACT FROM AUTHOR]

Linkage studies suggest that chromosome 22q12–13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample, we previously reported association between microsatellite markers located at 22q13.31-qtel and both disorders. The present study reports an association analysis across five genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case–control sample of 162 BPD, 103 SZ patients and 200 controls. The bromodomain-containing 1 gene (BRD1), which encodes a putative regulator of transcription showed association with both disorders with minimal P-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker ‘risk’ haplotype showed a frequency of ∼10% in the combined case group versus ∼1% in controls (P-value 2.8 × 10−7). Expression analysis of BRD1 mRNA revealed widespread expression in mammalian brain tissue, which was substantiated by immunohistochemical detection of BRD1 protein in the nucleus, perikaryal cytosol and proximal dendrites of the neurons in the adult rat, rabbit and human CNS. Quantitative mRNA analysis in developing fetal pig brain revealed spatiotemporal differences with high expression at early embryonic stages, with intense nuclear and cytosolar immunohistochemical staining of the neuroepithelial layer and early neuroblasts, whilst more mature neurons at later embryonic stages had less nuclear staining. The results implicate BRD1 with SZ and BPD susceptibility and provide evidence that suggests a role for BRD1 in neurodevelopment.Molecular Psychiatry (2006) 11, 1126–1138. doi:10.1038/sj.mp.4001885; published online 22 August 2006 [ABSTRACT FROM AUTHOR]

Objective: Three linkage studies of bipolar disorder have implicated chromosome 12q24.3, with significant lod scores of over 3.00. Several other linkage studies have found lod scores between 2.00 and 3.00. In order to identify which gene on this chromosome is responsible, the authors carried out tests of allelic association with bipolar disorder in order to fine map an affective disorder susceptibility gene. Method: DNA samples from 681 bipolar disorder patients and 570 comparison subjects from Denmark and the United Kingdom were genotyped with markers close to the region at which the authors had found maximum linkage in previous studies. Results: Single marker allelic association was found with four markers in the Danish cohort. Seven markers in exactly the same region were then found to show significant allelic association in the U.K. cohort. Tests of haplotypic association were also significant, confirming the single marker allelic associations. Conclusions: These positive fine mapping results validate earlier linkage studies and implicate a 278-kilobase region of chromosome 12 that contributes to the etiology of bipolar disorder. Several brain transcripts are transcribed from sequences in the region. The main candidate gene has no known function but is found in human brain cDNA and is homologous to a Macaque brain cDNA. Sequencing of expressed sequences and control regions in the area should identify etiological base pair changes that increase susceptibility to bipolar disorder. [ABSTRACT FROM AUTHOR]

The involvement of genetic factors in the etiology of autism has been clearly established. We undertook a genome-wide search for regions containing susceptibility genes for autism in 12 subjects with childhood autism and related pervasive developmental disorders (PDDs) and 44 controls from the relatively isolated population of the Faroe Islands. In total, 601 microsatellite markers distributed throughout the human genome with an average distance of 5.80 cM were genotyped, including 502 markers in the initial scan. The Faroese population structure and genetic relatedness of cases and controls were also evaluated. Based on a combined approach, including an assumption-free test as implemented in CLUMP, Fisher's exact test for specific alleles and haplotypes, and IBD0 probability calculations, we found association between autism and microsatellite markers in regions on 2q, 3p, 6q, 15q, 16p, and 18q. The most significant finding was on 3p25.3 (PT1=0.00003 and PT4=0.00007), which was also supported by other genetic studies. Furthermore, no evidence of population substructure was found, and a higher degree of relatedness among cases could not be detected, decreasing the risk of inflated P-values. Our data suggest that markers in these regions are in linkage disequilibrium with genes involved in the etiology of autism, and we hypothesize susceptibility genes for autism and related PDDs to be localized within these regions.Molecular Psychiatry (2006) 11, 37–46. doi:10.1038/sj.mp.4001754; published online 4 October 2005 [ABSTRACT FROM AUTHOR]

