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Mohit Chauhan,1 Rebecca Parry,1 William V Bobo1,2 1Department of Psychiatry & Psychology, Mayo Clinic Florida, Jacksonville, FL, USA; 2Center for Individualized Medicine, Mayo Clinic Florida, Jacksonville, FL, USACorrespondence: William V Bobo, Department of Psychiatry & Psychology, Mayo Clinic Florida, 4500 San Pablo Blvd, Jacksonville, FL, 32224, USA, Tel +1 904-953-7286, Email bobo.william@mayo.eduAbstract: This article provides an updated review of the pharmacological profile and available efficacy and tolerability/safety data for vilazodone, one of the most recent antidepressant drugs to be approved in the USA for the treatment of major depressive disorder (MDD) in adults. The efficacy of vilazodone for MDD in adults is supported by four positive short-term (8– 10 weeks), randomized, placebo-controlled trials. Beyond these pivotal trials, we review updated research findings pertaining to the clinical effects of vilazodone for MDD including the results of switch studies, small comparative efficacy trials, key pooled and secondary data analyses focused on important depressive subtypes (anxious depression) and predictors of treatment outcome, and safety studies including direct studies of sexual side-effects. Despite these additional research efforts and use for over a decade, important gaps in the clinical evidence base remain with vilazodone. Hypothesized differences in efficacy and adverse effects between other antidepressants and vilazodone based on its multimodal mechanism of action (combining serotonin reuptake inhibition with serotonin 5-HT1A partial agonist effects) have not been comprehensively demonstrated in clinical studies and its effectiveness as a continuation- or maintenance-phase therapeutic is not yet established. Questions remain regarding its reproductive and lactational safety profiles and its efficacy as a potential next-step therapeutic for patients with MDD who do not respond to first-line antidepressants such as selective serotonin reuptake inhibitors. Suggestions for clinical use of vilazodone and discussion of its place among the broad range of pharmacotherapies for adults with MDD are provided.Keywords: vilazodone, major depressive disorder, depression, efficacy, safety, comparative effectiveness

Marc Kelliny, Paul E Croarkin, Katherine M Moore, William V Bobo Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA Abstract: This article reviews the pharmacological profile and available efficacy and tolerability/safety data for vortioxetine, one of the most recent antidepressant drugs to be approved in the USA for the treatment of major depressive disorder (MDD) in adults. The efficacy of vortioxetine for treating MDD in adults is supported by eight positive short-term (6- to 12-weeks) randomized, placebo-controlled trials, and one positive randomized, double-blind, 52-week relapse prevention trial. Based on pooled data from short-term randomized trials and from longer-term studies, vortioxetine appears to be well tolerated and to have a low incidence of adverse effects on sexual functioning. Vortioxetine also appears to be effective for treating symptoms of MDD in the elderly based on the results of one randomized trial for which recruitment was focused on this specific population. Nevertheless, effectiveness studies that directly compare the clinical effects of vortioxetine with other established antidepressant drugs are lacking, and there is no evidence as yet that vortioxetine is more clinically effective than other types of antidepressants. Some preliminary suggestions concerning the place of vortioxetine among the broad range of pharmacological treatments for adults with MDD are provided. Keywords: vortioxetine, Lu AA21004, pharmacological profile, pharmacokinetics, drug interactions, adverse effects/side effects/safety, depression, major depression

Richard A Epstein,1 Katherine M Moore,2 William V Bobo2 1Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, 2Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA Abstract: Treating pregnant women with bipolar disorder is among the most challenging clinical endeavors. Patients and clinicians are faced with difficult choices at every turn, and no approach is without risk. Stopping effective pharmacotherapy during pregnancy exposes the patient and her baby to potential harms related to bipolar relapses and residual mood symptom-related dysfunction. Continuing effective pharmacotherapy during pregnancy may prevent these occurrences for many; however, some of the most effective pharmacotherapies (such as valproate) have been associated with the occurrence of congenital malformations or other adverse neonatal effects in offspring. Very little is known about the reproductive safety profile and clinical effectiveness of atypical antipsychotic drugs when used to treat bipolar disorder during pregnancy. In this paper, we provide a clinically focused review of the available information on potential maternal and fetal risks of untreated or undertreated maternal bipolar disorder during pregnancy, the effectiveness of interventions for bipolar disorder management during pregnancy, and potential obstetric, fetal, and neonatal risks associated with core foundational pharmacotherapies for bipolar disorder. Keywords: bipolar disorder, pregnancy, anticonvulsants, antiepileptics, antipsychotics, safety

Richard A Epstein,1 Katherine M Moore,2 William V Bobo2 1Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, 2Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA Abstract: In pregnant women with major depression, the overarching goal of treatment is to achieve or maintain maternal euthymia, thus limiting both maternal and fetal exposure to the harmful effects of untreated or incompletely treated depression. However, the absence of uniformly effective therapies with guaranteed obstetric and fetal safety makes the treatment of major depression during pregnancy among the most formidable of clinical challenges. Clinicians and patients are still faced with conflicting data and expert opinion regarding the reproductive safety of antidepressants in pregnancy, as well as large gaps in our understanding of the effectiveness of most antidepressants and nonpharmacological alternatives for treating antenatal depression. In this paper, we provide a clinically focused review of the available information on potential maternal and fetal risks of untreated maternal depression during pregnancy, the effectiveness of interventions for maternal depression during pregnancy, and potential obstetric, fetal, and neonatal risks associated with antenatal antidepressant use. Keywords: depression, major depressive disorder, pregnancy, antidepressants, safety

Population-level research into the association between sleep problems and school problems among high-risk youth is limited. This study uses cross-sectional administrative and standardized assessment information for youth entering Tennessee state custody in fiscal year 2009 (n = 4280) to examine whether sleep problems are independently associated with school problems. Sleep problems were identified in 9.8% of the sample. There was no association between sleep and school problems for youth adjudicated delinquent. Among youth adjudicated dependent-neglect/unruly, multivariate logistic regression analysis indicates that youth at risk for sleep problems are 1.78 (95% confidence interval = 1.24-2.55) and youth with actionable sleep problems are 3.30 (95% confidence interval = 1.78-6.14) times more likely than youth without sleep problems to have school problems. Results suggest that the school performance of youth entering state custody adjudicated dependent-neglect/unruly may benefit from systematic screening and intervention for sleep problems. [ABSTRACT FROM AUTHOR]

Dextromethorphan (DM) is a popular over-the-counter antitussive medication. Although adverse effects from appropriate use are rare, a specific toxidrome with significant psychomimetic effects occurs with ingestions in excess of those recommended. Both DM and its active metabolite, dextrorphan (DOR), share pharmacologic and neurobehavioral properties similar to opiates and phencyclidine (PCP). As such, cases of recreational DM abuse and, rarely, dependence, have been reported, and some data suggest that such abuse is on the rise. DM may be considered by substance abusers, especially adolescents, to be a dissociative agent devoid of financial concerns, legal limitations, negative stigma, problems with access or adverse health consequences. However, DM's popularity among adolescent substance abusers is generally not matched by adequate health care provider awareness, pharmacological understanding or epidemiological characterization. In this review, we summarize the current understanding of DM's addiction medicine-based neuropharmacology and epidemiology, describe social characteristics more unique to DM as an agent of abuse, review treatment and prevention issues, and identify areas in need of further research. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to identify clinical and demographic variables that correlated with readmission to a large tertiary care military psychiatric inpatient service located in the Washington, DC area.Methods: Data from 983 consecutive inpatient admissions (comprised of 814 individual patients) over a 13-month period (July 1999-July 2000) were abstracted from medical records for retrospective analysis. Repeat users were defined as those individuals receiving two or more inpatient admissions to Walter Reed Army Medical Center during the study period. Statistical comparisons were made between repeat and single admission groups to identify variables predictive of rehospitalization.Results: Of 814 individual patients under study, 117 (14%) were identified as repeat users. A history of childhood psychiatric problems, previous psychiatric hospitalization, current or past substance abuse, legal problems, and presence of a psychotic or nonbipolar mood disorder were associated with readmission after controlling for active duty status. Current comorbid substance use or personality disorder diagnoses were not predictive. Having at least one child was protective against readmission. The 117 repeat users accounted for 3,838 (37%) of the total 10,393 hospital bed-days during the study period. Logistic regression analysis of all variables correlated with readmission demonstrated statistical significance for past psychiatric hospitalization and age of onset of psychiatric problems before age 18 when active duty status, age, and gender variables were included in the equation.Conclusions: This study is one of the largest to investigate predictors of rehospitalization in a population that enjoys universal "free" access to comprehensive mental health care services and other benefits of employment. This retrospective analysis documented three important facts: That there seem to be only minor differences between military and civilians with respect to variables associated with psychiatric rehospitalization, that a relatively small proportion of patients accounted for a disproportionately large number of inpatient bed-days, and that an unexpectedly high proportion of active duty patients admitted to this study site reported childhood psychiatric problems and psychiatric hospitalizations before their first hospitalization at Walter Reed Army Medical Center. [ABSTRACT FROM AUTHOR]

