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Key Points: Question: To what extent do differences in clinician setting explain variability in major depression treatments and outcomes? Findings: In this cohort study derived from electronic health record data, antidepressant prescribing patterns and outcomes varied significantly between prescriber groups. Clinician clusters were significantly associated with clinical outcomes. Meaning: Studies of antidepressant prescribing in real-world settings, and efforts at risk stratification or personalization of care, should include information on treatment setting and other clinician-level factors alongside individual patient characteristics. Importance: While abundant work has examined patient-level differences in antidepressant treatment outcomes, little is known about the extent of clinician-level differences. Understanding these differences may be important in the development of risk models, precision treatment strategies, and more efficient systems of care. Objective: To characterize differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. Design, Setting, and Participants: This was a longitudinal cohort study using data derived from electronic health records at 2 large academic medical centers and 6 community hospitals, and their affiliated outpatient networks, in eastern Massachusetts. Participants were deidentified clinicians who billed at least 10 International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses of major depressive disorder per year between 2008 and 2022. Data analysis occurred between September 2023 and January 2024. Main Outcomes and Measures: Heterogeneity of prescribing, defined as the number of distinct antidepressants accounting for 75% of prescriptions by a given clinician; proportion of patients who did not return for follow-up after an index prescription; and proportion of patients receiving stable, ongoing antidepressant treatment. Results: Among 11 934 clinicians treating major depressive disorder, unsupervised learning identified 10 distinct clusters on the basis of ICD codes, corresponding to outpatient psychiatry as well as oncology, obstetrics, and primary care. Between these clusters, substantial variability was identified in the proportion of selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and tricyclic antidepressants prescribed, as well as in the number of distinct antidepressants prescribed. Variability was also detected between clinician clusters in loss to follow-up and achievement of stable treatment, with the former ranging from 27% to 69% and the latter from 22% to 42%. Clinician clusters were significantly associated with treatment outcomes. Conclusions and Relevance: Groups of clinicians treating individuals diagnosed with major depressive disorder exhibit marked differences in prescribing patterns as well as longitudinal patient outcomes defined by electronic health records. Incorporating these group identifiers yielded similar prediction to more complex models incorporating individual codes, suggesting the importance of considering treatment context in efforts at risk stratification. This cohort study investigates differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. [ABSTRACT FROM AUTHOR]

Objective Maternal risk stratification systems are increasingly employed in predicting and preventing obstetric complications. These systems focus primarily on maternal morbidity, and few tools exist to stratify neonatal risk. We sought to determine if a maternal risk stratification score was associated with neonatal morbidity. Study Design Retrospective cohort study of patients with liveborn infants born at ≥24 weeks at four hospitals in one health system between January 1, 2020, and December 31, 2020. The Expanded Obstetric Comorbidity Score (EOCS) is used as the maternal risk score. The primary neonatal outcome was 5-minute Apgar <7. Logistic regression models determined associations between EOCS and neonatal morbidity. Secondary analyses were performed, including stratifying outcomes by gestational age and limiting analysis to "low-risk" term singletons. Model discrimination assessed using the area under the receiver operating characteristic curves (AUC) and calibration via calibration plots. Results A total of 14,497 maternal–neonatal pairs were included; 236 (1.6%) had 5-minute Apgar <7; EOCS was higher in 5-minute Apgar <7 group (median 41 vs. 11, p < 0.001). AUC for EOCS in predicting Apgar <7 was 0.72 (95% Confidence Interval (CI) 0.68, 0.75), demonstrating relatively good discrimination. Calibration plot revealed that those in the highest EOCS decile had higher risk of neonatal morbidity (7.6 vs. 1.7%, p < 0.001). When stratified by gestational age, discrimination weakened with advancing gestational age: AUC 0.70 for <28 weeks, 0.63 for 28 to 31 weeks, 0.64 for 32 to 36 weeks, and 0.61 for ≥37 weeks. When limited to term low-risk singletons, EOCS had lower discrimination for predicting neonatal morbidity and was not well calibrated. Conclusion A maternal morbidity risk stratification system does not perform well in most patients giving birth, at low risk for neonatal complications. The findings suggest that the association between EOCS and 5-minute Apgar <7 likely reflects a relationship with prematurity. This study cautions against intentional or unintentional extrapolation of maternal morbidity risk for neonatal risk, especially for term deliveries. Key Points EOCS had moderate discrimination for Apgar <7. Predictive performance declined when limited to low-risk term singletons. Relationship between EOCS and Apgar <7 was likely driven by prematurity. [ABSTRACT FROM AUTHOR]

