Associations of Smoking, Physical Inactivity, Heavy Drinking, and Obesity with Quality-Adjusted Life Expectancy among US Adults with Depression.

OBJECTIVES: To examine associations between four health behaviors (smoking, physical inactivity, heavy alcohol drinking, and obesity) and three health indices (health-related quality of life, life expectancy, and quality-adjusted life expectancy (QALE)) among US adults with depression. METHODS: Data were obtained from the 2006, 2008, and 2010 Behavioral Risk Factor Surveillance System data. The EuroQol five-dimensional questionnaire (EQ-5D) health preference scores were estimated on the basis of extrapolations from the Centers for Disease Control and Prevention's healthy days measures. Depression scores were estimated using the eight-item Patient Health Questionnaire. Life expectancy estimates were obtained from US life tables, and QALE was estimated from a weighted combination of the EQ-5D scores and the life expectancy estimates. Outcomes were summarized by depression status for the four health behaviors (smoking, physical inactivity, heavy alcohol drinking, and obesity). RESULTS: For depressed adults, current smokers and the physically inactive had significantly lower EQ-5D scores (0.040 and 0.171, respectively), shorter life expectancy (12.9 and 10.8 years, respectively), and substantially less QALE (8.6 and 10.9 years, respectively). For nondepressed adults, estimated effects were similar but smaller. Heavy alcohol drinking among depressed adults, paradoxically, was associated with higher EQ-5D scores but shorter life expectancy. Obesity was strongly associated with lower EQ-5D scores but only weakly associated with shorter life expectancy. CONCLUSIONS: Among depressed adults, physical inactivity and smoking were strongly associated with lower EQ-5D scores, life expectancy, and QALE, whereas obesity and heavy drinking were only weakly associated with these indices. These results suggest that reducing physical inactivity and smoking would improve health more among depressed adults.

Oxytocin enhances observational fear in mice.

Empathy is fundamental to human relations, but its neural substrates remain largely unknown. Here we characterize the involvement of oxytocin in the capacity of mice to display emotional state-matching, an empathy-like behavior. When exposed to a familiar conspecific demonstrator in distress, an observer mouse becomes fearful, as indicated by a tendency to freeze and subsequent efforts to escape. Both intranasal oxytocin administration and chemogenetic stimulation of oxytocin neurons render males sensitive to the distress of an unfamiliar mouse. Acute intranasal oxytocin penetrates the brain and enhances cellular activity within the anterior cingulate cortex, whereas chronic administration produces long-term facilitation of observational fear and downregulates oxytocin receptor expression in the amygdala. None of these manipulations affect fear acquired as a result of direct experience with the stressor. Hence, these results implicate oxytocin in observational fear in mice (rather than fear itself) and provide new avenues for examining the neural substrates of empathy.

Schizophrenia spectrum personality disorders in psychometrically identified schizotypes at two-year follow-up.

Earlier (Bolinskey et al., 2015), we reported that psychometrically identified schizotypes displayed greater symptom levels and higher incidences of schizophrenia spectrum (schizotypal, schizoid, paranoid, and avoidant) personality disorders (PDs). In this study, 49 schizotypes and 39 matched controls participated in follow-up assessments after two years. Participants were previously identified as schizotypes or controls based on scores on the Chapman Psychosis Proneness Scales (CPPS), and were interviewed at baseline and follow-up with the Personality Disorder Interview for DSM-IV (PDI-IV). At follow-up, schizotypes displayed significantly higher symptom levels compared to controls, with medium to large effects, and appeared to meet criteria for diagnosis of each PD more often than controls, although significant differences were only observed for paranoid PD. Overall, schizotypes were more likely to have met criteria for a diagnosis at either baseline or follow-up. Finally, we observed a widening disparity over time between schizotypes and controls in avoidant and schizoid PDs. These results suggest that schizophrenia spectrum PDs, as well as subthreshold symptoms of these disorders, can represent a greater liability for schizophrenia in individuals identified as at-risk on the basis of psychometric means only. Furthermore, these findings demonstrate that such differences persist, and in some cases increase, over time.

Stratifying empiric risk of schizophrenia among first degree relatives using multiple predictors in two independent Indian samples.

