Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms.

We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls).

Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (−1019, −1007, −681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF.

Recent stress correlated positively with blood monocyte methylation at the −681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the −1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD.

These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

Depression and anxiety are common and highly comorbid, and their comorbidity is associated with poorer outcomes posing clinical and public health concerns. We evaluated the polygenic contribution to comorbid depression and anxiety, and to each in isolation.

Diagnostic codes were extracted from electronic health records for four biobanks [N = 177 865 including 138 632 European (77.9%), 25 612 African (14.4%), and 13 621 Hispanic (7.7%) ancestry participants]. The outcome was a four-level variable representing the depression/anxiety diagnosis group: neither, depression-only, anxiety-only, and comorbid. Multinomial regression was used to test for association of depression and anxiety polygenic risk scores (PRSs) with the outcome while adjusting for principal components of ancestry.

In total, 132 960 patients had neither diagnosis (74.8%), 16 092 depression-only (9.0%), 13 098 anxiety-only (7.4%), and 16 584 comorbid (9.3%). In the European meta-analysis across biobanks, both PRSs were higher in each diagnosis group compared to controls. Notably, depression-PRS (OR 1.20 per s.d. increase in PRS; 95% CI 1.18–1.23) and anxiety-PRS (OR 1.07; 95% CI 1.05–1.09) had the largest effect when the comorbid group was compared with controls. Furthermore, the depression-PRS was significantly higher in the comorbid group than the depression-only group (OR 1.09; 95% CI 1.06–1.12) and the anxiety-only group (OR 1.15; 95% CI 1.11–1.19) and was significantly higher in the depression-only group than the anxiety-only group (OR 1.06; 95% CI 1.02–1.09), showing a genetic risk gradient across the conditions and the comorbidity.

This study suggests that depression and anxiety have partially independent genetic liabilities and the genetic vulnerabilities to depression and anxiety make distinct contributions to comorbid depression and anxiety.

Reported childhood adversity (CA) is associated with development of depression in adulthood and predicts a more severe course of illness. Although elevated serotonin 1A receptor (5-HT1AR) binding potential, especially in the raphe nuclei, has been shown to be a trait associated with major depression, we did not replicate this finding in an independent sample using the partial agonist positron emission tomography tracer [11C]CUMI-101. Evidence suggests that CA can induce long-lasting changes in expression of 5-HT1AR, and thus, a history of CA may explain the disparate findings.

Following up on our initial report, 28 unmedicated participants in a current depressive episode (bipolar n = 16, unipolar n = 12) and 19 non-depressed healthy volunteers (HVs) underwent [11C]CUMI-101 imaging to quantify 5-HT1AR binding potential. Participants in a depressive episode were stratified into mild/moderate and severe CA groups via the Childhood Trauma Questionnaire. We hypothesized higher hippocampal and raphe nuclei 5-HT1AR with severe CA compared with mild/moderate CA and HVs.

There was a group-by-region effect (p = 0.011) when considering HV, depressive episode mild/moderate CA, and depressive episode severe CA groups, driven by significantly higher hippocampal 5-HT1AR binding potential in participants in a depressive episode with severe CA relative to HVs (p = 0.019). Contrary to our hypothesis, no significant binding potential differences were detected in the raphe nuclei (p-values > 0.05).

With replication in larger samples, elevated hippocampal 5-HT1AR binding potential may serve as a promising biomarker through which to investigate the neurobiological link between CA and depression.

Suicidal behavior is moderately heritable and a consequence of a combination of the diathesis traits for suicidal behavior and suicide-related major psychiatric disorders. Here, we sought to examine shared polygenic effects between various psychiatric disorders/traits and suicidal behavior and to compare the shared polygenic effects of various psychiatric disorders/traits on non-fatal suicide attempt and suicide death.

We used our genotyped European ancestry sample of 260 non-fatal suicide attempters, 317 suicide decedents and 874 non-psychiatric controls to test whether polygenic risk scores (PRSs) obtained from large GWASs for 22 suicide-related psychiatric disorders/traits were associated with suicidal behavior. Results were compared between non-fatal suicide attempt and suicide death in a sensitivity analysis.

PRSs for major depressive disorder, bipolar disorder, schizophrenia, ADHD, alcohol dependence, sensitivity to environmental stress and adversity, educational attainment, cognitive performance, and IQ were associated with suicidal behavior (Bonferroni-corrected p < 2.5 × 10−4). The polygenic effects of all 22 psychiatric disorders/traits had the same direction (p for binomial tests = 4.8 × 10−7) and were correlated (Spearman's ρ = 0.85) between non-fatal suicide attempters and suicide decedents.

We found that polygenic effects for major psychiatric disorders and diathesis-related traits including stress responsiveness and intellect/cognitive function contributed to suicidal behavior. While we found comparable polygenic architecture between non-fatal suicide attempters and suicide decedents based on correlations with PRSs of suicide-related psychiatric disorders/traits, our analyses are limited by small sample size resulting in low statistical power to detect difference between non-fatal suicide attempt and suicide death.