We report the case of a patient who, as a result of exposure to the proton pump inhibitor rabeprazole, developed a severe and disabling admixture of neuropsychiatric symptoms. Because of its widely appreciated placebo-like side effect profile, rabeprazole was never suspected as being the cause of his symptoms. Instead, a somatoform spectrum disorder was assigned based on the patient's atypical symptom presentation, progressive course, subjective psychological distress, intemperate consumption of healthcare resources over a relatively brief period of time and lack of any medical explanation for his symptoms at that time, despite exhaustive laboratory and radiologic work-ups. This case report reinforces the notion that even a medication such as rabeprazole, with an established safety and tolerability profile, may be associated with side effects severe enough to mimic disabling neuropsychiatric illness. [ABSTRACT FROM AUTHOR]

Since the Persian Gulf War of 1990-1991, the operational tempo for soldiers has steadily increased, whereas the numbers of soldiers available to fulfill these missions has decreased. As a result, soldiers and their families are experiencing increased levels of stress that continue to manifest in ways that can often be destructive for the soldiers, their families, and the Army community. Current mitigation and identification support systems such as the Chain of Command, noncommissioned officer leadership, chaplains, and family support systems have all provided critical services, but may not be expected to optimally perform necessary early risk management assessment. Behavioral health care as a self-referral system is often still perceived as career ending, shameful, or even culturally unacceptable. Our allies have also experienced similar family, operational, and combat concerns. In 1996, at the direction of their Commandant General, the British Royal Marines developed and instituted a peer-driven risk management and support system that has experienced a high degree of success and acceptance among its forces-enough so that the Royal Navy is now in the process of implementing a similar program. The Soldier Peer Mentoring and Support program, as part of the proposed deployment Cycle Support Program, is a model for peer group assessment based on the British Royal Marines psychological risk management and support system. This article presents and describes this project, which has been considered for use within the U.S. Army, as a potential augmenter of existing behavioral health support assets as a culturally acceptable, company-level support program in deployment and home stations. [ABSTRACT FROM AUTHOR]

Purpose: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS., Methods: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC ( BRCA1 and BRCA1 ) and LS ( MLH1 , MSH2 , MSH6 , PMS2 , and EPCAM ). Chart review was performed to collect demographics and personal and family cancer history., Results: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1 , 42.8% BRCA2 ) and 163 with LS (12.3% MSH6 , 8.8% PMS2 , 4.5% MLH1 , 3.8% MSH2 , and 0.2% EPCAM ). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028)., Conclusion: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.

Background: The occupational burnout epidemic is a growing issue, and in the United States, up to 60% of medical students, residents, physicians, and registered nurses experience symptoms. Wearable technologies may provide an opportunity to predict the onset of burnout and other forms of distress using physiological markers., Objective: This study aims to identify physiological biomarkers of burnout, and establish what gaps are currently present in the use of wearable technologies for burnout prediction among health care professionals (HCPs)., Methods: A comprehensive search of several databases was performed on June 7, 2022. No date limits were set for the search. The databases were Ovid: MEDLINE(R), Embase, Healthstar, APA PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection via Clarivate Analytics, Scopus via Elsevier, EBSCOhost: Academic Search Premier, CINAHL with Full Text, and Business Source Premier. Studies observing anxiety, burnout, stress, and depression using a wearable device worn by an HCP were included, with HCP defined as medical students, residents, physicians, and nurses. Bias was assessed using the Newcastle Ottawa Quality Assessment Form for Cohort Studies., Results: The initial search yielded 505 papers, from which 10 (1.95%) studies were included in this review. The majority (n=9) used wrist-worn biosensors and described observational cohort studies (n=8), with a low risk of bias. While no physiological measures were reliably associated with burnout or anxiety, step count and time in bed were associated with depressive symptoms, and heart rate and heart rate variability were associated with acute stress. Studies were limited with long-term observations (eg, ≥12 months) and large sample sizes, with limited integration of wearable data with system-level information (eg, acuity) to predict burnout. Reporting standards were also insufficient, particularly in device adherence and sampling frequency used for physiological measurements., Conclusions: With wearables offering promise for digital health assessments of human functioning, it is possible to see wearables as a frontier for predicting burnout. Future digital health studies exploring the utility of wearable technologies for burnout prediction should address the limitations of data standardization and strategies to improve adherence and inclusivity in study participation., (©Milica Barac, Samantha Scaletty, Leslie C Hassett, Ashley Stillwell, Paul E Croarkin, Mohit Chauhan, Sherry Chesak, William V Bobo, Arjun P Athreya, Liselotte N Dyrbye. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 25.06.2024.)

This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03-1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (β =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD. Trial Registration: ClinicalTrials.gov: NCT03156504., Competing Interests: Declaration of competing interest BS received research grant support from Mayo Clinic, National Network of Depression Centers (NNDC), and BD2 (Breakthrough Discoveries for thriving with Bipolar Disorder). SVP has received honoraria for consulting or research funds from the Canadian Institutes for Health Research, Ontario Brain Institute, and Aifred, Janssen, Merck, Mensante, Neonmind, Otsuka, Sage, and Takeda. JLVV has received a grant-in-kind for supplies and genotyping from Assurex Health. EDA has received research support from the following entities in the preceding 12 months: Alkermes, Boehringer-Ingelheim, Janssen, Karuna, Neurocrine Biosciences, Takeda, Teva, and the Vanguard Research Group. EDA also has served on advisory boards or consulted with Alkermes, Clinical Care Options, CMEology, CME Outfitters, Indivior, Karuna, and Teva. FSG has received research grant support from Janssen Therapeutics. WVB has received grant funding or research support from the NIH, AHRQ, National Science Foundation, the Watzinger Foundation, the Myocarditis Foundation, the Blue Gator Foundation, and the Mayo Foundation for Medical Education and Research. MAF has received Grant Support from Assurex Health, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and Mayo Foundation. CME/Travel/Honoraria or Consultant Carnot Laboratories, American Physician Institute. He also has financial interests in Chymia LLC. KEB has received grants from Janssen Pharmaceuticals and has received honorarium as an advisory board member for The Bipolar Roadmap Initiative (Milken Institute for Strategic Philanthropy) and Breakthrough Discoveries for thriving with Bipolar Disorder (BD2). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: We conducted an open-label clinical trial ("Bio-K") using IV ketamine for treatment-resistant depression to identify biomarkers linked to remission. Here, we report the clinical efficacy and side effect outcomes of Bio-K., Methods: Across 4 US sites, 75 patients ages 18-65 with treatment-refractory unipolar or bipolar depression received 3 IV ketamine infusions over an 11-day period. Key exclusion criteria were psychotic symptoms, significant substance abuse, unstable medical conditions, and any use of cannabis. Pre-existing antidepressant medication was maintained. Primary outcome was remission as measured by Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcome of 50 % reduction in Beck Suicide Scale score. Safety monitoring and varying durations of infusions were also key parameters., Results: Using remission as MADRS score <10, after 3 infusions 52 % achieved remission, with 67 % achieving response. Of those achieving response after a single infusion, 66 % (22 of 33) reached remission after 3 infusions, while 40 % (16 of 40) non-responders after the first infusion went on to achieve remission after 3 infusions. Only 20 % of non-responders after 2 infusions achieved remission. Most (81 %) participants had significant suicidal ideation at baseline; of these, two-thirds (67 %) experienced at least a 50 % reduction in suicidality. Side effects were minimal. Uniquely, we had three different types of infusion categories, with individuals receiving: (1) slow (100-min) infusions only or (2) regular (40-min) infusions only or (3) a mix of infusion durations. These three infusion groups showed comparable safety and efficacy. Exploration of clinical factors revealed no link between BMI, age, or gender to remission., Conclusions: The consistency of outcomes across 4 clinical sites and across multiple instruments, suggests high acute efficacy and safety of IV ketamine for serious depressive episodes. Duration of infusion did not alter outcomes. Meaningfully, 40 % of non-responders after a single infusion did reach remission subsequently, while only 20 % of non-responders after 2 infusions achieved remission, suggesting early response is suggestive for eventual remission. Our data on varying ketamine infusion duration adds novel insights into the clinical administration of this new treatment for refractory and severe patients. Our limitations included a lack of a control group, necessitating caution about conclusions of efficacy, balanced by the utility of reporting "real-world" outcomes across multiple clinical sites. We could also not separately analyze results for bipolar disorder due to small numbers. Together, the Bio-K clinical results are promising and provide significant sample sizes for forthcoming biological markers analyses., Competing Interests: Declaration of competing interest Anastasia Yocum, Alexis Becerra, William Bobo, Jennifer Severe, Steven Bartek, Daniel Maixner, Christina Miller, Louis Nykamp, Daniela Lopez-Vives, Cortney E. Sera, LeAnn Smart, Susannah Tye, Jose Rico, Cynthia Stoppel, and John Greden have no conflicts of interest to declare. Dr. Parikh has received honoraria for consulting or research funds from the Canadian Institutes for Health Research, Ontario Brain Institute, and Aifred, Janssen, Merck, Mensante, Neonmind, Otsuka, Sage, and Takeda. Dr. Vande Voort has received grant-in-kind support for supplies and genotyping from Assurex Health. Dr. Achtyes has served on advisory boards or consulted for Alkermes, Atheneum, Janssen, Karuna, Lundbeck/Otsuka, Roche, Sunovion and Teva and reports previous stock holdings in AstraZeneca, Johnson & Johnson, Moderna, and Pfizer. Dr. Achtyes has received research support from Alkermes, Astellas, Biogen, Boehringer-Ingelheim, InnateVR, Janssen, National Network of Depression Centers, Neurocrine Biosciences, Novartis, Otsuka, Pear Therapeutics, and Takeda. Dr. Achtyes serves as an advisor to CAPNOS Zero, the World Psychiatric Association and Clubhouse International, and the SMI Adviser LAI Center of Excellence (all unpaid). Dr. Goes has received research grant support from Janssen Therapeutics. Dr. Tarnal has received research support from TRYP Therapeutics. Dr. Frye has received Grant Support from Assurex Health, and Mayo Foundation. He also has financial interests in Chymia LLC. Dr. Singh has received research support from the Mayo Clinic., (Copyright © 2023. Published by Elsevier B.V.)

