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1.  Altered resting-state functional connectivity in late-life depression: a cross-sectional study 
Journal of affective disorders  2015;189:126-133.
Disrupted brain connectivity is implicated in the pathophysiology of late-life depression (LLD). There are few studies in this area using resting-state functional magnetic resonance imaging (rs-fMRI). In this pilot case-control study, we compare rs-fMRI data between age-matched depressed and non-depressed older adults.
Older participants (≥ 55 years) with current major depressive disorder (MDD) were recruited to participate in an ongoing study of LLD, and were compared to the age-matched, non-depressed controls. Rs-fMRI data were collected using a 3-Tesla MRI system. In this study, a data-driven approach was chosen and an independent component analysis (ICA) was performed.
Seventeen subjects with MDD were compared to 31 controls. The depressed group showed increased connectivity in three main networks compared to the controls (p(corr) < 0.05), including connectivity between the default mode network (DMN) and the posterior superior temporal sulcus (pSTS). Increased connectivity was also observed within the visual network in the medial, lateral and ventral regions of the occipital lobes, and within the auditory network throughout the right superior temporal cortex.
This data-driven, pilot study finds patterns of increased connectivity that may be unique to LLD in the DMN, as well as visual and auditory networks. The functional implications of this aberrant connectivity remains to be determined. These findings should be further explored in larger samples.
PMCID: PMC4640990  PMID: 26433760
Late-life; geriatric depression; functional connectivity; neuroimaging; fMRI
2.  NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression 
Neuropsychopharmacology  2015;40(11):2510-2516.
Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors.
PMCID: PMC4569958  PMID: 25801500
3.  Clinical advances in geriatric psychiatry: a focus on prevention of mood and cognitive disorders 
The world’s population is ageing in the 21st century at a rate unprecedented in human history, and this will place substantial pressure on health systems across the world along with concurrent rises in chronic diseases. In particular, rates of cognitive disorders and late-life affective disorders are expected to rise. In correlation with ageing, there are robust predictions suggesting rates of age-related cognitive decline and dementia, and geriatric depression, will rise with serious consequences. Clearly innovative prevention and treatment strategies are needed. Here we reviewed the latest promising clinical advances which hold promise for assisting the prevention and treatment of depression and cognitive decline and dementia.
PMCID: PMC4548274  PMID: 26300035
Late-life; psychiatry; cognitive decline; mood disorder; depression; prevention; treatment
4.  Clinical, Functional, and Biological Correlates of Cognitive Dimensions in Major Depressive Disorder – Rationale, Design, and Characteristics of the Cognitive Function and Mood Study (CoFaM-Study) 
Cross-sectional and longitudinal studies exploring clinical, functional, and biological correlates of major depressive disorder are frequent. In this type of research, depression is most commonly defined as a categorical diagnosis based on studies using diagnostic instruments. Given the phenotypic and biological heterogeneity of depression, we chose to focus the phenotypic assessments on three cognitive dimensions of depression including (a) cognitive performance, (b) emotion processing, and (c) social cognitive functioning. Hence, the overall aim of the study is to investigate the long-term clinical course of these cognitive dimensions in depression and its functional (psychosocial) correlates. We also aim to identify biological “genomic” correlates of these three cognitive dimensions of depression. To address the above overall aim, we created the Cognition and Mood Study (CoFaMS) with the key objective to investigate the clinical, functional, and biological correlates of cognitive dimensions of depression by employing a prospective study design and including a healthy control group. The study commenced in April 2015, including patients with a primary diagnosis of a major depressive episode of major depressive disorder or bipolar disorder according to DSM-IV-TR criteria. The assessments cover the three cognitive dimensions of depression (cognitive performance, emotion processing, and social cognition), cognitive function screening instrument, plus functional scales to assess general, work place, and psychosocial function, depression symptom scales, and clinical course of illness. Blood is collected for comprehensive genomic discovery analyses of biological correlates of cognitive dimensions of depression. The CoFaM-Study represents an innovative approach focusing on cognitive dimensions of depression and its functional and biological “genomic” correlates. The CoFaMS team welcomes collaborations with both national and international researchers.
PMCID: PMC4999943  PMID: 27616997
depression; cognitive dimensions; cognitive function; emotion processing; social cognition; biological correlates; genomic biomarkers
5.  Online information seeking by patients with bipolar disorder: results from an international multisite survey 
Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information.
A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data.
976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor.
Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.
Electronic supplementary material
The online version of this article (doi:10.1186/s40345-016-0058-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4995194  PMID: 27552813
6.  Health Behaviors, Knowledge, Life Satisfaction, and Wellbeing in People with Mental Illness across Four Countries and Comparisons with Normative Sample 
People with chronic mental illness have poorer physical health and higher mortality than the general population. We investigated lifestyle factors in people with mental illness across four countries and compared with a normative sample.