BACKGROUND: Schizophrenia (SZ) has an estimated heritability of 64-88%, with the higher values based on twin studies. Conventionally, family history of psychosis is the best individual-level predictor of risk, but reliable risk estimates are unavailable for Indian populations. Genetic, environmental, and epigenetic factors are equally important and should be considered when predicting risk in 'at risk' individuals. OBJECTIVE: To estimate risk based on an Indian schizophrenia participant's family history combined with selected demographic factors. METHODS: To incorporate variables in addition to family history, and to stratify risk, we constructed a regression equation that included demographic variables in addition to family history. The equation was tested in two independent Indian samples: (i) an initial sample of SZ participants (N=128) with one sibling or offspring; (ii) a second, independent sample consisting of multiply affected families (N=138 families, with two or more sibs/offspring affected with SZ). RESULTS: The overall estimated risk was 4.31±0.27 (mean±standard deviation). There were 19 (14.8%) individuals in the high risk group, 75 (58.6%) in the moderate risk and 34 (26.6%) in the above average risk (in Sample A). In the validation sample, risks were distributed as: high (45%), moderate (38%) and above average (17%). Consistent risk estimates were obtained from both samples using the regression equation. CONCLUSIONS: Familial risk can be combined with demographic factors to estimate risk for SZ in India. If replicated, the proposed stratification of risk may be easier and more realistic for family members.

Understanding autism and other neurodevelopmental disorders through experimental translational neurobehavioral models.

Neurodevelopmental disorders (NDDs) are highly prevalent and severely debilitating brain illnesses caused by aberrant brain growth and development. Resulting in cognitive, social, motor, language and affective disabilities, common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Affecting neurogenesis, glia/neuronal proliferation and migration, synapse formation and myelination, aberrant neural development occurs over a substantial period of time. Genetic, epigenetic, and environmental factors play a key role in NDD pathogenesis. Animal models are an indispensable tool to study NDDs. Paralleling clinical findings, we comprehensively evaluate various preclinical tests and models which target key (social, cognitive, motor) neurobehavioral domains of ASD and other common NDDs. Covering both traditional (rodent) and alternative NDD models, we outline the emerging areas of research and emphasize how preclinical models play a key role in gaining translational and mechanistic insights into NDDs and their therapy.

Epigenetic assimilation in the aging human brain.

BACKGROUND: Epigenetic drift progressively increases variation in DNA modification profiles of aging cells, but the finale of such divergence remains elusive. In this study, we explored the dynamics of DNA modification and transcription in the later stages of human life. RESULTS: We find that brain tissues of older individuals (>75 years) become more similar to each other, both epigenetically and transcriptionally, compared with younger individuals. Inter-individual epigenetic assimilation is concurrent with increasing similarity between the cerebral cortex and the cerebellum, which points to potential brain cell dedifferentiation. DNA modification analysis of twins affected with Alzheimer's disease reveals a potential for accelerated epigenetic assimilation in neurodegenerative disease. We also observe loss of boundaries and merging of neighboring DNA modification and transcriptomic domains over time. CONCLUSIONS: Age-dependent epigenetic divergence, paradoxically, changes to convergence in the later stages of life. The newly described phenomena of epigenetic assimilation and tissue dedifferentiation may help us better understand the molecular mechanisms of aging and the origins of diseases for which age is a risk factor.

Genetic and environmental modulation of neurodevelopmental disorders: Translational insights from labs to beds.

Neurodevelopmental disorders (NDDs) are a heterogeneous group of prevalent neuropsychiatric illnesses with various degrees of social, cognitive, motor, language and affective deficits. NDDs are caused by aberrant brain development due to genetic and environmental perturbations. Common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Genetic and epigenetic/environmental factors play a key role in these NDDs with significant societal impact. Given the lack of their efficient therapies, it is important to gain further translational insights into the pathobiology of NDDs. To address these challenges, the International Stress and Behavior Society (ISBS) has established the Strategic Task Force on NDDs. Summarizing the Panel's findings, here we discuss the neurobiological mechanisms of selected common NDDs and a wider NDD+ spectrum of associated neuropsychiatric disorders with developmental trajectories. We also outline the utility of existing preclinical (animal) models for building translational and cross-diagnostic bridges to improve our understanding of various NDDs.

A Danish Twin Study of Schizophrenia Liability: Investigation from Interviewed Twins for Genetic Links to Affective Psychoses and for Cross-Cohort Comparisons.

We studied schizophrenia liability in a Danish population-based sample of 44 twin pairs (13 MZ, 31 DZ, SS plus OS) in order to replicate previous twin study findings using contemporary diagnostic criteria, to examine genetic liability shared between schizophrenia and other disorders, and to explore whether variance in schizophrenia liability attributable to environmental factors may have decreased with successive cohorts exposed to improvements in public health. ICD-10 diagnoses were determined by clinical interview. Although the best-fitting, most parsimonious biometric model of schizophrenia liability specified variance attributable to additive genetic and non-shared environmental factors, this model did not differ significantly from a model that also included non-additive genetic factors, consistent with recent interview-based twin studies. Schizophrenia showed strong genetic links to other psychotic disorders but much less so for the broader category of psychiatric disorders in general. We also observed a marginally significant decline in schizophrenia variance attributable to environmental factors over successive Western European cohorts, consistent perhaps with improvements in diagnosis and in prenatal and perinatal care and with a secular decline in the prevalence of schizophrenia in that region.

