Friday, April 1, 2016

April 2016

Distress During Pregnancy: Epigenetic Regulation of Placenta Glucocorticoid-Related Genes and Fetal Neurobehavior 


The American Journal of Psychiatry

Abstract

Objective
Increased risk of psychopathology is observed in children exposed to maternal prenatal distress, and elevated maternal cortisol and epigenetic regulation of placental glucocorticoid-pathway genes are potential mechanisms. The authors examined maternal distress and salivary cortisol in relation to fetal movement and heart rate (“coupling”) and DNA methylation of three glucocorticoid pathway genes—HSD11B2, NR3C1, and FKBP5—in term placentas.

Method
Mood questionnaires and salivary cortisol were collected from 61 women between 24–27 gestational weeks, and fetal assessment was conducted at 34–37 weeks. Placental CpG methylation in the three genes was analyzed using 450K Beadchips and bisulfite sequencing; correlations between maternal and fetal variables and DNA methylation were tested; and maternal distress effects on fetal behavior via DNA methylation were investigated.

Results
Perceived stress (Perceived Stress Scale), but not cortisol, was associated with altered CpG methylation in placentas. In the highest tertile of the Perceived Stress Scale, the Beadchip data revealed modestly elevated methylation of HSD11B2, associated with lower fetal coupling (β=−0.51), and modestly elevated methylation of FKBP5, also with lower fetal coupling (β=−0.47). These increases in methylation were validated by bisulfite sequencing, where they occurred in a minority of clones.

Conclusions
This is the first study to link the effects of pregnant women's distress on the fetus and epigenetic changes in placental genes. Since increased DNA methylation in HSD11B2 and FKBP5 are seen in a minority of bisulfite sequencing clones, these epigenetic changes, and functional consequences, may affect subpopulations of placental cells.



Toxoplasma gondii Infection: Relationship With Aggression in Psychiatric Subjects


The Journal of Clinical Psychiatry

Abstract

Objective 
Toxoplasma gondii (T. gondii), a protozoan parasite that persists in host tissues, including brain, has been associated with several psychiatric disorders and with suicidal behavior. We sought to test the hypothesis that latent T. gondii infection, as manifest by circulating immunoglobulin G (IgG) antibodies to T. gondii, is associated with both categorical and dimensional measures of aggression.

Method
IgG antibodies to T. gondii were collected between 1991 and 2008 from 358 adult subjects with DSM-5 intermittent explosive disorder (IED), non-IED psychiatric disorders (psychiatric controls), or no evidence of any psychiatric diagnosis (healthy controls). Assessments of aggression, anger, and impulsivity, as well as state/trait anger, depression, and anxiety were completed. T. gondii seropositive status (IgG > 12 IU) was the primary outcome measure for this study.

Results
T. gondii seropositive status (IgG > 12 IU) was associated with higher aggression (P = .022) and impulsivity (P = .05) scores. When both aggression and impulsivity scores were controlled for, however, only aggression scores were higher in seropositive subjects (P = .011). In addition, T. gondii seropositive status and marginal mean ± SE aggression scores increased from healthy controls (9.1% and −0.66 ± 0.05) to psychiatric controls (16.7% and −0.27 ± 0.05) to subjects with IED (21.8% and 1.15 ± 0.06; P ≤ .05). These findings were not accounted for by the presence of other syndromal/personality disorders or by states or traits related to depressed or anxious moods.

Conclusions
These data are consistent with previous studies suggesting a relationship between T. gondii and self-directed aggression (ie, suicidal behavior) and further add to the biological complexity of impulsive aggression both from a categorical and a dimensional perspective.



The red-hot debate about transmissible Alzheimer's:A controversial study has suggested that the neurodegenerative disease might be transferred from one person to another. Now scientists are racing to find out whether that is true.


Nature

HIn the 25 years that John Collinge has studied neurology, he has seen hundreds of human brains. But the ones he was looking at under the microscope in January 2015 were like nothing he had seen before.

He and his team of pathologists were examining the autopsied brains of four people who had once received injections of growth hormone derived from human cadavers. It turned out that some of the preparations were contaminated with a misfolded protein — a prion — that causes a rare and deadly condition called Creutzfeldt–Jakob disease (CJD), and all four had died in their 40s or 50s as a result. But for Collinge, the reason that these brains looked extraordinary was not the damage wrought by prion disease; it was that they were scarred in another way. “It was very clear that something was there beyond what you'd expect,” he says. The brains were spotted with the whitish plaques typical of people with Alzheimer's disease. They looked, in other words, like young people with an old person's disease.

