Early life adversity and telomere length: a meta-analysis.

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 regard 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 2462 studies. Multiple reviewers appraised studies for inclusion or exclusion using a priori criteria; 3.9% met inclusion criteria. Data were 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<0.0001 and P=0.0025, respectively). Subgroup and meta-regression analyses revealed that medication use, medical or psychiatric conditions, case-control vs 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.

Methylation of the leukocyte glucocorticoid receptor gene promoter in adults: associations with early adversity and depressive, anxiety and substance-use disorders.

Early adversity increases risk for developing psychopathology. Epigenetic modification of stress reactivity genes is a likely mechanism contributing to this risk. The glucocorticoid receptor (GR) gene is of particular interest because of the regulatory role of the GR in hypothalamic-pituitary-adrenal (HPA) axis function. Mounting evidence suggests that early adversity is associated with GR promoter methylation and gene expression. Few studies have examined links between GR promoter methylation and psychopathology, and findings to date have been mixed. Healthy adult participants (N=340) who were free of psychotropic medications reported on their childhood experiences of maltreatment and parental death and desertion. Lifetime depressive and anxiety disorders and past substance-use disorders were assessed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Methylation of exon 1F of the GR gene (NR3C1) was examined in leukocyte DNA via pyrosequencing. On a separate day, a subset of the participants (n=231) completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Childhood adversity and a history of past substance-use disorder and current or past depressive or anxiety disorders were associated with lower levels of NR3C1 promoter methylation across the region as a whole and at individual CpG sites (P<0.05). The number of adversities was negatively associated with NR3C1 methylation in participants with no lifetime disorder (P=0.018), but not in those with a lifetime disorder. GR promoter methylation was linked to altered cortisol responses to the Dex/CRH test (P<0.05). This study presents evidence of reduced methylation of NR3C1 in association with childhood maltreatment and depressive, anxiety and substance-use disorders in adults. This finding stands in contrast to our prior work, but is consistent with emerging findings, suggesting complexity in the regulation of this gene.

Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to examine whether gender differences may have affected treatment response to S-adenosyl methionine (SAMe) in a recent failed randomized clinical trial (RCT) for adults with major depressive disorder. METHODS: Data from a 2-site, 12-week, double-blind RCT (n=189) assessing the efficacy of SAMe vs. placebo and a comparator selective serotonin reuptake inhibitor (escitalopram) were subjected to post-hoc analyses to evaluate effects of patient gender on treatment response. RESULTS: When assessing the efficacy outcomes within each gender separately, SAMe was superior to placebo among males (n=51), but not among females (n=62). Males showed a significant reduction of depression severity from baseline to study endpoint on the 17-item Hamilton Depression Rating Scale (4.3 point difference; p=0.034; d=0.95), while females did not show significant change. This finding emerged despite equivalence on baseline measures of depression severity between the gender groups. CONCLUSION: RESULTS of this secondary data analysis suggest that gender might impact the antidepressant efficacy of SAMe, with greater therapeutic effect found in males. The underlying mechanism is still relatively unknown. Further work is needed to replicate this observation in independent samples.Clinicaltrials.gov identifier: NCT00101452.

Exaggerated smooth muscle contraction segments on esophageal high-resolution manometry: prevalence and clinical relevance.

