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1.  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.
doi:10.3389/fpsyt.2014.00179
PMCID: PMC4263091  PMID: 25566100
social cognition; major depressive disorder; depression; facial affect; theory of mind
2.  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.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc12-2196
PMCID: PMC3714491  PMID: 23474589
3.  Establishing the bidirectional relationship between depression and subclinical arteriosclerosis – rationale, design, and characteristics of the BiDirect Study 
BMC Psychiatry  2014;14:174.
Background
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.
Methods/design
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.
Discussion
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.
doi:10.1186/1471-244X-14-174
PMCID: PMC4065391  PMID: 24924233
Depression; Depression subtypes; Arteriosclerosis; Cardiovascular; Cerebrovascular; (f)MRI; White matter hyperintensities; Prospective cohort study; Bidirectional
4.  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 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1007/s13539-014-0134-1
PMCID: PMC4053559  PMID: 24687180
PRT; Inflammation; Body composition; Skeletal muscle; Adiposity
5.  Knockout of CXCR5 increases the population of immature neural cells and decreases proliferation in the hippocampal dentate gyrus 
Background
The process of neurogenesis in which new neurons are generated by proliferation and differentiation of neural stem/progenitor cells (NSCs/NPCs) has been a topic of intensive recent investigation. Investigations of the factors which regulate this process have recently begun to include immune factors including immune cells and cytokines, however the class of immune proteins designated as chemokines have been relatively neglected. Increasing evidence for novel brain-specific mechanisms of chemokines beyond their classical chemotactic functions has suggested that they may play a role in the regulation of NSC/NPC biology.
Methods
We have investigated the role of the chemokine receptor CXCR5 (ligand is CXCL13) in the activity of these cells through neurobiological and behavioural analysis of CXCR5-deficient mice (CXCR5-/-). These investigations included: immunohistochemistry for the markers Ki67, nestin, doublecortin, and IBA-1, neurosphere assays, and the baseline behavioural tests: open field test and sucrose preference test.
Results
We observed a significant increase in doublecortin and nestin staining in the hippocampal dentate gyrus (P = 0.02 and P = 0.0008, respectively) of CXCR5-/- animals as compared to wild-type controls. This was accompanied by a decrease in Ki67 staining subgranular zone (P = 0.009). Behavioural correlates included a significant increase in baseline locomotor activity in an open field test (P <0.00018) and a decrease in stress reactivity in that test (P = 0.015). Deficiency in CXCR5 was not associated with alterations in hippocampal microglial density, microglial activation or systemic cytokine levels, nor with loss of NSC/NPC populations in the neurosphere assay.
Conclusions
These findings are the first to describe a brain-specific function of CXCR5 under physiological conditions. CXCR5 reduces maintenance of immature neural cell populations and enhances proliferation of subgranular zone cells in the hippocampal dentate gyrus, however the mechanism of these effects remains unclear. Further research into the regulation of NSC/NPC activity should consider investigation of CXCR5 and other chemokines which may be relevant to the pathophysiology of psychiatric disorders including depression, anxiety and cognitive impairment/dementia.
doi:10.1186/1742-2094-11-31
PMCID: PMC3928586  PMID: 24528805
CXCR5; CXCL13; Chemokine; Proliferation; Stem cell; Progenitor cell; Hippocampus; Depression; Cognition
6.  Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment 
Recent studies on environmental enrichment (EE) have shown cytokines, cellular immune components [e.g., T lymphocytes, natural killer (NK) cells], and glial cells in causal relationship to EE in bringing out changes to neurobiology and behavior. The purpose of this review is to evaluate these neuroimmune mechanisms associated with neurobiological and behavioral changes in response to different EE methods. We systematically reviewed common research databases. After applying all inclusion and exclusion criteria, 328 articles remained for this review. Physical exercise (PE), a form of EE, elicits anti-inflammatory and neuromodulatory effects through interaction with several immune pathways including interleukin (IL)-6 secretion from muscle fibers, reduced expression of Toll-like receptors on monocytes and macrophages, reduced secretion of adipokines, modulation of hippocampal T cells, priming of microglia, and upregulation of mitogen-activated protein kinase phosphatase-1 in central nervous system. In contrast, immunomodulatory roles of other enrichment methods are not studied extensively. Nonetheless, studies showing reduction in the expression of IL-1β and tumor necrosis factor-α in response to enrichment with novel objects and accessories suggest anti-inflammatory effects of novel environment. Likewise, social enrichment, though considered a necessity for healthy behavior, results in immunosuppression in socially defeated animals. This has been attributed to reduction in T lymphocytes, NK cells and IL-10 in subordinate animals. EE through sensory stimuli has been investigated to a lesser extent and the effect on immune factors has not been evaluated yet. Discovery of this multidimensional relationship between immune system, brain functioning, and EE has paved a way toward formulating environ-immuno therapies for treating psychiatric illnesses with minimal use of pharmacotherapy. While the immunomodulatory role of PE has been evaluated extensively, more research is required to investigate neuroimmune changes associated with other enrichment methods.