Design and methods
Data were collected from N = 672 people (Germany, n = 375; Palestine, n = 192; London, n = 63; Australia, n = 42) with substance abuse disorder (n = 224), schizophrenia (n = 158), mood disorders (n = 227), and somatoform disorders (n = 63). The General Health Behaviour Questionnaire measured behaviors and knowledge related to nutrition, physical activity, alcohol, smoking, sleep, life satisfaction, and wellbeing. The normative samples were derived from a German population (N = 1,019). Data were analyzed using ANOVAs and t-tests.
The Palestine sample did not differ from the Western samples on reported life satisfaction and wellbeing. However, they reported unhealthier diets, less physical activity, and lower knowledge about the impact of diet, physical activity, smoking, and sleep on health than the Western samples. Comparing the Western and normative samples, people with mental illness reported lower intake of healthy foods/drinks, higher intake of unhealthy foods, higher exercise, higher alcohol consumption, less cigarettes, less sleep, and more sleep problems. Their knowledge was lower for nutrition, physical activity, and smoking. All participants reported lower life satisfaction and wellbeing than the normative sample (P-values <0.001).
Education on health-related lifestyle factors present important targets for primary care, quality of life and prevention of illness in people with mental illness. Further research will clarify specific predictors of health behaviors in each country.
PMCID: PMC4993073  PMID: 27597833
mental illness; diet; lifestyle; sleep; health knowledge; education
7.  Elevated neutrophil to lymphocyte ratio predicts mortality in medical inpatients with multiple chronic conditions 
Medicine  2016;95(23):e3832.
Neutrophil to lymphocyte ratio (NLR) is an easy measurable laboratory marker used to evaluate systemic inflammation. Elevated NLR is associated with poor survival and increased morbidity in cancer and cardiovascular disease. However, the usefulness of NLR to predict morbidity and mortality in a hospital setting for patients with multiple chronic conditions has not been previously examined. In this study, we investigate the association between NLR and mortality in multimorbid medical inpatients. Two hundred thirty medical in-patients with chronic conditions were selected from a single academic medical center in Taiwan. Retrospective NLRs were calculated from routine full blood counts previously obtained during the initial hospital admission and at the time of discharge. Self-rated health (using a single-item question), medical disorders, depressive symptoms, and medical service utilization over a 1-year period were included in the analyses. Mortality outcomes were ascertained by reviewing electronic medical records and follow-up. The mortality rate at 2-year follow-up was 23%. Depression (odds ratio [OR] 1.9 [95% CI 1.0–3.7]), poor self-rated health (OR 2.1 [95% CI 1.1–3.9]), being hospitalized 2 or more times in the previous year (OR 2.3 [95% CI 1.2–4.6]), metastatic cancer (OR 4.7 [95% CI 2.3–9.7]), and chronic liver disease (OR 4.3 [95% CI 1.5–12.1]) were associated with 2-year mortality. The median (interquartile range) NLR at admission and discharge were 4.47 (2.4–8.7) and 3.65 (2.1–6.5), respectively. Two-year mortality rates were higher in patients with an elevated NLR at admission (NLR <3 = 15.5%, NLR >3 = 27.6%) and discharge (NLR < 3 = 14.7%, NLR >3 = 29.1%). Multivariate logistic regression demonstrated that an elevated NLR >3.0 at admission (OR 2.3 [95% CI 1.0–5.2]) and discharge (OR 2.3 [95% CI 1.1–5.0]) were associated with mortality independent of baseline age, sex, education, metastatic cancer, liver disease, depression, and previous hospitalization. Increased NLR is associated with mortality among medical inpatients with multiple chronic conditions. NLR may provide added value to predict both risk of mortality for the inpatients with chronic conditions, in addition to allowing predictions of likely hospital service needs such as re-admissions that are associated with long-term mortality.
PMCID: PMC4907663  PMID: 27281085
chronic conditions; medical service use; mortality; neutrophil-lymphocyte ratio
8.  Pcdh19 Loss-of-Function Increases Neuronal Migration In Vitro but is Dispensable for Brain Development in Mice 
Scientific Reports  2016;6:26765.
Protocadherin 19 (Pcdh19) is an X-linked gene belonging to the protocadherin superfamily, whose members are predominantly expressed in the central nervous system and have been implicated in cell-cell adhesion, axon guidance and dendrite self-avoidance. Heterozygous loss-of-function mutations in humans result in the childhood epilepsy disorder PCDH19 Girls Clustering Epilepsy (PCDH19 GCE) indicating that PCDH19 is required for brain development. However, understanding PCDH19 function in vivo has proven challenging and has not been studied in mammalian models. Here, we validate a murine Pcdh19 null allele in which a β-Geo reporter cassette is expressed under the control of the endogenous promoter. Analysis of β-Geo reporter activity revealed widespread but restricted expression of PCDH19 in embryonic, postnatal and adult brains. No gross morphological defects were identified in Pcdh19+/β-Geo and Pcdh19Y/β-Geo brains and the location of Pcdh19 null cells was normal. However, in vitro migration assays revealed that the motility of Pcdh19 null neurons was significantly elevated, potentially contributing to pathogenesis in patients with PCDH19 mutations. Overall our initial characterization of Pcdh19+/β-Geo, Pcdh19β-Geo/β-Geo and Pcdh19Y/β-Geomice reveals that despite widespread expression of Pcdh19 in the CNS, and its role in human epilepsy, its function in mice is not essential for brain development.