For Collinge, this led to a worrying conclusion: that the plaques might have been transmitted, alongside the prions, in the injections of growth hormone — the first evidence that Alzheimer's could be transmitted from one person to another. If true, that could have far-reaching implications: the possibility that 'seeds' of the amyloid-β protein involved in Alzheimer's could be transferred during other procedures in which fluid or tissues from one person are introduced into another, such as blood transfusions, organ transplants and other common medical procedures.



Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder


Translational Psychiatry
  
Abstract

Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants’ age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114–0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I2=73.36, P<0.001), meta-regression showed that higher EPA dose (β=0.00037 (0.00009–0.00065), P=0.009), higher percentage antidepressant users (β=0.0058 (0.00017–0.01144), P=0.044) and earlier publication year (β=−0.0735 (−0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.



Antidepressant use and risk of cardiovascular outcomes in people aged 20 to 64: cohort study using primary care database 


BMJ

Abstract

Objective
To assess associations between different antidepressant treatments and rates of three cardiovascular outcomes (myocardial infarction, stroke or transient ischaemic attack, and arrhythmia) in people with depression.

Design 
Cohort study.

Setting 
UK general practices contributing to the QResearch primary care database.

Participants 
238 963 patients aged 20 to 64 years with a first diagnosis of depression between 1 January 2000 and 31 July 2011.

Exposures 
Antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, duration of use, and commonly prescribed individual antidepressant drugs.

Main outcome measures 
First diagnoses of myocardial infarction, stroke or transient ischaemic attack, and arrhythmia during five years’ follow-up. Cox proportional hazards models were used to estimate hazard ratios, adjusting for potential confounding variables.

Results 
During five years of follow-up, 772 patients had a myocardial infarction, 1106 had a stroke or transient ischaemic attack, and 1452 were diagnosed as having arrhythmia. No significant associations were found between antidepressant class and myocardial infarction over five years’ follow-up. In the first year of follow-up, patients treated with selective serotonin reuptake inhibitors had a significantly reduced risk of myocardial infarction (adjusted hazard ratio 0.58, 95% confidence interval 0.42 to 0.79) compared with no use of antidepressants; among individual drugs, fluoxetine was associated with a significantly reduced risk (0.44, 0.27 to 0.72) and lofepramine with a significantly increased risk (3.07, 1.50 to 6.26). No significant associations were found between antidepressant class or individual drugs and risk of stroke or transient ischaemic attack. Antidepressant class was not significantly associated with arrhythmia over five years’ follow-up, although the risk was significantly increased during the first 28 days of treatment with tricyclic and related antidepressants (adjusted hazard ratio 1.99, 1.27 to 3.13). Fluoxetine was associated with a significantly reduced risk of arrhythmia (0.74, 0.59 to 0.92) over five years, but citalopram was not significantly associated with risk of arrhythmia even at high doses (1.11, 0.72 to 1.71 for doses ≥40 mg/day).

Conclusions 
This study found no evidence that selective serotonin reuptake inhibitors are associated with an increased risk of arrhythmia or stroke/transient ischaemic attack in people diagnosed as having depression between the ages of 20 to 64 or that citalopram is associated with a significantly increased risk of arrhythmia. It found some indication of a reduced risk of myocardial infarction with selective serotonin reuptake inhibitors, particularly fluoxetine, and of an increased risk with lofepramine.



A Randomized Trial to Assess the Efficacy and Safety of ABT-126, a Selective α7 Nicotinic Acetylcholine Receptor Agonist, in the Treatment of Cognitive Impairment in Schizophrenia


The American Journal of Psychiatry

Abstract

Objective
The authors sought to evaluate the efficacy and safety of ABT-126, a selective α7 nicotinic receptor partial agonist, in stable patients with schizophrenia.

Method
A 12-week, double-blind, placebo-controlled, parallel-group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests.

Results
A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence).

Conclusions
ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention.



Observational Evidence for Buprenorphine’s Impact on Posttraumatic Stress Symptoms in Veterans With Chronic Pain and Opioid Use Disorder


The Journal of Clinical Psychiatry

Abstract

Objective
Posttraumatic stress disorder (PTSD), chronic pain, and substance use disorders are prevalent co-occurring conditions that are challenging to treat individually, and there is no evidence-based treatment for all 3. Buprenorphine, used to treat opioid use disorder and chronic pain, is a partial nociceptin opioid receptor agonist. In preclinical studies, a nociceptin opioid receptor agonist was shown to mitigate PTSD symptoms in acute trauma. We compared buprenorphine to other opioid medications in its impact on PTSD symptoms in patients with chronic pain and opioid and/or other substance use disorders.