doi:10.3389/fncel.2014.00097
PMCID: PMC3982075  PMID: 24772064
environmental enrichment; immune; cytokines; glial cells; T cells; neurobiology; cognition; behavior
7.  Inflammasomes in neuroinflammation and changes in brain function: a focused review 
Recent literature has pointed to the existence of inflammasome-mediated inflammatory pathways in central nervous system (CNS) disorders and associated changes in behavior. Neuroinflammation, which is an innate immune response in the CNS against harmful and irritable stimuli such as pathogens and metabolic toxic waste, as well as to chronic mild stress, is mediated by protein complexes known as inflammasomes. Inflammasomes activate pro-inflammatory caspases 1 and 5, which then cleave the precursor forms of pro-inflammatory cytokines IL-1β, IL-18, and IL-33 into their active forms. These pro-inflammatory cytokines have been shown to promote a variety of innate immune processes associated with infection, inflammation, and autoimmunity, and thereby play an instrumental role in the instigation of neuroinflammation during old age and subsequent occurrence of neurodegenerative diseases, cognitive impairment, and dementia. In particular, NLRP inflammasomes may also have a role in the etiologies of depression, Alzheimer's disease (AD) and in metabolic disorders, such as Type II diabetes, obesity and cardiovascular diseases that have been shown to be co-morbid with psychiatric illnesses. It has been reported that while these inflammasomes may be activated through TNF-α dependent pathways, other cytokines, like IFN-γ, may assist in inhibiting their activation and thus delay disease progression. Furthermore, some other cytokines, including IL-6, may not have a direct role in inflammasome-mediated diseases. An array of recent research suggests that NLRP inflammasomes targeted therapies could be used for alleviating neuroinflammation and for treatment of associated psychiatric illnesses, although this still remains a challenge and necessitates further extensive research. This review examines the complex inflammatory signaling pathways involved in the activation of NLRP inflammasomes and the role they play in promoting neuroinflammation and subsequent behavioral changes.
doi:10.3389/fnins.2014.00315
PMCID: PMC4188030  PMID: 25339862
inflammasomes; NLRP; neuroinflammation; cytokines; IL-1; aging; depression; Alzheimer's disease
8.  Long-term omega-3 supplementation modulates behavior, hippocampal fatty acid concentration, neuronal progenitor proliferation and central TNF-α expression in 7 month old unchallenged mice 
Dietary polyunsaturated fatty acid (PUFA) manipulation is being investigated as a potential therapeutic supplement to reduce the risk of developing age-related cognitive decline (ARCD). Animal studies suggest that high omega (Ω)-3 and low Ω-6 dietary content reduces cognitive decline by decreasing central nervous system (CNS) inflammation and modifying neuroimmune activity. However, no previous studies have investigated the long term effects of Ω-3 and Ω-6 dietary levels in healthy aging mice leaving the important question about the preventive effects of Ω-3 and Ω-6 on behavior and underlying molecular pathways unaddressed. We aimed to investigate the efficacy of long-term Ω-3 and Ω-6 PUFA dietary supplementation in mature adult C57BL/6 mice. We measured the effect of low, medium, and high Ω-3:Ω-6 dietary ratio, given from the age of 3–7 months, on anxiety and cognition-like behavior, hippocampal tissue expression of TNF-α, markers of neuronal progenitor proliferation and gliogenesis and serum cytokine concentration. Our results show that a higher Ω-3:Ω-6 PUFA diet ratio increased hippocampal PUFA, increased anxiety, improved hippocampal dependent spatial memory and reduced hippocampal TNF-α levels compared to a low Ω-3:Ω-6 diet. Furthermore, serum TNF-α concentration was reduced in the higher Ω-3:Ω-6 PUFA ratio supplementation group while expression of the neuronal progenitor proliferation markers KI67 and doublecortin (DCX) was increased in the dentate gyrus as opposed to the low Ω-3:Ω-6 group. Conversely, Ω-3:Ω-6 dietary PUFA ratio had no significant effect on astrocyte or microglia number or cell death in the dentate gyrus. These results suggest that supplementation of PUFAs may delay aging effects on cognitive function in unchallenged mature adult C57BL/6 mice. This effect is possibly induced by increasing neuronal progenitor proliferation and reducing TNF-α.
doi:10.3389/fncel.2014.00399
PMCID: PMC4240169  PMID: 25484856
polyunsaturated fatty acid; omega 3; TNF-α; neurogenesis; cognition
9.  Brain-derived neurotrophic factor gene polymorphisms, neurotransmitter levels, and depressive symptoms in an elderly population 
Age  2011;34(6):1529-1541.