PMCID: PMC4886214  PMID: 27240640
9.  Hot Topics in Research: Preventive Neuroradiology in Brain Aging and Cognitive Decline 
Preventive neuroradiology is a new concept supported by a growing literature. The main rationale of preventive neuroradiology is the application of multi-modal brain imaging towards early and subclinical detection of brain disease and subsequent preventive actions through identification of modifiable risk factors. An insightful example of this is in the area of age-related cognitive decline, mild cognitive impairment and dementia with potentially modifiable risk factors such as obesity, diet, sleep, hypertension, diabetes, depression, supplementation, smoking and physical activity. In studying this link between lifestyle and cognitive decline, brain imaging markers may be instrumental as quantitative measures or even indicators of early disease. The purpose of this article is to provide an overview of the major studies reflecting how lifestyle factors affect the brain and cognition ageing. In this hot topics review we will specifically focus on obesity and physical activity.
PMCID: PMC4600413  PMID: 26045577
10.  Cardiovascular Health in Anxiety or Mood Problems Study (CHAMPS): study protocol for a randomized controlled trial 
Trials  2016;17:18.
Previous psychological and pharmacological interventions have primarily focused on depression disorders in populations with cardiovascular diseases (CVDs) and the efficacy of anxiety disorder interventions is only more recently being explored. Transdiagnostic interventions address common emotional processes and the full range of anxiety and depression disorders often observed in populations with CVDs. The aim of CHAMPS is to evaluate the feasibility of a unified protocol (UP) for the transdiagnostic treatment of emotional disorders intervention in patients recently hospitalized for CVDs. The current study reports the protocol of a feasibility randomized controlled trial to inform a future trial.
This is a feasibility randomized, controlled trial with a single-center design. A total of 50 participants will be block-randomized to either a UP intervention or enhanced usual care. Both groups will receive standard CVD care. The UP intervention consists of 1) enhancing motivation, readiness for change, and treatment engagement; (2) psychoeducation about emotions; (3) increasing present focused emotion awareness; (4) increasing cognitive flexibility; (5) identifying and preventing patterns of emotion avoidance and maladaptive emotion-driven behaviors (EDBs, including tobacco smoking, and alcohol use); (6) increasing tolerance of emotion-related physical sensations; (7) interoceptive and situation-based emotion-focused exposure; and (8) relapse prevention strategies. Treatment duration is 12 to 18 weeks. Relevant outcomes include the standard deviation of self-rated anxiety, depression and quality of life symptoms. Other outcomes include intervention acceptability, satisfaction with care, rates of EDBs, patient adherence, physical activity, cardiac and psychiatric readmissions. Parallel to the main trial, a nonrandomized comparator cohort will be recruited comprising 150 persons scoring below the predetermined depression and anxiety severity thresholds.
CHAMPS is designed to evaluate the UP for the transdiagnostic treatment of emotional disorders targeting emotional disorder processes in a CVD population. The design will provide preliminary evidence of feasibility, attrition, and satisfaction with treatment to design a definitive trial. If the trial is feasible, it opens up the possibility for interventions to target broader emotional processes in the precarious population with CVD and emotional distress.
Trial registration
ACTRN12615000555550, registered on 29/05/2015
PMCID: PMC4707770  PMID: 26754447
Depression; major depression; anxiety; anxiety disorders; cardiovascular disease; coronary heart disease; randomized controlled trial; cognitive behavioral therapy; diagnosis; prognosis
11.  The Enemy within: Innate Surveillance-Mediated Cell Death, the Common Mechanism of Neurodegenerative Disease 
Neurodegenerative diseases comprise an array of progressive neurological disorders all characterized by the selective death of neurons in the central nervous system. Although, rare (familial) and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death. Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response. Innate surveillance is the cell's quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an “intelligent system,” in that the manner of response is relevant to the magnitude and duration of the threat. If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site. If the danger signal persists, then the ultimate response can include not only the programmed cell death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitized cells. These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes. Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harboring these mutations may have an amplified response to innate-mediated damage in neural tissues, and renders innate surveillance mediated cell death a plausible common pathogenic pathway responsible for neurodegenerative diseases, in both familial and sporadic forms. Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death.
PMCID: PMC4862319  PMID: 27242399
dementia; innate autoimmunity; inflammation; neurodegeneration; Alzheimer's; Parkinson's; Huntington's
12.  Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge 
Neuropsychopharmacology  2014;40(2):502-512.
