Objective Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. Method This randomized clinical trial tested the effect of adjunctive sub-anesthetic intravenous ketamine on clinically significant suicidal ideation in major depressive disorder (MDD). Adults (N=80) with current MDD and score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomized to ketamine or midazolam infusion. The primary outcome was Day 1 SSI score (24 hours post-infusion). Other outcomes included global depression and adverse effects. Results Reduction of SSI score was 4.96 points greater after ketamine compared with midazolam at Day 1 (95% confidence interval (CI)=2.33 to 7.59; p=0.0003; Cohen’s d=0.75). Proportion of responders (≥50% reduction in SSI) at Day 1 was 55% after ketamine and 30% after midazolam (OR=2.85 (95% CI=1.14 to 7.15); p=0.0237; NNT=4.00). Improvement in the Profile of Mood States (POMS) depression subscale was greater at Day 1 compared with midazolam treatment (Estimate=7.65 (95% CI=1.36 to 13.94), df=75, t=2.42, p=0.0178), and this effect mediated 33.6% of ketamine’s effect on SSI score. Side effects were short-lived. Benefit was sustained for up to six weeks with clinical pharmacotherapy. Conclusions Adjunctive ketamine demonstrated greater reduction of clinically significant suicidal ideation in depressed patients within 24 hours compared to midazolam, partially independent of antidepressant effect. Research is needed to understand ketamine’s mechanism of action and to develop safe, longer-term treatment.

Objective Causes of placebo effects in antidepressant trials have been inferred from observational studies and meta-analyses, but their mechanisms have not been directly established. The goal of this study was to examine in a prospective, randomized controlled trial (RCT) whether patient expectancy mediates placebo effects in antidepressant studies. Method Adult outpatients with Major Depressive Disorder (MDD) were randomized to Open or Placebo-controlled citalopram treatment. Following measurement of pre- and post-randomization expectancy, subjects were treated with citalopram or placebo for 8 weeks. Independent samples t tests determined whether patient expectancy differed between the Open and Placebo-controlled Groups, and mixed-effects models assessed Group effects on Hamilton Rating Scale for Depression (HRSD) scores over time while controlling for treatment assignment. Finally, mediation analyses tested whether between-Group differences in patient expectancy mediated the Group effect on HRSD scores. Results Post-randomization expectancy scores were significantly higher in the Open Group (12.1 ± 2.1) as compared to the Placebo-controlled Group (11.0 ± 2.0, t=2.32, df 45, p=0.03). Mixed-effects modeling revealed a significant Week × Group interaction (F(1,296)=8.61, p=0.0036), indicating that HRSD scores for citalopram-treated subjects declined at a faster rate in the Open Group compared to the Placebo-controlled Group. Patient expectations post-randomization partially mediated Group effects on Week 8 HRSD (p=0.046). Conclusions Patient expectancy is a significant mediator of placebo effects in antidepressant trials. Expectancy-related interventions should be investigated as a means of controlling placebo responses in antidepressant clinical trials and improving patient outcome in clinical treatment.

Evidence from numerous animal models shows that vagal activity regulates inflammatory responses by decreasing cytokine release. Heart rate variability (HRV) is a reliable index of cardiac vagal regulation and should be inversely related to levels of inflammatory markers. Inflammation is also regulated by sympathetic inputs, but only one previous paper controlled for this. In a larger and more representative sample, we sought to replicate those results and examine potential sex differences in the relationship between HRV and inflammatory markers. Using data from the MIDUS II study, we analyzed the relationship between 6 inflammatory markers and both HF-HRV and LF-HRV. After controlling for sympathetic effects measured by urinary norepinephrine as well as a host of other factors, LF-HRV was found to be inversely associated with fibrinogen, CRP and IL-6, while HF-HRV was inversely associated with fibrinogen and CRP. We did not observe consistent sex differences. These results support the existence of the vagal anti-inflammatory pathway and suggest that it has similar effects in men and women.

