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The impact of childhood abuse on the presentation of bipolar disorder could be further elucidated by comparing the networks of affective symptoms among individuals with and with no history of childhood abuse. Data from 476 participants in the Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study were used to fit several regularised Gaussian Graphical Models. Differences in the presentation of depressive and manic symptoms were uncovered: only among participants with a history of childhood abuse, inadequacy and pessimism were central symptoms in the network of depressive symptoms, while racing thoughts was an important symptom in the network of manic symptoms. Following network theory, focusing treatments at the symptom-level and on central symptoms - like inadequacy, pessimism, and racing thoughts - could be an effective approach for managing affective symptoms among the sizeable proportion of people with bipolar disorder who have experienced childhood abuse. This study contributes a thorough investigation of the networks of affective symptoms among participants with and with no history of childhood abuse, albeit limited by the use of a binary, self-report measure of childhood abuse, thereby emphasising the importance of assessing for childhood abuse and taking needed steps towards identifying novel targets for treating bipolar disorder., Competing Interests: Declaration of competing interest ALW has received grant/research support from Deakin University and the Rotary Club of Geelong. MT has received grant/research support from Deakin University. OMD has received grant/research support from the Brain and Behavior Foundation, Simons Autism Foundation, Stanley Medical Research Institute, Deakin University, Lilly, NHMRC, and Australasian Society for Bipolar and Depressive Disorders (ASBDD)/Servier. OMD has also received in kind support from BioMedica Nutracuticals, NutritionCare and Bioceuticals. MB has received grant/research support from MRFF, NHMRC, Congressionally Directed Medical Research Programs (CDMRP) USA, AEDRTC Australian Eating Disorders Research and Translation Centre, Patient-Centered Outcomes Research Institute (PCORI), Baszucki Brain Research Fund, Danmarks Frie Forskningsfond. Psykiatrisk Center Kobenhavn, Stanley Medical Research Institute, Victorian Government Department of Jobs, Precincts and Regions, Wellcome Trust, Victorian Medical Research Acceleration Fund, Controversias Psiquiatria Barcelona, CRE, Victorian COVID-19 Research Fund, Consultancies: Lundbeck, Sandoz, Servier, Medisquire, HealthEd, ANZJP, EPA, Janssen, Medplan, RANZCP, Abbott India, ASCP, International Society of Bipolar Disorder, Precision Psychiatry, Penn State College of Medicine, Shanghai Mental Health Centre in the past 3 years – all unrelated to this work. LGS has received grant/research support from PCORI, NIH, HRSA, Tiny Blue Dot Foundation, and AFSP. She has also received support as a member of the Miliken Institute's Scientific Advisory Board as well as royalties form New Harbinger for her two, published books on bipolar disorder. MT was an employee of Lilly (1997 to 2008) and has received honoraria from or consulted for Abbott, Abbvie, AstraZeneca, Alkermes, Atai, Biohaven Pharmaceuticals, Squibb, Rapport Neurosciences, Lilly, Johnson & Johnson, Otsuka, Merck, Sunovion, Intra-Cellular Therapies, NeuroRX, Roche, Elan, Lundbeck, Teva, Minerva, Neurocrine Biosciences, NoemaPharma, Pfizer; his spouse was a full time employee at Lilly (1998–2013). MGM has received grant/research support from Janseen Pharmaceuticals. RCS has received grant/research support from the National Institutes of Mental Health, the Patient Centered Outcomes Research Institute, AbbVie Inc, Alto Pharmaceuticals, Boehringer Ingelheim, Denovo Biopharma, Gate Neuroscience, InMune Bio, Intra-cellular Therapies, Johnson & Johnson Innovative Medicine, LivaNova PLC, Navitor Pharmaceuticals, Neumora, Neurocrine Biosciences, Neurorx, Novartis AG, Otsuka Pharmaceuticals, Sumitomo Pharma America, and Supernus Pharmaceuticals. RCS has also consulted for Boehringer Ingelheim, Denovo Biopharma, Equulus Therapeutics, Evecxia Therapeutics LLC, Johnson & Johnson Innovative Medicine, Neurorx, Novartis AG, Otsuka Pharmaceuticals, Seelos Therapeutics, Inc., Sumitomo Pharma America, and Supernus Pharmaceuticals and has received royalties from Springer-Nature Group and Wolters-Kluwer NV. MJO has received grant/research support from Otsuka and is a consultant to Neurocrine, Inc., both unrelated to this work. In the last 10 years, DVI has served as a consultant for Alkermes, Allergan, Angelini, Autobahn, Axsome, Biogen, Boehringer Ingelheim, the Centers for Psychiatric Excellence, Clexio, Delix, Jazz, Lundbeck, Neumora, Otsuka, Precision Neuroscience, Relmada, Sage Therapeutics, and Sunovion. He has received grant/research support (paid to his institutions) from Alkermes, AstraZeneca, Brainsway, LiteCure, NeoSync, Otsuka, Roche, and Shire. SLM has been a consultant to or member of the scientific advisory boards of Axsome, Idorsia, Kallyope, Levo, Neurocrine, Novo Nordisk, Otsuka, Sunovion, and Takeda. She has been a principal or co-investigator on studies sponsored by Neurocrine, Novo Nordisk, Otsuka, and Sunovion. She is also an inventor on United States Patent No 6323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and along with the patent's assignee, University of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & Johnson, which has exclusive rights under the patent. AT has received travel/grant support from NHMRC, AMP Foundation, Stroke Foundation, Hunter Medical Research Institute, Helen Macpherson Smith Trust, Schizophrenia Fellowship NSW, SMHR, ISAD, the University of Newcastle, and Deakin University. AAN is a consultant for Alkermes, Clexio, Ginger/Headspace Health, Janssen, Merck, Neuronetics, NeuroRx, Otsuka, Protagenics, SAGE, Sunovion, Unravel Bioscience, received honoraria from Belvior, EISAI, Psychiatric Annals Slack Publications, Wiley Depression and Anxiety, received royalties from Guilford Publications, Up-to-Date Wolters Kluwer Health, has been a scientific advisory board member for Altimate, Flow, Milken Center for Strategic Philanthropy, Myriad, and adjudication committee member for Novartis., (Copyright © 2024. Published by Elsevier B.V.)