Peripheral cytokines affect central nervous system (CNS) function, manifesting in symptoms of anxiety and cognitive decline. Although the peripheral blockage of tumor necrosis factor (TNF)-α has been effective in alleviating depression and rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated the effects of central etanercept administration following a peripheral immune challenge on anxiety-like and cognition-like behaviors and microglia and astrocyte numbers. Twelve-week-old C57BL/6 mice (n=40) were treated with either LPS or saline administered peripherally 24 h before being treated with either etanercept or artificial CSF (aCSF) by intracerebroventricular injection. Mice underwent behavioral analyses for locomotion, memory, and anxiety-like behavior 24 h post-etanercept/aCSF treatment, and tissue was collected to estimate the numbers of hippocampal microglia and astrocytes. Following peripheral immune challenge with LPS, mice showed increased anxiety-like behavior, which was significantly improved following treatment with etanercept (two-way ANOVA: Interaction: F(1,30)=0.60, P=0.44; Saline/LPS challenge: F(1,30)=23.92, P<0.0001, etanercept vs aCSF: F(1,30)=11.09, P=0.0023). For cognition, a significant interaction effect found by two-way ANOVA (Interaction: F(1,20)=4.96, P=0.037, Saline/LPS challenge: F(1,20)=4.966, P=0.31, aCSF/etanercept treatment: F(1,20)=0.06, P=0.80) and post-hoc analysis revealed a significant decrease in cognition in LPS-aCSF compared with Sal-aCSF mice (P=0.038), but no significant difference was noted between LPS-aCSF and LPS-Etan mice (P>0.9). A significant reduction in the number of microglia within the hippocampus of these mice was noted (two-way ANOVA: Interaction: F(1,15)=11.41, P=0.0041; Saline/LPS challenge: F(1,15)=50.13, P<0.0001, etanercept vs aCSF: F(1,15)=3.36, P=0.08). Centrally administered etanercept improved anxiety-like behavior but not spatial memory under a peripheral immune challenge and was associated with a decrease in the hippocampal microglia numbers. This suggests that etanercept recovers anxiety-like behavior possibly mediated by a reduction of TNF-α-related central inflammation.
PMCID: PMC4443965  PMID: 25103178
13.  Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders 
Clinical Epigenetics  2015;7:122.
Stressor exposure during early life has the potential to increase an individual’s susceptibility to a number of neuropsychiatric conditions such as mood and anxiety disorders and schizophrenia in adulthood. This occurs in part due to the dysfunctional stress axis that persists following early adversity impairing stress responsivity across life. The mechanisms underlying the prolonged nature of this vulnerability remain to be established. Alterations in the epigenetic signature of genes involved in stress responsivity may represent one of the neurobiological mechanisms. The overall aim of this review is to provide current evidence demonstrating changes in the epigenetic signature of candidate gene(s) in response to early environmental adversity. More specifically, this review analyses the epigenetic signatures of postnatal adversity such as childhood abuse or maltreatment and later-life psychopathology in human and animal models of early life stress. The results of this review shows that focus to date has been on genes involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and its correlation to subsequent neurobiology, for example, the role of glucocorticoid receptor gene. However, epigenetic changes in other candidate genes such as brain-derived neurotrophic factor (BDNF) and serotonin transporter are also implicated in early life stress (ELS) and susceptibility to adult psychiatric disorders. DNA methylation is the predominantly studied epigenetic mark followed by histone modifications specifically acetylation and methylation. Further, these epigenetic changes are cell/tissue-specific in regulating expression of genes, providing potential biomarkers for understanding the trajectory of early stress-induced susceptibility to adult psychiatric disorders.
PMCID: PMC4650349  PMID: 26583053
Early life stress; Maternal separation; Epigenetics; DNA methylation; Stress-responsive genes; Histone acetylation; Psychopathology
14.  Poor Self-Rated Health Influences Hospital Service Use in Hospitalized Inpatients With Chronic Conditions in Taiwan 
Medicine  2015;94(36):e1477.
Our aim was to investigate the association between self-rated health (SRH) and use of hospital services (ie, medical outpatient department, emergency department, and general ward. admissions). Cross-sectional study data were collected from 230 consecutive patients admitted to medical departments of a 2000-bed academic medical center in Taiwan using standardized operating procedures for data collection of SRH (ie, a single-item question inquiring overall perceived health status), medical disorders, depressive symptoms, and combined service utilization over a 1-year period (ie, number of visits to outpatient department, number of visits to emergency department, and number of hospitalizations). Electronic medical records were retrieved, with self-reported external medical visits added to in-hospital frequencies of service use to provide better estimation of health service utilization. Fifty-two percent of study patients rated their health as poor or very poor. Poor SRH was associated with more visits to medical outpatient department, emergency department, and hospital admission. Multivariate logistic regression demonstrated an independent association between poor SRH and services utilization after adjustment for age, gender, hypertension, diabetes, metastatic cancer, number of chronic illness, life-threatening event, life-time suicidal ideation, and depression. SRH may be a useful research tool to model medical service use for inpatients with chronic conditions.