BACKGROUND: Two smooth muscle contraction segments (S2, S3) on esophageal high-resolution manometry (HRM) demonstrate varying contraction vigor in symptomatic patients. Significance of isolated exaggerated smooth muscle contraction remains unclear. METHODS: High-resolution manometry studies were reviewed in 272 consecutive patients (56.4 ± 0.8 years, 62% F) and compared to 21 healthy controls (27.6 ± 0.6 years, 52% F), using HRM tools (distal contractile integral, DCI; distal latency, DL; integrated relaxation pressure, IRP), Chicago Classification (CC) and multiple rapid swallows (MRS). Segments were designated merged when the trough between S2 and S3 was ≥150 mmHg, and exaggerated S3 when peak S3 amplitude was ≥150 mmHg without merging with S2. Presenting symptoms and global symptom severity (on 100 mm visual analog scale) were recorded. Prevalence of merged and exaggerated segments was determined, and characteristics compared to symptomatic patients with normal HRM, and to healthy controls. KEY RESULTS: Merged segments were identified in 5.6%, and exaggerated S3 in another 12.5%, but only 17-50% had a CC diagnosis; one healthy control had merged segments. DCI with wet swallows was similar in cohorts with merged and exaggerated segments (p = 0.7), significantly higher than symptomatic patients with normal HRM and healthy controls (p ≤ 0.003 for each comparison). Incomplete inhibition and prominent DCI augmentation on MRS (p ≤ 0.01), and presenting symptoms (chest pain and dysphagia, p = 0.04) characterized exaggerated segments, but not demographics or symptom burden. CONCLUSIONS & INFERENCES: Merged esophageal smooth muscle segments and exaggerated S3 may represent hypermotility phenomena from abnormal inhibition and/or excitation, and are not uniformly identified by the CC algorithm.

Reproducibility patterns of multiple rapid swallows during high resolution esophageal manometry provide insights into esophageal pathophysiology.

BACKGROUND: Multiple rapid swallows (MRS) during esophageal high resolution manometry (HRM) assess esophageal neuromuscular integrity by evaluating postdeglutitive inhibition and rebound contraction, but most reports performed only a single MRS sequence. We assessed patterns of MRS reproducibility during clinical HRM in comparison to a normal cohort. METHODS: Consecutive clinical HRM studies were included if two separate MRS sequences (four to six rapid swallows ≤4 s apart) were successfully performed. Chicago Classification diagnoses were identified; contraction wave abnormalities were additionally recorded. MRS-induced inhibition (contraction ≤3 cm during inhibition phase) and rebound contraction was assessed, and findings compared to 18 controls (28.0 ± 0.7 year, 50.0% female). Reproducibility consisted of similar inhibition and contraction responses with both sequences; discordance was segregated into inhibition and contraction phases. KEY RESULTS: Multiple rapid swallows were successfully performed in 89.3% patients and all controls; 225 subjects (56.2 ± 0.9 year, 62.7% female) met study inclusion criteria. Multiple rapid swallows were reproducible in 76.9% patients and 94.4% controls (inhibition phase: 88.0% vs 94.4%, contraction phase 86.7% vs 100%, respectively, p = ns). A gradient of reproducibility was noted, highest in well-developed motor disorders (achalasia spectrum, hypermotility disorders, and aperistalsis, 91.7-100%, p = ns compared to controls); and lower in lesser motor disorders (contraction wave abnormalities, esophageal body hypomotility) or normal studies (62.2-70.8%, p < 0.0001 compared to well-developed motor disorders). Inhibition phase was most discordant in contraction wave abnormalities, while contraction phase was most discordant when studies were designated normal. CONCLUSIONS & INFERENCES: Multiple rapid swallows are highly reproducible, especially in well-developed motor disorders, and complement the standard wet swallow manometry protocol.

The neurobiological correlates of childhood adversity and implications for treatment.

OBJECTIVE: This article provides an overview of research on the neurobiological correlates of childhood adversity and a selective review of treatment implications. METHOD: Findings from a broad array of human and animal studies of early adversity were reviewed. RESULTS: Topics reviewed include neuroendocrine, neurotrophic, neuroimaging, and cognitive effects of adversity, as well as genetic and epigenetic influences. Effects of early-life stress on treatment outcome are considered, and development of treatments designed to address the neurobiological abnormalities is discussed. CONCLUSION: Early adversity is associated with abnormalities of several neurobiological systems that are implicated in the development of psychopathology and other medical conditions. Early-life stress negatively impacts treatment outcome, and individuals may require treatments that are specific to this condition.

C-reactive protein, early life stress, and wellbeing in healthy adults.

