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.

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.

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.

BACKGROUND: Major depressive disorder (MDD) is a debilitating, chronic, biologically based condition. Current oral antidepressants act mainly via monoamine mechanisms and are associated with high rates of inadequate response and suboptimal time to response (Rush AJ et al. Am J Psychiatry 2006). There is an urgent need for faster-acting, more effective, and mechanistically novel treatments. AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. AXS-05 utilizes a proprietary formulation and dose of dextromethorphan and bupropion, and metabolic inhibition technology, to modulate the delivery of the components. The dextromethorphan component of AXS-05 is an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, and the bupropion component serves to increase the bioavailability of dextromethorphan.
OBJECTIVE(S): To evaluate the efficacy and safety of AXS-05 versus placebo in MDD.
METHOD(S): GEMINI was a phase 3, randomized, double-blind, placebo-controlled, multicenter, U.S. trial that enrolled subjects with a confirmed diagnosis of moderate-severe MDD. Subjects (N=327) were randomized (1:1) to receive AXS-05 (dextromethorphan 45 mg-bupropion 105 mg) or placebo, twice daily for 6 weeks. The primary efficacy endpoint was the change in the MADRS total score from baseline to week 6.
RESULT(S): On the primary endpoint, AXS-05 demonstrated a statistically significant mean reduction from baseline in the MADRS total score of 16.6 points versus 11.9 for placebo (P = .002). AXS-05 demonstrated rapid, statistically significant improvement versus placebo on the key secondary endpoint of change from baseline in the MADRS total score at week 1, the earliest time point measured (P = .007), and all time points thereafter. Rates of response were statistically significantly greater for AXS-05 versus placebo at week 1 (P = .035) and at all time points thereafter, being achieved by 54% of AXS-05 patients versus 34% of placebo patients at week 6 (P < .001). Remission rates were statistically significantly greater for AXS-05 versus placebo at week 2 (P = .013) and at all time points thereafter, being achieved by 40% of AXS-05 patients versus 17% of placebo patients at week 6 (P < .001). Antidepressant effects translated into early and statistically significant improvements in daily functioning and quality of life. AXS-05 was safe and well tolerated, with the most common adverse events being dizziness, nausea, and headache. AXS-05 was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.
CONCLUSION(S): Treatment with AXS-05 resulted in rapid, substantial, durable, and statistically significant improvements in depressive symptoms across multiple efficacy endpoints versus placebo in patients with MDD. Symptomatic benefits translated into statistically significant improvements in daily functioning and quality of life. AXS-05 was safe and well tolerated

BACKGROUND:The heterogenous nature of depression continues to stymie efforts to identify biomarkers or predict treatment response. Efforts leveraging large datasets to define more uniform subtypes of depression or subgroups of depressed patients have considered only small subsets of symptoms. We aimed to understand how inclusion of more diverse complaints would impact data-emergent symptom and patient clusters. METHODS:We applied principal components analysis to baseline IDS data from 1491 STAR-D patients with major depressive disorder to derive naturally co-occurring symptom subsets before utilizing k-means clustering to divide patients into groups based on standardized residuals of each symptom subset score. We evaluated the clinical utility of our approach by comparing how cluster membership impacted response to citalopram. RESULTS:PCA identified nine naturally co-occurring symptom clusters: core affective symptoms, appetite/weight loss, anxiety, somatic symptoms, insomnia, negative intrusive thoughts, leaden paralysis/mood quality, diurnal mood variation, and irritability. Cluster analysis identified two patient groups, differing significantly in 7 of 9 clusters. Patients distinguished by the prominence of somatic vs. core affective symptoms exhibited greater reduction in depression severity with citalopram treatment. LIMITATIONS/CONCLUSIONS:Results depend not only on raw data, but also parameter selection, and interpretation. Replication is indicated. CONCLUSIONS:Findings are consistent with previous reports linking somatic symptoms and treatment resistance and demonstrating that SSRIs are most effective in treating affective symptoms. A novel distinction between physical somatic symptoms and psychic anxiety highlights the utility of assessing a broad spectrum of symptoms when exploring heterogeneity in depression and the need for treatments targeting physical somatic symptoms specifically.

Reports an error in "Selective kappa-opioid antagonism ameliorates anhedonic behavior: Evidence from the fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS)" by Diego A. Pizzagalli, Moria Smoski, Yuen-Siang Ang, Alexis E. Whitton, Gerard Sanacora, Sanjay J. Mathew, John Nurnberger Jr., Sarah H. Lisanby, Dan V. Iosifescu, James W. Murrough, Hongqiu Yang, Richard D. Weiner, Joseph R. Calabrese, Wayne Goodman, William Z. Potter and Andrew D. Krystal (Neuropsychopharmacology, 2020[Sep], Vol 45[10], 1656-1663). In the original article, conflict of interest was missing. The co-author Sanjay J. Mathew served as a consultant to Alkermes. The original article has been corrected. (The following abstract of the original article appeared in record 2020-45589-001). Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted. (PsycInfo Database Record (c) 2021 APA, all rights reserved)