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Treatment resistance is common in major depressive disorder (MDD), yet clinical risk factors are not well understood. Using a discovery-replication design, we conducted phenome-wide association studies (PheWASs) of MDD treatment resistance in two electronic health record (EHR)-linked biobanks. The PheWAS included participants with an MDD diagnosis in the EHR and at least one antidepressant (AD) prescription. Participant lifetime diagnoses were mapped to phecodes. PheWASs were conducted for three treatment resistance outcomes based on AD prescription data: number of unique ADs prescribed, ≥1 and ≥2 CE switches. Of the 180 phecodes significantly associated with these outcomes in the discovery cohort (n = 12,558), 71 replicated (n = 8,206). In addition to identifying known clinical factors for treatment resistance in MDD, the total unique AD prescriptions was associated with additional clinical variables including irritable bowel syndrome, gastroesophageal reflux disease, symptomatic menopause, and spondylosis. We calculated polygenic risk of specific-associated conditions and tested their association with AD outcomes revealing that genetic risk for many of these conditions is also associated with the total unique AD prescriptions. The number of unique ADs prescribed, which is easily assessed in EHRs, provides a more nuanced measure of treatment resistance, and may facilitate future research and clinical application in this area., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Mann receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene and from Columbia University from sales of the Columbia Pathways app. Dr. Weissman has received funding from NIMH and Columbia University Institute for Developmental Sciences and receives book royalties from Perseus Press and Oxford Press. None of these represent a conflict of interest. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Social support (SS) and social isolation (SI) are social determinants of health (SDOH) associated with psychiatric outcomes. In electronic health records (EHRs), individual-level SS/SI is typically documented in narrative clinical notes rather than as structured coded data. Natural language processing (NLP) algorithms can automate the otherwise labor-intensive process of extraction of such information., Materials and Methods: Psychiatric encounter notes from Mount Sinai Health System (MSHS, n = 300) and Weill Cornell Medicine (WCM, n = 225) were annotated to create a gold-standard corpus. A rule-based system (RBS) involving lexicons and a large language model (LLM) using FLAN-T5-XL were developed to identify mentions of SS and SI and their subcategories (eg, social network, instrumental support, and loneliness)., Results: For extracting SS/SI, the RBS obtained higher macroaveraged F1-scores than the LLM at both MSHS (0.89 versus 0.65) and WCM (0.85 versus 0.82). For extracting the subcategories, the RBS also outperformed the LLM at both MSHS (0.90 versus 0.62) and WCM (0.82 versus 0.81)., Discussion and Conclusion: Unexpectedly, the RBS outperformed the LLMs across all metrics. An intensive review demonstrates that this finding is due to the divergent approach taken by the RBS and LLM. The RBS was designed and refined to follow the same specific rules as the gold-standard annotations. Conversely, the LLM was more inclusive with categorization and conformed to common English-language understanding. Both approaches offer advantages, although additional replication studies are warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Despite uncertainty about the specific molecular mechanisms driving major depressive disorder (MDD), the Wnt signaling pathway stands out as a potentially influential factor in the pathogenesis of MDD. Known for its role in intercellular communication, cell proliferation, and fate, Wnt signaling has been implicated in diverse biological phenomena associated with MDD, spanning neurodevelopmental to neurodegenerative processes. In this systematic review, we summarize the functional differences in protein and gene expression of the Wnt signaling pathway, and targeted genetic association studies, to provide an integrated synthesis of available human data examining Wnt signaling in MDD. Thirty-three studies evaluating protein expression (n = 15), gene expression (n = 9), or genetic associations (n = 9) were included. Only fifteen demonstrated a consistently low overall risk of bias in selection, comparability, and exposure. We found conflicting observations of limited and distinct Wnt signaling components across diverse tissue sources. These data do not demonstrate involvement of Wnt signaling dysregulation in MDD. Given the well-established role of Wnt signaling in antidepressant response, we propose that a more targeted and functional assessment of Wnt signaling is needed to understand its role in depression pathophysiology. Future studies should include more components, assess multiple tissues concurrently, and follow a standardized approach., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alfredo B. Cuellar-Barboza reports financial support was provided by National Council on Science and Technology. Alfredo B. Cuellar-Barboza reports a relationship with Asofarma De Mexico that includes: consulting or advisory and speaking and lecture fees. Alfredo B. Cuellar-Barboza reports a relationship with Exeltis Mexico that includes: consulting or advisory and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bipolar disorder is a chronic and complex polygenic disease with high rates of comorbidity. However, the independent contribution of either diagnosis or genetic risk of bipolar disorder to the medical comorbidity profile of individuals with the disease remains unresolved. Here, we conducted a multi-step phenome-wide association study (PheWAS) of bipolar disorder using phenomes derived from the electronic health records of participants enrolled in the Mayo Clinic Biobank and the Mayo Clinic Bipolar Disorder Biobank. First, we explored the conditions associated with a diagnosis of bipolar disorder by conducting a phenotype-based PheWAS followed by LASSO-penalized regression to account for correlations within the phenome. Then, we explored the conditions associated with bipolar disorder polygenic risk score (BD-PRS) using a PRS-based PheWAS with a sequential exclusion approach to account for the possibility that diagnosis, instead of genetic risk, may drive such associations. 