Abstract Background Evidence suggests that long-term trajectories of depressive symptoms vary greatly throughout the population, with some individuals experiencing few or no symptoms, some ...experiencing transient symptoms and others experiencing chronic depression. The goal of this paper is to review studies that examined heterogeneity in long-term trajectories of depressive symptoms and summarize the current knowledge regarding (a) the number and patterns of trajectories and (b) antecedents and outcomes associated with different trajectory patterns. Methods We conducted a systematic review of literature in the Medline and PsychINFO databases. Articles were included if they (a) modeled trajectories of depressive symptoms, (b) used a group-based trajectory modeling approach, (c) followed participants for 5+ years and (d) had a sample size of at least 200. Results We identified 25 studies from 24 separate cohorts. Most of the studies identified either 3 or 4 distinct trajectory classes. Trajectories varied in terms of severity (low, medium, high) and stability (stable, increasing, decreasing). In most studies, the majority of participants had consistently few or no depressive symptoms, but a notable minority (usually <10%) reported persistent symptoms. Predictors of trajectories with greater symptom burden included female gender, lower income/education and non-white race. Other predictors were specific to different populations (e.g. mothers, older adults). High symptom burden trajectories were associated with poor psychiatric and social outcomes. Limitations Comparisons between studies were qualitative. Conclusions Trajectories of depression symptoms in the general population are heterogeneous, with most individuals showing minimal symptoms but a notable minority experiencing chronic high symptom burden.
Accumulating evidence indicates that DNA copy number variation (CNV) is likely to make a significant contribution to human diversity and also play an important role in disease susceptibility. Recent ...advances in genome sequencing technologies have enabled the characterization of a variety of genomic features, including CNVs. This has led to the development of several bioinformatics approaches to detect CNVs from next-generation sequencing data. Here, we review recent advances in CNV detection from whole genome sequencing. We discuss the informatics approaches and current computational tools that have been developed as well as their strengths and limitations. This review will assist researchers and analysts in choosing the most suitable tools for CNV analysis as well as provide suggestions for new directions in future development.
•Lithium declined by more than double to ~15% of visits for bipolar disorder in the US.•SGAs or mood stabilizing anticonvulsants increased to ~75%.•Polytherapy increased by ~3% every two ...years.•Antidepressants without other mood stabilizers decreased to ~7.5%.
Studies have shown that rates of lithium use for bipolar disorder in the United States declined through the 1990s as other mood stabilizing anticonvulsants and second-generation antipsychotics (SGAs) became more popular. We examined trends of medications for bipolar disorder from 1996 to 2015.
Twenty years of data from the National Ambulatory Medical Care Survey (NAMCS) were used. Weighted percentages of reported use of lithium, anticonvulsants, SGAs and antidepressants were calculated over two-year intervals. Logistic regression was used to examine factors related to polytherapy.
Reported use of lithium declined from 38.1% (95%CI: 29.8% - 46.3%) in 1996–97 to 14.3% (95%CI: 10.6% - 18.1%) in 2006–07 and has remained stable since. During this time, reports of SGAs more than doubled. SGAs and/or anticonvulsants were reported in 75.4% (95%CI: 69.5% - 81.3%) of visits with bipolar diagnoses in 2014–15. Polytherapy increased by approximately 3% every two years and in 2014–15 occurred in over 30% of visits. Antidepressants were reported in 40–50% of visits, but their reported use without other mood stabilizers decreased from 18.2% (95%CI: 11.7% - 24.8%) in 1998–99 to 7.5% (95%CI: 4.2% - 10.9%) in 2014–15.
The sample had limited power to study the effect of individual medications or the potential for differing effects in certain sub-groups of patients.
This study further documents the declining use of lithium for bipolar disorder, and corresponding increase in use of anticonvulsants and SGAs, despite the fact that lithium is typically recommended as a first line therapy for bipolar disorder.
Item 9 of the Patient Health Questionnaire (PHQ) evaluates passive thoughts of death or self-injury within the last two weeks, and is often used to screen depressed patients for suicide risk. We ...aimed to validate the PHQ-9 item 9 with a brief electronic version of the Columbia Suicide Severity Rating Scale (eC-SSRS).
