Faculty Bibliography

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery-Ã…sberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t₃₂ = 0.11, p = 0.91, 95% CI [-7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.

After exposure to a traumatic event, a subset of people develop post-traumatic stress disorder (PTSD). One of the key deficits in PTSD is regulation of fear, and impaired inhibition of fear-potentiated startle (FPS) has been identified as a potential physiological biomarker specific to PTSD. As part of a larger clinical trial, this study investigated the effects of a CRF receptor 1 antagonist, GSK561679, on inhibition of fear-potentiated startle during a conditional discrimination fear-conditioning paradigm, termed AX+/BX-. Prior research using this paradigm has demonstrated deficits in inhibition of conditioned fear in several PTSD populations. The randomized, double-blind, placebo-controlled clinical trial compared fear inhibition between female PTSD participants taking 350 mg/day GSK561679 (n = 47 pre- and 29 post-treatment) and patients taking a placebo pill (n = 52 pre- and 30 post-treatment) daily for 6 weeks. There was no significant difference between the two groups in their acquisition of fear or discrimination between threat and safety cues, and no pre-post-treatment effect on these measures. However, there was a significant effect of treatment on inhibition of FPS during the AB trials in the AX+/BX- transfer test (p < 0.05). While all PTSD participants showed typical impairments in fear inhibition prior to treatment, GSK561679 enhanced fear inhibition post-treatment, independent of clinical effects. The current study suggests that CRF receptor 1 antagonism may have specific effects within neural circuitry mediating fear inhibition responses, but not overall symptom presentation, in PTSD.

Supplementary Figure 1 and Supplementary Tables 1-4 have been re-uploaded so as to reflect the versions supplied during proofs stage. The publisher apologizes for the error in versioning. The HTML version of the paper has been updated.

OBJECTIVE:To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment-resistant depression (TRD). METHODS:In a multisite, double-blind, placebo-controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or midazolam 0.045 mg/kg. The primary outcome measure was change in the six-item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion. RESULTS:N = 45 subjects had anxious TRD, compared to N = 54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84) = 0.02, P = 0.88; Day 3: F(1, 82) = 0.12, P = 0.73). CONCLUSION/CONCLUSIONS:In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.

BACKGROUND:Although most studies have suggested that mitral valve prolapse (MVP) is more prevalent in patients with panic disorder (PD) than in healthy controls, there is a substantial uncertainty in the rates of MVP across studies. OBJECTIVE:To investigate, through systematic review and meta-analysis, the relative risk of MVP in patients with PD compared to controls. METHODS:Embase, Proquest, Pubmed, and Google Scholar electronic databases were searched up to September 2018. All studies published in peer-reviewed journals, which included both PD and controls groups, were selected. Events (presence of MVP) and nonevents (absence of MVP) in PD and control groups were recorded. The main outcome was the measure of relative risk (RR) pooled with 95% confidence intervals, using fixed-effects model. Heterogeneity, small publication effect, and publication bias were evaluated. RESULTS:Fourteen studies, including 1146 participants, met eligibility criteria. There was no significant heterogeneity or publication bias. The prevalence of MVP in PD and healthy controls was 27.20% and 9.21%, respectively. Patients with PD had a significantly increased relative risk of MVP compared to controls in the pooled sample (RR = 2.469, 95% confidence interval = 1.848-3.300). Age did not significantly modify the RR. CONCLUSIONS:MVP is significantly more prevalent in patients with PD than in controls. This meta-analysis of published studies is sufficient to establish an association between PD and MVP; nevertheless, it is not clear that the association is specific to PD. Patients with PD should be evaluated for MVP to decrease possible negative adverse consequences of MVP.

OBJECTIVES/OBJECTIVE:Transcranial photobiomodulation (t-PBM) consists of the delivery of near-infrared (NIR) or red light to the scalp designed to penetrate to subjacent cortical areas of the brain. NIR t-PBM has recently emerged as a potential therapy for brain disorders. This study assessed the efficacy of repeated sessions of NIR t-PBM on sexual dysfunction. METHODS:We performed a secondary analysis of a double-blind clinical trial on t-PBM for major depressive disorder (MDD). Twenty individuals received NIR t-PBM (n = 9) or sham therapy (n = 11) twice a week for 8 weeks. Sexual desire, arousal, and orgasm were assessed using the Systematic Assessment for Treatment-Emergent Effects-Specific Inquiry (SAFTEE-SI). RESULTS:The mean improvement in sexual function (decrease in SAFTEE sex total score) in subjects receiving t-PBM in NIR-mode was significantly greater than in subjects receiving sham-mode in the whole sample (NIR [n = 9] -2.55 ± 1.88 vs. sham [n = 11] -0.45 ± 1.21; z = 2.548, P = 0.011]) and in the completers (NIR [n = 5] -3.4 ± 1.95 vs. sham [n = 7] -0.14 ± 1.21; z = 2.576, P = 0.010]). CONCLUSION/CONCLUSIONS:This exploratory study with a small sample size indicates that repeated sessions of NIR t-PBM may be associated with therapeutic effects on sexual dysfunction. The latter appeared unrelated to the antidepressant effect of t-PBM in our cohort. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc.