53,386 participants (58.7% women) with a mean age at analysis of 67.8 years (SD = 15.6) were included. A bipolar disorder diagnosis (n = 1479) was associated with higher rates of psychiatric conditions, injuries and poisonings, endocrine/metabolic and neurological conditions, viral hepatitis C, and asthma. BD-PRS was associated with psychiatric comorbidities but, in contrast, had no positive associations with general medical conditions. While our findings warrant confirmation with longitudinal-prospective studies, the limited associations between bipolar disorder genetics and medical conditions suggest that shared environmental effects or environmental consequences of diagnosis may have a greater impact on the general medical comorbidity profile of individuals with bipolar disorder than its genetic risk., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically., Methods: We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk., Results: Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies., Limitations: Substantial heterogeneity among the studies precluded performing a meta-analysis., Conclusion: Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention., Competing Interests: Declaration of competing interest ME's spouse is an employee of Sanofi. MAF has received grant support from Assurex Health and Mayo Foundation, received CME travel and honoraria from Carnot Laboratories and American Physician Institute, and has Financial Interest / Stock ownership / Royalties from Chymia LLC. All other authors report no financial relationships with commercial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder (BD) with oftentimes, an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in BD. We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association in a subset of BD-type I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic depressed cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement from response to emergent mania., (© 2024. The Author(s).)

Background: Antidepressants are among the most prescribed medications in the United States. The aim of this study was to explore the prevalence of antidepressant prescriptions and investigate sex differences and age-sex interactions in adults enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment (RIGHT) study. Materials and Methods: We conducted a retrospective analysis of the RIGHT study. Using electronic prescriptions, we assessed 12-month prevalence of antidepressant treatment. Sex differences and age-sex interactions were evaluated using multivariable logistic regression and flexible recursive smoothing splines. Results: The sample consisted of 11,087 participants (60% women). Antidepressant prescription prevalence was 22.24% (27.96% women, 13.58% men). After adjusting for age and enrollment year, women had significantly greater odds of antidepressant prescription (odds ratio = 2.29; 95% confidence interval = 2.07, 2.54). Furthermore, selective serotonin reuptake inhibitors (SSRIs) had a significant age-sex interaction. While SSRI prescriptions in men showed a sustained decrease with age, there was no such decline for women until after reaching ∼50 years of age. There are important limitations to consider in this study. Electronic prescription data were cross-sectional; information on treatment duration or adherence was not collected; this cohort is not nationally representative; and enrollment occurred over a broad period, introducing confounding by changes in temporal prescribing practices. Conclusions: Underscored by the significant interaction between age and sex on odds of SSRI prescription, our results warrant age to be incorporated as a mediator when investigating sex differences in mental illness, especially mood disorders and their treatment.

Background: The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression., Methods: Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model., Results: Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters., Conclusion: Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Although insulin resistance (IR) and cardiometabolic syndrome are prevalent in patients with bipolar disorder (BD), only a few studies have attempted to precisely assess the degree and clinical impact of IR in BD., Methods: A comprehensive search was conducted from multiple research databases through May 2022, following a pre-defined protocol (PROSPERO: CRD42022359259). We extracted neuroimaging, cognition, illness course, and treatment response findings from individuals with BD with evidence of IR compared with euglycemic BD individuals., Results: Of 1436 identified articles, 10 reports fulfilling inclusion criteria were included (n = 1183). BD patients with IR displayed worse composite verbal memory scores and worse executive function and exhibited smaller hippocampal volumes along with prefrontal neurochemical alterations compared to euglycemic BD patients. Fixed-effect meta-analysis revealed that BD patients with impaired glucose metabolism (IGM) were more likely to develop a chronic and rapid cycling