OBJECTIVE: To determine whether C-reactive protein (CRP) can serve as a marker for alterations in immune function prior to the manifestation of significant psychiatric and medical disorders. METHOD: Ninety-two healthy adults were recruited from the community and determined to be free of psychiatric or medical disorders. The concentration of plasma CRP from a single resting sample was examined in relation to current mental and physical health as well as to self-reported history of early life adversity. RESULTS: C-reactive protein showed a significant positive correlation with body mass index (BMI; r = 0.477, P < 0.001). Non-specific pain, fatigue, and lower overall quality of physical health were all associated with higher CRP concentrations (all P < 0.05 or P < 0.01), after controlling for effect of BMI and other relevant covariates. Subthreshold depression symptoms and other indices of mental/emotional wellbeing were not associated with CRP, nor was CRP significantly linked to any measures of early life adversity. CONCLUSION: Lower-quality physical health and wellbeing, but not the presence of mood/anxiety symptoms or early life stress (ELS), were significantly related to plasma CRP. Elevated CRP does not appear to be a fundamental consequence of ELS among healthy adults.

Altered response to neuroendocrine challenge linked to indices of the metabolic syndrome in healthy adults.

Metabolic syndrome (MetS) is characterized by central obesity, hypertension, insulin resistance, and hypercholesterolemia. Hypothalamic-pituitary-adrenal (HPA) axis activity is frequently abnormal in MetS, and excessive cortisol exposure may be implicated in metabolic derangements. We investigated the hypothesis that cortisol and adrenocorticotropic hormone (ACTH) responses to a standardized neuroendocrine challenge test would be associated with indices of MetS in a community sample of healthy adults. Healthy adults, 125 men and 170 women, without significant medical problems or chronic medications were recruited from the community. Participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, and anthropometric measurements, blood pressure, glycosylated hemoglobin (HbA1c), and cholesterol were measured. Participants reported on their history of early life stress and recent stress, as well as mood and anxiety symptoms. Cortisol and ACTH responses to the Dex/CRH test were negatively associated with measures of central adiposity (p<0.001) and blood pressure (p<0.01), and positively associated with HDL cholesterol (p<0.01). These findings remained significant after controlling for body mass index (BMI). Measures of stress and anxiety and depressive symptoms were negatively correlated with cortisol and ACTH responses in the Dex/CRH test but were not related to MetS indices. That altered HPA axis function is linked to MetS components even in a healthy community sample suggests that these processes may be involved in the pathogenesis of MetS. Identification of premorbid risk processes might allow for detection and intervention prior to the development of disease.

Vagus nerve stimulation for depression: rationale, anatomical and physiological basis of efficacy and future prospects.

Treatment-resistant depression (TRD) is a major public health concern due to its high costs to society. One of the novel approaches for the treatment of depression is the vagus nerve stimulation (VNS). Therapeutic brain stimulation through delivery of pulsed electrical impulses to the left cervical vagus nerve now has established safety and efficacy as an adjunct treatment for medication-resistant epilepsy and has recently been approved as an adjunct long-term treatment for chronic or recurrent depression. There is considerable evidence from both animal and human neurochemical and neuroimaging studies, that the vagus nerve and its stimulation influence limbic and higher cortical brain regions implicated in mood disorders, providing a rationale for its possible role in the treatment of psychiatric disorders. Clinical studies (open-label and comparator with treatment in naturalistic setting) in patients with TRD have produced promising results, especially when the response rates at longer-term (one- and two-year) follow-up time points are considered. Ongoing research efforts will help determine the place of VNS in the armament of therapeutic modalities available for major depression.

Temperament and response to the Trier Social Stress Test.

OBJECTIVE: The personality characteristics behavioural inhibition and neuroticism have been associated with mood and anxiety disorders and, in some studies, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We recently reported that low levels of Novelty Seeking were associated with elevated plasma cortisol responses to the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test in healthy adults with no psychiatric disorder. The present study tested the association between temperament and HPA axis function in the same group of subjects using a standardized psychosocial neuroendocrine stress test. METHOD: Subjects completed diagnostic interviews, questionnaires, and the Trier Social Stress Test (TSST). RESULTS: Novelty Seeking was inversely associated with plasma cortisol concentrations at baseline and throughout the TSST, but was not related to adrenocorticotropic hormone (ACTH) levels. CONCLUSION: Results of this study extend our previous finding in the Dex/CRH test to a psychosocial stress test. Future investigations are needed to replicate these findings and further elucidate how temperament and personality are linked to HPA function.