PurposeCollege-bound young people experience sexual assault, both before and after they enter college. This study examines historical risk factors (experiences and exposures that occurred prior to college) for penetrative sexual assault (PSA) victimization since entering college.MethodsA cross-sectional study, including an online population-based quantitiative survey with undergraduate students was conducted in spring 2016. Bivariate analyses and multivariable regressions examined risk and protective factors associated with ever experiencing PSA since entering college. Concurrently-collected in-depth ethnographic interviews with 151 students were reviewed for information related to factors identified in the survey.ResultsIn bivariate analyses, multiple historical factors were significantly associated with PSA in college including adverse childhood experiences and having experienced unwanted sexual contact before college (for women) and initiation of alcohol, marijuana, and sexual behaviors before age 18. Significant independent risk factors for college PSA included female gender, experiencing unwanted sexual contact before college, first oral sex before age 18, and “hooking up” (e.g., causual sex or sex outside a committed partnership) in high school. Receipt of school-based sex education promoting refusal skills before age 18 was an independent protective factor; abstinence-only instruction was not. In the ethnographic interviews, students reported variable experiences with sex education before college; many reported it was awkward and poorly delivered.ConclusionsMultiple experiences and exposures prior to college influenced the risk of penetrative sexual assault in college. Pre-college comprehensive sexuality education, including skills-based training in refusing unwanted sex, may be an effective strategy for preventing sexual assault in college. Sexual assault prevention needs to begin earlier; successful prevention before college should complement prevention efforts once students enter college.

Background Temporal discounting refers to the tendency for rewards to lose value as the expected delay to receipt increases. Individuals with anorexia nervosa (AN) have been found to show reduced temporal discounting rates, indicating a greater preference for delayed rewards compared to healthy peers. Obsessive–compulsive disorder (OCD) and social anxiety disorder (SAD) commonly co-occur with AN, and anxiety has been related to development and prognosis of AN. We examined whether reduced temporal discounting is present across these potentially related disorders, and explored the relationship between temporal discounting and anxiety trans-diagnostically. Methods One hundred ninety six individuals (75 healthy controls (HC); 50 OCD; 27 AN; 44 SAD) completed two temporal discounting tasks in which they chose between smaller-sooner and larger-later monetary rewards. Two measures of discounting—discount rate and discount factor—were compared between diagnostic groups, and associations with anxious traits were examined. Results Individuals with AN showed decreased temporal discounting compared to HC. OCD and SAD groups did not differ significantly from HC. Across the sample, anxiety was associated with decreased discounting; more anxious individuals showed a greater preference for delayed reward. Conclusions We replicated the findings that individuals with AN show an increased preference for delayed reward relative to HC and that individuals with OCD do not differ from HC. We also showed that individuals with SAD do not differ from HC in discounting. Across this large sample, two measures of anxious temperament were associated with temporal discounting. These data raise new questions about the relationship between this dimensional trait and psychopathology.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

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Objective: Suicidal ideation (SI) is heterogeneous with different patterns and risk factors. SI can be persistent with stable severity but may also fluctuate rapidly over a short period of time. The latter pattern is likely associated with affective instability and may consist of activation of SI at times of stress, that then subside. Although affective instability is a hallmark of borderline personality disorder (BPD), little is known about SI variability in BPD. We hypothesized that SI variability would be associated with affective instability in BPD suicide attempters. Method: Sample included 38 females with BPD and history of suicidal behavior. SI was assessed over one week using ecological momentary assessment (EMA) at 6 epochs daily. The relationship between SI variability (i.e., change of SI from one epoch to another) and SI severity (i.e., average scores across epochs), and affective instability, assessed using the Affective Lability Scale (ALS), were examined. Possible confounding effects of depression severity and impulsiveness were tested. Results: Participants demonstrated high ALS scores and wide range of SI variability. ALS scores predicted SI variability, even after controlling for depression severity. Although ALS also predicted SI severity, this association was driven by depression severity. ALS did not correlate with impulsiveness score. Conclusions: Affective instability may predict SI variability in BPD suicide attempters independent of depression severity. This supports our model of suicidal subgroups with different