Several social determinants of health (SDoH) have been associated with the onset of major depressive disorder (MDD). However, prior studies largely focused on individual SDoH and thus less is known about the relative importance (RI) of SDoH variables, especially in older adults. Given that risk factors for MDD may differ across the lifespan, we aimed to identify the SDoH that was most strongly related to newly diagnosed MDD in a cohort of older adults.

We used self-reported health-related survey data from 41 174 older adults (50–89 years, median age = 67 years) who participated in the Mayo Clinic Biobank, and linked ICD codes for MDD in the participants' electronic health records. Participants with a history of clinically documented or self-reported MDD prior to survey completion were excluded from analysis (N = 10 938, 27%). We used Cox proportional hazards models with a gradient boosting machine approach to quantify the RI of 30 pre-selected SDoH variables on the risk of future MDD diagnosis.

Following biobank enrollment, 2073 older participants were diagnosed with MDD during the follow-up period (median duration = 6.7 years). The most influential SDoH was perceived level of social activity (RI = 0.17). Lower level of social activity was associated with a higher risk of MDD [hazard ratio = 2.27 (95% CI 2.00–2.50) for highest v. lowest level].

Across a range of SDoH variables, perceived level of social activity is most strongly related to MDD in older adults. Monitoring changes in the level of social activity may help identify older adults at an increased risk of MDD.

Aberrant activity of the subcallosal cingulate (SCC) is a common theme across pharmacologic treatment efficacy prediction studies. The functioning of the SCC in psychotherapeutic interventions is relatively understudied, as are functional differences among SCC subdivisions. We conducted functional connectivity analyses (rsFC) on resting-state functional magnetic resonance imaging (fMRI) data, collected before and after a course of cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), using seeds from three SCC subdivisions.

Resting-state data were collected from unmedicated patients with current MDD (Hamilton Depression Rating Scale-17 > 16) before and after 14-sessions of CBT monotherapy. Treatment outcome was assessed using the Beck Depression Inventory (BDI). Rostral anterior cingulate (rACC), anterior subcallosal cingulate (aSCC), and Brodmann’s area 25 (BA25) masks were used as seeds in connectivity analyses that assessed baseline rsFC and symptom severity, changes in connectivity related to symptom improvement after CBT, and prediction of treatment outcomes using whole-brain baseline connectivity.

Pretreatment BDI negatively correlated with pretreatment rACC ~ dorsolateral prefrontal cortex and aSCC ~ lateral prefrontal cortex rsFC. In a region-of-interest longitudinal analysis, rsFC between these regions increased post-treatment (p < 0.05FDR). In whole-brain analyses, BA25 ~ paracentral lobule and rACC ~ paracentral lobule connectivities decreased post-treatment. Whole-brain baseline rsFC with SCC did not predict clinical improvement.

rsFC features of rACC and aSCC, but not BA25, correlated inversely with baseline depression severity, and increased following CBT. Subdivisions of SCC involved in top-down emotion regulation may be more involved in cognitive interventions, while BA25 may be more informative for interventions targeting bottom-up processing. Results emphasize the importance of subdividing the SCC in connectivity analyses.

Suicide is the leading cause of death among Israeli youths but data on causes are scarce. This study used psychological autopsies of 70 Israeli school students who committed suicide during 2004–2011, attempting to determine the causes.

Four narratives of the self were identified (qualitative analysis) and compared (quantitative analysis): (1) regressive: functioning and mood deteriorated continuously (45%); (2) tragic: doing well until rapid decline around suicidal crisis (20%); (3) unstable: peaks and crises throughout life (20%); and (4) stable: long lasting state of adverse living circumstances (15%). Functioning, mental disorders, stressful life events and substance abuse were examined.

A representative profile of the suicide-completer emerged. Suicidality in the tragic narrative involved shorter crisis, fewer risk factors and less psychopathology than the other narratives, also better general functioning and better school performance. Though decrease in functioning was evident in all groups, in the tragic group it tended to be disregarded.

This study presents an in-depth analysis of a unique suicide population of high school students. A combined methodology of qualitative and quantitative analyses reveals a distinct subpopulation of suicidal adolescents with little or no overt psychopathology that poses a challenge to suicide prevention strategies.

Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence.

Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence.

No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value = 6.63 × 10−3); 5′-adenosine monophosphate-activated protein kinase signalling (P-value = 9.57 × 10−3); and apoptosis (P-value = 1.75 × 10−2) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status.

The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.

There is an ongoing debate on the effectiveness of suicidal behavior prevention measures in the military. The association of three widely used tools with severe suicide attempts was assessed in this setting.

Thirty-nine Israeli soldiers (59% males), mean age 19 yrs., who attempted suicide during military service were divided into two groups: severe (n = 14; 35.9%) and moderate suicide attempts, and were assessed using the Scale for Suicide Ideation (SSI), Suicide Intent Scale (SIS) and the Columbia Suicide Severity Rating Scale (C-SSRS).