PMCID: PMC4616650  PMID: 26356706
15.  Symptom severity of depressive symptoms impacts on social cognition performance in current but not remitted major depressive disorder 
Frontiers in Psychology  2015;6:1118.
The aim of the present study was to investigate the social cognitive functioning of participants with depression when compared with healthy controls, and to assess the impact of symptom severity. One hundred and eight patients with depression (66 remitted and 42 current) and 52 healthy controls were assessed using the Wechsler Advanced Clinical Solutions: Social Perception Subtest, measuring facial affect recognition in isolation and in combination with prosody and body language interpretation. When healthy controls, remitted depression and currently depressed groups were compared, no associations were found on any of the social cognition subscales. Severity of depressive and anxious symptoms predicted performance on all social cognition subscales in currently depressed participants, controlling for age, gender, education and psychotropic medication. Affective depressive symptoms were inversely related to ACS Pairs and Prosody subscales, while somatic symptoms were inversely related to the ACS Affect Recognition and Total scores. There was no association between severity and the WAIS ACS in remitted depression participants. People with MDD exhibiting more severe depressive and anxious symptoms and a cluster of affective symptoms have greater difficulty undertaking complex social cognitive tasks. Given the state like nature to these deficits, these impairments may cause problems with day to day functioning and have implications in targeted therapeutic interventions.
PMCID: PMC4523699  PMID: 26300814
major depressive disorder; social cognition; facial affect; prosody; depressive symptoms
16.  14-3-3ζ deficient mice in the BALB/c background display behavioural and anatomical defects associated with neurodevelopmental disorders 
Scientific Reports  2015;5:12434.
Sequencing and expression analyses implicate 14-3-3ζ as a genetic risk factor for neurodevelopmental disorders such as schizophrenia and autism. In support of this notion, we recently found that 14-3-3ζ−/− mice in the Sv/129 background display schizophrenia-like defects. As epistatic interactions play a significant role in disease pathogenesis we generated a new congenic strain in the BALB/c background to determine the impact of genetic interactions on the 14-3-3ζ−/− phenotype. In addition to replicating defects such as aberrant mossy fibre connectivity and impaired spatial memory, our analysis of 14-3-3ζ−/− BALB/c mice identified enlarged lateral ventricles, reduced synaptic density and ectopically positioned pyramidal neurons in all subfields of the hippocampus. In contrast to our previous analyses, 14-3-3ζ−/− BALB/c mice lacked locomotor hyperactivity that was underscored by normal levels of the dopamine transporter (DAT) and dopamine signalling. Taken together, our results demonstrate that dysfunction of 14-3-3ζ gives rise to many of the pathological hallmarks associated with the human condition. 14-3-3ζ-deficient BALB/c mice therefore provide a novel model to address the underlying biology of structural defects affecting the hippocampus and ventricle, and cognitive defects such as hippocampal-dependent learning and memory.
PMCID: PMC4513550  PMID: 26207352
17.  A genome-wide association study points to multiple loci predicting antidepressant treatment outcome in depression 
Archives of general psychiatry  2009;66(9):966-975.
Efficacy of antidepressant treatment in depression is unsatisfactory as one in three patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome.
To identify genetic and clinical determinants of antidepressant treatment outcome in depression.
Genome-wide pharmacogenetic association study with two independent replication samples.
We performed a genome-wide association (GWA) study in patients from the Munich-Antidepressant-Response-Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single nucleotide polymorphisms (SNPs) highly related to outcome in both GWA studies was genotyped in a sample of the Sequenced-Treatment-Alternatives-to-Relieve-Depression (STAR*D) study.
339 inpatients suffering from a depressive episode (MARS sample), further 361 depressed inpatients (German replication sample), and 832 outpatients with major depression (STAR*D sample).
Main Outcome Measures
We generated a multi-locus genetic variable describing the individual number of alleles of the selected SNPs associated with beneficial treatment outcome in the MARS sample (“response” alleles) to evaluate additive genetic effects on antidepressant treatment outcome.
Multi-locus analysis revealed a significant contribution of a binary variable categorizing patients as carriers of a high vs. low number of response alleles in predicting antidepressant treatment outcome in both samples, MARS and STAR*D. In addition, we observed that patients with a comorbid anxiety disorder in combination with a low number of response alleles showed the least favorable outcome.
Our results demonstrate the importance of multiple genetic factors in combination with clinical features to predict antidepressant treatment outcome underscoring the multifactorial nature of this trait.
