Faculty Bibliography

BACKGROUND:Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied. METHODS:The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool). RESULTS:A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment. CONCLUSION/CONCLUSIONS:This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.

OBJECTIVE/UNASSIGNED:Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 trial assessed the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder. METHODS/UNASSIGNED:This randomized, double-blind, multicenter, parallel-group trial evaluated dextromethorphan-bupropion versus the active comparator sustained-release bupropion in patients 18-65 years old with a diagnosis of major depressive disorder of moderate or greater severity. Patients were randomly assigned to receive either dextromethorphan-bupropion (45 mg/105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks. The primary endpoint was overall treatment effect on Montgomery-Åsberg Depression Rating Scale (MADRS) score (average of the change from baseline for weeks 1-6), assessed in all randomized patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of study medication and had at least one postbaseline assessment. RESULTS/UNASSIGNED:Of 97 patients randomized, 17 did not have a confirmed diagnosis and severity based on the independent assessment, resulting in 80 patients in the efficacy population (dextromethorphan-bupropion, N=43; bupropion, N=37). The mean change from baseline in MADRS score over weeks 1-6 (overall treatment effect) was significantly greater with dextromethorphan-bupropion than with bupropion (-13.7 points vs. -8.8 points; least-squares mean difference=-4.9; 95% CI=-3.1, -6.8). MADRS score change with dextromethorphan-bupropion was significantly greater than with bupropion at week 2 and every time point thereafter (week 6: -17.3 vs. -12.1 points; least-squares mean difference=-5.2, 95% CI=-1.1, -9.3). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs. 16.2%; least-squares mean difference=30.3%, 95% CI=11.2, 49.4). Response rates (≥50% decrease in MADRS score from baseline) at week 6 were 60.5% with dextromethorphan-bupropion and 40.5% with bupropion (least-squares mean difference=19.9%, 95% CI=-1.6, 41). Most secondary outcomes favored dextromethorphan-bupropion. The most common adverse events with dextromethorphan-bupropion were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction. CONCLUSIONS/UNASSIGNED:In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.