Patients with schizophrenia (n=11) and bipolar affective disorder (n=17) from the relatively isolated population of the Faroe Islands were genotyped for 34 polymorphic markers on chromosome 4 in a search for allelic association and haplotype sharing among distantly related patients. When considering bipolar patients only, there was no clearcut support for any region on chromosome 4. The two-marker segment D4S394-D4S2983 at 4p16.1 was, however, supported by a P-value of 0.0162. For patients with schizophrenia, there was reasonable support for 4p16.1 as marker D4S2281 (P=0.0019), a two-marker segment (D4S2281-D4S1605, P=0.0009) and a three-marker segment (D4S2923-D4S2928-D4S1582, P-0.0005) appeared to be associated with schizophrenia, with some alleles/haplotypes occurring with different frequencies in patients compared to controls. When combining both psychiatric disorders, chromosome 4p16.1 received further support from five partially overlapping two- and three-marker segments (D4S394-D4S2983, P=0.0039; D4S2281-D4S1605, P=0.0027 and D4S394-D4S2983-D4S2923, P=0.006; D4S2923-D4S2928-D4S1582, P=0.00007; D4S1582-D4S1599-D4S2281, P=0.005). Increased haplotype sharing in patients with schizophrenia and in the combined data set was partly supported by Fisher's exact test and tests based on the genealogy. Our study yields support for a common risk gene for schizophrenia and bipolar affective disorder on the short arm of chromosome 4, as suggested by previous findings in the neighbouring Scottish population.Molecular Psychiatry (2004) 9, 93-98. doi:10.1038/sj.mp.4001393 [ABSTRACT FROM AUTHOR]

Background: Few population-based studies have addressed risk factors for bipolar affective disorder. Objective: To study the possible association between bipolar affective disorder and history of mental illness in a parent or sibling; urbanicity of birth place; season of birth; sibship characteristics, including birth order; influenza epidemics during pregnancy; and early parental loss. Design: We used a population-based cohort of 2.1 million individuals based on data from the Danish Civil Registration System linked with the Danish Psychiatric Central Register. Setting: Nationwide population-based sample of all individuals hospitalized or in outpatient clinic contact for the first time with bipolar affective disorder. Patients: Overall, 2299 individuals were first diagnosed with bipolar affective disorder during the 31.8 million person-years of follow-up. Results: Risk of bipolar affective disorder was associated with a history of bipolar affective disorder as well as other psychiatric disorders, including schizophrenia and schizoaffective disorder, in parents or siblings. People with a first-degree relative with bipolar affective disorder had a 13.63-fold (95% confidence interval, 11.81-15.71) increased risk of bipolar affective disorder. No other consistent associations were found with the exception of an association between early parental loss, in particular maternal, and bipolar affective disorder. Children who experienced maternal loss before their fifth birthday had a 4.05 (95% confidence interval, 1.68-9.77) increased risk of bipolar affective disorder. Conclusions: Early parental loss may represent both environmental and genetic risk factors for bipolar affective disorder. Most of the risk factors included in our study that previously have been associated with schizophrenia were not associated with bipolar affective disorder, supporting that the 2 disorders may be at least partially separate etiological entities. [ABSTRACT FROM AUTHOR]

The present study reports a genomewide scan using linkage analysis for risk genes involved in bipolar disorder with 613 microsatellite markers including additional testing of promising regions. As previously published significant linkage was obtained at chromosome 12q24.3 with a two-point parametric lod score of 3.42 at D12S1639 including all members in both families (empirical P-value 0.00004, genome-wide P-value 0.0417). The multipoint parametric lod score at D12S1639 was 3.63 (genome-wide P-value 0.0265). At chromosome 1p22-p21 a parametric, affecteds-only two-point lod score of 2.75 at marker D1S216 was found (empirical Pvalue 0.0002, genome-wide P-value 0.1622). A three-point lod score of 2.98 (genome-wide Pvalue 0.1022) at D1S216, and a multipoint non-parametric analysis with a maximum NPL-all score of 17.60 (P-value 0.00079) at D1S216 further supported this finding. A number of additional loci on chromosomes 4p16, 6q14-q22, 10q26 and 16p13.3 yielded parametric lod scores around or above 2. [ABSTRACT FROM AUTHOR]