Background: Almost eight million Americans suffer from Posttraumatic Stress Disorder (PTSD). Current PTSD drug therapies rely on repurposed antidepressants and anxiolytics, which produce undesirable side effects and have recognized compliance issues. Vasopressin represents a promising and novel target for pharmacological intervention. Logistical issues implementing a clinical trial for a novel PTSD pharmaceutical are relatively uncharted territory as trials concerning a new agent have not been published in the past several decades. All published trials have repurposed FDA-approved psychoactive medications with known risk profiles. Our recruitment challenges are discussed in this context., Methods: An 18-week proof-of-concept randomized crossover clinical trial of a first-in-class vasopressin 1a receptor antagonist (SRX246) for PTSD was conducted. All participants received SRX246 for 8 weeks, the placebo for 8 weeks, and the drug vs. placebo arms were compared. Participants were assessed every 2 weeks for PTSD symptoms as well as other medication effects. Results were expected to provide an initial demonstration of safety and tolerability in this clinical population and potentially clinical efficacy in SRX246-treated patients measured by Clinician Administered PTSD Scale (CAPS) score changes, clinical impression, and other indices compared to placebo. The primary hypothesis was that SRX246 would result in a clinically meaningful 10-point reduction in mean CAPS score compared to placebo., Discussion: This study is the first to investigate an oral vasopressin 1a receptor antagonist for PTSD. As a wave of PTSD clinical trials with new pharmaceutical compounds are beginning now, lessons learned from our recruitment challenges may be invaluable to these endeavors., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors, with the exception of Dr. Difede, Dr. Simon, Ms. Damiano, Ms. Itzkowitz, Dr. Lu, Dr. Brownstein, and Dr. Spielman, declare no conflicts of interest. Dr. Difede has funding from Department of Defense Clinical Trial Grant (No. W81XWH-18-1-0262), and Weill Cornell Medical College. Dr. Difede serves as a member of the advisory board at Pear Therapeutics, Inc. Dr. Simon and Dr. Brownstein serve as officers at Azevan Pharmaceuticals, Inc., and hold equity in the company. Dr. Spielman served as a paid consultant to Azevan Pharmaceuticals, Inc. for this project. Dr. S. Lu is an employee, holds equity, and receives compensation. Ms. E. Damiano is an officer and receives compensation; Ms. D. Itzkowitz is an employee and receives compensation., (©2023PublishedbyElsevierInc.)

Objective: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied., Methods: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment., Results: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP ( N  = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N  = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) ( p  = 0.59). Users of Li+AC ( N  = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC ( N  = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p  < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general ( p  = 0.05) and manic symptoms ( p  = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome., Conclusion: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

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: 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., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

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., (Copyright © 2021. Published by Elsevier B.V.)

Background: We aimed to study the probability of bipolar depression response at 24 weeks given initial non-response., Methods: We combined two multi-site, 24-week trials including similar populations following the same evidence-based guidelines randomizing patients to lithium or quetiapine. Additional mood-stabilizing treatment was possible if clinically indicated. We report cumulative proportions of response (>50% improvement in MADRS) and remission (MADRS<10)., Results: We included 592 participants with bipolar depression (mean 39 years, 59% female, mean MADRS 25). Among 393 (66%) participants without response after 2 weeks, 46% responded by 24 weeks; for 291 (49%) without response at 4 weeks, 40% responded and 33% remitted by 24 weeks; for 222 (38%) without a response at 6 weeks, 36% responded and 29% remitted by 24 weeks; for 185 (31%) without a response at 8 weeks, 29% responded and 24% remitted by 24 weeks. Rates were similar for participants who had started an additional mood-stabilizing drug during the first 6 or 8 weeks., Conclusions: Among patients with bipolar depression and non-response after 6 weeks treatment, representing an adequate bipolar depression trial, only one-third responded by 24 weeks. These results highlight the need for better treatment alternatives for non-responders to evidence-based treatments for bipolar depression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study assessed the impact of duloxetine (serotonin and norepinephrine reuptake inhibitor) on semen parameters, sperm DNA fragmentation and serum hormones. We performed a double-blind, placebo-controlled, randomised clinical trial of duloxetine 60mg or placebo daily for 6 weeks (5 weeks full dose and 1 week taper). The primary outcome was the proportion of men with abnormal DNA fragmentation during and after duloxetine administration. Secondary outcomes were changes in semen parameters and hormones on treatment (2 and 6 weeks) and after discontinuation (8 and 10 weeks). Sixty-eight healthy males aged 18-65 were included. Duloxetine was not associated with an increase in the proportion of participants with abnormal sperm DNA fragmentation terminal deoxynucleotidyl transferase dUTP nick-end labelling scores (>25%) on treatment (p = 0.09) or after treatment (p = 0.56), nor did median sperm DNA fragmentation increase on treatment. Compared with placebo, there were no changes in bulk semen parameters during treatment. Limited changes in hormonal values were detected. This first published human study of a serotonin and norepinephrine reuptake inhibitor on male fertility revealed no clinically meaningful effects on sperm DNA fragmentation, semen parameters or serum hormones. Duloxetine, and possibly other serotonin and norepinephrine reuptake inhibitors, may be considered for men desiring fertility who require antidepressant treatment., (© 2021 Wiley-VCH GmbH.)