We analyzed data from 841 patients enrolled in the National Network of Depression Centers Clinical Care Registry. We performed a validation analysis of PHQ-9 item 9 for suicide risk and ideation, using the eC-SSRS as a gold standard (defined as positive response to suicidal ideation with intent to act or recent suicidal behavior).
Of the 841 patients, 13.4% and 41.1% were assessed as being positive for suicide risk by the eC-SSRS and PHQ-9 item 9, respectively. For the overall cohort, sensitivity was 87.6% (95%CI 80.2–92.5%), specificity was 66.1% (95%CI 62.6–69.4%), PPV was 28.6% (95%CI 24.1–33.6%), and NPV was 97.2% (95%CI 95.3–98.3%) for the PHQ-9 suicide item. These performance measures varied within subgroups defined by demographic and clinical characteristics. In addition, the validity of PHQ-9 item 9 (cutoff score of 1) with eC-SSRS-defined suicide ideation showed overall poor results.
The gold standard used in our study was a surrogate measure of suicidality based on eC-SSRS scores.
The results of our study suggest that item 9 of the PHQ-9 is an insufficient assessment tool for suicide risk and suicide ideation, with limited utility in certain demographic and clinical subgroups that requires further investigation.
•The PHQ-9 item 9 is an insufficient assessment tool for suicide risk and ideation.•The PHQ-9 item 9 has limited utility in certain subgroups.•The PHQ-9 item 9 should be used with a validated suicide risk inventory.
Observational studies suggest reduced risk of Alzheimer disease (AD) in users of hormone therapy (HT), but trials show higher risk. We examined whether the association of HT with AD varies with ...timing or type of HT use.
Between 1995 and 2006, the population-based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT. During this interval, 176 women developed incident AD. Cox proportional hazard models evaluated the association of HT use with AD, overall and in relation to timing, duration of use, and type (opposed vs unopposed) of HT.
Women who used any type of HT within 5 years of menopause had 30% less risk of AD (95% confidence interval 0.49-0.99), especially if use was for 10 or more years. By contrast, AD risk was not reduced among those who had initiated HT 5 or more years after menopause. Instead, rates were increased among those who began "opposed" estrogen-progestin compounds within the 3 years preceding the Cache County Study baseline (adjusted hazard ratio 1.93; 95% confidence interval 0.94-3.96). This last hazard ratio was similar to the ratio of 2.05 reported in randomized trial participants assigned to opposed HT.
Association of HT use and risk of AD may depend on timing of use. Although possibly beneficial if taken during a critical window near menopause, HT (especially opposed compounds) initiated in later life may be associated with increased risk. The relation of AD risk to timing and type of HT deserves further study.
Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ...ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Rationale
Chronic dysregulation of hypothalamus–pituitary–adrenal (HPA) axis activity is related to several neuropsychiatric disorders. Studies suggest that cortisol response to stress has a strong ...genetic etiology, and that FK506 binding protein 5 (FKBP5) and G-protein coupled type-I CRH receptor (CRHR1) are key proteins regulating response. Variations in the genes encoding these proteins,
FKBP5
and
CRHR1
, have been associated with several neuropsychiatric disorders.
Objectives
We examined variation in these genes in relation to cortisol response to psychological stress in one of the largest Trier Social Stress Test (TSST) cohorts yet examined.
Methods
A total of 368 healthy, young adults underwent the TSST. Salivary cortisol was measured at multiple time points before and after the stressor. Nine variants in
FKBP5
and four in
CRHR1
were assessed. Single marker analyses were conducted. Secondary analyses assessed haplotypes and interaction with stress-related variables.
Results
The strongest association was for rs4713902 in
FKBP5
with baseline cortisol (
p
dom
= 0.0004). We also identified a male-specific effect of
FKBP5
polymorphisms on peak response and response area under the curve (
p
= 0.0028 for rs3800374). In
CRHR1,
rs7209436, rs110402, and rs242924 were nominally associated with peak response (
p
rec
= 0.0029–0.0047). We observed interactions between trait anxiety and rs7209436 and rs110402 in
CRHR1
in association with baseline cortisol (
p
LRT
= 0.0272 and
p
LRT
= 0.0483, respectively).
