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Childhood trauma and treatment outcomes during mood-stabilising treatment with lithium or quetiapine among outpatients with bipolar disorder

Wrobel, Anna L; Köhler-Forsberg, Ole; Sylvia, Louisa G; Russell, Samantha E; Dean, Olivia M; Cotton, Sue M; Thase, Michael; Calabrese, Joseph R; Deckersbach, Thilo; Tohen, Mauricio; Bowden, Charles L; McInnis, Melvin; Kocsis, James H; Friedman, Edward S; Ketter, Terence A; Shelton, Richard C; Ostacher, Michael J; Iosifescu, Dan V; Berk, Michael; Turner, Alyna; Nierenberg, Andrew A
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.
PMID: 35243620
ISSN: 1600-0447
CID: 5174722

Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI)

Iosifescu, Dan V; Jones, Amanda; O'Gorman, Cedric; Streicher, Caroline; Feliz, Samantha; Fava, Maurizio; Tabuteau, Herriot
PMID: 35649167
ISSN: 1555-2101
CID: 5282992

Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial

Tabuteau, Herriot; Jones, Amanda; Anderson, Ashley; Jacobson, Mark; Iosifescu, Dan V
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.
PMID: 35582785
ISSN: 1535-7228
CID: 5249232

P678. Promoting Healthy Sexual Functioning: Exploring the Impact of Gender Role Non-Conformity on Sexual Dysfunction [Meeting Abstract]

Irvin, M; Arnold, M; Sparpana, A; Sullivan, E; Collins, K; Hoptman, M; Iosifescu, D
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
Copyright
EMBASE:2017547151
ISSN: 1873-2402
CID: 5240702

P295. Transcranial Photobiomodulation in Major Depressive Disorder: Dose Dependent Effects on MADRS Score [Meeting Abstract]

Cassano, P; Hurtado, A M; Collins, K; Gersten, M B; De, Taboada L; Clancy, J A; Irvin, M; Sparpana, A; Sullivan, E; Song, X; Adib, A; McEachern, K M; Funes, C J; Camprodon, J A; Iosifescu, D V
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
Copyright
EMBASE:2017547589
ISSN: 1873-2402
CID: 5240652

P374. Specific Parameters of Transcranial Near Infrared Light Modulate its Impact on Cerebral Blood Flow [Meeting Abstract]

Iosifescu, D; Collins, K; Hurtado, A M; Dmochowski, J; DeTaboada, L; Irvin, M K; Sparpana, A; Sullivan, E; Song, X; Adib, A; Clancy, J A; Gersten, M B; McEachern, K M; Cassano, P
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
Copyright
EMBASE:2017554394
ISSN: 1873-2402
CID: 5240602

Comparison of Sodium Lactate Infusion and Carbon Dioxide Inhalation Panic Provocation Tests: A Meta-analysis

Tural, Umit; Iosifescu, Dan V
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.
PMID: 34666404
ISSN: 1439-0795
CID: 5043272

Imbalance between default mode and sensorimotor connectivity is associated with perseverative thinking in obsessive-compulsive disorder

Stern, Emily R; Eng, Goi Khia; De Nadai, Alessandro S; Iosifescu, Dan V; Tobe, Russell H; Collins, Katherine A
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.
PMID: 35022398
ISSN: 2158-3188
CID: 5118862

Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study

Feeney, Anna; Hoeppner, Bettina B.; Freeman, Marlene P.; Flynn, Martina; Iosifescu, Dan V.; Trivedi, Madhukar H.; Sanacora, Gerard; Mathew, Sanjay J.; DeBattista, Charles; Ionescu, Dawn F.; Cusin, Cristina; Papakostas, George I.; Jha, Manish K.; Fava, Maurizio
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.
SCOPUS:85147541295
ISSN: 1076-9757
CID: 5424892

Affective and somatic symptom clusters in depression and their relationship to treatment outcomes in the STAR*D sample

Collins, Katherine A; Eng, Goi Khia; Tural, Ãœmit; Irvin, Molly K; Iosifescu, Dan V; Stern, Emily R
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.
PMID: 34952119
ISSN: 1573-2517
CID: 5109172