The somatostatin receptor 5 (SSTR5) gene is a candidate gene for bipolar affective disorder (BPAD) as well as for other neuropsychiatric disorders. The gene is positioned on chromosome 16p13.3, a region that has been implicated by a few linkage studies to potentially harbor a disease susceptibility gene for BPAD. Recent evidence shows that the dopamine D2 receptor (DRD2) and SSTR5 interact physically to form heterodimers with enhanced functional activity. Brain D2 dopamine receptors are one of the major targets of neuroleptic treatments in psychiatric disorders, in this study we systematically screened the promoter and coding region of the SSTR5 gene for genetic variation that could contribute to the development of neuropsychiatric disorders. Eleven novel single nucleotide polymorphisms (SNPs) were identified including four missense SNPs, Leu48Met, Ala52Val, Prol09Ser and Pro335Leu. We carried out an association study of BPAD using 80 Danish cases and 144 control subjects, and replication analysis using 55 British cases and 88 control subjects. For the Danish population, association was suggested between silent SNP G573A and BPAD (P = 0.008). For the British population we found association to BPAD with missense mutation Leu48Met (P=0.003) and missense mutation Pro335Leu (P=0.004). The statistical significance of the association was, however, greatly reduced after correcting for multiple testing. When combining genotypes from Leu48Met and Pro335Leu into haplotypes, association to BPAD was found in the British population (P = 0.0007). This haplotype association was not replicated in the Danish population. Our results may indicate that the SSTR5 gene is involved in the etiology of BPAD or may exist in linkage disequilibrium with a susceptibility gene close to SSTR5. However, given the marginal statistical significance and the potential for false-positive results in association studies with candidate genes, further studies are needed to clarify this hypothesis. [ABSTRACT FROM AUTHOR]

Possible associations between autism and specific medical disorders have been suggested, and this could be of relevance in the clinical examination and treatment of patients and may help to identify factors involved in the etiology or pathophysiology of autism. Two population-based Danish registers were used to investigate the occurrence of medical disorders in patients with autism according to ICD-8 and in a matched control sample. A total of 29 of the 244 patients (11.9%) diagnosed with autism had one or more medical disorders. In contrast to previous studies, we did not find an increased occurrence of almost any medical disorders. A highly significant increased frequency of congenital malformations was found, which may indicate abnormalities in embryogenesis in the etiology of autism. [ABSTRACT FROM AUTHOR]

Several lines of evidence implicate dopa decarboxylase (DDC) with schizophrenia. By analysis of two putative functional DDC variants in 173 schizophrenic patients and 204 controls we tested the hypotheses that DDC is involved in: (1) predisposition to schizophrenia; and (2) modulation of age at disease onset. No association was observed with schizophrenia as a whole, whereas an association between DDC genotypes and age at disease onset was suggested in males (P = 0.03). This association was most pronounced in relation to genotypes of haplotypes comprising both variants, suggesting an additive model where one variant mediates early and the other late onset. Accordingly, the haplotype-based genotypes could be assigned into three groups by their possible relative effect on age at onset: an 'early', 'neutral' and 'late' group. Dividing the male schizophrenics into four groups with increasing age at onset, the 'early' genotypes were seen to decrease in frequency from 51.5% to 16.7% while the 'late' genotypes increased from 12.1% to 33.3% (P = 0.02). The difference in mean age at onset between male patients with 'early' genotypes vs patients with 'late' genotypes was close to 5 years (95% CI: 0.7-8.8). Thus, DDC may possibly act as a modulator of age at onset in male schizophrenics. [ABSTRACT FROM AUTHOR]