A large number of studies have examined associations between brain-derived neurotrophic factor (BDNF) gene polymorphisms and depressive symptoms. However, results still remain controversial. Recent studies suggested a significant age and gender effect on the heritability of depression. The potential neurobiological pathways that could possibly mediate this relationship have not been examined so far. Since BDNF is involved in the regulation of neurotransmitter production, a mediating role of neurotransmitters seems plausible. The present study aims to examine the association between three common BDNF single-nucleotid polymorphisms (SNPs; rs7103411, rs7124442, and rs6265) and depressive symptoms in a community-based elderly population taking into account the serum levels of four neurotransmitters, serotonin, dopamine, adrenalin, and noradrenalin, as potential mediating factors. We also examined whether age and gender had a modifying effect on this association. We collected and analyzed the genetic and laboratory data as well as Center for Epidemiologic Studies-Depression scores of 350 community-dwelling elderly individuals (aged 65+ years). We found that the BDNF rs6265 polymorphism was related to the severity of depressive symptoms, and that this association was independent of neurotransmitter levels. Stratified analyses showed that this association was restricted to older individuals (≥74 years) and men. The associations of SNPs rs7103411 or rs7124442 SNP with depressive symptoms were not statistically significant. This study importantly adds to the existing literature by affirming previous assumptions on an age and gender difference in the relation between BDNF genotype and depression. We moreover first-time report a missing mediating role of neurotransmitters in this association.
doi:10.1007/s11357-011-9313-6
PMCID: PMC3528367  PMID: 21898033
Elderly; Depression; Brain-derived neurotrophic factor; Gene polymorphism; Neurotransmitter
10.  The association between systemic inflammation and cognitive performance in the elderly: the Sydney Memory and Ageing Study 
Age  2011;34(5):1295-1308.
Inflammation may contribute to cognitive decline and dementia. This study examined the cross-sectional relationships between markers of systemic inflammation (C-reactive protein, interleukins-1β, -6, -8, -10, -12, plasminogen activator inhibitor, serum amyloid A, tumour necrosis factor-α and vascular adhesion molecule-1) and cognitive function in 873 non-demented community-dwelling elderly participants aged 70–90 years. Regression analyses were performed to determine the relationships between cognitive domains and inflammatory markers, controlling for age, sex, education, cardiovascular risk factors, obesity and other metabolic factors, smoking, alcohol consumption, depression and presence of the apolipoprotein ε4 genotype. Regression analyses were repeated using four factors derived from a factor analysis of the cognitive tests. After Bonferroni correction for multiple testing, associations remained between raised levels of interleukin-12 and reduced performance in processing speed. Marked sex differences were noted in the abovementioned findings, with only females being significantly affected. Using the four factors derived from the factor analyses of cognitive test as dependent variables, interleukins-12 and -6 were both associated with the processing speed/executive function factor, even after controlling for relevant confounding factors. Thus, markers of systemic inflammation are related to cognitive deficits in a non-clinical community-dwelling elderly population, independent of depression, cardiovascular or metabolic risk factors, or presence of apolipoprotein ε4 genotype. Additional research is required to elucidate the pathophysiology and longitudinal development of these relationships.
doi:10.1007/s11357-011-9301-x
PMCID: PMC3448981  PMID: 21853262
Inflammation; Ageing; Cytokines; Inflammaging; Cognition; Dementia
11.  Brain-derived neurotrophic factor (BDNF) gene: a gender-specific role in cognitive function during normal cognitive aging of the MEMO-Study? 
Age  2011;34(4):1011-1022.