Background: While brain target engagement has been demonstrated, the relationship between the dose of transcranial photobiomodulation (t-PBM) with near-infrared light and its clinical effects in major depressive disorder (MDD) is unclear. We evaluated the dose-dependent, clinical effects of t-PBM in MDD subjects.
Method(s): We enrolled currently depressed subjects on stable antidepressant regimen or none. Subjects underwent four randomized, weekly t-PBM sessions with sham and three combinations of t-PBM parameters: 1) High dose - pulse wave (PW), average irradiance 300mW/cm2, 42Hz, 33% duty cycle, 4.3kJ total energy; 2) Medium dose - continuous Wave (CW), 300mW/cm2 irradiance, 2.4kJ total energy; 3) Low dose - CW, 50mW/cm2 irradiance; 1.4kJ total energy. Other t-PBM parameters were kept unchanged (808nm; 12cm2 x 2 treatment area; delivered to prefrontal cortex, bilaterally, F3 and F4). Depression severity was rated by investigators with the Montgomery-Asberg Depression Rating Scale (MADRS) before and about one week after each t-PBM session. Mean changes in MADRS total scores obtained after each t-PBM dose were compared to the effect of sham (paired 2-tailed t-test, with significance at 0.05).
Result(s): We analyzed data from 27 MDD subjects (age= 35.2+/-13.9; 70% female; 33% diverse). We found that low CW was significantly (DELTA -4.74+/-5.29, t=2.59, df=26, p<0.05) more effective than sham (DELTA -0.30+/-6.42).
Conclusion(s): Findings suggest that a single session of t-PBM might induce significant antidepressant effects. This is important as t-PBM could become a candidate treatment to expedite antidepressant response in patients with MDD. Only the low CW t-PBM dose was statistically superior to sham in this small study. Supported By: R61MH122647-01 Keywords: Photobiomodulation, PBM, Low Level Laser Therapy, Neuromodulation, Neurostimulation
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Background: Uncertainty remains about psychological and sexual implications of gender role non-conformity (GRNC) defined as men endorsing or performing femininity, and women endorsing or performing masculinity. Previous studies have indicated that variance in gender presentation is associated with negative psychological consequences. Homophobic stigmatization and internalized homophobia partially mediate this association, suggesting it is not the practice of GRNC that causes distress but subjective or perceived reactions to it. Here, we test the hypothesis that people reporting sexual dysfunction have higher levels of GRNC.
Method(s): We analyzed data from the Nathan Kline Institute Rockland Sample. 797 subjects (age=48.4 +/- 17.7, sex=66% female) completed the Sex Role Identity Scale (SRIS) and the Trauma Symptom Checklist (TSC-40). GRNC was quantified by SRIS questions-subjective GRNC (S-GRNC) was assessed using the question "How feminine/masculine do you think you are?" and perceived GRNC (P-GRNC) was assessed with "How feminine/masculine do you think you appear and come across to others?" Sexual dysfunction was measured with a TSC-40 subscale. We performed sex-specific stepwise linear regressions to explore the relationships between S-GRNC, P-GRNC, and sexual dysfunction.
Result(s): In male subjects, a model including only S-GRNC significantly predicted sexual dysfunction, F(1, 267)=5.027, p=0.026, adj. R2=0.015. In female subjects, a model including only P-GRNC significantly predicted sexual dysfunction, F(1, 526)=14.854, p<0.001, adj. R2=0.026.
Conclusion(s): GRNC significantly predicts sexual dysfunction; different aspects of GRNC are more relevant for male vs. female subjects. While limited, these results highlight the clinical significance of understanding GRNC to promote healthy sexual functioning for all individuals. Keywords: Sexual Dysfunction, Sex Differences, Gender
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Background: Transcranial photobiomodulation (t-PBM) with near-infrared light penetrates the cerebral cortex and stimulates mitochondria; it may also have antidepressant effects. In this study we evaluated the dose-dependent effects of t-PBM on cerebral blood flow (CBF) in major depressive disorder (MDD).
Method(s): We enrolled 18 subjects (age 36.7+/-13.7 years, 56% female) meeting DSM-5 criteria for MDD. All subjects underwent 4 t-PBM sessions, 1/week, in the MRI scanner with 1) Sham; 2) High dose: Pulse wave (PW), irradiance ~300 mW/cm2, 4.0 KJ; 3) Medium dose: Continuous Wave (CW), ~300 mW/cm2 irradiance, 2.3 KJ; and 4) Low dose: CW, ~50 mW/cm2 irradiance; 1.2 kJ. t-PBM (808 nm) was delivered to the prefrontal cortex, bilaterally. Resting state fMRI was recorded at 3T before, during and after t-PBM, using the change in the BOLD signal to evaluate t-PBM effects on CBF. We performed region-of-interest (ROI) analyses for all cortical ROIs in the Destrieux atlas. We tested for significant differences in BOLD power spectrum during stimulation compared to sham using Wilcoxon rank sum tests, corrected for multiple comparisons (FDR=0.05) Results: We found a bidirectional, dose-dependent effect of t-PBM: BOLD power was significantly reduced during low dose t-PBM in 96 of 150 cortical ROIs (p<0.05), and increased during medium dose t-PBM in 140 out of 150 cortical ROIs (p<0.05). No effects were found at the high dose.
Conclusion(s): The effect of t-PBM on cerebral hemodynamics is dose-dependent, bidirectional, and extends to regions beyond the illuminated areas. This is important: dose optimization based on fMRI response may confer superior clinical efficacy. Supported By: NIMH R61/33 MH122647 Keywords: Major Depressive Disorder, Photobiomodulation, BOLD fMRI
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BACKGROUND:Patients with bipolar disorder have higher rates of cardiometabolic comorbidities and mortality. Although guidelines emphasize the importance of cardiovascular monitoring, few studies characterized the cardiometabolic risk profile during treatment and their relation to symptomatology and treatment response. METHODS:We analyzed data from two similar 24-weeks comparative effectiveness trials, with a combined sample of 770 participants randomized to two different lithium doses, quetiapine (300 mg/day), or standard treatment without lithium. Glucose, lipids and vital signs were measured before and after 24 weeks of treatment. We calculated several cardiovascular risk scores, assessed baseline correlations and compared the four treatment arms via multiple linear regression models. RESULTS:Higher cholesterol and LDL levels were associated with greater depression severity, showing differential correlations to specific symptoms, particularly agitation, low energy and suicidality. Those randomized to quetiapine showed a significant worsening of cardiometabolic markers during the 24-week trial. Neither baseline nor change in lipid levels correlated with differential treatment response. LIMITATIONS:Study duration was short from the perspective of cardiometabolic risk markers, and all treatment arms included patients taking adjunct antipsychotics. The trials compared quetiapine to lithium, but not to other medications known to affect similar risk factors. CONCLUSIONS:Treatment with 300 mg/day quetiapine for 24 weeks, representing a short and common dose course, resulted in increased cardiometabolic risk markers, emphasizing the importance of monitoring during mood-stabilizing treatment. The symptom-specific associations are in line with previous studies in unipolar depression, suggesting a cardiometabolic-depression link that needs to be further studied in bipolar depression.

