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Background: Difficult temperament in infancy is a risk factor for forms of later internalizing and externalizing psychopathology, including depression and anxiety. A better understanding of the roots of difficult temperament requires assessment of its early development with a genetically informative design. The goal of this study was to estimate genetic and environmental contributions to individual differences in infant negative emotionality, their persistence over time and their influences on stability between 5 and 18 months of age. Method: Participants were 244 monozygotic and 394 dizygotic twin pairs (49.7% male) recruited from birth. Mothers rated their twins for negative emotionality at 5 and 18 months. Longitudinal analysis of stability and innovation between the two time points was performed in Mplus. Results: There were substantial and similar heritability (approximately 31%) and shared environmental (57.3%) contributions to negative emotionality at both 5 and 18 months. The trait’s interindividual stability across time was both genetically- and environmentally- mediated. Evidence of innovative effects (i.e., variance at 18 months independent from variance at 5 months) indicated that negative emotionality is developmentally dynamic and affected by persistent and new genetic and environmental factors at 18 months. Conclusions: In the first two years of life, ongoing genetic and environmental influences support temperamental negative emotionality but new genetic and environmental factors also indicate dynamic change of those factors across time. A better understanding of the source and timing of factors on temperament in early development, and role of sex, could improve efforts to prevent related psychopathology. [ABSTRACT FROM AUTHOR]

Over the past decade, epigenetic analyses have made important contributions to our understanding of healthy development and a wide variety of adverse conditions such as cancer and psychopathology. There is increasing evidence that DNA methylation is a mechanism by which environmental factors influence gene transcription and, ultimately, phenotype. However, differentiating the effects of the environment from those of genetics on DNA methylation profiles remains a significant challenge. Monozygotic (MZ) twin study designs are unique in their ability to control for genetic differences because each pair of MZ twins shares essentially the same genetic sequence with the exception of a small number of de novo mutations and copy number variations. Thus, differences within twin pairs in gene expression and phenotype, including behavior, can be attributed in the majority of cases to environmental effects rather than genetic influence. In this article, we review the literature showing how MZ twin designs can be used to study basic epigenetic principles, contributing to understanding the role of early in utero and postnatal environmental factors on the development of psychopathology. We also highlight the importance of initiating longitudinal and experimental studies with MZ twins during pregnancy. This approach is especially important to identify: (1) critical time periods during which the early environment can impact brain and mental health development, and (2) the specific mechanisms through which early environmental effects may be mediated. These studies may inform the optimum timing and design for early preventive interventions aimed at reducing risk for psychopathology. [ABSTRACT FROM AUTHOR]

Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD) (23 females) and 36 matched healthy controls (21 females) were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology. [ABSTRACT FROM AUTHOR]

Background: Despite more than 60 years of research in the role of serotonin (5-HT) in psychopathology, many questions still remain. From a developmental perspective, studies have provided more insight into how 5-HT dysfunctions acquired in utero or early in life may modulate brain development. This paper discusses the relevance of the developmental role of 5-HT for the understanding of psychopathology. We review developmental milestones of the 5-HT system, how genetic and environmental 5-HT disturbances could affect brain development and the potential role of DNA methylation in 5-HT genes for brain development. Methods: Studies were identified using common databases (e.g., PubMed, Google Scholar) and reference lists. Results: Despite the widely supported view that the 5-HT system matures in early life, different 5-HT receptors, proteins and enzymes have different developmental patterns, and development is brain region-specific. A disruption in 5-HT homeostasis during development may lead to structural and functional changes in brain circuits that modulate emotional stress responses, including subcortical limbic and (pre)frontal areas. This may result in a predisposition to psychopathology. DNA methylation might be one of the underlying physiologic mechanisms. Limitations: There is a need for prospective studies. The impact of stressors during adolescence on the 5-HT system is understudied. Questions regarding efficacy of drugs acting on 5-HT still remain. Conclusion: A multidisciplinary and longitudinal approach in designing studies on the role of 5-HT in psychopathology might help to bring us closer to the understanding of the role of 5-HT in psychopathology. [ABSTRACT FROM AUTHOR]

Background: Some authors have hypothesized that Treatment-Resistant Unipolar Depression (TRD-UP) should be considered within the bipolar spectrum disorders and that hidden bipolarity may be a risk factor for TRD-UP. However, there are neither studies comparing clinical and sociodemographic data of patients with TRD-UP versus Bipolar (BP) disorders nor are there any examining differences versus Bipolar type I (BP-I) and Bipolar type II (BP-II). Methods: Charts analysis was conducted on 194 patients followed at the Mood Disorders Clinic of the McGill University Health Center. Sociodemographic, clinical features and depression scales were collected from patients meeting DSM-IV criteria for TRD-UP (n = 100) and BP (n = 94). Binary logistic regression analysis was conducted to examine clinical predictors independently associated with the two disorders. Results: Compared to BP, TRD-UP patients exhibited greater severity of depression, prevalence of anxiety and panic disorders, melancholic features, Cluster-C personality disorders, later onset of depression and fewer hospitalizations. Binary logistic regression indicated that higher comorbidity with anxiety disorders, higher depression scale scores and lower global assessment of functioning (GAF) scores, and lower number of hospitalizations and psychotherapies differentiated TRD-UP from BP patients. We also found that the rate of unemployment and the number of hospitalizations for depression was higher in BP-I than in BP-II, while the rate of suicide attempts was lower in BP-I than in BP-II depressed patients. Conclusions: These results suggest that TRD-UP constitutes a distinct psychopathological condition and not necessarily a prodromal state of BP depression. [ABSTRACT FROM AUTHOR]

Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin synthesis. The TPH2 gene has frequently been investigated in relation to psychiatric morbidity. The aim of the present review is to integrate results from association studies between TPH2 single nucleotide polymorphisms (SNPs) and various psychiatric disorders, which we furthermore quantified with meta-analysis. We reviewed 166 studies investigating 69 TPH2 SNPs in a broad range of psychiatric disorders, including over 30,000 patients. According to our meta-analysis, TPH2 polymorphisms show strongest associations with mood disorders, suicide (attempt) and schizophrenia. Despite small effect sizes, we conclude that TPH2 SNPs in the coding and non-coding areas (rs4570625, rs11178997, rs11178998, rs10748185, rs1843809, rs4290270, rs17110747) are each associated with one or more psychopathological conditions. Our findings highlight the possible common serotonergic mechanisms of the investigated psychiatric disorders. Yet, the functional relevance of most TPH2 polymorphisms is unclear. Characterizing how exactly the different TPH2 variants influence the serotonergic neurotransmission is a next necessary step in understanding the psychiatric disorders where serotonin is implicated. [ABSTRACT FROM AUTHOR]