Seven items from the SSI (p = 0.008), two items from SIS and one item from C-SSRS were associated with severe suicide attempts. Kendall’s tau-b correlation with bootstrap demonstrated stability of these correlations.

Greater severity of suicidal ideation was associated with more severe suicide attempts. The combination of male gender, available firearms and current severe suicide ideation is high-risk danger sign in a military setting, even when reported intent to die is low.

Suicide is a serious and not uncommon consequence of mood disorders that occurs primarily when individuals are depressed. Understanding the neurobiology of suicidal activity (thoughts or behaviors) is likely to facilitate prevention.

Seventy-nine adult depressed mood disorder patients (MDP), of which 25 had attempted suicide at least once, and 66 healthy controls (HC) participated in this study. Resting-state functional MRI was used to identify neural activity differences between suicide attempters (SA) and non-attempters (NA). Specifically, differences were examined in functional connectivity both within and between four large cognitive networks [Executive Control (ECN), Default Mode (DMN), Salience (SN), and Basal Ganglia (BGN)] and their respective associations with suicidal activity.

Compared to HCs, patients had greater posterior DMN activity, but less activity in the BGN, and less low-frequency spectral power in the dorso-medial DMN. Furthermore, increased posterior DMN activity in SA was associated with recent suicidal activity, whereas NA had reduced BGN activity and less dorso-medial DMN spectral power, the latter being associated with lifelong suicidal thinking. SA also had greater activity in midline circuitry compared to both HC and NA, and the pattern of BGN and DMN co-activity differed between SA and NA.

DMN engagement raises the possibility that suicidal activity in mood disorder patients may be a consequence of impaired self-referential thought processing. Furthermore, differential BGN and DMN co-activation according to suicide attempt status suggests that attempting suicide perhaps alters cognitive flexibility. These insights are potentially useful for understanding the neural basis of suicide activity.

The hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)].

Thirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes.

Baseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome.

This is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the ‘limbic’ AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.

Cognitive behavioral therapy (CBT) is an effective treatment for many patients suffering from major depressive disorder (MDD), but predictors of treatment outcome are lacking, and little is known about its neural mechanisms. We recently identified longitudinal changes in neural correlates of conscious emotion regulation that scaled with clinical responses to CBT for MDD, using a negative autobiographical memory-based task.

We now examine the neural correlates of emotional reactivity and emotion regulation during viewing of emotionally salient images as predictors of treatment outcome with CBT for MDD, and the relationship between longitudinal change in functional magnetic resonance imaging (fMRI) responses and clinical outcomes. Thirty-two participants with current MDD underwent baseline MRI scanning followed by 14 sessions of CBT. The fMRI task measured emotional reactivity and emotion regulation on separate trials using standardized images from the International Affective Pictures System. Twenty-one participants completed post-treatment scanning. Last observation carried forward was used to estimate clinical outcome for non-completers.

Pre-treatment emotional reactivity Blood Oxygen Level-Dependent (BOLD) signal within hippocampus including CA1 predicted worse treatment outcome. In contrast, better treatment outcome was associated with increased down-regulation of BOLD activity during emotion regulation from time 1 to time 2 in precuneus, occipital cortex, and middle frontal gyrus.

CBT may modulate the neural circuitry of emotion regulation. The neural correlates of emotional reactivity may be more strongly predictive of CBT outcome. The finding that treatment outcome was predicted by BOLD signal in CA1 may suggest overgeneralized memory as a negative prognostic factor in CBT outcome.

To conduct a full economic evaluation assessing the costs and consequences related to probiotic use for the primary prevention of Clostridium difficile–associated diarrhea (CDAD).

Cost-effectiveness analysis using decision analytic modeling.

A cost-effectiveness analysis was used to evaluate the risk of CDAD and the costs of receiving oral probiotics versus not over a time horizon of 30 days. The target population modeled was all adult inpatients receiving any therapeutic course of antibiotics from a publicly funded healthcare system perspective. Effectiveness estimates were based on a recent systematic review of probiotics for the primary prevention of CDAD. Additional estimates came from local data and the literature. Sensitivity analyses were conducted to assess how plausible changes in variables impacted the results.

Treatment with oral probiotics led to direct costs of CDN $24 per course of treatment per patient. On average, patients treated with oral probiotics had a lower overall cost compared with usual care (CDN $327 vs $845). The risk of CDAD was reduced from 5.5% in those not receiving oral probiotics to 2% in those receiving oral probiotics. These results were robust to plausible variation in all estimates.

Oral probiotics as a preventive strategy for CDAD resulted in a lower risk of CDAD as well as cost-savings. The cost-savings may be greater in other healthcare systems that experience a higher incidence and cost associated with CDAD.

Infect Control Hosp Epidemiol 2016;37:1079–1086