Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and ...single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.
The arginine-serine (RS)-rich domain of the SR protein ASF/SF2 is phosphorylated by SR protein kinases (SRPKs) and Clk/Sty kinases. However, the mode of phosphorylation by these kinases and their ...coordination in the biological regulation of ASF/SF2 is unknown. Here, we report the crystal structure of an active fragment of human SRPK1 bound to a peptide derived from an SR protein. This structure led us to identify a docking motif in ASF/SF2. We find that this docking motif restricts phosphorylation of ASF/SF2 by SRPK1 to the N-terminal part of the RS domain — a property essential for its assembly into nuclear speckles. We further show that Clk/Sty causes release of ASF/SF2 from speckles by phosphorylating the C-terminal part of its RS domain. These results suggest that the docking motif of ASF/SF2 is a key regulatory element for sequential phosphorylation by SRPK1 and Clk/Sty and, thus, is essential for its subcellular localization.
A number of recent longitudinal outcome studies have found substantial long-term morbidity in patients with bipolar disorder. The detailed course and pattern of illness emerging despite comprehensive ...treatment with mood stabilizers and adjunctive agents have previously not been well delineated.
258 consecutive outpatients admitted from 1996 to 1999 to the Stanley Foundation Bipolar Network who had a full year of prospective daily clinician ratings on the National Institute of Mental Health-Life Chart Method were included in the analysis. Patients were diagnosed by the Structured Clinical Interview for DSM-IV, with the majority (76%) having bipolar I disorder. They completed a questionnaire on demographics and prior illness course, and variables associated with outcome were examined in a hierarchical multinomial logistic regression analysis. Patients were treated naturalistically with a mean of 4.1 psychotropic medications during the year.
Despite comprehensive pharmacologic treatment, mean time depressed (33.2% of the year) was 3-fold higher than time manic (10.8%); 62.8% of patients had 4 or more mood episodes per year. Two thirds of the patients were substantially impacted by their illness; 26.4% were ill for more than three fourths of the year, and 40.7% were intermittently ill with major affective episodes. After logistic regression analysis, those who were ill most of the year, compared with the largely well group, had a significantly greater family history of substance abuse, 10 or more depressive episodes, and limited occupational functioning prior to Network entry.
A majority of outpatients with bipolar illness, even with intense monitoring and treatment in specialty clinics, have a considerable degree of residual illness-related morbidity, including a 3-fold greater amount of time spent depressed versus time spent manic. A personal or family history of substance abuse, 10 or more prior depressions, and limited occupational functioning predicted the poorest outcomes. Additional interventions, particularly those targeted at treating depressive phases of bipolar illness, are greatly needed.
Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman ATF. Prevalence and predictors of recurrence of major depressive disorder in the adult population.
Objective: Knowledge of the risk of ...recurrence after recovery of a major depressive disorder (MDD) is of clinical and scientific importance. The purpose of this paper was to provide a systematic review of the prevalence and predictors of recurrence of MDD.
Method: Studies were searched in Medline en PsychINFO using the search terms ‘recur*’, ‘relaps*’, ‘depress*’, ‘predict*’ and course.
Results: Recurrence of MDD in specialised mental healthcare settings is high (60% after 5 years, 67% after 10 years and 85% after 15 years) and seems lower in the general population (35% after 15 years). Number of previous episodes and subclinical residual symptoms appear to be the most important predictors. Gender, civil status and socioeconomic status seem not related to the recurrence of MDD.
Conclusion: Clinical factors seem the most important predictors of recurrence. Data from studies performed in the general population and primary care on the recurrent course of MDD are scarce.
Background: There is growing awareness of the association between physical and sexual abuse and subsequent development of psychopathology, but little is known, however, about their relationship to ...the longitudinal course of bipolar disorder.
Methods: We evaluated 631 outpatients with bipolar I or II disorder for general demographics, a history of physical or sexual abuse as a child or adolescent, course of illness variables, and prior suicide attempts, as well as SCID-derived Axis I and patient endorsed Axis II comorbidity.
Results: Those who endorsed a history of child or adolescent physical or sexual abuse, compared with those who did not, had a history of an earlier onset of bipolar illness, an increased number of Axis I, II, and III comorbid disorders, including drug and alcohol abuse, faster cycling frequencies, a higher rate of suicide attempts, and more psychosocial stressors occurring before the first and most recent affective episode. The retrospectively reported associations of early abuse with a more severe course of illness were validated prospectively.
Conclusions: Greater appreciation of the association of early traumatic experiences and an adverse course of bipolar illness should lead to preventive and early intervention approaches that may lessen the associated risk of a poor outcome.
Knowledge of the risk of recurrence after recovery from major depressive disorder (MDD) in the general population is scarce.
Data were derived from 687 subjects in the general population with a ...lifetime DSM-III-R diagnosis of MDD but without a current major depressive episode (MDE) or dysthymia. Participants had to be at least 6 months in remission, and were recruited from The Netherlands Mental Health Survey and Incidence Study (NEMESIS), using the composite international diagnostic interview (CIDI). Recency and severity of the last MDE were assessed retrospectively at baseline. Recurrence of MDD was measured prospectively during the 3-year follow-up. Kaplan-Meier survival curves were used to measure time to recurrence. Determinants of time to recurrence were analyzed using proportional hazard models.
The estimated cumulative recurrence of MDD was 13.2% at 5 years, 23.2% at 10 years and 42.0% at 20 years. In bivariate analysis, the following variables predicted a shorter time to recurrence: younger age, younger age of onset, higher number of previous episodes, a severe last depressive episode, negative youth experiences, ongoing difficulties before recurrence and high neuroticism. Multivariably, younger age, a higher number of previous episodes, a severe last depressive episode, negative youth experiences and ongoing difficulties remained significant.
In this community sample, the long-term risk of recurrence was high, but lower than that found in clinical samples. Subjects who had had an MDE had a long-term vulnerability for recurrence. Factors predicting recurrence included illness- and stress-related factors.
The Office of Science of the Department of Energy is currently considering options for an advanced radioactive beam facility in the U.S. A committee, the Rare Isotope Science Assessment Committee, ...has been formed under the auspices of the Board of Physics and Astronomy of the National Academies of Science and Engineering with the charge of assessing the importance of and prospects for future research in this field world-wide. There is interest in identifying opportunities for a facility in the U.S. that will complement the capabilities that will exist elsewhere. There is an on-going R&D program sponsored by the DOE to develop the technologies that are essential to both the production of and use of beams of intense exotic beams at next-generation facilities. This paper presents the status of planning and options for such a facility, as well as, progress in the R&D. This program is developing concepts and prototypes for high power superconducting heavy ion linacs for rare isotope production and high power targets, ion sources, fragment separators, gas catchers, and reacceleration technologies that support the delivery of high quality, intense beams of exotic isotopes for research.
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