Cognitive aging processes are underpinned by multiple processes including genetic factors. The brain-derived neurotrophic factor (BDNF) has been suggested to be involved in age-related cognitive decline in otherwise healthy individuals. The gender-specific role of the BDNF gene in cognitive aging remains unclear. The identification of genetic biomarkers might be a useful approach to identify individuals at risk of cognitive decline during healthy aging processes. The aim of this study was to investigate the associations between three single-nucleotide polymorphisms (SNPs) in the BDNF gene and domains of cognitive functioning in normal cognitive aging. The sample, comprising 369 participants (M = 72.7 years, SD = 4.45 years), completed an extensive neuropsychological test battery measuring memory, motor function, and perceptual speed. The relationships between the SNPs rs6265, rs7103411, and rs7124442 and cognitive domains were examined. While significant main effects of BDNF SNPs on cognitive function were found for the association between rs7103411 and memory performance, gender-specific analyses revealed for females significant main effects of rs7103411 for memory and of rs6265 for perceptual speed independent of the APOE*E4 status and education. The finding for the association between rs6265 and perceptual speed in females remained significant after Bonferroni correction for multiple comparisons. None of the analyses showed significant results for males. This study is the first to implicate that the SNPs rs6265 and rs7103411 affect cognitive function in the elderly in a gender-specific way.
doi:10.1007/s11357-011-9275-8
PMCID: PMC3682062  PMID: 21695421
BDNF; BDNF gene; Memory; Motor function; Perceptual speed; Elderly; Gender
12.  Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report 
Manchia, Mirko | Adli, Mazda | Akula, Nirmala | Ardau, Raffaella | Aubry, Jean-Michel | Backlund, Lena | Banzato, Claudio EM. | Baune, Bernhard T. | Bellivier, Frank | Bengesser, Susanne | Biernacka, Joanna M. | Brichant-Petitjean, Clara | Bui, Elise | Calkin, Cynthia V. | Cheng, Andrew Tai Ann | Chillotti, Caterina | Cichon, Sven | Clark, Scott | Czerski, Piotr M. | Dantas, Clarissa | Zompo, Maria Del | DePaulo, J. Raymond | Detera-Wadleigh, Sevilla D. | Etain, Bruno | Falkai, Peter | Frisén, Louise | Frye, Mark A. | Fullerton, Jan | Gard, Sébastien | Garnham, Julie | Goes, Fernando S. | Grof, Paul | Gruber, Oliver | Hashimoto, Ryota | Hauser, Joanna | Heilbronner, Urs | Hoban, Rebecca | Hou, Liping | Jamain, Stéphane | Kahn, Jean-Pierre | Kassem, Layla | Kato, Tadafumi | Kelsoe, John R. | Kittel-Schneider, Sarah | Kliwicki, Sebastian | Kuo, Po-Hsiu | Kusumi, Ichiro | Laje, Gonzalo | Lavebratt, Catharina | Leboyer, Marion | Leckband, Susan G. | López Jaramillo, Carlos A. | Maj, Mario | Malafosse, Alain | Martinsson, Lina | Masui, Takuya | Mitchell, Philip B. | Mondimore, Frank | Monteleone, Palmiero | Nallet, Audrey | Neuner, Maria | Novák, Tomás | O’Donovan, Claire | Ösby, Urban | Ozaki, Norio | Perlis, Roy H. | Pfennig, Andrea | Potash, James B. | Reich-Erkelenz, Daniela | Reif, Andreas | Reininghaus, Eva | Richardson, Sara | Rouleau, Guy A. | Rybakowski, Janusz K. | Schalling, Martin | Schofield, Peter R. | Schubert, Oliver K. | Schweizer, Barbara | Seemüller, Florian | Grigoroiu-Serbanescu, Maria | Severino, Giovanni | Seymour, Lisa R. | Slaney, Claire | Smoller, Jordan W. | Squassina, Alessio | Stamm, Thomas | Steele, Jo | Stopkova, Pavla | Tighe, Sarah K. | Tortorella, Alfonso | Turecki, Gustavo | Wray, Naomi R. | Wright, Adam | Zandi, Peter P. | Zilles, David | Bauer, Michael | Rietschel, Marcella | McMahon, Francis J. | Schulze, Thomas G. | Alda, Martin
PLoS ONE  2013;8(6):e65636.
Objective
The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.
Materials and Methods
Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.
Results
Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).
Conclusions
We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
doi:10.1371/journal.pone.0065636
PMCID: PMC3686769  PMID: 23840348
13.  Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach 
PLoS ONE  2013;8(6):e64947.
Background
Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment.
Methods
We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples.
Results
In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (Pcorr = .018, Pcorr = .015 and Pcorr = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients.