Background: When job demand exceeds job resources, burnout occurs. Burnout in healthcare workers extends beyond negatively affecting their functioning and physical and mental health; it also has been associated with poor medical outcomes for patients. Data-driven technology holds promise for the prediction of occupational burnout before it occurs. Early warning signs of burnout would facilitate preemptive institutional responses for preventing individual, organizational, and public health consequences of occupational burnout. This protocol describes the design and methodology for the decentralized Burnout PRedictiOn Using Wearable aNd ArtIficial IntelligEnce (BROWNIE) Study. This study aims to develop predictive models of occupational burnout and estimate burnout-associated costs using consumer-grade wearable smartwatches and systems-level data., Methods: A total of 360 registered nurses (RNs) will be recruited in 3 cohorts. These cohorts will serve as training, testing, and validation datasets for developing predictive models. Subjects will consent to one year of participation, including the daily use of a commodity smartwatch that collects heart rate, step count, and sleep data. Subjects will also complete online baseline and quarterly surveys assessing psychological, workplace, and sociodemographic factors. Routine administrative systems-level data on nursing care outcomes will be abstracted weekly., Discussion: The BROWNIE study was designed to be decentralized and asynchronous to minimize any additional burden on RNs and to ensure that night shift RNs would have equal accessibility to study resources and procedures. The protocol employs novel engagement strategies with participants to maintain compliance and reduce attrition to address the historical challenges of research using wearable devices., Trial Registration: NCT05481138., (© 2024. The Author(s).)

Background: Severe persistent mental illness (SPMI) is associated with worse outcomes in cancer patients. Less is known about the relationship between SPMI and surgical outcomes after mastectomy for breast cancer., Methods: We selected patients with breast cancer and SPMI from the National Inpatient Sample (2016-2018) and used propensity score matching. We then used multivariate analysis, Kruskal-Wallis tests, and conditional logistic regression to compare demographics and outcomes., Results: The study sample consisted of 670 patients: 536 without SPMI and 134 with SPMI. SPMI was associated with bilateral mastectomy (bilateral: 53% vs. unilateral: 42.7%, p = 0.033) and decreased frequency of breast reconstruction (p < 0.001). SPMI was associated with more extended hospitalization (4 days vs. 2 days, p < 0.001) and increased risk of developing post-procedural infection and sepsis (OR 2.909)., Conclusions: SPMI is associated with bilateral mastectomy, more extended hospitalization, and increased risk for post-procedural infection and sepsis - suggesting the need for increased use of standardized screening tools to identify SPMI in patients and inform perioperative management correctly., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Published by Elsevier Inc.)

This systematic review evaluated the animal and human evidence for pharmacomicrobiomics (PMx) interactions of antidepressant medications. Studies of gut microbiota effects on functional and behavioral effects of antidepressants in human and animal models were identified from PubMed up to December 2022. Risk of bias was assessed, and results are presented as a systematic review following PRISMA guidelines. A total of 28 (21 animal, 7 human) studies were included in the review. The reviewed papers converged on three themes: (1) Antidepressants can alter the composition and metabolites of gut microbiota, (2) gut microbiota can alter the bioavailability of certain antidepressants, and (3) gut microbiota may modulate the clinical or modeled mood modifying effects of antidepressants. The majority (n = 22) of studies had at least moderate levels of bias present. While strong evidence is still lacking to understand the clinical role of antidepressant PMx in human health, there is evidence for interactions among antidepressants, microbiota changes, microbiota metabolite changes, and behavior. Well-controlled studies of the mediating and moderating effects of baseline and treatment-emergent changes in microbiota on therapeutic and adverse responses to antidepressants are needed to better establish a potential role of PMx in personalizing antidepressant treatment selection and response prediction.

Objective: To examine the associations between antidepressant exposure during the third trimester of pregnancy, including individual drugs, drug doses, and antidepressant combinations, and the risk of poor neonatal adaptation (PNA)., Patients and Methods: The Rochester Epidemiology Project medical records-linkage system was used to study infants exposed to selective serotonin reuptake inhibitors (SSRIs; n=1014), bupropion, (n=118), serotonin-norepinephrine reuptake inhibitors (n=80), antidepressant combinations (n=20), or other antidepressants (n=22) during the third trimester (April 11, 2000-December 31, 2013). Poor neonatal adaptation was defined based on a review of medical records. Poisson regression was used to examine the risk of PNA with serotonergic antidepressant and drug combinations compared with that with bupropion monotherapy as well as with high- vs standard-dose antidepressants. When possible, analyses were performed using propensity score (PS) weighting., Results: Forty-four infants were confirmed cases of PNA. Serotonin-norepinephrine reuptake inhibitor monotherapy, antidepressant combinations, and paroxetine monotherapy were associated with a significantly higher risk of PNA than bupropion monotherapy in unweighted analyses. High-dose SSRI exposure was associated with a significantly increased risk of PNA in unadjusted (relative risk, 2.61; 95% confidence interval, 1.35-5.04) and PS-weighted models (relative risk, 2.29; 95% confidence interval, 1.17-4.48) compared with standard-dose SSRI exposure. The risk of PNA was significantly higher with high-dose paroxetine and sertraline than with standard doses in the PS-weighted analyses. The other risk factors for PNA included maternal anxiety disorders., Conclusion: Although the frequency of PNA in this cohort was low (3%-4%), the risk of PNA was increased in infants exposed to serotonergic antidepressants, particularly with SSRIs at higher doses, during the third trimester of pregnancy compared with that in infants exposed to standard doses. Potential risk factors for PNA also included third-trimester use of paroxetine (especially at higher doses) and maternal anxiety., Competing Interests: Dr Bobo reports having received royalties or licenses from UpToDate for chapters contributed on pharmacotherapy for people with bipolar disorders. Dr Brumbaugh reports internal funding from institution for statistician time from the Department of Development and Department of Pediatric and Adolescent Medicine Small Grants Program, Department of Medicine Small Grants Program – Influence of Language Barriers on Hospital Readmission and ED Re-visitations, CCaTS-CBD Pilot Award for Team Science – Understanding the connection between mother and infant in breast milk driven protection of neonatal sepsis, and Ultrasound Research Pilot– Assessment of metabolic bone disease of prematurity using an acoustic method; receiving external funding from the National institute of Arthritis and Musculoskeletal and Skin Diseases; being the Past President of District VI Association of Neonatologists (2019-2021); and being the Past Secretary of District VI Association of Neonatologists (2016-2019)., (© 2023 The Authors.)