Objective: Amphetamine prescribing has increased in the United States in recent years. Previous research identified an increased risk of incident psychosis with prescription amphetamines. The purpose of this study was to examine the impact of dose levels of prescription amphetamines on the risk of this rare but serious adverse outcome. Methods: A case-control study using electronic health records was conducted to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients ages 16–35 hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and/or anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use. Results: Among 1,374 case subjects and 2,748 control subjects, the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio=2.68, 95% CI=1.90–3.77). A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania. Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio=0.91, 95% CI=0.54–1.55). Conclusions: Although use of hospitalized control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania. [ABSTRACT FROM AUTHOR]

Background: The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. Methods and results: We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls. Conclusion: These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to determine whether in utero exposure to SARS‐CoV‐2 is associated with increased risk for a cardiometabolic diagnosis by 18 months of age. Methods: This retrospective electronic health record (EHR)‐based cohort study included the live‐born offspring of all individuals who delivered during the COVID‐19 pandemic (April 1, 2020–December 31, 2021) at eight hospitals in Massachusetts. Offspring exposure was defined as a positive maternal SARS‐CoV‐2 polymerase chain reaction test during pregnancy. The primary outcome was presence of an ICD‐10 code for a cardiometabolic disorder in offspring EHR by 18 months. Weight‐, length‐, and BMI‐for‐age z scores were calculated and compared at 6‐month intervals from birth to 18 months. Results: A total of 29,510 offspring (1599 exposed and 27,911 unexposed) were included. By 18 months, 6.7% of exposed and 4.4% of unexposed offspring had received a cardiometabolic diagnosis (crude odds ratio [OR] 1.47 [95% CI: 1.10 to 1.94], p = 0.007; adjusted OR 1.38 [1.06 to 1.77], p = 0.01). Exposed offspring had a significantly greater mean BMI‐for‐age z score versus unexposed offspring at 6 months (z score difference 0.19 [95% CI: 0.10 to 0.29], p < 0.001; adjusted difference 0.04 [−0.06 to 0.13], p = 0.4). Conclusions: Exposure to maternal SARS‐CoV‐2 infection was associated with an increased risk of receiving a cardiometabolic diagnosis by 18 months preceded by greater BMI‐for‐age at 6 months. [ABSTRACT FROM AUTHOR]

Depression can affect individuals' attitudes by enhancing cognitive biases and altering perceptions of control. We investigate the relationship between depressive symptoms and Americans' attitudes regarding domestic extremist violence. We develop a theory that suggests the association between depression and support for political violence depends on conspiracy beliefs, participatory inclinations, and their combination. We test our theory using a two‐wave national survey panel from November 2020 and January 2021. We find that among those who hold conspiracy beliefs and/or have participatory inclinations, depression is positively associated with support for election violence and the January 6 Capitol riots. The participatory inclination dynamic is particularly strong for men. Our findings reveal how the intersection of two concerning features of American society—poor mental health and conspiratorial beliefs—strongly relate to another feature: support for political violence. The results also make clear that interventions aimed at addressing depression can potentially have substantial political consequences. [ABSTRACT FROM AUTHOR]

Background: Longitudinal studies show that lower cognitive performance in adolescence and early adulthood is associated with higher risk of suicide death throughout adulthood. However, it is unclear whether this cognitive vulnerability originates earlier in childhood since studies conducted in children are scarce and have inconsistent results. Methods: Vital status of 49,853 individuals born between 1959 and 1966 to participants in the Collaborative Perinatal Project cohort was determined by a probabilistic linkage to the National Death Index, covering all US deaths occurring from 1979 through 2016. Cox proportional hazard models were used to examine associations of general, verbal, and non‐verbal intelligence at ages 4 and 7, and academic skills at age 7 with suicide death coded according to ICD‐9/10 criteria, while accounting for sociodemographic and pregnancy factors previously associated with suicide in this sample. Results: By the end of 2016, 288 cohort members had died by suicide. Cognitive performance at 7 years on tests with verbal components was associated with suicide risk (average vs. high verbal intelligence, HR = 1.97, 95% CI 1.05–3.71; low vs. high spelling skills, HR = 2.02, 95% CI 1.16–3.51; low vs. high reading skills, HR = 2.01, 95% CI 1.27–3.17). Associations were still evident, especially for verbal intelligence and reading skills, but hazard ratios were attenuated after adjusting for prenatal and sociodemographic factors at birth (verbal intelligence, HR = 1.97, 95% CI 1.03–3.78; spelling, HR = 1.61, 95% CI 0.90–2.88; reading, HR = 1.67, 95% CI 1.02–2.72). Conclusions: Childhood neurocognitive performance is associated with vulnerability to suicide mortality through middle‐adulthood, suggesting that there might be a cognitive diathesis for suicide originating in early childhood. Future studies should examine how multiple domains of childhood cognitive performance contribute to vulnerability to suicide risk, including by increasing risk for social and environmental factors that are associated not only with suicide but also with many types of psychiatric disorders. [ABSTRACT FROM AUTHOR]

