Genome-Wide Association Study of Treatment-Resistant Depression: Shared Biology With Metabolic Traits.

OBJECTIVE: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, no replicated genetic loci have been identified, and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype. The objective of this study was to perform a well-powered genetic study of TRD. METHODS: Using receipt of electroconvulsive therapy (ECT) as a surrogate for TRD, the authors applied standard machine learning methods to electronic health record data to derive predicted probabilities of receiving ECT. These probabilities were then applied as a quantitative trait in a genome-wide association study of 154,433 genotyped patients across four large biobanks. RESULTS: Heritability estimates ranged from 2% to 4.2%, and significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index. Two genome-wide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. CONCLUSIONS: This work provides support for the utility of estimation of disease probability for genomic investigation and provides insights into the genetic architecture and biology of TRD.

Improving risk prediction for target subpopulations: Predicting suicidal behaviors among multiple sclerosis patients.

Several recent studies have applied machine learning techniques to develop risk algorithms that predict subsequent suicidal behavior based on electronic health record data. In this study we used a retrospective cohort study design to test whether developing more tailored predictive models-within specific subpopulations of patients-would improve predictive accuracy. A retrospective cohort of 15,117 patients diagnosed with multiple sclerosis (MS), a diagnosis associated with increased risk of suicidal behavior, was used. The cohort was randomly divided into equal sized training and validation sets. Overall, suicidal behavior was identified among 191 (1.3%) of the patients with MS. A Naïve Bayes Classifier model was trained on the training set to predict future suicidal behavior. With 90% specificity, the model detected 37% of subjects who later demonstrated suicidal behavior, on average 4.6 years before the first suicide attempt. The performance of a model trained only on MS patients was better at predicting suicide in MS patients than that a model trained on a general patient sample of a similar size (AUC of 0.77 vs. 0.66). Unique risk factors for suicidal behavior among patients with MS included pain-related codes, gastroenteritis and colitis, and history of smoking. Future studies are needed to further test the value of developing population-specific risk models.

Prediction of Suicide Attempts Using Clinician Assessment, Patient Self-report, and Electronic Health Records.

Importance: Half of the people who die by suicide make a health care visit within 1 month of their death. However, clinicians lack the tools to identify these patients. Objective: To predict suicide attempts within 1 and 6 months of presentation at an emergency department (ED) for psychiatric problems. Design, Setting, and Participants: This prognostic study assessed the 1-month and 6-month risk of suicide attempts among 1818 patients presenting to an ED between February 4, 2015, and March 13, 2017, with psychiatric problems. Data analysis was performed from May 1, 2020, to November 19, 2021. Main Outcomes and Measures: Suicide attempts 1 and 6 months after presentation to the ED were defined by combining data from electronic health records (EHRs) with patient 1-month (n = 1102) and 6-month (n = 1220) follow-up surveys. Ensemble machine learning was used to develop predictive models and a risk score for suicide. Results: A total of 1818 patients participated in this study (1016 men [55.9%]; median age, 33 years [IQR, 24-46 years]; 266 Hispanic patients [14.6%]; 1221 non-Hispanic White patients [67.2%], 142 non-Hispanic Black patients [7.8%], 64 non-Hispanic Asian patients [3.5%], and 125 non-Hispanic patients of other race and ethnicity [6.9%]). A total of 137 of 1102 patients (12.9%; weighted prevalence) attempted suicide within 1 month, and a total of 268 of 1220 patients (22.0%; weighted prevalence) attempted suicide within 6 months. Clinicians' assessment alone was little better than chance at predicting suicide attempts, with externally validated area under the receiver operating characteristic curve (AUC) of 0.67 for the 1-month model and 0.60 for the 6-month model. Prediction accuracy was slightly higher for models based on EHR data (1-month model: AUC, 0.71; 6 month model: AUC, 0.65) and was best using patient self-reports (1-month model: AUC, 0.76; 6-month model: AUC, 0.77), especially when patient self-reports were combined with EHR and/or clinician data (1-month model: AUC, 0.77; and 6 month model: AUC, 0.79). A model that used only 20 patient self-report questions and an EHR-based risk score performed similarly well (1-month model: AUC, 0.77; 6 month model: AUC, 0.78). In the best 1-month model, 30.7% (positive predicted value) of the patients classified as having highest risk (top 25% of the sample) made a suicide attempt within 1 month of their ED visit, accounting for 64.8% (sensitivity) of all 1-month attempts. In the best 6-month model, 46.0% (positive predicted value) of the patients classified at highest risk made a suicide attempt within 6 months of their ED visit, accounting for 50.2% (sensitivity) of all 6-month attempts. Conclusions and Relevance: This prognostic study suggests that the ability to identify patients at high risk of suicide attempt after an ED visit for psychiatric problems improved using a combination of patient self-reports and EHR data.