Objectives: To compare the agreement between percentile ranks from 4 multi-morbidity scores., Design: Population-based descriptive study., Setting: Olmsted County, Minnesota (USA)., Participants: We used the medical records-linkage system of the Rochester Epidemiology Project (REP; http://www.rochesterproject.org) to identify all residents of Olmsted County, Minnesota who reached one or more birthdays between 1 January 2005 and 31 December 2014 (10 years)., Methods: For each person, we calculated 4 multi-morbidity scores using readily available diagnostic code lists from the US Department of Health and Human Services, the Clinical Classifications Software, and the Elixhauser Comorbidity Index. We calculated scores using diagnostic codes received in the 5 years before the index birthday and fit quantile regression models across age and separately by sex to transform unweighted, simple counts of conditions into percentile ranks as compared to peers of same age and of same sex. We compared the percentile ranks of the 4 multi-morbidity scores using intra-class correlation coefficients (ICCs)., Results: We assessed agreement in 181,553 persons who reached a total of 1,075,433 birthdays at ages 18 years through 85 years during the study period. In general, the percentile ranks of the 4 multi-morbidity scores exhibited high levels of agreement in 6 score-to-score pairwise comparisons. The agreement increased with older age for all pairwise comparisons, and ICCs were consistently greater than 0.65 at ages 50 years and older., Conclusions: The assignment of percentile ranks may be a simple and intuitive way to assess the underlying trait of multi-morbidity across studies that use different measures., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: The treatment of depression in children and adolescents is a substantial public health challenge. This study examined artificial intelligence tools for the prediction of early outcomes in depressed children and adolescents treated with fluoxetine, duloxetine, or placebo., Methods: The study samples included training datasets (N = 271) from patients with major depressive disorder (MDD) treated with fluoxetine and testing datasets from patients with MDD treated with duloxetine (N = 255) or placebo (N = 265). Treatment trajectories were generated using probabilistic graphical models (PGMs). Unsupervised machine learning identified specific depressive symptom profiles and related thresholds of improvement during acute treatment., Results: Variation in six depressive symptoms (difficulty having fun, social withdrawal, excessive fatigue, irritability, low self-esteem, and depressed feelings) assessed with the Children's Depression Rating Scale-Revised at 4-6 weeks predicted treatment outcomes with fluoxetine at 10-12 weeks with an average accuracy of 73% in the training dataset. The same six symptoms predicted 10-12 week outcomes at 4-6 weeks in (a) duloxetine testing datasets with an average accuracy of 76% and (b) placebo-treated patients with accuracies of 67%. In placebo-treated patients, the accuracies of predicting response and remission were similar to antidepressants. Accuracies for predicting nonresponse to placebo treatment were significantly lower than antidepressants., Conclusions: PGMs provided clinically meaningful predictions in samples of depressed children and adolescents treated with fluoxetine or duloxetine. Future work should augment PGMs with biological data for refined predictions to guide the selection of pharmacological and psychotherapeutic treatment in children and adolescents with depression., (© 2022 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Individuals with major depressive disorder (MDD) and a lifetime history of attempted suicide demonstrate lower antidepressant response rates than those without a prior suicide attempt. Identifying biomarkers of antidepressant response and lifetime history of attempted suicide may help augment pharmacotherapy selection and improve the objectivity of suicide risk assessments. Towards this goal, this study sought to use network science approaches to establish a multi-omics (genomic and metabolomic) signature of antidepressant response and lifetime history of attempted suicide in adults with MDD. Methods: Single nucleotide variants (SNVs) which associated with suicide attempt(s) in the literature were identified and then integrated with a) p180-assayed metabolites collected prior to antidepressant pharmacotherapy and b) a binary measure of antidepressant response at 8 weeks of treatment using penalized regression-based networks in 245 'Pharmacogenomics Research Network Antidepressant Medication Study (PGRN-AMPS)' and 103 'Combining Medications to Enhance Depression Outcomes (CO-MED)' patients with major depressive disorder. This approach enabled characterization and comparison of biological profiles and associated antidepressant treatment outcomes of those with ( N = 46) and without ( N = 302) a self-reported lifetime history of suicide attempt. Results: 351 SNVs were associated with suicide attempt(s) in the literature. Intronic SNVs in the circadian genes CLOCK and ARNTL (encoding the CLOCK:BMAL1 heterodimer) were amongst the top network analysis features to differentiate patients with and without a prior suicide attempt. CLOCK and ARNTL differed in their correlations with plasma phosphatidylcholines, kynurenine, amino acids, and carnitines between groups. CLOCK and ARNTL -associated phosphatidylcholines showed a positive correlation with antidepressant response in individuals without a prior suicide attempt which was not observed in the group with a prior suicide attempt. Conclusion: Results provide evidence for a disturbance between CLOCK:BMAL1 circadian processes and circulating phosphatidylcholines, kynurenine, amino acids, and carnitines in individuals with MDD who have attempted suicide. This disturbance may provide mechanistic insights for differential antidepressant pharmacotherapy outcomes between patients with MDD with versus without a lifetime history of attempted suicide. Future investigations of CLOCK:BMAL1 metabolic regulation in the context of suicide attempts may help move towards biologically-augmented pharmacotherapy selection and stratification of suicide risk for subgroups of patients with MDD and a lifetime history of attempted suicide., Competing Interests: LW and RMW are co-founders of and stockholders in OneOme, LLC. WVB research has been supported by the National Institute of Mental Health, the Agency for Healthcare Quality and Research, the National Science Foundation, the Myocarditis Foundation, and the Mayo Foundation for Medical Education and Research. He has contributed chapters to UpToDate concerning the pharmacological treatment of adults with bipolar major depression. PEC has received research grant support from Neuronetics, Inc., NeoSync, Inc., and Pfizer, Inc. He has received grant in-kind (equipment, supply, and genotyping support for research studies) from Assurex Health, Neuronetics, Inc., and MagVenture, Inc. PEC has served as a consultant for Engrail Therapeutics, Myriad Neuroscience, Procter & Gamble, and Sunovion. MHT has provided consulting services to Acadia Pharmaceuticals, Inc., Alkermes Inc, Alto Neuroscience Inc, Axsome Therapeutics, GH Research Limited, GreenLight VitalSign6 Inc, Janssen, Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc., Neurocrine Biosciences Inc, Orexo US Inc, Otsuka, SAGE Therapeutics, Signant Health, Titan Pharmaceuticals, Inc. He has received grant/research funding from NIMH, NIDA, NCATS, American Foundation for Suicide Prevention, Patient-Centered Outcomes Research Institute (PCORI), and Blue Cross Blue Shield of Texas. Additionally, he has received editorial compensation from Oxford University Press. TC has provided consulting services to Alkermes, Inc. RK-D is an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix. All other authors declared no competing interests for this work., (Copyright © 2022 Grant, Wilton, Kaddurah-Daouk, Skime, Biernacka, Mayes, Carmody, Wang, Lazaridis, Weinshilboum, Bobo, Trivedi, Croarkin and Athreya.)

Introduction: The efficacy of antidepressants for patients with major depressive disorder (MDD) varies from individual to individual, making the prediction of therapeutic outcomes difficult. Better methods for predicting antidepressant outcomes are needed. However, complex interactions between biological, psychological, and environmental factors affect outcomes, presenting immense computational challenges for prediction. Using machine learning (ML) techniques with pharmacogenomics data provides one pathway toward individualized prediction of therapeutic outcomes of antidepressants., Areas Covered: This report systematically reviews the methods, results, and limitations of individual studies of ML and pharmacogenomics for predicting response and/or remission with antidepressants in patients with MDD. Future directions for research and pragmatic considerations for the clinical implementation of ML-based pharmacogenomic algorithms are also discussed., Expert Opinion: ML methods utilizing pharmacogenomic and clinical data demonstrate promising results for predicting short-term antidepressant response. However, predictions of antidepressant treatment outcomes depend on contextual factors that ML algorithms may not be able to capture. As such, ML-driven prediction is best viewed as a companion to clinical judgment, not its replacement. Successful implementation and adoption of methods predicting antidepressant response warrants provider education about ML and close collaborations between computing scientists, pharmacogenomic experts, health system engineers, laboratory medicine experts, and clinicians.

Background: Many patients with major depressive disorder (MDD) who experience no meaningful benefit (NMB) from antidepressive treatment go undetected. However, there is a lack of consensus on the definition of NMB from antidepressants., Methods: Equipercentile linking was used to identify a threshold for percent change in 17-item Hamilton Depression Rating Scale (HDRS-17) scores that equated with a Clinical Global Impressions-Improvement (CGI-I) score of 3 (minimally improved), a proxy for NMB, after 4 and 8 weeks of citalopram or escitalopram treatment, using data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS). The NMB threshold for the HDRS-17 was validated by equating a CGI-I rating of 3 with percent change values from the clinician- and patient-rated versions of the Quick Inventory of Depressive Symptomatology (QIDS-C and QIDS-SR) using data from PGRN-AMPS and phase 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. This study was conducted between June 2021 and September 2021., Results: In PGRN-AMPS, a 30% improvement in HDRS-17 score corresponded to a CGI-I rating of 3 at 4 and 8 weeks. The 30% improvement threshold was also observed for QIDS-C and QIDS-SR scores in both PGRN-AMPS and STAR*D. Similar results were observed for percent change in HDRS-17 and QIDS-based measures in lower- and higher-severity groups based on a median split of baseline total scores., Conclusions: Improvement in depressive severity of ≤ 30%, as assessed using the HDRS-17, QIDS-C, and QIDS-SR, may validly define NMB from antidepressants during short-term treatment., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Introduction: The Clinical Global Impressions-Improvement (CGI-I) scale is widely used in clinical research to assess symptoms and functioning in the context of treatment. The correlates of the CGI-I with efficacy scales for adolescent major depressive disorder are poorly understood. This study focused on benchmarking CGI-I scores with changes in the Children's Depression Rating Scale-Revised (CDRS-R) and the Quick Inventory of Depressive Symptomatology-Adolescent (17-item) Self-Report (QIDS-A17-SR). Methods: We examined three datasets with the clinician-rated CDRS-R to ascertain equivalent percent changes in total scores and CGI-I ratings. Exploratory analyses examined corresponding percentage changes in the QIDS-A17-SR and the CGI-I ratings. The CGI-I was the reference scale for nonparametric equipercentile linking with the Equate package in R. Results: CGI-I scores of 1 mapped to ≥78%-95% change in CDRS-R scores at 4-6 weeks across three datasets. CGI-I scores of 2 mapped to 56%-94% change in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 3 mapped to 30%-68% changes in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 4 mapped to a range of 29%-44% at 4-6 weeks across three studies. There was no significant difference ( p  ≥ 0.6) between treatment groups in both the Treatment of Adolescents with Depression and Treatment of Resistant Depression in Adolescents studies, for each CGI-I score ( = 1, or = 2 or = 3, or ≥4), associated mapping of total depression severity score, or associated percent change from baseline for corresponding follow-up visits. There was no significant sex difference ( p  > 0.2) in CGI-I linkages to CDRS-R total or percentage changes. Conclusions: These findings establish clear relationships among CGI-I scores and the CDRS-R and the QIDS-A17-SR. These benchmarks have utility for clinical trial study design, inter-rater reliability training, and clinical implementation.

