The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize ...that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to ∼0.7% of the variance in depression in Rotterdam Study and up to ∼1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples.
Over the last decades, several individual studies on sex differences in carotid atherosclerosis have been performed covering a wide range of plaque characteristics and including different ...populations. This systematic review and meta-analysis aims to summarize previously reported results on sex differences in carotid atherosclerosis and present a roadmap explaining next steps needed for implementing this knowledge in clinical practice.
We systematically searched PubMed, Embase, Web of Science, Cochrane Central, and Google Scholar for eligible studies including both male and female participants reporting prevalence of imaging characteristics of carotid atherosclerosis and meta-analyzed these studies. Studies had to report at least the following: (1) calcifications; (2) lipid-rich necrotic core; (3) intraplaque hemorrhage; (4) thin-or-ruptured fibrous cap; (5) plaque ulceration; (6) degree of stenosis; (7) plaque size; or (8) plaque inflammation. We prespecified which imaging modalities had to be used per plaque characteristic and excluded ultrasonography.
We included 42 articles in our meta-analyses (ranging from 2 through 23 articles per plaque characteristic). Men had more frequently a larger plaque compared to women and, moreover, had more often plaques with calcifications (odds ratio=1.57 95% CI, 1.23-2.02), lipid-rich necrotic core (odds ratio=1.87 95% CI, 1.36-2.57), and intraplaque hemorrhage (odds ratio=2.52 95% CI, 1.74-3.66), or an ulcerated plaque (1.81 95% CI, 1.30-2.51). Furthermore, we found more pronounced sex differences for lipid-rich necrotic core in symptomatic opposed to asymptomatic participants.
In this systematic review and meta-analysis, we demonstrate convincing evidence for sex differences in carotid atherosclerosis. All kinds of plaque features-plaque size, composition, and morphology-were more common or larger in men compared to women. Our results highlight that sex is an important variable to include in both study design and clinical-decision making. Further investigation of sex-specific stroke risks with regard to plaque composition is warranted.
Highlight • There is increased 11 C-( R )-PK11195 binding in the right hippocampus in bipolar I disorder, consistent with the monocyte-T-cell theory of mood disorders.
Few studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression.
To examine the relative acute effects ...of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers.
In a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers.
A total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49-53%) and remission (34-41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline.
More caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.
Highlights • This study integrates hippocampal volume, metabolites and neuroinflammation. • Hippocampal volumes did not differ between patient and control group. • Some metabolites were decreased in ...the left hippocampus of patients. • There was a positive relation between microglial activation and neuronal viability. • This supports a differentiated microglial function.
Clinical differentiation between bipolar disorder (BD) and major depressive disorder (MDD) is difficult. Research has therefore focused on discriminatory biological markers. Previous studies in MDD ...reported T cell deficits, while the limited studies in BD reported T cell activation. Studies directly comparing circulating numbers of T cells and T cell subsets between BD and MDD are lacking. The studies in the MOODINFLAME consortium make such a comparison possible.
The number of circulating leukocyte populations (lymphocytes, monocytes, NK cells, B cells, T cells, CD3+CD8+ T cytotoxic cells, CD3+CD4+ T helper cells, Th1, Th2, Th17 and T regulatory cells) was determined using FACS technology in a cohort of 83 euthymic BD patients, 8 BD patients with a current mood episode and 165 healthy controls (HC). Data were compared to those of 34 moderately and 56 severely depressed MDD patients.
Compared to MDD patients, BD patients showed significantly increased levels of Th17, Th2, Th1 and T regulatory cells (all p < .02). In BD patients, levels of Th17 and T regulatory cells were increased compared to HC (p = .03, p = .02, respectively), while MDD patients showed decreased levels of Th17 and Th2 compared to HC (p = .03, p = .01, respectively). Of the various medications only SSRI/SNRI usage could explain part of the Th2 decrease in MDD.
This study shows CD4+ T helper cell deficits in MDD patients, while normal or even raised levels of these cells were found in BD patients. The differences in CD4+ T helper cell differentiation was most outspoken for Th17 cells.
•There are T helper cell differentiation deficits in MDD patients compared to HC.•There may be overactive T cell differentiation in BD patients compared to HC.•BD patients show increased levels of Th17, Th2, Th1 an Treg cells compared to MDD.•Th17 cell levels may differentiate MDD from BD patients.
The Plaque At RISK (PARISK) study demonstrated that patients with a carotid plaque with intraplaque hemorrhage (IPH) have an increased risk of recurrent ipsilateral ischemic cerebrovascular events. ...It was previously reported that symptomatic carotid plaques with IPH showed higher IPH signal intensity ratios (SIR) and larger IPH volumes than asymptomatic plaques. We explored whether IPH SIR and IPH volume are associated with future ipsilateral ischemic cerebrovascular events beyond the presence of IPH.
Transient ischemic attack and ischemic stroke patients with mild-to-moderate carotid stenosis and an ipsilateral IPH-positive carotid plaque (n = 89) from the PARISK study were included. The clinical endpoint was a new ipsilateral ischemic cerebrovascular event during 5 years of follow-up, while the imaging-based endpoint was a new ipsilateral brain infarct on brain magnetic resonance imaging (MRI) after 2 years (n = 69). Trained observers delineated IPH, a hyperintense region compared to surrounding muscle tissue on hyper T1-weighted magnetic resonance images. The IPH SIR was the maximal signal intensity in the IPH region divided by the mean signal intensity of adjacent muscle tissue. The associations between IPH SIR or volume and the clinical and imaging-based endpoint were investigated using Cox proportional hazard models and logistic regression, respectively.