The author reflects on the launch of JAMA+ AI, which aims to centralize and enhance resources on artificial intelligence (AI) in healthcare for clinicians, researchers, and technologists. Topics include the platform's goals to facilitate understanding and collaboration on AI's role in healthcare, the need to address challenges like bias and health disparities in AI applications, and the importance of educating future clinicians on integrating AI into practice.

Politics and science have become increasingly intertwined. Salient scientific issues, such as climate change, evolution, and stem-cell research, become politicized, pitting partisans against one another. This creates a challenge of how to effectively communicate on such issues. Recent work emphasizes the need for tailored messages to specific groups. Here, we focus on whether generalized messages also can matter. We do so in the context of a highly polarized issue: extreme COVID-19 vaccine resistance. The results show that science-based, moral frame, and social norm messages move behavioral intentions, and do so by the same amount across the population (that is, homogeneous effects). Counter to common portrayals, the politicization of science does not preclude using broad messages that resonate with the entire population. [ABSTRACT FROM AUTHOR]

Conspiratorial beliefs can endanger individuals and societies by increasing the likelihood of harmful behaviors such as the flouting of public health guidelines. While scholars have identified various correlates of conspiracy beliefs, one factor that has received scant attention is depressive symptoms. We use three large surveys to explore the connection between depression and conspiracy beliefs. We find a consistent association, with the extent of the relationship depending on individual and situational factors. Interestingly, those from relatively advantaged demographic groups (i.e., White, male, high income, educated) exhibit a stronger relationship between depression and conspiracy beliefs than those not from such groups. Furthermore, situational variables that ostensibly increase stress—such as having COVID‐19 or parenting during COVID‐19—exacerbate the relationship while those that seem to decrease stress, such as social support, vitiate it. The results provide insight about the development of targeted interventions and accentuate the need for theorizing about the mechanisms that lead depression to correlate with conspiracy beliefs. [ABSTRACT FROM AUTHOR]

Importance: Suicide rates have been increasing among youth in the US. While the heritability of suicide risk is well established, there is limited understanding of how genetic risk is associated with suicidal thoughts and behaviors in young children.Objective: To examine whether genetic susceptibility to suicide attempts (SAs) is associated with suicidal thoughts and behaviors in children.Design, Setting, and Participants: This case-control study examined data from the Adolescent Brain Cognitive Development (ABCD) study, a population-based longitudinal study of 11 878 US children enrolled at age 9 and 10 years from September 2016 to November 2018. Youth reports of suicidal ideation (SI) and SAs were obtained from the Kiddie Schedule for Affective Disorder and Schizophrenia at baseline and 2 subsequent years. After conservative quality control of genotype data, this analysis focused on 4344 unrelated individuals of European ancestry. Data analysis was conducted from November 2020 to February 2022.Main Outcomes and Measures: Children's lifetime experiences of SI and SAs were assessed each year from ages 9 to 10 years to ages 11 to 12 years. Polygenic risk scores (PRSs) for SAs were calculated for ABCD study participants based on the largest genome-wide association study of SA cases and controls of European ancestry (total sample n = 518 612).Results: Of 4344 children of European ancestry (2045 [47.08%] female; mean [SD] age, 9.93 [0.62] years), significant associations were found between children's SA PRSs and their lifetime SAs with the most robust association in the follow-up year 2 (odds ratio, 1.43 [95% CI, 1.18-1.75]; corrected P = 1.85 × 10-3; Nagelkerke pseudo R2 = 1.51%). These associations remained significant after accounting for children's sociodemographic backgrounds, psychopathology symptoms, parental histories of suicide and mental health, and PRSs for major depression and attention-deficit/hyperactivity disorder (likelihood ratio test P < .05). Children's depressive mood and aggressive behavior were the most significant partial mediators of SA genetic risk on SAs (mediation analysis P < 1 × 10-16). Children's behavioral problems, such as attention problems, rule-breaking behavior, and social problems, also partially mediated the association of SA PRSs with SAs (mediation analysis false discover rate < 0.05).Conclusions and Relevance: This study's findings indicate that there may be genetic factors associated with SA risk across the life span and suggest behaviors and conditions through which the risk could be mediated in childhood. Further research is warranted to examine whether incorporating genetic data could improve the identification of children at risk for suicide. [ABSTRACT FROM AUTHOR]