Conclusions/Limitations
Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies.
doi:10.1371/journal.pone.0064947
PMCID: PMC3672143  PMID: 23750220
14.  Treating Depression and Depression-Like Behavior with Physical Activity: An Immune Perspective 
The increasing burden of major depressive disorder makes the search for an extended understanding of etiology, and for the development of additional treatments highly significant. Biological factors may be useful biomarkers for treatment with physical activity (PA), and neurobiological effects of PA may herald new therapeutic development in the future. This paper provides a thorough and up-to-date review of studies examining the neuroimmunomodulatory effects of PA on the brain in depression and depression-like behaviors. From a neuroimmune perspective, evidence suggests PA does enhance the beneficial and reduce the detrimental effects of the neuroimmune system. PA appears to increase the following factors: interleukin (IL)-10, IL-6 (acutely), macrophage migration inhibitory factor, central nervous system-specific autoreactive CD4+ T cells, M2 microglia, quiescent astrocytes, CX3CL1, and insulin-like growth factor-1. On the other hand, PA appears to reduce detrimental neuroimmune factors such as: Th1/Th2 balance, pro-inflammatory cytokines, C-reactive protein, M1 microglia, and reactive astrocytes. The effect of other mechanisms is unknown, such as: CD4+CD25+ T regulatory cells (T regs), CD200, chemokines, miRNA, M2-type blood-derived macrophages, and tumor necrosis factor (TNF)-α [via receptor 2 (R2)]. The beneficial effects of PA are likely to occur centrally and peripherally (e.g., in visceral fat reduction). The investigation of the neuroimmune effects of PA on depression and depression-like behavior is a rapidly developing and important field.
doi:10.3389/fpsyt.2013.00003
PMCID: PMC3562851  PMID: 23382717
physical activity; exercise; depression; psychiatry; immune; neurobiology
15.  Genome-Wide Association Study of Antidepressant Treatment-Emergent Suicidal Ideation 
Neuropsychopharmacology  2011;37(3):797-807.
Emergence of suicidal ideation (TESI) during treatment with antidepressants in major depression led to a black box warning. We performed a genome-wide association study to identify genetic markers, which increase the risk for this serious side effect. TESI was evaluated in depressed in-patients (N=397) and defined by an emergence of suicidal thoughts during hospitalization without suicidal thoughts at admission using the suicide item (3) of the Hamilton Depression Rating Scale. Genotype distribution of 405.383 single-nucleotide polymorphisms (SNPs) in patients with TESI (N=32/8.1%) was compared to patients without increase in suicidal ideation (N=329/82.9%) and to a subgroup never reported suicidal ideation (N=79/19.9%). Top results were analyzed in an independent sample (N=501). None variant reached genome-wide significance, the best associated SNP was rs1630535 (p-value=1.3 × 10−7). The top 79 SNPs could be analyzed in an independent sample, and 14 variants showed nominal significant association with the same risk allele in the replication sample. A discriminant analysis classifying patients using these 79 SNPs revealed a 91% probability to classify TESI vs non-TESI cases correctly in the replication sample. Although our data need to be interpreted carefully owing to the small numbers in both cohorts, they suggest that a combination of genetic markers might indeed be used to identify patients at risk for TESI.
doi:10.1038/npp.2011.257
PMCID: PMC3260972  PMID: 22030708
suicidal ideation; TESI; suicide; major depression; antidepressants; genetic markers; molecular & cellular neurobiology; psychopharmacology; depression; unipolar; bipolar, pharmacogenetics; pharmacogenomics; suicidal ideation; TESI; suicide; genetic markers; GWAS
16.  Individual development of preschool children-prevalences and determinants of delays in Germany: a cross-sectional study in Southern Bavaria 
BMC Pediatrics  2012;12:188.
Background
Even minor abnormalities of early child development may have dramatic long term consequences. Accurate prevalence rates for a range of developmental impairments have been difficult to establish. Since related studies have used different methodological approaches, direct comparisons of the prevalence of developmental delays are difficult. The understanding of the key factors affecting child development, especially in preschool aged children remains limited. We used data from school entry examinations in Bavaria to measure the prevalence of developmental impairments in pre-school children beginning primary school in 1997–2009.
Methods
The developmental impairments of all school beginners in the district of Dingolfing- Landau, Bavaria were assessed using modified “Bavarian School Entry Model” examination from 1997 to 2009 (N=13,182). The children were assessed for motor, cognitive, language and psychosocial impairments using a standardised medical protocol. Prevalence rates of impairments in twelve domains of development were estimated. Using uni- and multivariable logistic regression models, association between selected factors and development delays were assessed.