BACKGROUND:) inhalation are proven to provoke acute panic attacks (PAs) in patients with panic disorder (PD). A systematic literature search and meta-analysis were performed to compare the effect sizes of these methods. METHODS:Odds ratios were calculated for each of the original studies and were pooled using the random-effects model. RESULTS:=7.88-14.21). CONCLUSION/CONCLUSIONS:for the brain suffocation detector.

Obsessive-compulsive disorder (OCD) is highly heterogeneous. Although perseverative negative thinking (PT) is a feature of OCD, little is known about its neural mechanisms or relationship to clinical heterogeneity in the disorder. In a sample of 85 OCD patients, we investigated the relationships between self-reported PT, clinical symptom subtypes, and resting-state functional connectivity measures of local and global connectivity. Results indicated that PT scores were highly variable within the OCD sample, with greater PT relating to higher severity of the "unacceptable thoughts" symptom dimension. PT was positively related to local connectivity in subgenual anterior cingulate cortex (ACC), pregenual ACC, and the temporal poles-areas that are part of, or closely linked to, the default mode network (DMN)-and negatively related to local connectivity in sensorimotor cortex. While the majority of patients showed higher local connectivity strengths in sensorimotor compared to DMN regions, OCD patients with higher PT scores had less of an imbalance between sensorimotor and DMN connectivity than those with lower PT scores, with healthy controls exhibiting an intermediate pattern. Clinically, this imbalance was related to both the "unacceptable thoughts" and "symmetry/not-just-right-experiences" symptom dimensions, but in opposite directions. These effects remained significant after accounting for variance related to psychiatric comorbidity and medication use in the OCD sample, and no significant relationships were found between PT and global connectivity. These data indicate that PT is related to symptom and neural variability in OCD. Future work may wish to target this circuity when developing personalized interventions for patients with these symptoms.

Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression (DSM-IV-TR MDD) and to assess whether the use of concomitant oral benzodiazepines differentially affected treatment response to ketamine versus midazolam. Methods: This trial ran from December 2015 to December 2016. Subjects who were taking oral benzodiazepines (n = 44) were compared to those who were not (n = 55). A significant treatment-by-benzodiazepine effect could be interpreted as a possible moderator of differential treatment response to ketamine versus midazolam. Benzodiazepine use was examined as both a binary and a continuous predictor, to assess the impact of dosage. Results: Benzodiazepine users did not differ from non-users on the original study's primary outcome measure, score on the 6-item Hamilton Depression Rating Scale (HDRS-6), at baseline, but the former had more severe anxiety. When oral benzodiazepine use was modeled as a binary predictor, benzodiazepine use did not impact differential treatment response. However, when benzodiazepine dosage was considered, there was a significant impact of benzodiazepine use on differential treatment response. Oral benzodiazepines significantly impacted HDRS-6 (P = .018) and Clinical Global Impressions-Severity of Illness scale (CGI-S; P = .008) scores at day 1 (24 hours post treatment); effects were nonsignificant for all day 3 outcomes. Among ketamine subjects, higher doses of benzodiazepines were associated with less improvement in depression scores at day 1. Conclusions: Concomitant oral benzodiazepines at higher doses may attenuate the antidepressant effects of IV ketamine at day 1 but not day 3 post-infusion.