PMCID: PMC4465570  PMID: 19736353
18.  Effects of physical exercise on central nervous system functions: a review of brain region specific adaptations 
Pathologies of central nervous system (CNS) functions are involved in prevalent conditions such as Alzheimer’s disease, depression, and Parkinson’s disease. Notable pathologies include dysfunctions of circadian rhythm, central metabolism, cardiovascular function, central stress responses, and movement mediated by the basal ganglia. Although evidence suggests exercise may benefit these conditions, the neurobiological mechanisms of exercise in specific brain regions involved in these important CNS functions have yet to be clarified. Here we review murine evidence about the effects of exercise on discrete brain regions involved in important CNS functions. Exercise effects on circadian rhythm, central metabolism, cardiovascular function, stress responses in the brain stem and hypothalamic pituitary axis, and movement are examined. The databases Pubmed, Web of Science, and Embase were searched for articles investigating regional brain adaptations to exercise. Brain regions examined included the brain stem, hypothalamus, and basal ganglia. We found evidence of multiple regional adaptations to both forced and voluntary exercise. Exercise can induce molecular adaptations in neuronal function in many instances. Taken together, these findings suggest that the regional physiological adaptations that occur with exercise could constitute a promising field for elucidating molecular and cellular mechanisms of recovery in psychiatric and neurological health conditions.
PMCID: PMC4461979  PMID: 26064521
Exercise; Neurophysiology; Neurobiology; Brain stem; Hypothalamus; Basal nuclei; Disease; Depression; Stress; Neurodegenerative Diseases
19.  The Relationship of Serum Macrophage Inhibitory Cytokine – 1 Levels with Gray Matter Volumes in Community-Dwelling Older Individuals 
PLoS ONE  2015;10(4):e0123399.
Using circulating inflammatory markers and magnetic resonance imaging (MRI), recent studies have associated inflammation with brain volumetric measures. Macrophage Inhibitory Cytokine–1 (MIC-1/GDF15) is a divergent transforming growth factor – beta (TGF-β) superfamily cytokine. To uncover the underlying mechanisms of the previous finding of a negative association between MIC-1/GDF15 serum levels and cognition, the present study aimed to examine the relationship of circulating MIC-1/GDF15 levels with human brain gray matter (GM) volumes, in a community-dwelling sample aged 70–90 years over two years (Wave 1: n = 506, Wave 2: n = 327), of which the age-related brain atrophy had been previously well defined. T1-weighted MRI scans were obtained at both waves and analyzed using the FMRIB Software Library and FreeSurfer. The results showed significantly negative associations between MIC-1/GDF15 serum levels and both subcortical and cortical GM volumes. GM volumes of the whole brain, cortex, temporal lobe, thalamus and accumbens showed significant mediating effects on the associations between MIC-1/GDF15 serum levels and global cognition scores. Increases in MIC-1/GDF15 serum levels were associated with decreases in cortical and subcortical GM volume over two years. In conclusion, MIC-1/GDF15 serum levels were inversely associated with GM volumes both cross-sectionally and longitudinally.
PMCID: PMC4395016  PMID: 25867953
20.  Associations between depression subtypes, depression severity and diet quality: cross-sectional findings from the BiDirect Study 
BMC Psychiatry  2015;15:38.
Depression is supposed to be associated with an unhealthy lifestyle including poor diet. The objective of this study was to investigate differences in diet quality between patients with a clinical diagnosis of depression and population-based controls. Additionally, we aimed to examine effects of specific depression characteristics on diet by analyzing if diet quality varies between patients with distinct depression subtypes, and if depression severity is associated with diet quality.
The study included 1660 participants from the BiDirect Study (n = 840 patients with depression, n = 820 population-based controls). The psychiatric assessment was based on clinical interviews and a combination of depression scales in order to provide the classification of depression subtypes and severity. Diet quality scores, reflecting the adherence to a healthy dietary pattern, were calculated on the basis of an 18-item food frequency questionnaire. Using analysis of covariance, we calculated adjusted means of diet quality scores and tested differences between groups (adjusted for socio-demographic, lifestyle-, and health-related factors).
We found no differences in diet quality between controls and patients with depression if depression was considered as one entity. However, we did find differences between patients with distinct subtypes of depression. Patients with melancholic depression reported the highest diet quality scores, whereas patients with atypical depression reported the lowest scores. Depression severity was not associated with diet quality.