The use of antibody D8/17 to identify B cells in adults with obsessive-compulsive disorder.

Compared with healthy control subjects, individuals with childhood-onset obsessive-compulsive disorder (OCD) have been reported to have a higher percentage of B cells that react with the monoclonal antibody D8/17, a marker for rheumatic fever. This study sought to replicate these findings in adults with OCD. Double-blind analyses of blood samples from 29 consecutive adults with primary OCD and 26 healthy control subjects were conducted to determine the percentage of B cells identified by D8/17. Using a standard criterion of > or =12% labeled B cells to denote positivity, rates of D8/17 positive individuals did not significantly differ between the OCD (58.6%) and control (42.3%) groups. Early age of onset was not a predictor of D8/17 positivity in the OCD group. The percentage of B cells identified by the monoclonal antibody marker D8/17 did not distinguish adults with OCD from control subjects, nor did it distinguish a sub-group of adults with OCD who described pre-pubertal onset of their OCD symptoms.

Insight and treatment outcome in obsessive-compulsive disorder.

To determine whether (1) insight in obsessive-compulsive disorder (OCD) improves when OCD symptoms improve, and whether (2) degree of insight in OCD predicts response to sertraline, data were obtained from five sites participating in a larger multisite study of relapse in OCD. During the first 16 weeks of the study, 71 patients received open-label treatment with sertraline and were assessed using the Yale-Brown Obsessive-Compulsive Rating Scale (Y-BOCS) and a rating scale to evaluate insight, the Brown Assessment of Beliefs Scale (BABS), at study baseline and termination. Baseline total BABS score was not significantly correlated with change in Y-BOCS score. Change in BABS total score and change in Y-BOCS total score were significantly correlated. There was no significant difference in mean endpoint Y-BOCS scores for patients with poor insight (n = 14) compared to patients with good insight at baseline (n = 57). Thus, insight improved with decrease in OCD symptom severity. Degree of insight at baseline did not predict response to sertraline, i.e., patients with poor insight were just as likely to respond to sertraline as patients with good insight.

Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review.

BACKGROUND: Previous studies in predominantly bipolar patients have suggested that gabapentin may be useful in treating mood disorders. This report describes its efficacy and tolerability as an adjunctive agent in treatment-resistant depression. METHODS: A chart review was conducted on 27 outpatients presenting with a depressive disorder in whom gabapentin was added to ongoing treatment with a conventional antidepressant to which patients had not responded after at least 6 weeks. The majority of patients had either prominent anxiety or a history of soft bipolar features, but patients with bipolar I disorder were excluded. Clinical state and adverse effects were assessed retrospectively at each visit. RESULTS: Mean gabapentin trial duration was 15.2+/-7.8 weeks, with a mean final dose of 904+/-445 mg/day (range, 300-1800 mg/day). Clinician-rated measures of clinical state improved significantly from baseline to endpoint. Overall, 37.0% (n=10) of patients were responders at endpoint; another 18.5% (n=5) manifested a transient response not sustained to endpoint. Gabapentin was well tolerated; the most common adverse effects were fatigue, sedation, dizziness, and gastrointestinal symptoms. LIMITATIONS: Treatment was uncontrolled and efficacy assessments were retrospective. CONCLUSION: These findings suggest that gabapentin may be of adjunctive benefit in the management of treatment-resistant depression.