Method
We assembled a retrospective cohort of 382 Iraq and Afghanistan veterans in US Department of Veterans Affairs health care from October 1, 2007, to July 29, 2013, with ICD-9-CM diagnoses of PTSD, chronic pain, and substance use disorders. We used time-varying general estimating equation models to assess the primary outcome, which was change in PTSD symptoms (measured using the PTSD Checklist and the Primary Care PTSD Screen) among veterans initiated on sublingual buprenorphine versus those maintained on moderately high-dose opioid therapy.

Results 
Twice as many veterans in the buprenorphine group (23.7%) compared to those in the opioid therapy group (11.7%) experienced improvement in PTSD symptoms (P = .001). Compared to veterans in the opioid therapy group, veterans receiving buprenorphine showed significant improvement in PTSD symptoms after 8 months, with increasing improvement up to 24 months (incidence rate ratio = 1.79; 95% CI, 1.16–2.77; P = .009). There were no differences in the longitudinal course of pain ratings between groups.

Conclusions 
This observational study is the first to report an incidental effect of buprenorphine compared to opioid therapy in improving PTSD symptoms in veterans.



Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study


The Lancet Psychiatry

Summary

Background
Identification of patients at high risk of treatment-resistant schizophrenia at the time of schizophrenia diagnosis would be of great clinical benefit in minimising the delay to clozapine treatment in patients unlikely to respond to non-clozapine antipsychotics. However, little is known about predictors of treatment resistance in this patient population. We used a treatment-based proxy for treatment-resistant schizophrenia to identify candidate predictors of treatment resistance at first hospital contact with a schizophrenia diagnosis.

Methods
In this population-based cohort study, we obtained Danish national registry data for all adult patients (≥18 years) with incident schizophrenia diagnosed between Jan 1, 1996, and Dec 31, 2006, and followed up until Dec 31, 2010. Our main proxy definition of treatment-resistant schizophrenia was the earliest instance of either clozapine initiation or hospital admission for schizophrenia after having had two periods of different antipsychotic monotherapy. We did multivariable Cox proportional hazards regression analysis to estimate the association between baseline candidate predictors and treatment resistance.

Findings
8624 patients fulfilled the criteria for inclusion. In multivariable complete-case analyses, 1703 (21%) of 8044 patients fulfilled the main proxy definition of treatment-resistant schizophrenia during a median follow-up of 9·1 years (IQR 6·3–11·9). Younger age (hazard ratio 0·96 [95% CI 0·95–0·97]), living in a less urban area (provincial 1·38 [1·23–1·56], rural 1·44 [1·25–1·65]), primary education level (0·88 [0·79–0·98]), more than 30 bed-days in psychiatric hospital in the year before first schizophrenia diagnosis (1·54 [1·35–1·75]), inpatient at first schizophrenia diagnosis (2·07 [1·87–2·29]), paranoid subtype (1·24 [1·13–1·37]), comorbid personality disorder (1·24 [1·11–1·39]), psychotropic drug use (antipsychotics 1·51 [1·35–1·69], antidepressants 1·15 [1·03–1·29], and benzodiazepines 1·22 [1·10–1·37]), and previous suicide attempt (1·21 [1·07–1·39]) were all significantly associated with treatment-resistant schizophrenia.

Interpretation
Our study identifies several candidate predictors that could potentially be included in future prediction models for treatment-resistant schizophrenia. Notably, established risk factors for schizophrenia did not predict treatment resistance, suggesting that treatment-resistant disease might be a distinct subtype of schizophrenia and not merely a more severe form.



Predictors and Moderators of Remission With Aripiprazole Augmentation in Treatment-Resistant Late-Life Depression


JAMA Psychiatry

Abstract

Importance  
Safe, efficacious, second-line pharmacological treatment options exist for the large portion of older adults with major depressive disorder who do not respond to first-line pharmacotherapy. However, limited evidence exists to aid clinical decision making regarding which patients will benefit from which second-line treatments.

Objective  
To test the moderating role of pretreatment executive function, severity of anxiety, and severity of medical comorbidity in remission of treatment-resistant late-life depression after aripiprazole augmentation.

Design, Setting, and Participants  
As follow-up to a 12-week randomized clinical trial of aripiprazole augmentation for first-line treatment-resistant late-life depression (Incomplete Response in Late-Life Depression: Getting to Remission [IRL-GRey]), we evaluated the effects of the following potential moderators and their interactions with treatment: baseline assessments of executive function (set shifting measured by the Trail Making Test) and response inhibition control (measured by a Color-Word Interference task), anxiety symptoms, and medical comorbidity. Analyses were conducted in May and June 2015.