A number of studies have strongly suggested a susceptibility locus for bipolar affective disorder on chromosome 12q24. The present study investigates for a shared chromosomal segment among distantly related patients with bipolar affective disorder from the Faroe Islands, using 17 microsatellite markers covering 24 cM in the previously suggested region on chromosome 12q24. D12S342 showed possible allelic association to bipolar affective disorder (P-value using CLUMP below 0.01). Increased sharing among cases of two-marker haplotypes were suggested at D12S1614-D12S342 (Pvalues using CLUMP below 0.01), and D12S2075-D12S1675 (P-values using CLUMP around 0.001). The region of most interest is around 6 cM and bounded by markers D12S1614 and D12S1675 as suggested by the interesting two-marker haplotypes. [ABSTRACT FROM AUTHOR]

Objective: There is an increased risk in schizophrenia for premature death from illnesses in almost all organic systems. The present study analyses the Rate Ratio (RR) for schizophrenic patients' admissions to somatic departments in Denmark. Method: 20 000 schizophrenic patients were identified in the Danish Psychiatric Central Register and 200 000 sex- and age-matched controls were identified in the Danish Central Person Register. Both groups were searched for in the Danish National Patient Register in which admissions to all somatic departments are registered. Pulmonary and cardiovascular diseases are used as examples. Results: RR is increased for several diseases, especially infectious, up to a maximum of RR=4.15 for severe heart failures and decreased to as low as RR=0.35 for atherosclerotic diseases of the brain vessels. Conclusion: It seems that individuals with schizophrenia are rarely treated for their physical illness in its early, less severe phases, but more likely in its acute phases when the disease is severe, life-threatening or painful. [ABSTRACT FROM AUTHOR]

Infantile autism is a heterogenous disorder with unknown aetiology. Evidence from the relatively few family and twin studies suggests a genetic component. Co-occurrence or cosegregation between infantile autism and chromosomal abnormalities may identify candidate regions, which could be tested in linkage or association studies. The purpose of this study was to use the Danish Cytogenetic Central Register in order to detect autosomal chromosome abnormalities associated with infantile autism, and to review the literature for cases of autism associated with autosomal chromosome abnormalities to identify candidate chromosomal regions. The register-based study identified possible candidate regions on chromosome 7q21 and 10q21.2, which have not previously been reported. A few interesting candidate regions, 15q11-13, 16q23, and 17p11.2 were found in the literature survey. [ABSTRACT FROM AUTHOR]

DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase (AADC), is an enzyme involved in the synthesis of the important neurotransmitters dopamine, norepinephrine, and serotonin. In addition, it participates in the synthesis of trace amines; compounds suggested to act as endogenous modulators of central neurotransmission. Thus, DDC is regarded as a potential susceptibility gene for a variety of neuropsychiatric disorders. The aim of the present study was to examine the role of DDC in bipolar affective disorder (BPAD). By screening 10 individuals for sequence variations in the coding region of the DDC gene as well as in the neuron-specific promoter and 5' untranslated regions we were able to identify two fairly frequent variants: a 1-bp deletion in the promoter and a 4-bp deletion in the untranslated exon 1. Both deletions affect putative binding sites for known transcription factors, suggesting a possible functional impact at the level of expression. The two variants were applied in an association study including 80 Danish bipolar patients, 112 English bipolar patients, 223 Danish controls, and 349 English controls. Analyzing the combined material, a significant association was found between the 1-bp deletion and BPAD with P-values of 0.037 (allelic) and 0.021 (genotypic). The frequency of the 1-bp deletion was 13.3% in patients and 9.4% in controls with a corresponding odds ratio of 1.48 (95% CI: 1.02-2.15). The results presented suggest that DDC may act as a minor susceptibility gene for bipolar affective disorder. [ABSTRACT FROM AUTHOR]