Importance: Longitudinal associations between comorbid depression and anxiety with the accumulation of chronic illnesses are unclear, and questions remain about the contributions associated with each condition in the increasing prevalence of multimorbidity., Objective: To compare the risk and rate of accumulating chronic conditions in people with depression, anxiety, and comorbid depression and anxiety vs individuals with neither depression nor anxiety., Design, Setting, and Participants: This cohort study used the Rochester Epidemiology Project medical records-linkage system to identify residents of Olmsted County, Minnesota, from January 1, 2005, to December 31, 2014, with follow-up ending December 31, 2017. The sample was divided into cohorts anchored at birthday ages of 20, 40, and 60 years. Individuals were classified at anchoring birthday age as having depression alone, anxiety alone, comorbid depression and anxiety, or neither depression nor anxiety (reference group), using electronically extracted diagnosis codes from the International Classification of Diseases, Ninth Revision (ICD-9) in the 5 years before each anchoring birthday. Data were analyzed from August 2020 through November 2021., Exposures: Depression alone, anxiety alone, comorbid depression and anxiety, or neither depression nor anxiety (reference group)., Main Outcomes and Measures: The main outcome was sex-specific risk, calculated as hazard ratios (HRs) and rates of accumulation, calculated as mean annual incidence rates per 100 person-years, of 15 common chronic conditions within each birthday age cohort through the end of study., Results: Among the 40 360 individuals included across all 3 age cohorts, 21 516 (53.3%) were women. After balancing cohorts on race, Hispanic ethnicity, education level, body mass index, smoking status, and calendar year at index birthday, the risk of accumulating chronic conditions was significantly increased among women with depression alone (cohort aged 20 years: HR, 1.20 [95% CI, 1.02-1.42]; cohort aged 40 years: HR, 1.20 [95% CI, 1.10-1.31]; cohort aged 60 years: HR, 1.09 [95% CI, 1.02-1.16]) and women with comorbid depression and anxiety (cohort aged 20 years: HR, 1.60 [95% CI, 1.28-1.99]; cohort aged 40 years: HR, 1.41 [95% CI, 1.21-1.65]; cohort aged 60 years: HR, 1.29 [95% CI, 1.15-1.44]) compared with referent women in the same birthday cohorts and in men with comorbid depression and anxiety compared with referent men in the cohort aged 20 years (HR, 1.77 [95% CI, 1.08-2.91]). For women, the rates of accumulation of conditions were significantly higher across birthday cohorts in the comorbid depression and anxiety group compared with the depression alone group (eg, cohort aged 20 years: difference, 1.2 [95% CI, 0.2-2.1] per 100 person-years) and reference group (eg, cohort aged 20 years: difference, 1.7 [95% CI, 0.9-2.6] per 100 person-years). For men, compared with the reference group, the rates of accumulation of conditions were significantly higher in men with comorbid depression and anxiety in the cohort aged 20 years (difference, 1.4 [95% CI, 0.1-2.6] per 100 person-years) and in men with depression in the cohort aged 40 years (difference, 2.0 [95% CI, 0.8-3.2] per 100 person-years)., Conclusions and Relevance: In this cohort study, the risk of accumulating chronic conditions was increased with depression and comorbid depression and anxiety in women across the age span and in younger men with comorbid depression and anxiety. Compared with women without depression or anxiety, there was a more rapid rate of accumulation of chronic conditions in women with depression and anxiety individually and an even higher rate when depression and anxiety cooccurred.

Age at depressive onset (AAO) corresponds to unique symptomatology and clinical outcomes. Integration of genome-wide association study (GWAS) results with additional “omic” measures to evaluate AAO has not been reported and may reveal novel markers of susceptibility and/or resistance to major depressive disorder (MDD). To address this gap, we integrated genomics with metabolomics using data-driven network analysis to characterize and differentiate MDD based on AAO. This study first performed two GWAS for AAO as a continuous trait in (a) 486 adults from the Pharmacogenomic Research Network-Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS), and (b) 295 adults from the Combining Medications to Enhance Depression Outcomes (CO-MED) study. Variants from top signals were integrated with 153 p180-assayed metabolites to establish multi-omics network characterizations of early (

Background: Due to invasive treatments and stressors related to heart health, adults with congenital heart defects (CHDs) may have an increased risk of post-traumatic stress disorder (PTSD), anxiety, and/or depressive disorders. Our objectives were to estimate the prevalence of these disorders among individuals with CHDs., Methods: Using IBM® MarketScan® Databases, we identified adults age 18-49 years with ≥2 outpatient anxiety/depressive disorder claims on separate dates or ≥1 inpatient anxiety/depressive disorder claim in 2017. CHDs were defined as ≥2 outpatient CHD claims ≥30 days apart or ≥1 inpatient CHD claim documented in 2007-2017. We used log-binomial regression to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for associations between CHDs and anxiety/depressive disorders., Results: Of 13,807 adults with CHDs, 12.4% were diagnosed with an anxiety or depressive disorder. Adults with CHDs, compared to the 5,408,094 without CHDs, had higher prevalence of PTSD (0.8% vs. 0.5%; aPR: 1.5 [CI: 1.2-1.8]), anxiety disorders (9.9% vs. 7.5%; aPR: 1.3 [CI: 1.3-1.4]), and depressive disorders (6.3% vs. 4.9%; aPR: 1.3 [CI: 1.2-1.4]). Among individuals with CHDs, female sex (aPR range: 1.6-3.3) and inpatient admission (aPR range 1.1-1.9) were associated with anxiety/depressive disorders., Conclusion: Over 1 in 8 adults with CHDs had diagnosed PTSD and/or other anxiety/depressive disorders, 30-50% higher than adults without CHDs. PTSD was rare, but three times more common in women with CHDs than men. Screening and referral for services for these conditions in people with CHDs may be beneficial., (© 2021 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: To examine whether a positive urine drug of abuse screen in youth who receive medical care is associated with subsequent risk of external mortality (eg, overdose, suicide, homicide, accident)., Methods: This was a population-based retrospective cohort study of all Olmsted County (Minnesota) residents who were 13-18 years of age at the time of urine drug screen (UDS) testing (January 1, 1999, to November 28, 2012). Cox regression models were used to examine the relationships between having a positive UDS and external mortality, adjusted for sex, race, age, alcohol exposure, psychiatric diagnoses as defined by the International Classification of Diseases ( ICD-9 / ICD-10 ), and medical setting of UDS testing. Separate analyses were done for (1) overall UDS results, (2) tetrahydrocannabinol (THC), and (3) cocaine., Results: Of the 2,772 teenagers included in this study (47.2% male), a total of 26 died of external causes during a median follow-up period of 11.8 years. Testing positive for any illicit substance was not associated with significantly increased risk of external mortality (hazard ratio [HR] = 1.9; 95% CI, 0.9-4.2). Testing positive for cocaine was associated with significantly increased risk of external mortality (HR = 7.0; 95% CI, 1.9-25.0). Testing positive for THC was associated with a marginally significantly increased risk of external mortality (HR = 2.1; 95% CI, 1.0-4.7); however, when cocaine was added as a covariate in the analysis, the relationship between THC-positive UDS and mortality was still elevated but was no longer statistically significant (HR = 1.8; 95% CI, 0.8-4.1)., Conclusions: History of cocaine-positive UDS may help identify a population of young people who are at high risk of premature death., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Objective: Relative age refers to a difference in age between peers in the same academic year. Although younger age of alcohol use is associated with a higher risk of lifetime problematic alcohol use, the potential effects of relative age are poorly understood. We hypothesized that a younger relative age would be associated with a younger chronological age of testing positive for alcohol in a medical setting. Methods: Problematic alcohol use was operationalized and identified as a positive alcohol test (PAT) in a medical setting. This was a retrospective population study of all 12 to 18-year-old residents ( n  = 4610) of Olmsted County, Minnesota (USA), who were tested for alcohol in a medical care setting from 1998 through 2016. Cox regression models examined the relationship between relative age and the age at testing positive for alcohol. Results: Relative age was not associated with age at first PAT. Results remained nonsignificant after stratifying by gender, and after adjusting for race, number of nonalcohol-related psychiatric comorbidities, and type of alcohol testing. Conclusions: The results did not support a relative age effect as a risk factor for alcohol use in adolescents in Olmsted County, Minnesota. These results contrast with findings from previous studies on this topic, which suggested older relative age increases risk of alcohol use in adolescence.