Classical and Molecular Genetic Research on General Cognitive Ability.

Arguably, no psychological variable has received more attention from behavioral geneticists than what has been called "general cognitive ability" (as well as "general intelligence" or "g"), and for good reason. GCA has a rich correlational network, implying that it may play an important role in multiple domains of functioning. GCA is highly correlated with various indicators of educational attainment, yet its predictive utility is not limited to academic achievement. It is also correlated with work performance, navigating the complexities of everyday life, the absence of various social pathologies (such as criminal convictions), and even health and mortality. Although the causal basis for these associations is not always known, it is nonetheless the case that research on GCA has the potential to provide insights into the origins of a wide range of important social outcomes. In this essay, our discussion of why GCA is considered a fundamentally important dimension of behavior on which humans differ is followed by a look at behavioral genetics research on CGA. We summarize behavioral genetics research that has sought to identify and quantify the total contributions of genetic and environmental factors to individual differences in GCA as well as molecular genetic research that has sought to identify genetic variants that underlie inherited effects.

Endophenotypes for Alcohol Use Disorder: An Update on the Field.

The endophenotype concept was first proposed as a strategy to use (purportedly) genetically simpler phenotypes in gene identification studies for psychiatric disorders, and is distinct from the closely related concept of intermediate phenotypes. In the area of alcohol use disorder (AUD) research, two candidate endophenotypes have produced replicable genetic associations: level of response to alcohol and neurophysiology markers (e.g., event-related oscillations and event-related potentials). Additional candidate endophenotypes from the cognitive, sensory, and neuroimaging literatures show promise, although more evidence is needed to fully evaluate their potential utility. Translational approaches to AUD endophenotypes have helped characterize the underlying neurobiology and genetics of AUD endophenotypes and identified relevant pharmacological interventions. Future research that capitalizes on the polygenic nature of endophenotypes and emphasizes endophenotypes that may change across development will enhance the usefulness of this concept to understand the genetically-influenced pathways toward AUD.

Targeting drug sensitivity predictors: New potential strategies to improve pharmacotherapy of human brain disorders.

One of the main challenges in medicine is the lack of efficient drug therapies for common human disorders. For example, although depressed patients receive powerful antidepressants, many often remain resistant to psychopharmacotherapy. The growing recognition of complex interplay between the drug targets and the predictors of drug sensitivity requires an improved understanding of these two key aspects of drug action and their potentially shared molecular networks. Here, we apply the concept of endophenotypes and their interplay to drug action and sensitivity. Based on these analyses, we postulate that novel drugs may be developed by targeting specific molecular pathways that integrate drug targets with drug sensitivity predictors.

Targeting dynamic interplay among disordered domains or endophenotypes to understand complex neuropsychiatric disorders: Translational lessons from preclinical models.

Contemporary biological psychiatry uses clinical and experimental (animal) models to increase our understanding of brain pathogenesis. Modeling psychiatric disorders is currently performed by targeting various key neurobehavioral clusters of phenotypic traits (domains), including affective, cognitive, social, motor and reward. Analyses of such domains and their 'smaller units' - individual endophenotypes - are critical for the study of complex brain disorders and their neural underpinnings. The spectrum nature of brain disorders and the importance of pathogenetic linkage among various disordered domains or endophenotypes have also been recognized as an important strategic direction of translational research. Here, we discuss cross-domain analyses of animal models, and focus on their value for mimicking the clinical overlap between disordered neurobehavioral domains in humans. Based on recent experimental evidence, we argue that understanding of brain pathogenesis requires modeling the clinically relevant inter-relationships between various individual endophenotypes (or their domains).

Impact of depression on quality-adjusted life expectancy (QALE) directly as well as indirectly through suicide.

PURPOSE: To estimate quality-adjusted life expectancy (QALE) loss among US adults due to depression and QALE losses associated with the increased risk of suicide attributable to depression. METHOD: We ascertained depressive symptoms using the eight-item Patient Health Questionnaire (PHQ-8) on the 2006, 2008, and 2010 Behavioral Risk Factor Surveillance System (BRFSS) surveys. We estimated health-related quality of life (HRQOL) scores from BRFSS data (n = 276,442) and constructed life tables from US Compressed Mortality Files to calculate QALE by depression status. QALE loss due to depression is the difference in QALE between depressed and non-depressed adults. QALE loss associated with suicide deaths is the difference between QALE from only those deaths that did not have suicide recorded on the death certificate and QALE from all deaths including those with a suicide recorded on the death certificate. RESULTS: At age 18, QALE was 28.0 more years for depressed adults and 56.8 more years for non-depressed adults, a 28.9-year QALE loss due to depression. For depressed adults, only 0.41 years of QALE loss resulted from deaths by suicide, and only 0.26 years of this loss could be attributed to depression. CONCLUSION: Depression symptoms lead to a significant burden of disease from both mortality and morbidity as assessed by QALE loss. The 28.9-year QALE loss at age 18 associated with depression markedly exceeds estimates reported elsewhere for stroke (12.4-year loss), heart disease (10.3-year loss), diabetes mellitus (11.1-year loss), hypertension (6.3-year loss), asthma (7.0-year loss), smoking (11.0-year loss), and physical inactivity (8.0-year loss).