Previous literature has commonly treated depression as a homogeneous entity. However, subtypes of depression may be associated with diet quality in different ways. Further studies are needed to enlighten the diet-depression relationship and the role of distinct depression subtypes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-015-0426-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4355144  PMID: 25886444
Depression; Depression subtypes; Depression severity; Nutrition; Diet; Diet quality; Lifestyle
21.  Systematic Review of the Neurobiological Relevance of Chemokines to Psychiatric Disorders 
Psychiatric disorders are highly prevalent and disabling conditions of increasing public health relevance. Much recent research has focused on the role of cytokines in the pathophysiology of psychiatric disorders; however, the related family of immune proteins designated chemokines has been relatively neglected. Chemokines were originally identified as having chemotactic function on immune cells; however, recent evidence has begun to elucidate novel, brain-specific functions of these proteins of relevance to the mechanisms of psychiatric disorders. A systematic review of both human and animal literature in the PubMed and Google Scholar databases was undertaken. After application of all inclusion and exclusion criteria, 157 references were remained for the review. Some early mechanistic evidence does associate select chemokines with the neurobiological processes, including neurogenesis, modulation of the neuroinflammatory response, regulation of the hypothalamus–pituitary–adrenal axis, and modulation of neurotransmitter systems. This early evidence however does not clearly demonstrate any specificity for a certain psychiatric disorder, but is primarily relevant to mechanisms which are shared across disorders. Notable exceptions include CCL11 that has recently been shown to impair hippocampal function in aging – of distinct relevance to Alzheimer’s disease and depression in the elderly, and pre-natal exposure to CXCL8 that may disrupt early neurodevelopmental periods predisposing to schizophrenia. Pro-inflammatory chemokines, such as CCL2, CCL7, CCL8, CCL12, and CCL13, have been shown to drive chemotaxis of pro-inflammatory cells to the inflamed or injured CNS. Likewise, CX3CL has been implicated in promoting glial cells activation, pro-inflammatory cytokines secretion, expression of ICAM-1, and recruitment of CD4+ T-cells into the CNS during neuroinflammatory processes. With further translational research, chemokines may present novel diagnostic and/or therapeutic targets in psychiatric disorders.
PMCID: PMC4564736  PMID: 26441528
depression; Alzheimer’s disease; neurogenesis; chemokine; schizophrenia; inflammation; immune; neurodegeneration
22.  A Review of the Role of Social Cognition in Major Depressive Disorder 
Background: Social cognition – the ability to identify, perceive, and interpret socially relevant information – is an important skill that plays a significant role in successful interpersonal functioning. Social cognitive performance is recognized to be impaired in several psychiatric conditions, but the relationship with major depressive disorder is less well understood. The aim of this review is to characterize the current understanding of: (i) the different domains of social cognition and a possible relationship with major depressive disorder, (ii) the clinical presentation of social cognition in acute and remitted depressive states, and (iii) the effect of severity of depression on social cognitive performance.
Methods: Electronic databases were searched to identify clinical studies investigating social cognition in a major depressive disorder population, yielding 31 studies for this review.
Results: Patients with major depressive disorder appear to interpret social cognitive stimuli differently to healthy controls: depressed individuals may interpret emotion through a mood-congruent bias and have difficulty with cognitive theory of mind tasks requiring interpretation of complex mental states. Social cognitive performance appears to be inversely associated with severity of depression, whilst the bias toward negative emotions persists even in remission. Some deficits may normalize following effective pharmacotherapy.
Conclusions: The difficulties with social interaction observed in major depressive disorder may, at least in part, be due to an altered ability to correctly interpret emotional stimuli and mental states. These features seem to persist even in remission, although some may respond to intervention. Further research is required in this area to better understand the functional impact of these findings and the way in which targeted therapy could aid depressed individuals with social interactions.
PMCID: PMC4263091  PMID: 25566100
social cognition; major depressive disorder; depression; facial affect; theory of mind
23.  Changes in Insulin Resistance and HbA1c Are Related to Exercise-Mediated Changes in Body Composition in Older Adults With Type 2 Diabetes 
Diabetes Care  2013;36(8):2372-2379.
To investigate changes in body composition after 12 months of high-intensity progressive resistance training (PRT) in relation to changes in insulin resistance (IR) or glucose homeostasis in older adults with type 2 diabetes.
One-hundred three participants were randomized to receive either PRT or sham exercise 3 days per week for 12 months. Homeostasis model assessment 2 of insulin resistance (HOMA2-IR) and glycosylated hemoglobin (HbA1c) were used as indices of IR and glucose homeostasis. Skeletal muscle mass (SkMM) and total fat mass were assessed using bioelectrical impedance. Visceral adipose tissue, mid-thigh cross-sectional area, and mid-thigh muscle attenuation were quantified using computed tomography.
Within the PRT group, changes in HOMA2-IR were associated with changes in SkMM (r = −0.38; P = 0.04) and fat mass (r = 0.42; P = 0.02). Changes in visceral adipose tissue tended to be related to changes in HOMA2-IR (r = 0.35; P = 0.07). Changes in HbA1c were related to changes in mid-thigh muscle attenuation (r = 0.52; P = 0.001). None of these relationships were present in the sham group (P > 0.05). Using ANCOVA models, participants in the PRT group who had increased SkMM had decreased HOMA2-IR (P = 0.05) and HbA1c (P = 0.09) compared with those in the PRT group who lost SkMM. Increases in SkMM in the PRT group decreased HOMA2-IR (P = 0.07) and HbA1c (P < 0.05) compared with those who had increased SkMM in the sham group.