Activity-induced neurogenesis has been extensively studied in rodents but the lack of ante mortem accessibility to human brain at the cellular and molecular levels limits studies of the process in humans. Using cerebral spheroids derived from human induced pluripotent stem cells (iPSCs), we investigated the effects of 4-aminopyridine (4AP) on neuronal activity and associated neurogenesis. Our studies demonstrate that 4AP increases neuronal activity in 3-month-old cerebral spheroids while increasing numbers of new neurons and decreasing the population of new glial cells. We also observed a significant decrease in the expression of miR-135a, which has previously been shown to be decreased in exercise-induced neurogenesis. Predicted targets of miR-135a include key participants in the SMAD2/3 and BDNF pathways. Together, our results suggest that iPSC-derived cerebral spheroids are an attractive model to study several aspects of activity-induced neurogenesis. [ABSTRACT FROM AUTHOR]

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide insights into fetal brain microglial programs and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders. [Display omitted] • Microglia and fetal placental macrophages (Hofbauer cells) share a common yolk-sac origin • scRNA-seq reveals shared transcriptional programs in these two cell types in maternal obesity • There are sex differences in the impact of maternal obesity on Hofbauer cells and microglia • Hofbauer cells may serve as biomarkers of the impact of maternal exposures on microglia Batorsky et al. employ lineage tracing to demonstrate that fetal microglia and Hofbauer cells both originate in the yolk sac and exhibit shared transcriptional programs in the setting of maternal obesity. Hofbauer cells may serve as biomarkers for fetal microglia, providing insight into the impact of maternal exposures on neurodevelopment. [ABSTRACT FROM AUTHOR]

Introduction: The major stressors associated with the COVID‐19 pandemic provide an opportunity to understand the extent to which protective factors against depression may exhibit gender‐specificity. Method: This study examined responses from multiple waves of a 50 states non‐probability internet survey conducted between May 2020 and January 2021. Participants completed the PHQ‐9 as a measure of depression, as well as items characterizing social supports. We used logistic regression models with population reweighting to examine association between absence of even mild depressive symptoms and sociodemographic features and social supports, with interaction terms and stratification used to investigate sex‐specificity. Results: Among 73,917 survey respondents, 31,199 (42.2%) reported absence of mild or greater depression—11,011/23,682 males (46.5%) and 20,188/50,235 (40.2%) females. In a regression model, features associated with greater likelihood of depression‐resistance included at least weekly attendance of religious services (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04–1.16) and greater trust in others (OR: 1.04 for a 2‐unit increase, 95% CI: 1.02–1.06), along with level of social support measured as number of social ties available who could provide care (OR: 1.05, 95% CI: 1.02–1.07), talk to them (OR: 1.10, 95% CI: 1.07–1.12), and help with employment (OR: 1.06, 95% CI: 1.04–1.08). The first two features showed significant interaction with gender (p <.0001), with markedly greater protective effects among women. Conclusion: Aspects of social support are associated with diminished risk of major depressive symptoms, with greater effects of religious service attendance and trust in others observed among women than men. [ABSTRACT FROM AUTHOR]