Conclusions
We show association of variants in
FKBP5
and
CRHR1
with cortisol response to psychosocial stress. These variants were previously shown to be associated with neuropsychiatric disorders. These findings have implications for interindividual variation in HPA axis activity and potentially for the etiology of neuropsychiatric disorders.
The synapse is integral to the function of the brain and may be an important source of dysfunction underlying many neuropsychiatric disorders. Consequently, it is an excellent candidate for ...large-scale genomic and proteomic study. However, while the tools and databases available for the annotation of high-throughput DNA and protein are generally robust, a comprehensive resource dedicated to the integration of information about the synapse is lacking.
We present an integrated database, called SynaptomeDB, to retrieve and annotate genes comprising the synaptome. These genes encode components of the synapse including neurotransmitters and their receptors, adhesion/cytoskeletal proteins, scaffold proteins, membrane transporters. SynaptomeDB integrates various and complex data sources for synaptic genes and proteins.
Numerous genome-wide gene expression studies of bipolar disorder (BP) have been carried out. These studies are heterogeneous, underpowered and use overlapping samples. We conducted a systematic ...review of these studies to synthesize the current findings.
We identified all genome-wide gene expression studies on BP in humans. We then carried out a quantitative mega-analysis of studies done with post-mortem brain tissue. We obtained raw data from each study and used standardized procedures to process and analyze the data. We then combined the data and conducted three separate mega-analyses on samples from 1) any region of the brain (9 studies); 2) the prefrontal cortex (PFC) (6 studies); and 3) the hippocampus (2 studies). To minimize heterogeneity across studies, we focused primarily on the most numerous, recent and comprehensive studies.
A total of 30 genome-wide gene expression studies of BP done with blood or brain tissue were identified. We included 10 studies with data on 211 microarrays on 57 unique BP cases and 229 microarrays on 60 unique controls in the quantitative mega-analysis. A total of 382 genes were identified as significantly differentially expressed by the three analyses. Eleven genes survived correction for multiple testing with a q-value < 0.05 in the PFC. Among these were FKBP5 and WFS1, which have been previously implicated in mood disorders. Pathway analyses suggested a role for metallothionein proteins, MAP Kinase phosphotases, and neuropeptides.
We provided an up-to-date summary of results from gene expression studies of the brain in BP. Our analyses focused on the highest quality data available and provided results by brain region so that similarities and differences can be examined relative to disease status. The results are available for closer inspection on-line at Metamoodics http://metamoodics.igm.jhmi.edu/, where investigators can look up any genes of interest and view the current results in their genomic context and in relation to leading findings from other genomic experiments in bipolar disorder.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cognitive impairment is a common feature of the major psychotic disorders, with deficits often present in at risk individuals and unaffected first-degree relatives. Previous studies have suggested ...that polygenic risk scores (PRS) for schizophrenia (SCZ) are associated with cognitive deficits, but there has been little examination of this association in longitudinal datasets, or comparison with other disorders. We used mixed models to study the association between PRS for 4 adult onset psychiatric disorders with cross-sectional cognitive performance and longitudinal cognitive decline in 8616 older adults from the Health and Retirement Study (HRS), followed for an average of 10 years. PRS were computed for SCZ, bipolar disorder (BD), Major Depressive Disorder (MDD), and Alzheimer's disease (ALZ). SCZ PRS associated with decreased cognitive function (z = -3.00, P = .001, ΔR (2) = 0.04%), which was largely driven by an association with impaired attention and orientation (z = -3.33, P = 4.3×10(-4), ΔR (2) = 0.08%). We found no effect of BD or MDD PRS on cognition, in contrast to a robust effect of the APOE4/TOMM40 locus (z = -5.05, P = 2.2×10(-7), ΔR (2) = 0.36%), which was primarily associated with impaired verbal memory (z = -5.15, P = 1.3×10(-7), ΔR (2) = 0.21%). APOE4/TOMM40 locus and the ALZ PRS, but not the PRS for SCZ, were associated with greater cognitive decline. In summary, using a large, representative sample of older adults, we found evidence for different degrees of association between polygenic risk for SCZ and genetic risk factors for ALZ on cognitive function and decline, highlighting potential differences in the pathophysiology of cognitive deficits seen in SCZ and ALZ.
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