Background We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. Methods Fifteen patients with chronic, severe, highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale—24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). Results Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. Conclusions Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.

In adults without diagnosable psychopathology, childhood maltreatment is associated with diminished HPA axis response to a psychosocial stressor. Possible explanations for the finding are discussed.

BackgroundA history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans.MethodsWe examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test.ResultsDisruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05).ConclusionsThese findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.

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Increased production of peripheral cytokines and other pro-inflammatory markers has been linked to psychiatric disorders such as major depressive disorder and posttraumatic stress disorder (PTSD). Recent research has pointed to early life stress, particularly childhood maltreatment, as an independent and preventable risk factor for systemic inflammation in adulthood. Some data suggest that adults with a history of childhood maltreatment exhibit a heightened inflammatory response to acute stress challenge. To further elucidate the relationship between childhood maltreatment and pro-inflammatory cytokine production, we examined plasma IL-6 response to the Trier Social Stress Test (TSST) in 69 healthy adult subjects without depression or PTSD. Serial plasma IL-6 concentrations were measured during a standardized psychosocial stressor in n=19 subjects with moderate-severe childhood maltreatment (MAL) and n=50 controls without maltreatment (CTL), as indicated by self-ratings on the Childhood Trauma Questionnaire (CTQ). CTQ total scores were positively correlated with change in overall change in IL-6 response, as well as the maximum IL-6 concentration during the TSST. Greater acute IL-6 release and higher IL-6 concentrations over time were observed for the MAL group relative to the CTL group. Inflammation may be an important developmental mediator linking adverse experiences in early life to poor adult physical and mental health. The results of this preliminary study warrant further investigation in a larger sample.

Objective Psychological stress and trauma are risk factors for several medical and psychiatric illnesses. Recent studies have implicated advanced cellular aging as a potential mechanism of this association. Telomeres, DNA repeats that cap the ends of chromosomes and promote stability, shorten progressively with each cell division; their length is a marker of biological aging. Based on previous evidence linking psychosocial stress to shorter telomere length, this study was designed to evaluate the effect of childhood adversity on telomere length. Method Thirty-one adults with no current or past major Axis I psychiatric disorder participated. Subjects reported on their history of childhood maltreatment and telomere length was measured from DNA extracted from frozen whole blood using quantitative PCR. Results Participants reporting a history of childhood maltreatment had significantly shorter telomeres than those who did not report a history of maltreatment. This finding was not due to effects of age, sex, smoking, BMI, or other demographic factors. Analysis of subscales showed that both physical neglect and emotional neglect were significantly linked to telomere length. Conclusions These results extend previous reports linking shortened leukocyte telomere length and caregiver stress to more remote stressful experiences in childhood, and suggest that childhood maltreatment could influence cellular aging.

The long-term sequelae of adverse early-life experiences have long been a focus in psychiatry, with a historic neurobiological emphasis on physiological systems that are demonstrably stress-responsive, such as the hypothalamic-pituitary-adrenal (HPA) axis and neuroimmune function. However, there has been increasing recognition in the general medical literature that such sequelae might encompass more pervasive alterations in health status and physiology. Recent findings in telomere biology have suggested a new avenue for exploring the adverse health effects of childhood maltreatment. Telomere length in proliferative tissues declines with cell replication, and the effect can be accelerated by such factors as inflammation, oxidative stress, radiation, and toxins. Reduced telomere length, as a proxy for cellular aging, has been associated with numerous chronic somatic diseases that are generally considered to be diseases of aging, such as diabetes, cancer, and heart disease. More recently, shorter telomeres have been demonstrated in several psychiatric conditions, particularly depression. Sustained psychosocial stress of a variety of types in adulthood appears to be associated with shorter telomeres. Now, emerging work suggests a robust, and perhaps dose-dependent, relationship with early-life stress. These findings present new opportunities to re-conceptualize the complex relationships between experience, physical and psychiatric disease, and aging.

Early adversity, in the form of abuse, neglect, socioeconomic status, and other adverse experiences, is associated with poor physical and mental health outcomes. To understand the biologic mechanisms underlying these associations, studies have evaluated the relationship between early adversity and telomere length, a marker of cellular senescence. Such results have varied in regards to the size and significance of this relationship. Using meta-analytic techniques, we aimed to clarify the relationship between early adversity and telomere length while exploring factors affecting the association, including adversity type, timing, and study design. A comprehensive search in July 2016 of PubMed/MEDLINE, PsycINFO, and Web of Science identified 2 462 studies. Multiple reviewers appraised studies for inclusion or exclusion using a priori criteria; 3.9% met inclusion criteria. Data was extracted into a structured form; the Newcastle-Ottawa Scale assessed study quality, validity and bias. Forty-one studies (N =30 773) met inclusion criteria. Early adversity and telomere length were significantly associated (Cohen’s d effect size = −0.35; 95% CI, –0.46 to –0.24, p < 0.0001). Sensitivity analyses revealed no outlier effects. Adversity type and timing significantly impacted the association with telomere length (p < .0001 and p = .0025, respectively). Subgroup and meta-regression analyses revealed that medication use, medical or psychiatric conditions, case-control versus longitudinal study design, methodological factors, age and smoking significantly affected the relationship. Comprehensive evaluations of adversity demonstrated more extensive telomere length changes. These results suggest that early adversity may have long-lasting physiological consequences contributing to disease risk and biological aging.