Concerns about misperceptions among the public are rampant. Yet, little work explores the correlates of misperceptions in varying contexts – that is, how do factors such as group affiliations, media exposure, and lived experiences correlate with the number of misperceptions people hold? We address these questions by investigating misperceptions about COVID-19, focusing on the role of racial/ethnic, religious, and partisan groups. Using a large survey, we find the number of correct beliefs held by individuals far dwarfs the number of misperceptions. When it comes to misperceptions, we find that minorities, those with high levels of religiosity, and those with strong partisan identities – across parties – hold a substantially greater number of misperceptions than those with contrasting group affiliations. Moreover, we show other variables (e.g., social media usage, number of COVID-19 cases in one's county) do not have such strong relationships with misperceptions, and the group-level results do not reflect acquiescence to believing any information regardless of its truth value. Our results accentuate the importance of studying group-level misperceptions on other scientific and political issues and developing targeted interventions for these groups. [ABSTRACT FROM AUTHOR]

Objective: The authors sought to characterize the association between prior mood disorder diagnosis and hospital outcomes among individuals admitted with COVID-19 to six Eastern Massachusetts hospitals.Methods: A retrospective cohort was drawn from the electronic health records of two academic medical centers and four community hospitals between February 15 and May 24, 2020. Associations between history of mood disorder and in-hospital mortality and hospital discharge home were examined using regression models among any hospitalized patients with positive tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Results: Among 2,988 admitted individuals, 717 (24.0%) had a prior mood disorder diagnosis. In Cox regression models adjusted for age, sex, and hospital site, presence of a mood disorder prior to admission was associated with greater in-hospital mortality risk beyond hospital day 12 (crude hazard ratio=2.156, 95% CI=1.540, 3.020; fully adjusted hazard ratio=1.540, 95% CI=1.054, 2.250). A mood disorder diagnosis was also associated with greater likelihood of discharge to a skilled nursing facility or other rehabilitation facility rather than home (crude odds ratio=2.035, 95% CI=1.661, 2.493; fully adjusted odds ratio=1.504, 95% CI=1.132, 1.999).Conclusions: Hospitalized individuals with a history of mood disorder may be at risk for greater COVID-19 morbidity and mortality and are at increased risk of need for postacute care. Further studies should investigate the mechanism by which these disorders may confer elevated risk. [ABSTRACT FROM AUTHOR]

Gene expression data can offer deep, physiological insights beyond the static coding of the genome alone. We believe that realizing this potential requires specialized, high-capacity machine learning methods capable of using underlying biological structure, but the development of such models is hampered by the lack of published benchmark tasks and well characterized baselines. In this work, we establish such benchmarks and baselines by profiling many classifiers against biologically motivated tasks on two curated views of a large, public gene expression dataset (the LINCS corpus) and one privately produced dataset. We provide these two curated views of the public LINCS dataset and our benchmark tasks to enable direct comparisons to future methodological work and help spur deep learning method development on this modality. In addition to profiling a battery of traditional classifiers, including linear models, random forests, decision trees, K nearest neighbor (KNN) classifiers, and feed-forward artificial neural networks (FF-ANNs), we also test a method novel to this data modality: graph convolugtional neural networks (GCNNs), which allow us to incorporate prior biological domain knowledge. We find that GCNNs can be highly performant, with large datasets, whereas FF-ANNs consistently perform well. Non-neural classifiers are dominated by linear models and KNN classifiers. [ABSTRACT FROM AUTHOR]

Background: Investigation of personality traits and pathology in large, generalizable clinical cohorts has been hindered by inconsistent assessment and failure to consider a range of personality disorders (PDs) simultaneously. Methods: We applied natural language processing (NLP) of electronic health record notes to characterize a psychiatric inpatient cohort. A set of terms reflecting personality trait domains were derived, expanded, and then refined based on expert consensus. Latent Dirichlet allocation was used to score notes to estimate the extent to which any given note reflected PD topics. Regression models were used to examine the relationship of these estimates with sociodemographic features and length of stay. Results: Among 3623 patients with 4702 admissions, being male, non-white, having a low burden of medical comorbidity, being admitted through the emergency department, and having public insurance were independently associated with greater levels of disinhibition, detachment, and psychoticism. Being female, white, and having private insurance were independently associated with greater levels of negative affectivity. The presence of disinhibition, psychoticism, and negative affectivity were each significantly associated with a longer stay, while detachment was associated with a shorter stay. Conclusions: Personality features can be systematically and scalably measured using NLP in the inpatient setting, and some of these features associate with length of stay. Developing treatment strategies for patients scoring high in certain personality dimensions may facilitate more efficient, targeted interventions, and may help reduce the impact of personality features on mental health service utilization. [ABSTRACT FROM AUTHOR]