Combination antidepressant pharmacotherapies are frequently used to treat major depressive disorder (MDD). However, there is no evidence that machine learning approaches combining multi-omics measures (e.g., genomics and plasma metabolomics) can achieve clinically meaningful predictions of outcomes to combination pharmacotherapy. This study examined data from 264 MDD outpatients treated with citalopram or escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) and 111 MDD outpatients treated with combination pharmacotherapies in the Combined Medications to Enhance Outcomes of Antidepressant Therapy (CO-MED) study to predict response to combination antidepressant therapies. To assess whether metabolomics with functionally validated single-nucleotide polymorphisms (SNPs) improves predictability over metabolomics alone, models were trained/tested with and without SNPs. Models trained with PGRN-AMPS' and CO-MED's escitalopram/citalopram patients predicted response in CO-MED's combination pharmacotherapy patients with accuracies of 76.6% (p < 0.01; AUC: 0.85) without and 77.5% (p < 0.01; AUC: 0.86) with SNPs. Then, models trained solely with PGRN-AMPS' escitalopram/citalopram patients predicted response in CO-MED's combination pharmacotherapy patients with accuracies of 75.3% (p < 0.05; AUC: 0.84) without and 77.5% (p < 0.01; AUC: 0.86) with SNPs, demonstrating cross-trial replication of predictions. Plasma hydroxylated sphingomyelins were prominent predictors of treatment outcomes. To explore the relationship between SNPs and hydroxylated sphingomyelins, we conducted multi-omics integration network analysis. Sphingomyelins clustered with SNPs and metabolites related to monoamine neurotransmission, suggesting a potential functional relationship. These results suggest that integrating specific metabolites and SNPs achieves accurate predictions of treatment response across classes of antidepressants. Finally, these results motivate functional investigation into how sphingomyelins might influence MDD pathophysiology, antidepressant response, or both., (© 2021. The Author(s).)

Background: Some studies have reported associations between prenatal use of venlafaxine, a serotonin-norepinephrine reuptake inhibitor used for depressive and anxiety disorders, and some birth defects. We described the prevalence of venlafaxine prescription claims among privately insured women of reproductive age and pregnant women., Methods: Venlafaxine prescription claims were examined using the IBM MarketScan Commercial Databases. We included women of reproductive age (15-44 years) who had ≤45 days of lapsed enrollment during the calendar year of interest (2011-2016) in a non-capitated healthcare plan sponsored by a large, self-insured employer with prescription drug coverage and no mental health service carve-out. Annual cohorts of pregnant women were identified among eligible women of reproductive age via pregnancy diagnosis and procedure codes. Venlafaxine prescriptions were identified via National Drug Codes in outpatient pharmacy claims and we estimated the annual proportion of women with venlafaxine claims by pregnancy trimester (pregnant women only), age, and Census division., Results: Each year during 2011-2016, approximately 1.2% of eligible reproductive-aged and 0.3% of eligible pregnant women filled a venlafaxine prescription. Among pregnant women, the proportion with venlafaxine claims was highest during the first trimester and decreased during the second and third trimesters. Small temporal increases in venlafaxine claims were observed for reproductive-aged and pregnant women, with the largest among women aged 15-19 years., Conclusions: Venlafaxine prescription claims were low among women of reproductive age and pregnant women during 2011-2016, with some increasing use over time among women aged 15-19 years., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Heterogeneity in the clinical presentation of major depressive disorder and response to antidepressants limits clinicians' ability to accurately predict a specific patient's eventual response to therapy. Validated depressive symptom profiles may be an important tool for identifying poor outcomes early in the course of treatment. To derive these symptom profiles, we first examined data from 947 depressed subjects treated with selective serotonin reuptake inhibitors (SSRIs) to delineate the heterogeneity of antidepressant response using probabilistic graphical models (PGMs). We then used unsupervised machine learning to identify specific depressive symptoms and thresholds of improvement that were predictive of antidepressant response by 4 weeks for a patient to achieve remission, response, or nonresponse by 8 weeks. Four depressive symptoms (depressed mood, guilt feelings and delusion, work and activities and psychic anxiety) and specific thresholds of change in each at 4 weeks predicted eventual outcome at 8 weeks to SSRI therapy with an average accuracy of 77% (p = 5.5E-08). The same four symptoms and prognostic thresholds derived from patients treated with SSRIs correctly predicted outcomes in 72% (p = 1.25E-05) of 1996 patients treated with other antidepressants in both inpatient and outpatient settings in independent publicly-available datasets. These predictive accuracies were higher than the accuracy of 53% for predicting SSRI response achieved using approaches that (i) incorporated only baseline clinical and sociodemographic factors, or (ii) used 4-week nonresponse status to predict likely outcomes at 8 weeks. The present findings suggest that PGMs providing interpretable predictions have the potential to enhance clinical treatment of depression and reduce the time burden associated with trials of ineffective antidepressants. Prospective trials examining this approach are forthcoming.

The efficacy of subanesthetic intravenous ketamine for treatment resistant depression (TRD) has spurred a growth of clinics nationwide that provide this service. Ketamine is an FDA-approved drug as an anesthetic but remains unapproved for psychiatric indications, and this status raises a number of short- and long-term safety and efficacy concerns that need to be addressed when implementing and developing this type of clinic. Using a framework of systems, provider, and patient domains, we provide a review of the key challenges in providing ketamine infusions and suggest potential approaches. Under systems issues, we highlight broad stakeholder engagement involving cross-departmental and multidisciplinary considerations, business case development, and delineation of administrative standard operating procedures. In the provider domain, we highlight specific roles for different treatment team members as well as suggested training requirements. In the patient domain, we identify a variety of standard operating procedures involving initial patient assessment parameters, ketamine dosing and administration guidelines, and safety monitoring procedures. Together, this review provides key considerations for developing a ketamine clinic for depression, in an effort to meet the pressing demand for this novel treatment option while helping to ensure its safe implementation., (Copyright © 1964–2021 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Objective: To assess the validity of the US Department of Health and Human Services (DHHS) definition of multimorbidity using International Classification of Diseases, ninth edition (ICD-9) codes from administrative data., Design: Cross-sectional comparison of two ICD-9 billing code algorithms to data abstracted from medical records., Setting: Olmsted County, Minnesota, USA., Participants: An age-stratified and sex-stratified random sample of 1509 persons ages 40-84 years old residing in Olmsted County on 31 December 2010., Study Measures: Seventeen chronic conditions identified by the US DHHS as important in studies of multimorbidity were identified through medical record review of each participant between 2006 and 2010. ICD-9 administrative billing codes corresponding to the 17 conditions were extracted using the Rochester Epidemiology Project records-linkage system. Persons were classified as having each condition using two algorithms: at least one code or at least two codes separated by more than 30 days. We compared the ICD-9 code algorithms with the diagnoses obtained through medical record review to identify persons with multimorbidity (defined as ≥2, ≥3 or ≥4 chronic conditions)., Results: Use of a single code to define each of the 17 chronic conditions resulted in sensitivity and positive predictive values (PPV) ≥70%, and in specificity and negative predictive values (NPV) ≥70% for identifying multimorbidity in the overall study population. PPV and sensitivity were highest in persons 65-84 years of age, whereas NPV and specificity were highest in persons 40-64 years. The results varied by condition, and by age and sex. The use of at least two codes reduced sensitivity, but increased specificity., Conclusions: The use of a single code to identify each of the 17 chronic conditions may be a simple and valid method to identify persons who meet the DHHS definition of multimorbidity in populations with similar demographic, socioeconomic, and health care characteristics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To describe the percentile distribution of multimorbidity across age by sex, race and ethnicity, and to demonstrate the utility of multimorbidity percentiles to predict mortality., Design: Population-based descriptive study and cohort study., Setting: Olmsted County, Minnesota (USA)., Participants: We used the medical records-linkage system of the Rochester Epidemiology Project (REP; http://www.rochesterproject.org) to identify all residents of Olmsted County, Minnesota who reached one or more birthdays between 1 January 2005 and 31 December 2014 (10 years)., Methods: For each person, we obtained the count of chronic conditions (out of 20 conditions) present on each birthday by extracting all of the diagnostic codes received in the 5 years before the index birthday from the electronic indexes of the REP. To compare each person's count to peers of same age, the counts were transformed into percentiles of the total population and displayed graphically across age by sex, race and ethnicity. In addition, quintiles 1, 2, 4 and 5 were compared with quintile 3 (reference) to predict the risk of death at 1 year, 5 years and through end of follow-up using time-to-event analyses. Follow-up was passive using the REP., Results: We identified 238 010 persons who experienced a total of 1 458 094 birthdays during the study period (median of 6 birthdays per person; IQR 3-10). The percentiles of multimorbidity across age did not vary noticeably by sex, race or ethnicity. In general, there was an increased risk of mortality at 1 and 5 years for quintiles 4 and 5 of multimorbidity. The risk of mortality for quintile 5 was greater for younger age groups and for women., Conclusions: The assignment of multimorbidity percentiles to persons in a population may be a simple and intuitive tool to assess relative health status, and to predict short-term mortality, especially in younger persons and in women., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine whether a bi-directional relationship exists between depression and HF within a single population of individuals receiving primary care services, using longitudinal electronic health records (EHRs)., Methods: This retrospective cohort study utilized EHRs for adults who received primary care services within a large healthcare system in 2006. Validated EHR-based algorithms identified 10,649 people with depression (depression cohort) and 5,911 people with HF (HF cohort) between January 1, 2006 and December 31, 2018. Each person with depression or HF was matched 1:1 with an unaffected referent on age, sex, and outpatient service use. Each cohort (with their matched referents) was followed up electronically to identify newly diagnosed HF (in the depression cohort) and depression (in the HF cohort) that occurred after the index diagnosis of depression or HF, respectively. The risks of these outcomes were compared (vs. referents) using marginal Cox proportional hazard models adjusted for 16 comorbid chronic conditions., Results: 2,024 occurrences of newly diagnosed HF were observed in the depression cohort and 944 occurrences of newly diagnosed depression were observed in the HF cohort over approximately 4-6 years of follow-up. People with depression had significantly increased risk for developing newly diagnosed HF (HR 2.08, 95% CI 1.89-2.28) and people with HF had a significantly increased risk of newly diagnosed depression (HR 1.34, 95% CI 1.17-1.54) after adjusting for all 16 comorbid chronic conditions., Conclusion: These results provide evidence of a bi-directional relationship between depression and HF independently of age, sex, and multimorbidity from chronic illnesses., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: WVB’s research has been supported by AHRQ, NIMH, and the Mayo Foundation for Medical Education and Research. He has contributed chapters on the treatment of bipolar disorders to UpToDate. LTC’s research has been supported by NHLBI and the Mayo Foundation for Medical Education and Research. VLR’s research has been supported by NHLBI, PCORI and the Mayo Foundation for Medical Education and Research. JP’s research has been supported by NIH, AHRQ, PCORI, NSF, Weill Cornell Medicine BioVentures, American Heart Association and Merck Pharmaceuticals. He is the founder of and has equity ownership at Iris OB Health Inc. The remaining authors declare no conflict of interest., (© The Author(s) 2020.)