Efficacy of continuation ECT and antidepressant drugs compared to long-term antidepressants alone in depressed patients.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of continuation ECT in depression. METHOD: The authors used retrospective chart review to identify 29 patients who received continuation ECT plus long-term antidepressant treatment after a positive response to acute treatment with ECT for a depressive episode (continuation ECT group). A retrospective case-controlled approach was used to ascertain a matching group of 29 patients who received long-term antidepressant treatment alone after responding positively to acute ECT (antidepressant-alone group). All 58 patients (46 with unipolar depression, 12 with bipolar disorder) had been chronically depressed before receiving acute ECT. Data from medical records were analyzed by using survival analysis and proportional hazards regression to determine outcome and risk factors. RESULTS: The mean duration of the follow-up period for all patients was 3.9 years (5.4 years for the continuation ECT patients and 2.4 years for the antidepressant-alone patients). Outcome was significantly better in the continuation ECT group. The cumulative probability of surviving without relapse or recurrence at 2 years was 93% for continuation ECT patients and 52% for antidepressant-alone patients. At 5 years, survival declined to 73% for continuation ECT patients, but fell to 18% for antidepressant-alone patients. Mean survival times were 6.9 years for the continuation ECT patients and 2.7 years for the antidepressant-alone patients. CONCLUSIONS: The findings provide strong support for the efficacy of continuation ECT plus long-term antidepressant treatment in preventing relapse and recurrence in chronically depressed patients who have responded to acute treatment with ECT.

A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder.

BACKGROUND: To date, only 1 controlled study has found a drug (haloperidol) to be efficacious in augmenting response in patients with obsessive-compulsive disorder (OCD) refractory to serotonin reuptake inhibitor (SRI) monotherapy; patients with comorbid chronic tic disorders showed a preferential response. This report describes the first controlled study of risperidone addition in patients with OCD refractory to treatment with SRI alone. METHODS: Seventy adult patients with a primary DSM-IV diagnosis of OCD received 12 weeks of treatment with an SRI. Thirty-six patients were refractory to the SRI and were randomized in a double-blind manner to 6 weeks of risperidone (n = 20) or placebo (n = 16) addition. Behavioral ratings, including the Yale-Brown Obsessive Compulsive Scale, were obtained at baseline and throughout the trial. Placebo-treated patients subsequently received an identical open-label trial of risperidone addition. RESULTS: For study completers, 9 (50%) of 18 risperidone-treated patients were responders (mean daily dose, 2.2 +/-0.7 mg/d) compared with 0 of 15 in the placebo addition group (P<. 005). Seven (50%) of 14 patients who received open-label risperidone addition responded. Risperidone addition was superior to placebo in reducing OCD (P<.001), depressive (P<.001), and anxiety (P =.003) symptoms. There was no difference in response between OCD patients with and without comorbid diagnoses of chronic tic disorder or schizotypal personalty disorder. Other than mild, transient sedation, risperidone was well tolerated. CONCLUSION: These results suggest that OCD patients with and without comorbid chronic tic disorders or schizotypal personality disorder may respond to the addition of low-dose risperidone to ongoing SRI therapy.

Genetic polymorphism at the CLOCK gene locus and major depression.

Genetic analysis in both mouse and Drosophila has indicated that the product of the CLOCK gene is an essential component of a circadian rhythm timing system. A single nucleotide polymorphism (SNP), T3111C, in the 3' flanking region of the human CLOCK gene has been identified. Homozygotes or heterozygotes for the 3111C allele have been reported to have higher mean scores on a measure of evening preference for activity (vs. morning preference) than subjects homozygous for the 3111T allele. Since major depression is hypothesized to be closely linked to circadian rhythms, we explored whether this polymorphism might be related to susceptibility to major depression. We also ascertained allele frequency in an African-American control population, to begin to evaluate population variation at this locus. CLOCK T3111C allele frequencies were determined in 280 European American (EA) subjects, 143 with a history of major depression and 137 screened controls, and in 58 African American (AA) screened control subjects, using a polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) method. There was no significant difference between EA depressed and control subjects in allele frequency. There was a significant difference in allele frequency between EA and AA subjects, demonstrating a potential for population stratification. In none of these groups were significant deviations from Hardy-Weinberg equilibrium found. The present data do not support an association between CLOCK gene alleles at the T3111C locus and major depression.

A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia.

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.