Interventions  
Aripiprazole or placebo tablets were started at 2 mg daily and titrated as tolerated, to a maximal dose of 15 mg daily.

Main Outcomes and Measures  
Remission of treatment-resistant late-life depression (defined as a Montgomery-Åsberg Depression Rating Scale score of ≤10 at both of the last 2 consecutive visits).

Results  
Of 181 trial participants (103 female [56.9%]) who were 60 years of age or older and whose major depression had failed to remit with venlafaxine hydrochloride monotherapy, 91 received aripiprazole and 90 received placebo. Remission occurred in 40 (43%) who received aripiprazole and 26 (29%) who received placebo. Baseline set shifting moderated the efficacy of aripiprazole augmentation (odds ratio [OR], 1.66 [95% CI, 1.05-2.62]; P = .03 for interaction with treatment). Among participants with a Trail Making Test scaled score of 7 or higher, the odds of remission were significantly higher with aripiprazole than with placebo (53% vs 28%; number needed to treat, 4; OR, 4.11 [95% CI, 1.83-9.20]). Among participants with a Trail Making Test scaled score of less than 7, aripiprazole and placebo were equally efficacious (OR, 0.64 [95% CI, 0.15-2.80]). Greater severity of anxiety at baseline predicted a lower remission rate but did not moderate aripiprazole efficacy; each standard deviation greater anxiety severity was associated with 50% reduced odds of remission in both aripiprazole and placebo arms. Medical comorbidity and Color-Word Interference test performance were neither general predictors nor treatment-moderating factors.

Conclusions and Relevance  
Set-shifting performance indicates which older adults with treatment-resistant depression may respond favorably to augmentation with aripiprazole and thus may help to personalize treatment.



Trajectories of Depressive Symptoms in Older Adults and Risk of Dementia


JAMA Psychiatry

Abstract

Importance  
Depression has been identified as a risk factor for dementia. However, most studies have measured depressive symptoms at only one time point, and older adults may show different patterns of depressive symptoms over time.

Objective  
To investigate the association between trajectories of depressive symptoms and risk of dementia in older adults.

Design, Setting, and Participants  
This was a prospective cohort investigation of black and white community-dwelling older adults in the Health, Aging, and Body Composition study. Participants were enrolled between May 1997 and June 1998 and followed up through 2001-2002. The dates of this analysis were September 2014 to December 2015. The setting was community research centers in Memphis, Tennessee, and Pittsburgh, Pennsylvania. Trajectories of depressive symptoms were assessed from baseline to year 5. Symptoms were measured with the Center for Epidemiologic Studies Depression Scale Short Form, and trajectories were calculated using latent class growth curve analysis.

Main Outcomes and Measures  
Incident dementia through year 11, determined by dementia medication use, hospital records, or significant cognitive decline (≥1.5 SD race-specific decline on the Modified Mini-Mental State Examination). We examined the association between depressive symptom trajectories and dementia incidence using Cox proportional hazards regression models adjusted for demographics, health factors that differed between groups, and cognition during the depressive symptom assessment period (baseline to year 5).

Results  
The analytic cohort included 2488 black and white older adults with repeated depressive symptom assessments from baseline to year 5 who were free of dementia throughout that period. Their mean (SD) age at baseline was 74.0 (2.8) years, and 53.1% (n = 1322) were female. The following 3 depressive symptom trajectories were identified: consistently minimal symptoms (62.0% [n = 1542] of participants), moderate and increasing symptoms (32.2% [n = 801] of participants), and high and increasing symptoms (5.8% [n = 145] of participants). Compared with the consistently minimal trajectory, having a high and increasing depressive symptom trajectory was associated with significantly increased risk of dementia (fully adjusted hazard ratio, 1.94; 95% CI, 1.30-2.90), while the moderate and increasing trajectory was not associated with risk of dementia after full adjustment. Sensitivity analyses indicated that the high and increasing trajectory was associated with dementia incidence, while depressive symptoms at individual time points were not.

Conclusions and Relevance  
Older adults with a longitudinal pattern of high and increasing depressive symptoms are at high risk for dementia. Individuals’ trajectory of depressive symptoms may inform dementia risk more accurately than one-time assessment of depressive symptoms.



Online Journals:




Biological Psychiatry - Volume 79, Issue 8, April 2016



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