Improvements in metabolic health in older adults with type 2 diabetes were mediated through improvements in body composition only if they were achieved through high-intensity PRT.
PMCID: PMC3714491  PMID: 23474589
24.  Establishing the bidirectional relationship between depression and subclinical arteriosclerosis – rationale, design, and characteristics of the BiDirect Study 
BMC Psychiatry  2014;14:174.
Depression and cardiovascular diseases due to arteriosclerosis are both frequent and impairing conditions. Depression and (subclinical) arteriosclerosis appear to be related in a bidirectional way, and it is plausible to assume a partly joint causal relationship. However, the biological mechanisms and the behavioral pathways that lead from depression to arteriosclerosis and vice versa remain to be exactly determined.
This study protocol describes the rationale and design of the prospective BiDirect Study that aims at investigating the mutual relationship between depression and (subclinical) arteriosclerosis. BiDirect is scheduled to follow-up three distinct cohorts of individuals ((i) patients with acute depression (N = 999), (ii) patients after an acute cardiac event (N = 347), and (iii) reference subjects from the general population (N = 912)). Over the course of 12 years, four personal examinations are planned to be conducted. The core examination program, which will remain identical across follow-ups, comprises a personal interview (e.g. medical diagnoses, health care utilization, lifestyle and risk behavior), a battery of self-administered questionnaires (e.g. depressive symptoms, readiness to change health behavior, perceived health-related quality of life), sensory (e.g. olfaction, pain) and neuropsychological (e.g. memory, executive functions, emotional processing, manual dexterity) assessments, anthropometry, body impedance measurement, a clinical work-up regarding the vascular status (e.g. electrocardiogram, blood pressure, intima media thickness), the taking of blood samples (serum and plasma, DNA), and structural and functional resonance imaging of the brain (e.g. diffusion tensor imaging, resting-state, emotional faces processing). The present report includes BiDirect-Baseline, the first data collection wave.
Due to its prospective character, the integration of three distinct cohorts, the long follow-up time window, the diligent diagnosis of depression taking depression subtypes into account, the consideration of relevant comorbidities and risk factors, the assessment of indicators of (subclinical) arteriosclerosis in different vascular territories, and the structural and functional brain imaging that is performed for a large number of participants, the BiDirect Study represents an innovative approach that combines population-based cohorts with sophisticated clinical work-up methods and that holds the potential to overcome many of the drawbacks characterizing earlier investigations.
PMCID: PMC4065391  PMID: 24924233
Depression; Depression subtypes; Arteriosclerosis; Cardiovascular; Cerebrovascular; (f)MRI; White matter hyperintensities; Prospective cohort study; Bidirectional
25.  Reductions in C-reactive protein in older adults with type 2 diabetes are related to improvements in body composition following a randomized controlled trial of resistance training 
Reductions in skeletal muscle mass and increased adiposity are key elements in the aging process and in the pathophysiology of several chronic diseases. Systemic low grade inflammation associated with obesity has been shown to accelerate the age-related decline in skeletal muscle. The aim of this investigation was to determine the effects of 12 months of progressive resistance training (PRT) on systemic inflammation, and whether reductions in systemic inflammation were associated with changes in body composition. We hypothesized that reductions in systemic inflammation following 12 months of PRT in older adults with type 2 diabetes would be associated with reductions in adiposity and increases in skeletal muscle mass.
Participants (n = 103) were randomized to receive either PRT or sham-exercise, 3 days a week for 12 months. C-reactive protein (CRP) was used to assess systemic inflammation. Skeletal muscle mass and total fat mass were determined using bioelectrical impedance.
Twelve months of PRT tended to reduce CRP compared to sham exercise (β = −0.25, p = 0.087). Using linear mixed-effects models, the hypothesized relationships between body composition adaptations and CRP changes were significantly stronger for skeletal muscle mass (p = 0.04) and tended to be stronger for total fat mass (p = 0.07) following PRT when compared to sham-exercise. Using univariate regression models, stratified by group allocation, reductions in CRP were associated with increases in skeletal muscle mass (p = 0.01) and reductions in total fat mass (p = 0.02) in the PRT group, but not in the sham-exercise group (p = 0.87 and p = 0.32, respectively).
We have shown for the first time that reductions in systemic inflammation in older adults with type 2 diabetes following PRT were associated with increases in skeletal muscle mass. Furthermore, reductions in CRP were associated with reductions in adiposity, but only when associated with PRT. Lifestyle interventions aimed at reducing systemic inflammation in older adults with type 2 diabetes should therefore incorporate anabolic exercise such as PRT to optimize the anti-inflammatory benefits of favorable body composition adaptations.
PMCID: PMC4053559  PMID: 24687180
PRT; Inflammation; Body composition; Skeletal muscle; Adiposity

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