Results
The highest prevalence existed for impairments of pronunciation (13.8%) followed by fine motor impairments (12.2%), and impairments of memory and concentration (11.3%) and the lowest for impairments of rhythm of speech (3.1%). Younger children displayed more developmental delays. Male gender was strongly associated with all developmental impairments (highest risk for fine motor impairments = OR 3.22, 95% confidence interval 2.86-3.63). Preschool children with siblings (vs. children without any siblings) were at higher risk of having impairments in pronunciation (OR 1.31, 1.14-1.50). The influence of the non-German nationality was strong, with a maximum risk increase for the subareas of grammar and psychosocial development. Although children with non-German nationality had a reduced risk of disorders for the rhythm of speech and pronunciation, in all other 10 subareas their risk was increased.
Conclusions
In preschool children, most common were delays of pronunciation, memory and concentration. Age effects suggest that delays can spontaneously resolve, but providing support at school entry might be helpful. Boys and migrant children appear at high risk of developmental problems, which may warrant tailored intervention strategies.
doi:10.1186/1471-2431-12-188
PMCID: PMC3549452  PMID: 23216820
17.  KPNA3 Variation Is Associated with Schizophrenia, Major Depression, Opiate Dependence and Alcohol Dependence 
Disease markers  2012;33(4):163-170.
KPNA3 is a gene that has been linked to schizophrenia susceptibility. In this study we investigated the possible association between KPNA3 variation and schizophrenia. To investigate a wider role of KPNA3 across psychiatric disorders we also analysed major depression, PTSD, nicotine dependent, alcohol dependent and opiate dependent cohorts. Using a haplotype block-based gene-tagging approach we genotyped six KPNA3 single nucleotide polymorphisms (SNPs) in 157 schizophrenia patients, 121 post-traumatic stress disorder patients, 120 opiate dependent patients, 231 alcohol dependent patients, 147 nicotine dependent patients and 266 major depression patients. One SNP rs2273816 was found to be significantly associated with schizophrenia, opiate dependence and alcohol dependence at the genotype and allele level. Major depression was also associated with rs2273816 but only at the allele level. Our study suggests that KPNA3 may contribute to the genetic susceptibility to schizophrenia as well as other psychiatric disorders.
doi:10.3233/DMA-2012-0921
PMCID: PMC3810702  PMID: 22960338
KPNA3; genetic; schizophrenia; polymorphism; psychiatric disorder; cross-disorder
18.  Cross-Disorder Analysis of Bipolar Risk Genes: Further Evidence of DGKH as a Risk Gene for Bipolar Disorder, but also Unipolar Depression and Adult ADHD 
Neuropsychopharmacology  2011;36(10):2076-2085.
Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n=387) or adult attention-deficit/hyperactivity disorder (aADHD; n=535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65–243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH.
doi:10.1038/npp.2011.98
PMCID: PMC3158324  PMID: 21654738
association; bipolar disorder; depression; adult ADHD; NPAS3; CMTM8; depression; unipolar/bipolar; neurogenetics; signal transduction; biological psychiatry; association; adult ADHD; NPAS3; CMTM8; EGFR
19.  Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain 
Background
Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated.
Methodology
In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs.
Principal findings/results
In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses.
Conclusions/significance
These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.
doi:10.1186/1742-2094-9-125
PMCID: PMC3464888  PMID: 22695063
Genetics; Inflammation; Interleukin 6; Neuroprotection; Voxel-based morphometry
20.  Systemic inflammation (Interleukin 6) predicts all-cause mortality in men: results from a 9-year follow-up of the MEMO Study 
Age  2010;33(2):209-217.
This study aimed to investigate the association of biomarkers among circulating pro-inflammatory cytokines with all-cause mortality in elderly community dwellings of the MEMO study, Germany. All-cause mortality (cancer, cardiovascular diseases (CVD), and other causes of death) was assessed in a general population sample (N = 385) of the elderly (age 65–83 years) 9 years after baseline assessment in 1998. As markers of inflammation, a variety of cytokines (IL-1beta, IL-4sR, IL-6, IL-8, IL-10, IL-12, TNF-alpha) were assessed in serum. Cox proportional Hazard model was used to estimate the association of cytokines with all-cause mortality over 9 years. In total, 110 deaths had occurred during follow-up (cancer N = 36; CVD N = 56; other = 18). Deaths were more frequent in male (N = 76, 37.4%) as compared to females (N = 40, 21.9%; p = 0.001). Among individual cytokines, IL-1 beta, IL-6, IL-8, IL-10, and TNF-alpha were associated with all-cause mortality, of which IL-6, IL-8, and IL-10 remained significant after adjusting for confounders. When the upper tertiles of these cytokines were compared to the lower tertiles, only IL-6 was consistently related to all-cause mortality independently of the level of adjustment and showing a dose–response relationship between IL-6 tertiles and risk of death. This effect originated in the male population. The study shows that IL-6 is a powerful predictor of all-cause mortality in male elderly community dwellings. Higher levels of IL-6 may reflect a chronic low-level systemic inflammation prospectively increasing the risk of death in the elderly.