course when compared with euglycemic BD patients (k = 2, OR = 2.96, 95 % CI 1.69-5.17, OR = 2.88, 95 % CI 1.59-5.21, p < 0.001, respectively), with a trend for significantly lower Global Assessment of Functioning scores (k = 5, MD = -4, 95 % CI -8.23-0.23, p = 0.06). BD patients with IGM displayed a higher rate of poor response to mood stabilizers when compared with euglycemic BD patients (k = 2, OR = 6.74, 95 % CI 1.04-43.54, p = 0.04)., Limitations: Cross-sectional design and small sample sizes of studies included limit the generalizability of results., Conclusion: IR is associated with worse clinical outcomes of BD and inadequate treatment response. Implementing strategies to prevent and treat IR in BD is crucial to improve the prognosis of such a difficult-to-treat population., Competing Interests: Conflict of interest Dr. Romo-Nava is supported in part by a National Institute of Mental Health K23 Award (K23MH120503) and a 2017 NARSAD Young Investigator Award from the Brain and Behavior Research Foundation; has a U.S. Patent and Trademark Office patent # 10,857,356; receives consultant fees from Otsuka Pharmaceutical and has received non-financial research support from Soterix Medical. Dr. Prieto served on an advisory board of Janssen and received grant support from ANID FONDECYT Regular 1181365, FONDEF ID19I10116 and Basal Funding for Scientific and Technological Center of Excellence, IMPACT, #FB210024. Dr. Nuñez is supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685. Dr. Frye is supported by a grant from the Assurex Health, Mayo Foundation and Intellectual property licensed to Chymia LLC. He received honoraria from the Carnot Laboratories and the American Physician Institute. Other authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Individuals with bipolar disorder (BD) require chronic pharmacotherapy, typically including medication switches or polypharmacy due to persisting symptoms or intolerable side effects. Here, we quantified pharmacotherapy exposure (PE) of Mayo Clinic BD Biobank participants using the number of cross-sectional (at enrollment) and lifetime BD-specific medications and medication classes, to understand the relationship between PE and markers of disease severity or treatment failure, psychiatric comorbidities, and polygenic risk scores (PRS) for six major psychiatric disorders. Being female (p < 0.05), older (p < 0.01), having history of suicide attempts (p < 0.0001), and comorbid attention-deficit/hyperactivity disorder (p < 0.05) or generalized anxiety disorder (p < 0.05) were uniformly associated with higher PE. Lifetime exposure to unique medication classes among participants with BD-I was significantly lower than for those with schizoaffective disorder (estimate = -2.1, p < 0.0001) while significantly higher than for those with BD-II (estimate = 0.5, p < 0.01). Further, higher PRS for schizophrenia (SCZ) and anxiety resulted in greater lifetime medication counts (p < 0.01), both driven by antipsychotic (p < 0.001) and anxiolytic use (p < 0.05). Our results provide initial evidence of the utility of PE as a measure of disease complexity or treatment resistance, and that PE may be predicted by higher genetic risk for SCZ and anxiety., Competing Interests: Declaration of Competing Interests SLM reports receiving personal fees for advisory boards and/or consultation from Idorsia, Levo, Novo Nordisk, Otsuka, Sunovion, and Takeda; receiving grant support from Idorsia, Janssen, Marriott Foundation, Myriad, National Institute of Mental Health, Novo Nordisk, Otsuka, and Sunovion; and receiving payments from Johnson & Johnson for being an inventor on US Patent No. 6323,236 B2. ABCB has received lecture and consulting fees from Asofarma and Exeltis. MLP has served on an advisory board for Janssen and has received grant support from ANID FONDECYT Regular 1181365, FONDEF ID19I10116 and Basal Funding for Scientific and Technological Center of Excellence, IMPACT, #FB210024. MAF reports the following conflicts of interest: grant support from Assurex Health and Mayo Foundation; CME/travel/honoraria from Carnot Laboratories, American Physician Institute; and financial interest/stock ownership/royalties in Chymia LLC., (Copyright © 2023. Published by Elsevier B.V.)

Positive interactions are sensitive to human activities, necessitating synthetic approaches to elucidate broad patterns and predict future changes if these interactions are altered or lost. General understanding of freshwater positive interactions has been far outpaced by knowledge of these important relationships in terrestrial and marine ecosystems. We conducted a global meta-analysis to evaluate the magnitude of positive interactions across freshwater habitats. In 340 studies, we found substantial positive effects, with facilitators increasing beneficiaries by, on average, 81% across all taxa and response variables. Mollusks in particular were commonly studied as both facilitators and beneficiaries. Amphibians were one group benefiting the most from positive interactions, yet few studies investigated amphibians. Invasive facilitators had stronger positive effects on beneficiaries than non-invasive facilitators. We compared positive effects between high- and low-stress conditions and found no difference in the magnitude of benefit in the subset of studies that manipulated stressors. Future areas of research include understudied facilitators and beneficiaries, the stress gradient hypothesis, patterns across space or time and the influence of declining taxa whose elimination would jeopardise fragile positive interaction networks. Freshwater positive interactions occur among a wide range of taxa, influence populations, communities and ecosystem processes and deserve further exploration., (© 2020 John Wiley & Sons Ltd.)