Mental Health Care Center

Borough of Bronx, NY, United States

Mental Health Care Center

Borough of Bronx, NY, United States
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Daskalakis N.P.,Leiden University | Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Diamantopoulou A.,Leiden University | And 8 more authors.
Psychoneuroendocrinology | Year: 2014

Prolonged maternal separation (MS) activates the neonate's hypothalamus-pituitary-adrenal axis causing elevated basal and stress-induced corticosterone levels that may initiate amygdala-dependent fear learning. Here we test the hypothesis that the adult fearful phenotype is programmed by the pup's stressful experience during prolonged MS rather than by prolonged maternal absence per se. For this purpose, Wistar rat pups were exposed, on postnatal-day (pnd) 3, to: (i) repeated-MS in home-environment (HOME-SEP), 8h-MS daily for three days with the pups remaining together in the home-cage; (ii) repeated-MS in a novel-environment (NOVEL-SEP), with the same separation procedure, but now the pups were individually housed in a novel-environment during the 8. h dam's absence; (iii) repeated handling, which consisted of daily brief (15. min instead of 8. h) MS in the home-altogether or in a novel-environment individually (HOME-HAN and NOVEL-HAN, respectively); (iv) no-separation/no-handling (NON-SEP/NON-HAN) control condition, in which pups were left undisturbed in their home-cage. Compared to HOME-SEP rats, the NOVEL-SEP rats showed one day after the last MS enhanced stress-induced amygdala c-Fos expression and ACTH-release, despite of reduced adrenal corticosterone secretion. The higher amygdala c-Fos expression, ACTH-release and reduced corticosterone output observed postnatally, persisted into adulthood of the NOVEL-SEP animals. Behaviorally, NOVEL-SEP juvenile rats displayed deficits in social play, had intact spatial memory in the peri-pubertal period and showed more contextual fear memory compared to HOME-SEP in adulthood. Finally, NOVEL-HAN, compared to HOME-HAN, displayed increased stress-induced corticosterone output, no deficits in social play and reduced contextual fear. In conclusion, programming of an adult fearful phenotype linked to amygdala priming develops if pups are repeatedly isolated from peers in a novel-environment, while away from the dam for a prolonged period of time. © 2013 Elsevier Ltd.


PubMed | New York University, Emory University, U.S. Army, Frederick National Laboratory for Cancer Research and 2 more.
Type: Journal Article | Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | Year: 2015

Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N=147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N=147, =31.34, P=1.2810(-8) ) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N=2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N=2006, P=0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N=157, P=0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N=53, P<0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder.


Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Yehuda R.,Mount Sinai School of Medicine | Yehuda R.,Mental Health Care Center | And 2 more authors.
Psychoneuroendocrinology | Year: 2013

Understanding the neurobiological mechanisms of post-traumatic stress disorder (PTSD) is of vital importance for developing biomarkers and more effective pharmacotherapy for this disorder. The design of bidirectional translational studies addressing all facets of PTSD is needed. Animal models of PTSD are needed not only to capture the complexity of PTSD behavioral characteristics, but also to address experimentally the influence of variety of factors which might determine an individual's vulnerability or resilience to trauma, e.g., genetic predisposition, early-life experience and social support. The current review covers recent translational approaches to bridge the gap between human and animal PTSD research and to create a framework for discovery of biomarkers and novel therapeutics. © 2013.


Bowers M.E.,Mount Sinai School of Medicine | Yehuda R.,Mount Sinai School of Medicine | Yehuda R.,Mental Health Care Center
Neuropsychopharmacology | Year: 2016

The hypothesis that offspring are affected by parental trauma or stress exposure, first noted anecdotally, is now supported empirically by data from Holocaust survivor offspring cohorts and other populations. These findings have been extended to less extreme forms of stress, where differential physical, behavioral, and cognitive outcomes are observed in affected offspring. Parental stress-mediated effects in offspring could be explained by genetics or social learning theory. Alternatively, biological variations stemming from stress exposure in parents could more directly have an impact on offspring, a concept we refer to here as 'intergenerational transmission', via changes to gametes and the gestational uterine environment. We further extend this definition to include the transmission of stress to offspring via early postnatal care, as animal studies demonstrate the importance of early maternal care of pups in affecting offsprings' long-term behavioral changes. Here, we review clinical observations in offspring, noting that offspring of stress- or trauma-exposed parents may be at greater risk for physical, behavioral, and cognitive problems, as well as psychopathology. Furthermore, we review findings concerning offspring biological correlates of parental stress, in particular, offspring neuroendocrine, epigenetic, and neuroanatomical changes, in an attempt to determine the extent of parental stress effects. Although understanding the etiology of effects in offspring is currently impeded by methodological constraints, and limitations in our knowledge, we summarize current information and conclude by presenting hypotheses that have been prompted by recent studies in the field. © 2016 American College of Neuropsychopharmacology. All rights reserved.


Yehuda R.,Mount Sinai School of Medicine | Yehuda R.,Mental Health Care Center | Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | And 15 more authors.
Frontiers in Psychiatry | Year: 2013

Epigenetic alterations offer promise as diagnostic or prognostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders (n = 8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders (n = 8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3-month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained (i.e., plasma and 24 h-urinary cortisol, plasma ACTH, lymphocyte lysozyme IC50-DEX, and plasma neuropeptide-Y). Methylation of the GR gene (NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene (FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers were also associated with the epigenetic markers. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of "environmental regulation" that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respectively. © 2013 Yehuda, Daskalakis, Desarnaud, Makotkine, Lehrner, Koch, Flory, Buxbaum, Meaney and Bierer.


Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Binder E.B.,Max Planck Institute of Psychiatry | Binder E.B.,Emory University
Schizophrenia Bulletin | Year: 2015

Many studies have demonstrated that genotype (G) interacts with adverse life experiences (E) to produce individual differences in vulnerability and resilience to mental disorders, including schizophrenia. Genetic susceptibility to stress and the timing of the environmental exposure(s) are relevant for these interactions and represent common risk factors. We take the example of the FKBP5 gene to illustrate G × E interactions that predict pleiotropic psychiatric outcomes, including schizophrenia. © 2015 The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.


Yehuda R.,Mental Health Care Center | Yehuda R.,Mount Sinai School of Medicine | Lehrner A.,Mental Health Care Center | Lehrner A.,Mount Sinai School of Medicine | Rosenbaum T.Y.,Inner Stability Ltd.
Journal of Sexual Medicine | Year: 2015

Introduction: Difficulties in sexual desire and function often occur in persons with posttraumatic stress disorder (PTSD), but many questions remain regarding the mechanisms underlying the occurrence of sexual problems in PTSD. Aim: The aim of this review was to present a model of sexual dysfunction in PTSD underpinned by an inability to regulate and redirect the physiological arousal needed for healthy sexual function away from aversive hyperarousal and intrusive memories. Method: A literature review pertaining to PTSD and sexual function was conducted. Evidence for the comorbidity of sexual dysfunction and PTSD is presented, and biological and psychological mechanisms that may underlie this co-occurrence are proposed. Main Outcome Measures: This manuscript presents evidence of sexual dysfunction in conjunction with PTSD, and of the neurobiology and neuroendocrinology of PTSD and sexual function. Results: Sexual dysfunction following trauma exposure may be mediated by PTSD-related biological, cognitive, and affective processes. Conclusions: The treatment of PTSD must include attention to sexual dysfunction and vice versa. © 2015 International Society for Sexual Medicine.


Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Lehrner A.,Mount Sinai School of Medicine | Lehrner A.,Mental Health Care Center | And 2 more authors.
Endocrinology and Metabolism Clinics of North America | Year: 2013

Post-traumatic stress disorder (PTSD) is a serious, multisystem disorder with multiple medical comorbidities. This article reviews the current literature on the endocrine aspects of PTSD, specifically hypothalamic-pituitary-adrenal axis alterations indicative of low cortisol and increased glucocorticoid sensitivity, and the proposed mechanisms whereby these alterations increase risk or reflect pathophysiology. Discussion includes novel treatment innovations and directions for future research. © 2013 Elsevier Inc.


Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Daskalakis N.P.,Leiden University | Bagot R.C.,University of Quebec at Montréal | And 4 more authors.
Psychoneuroendocrinology | Year: 2013

Stressful experiences during early-life can modulate the genetic programming of specific brain circuits underlying emotional and cognitive aspects of behavioral adaptation to stressful experiences later in life. Although this programming effect exerted by experience-related factors is an important determinant of mental health, its outcome depends on cognitive inputs and hence the valence an individual assigns to a given environmental context. From this perspective we will highlight, with studies in rodents, non-human primates and humans, the three-hit concept of vulnerability and resilience to stress-related mental disorders, which is based on gene-environment interactions during critical phases of perinatal and juvenile brain development. The three-hit (i.e., hit-1: genetic predisposition, hit-2: early-life environment, and hit-3: later-life environment) concept accommodates the cumulative stress hypothesis stating that in a given context vulnerability is enhanced when failure to cope with adversity accumulates. Alternatively, the concept also points to the individual's predictive adaptive capacity, which underlies the stress inoculation and match/mismatch hypotheses. The latter hypotheses propose that the experience of relatively mild early-life adversity prepares for the future and promotes resilience to similar challenges in later-life; when a mismatch occurs between early and later-life experience, coping is compromised and vulnerability is enhanced. The three-hit concept is fundamental for understanding how individuals can either be prepared for coping with life to come and remain resilient or are unable to do so and succumb to a stress-related mental disorder, under seemingly identical circumstances. © 2013 Elsevier Ltd.


Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Yehuda R.,Mount Sinai School of Medicine | Yehuda R.,Mental Health Care Center
European Journal of Psychotraumatology | Year: 2014

The extent to which animal studies can be relevant to military posttraumatic stress disorder (PTSD) continues to be a matter of discussion. Some features of the clinical syndrome are more easily modeled than others. In the animal literature, a great deal of attention is focused on modeling the characteristics of military exposures and their impact on measurable behaviors and biological parameters. There are many issues to consider regarding the ecological validity of predator, social defeat or immobilization stress to combat-related experience. In contrast, less attention has been paid to individual variation following these exposures. Such variation is critical to understand how individual differences in the response to military trauma exposure may result to PTSD or resilience. It is important to consider potential differences in biological findings when comparing extremely exposed to non-exposed animals, versus those that result from examining individual differences. Animal models of military PTSD are also critical in advancing efforts in clinical treatment. In an ideal translational approach to study deployment related outcomes, information from humans and animals, blood and brain, should be carefully considered in tandem, possibly even computed simultaneously, to identify molecules, pathways and networks that are likely to be the key drivers of military PTSD symptoms. With the use novel biological methodologies (e.g., optogenetics) in the animal models, critical genes and pathways can be tuned up or down (rather than over-expressed or ablated completely) in discrete brain regions. Such techniques together with preand post-deployment human imaging will accelerate the identification of novel pharmacological and nonpharmacological intervention strategies. © 2014 Nikolaos P. Daskalakis and Rachel Yehuda.

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