Objective/UNASSIGNED:In addition to clinical symptoms, patients with posttraumatic stress disorder (PTSD) often experience considerable disability and may evidence minor impairments in performance on measures of cognition and functional capacity (FC). The objective of the present study was to determine if cognitive and functional skills manifest temporal stability as observed in other neuropsychiatric conditions in the presence of greater fluctuations in clinical symptoms. Method/UNASSIGNED:Assessments of cognition, FC, and clinical symptoms were conducted over two time points as part of a pre- and post-treatment assessment in a placebo-controlled clinical trial in 96 women with PTSD. The goal of these analyses was to examine the relative stability of scores and intercorrelations of measures of cognition, FC, and clinical symptoms. Results/UNASSIGNED:Cognitive and FC performance manifested considerably greater cross-temporal stability compared to clinical symptoms. FC performance did not change over time. Similar to previous findings in patients with schizophrenia and bipolar disorder measures of symptoms and self-reported disability did not correlate with measures of functional skills or cognitive performance. Conclusions/UNASSIGNED:Cognitive performance and functional capacity were temporally stable in women with PTSD. In contrast, clinical symptoms had much more cross-temporal fluctuation. Self-reported disability was correlated with current symptomatology but unrelated to objective measures of performance. Similar to other neuropsychiatric conditions, mood symptoms likely influence estimates of current level of functioning more than cognitive or functional skills.

There is an urgent need for more effective treatments for major depressive disorder (MDD). Digital therapeutics, such as computerized cognitive-emotional training interventions, represent a promising new strategy for treating MDD. Here we report a replication of efficacy of a digital cognitive-emotional training intervention designed to enhance cognitive control for emotional information-processing. In a randomized, double-blind, controlled study design, fifty-one participants with MDD in a current major depressive episode were randomly assigned to participate in a digital cognitive-emotional training regimen (Emotional Faces Memory Task (EFMT); n= 28) involving 18 sessions over 6 weeks, or an active control condition (CT; n= 23) involving computerized working memory training. MDD symptoms were assessed weekly using a clinician-rated measure (Hamilton Depression Rating Scale; Ham-D); and neurocognition (working memory), at baseline and study outcome. Mixed-effects model for repeated measures (MMRM) analysis of all participants randomized revealed a significantly greater reduction in MDD symptom severity (Ham-D) from baseline to outcome in the EFMT group (8.65 points) compared to the CT group (4.77 points) (F(6,205)= 3.23, p= .005, d= .46). Ten of 28 EFMT participants achieved clinical response (≥ 50% reduction in symptoms) compared to 4 of 23 in CT. Both groups exhibited similar, small improvements in working memory. This replicated the preliminary efficacy of a digital cognitive-emotional training approach for the treatment of MDD. EFMT may be a feasible and effective intervention strategy for MDD, but future studies to elucidate its mechanism of action are warranted. This study is registered with Clinicaltrials.gov (NCT: 01934491).

Background: The Maslach Burnout Inventory-Human Services Survey (MBI-HSS) is the most commonly used instrument to assess burnout. Although various factors have been reported to influence its validity, the influence of major depressive disorder (MDD) has not been previously considered. We developed this study to investigate the influence of MDD on the psychometric properties of the MBI-HSS in nursing assistants. Results: From a sample of 521 nursing assistants, we found in those with MDD (n = 138, 24.56%) a degree of data misfit into the model, revealed by non-acceptable values for the root mean square error of approximation (RMSEA; 0.073; p = 0.004) and for the comparative fit index (CFI; 0.912), while in the non-MDD group these indices were acceptable and good, respectively, for RMSEA (0.048; p = 0.639) and for CFI (0.951). Also, we found higher coefficients of correlation among MBI-HSS factors and less items loading properly in their respective factors in the MDD subset, when compared to the non-MDD subset. For the total sample, while original 3-factor solution was an acceptable model, the bifactor model fitted data better. Conclusions: MDD may impair the construct validity of MBI-HSS subscales, by increasing measurement error and decreasing model fitness. Therefore, researchers and health professionals should be aware of potential changes in the psychometric properties of the MBI-HSS when applied in subjects with depression.