doi:10.1007/s11357-010-9165-5
PMCID: PMC3127470  PMID: 20617391
Aging; Inflammation; Mortality; Gender
21.  Obesity and nutrition behaviours in Western and Palestinian outpatients with severe mental illness 
BMC Psychiatry  2011;11:159.
Background
While people with severe mental illness have been found to be more overweight and obese in Western nations, it is unknown to what extent this occurs in Middle Eastern nations and which eating behaviours contribute to obesity in Middle Eastern nations.
Method
A total of 665 responses were obtained from patients with serious mental illness attending out-patient clinics in Western developed countries (Germany, UK and Australia; n = 518) and Palestine (n = 147). Patients were evaluated by ICD-10 clinical diagnosis, anthropometric measurements and completed a self-report measure of frequencies of consuming different food items and reasons for eating. Nutritional habits were compared against a Western normative group.
Results
More participants from Palestine were overweight or obese (62%) compared to Western countries (47%). In the Western sample, obese patients reported consuming more low-fat products (OR 2.54, 95% CI 1.02-6.33) but also greater eating due to negative emotions (OR 1.84, 95% CI 1.31-2.60) than patients with a healthy body-mass index. In contrast, obese patients from Palestine reported increased consumption of unhealthy snacks (OR 3.73 95% CI 1.16-12.00).
Conclusion
Patients with mental illness have poorer nutritional habits than the general population, particularly in Western nations. Separate interventions to improve nutritional habits and reduce obesity are warranted between Western nations and Palestine.
doi:10.1186/1471-244X-11-159
PMCID: PMC3207934  PMID: 21970431
22.  Neuropsychiatric Symptoms in Patients with Aortic Aneurysms 
PLoS ONE  2011;6(7):e22632.
Background
Emerging evidence suggests that vascular disease confers vulnerability to a late-onset of depressive illness and the impairment of specific cognitive functions, most notably in the domains of memory storage and retrieval. Lower limb athero-thrombosis and abdominal aortic aneurysm (AAA) have both been previously associated with neuropsychiatric symptoms possibly due to associated intracerebral vascular disease or systemic inflammation, hence suggesting that these illnesses may be regarded as models to investigate the vascular genesis of neuropsychiatric symptoms. The aim of this study was to compare neuropsychiatric symptoms such as depression, anxiety and a variety of cognitive domains in patients who had symptoms of peripheral athero-thrombosis (intermittent claudication) and those who had an asymptomatic abdominal aortic aneurysm AAA.
Methodology/Principal Findings
In a cross-sectional study, 26 participants with either intermittent claudication or AAA were assessed using a detailed neuropsychiatric assessment battery for various cognitive domains and depression and anxiety symptoms (Hamilton Depression and Anxiety Scales). Student t test and linear regression analyses were applied to compare neuropsychiatric symptoms between patient groups. AAA participants showed greater levels of cognitive impairment in the domains of immediate and delayed memory as compared to patients who had intermittent claudication. Cognitive dysfunction was best predicted by increasing aortic diameter. CRP was positively related to AAA diameter, but not to cognitive function. AAA and aortic diameter in particular were associated with cognitive dysfunction in this study.
Conclusions/Significance
AAA patients are at a higher risk for cognitive impairment than intermittent claudication patients. Validation of this finding is required in a larger study, but if confirmed could suggest that systemic factors peculiar to AAA may impact on cognitive function.
doi:10.1371/journal.pone.0022632
PMCID: PMC3142179  PMID: 21799922
23.  Study of Mental Activity and Regular Training (SMART) in at risk individuals: A randomised double blind, sham controlled, longitudinal trial 
BMC Geriatrics  2011;11:19.
Background
The extent to which mental and physical exercise may slow cognitive decline in adults with early signs of cognitive impairment is unknown. This article provides the rationale and methodology of the first trial to investigate the isolated and combined effects of cognitive training (CT) and progressive resistance training (PRT) on general cognitive function and functional independence in older adults with early cognitive impairment: Study of Mental and Regular Training (SMART). Our secondary aim is to quantify the differential adaptations to these interventions in terms of brain morphology and function, cardiovascular and metabolic function, exercise capacity, psychological state and body composition, to identify the potential mechanisms of benefit and broader health status effects.