Tobacco use and age are associated with different morphologic features of anterior communicating artery aneurysms.

We present a cohort of patients with anterior communicating artery (ACoA) aneurysms to investigate morphological characteristics and clinical factors associated with rupture of the aneurysms. 505 patients with ACoA aneurysms were identified at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016, with available CT angiography (CTA). Three-dimensional (3D) reconstructions were performed to evaluate aneurysmal morphologic features, including location, projection, irregularity, the presence of daughter dome, height, height/width ratio, and relationships between surrounding vessels. Patient risk factors assessed included patient age, sex, tobacco use, alcohol use, and family history of aneurysms and aneurysmal subarachnoid hemorrhage. Logistic regression was used to build a predictive ACoA score for rupture. Morphologic features associated with ruptured ACoA aneurysms were the presence of a daughter dome (OR 21.4, 95% CI 10.6-43.1), smaller neck diameter (OR 0.55, 95% CI 0.42-0.71), larger aspect ratio (OR 3.57, 95% CI 2.05-6.24), larger flow angle (OR 1.03, 95% CI 1.02-1.05), and smaller ipsilateral A2-ACoA angle (OR 0.98, 95% CI 0.97-1.00). Tobacco use was predominantly associated with morphological factors intrinsic to the aneurysm that were associated with rupture while younger age was also associated with morphologic features extrinsic to the aneurysm that were associated with rupture. The ACoA score had good predictive capacity for rupture with AUC = 0.92 using the 0.632 bootstrap cross-validation for correction of overfitting bias. Ruptured ACoA aneurysms were associated with morphological features that are simple to assess using a simple scoring system. Tobacco use and younger age were predominantly associated with intrinsic and extrinsic morphological features characteristic of rupture, respectively.

Geometric variations associated with posterior communicating artery aneurysms.

BACKGROUND: Hemodynamic stress, conditioned by the morphology of the surrounding vasculature, plays an important role in aneurysm formation. Our goal was to identify image-based location-specific parameters that are associated with posterior communicating artery (PCoA) aneurysms. METHODS: Three-dimensional morphological parameters obtained from CT angiography or digital subtraction angiography from 187 patients with unilateral PCoA aneurysms, diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016, were evaluated. In order to control for genetic and clinical risk factors, we chose the contralateral unaffected PCoA as a control group. We examined diameters and angles of the surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with small aneurysms (≤5 mm) only and an unmatched analysis of 432 PCoA aneurysms and 197 control patients without PCoA aneurysms were also performed. RESULTS: In a multivariable conditional logistic regression model we showed that smaller diameter size ratio (OR 1.45×10-5, 95% CI 1.12×10-7 to 1.88×10-3) and larger daughter-daughter angle (OR 1.04, 95% CI 1.02 to 1.07) were significantly associated with PCoA aneurysm presence after correcting for other variables. In subgroup analyses of small aneurysms (≤5 mm) and in an unmatched analysis the significance and direction of these results were preserved. CONCLUSIONS: Larger daughter-daughter angles and smaller diameter size ratio are significantly associated with the presence of PCoA aneurysms. These simple parameters can be utilized to guide the risk assessment for the formation of PCoA aneurysms in high risk patients.

Decreased Total Iron Binding Capacity May Correlate with Ruptured Intracranial Aneurysms.

Iron and its derivatives play a significant role in various physiological and biochemical pathways, and are influenced by a wide variety of inflammatory, infectious, and immunological disorders. We hypothesized that iron and its related factors play a role in intracranial aneurysm pathophysiology and investigated if serum iron values are associated with ruptured intracranial aneurysms. 4,701 patients with 6,411 intracranial aneurysms, including 1201 prospective patients, who were diagnosed at the Massachusetts General Hospital and Brigham and Women's Hospital between 1990 and 2016 were evaluated. A total of 366 patients with available serum iron, ferritin and total iron binding capacity (TIBC) values were ultimately included in the analysis. 89% of included patients had anemia. Patients were categorized into ruptured and non-ruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the association between ruptured aneurysms and iron, ferritin, and TIBC. TIBC values (10-3 g/L) within 1 year of diagnosis (OR 0.41, 95% CI 0.28-0.59) and between 1 and 3 years from diagnosis (OR 0.52, 95% CI 0.29-0.93) were significantly and inversely associated with intracranial aneurysm rupture. In contrast, serum iron and ferritin were not significant. In this case-control study, low TIBC was significantly associated with ruptured aneurysms, both in the short- and long term. However, this association may not apply to the general population as there may be a selection bias as iron studies were done in a subset of patients only.