Importance: Antidepressants are commonly used during pregnancy, but limited information is available about individual antidepressants and specific birth defect risks., Objective: To examine associations between individual antidepressants and specific birth defects with and without attempts to partially account for potential confounding by underlying conditions., Design, Setting, and Participants: The population-based, multicenter case-control National Birth Defects Prevention Study (October 1997-December 2011) included cases with selected birth defects who were identified from surveillance systems; controls were randomly sampled live-born infants without major birth defects. Mothers of cases and controls participated in an interview after the expected delivery date. The data were analyzed after the completion of the National Birth Defects Prevent Study's data collection., Exposures: Self-reported antidepressant exposure was coded to indicate monotherapy exposure to antidepressants., Main Outcomes and Measures: We used multivariable logistic regression to calculate adjusted odds ratios (aORs) and 95% confidence intervals for associations between maternal antidepressant use and birth defects. We compared early pregnancy antidepressant-exposed women with those without antidepressant exposure and, to partially account for confounding by underlying maternal conditions, those exposed to antidepressants outside of the birth defect development critical period., Results: This study included 30 630 case mothers of infants with birth defects and 11 478 control mothers (aged 12-53 years). Early pregnancy antidepressant use was reported by 1562 case mothers (5.1%) and 467 control mothers (4.1%), for whom elevated aORs were observed for individual selective serotonin reuptake inhibitors (SSRIs) and selected congenital heart defects (CHD) (eg, fluoxetine and anomalous pulmonary venous return: aOR, 2.56; 95% CI, 1.10-5.93; this association was attenuated after partially accounting for underlying conditions: aOR, 1.89; 95% CI, 0.56-6.42). This pattern was observed for many SSRI-CHD combinations. Associations between SSRIs and non-CHD birth defects often persisted or strengthened after partially accounting for underlying conditions (eg, citalopram and diaphragmatic hernia: aOR, 5.11; 95% CI, 1.29-20.24). Venlafaxine had elevated associations with multiple defects that persisted after partially accounting for underlying conditions (eg, anencephaly and craniorachischisis: aOR, 9.14; 95% CI, 1.91-43.83)., Conclusions and Relevance: We found some associations between maternal antidepressant use and specific birth defects. Venlafaxine was associated with the highest number of defects, which needs confirmation given the limited literature on venlafaxine use during pregnancy and risk for birth defects. Our results suggest confounding by underlying conditions should be considered when assessing risk. Fully informed treatment decision-making requires balancing the risks and benefits of proposed interventions against those of untreated depression or anxiety.

Objectives: Sleep disturbances are prevalent in cancer patients, especially those with advanced disease. There are few published intervention studies that address sleep issues in advanced cancer patients during the course of treatment. This study assesses the impact of a multidisciplinary quality of life (QOL) intervention on subjective sleep difficulties in patients with advanced cancer., Method: This randomized trial investigated the comparative effects of a multidisciplinary QOL intervention (n = 54) vs. standard care (n = 63) on sleep quality in patients with advanced cancer receiving radiation therapy as a secondary endpoint. The intervention group attended six intervention sessions, while the standard care group received informational material only. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS), administered at baseline and weeks 4 (post-intervention), 27, and 52., Results: The intervention group had a statistically significant improvement in the PSQI total score and two components of sleep quality and daytime dysfunction than the control group at week 4. At week 27, although both groups showed improvements in sleep measures from baseline, there were no statistically significant differences between groups in any of the PSQI total and component scores, or ESS. At week 52, the intervention group used less sleep medication than control patients compared to baseline (p = 0.04) and had a lower ESS score (7.6 vs. 9.3, p = 0.03)., Significance of Results: A multidisciplinary intervention to improve QOL can also improve sleep quality of advanced cancer patients undergoing radiation therapy. Those patients who completed the intervention also reported the use of less sleep medication.

Aims: Decades of research show that people with schizophrenia have an increased risk of death from cancer; however, the relationship between schizophrenia and cancer incidence remains less clear. This population-based study investigates the incidence of seven common types of cancer among people with a hospital diagnosis of schizophrenia and accounting for the effects of age, sex and calendar time., Methods: This population-based study used 1990-2013 data from three nationwide Swedish registries to calculate the incidence (in total, by age group and by sex) of any cancer and of lung, oesophageal, pancreatic, stomach, colon, (in men) prostate and (in women) breast cancer in 111 306 people with a hospital diagnosis of schizophrenia. The incidence in people with diagnosed schizophrenia was compared with the incidence in the general population. Risk estimates accounted for the effects of calendar time., Results: In 1 424 829 person-years of follow-up, schizophrenia did not confer an overall higher cancer risk (IRR 1.02, 95% CI 0.91-1.13) but was associated with a higher risk for female breast (IRR 1.19, 95% CI 1.12-1.26), lung (IRR 1.42, 95% CI 1.28-1.58), oesophageal (IRR 1.25, 95% CI 1.07-1.46) and pancreatic (IRR 1.10, 95% CI 1.01-1.21) and a lower risk of prostate (IRR 0.66, 95% CI 0.55-0.79) cancer. Some age- and sex-specific differences in risk were observed., Conclusions: People with schizophrenia do not have a higher overall incidence of cancer than people in the general population. However, there are significant differences in the risk of specific cancer types overall and by sex calling for efforts to develop disease-specific prevention programmes. In people with schizophrenia, higher risk generally occurs in those <75 years.

Numerous short-term randomized trials support the acute-phase efficacy of low-dose intravenous (IV) ketamine for patients with treatment-resistant unipolar or bipolar depression. Ketamine's antidepressive effects generally have limited duration, highlighting the need for maintenance treatment after an acute-phase response. It is increasingly likely that psychiatrists will be called upon to manage the care of patients with treatment-resistant unipolar or bipolar depression who have responded acutely to ketamine and to recommend or initiate next-step treatments. However, there is a paucity of controlled evidence to guide best practices for managing treatment of patients with treatment-resistant unipolar or bipolar depression who have had a positive initial response to ketamine. This article reviews the available evidence supporting specific strategies for extending and maintaining acute antidepressive responses to low-dose IV ketamine in patients with treatment-resistant unipolar or bipolar depression and provides some preliminary considerations for clinical practice., Competing Interests: Dr. Riva-Posse served on an advisory board for Janssen Pharmaceuticals. Dr. Goes has received research support from Janssen Pharmaceuticals. Dr. Parikh has received research support from Assurex, Sage, and Takeda; has served as a consultant for Assurex, Janssen, Mensante, and Takeda; and owns shares of Mensante. Dr. Bobo reports no financial relationships with commercial interests., (Copyright © by the American Psychiatric Association.)