Methods
SMART is a double-blind randomized, double sham-controlled trial. One hundred and thirty-two community-dwelling volunteers will be recruited. Primary inclusion criteria are: at risk for cognitive decline as defined by neuropsychology assessment, low physical activity levels, stable disease, and age over 55 years. The two active interventions are computerized CT and whole body, high intensity PRT. The two sham interventions are educational videos and seated calisthenics. Participants are randomized into 1 of 4 supervised training groups (2 d/wk × 6 mo) in a fully factorial design. Primary outcomes measured at baseline, 6, and 18 months are the Alzheimer's Disease Assessment Scale (ADAS-Cog), neuropsychological test scores, and Bayer Informant Instrumental Activities of Daily Living (B-IADLs). Secondary outcomes are psychological well-being, quality of life, cardiovascular and musculoskeletal function, body composition, insulin resistance, systemic inflammation and anabolic/neurotrophic hormones, and brain morphology and function via Magnetic Resonance Imaging (MRI) and Spectroscopy (fMRS).
Discussion
SMART will provide a novel evaluation of the immediate and long term benefits of CT, PRT, and combined CT and PRT on global cognitive function and brain morphology, as well as potential underlying mechanisms of adaptation in older adults at risk of further cognitive decline.
Trial Registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ANZCTRN12608000489392
doi:10.1186/1471-2318-11-19
PMCID: PMC3110111  PMID: 21510896
24.  Free fatty acid receptors: emerging targets for treatment of diabetes and its complications 
Fatty acids (FAs) are important as metabolic substrates and as structural components of biological membranes. However, they also function as signalling molecules. Recently, a series of G protein-coupled receptors (GPRs) for FAs has been described and characterized. These receptors have differing specificities for FAs of differing chain length and degree of saturation, for FA derivatives such as oleoylethanolamide, and for oxidized FAs. They are a critical component of the body's nutrient sensing apparatus, and small molecule agonists and antagonists of these receptors show considerable promise in the management of diabetes and its complications. Agonists of the long-chain free fatty acid receptors FFAR1 and GPR119 act as insulin secretagogues, both directly and by increasing incretins. Although, drugs acting at short-chain FFA receptors (FFAR2 and FFAR3) have not yet been developed, they are attractive targets as they regulate nutrient balance through effects in the intestine and adipose tissue. These include regulation of the secretion of cholecystokinin, peptide YY and leptin. Finally, GPR132 is a receptor for oxidized FAs, which may be a sensor of lipid overload and oxidative stress, and which is involved in atherosclerosis. Regulation of its signalling pathways with drugs may decrease the macrovascular risk experienced by diabetic patients. In summary, FA receptors are emerging drug targets that are involved in the regulation of nutrient status and carbohydrate tolerance, and modulators of these receptors may well figure prominently in the next generation of antidiabetic drugs.
doi:10.1177/2042018810381066
PMCID: PMC3474614  PMID: 23148161
atherosclerosis; diabetes; drug therapies; free fatty acid; G protein-coupled receptor
25.  Hydroxyoctadecadienoic acids: novel regulators of macrophage differentiation and atherogenesis 
Hydroxyoctadecadienoic acids (HODEs) are stable oxidation products of linoleic acid, the generation of which is increased where oxidative stress is increased, such as in diabetes. In early atherosclerosis, 13-HODE is generated in macrophages by 15-lipoxygenase-1. This enhances protective mechanisms through peroxisome proliferator-activated receptor (PPAR)-g activation leading to increased clearance of lipid and lipid-laden cells from the arterial wall. In later atherosclerosis, both 9-HODE and 13-HODE are generated nonenzymatically. At this stage, early protective mechanisms are overwhelmed and pro-inflammatory effects of 9-HODE, acting through the receptor GPR132, and increased apoptosis predominate leading to a fragile, acellular plaque. Increased HODE levels thus contribute to atherosclerosis progression and the risk of clinical events such as myocardial infarction or stroke. Better understanding of the role of HODEs may lead to new pharmacologic approaches to modulate their production or action, and therefore lessen the burden of atherosclerotic disease in high-risk patients.
doi:10.1177/2042018810375656
PMCID: PMC3475286  PMID: 23148150
atherosclerosis; diabetes; oxidative stress; oxidized lipids; G protein-coupled receptors

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