DNA modification study of major depressive disorder: beyond locus-by-locus comparisons.

BACKGROUND: Major depressive disorder (MDD) exhibits numerous clinical and molecular features that are consistent with putative epigenetic misregulation. Despite growing interest in epigenetic studies of psychiatric diseases, the methodologies guiding such studies have not been well defined. METHODS: We performed DNA modification analysis in white blood cells from monozygotic twins discordant for MDD, in brain prefrontal cortex, and germline (sperm) samples from affected individuals and control subjects (total N = 304) using 8.1K CpG island microarrays and fine mapping. In addition to the traditional locus-by-locus comparisons, we explored the potential of new analytical approaches in epigenomic studies. RESULTS: In the microarray experiment, we detected a number of nominally significant DNA modification differences in MDD and validated selected targets using bisulfite pyrosequencing. Some MDD epigenetic changes, however, overlapped across brain, blood, and sperm more often than expected by chance. We also demonstrated that stratification for disease severity and age may increase the statistical power of epimutation detection. Finally, a series of new analytical approaches, such as DNA modification networks and machine-learning algorithms using binary and quantitative depression phenotypes, provided additional insights on the epigenetic contributions to MDD. CONCLUSIONS: Mapping epigenetic differences in MDD (and other psychiatric diseases) is a complex task. However, combining traditional and innovative analytical strategies may lead to identification of disease-specific etiopathogenic epimutations.

Gyrification differences in children and adolescents with velocardiofacial syndrome and attention-deficit/hyperactivity disorder: a pilot study.

We used magnetic resonance imaging to investigate brain gyrification patterns between 19 children with attention-deficit/hyperactivity disorder (ADHD), 9 children with velocardiofacial syndrome (VCFS), and 23 control children. We found that VCFS is associated with widespread decreases in gyrification. In ADHD, we found minor differences from control children. No evidence was found for common gyrification patterns between VCFS and ADHD children.

Arguments for the sake of endophenotypes: examining common misconceptions about the use of endophenotypes in psychiatric genetics.

Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically-based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high-throughput ways of assessing, and ranking potential endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of endophenotypes in the psychiatric genetics community.

Using summary data from the danish national registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder.

Estimates of heritability of psychiatric disorders quantify the genetic contribution to their etiology. Estimation of these parameters requires affected status on probands and their family members. Traditionally, heritabilities have been estimated from families ascertained from specific hospital registers, but accumulating sufficient numbers of families can be difficult. Larger sample sizes are achievable from national registries, but calculation of heritability from individual level data from these data sets is accompanied by other problems. Here, we use published summary data from a national population-based cohort of >2.6 million persons in Denmark to estimate heritabilities of schizophrenia, bipolar disorder, and major depressive disorder (MDD). The summary data comprised cumulative incidences up to 52 years of age for schizophrenia and bipolar disorder and up to 51 years for MDD in offspring where either one or both parents were diagnosed with one of these disorders. Estimates of the heritabilities of the liability to developing schizophrenia, bipolar disorder, and MDD are 0.67 (95% confidence interval (CI) 0.64-0.71), 0.62 (95% CI 0.58-0.65), and 0.32 (95% CI 0.30-0.34) respectively. The estimates may be inflated by common environmental effects, but despite this, they are somewhat lower for schizophrenia and bipolar disorder than those estimated from contemporary twin samples. The lower estimates may reflect the diverse environments (including diagnostic interpretation) that contribute to national data, compared to twin/family studies. Our estimates are similar to those estimated previously from national data of Sweden, and they may be more representative of the international samples brought together for large-scale genome-wide association studies. We investigated the estimation of genetic correlations from these data. We used simulation to conclude that estimates may not be interpretable and so report them only in the Section "Appendix."

Biologically flavored perspectives on Garmezian resilience.

Norman Garmezy devoted the better part of four decades developing and promoting the construct of resilience for developmental psychopathology. He proposed resilience as a paradigm to guide the understanding of how people can transcend adversity and go on to live healthy, productive lives. This tribute to Norman starts with a look at the early context for his work during his distinguished tenure in the Department of Psychology at the University of Minnesota. Resilience constructs are then compared from interdisciplinary perspectives across a variety of biological and physical sciences. All of these perspectives lead to similar conclusions: resilience is not a thing but a process. Furthermore, the processes are the product of energy-hungry systems. Finally, these insights are applied to difficult to modify maladaptive behaviors raising the question of a dark side to resilience.