Background: Cohort and cost-effectiveness studies suggest that measuring variation in genes that influence metabolism of common drugs could improve antidepressant treatment outcomes. Prior randomized trials have yielded inconsistent results.Method: Multicenter randomized double-blind (subject and rater), controlled trial of pharmacogenomic testing among outpatients with nonpsychotic major depressive disorder. Study participants (n = 304) were randomized 1:1 to assay-guided treatment (AGT; N = 151) or treatment-as-usual (TAU; N = 153). Participants and raters were blinded to study arm; unblinded clinicians received results of a pharmacogenomic test and adjusted treatment in light of the test report. Primary outcome was change over 8 weeks in Hamilton Depression Rating Scale (SIGH-D-17).Results: For the primary comparison of interest, change in SIGH-D-17, no significant difference was detected between AGT and TAU at Week 8 (p = .53). Rates of study completion also did not differ between the arms (AGT 92.7%, TAU 92.2% (χ2  = 0.03, df = 1, p = .86). Exploratory analyses suggested significantly fewer individuals experienced worsening of depressive symptoms following AGT, and that treatment concordant with assay results was associated with greater likelihood of remission.Conclusion: Pharmacogenomic testing using a panel of pharmacokinetic and pharmacodynamic variants was not associated with significant improvement in the primary efficacy outcome when providers were unconstrained by the assay results. Further investigation is needed to understand the discordance with cost-effectiveness results and among randomized trials. [ABSTRACT FROM AUTHOR]

Rationale: ADHD is a prevalent and morbid neurobiological disorder affecting up to 5% of adults. While stimulants have been documented to be safe and effective in adults with ADHD, uncertainties remain about adherence to these treatments. Objectives: The main aim of this article was to evaluate contemporaneous rates and correlates of adherence to stimulants in adults with ADHD using data from electronic medical records from a large healthcare organization focusing on timely renewal of an initial prescription. Methods: Subjects were patients 18 to 44 years of age who had been prescribed a stimulant between January 1, 2015, and December 31, 2016. Prescription and sociodemographic data were extracted from the Partners HealthCare Research Patient Data Registry (RPDR). Our outcome metric was renewal of the index stimulant prescription defined as the first prescription recorded in the electronic record for the period under investigation. Results: We identified 2689 patients with an index prescription for a stimulant medication. Results showed that only 42% of patients renewed their prescriptions in a timely enough fashion to be considered consistently medicated. Conclusions: Results indicate that adults with ADHD have a low rate of renewal of their initial stimulant prescription indicating poor patient engagement in their treatment for ADHD. [ABSTRACT FROM AUTHOR]

With brief psychiatric hospitalizations, the extent to which symptoms change is rarely characterized. We sought to understand symptomatic changes across Research Domain Criteria (RDoC) dimensions, and the extent to which such improvement might be associated with risk for readmission. We identified 3,634 individuals with 4,713 hospital admissions to the psychiatric inpatient unit of a large academic medical center between 2010 and 2015. We applied a natural language processing tool to extract estimates of the five RDoC domains to the admission note and discharge summary and calculated the change in each domain. We examined the extent to which symptom domains changed during admission, and their relationship to baseline clinical and sociodemographic features, using linear regression. Symptomatic worsening was rare in the negative valence (0.4%) and positive valence (5.1%) domains, but more common in cognition (25.8%). Most diagnoses exhibited improvement in negative valence, which was associated with significant reduction in readmission risk. Despite generally brief hospital stays, we detected reduction across multiple symptom domains, with greatest improvement in negative symptoms, and greatest probability of worsening in cognitive symptoms. This approach should facilitate investigations of other features or interventions which may influence pace of clinical improvement. [ABSTRACT FROM AUTHOR]