During 5.1 (interquartile range: 3.1–5.6) years of follow-up, 21 ipsilateral cerebrovascular ischemic events were identified. Twelve new ipsilateral brain infarcts were identified on the 2-year neuro MRI. There was no association for IPH SIR or IPH volume with the clinical endpoint (hazard ratio (HR): 0.89 95% confidence interval: 0.67–1.10 and HR: 0.91 0.69–1.19 per 100-µL increase, respectively) nor with the imaging-based endpoint (odds ratio (OR): 1.04 0.75–1.45 and OR: 1.21 0.87–1.68 per 100-µL increase, respectively).
IPH SIR and IPH volume were not associated with future ipsilateral ischemic cerebrovascular events. Therefore, quantitative assessment of IPH of SIR and volume does not seem to provide additional value beyond the presence of IPH for stroke risk assessment. Trial registration: The PARISK study was registered on ClinicalTrials.gov with ID NCT01208025 on September 21, 2010 (https://clinicaltrials.gov/study/NCT01208025).
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In the current DTI study we compared euthymic bipolar I disorder (BD-I) patients and healthy controls (HC). We subsequently divided the total patient group into lithium-users and non-lithium-users ...and estimated differences across the three groups.
Twenty-one euthymic BD-I patients and twenty-two HC participants were included in psychiatric interviews and MRI image acquisition (diffusion-weighted (DW) and T1-weighted scans). Fractional anisotropy (FA), radial, mean and axial diffusivity (RD, MD, AD) were estimated from the DW data, using DTI. These measures were then compared between groups using FSL Tract Based Spatial Statistics (TBSS). Correlations with age at onset, number of episodes and depression score were analyzed.
A difference in FA, MD, RD and AD between the whole sample of euthymic BD-I patients and healthy controls could not be detected. Amongst others, lithium-using patients demonstrated a higher FA and lower RD when compared to non-lithium-using BD-I patients in the corpus callosum and left anterior corona radiata. Widespread clusters demonstrated negative FA associations and positive RD and MD associations with minor depressive symptoms.
Patients were naturalistically treated. Although the sample size is comparable to several other DTI studies, a larger sample size would have been benificial. TBSS and DTI have their own limitations.
Our findings support the theory that previously described DTI-based microstructural differences between HC and BD patients could be less pronounced in euthymic BD patients. Differences in FA between patients using and not using lithium suggest a counteracting effect of lithium on white matter microstructural disturbances.
•White matter aberrations are less pronounced in euthymic BD patients.•Lithium probably has a counteracting effect on white matter disturbances.•FA is widespread negatively correlated with minor depressive symptoms.
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•Feature-expression heat maps provide insight into complex associations.•It utilizes effect ordered data display on two variable sets.•Effect size (color) and statistical significance ...(radius) are depicted in circles.•Its applications are found in complex biological systems.
Existing methods such as correlation plots and cluster heat maps are insufficient in the visual exploration of multiple associations between genetics and phenotype, which is of importance to achieve a better understanding of the pathophysiology of psychiatric and other illnesses. The implementation of a combined presentation of effect size and statistical significance in a graphical method, added to the ordering of the variables based on the effect-ordered data display principle was deemed useful by the authors to facilitate in the process of recognizing meaningful patterns in these associations.
The requirements, analyses and graphical presentation of the feature-expression heat map are described. The graphs display associations of two sets of ordered variables where a one-way direction is assumed. The associations are depicted as circles representing a combination of effect size (color) and statistical significance (radius).
An example dataset is presented and relation to other methods, limitations, areas of application and possible future enhancements are discussed.
The feature-expression heat map is a useful graphical instrument to explore associations in complex biological systems where one-way direction is assumed, such as genotype-phenotype pathophysiological models.
Abstract Palmar and finger dermatoglyphics are formed between the 10th and the 17th weeks of gestation and their morphology can be influenced by genetic or environmental factors, interfering with ...normal intrauterine development. As both the skin and the brain develop from the same embryonal ectoderm, dermatoglyphic alterations may be informative for early abnormal neurodevelopmental processes in the brain. We investigated whether dermatoglyphic alterations are related to structural brain abnormalities in bipolar disorder and to what extent they are of a genetic and of an environmental origin. Dermatoglyphics and volumetric data from structural MRI were obtained in 53 twin pairs concordant or discordant for bipolar disorder and 51 healthy matched control twin pairs. Structural equation modeling was used. Bipolar disorder was significantly positively associated with palmar a–b ridge count (ABRC), indicating higher ABRC in bipolar patients (rph=.17 (CI .04–.30)). Common genes appear to be involved because the genetic correlation with ABRC was significant (rph-A=.21 (CI .05-.36). Irrespective of disease, ABRC showed a genetically mediated association with brain volume, indicated by a significant genetic correlation rph-A of respectively −.36 (CI −.52 to −.22) for total brain, −.34 (CI −.51 to −.16) total cortical volume, −.27 (CI −.43 to −.08) cortical gray matter and −.23 (CI −.41 to −.04) cortical white matter. In conclusion, a genetically determined abnormal development of the foetal ectoderm between the 10th and 15th week of gestation appears related to smaller brain volumes in (subjects at risk for) bipolar disorder.
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