Background: Lithium and quetiapine can cause weight gain, but their comparative longer term anthropometric effects are unknown, as are the potential moderating effects of baseline binge-eating (BE) behavior., Methods: We assessed 6 month changes in body weight, body mass index (BMI) and waist circumference in 482 adults with DSM-IV bipolar disorders who participated in a comparative effectiveness study of lithium and quetiapine with evidence-based adjunctive treatment (Bipolar CHOICE). Anthropometric measurements were obtained at baseline, and at 2, 4, 6, 8, 12, 16, 20, and 24 weeks. BE behavior was defined as affirmative responses to MINI items M1 and M3 at baseline. Data were analyzed using a mixed model repeated measures approach, adjusted for baseline values of dependent measures., Results: On average, body weight and BMI increased over 6 months with lithium and quetiapine. However, those treated with quetiapine experienced greater increases from baseline in body weight (peak change, + 3.6 lbs. vs. + 1.4 lbs.) and BMI (peak change, + 0.6 kg/m 2 vs. + 0.3 kg/m 2 ), starting at 2 weeks (group x time, F 8,3052   = 2.9, p = 0.003 for body weight, F 8,3052   = 3.0, p = 0.002 for BMI). Significant increases in waist circumference were observed only with quetiapine. The relationship between drug treatment and changes in body weight (group x time x binge eating status, F 1,2770   = 2.0, p = 0.002), BMI (F 1,2767   = 2.0, p = 0.002), and waist circumference (women only, F 25,1621   = 2.9, p < 0.0001) were moderated by BE behavior. The largest increases over 24 weeks in body weight and BMI, and waist circumference in women, occurred for quetiapine-treated patients with baseline binge-eating, relative to quetiapine-treated patients without binge eating and lithium-treated patients with or without baseline binge-eating., Limitations: Bipolar CHOICE was not designed to study anthropometric outcomes., Conclusions: Greater changes in body weight, BMI, and waist circumference occurred with quetiapine- versus lithium-based treatment over 6 months of treatment. The effects of study drugs on these anthropometric measures were moderated by BE behavior at baseline., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Acylcarnitines have important functions in mitochondrial energetics and β-oxidation, and have been implicated to play a significant role in metabolic functions of the brain. This retrospective study examined whether plasma acylcarnitine profiles can help biochemically distinguish the three phenotypic subtypes of major depressive disorder (MDD): core depression (CD+), anxious depression (ANX+), and neurovegetative symptoms of melancholia (NVSM+)., Methods: Depressed outpatients (n = 240) from the Mayo Clinic Pharmacogenomics Research Network were treated with citalopram or escitalopram for eight weeks. Plasma samples collected at baseline and after eight weeks of treatment with citalopram or escitalopram were profiled for short-, medium- and long-chain acylcarnitine levels using AbsoluteIDQ®p180-Kit and LC-MS. Linear mixed effects models were used to examine whether acylcarnitine levels discriminated the clinical phenotypes at baseline or eight weeks post-treatment, and whether temporal changes in acylcarnitine profiles differed between groups., Results: Compared to ANX+, CD+ and NVSM+ had significantly lower concentrations of short- and long-chain acylcarnitines at both baseline and week 8. In NVSM+, the medium- and long-chain acylcarnitines were also significantly lower in NVSM+ compared to ANX+. Short-chain acylcarnitine levels increased significantly from baseline to week 8 in CD+ and ANX+, whereas medium- and long-chain acylcarnitines significantly decreased in CD+ and NVSM+., Conclusions: In depressed patients treated with SSRIs, β-oxidation and mitochondrial energetics as evaluated by levels and changes in acylcarnitines may provide the biochemical basis of the clinical heterogeneity of MDD, especially when combined with clinical characteristics., Competing Interests: Declaration of Competing Interest Richard Weinshilboum is a co-founder and stockholder in OneOme, LLC, a pharmacogenomic clinical decision support company. Dr. Kaddurah-Daouk is an inventor on patents related to metabolomics applications in the study of CNS diseases and holds equity in Metabolon, Inc., a biotechnology company that provides metabolic profiling capabilities. Dr. A. John Rush has received: consulting fees from Akili, Brain Resource Inc., Compass Inc., Curbstone Consultant LLC., Emmes Corp., Johnson and Johnson (Janssen), Liva-Nova, Mind Linc., Sunovion; speaking fees from Janssen and Liva-Nova; and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). Dr. Rush is also named co-inventor on two patents: U.S. Patent No. 7795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication and U.S. Patent No. 7906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication. Drew Neavin's stipend has been supported in part by NIH T32 GM072474 and the Mayo Graduate School. Ahmed Ahmed's research was supported by National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685. Dr. Matthias Arnold was supported by National Institute on Aging [R01AG057452, RF1AG051550, R01AG046171], National Institute of Mental Health [R01MH108348], and Qatar National Research Fund [NPRP8-061–3–011]. The funders listed above had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Dr. Dunlop has received research support from Acadia, Axsome, Janssen, Takeda and he serves as a consultant to Assurex Health and Aptinyx Inc. dr. Craighead is a board member of Hugarheill ehf, an Icelandic company dedicated to the prevention of depression, and he receives book royalties from John Wiley & Sons; his research is also supported by the Mary and John Brock Foundation and the Fuqua family foundations; he is a consultant to the George West Mental Health Foundation and is a member of the scientific advisory boards of the AIM for Mental Health Foundation and the Anxiety Disorders Association of America. dr. Bobo's research has been supported by the NIMH, AHRQ, Mayo Foundation for Medical Education and Research; he has contributed chapters to UpToDate on the treatment of bipolar disorders. Additional support was received from PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources, PHS Grant M01 RR0039 from the General Clinical Research Center program, and K23 MH086690 (BWD)., (Copyright © 2019. Published by Elsevier B.V.)

Purpose: To examine the prevalence of, and factors associated with, atypical antipsychotic use among U.S. pregnant women, and potential associations between early pregnancy atypical antipsychotic use and risk for 14 birth defects., Methods: We analyzed data from the National Birth Defects Prevention Study (1997-2011), a U.S. population-based case-control study examining risk factors for major structural birth defects., Results: Atypical antipsychotic use during pregnancy was more common among women with pre-pregnancy obesity, and women who reported illicit drug use before and during pregnancy, smoking during pregnancy, alcohol use during pregnancy, or use of other psychiatric medications during pregnancy. We observed elevated associations (defined as a crude odds ratio [cOR] ≥2.0) between early pregnancy atypical antipsychotic use and conotruncal heart defects (6 exposed cases; cOR: 2.3, 95% confidence interval [CI]: 0.9-6.1), and more specifically Tetralogy of Fallot (3 exposed cases; cOR: 2.5, 95% CI: 0.7-8.8), cleft palate (4 exposed cases, cOR: 2.5, 95% CI: 0.8-7.6), anorectal atresia/stenosis (3 exposed cases, cOR: 2.8, 95% CI: 0.8-9.9), and gastroschisis (3 exposed cases, cOR: 2.1, 95% CI: 0.6-7.3)., Conclusions: Our findings support the close clinical monitoring of pregnant women using atypical antipsychotics. Women treated with atypical antipsychotics generally access healthcare services before pregnancy; efforts to reduce correlates of atypical antipsychotic use might improve maternal and infant health in this population., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Published by Elsevier B.V.)

Importance: Infection-associated immune activation and inflammation are increasingly recognized in the pathophysiology of bipolar disorder., Objective: To determine whether antibodies to common infectious agents, including cytomegalovirus (CMV), Toxoplasma gondii, and measles, as well as the inflammatory marker C-reactive protein, in serum samples differ between patients with bipolar disorder and control individuals without bipolar disorder., Design, Setting, and Participants: In this case-control study, antibody titers were measured in serum samples from 1207 patients with bipolar disorder and 745 controls that were obtained from biobanks with participating sites in Rochester and Minneapolis, Minnesota (n = 1537), and Cincinnati, Ohio (n = 415), from January 5, 2009, through May 12, 2014. A subset of case patients and controls from Minnesota were matched by age, sex, and educational level. Bipolar type, age at onset, and history of psychosis were assessed for case patients as well as current drug treatment at the time of blood sample obtainment from the biobank. Data were analyzed from February 5, 2018, to January 4, 2019., Exposures: The CMV and T gondii antibodies with IgM titers were expressed as z scores and IgG titers dichotomized into seropositive and seronegative based on expected prevalence in the US population and further classified based on the joint CMV-positive/T gondii-negative IgG status, C-reactive protein z score, and drug treatments with antitoxoplasma activity., Main Outcomes and Measures: Patients were stratified by bipolar disorder type I or type II, nonearly (>19 years of age) and early (≤19 years of age) onset, and history of psychosis during mania or no psychosis., Results: Of 1207 patients with bipolar disorder (mean [SD] age, 43.2 [15.1] years; 742 [61.5%] female), the CMV-positive/T gondii-negative IgG status was significantly higher (odds ratio [OR], 1.33; 95% CI, 1.09-1.62; P = .004) compared with that in the 745 controls (mean [SD] age, 44.5 [15.5] years; 444 [59.6%] female). The CMV-positive/T gondii-negative IgG status was associated with bipolar cases type I (OR, 1.41; 95% CI, 1.14-1.75; P = .001), nonearly age at onset (OR, 1.41; 95% CI, 1.16-1.72; P = .001), and history of manic psychosis (OR, 1.46; 95% CI, 1.13-1.88; P = .004). Patients with bipolar disorder who received drug treatment with antitoxoplasma activity (n = 272) had significantly lower T gondii IgM titers (median, 1.59; interquartile range, 1.30-2.07) compared with those (n = 900) who did not receive this treatment (median, 1.69; interquartile range, 1.35-2.25) (P = .03)., Conclusions and Relevance: In this sample, increased long-term antibody response to CMV and decreased long-term antibody response to T gondii were associated with bipolar disorder and the subphenotypes of bipolar type I, nonearly disease onset, and manic psychosis. Further work appears to be needed to better understand genetic vs environmental disease risk and infection or immune activation contribution to overall disease pathogenesis with particular reference to disease onset.