Importance: Three-dimensional cerebral organoids generated from patient-derived induced pluripotent stem cells (iPSCs) may be used to interrogate cellular-molecular underpinnings of schizophrenia.Objective: To determine transcriptomic profiles and functional characteristics of cerebral organoids from patients with schizophrenia using gene expression studies, complemented with investigations of mitochondrial function through measurement of real-time oxygen consumption rate, and functional studies of neuronal firing with microelectrode arrays.Design, Setting, and Participants: This case-control study was conducted at Massachusetts General Hospital between 2017 and 2019. Transcriptomic profiling of iPSC-derived cerebral organoids from 8 patients with schizophrenia and 8 healthy control individuals was undertaken to identify cellular pathways that are aberrant in schizophrenia. Induced pluripotent stem cells and cerebral organoids were generated from patients who had been diagnosed as having schizophrenia and from heathy control individuals.Main Outcomes and Measures: Transcriptomic analysis of iPSC-derived cerebral organoids from patients with schizophrenia show differences in expression of genes involved in synaptic biology and neurodevelopment and are enriched for genes implicated in schizophrenia genome-wide association studies (GWAS).Results: The study included iPSC lines generated from 11 male and 5 female white participants, with a mean age of 38.8 years. RNA sequencing data from iPSC-derived cerebral organoids in schizophrenia showed differential expression of genes involved in synapses, in nervous system development, and in antigen processing. The differentially expressed genes were enriched for genes implicated in schizophrenia, with 23% of GWAS genes showing differential expression in schizophrenia and control organoids: 10 GWAS genes were upregulated in schizophrenia organoids while 15 GWAS genes were downregulated. Analysis of the gene expression profiles suggested dysregulation of genes involved in mitochondrial function and those involved in modulation of excitatory and inhibitory pathways. Studies of mitochondrial respiration showed lower basal consumption rate, adenosine triphosphate production, proton leak, and nonmitochondrial oxygen consumption in schizophrenia cerebral organoids, without any differences in the extracellular acidification rate. Microelectrode array studies of cerebral organoids showed no differences in baseline electrical activity in schizophrenia but revealed a diminished response to stimulation and depolarization.Conclusions and Relevance: Investigations of patient-derived cerebral organoids in schizophrenia revealed gene expression patterns suggesting dysregulation of a number of pathways in schizophrenia, delineated differences in mitochondrial function, and showed deficits in response to stimulation and depolarization in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Recent initiatives in psychiatry emphasize the utility of characterizing psychiatric symptoms in a multidimensional manner. However, strategies for applying standard self-report scales for multiaxial assessment have not been well-studied, particularly where the aim is to support both categorical and dimensional phenotypes. Methods: We propose a method for applying natural language processing to derive dimensional measures of psychiatric symptoms from questionnaire data. We utilized nine self-report symptom measures drawn from a large cellular biobanking study that enrolled individuals with mood and psychotic disorders, as well as healthy controls. To summarize questionnaire results we used word embeddings, a technique to represent words as numeric vectors preserving semantic and syntactic meaning. A low-dimensional approximation to the embedding space was used to derive the proposed succinct summary of symptom profiles. To validate our embedding-based disease profiles, these were compared to presence or absence of axis I diagnoses derived from structured clinical interview, and to objective neurocognitive testing. Results: Unsupervised and supervised classification to distinguish presence/absence of axis I disorders using survey-level embeddings remained discriminative, with area under the receiver operating characteristic curve up to 0.85, 95% confidence interval (CI) (0.74,0.91) using Gaussian mixture modeling, and cross-validated area under the receiver operating characteristic curve 0.91, 95% CI (0.88,0.94) using logistic regression. Derived symptom measures and estimated Research Domain Criteria scores also associated significantly with performance on neurocognitive tests. Conclusions: Our results support the potential utility of deriving dimensional phenotypic measures in psychiatric illness through the use of word embeddings, while illustrating the challenges in identifying truly orthogonal dimensions. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to evaluate rates and correlates of stimulant medication adherence in a sample of pediatric patients using data derived from electronic medical records (EMRs) from a large health care organization in a large metropolitan area. The study relied on a novel definition of medication adherence as a timely renewal of an index prescription determined using the electronically recorded issuance of a stimulant prescription in the EMR ("refill").Methods: Prescription and sociodemographic data were extracted from the Partners HealthCare Research Patient Data Registry to calculate adherence to stimulant medication treatment.Results: In the EMR, 2,206 patients with prescriptions for central nervous system stimulant medication were identified. Results showed that 46% of the index prescriptions were refilled within the timeframe necessary for the patient to be considered consistently medicated. A multivariable logistic regression model predicting medication adherence from patient demographic and treatment characteristics yielded an area-under-the-curve statistic of 0.57, indicating that these characteristics predicted adherence only modestly better than chance.Conclusions: EMR data from a large health care organization showed that 46% of pediatric patients were adherent to treatment with stimulants. Rates of medication adherence were worse among patients receiving care from a primary care provider than among those receiving care from a psychiatrist, in older patients, and in female patients and did not appear to be influenced by racial-ethnic group, economic class, stimulant type, or medication formulation (short or long acting). These findings, which show low rates of medication adherence among children and adolescents with ADHD, suggest the need for efforts to improve these rates. [ABSTRACT FROM AUTHOR]

Importance: Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia.Objective: To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 μg/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance.Design, Setting, and Participants: Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used.Interventions: Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses.Main Outcomes and Measures: Effectiveness of SNP compared with placebo in improving Positive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase.Results: Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted β = -1.04; z = -0.59; P = .57), PANSS-positive (weighted β = -0.62; z = -0.93; P = .35), or PANSS-negative (weighted β = -0.12; z = -0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified.Conclusions and Relevance: Although intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance.Trial Registration: ClinicalTrials.gov identifier: NCT02164981. [ABSTRACT FROM AUTHOR]

Background: Identification of individuals at increased risk for suicide is an important public health priority, but the extent to which considering clinical phenomenology improves prediction of longer term outcomes remains understudied. Hospital discharge provides an opportunity to stratify risk using readily available clinical records and details.Methods: We applied a validated natural language processing tool to generate estimated Research Domain Criteria (RDoC) scores for a cohort of 444,317 individuals drawn from 815,457 hospital discharges between 2005 and 2013. We used survival analysis to examine the association of this risk with suicide and accidental death, adjusted for sociodemographic features.Results: In adjusted models, symptoms in each of the five domains contributed to incremental risk (log rank P < 0.001), with greatest increase observed with positive valence. The contribution of each domain to risk was time dependent.Conclusions: RDoC symptom scores parsed from clinical documentation are associated with suicide and illustrates that multiple domains contribute to risk in a time-varying fashion. [ABSTRACT FROM AUTHOR]

Nonunion is a clinically significant complication of fracture associated with worse outcomes, including increased pain, disability, and higher healthcare costs. The risk for nonunion is likely to be complex and multifactorial, and as such, the biology underlying such risk remains poorly understood. Genetic studies represent one approach to identify implicated biology for further investigation, but to date the lack of large cohorts for study has limited such efforts. We utilized the electronic health records of two large academic medical centers in Boston to identify individuals with fracture nonunion and control individuals with fracture but no evidence of nonunion. We conducted a genomewide association study among 1760 individuals of Northern European ancestry with upper or lower extremity fracture, including 131 with nonunion, to examine whether common variants were associated with nonunion in this cohort. In all, one locus in the Calcyon (CALY) gene exceeded a genomewide threshold for statistical significance (p = 1.95e–8), with eight additional loci associated with p < 5e–7. Previously reported candidate genes were not supported by this analysis. Electronic health records should facilitate identification of common genetic variations associated with adverse orthopedic outcomes. The loci we identified in this small cohort require replication and further study to characterize mechanism of action, but represent a starting point for the investigation of genetic liability for this costly outcome. © 2018 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Background: Naturalistic and small randomized trials have suggested that pharmacogenetic testing may improve treatment outcomes in depression, but its cost-effectiveness is not known. There is growing enthusiasm for personalized medicine, relying on genetic variation as a contributor to heterogeneity of treatment effects. We sought to examine the relationship between a commercial pharmacogenetic test for psychotropic medications and 6-month cost of care and utilization in a large commercial health plan.Methods: We performed a propensity-score matched case-control analysis of longitudinal health claims data from a large US insurer. Individuals with a mood or anxiety disorder diagnosis (N = 817) who received genetic testing for pharmacokinetic and pharmacodynamic variation were matched to 2,745 individuals who did not receive such testing. Outcomes included number of outpatient visits, inpatient hospitalizations, emergency room visits, and prescriptions, as well as associated costs over 6 months.Results: On average, individuals who underwent testing experienced 40% fewer all-cause emergency room visits (mean difference 0.13 visits; P < 0.0001) and 58% fewer inpatient all-cause hospitalizations (mean difference 0.10 visits; P < 0.0001) than individuals in the control group. The two groups did not differ significantly in number of psychotropic medications prescribed or mood-disorder related hospitalizations. Overall 6-month costs were estimated to be $1,948 (SE 611) lower in the tested group.Conclusions: Pharmacogenetic testing represents a promising strategy to reduce costs and utilization among patients with mood and anxiety disorders. [ABSTRACT FROM AUTHOR]