Heroin Use Is Associated with Ruptured Saccular Aneurysms.

While cocaine use is thought to be associated with aneurysmal rupture, it is not known whether heroin use increases the risk of rupture in patients with non-mycotic saccular aneurysms. Our goal was to investigate the association between heroin and cocaine use and the rupture of saccular non-mycotic aneurysms. The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and non-ruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the association between heroin, cocaine, and methadone use and the presence of ruptured intracranial aneurysms. In multivariable analysis, current heroin use was significantly associated with rupture status (OR 3.23, 95% CI 1.33-7.83) whereas former heroin use (with and without methadone replacement therapy), and current and former cocaine use were not significantly associated with intracranial aneurysm rupture. In the present study, heroin rather than cocaine use is significantly associated with intracranial aneurysm rupture in patients with non-mycotic saccular cerebral aneurysms, emphasizing the possible role of heroin in the pathophysiology of aneurysm rupture and the importance of heroin cessation in patients harboring unruptured intracranial aneurysms.

Association of intracranial aneurysm rupture with smoking duration, intensity, and cessation.

OBJECTIVE: Although smoking is a known risk factor for intracranial aneurysm (IA) rupture, the exact relationship between IA rupture and smoking intensity and duration, as well as duration of smoking cessation, remains unknown. METHODS: In this case-control study, we analyzed 4,701 patients with 6,411 IAs diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016. We divided individuals into patients with ruptured aneurysms and controls with unruptured aneurysms. We performed univariable and multivariable logistic regression analyses to determine the association between smoking status and ruptured IAs at presentation. In a subgroup analysis among former and current smokers, we assessed the association between ruptured aneurysms and number of packs per day, duration of smoking, and duration since smoking cessation. RESULTS: In multivariable analysis, current (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.89-2.59) and former smoking status (OR 1.56, 95% CI 1.31-1.86) were associated with rupture status at presentation compared with never smokers. In a subgroup analysis among current and former smokers, years smoked (OR 1.02, 95% CI 1.01-1.03) and packs per day (OR 1.46, 95% CI 1.25-1.70) were significantly associated with ruptured aneurysms at presentation, whereas duration since cessation among former smokers was not significant (OR 1.00, 95% CI 0.99-1.02). CONCLUSIONS: Current cigarette smoking, smoking intensity, and smoking duration are significantly associated with ruptured IAs at presentation. However, the significantly increased risk persists after smoking cessation, and smoking cessation does not confer a reduced risk of aneurysmal subarachnoid hemorrhage beyond that of reducing the cumulative dose.

Improving discrimination in antepartum depression screening using the Edinburgh Postnatal Depression Scale.

BACKGROUND: Universal screening of pregnant women for postpartum depression has recently been recommended; however, optimal application of depression screening tools in stratifying risk has not been defined. The current study examines new approaches to improve the ability of the Edinburgh Postnatal Depression Scale (EPDS) to stratify risk for postpartum depression, including alternate cut points, use of a continuous measure, and incorporation of other putative risk factors. METHODS: An observational cohort study of 4939 women screened both antepartum and postpartum with a negative EPDS screen antepartum(i.e. EPDS<10). The primary outcome was a probable postpartum major depressive episode(EPDS cut-off ≥10). Area under the receiver operating characteristics curve(AUC), sensitivity, specificity, and predictive values were calculated. RESULTS: 287 women(5.8%) screened positive for postpartum depression. An antepartum EPDS cut-off<5 optimally identified women with a low risk of postpartum depression with a negative predictive value of 97.6%; however, overall discrimination was modest(AUC 0.66, 95%CI: 0.64-0.69); sensitivity was 78.7%, and specificity was 53.8%, and the positive predictive value was low at 9.5%. The negative predictive values were similar(>95%) at all antepartum EPDS cut-off values from 4 to 8. Discrimination was improved(AUC ranging from 0.70 to 0.73) when the antepartum EPDS was combined with a prior history of major depressive disorder before pregnancy. LIMITATIONS: An inability to assess EPDS subscales and a relatively low prevalence of depression in this cohort. CONCLUSIONS: Though an antepartum EPDS cut-off score <5 yielded the greatest discrimination identifying women at low risk for postpartum depression, the negative predictive value was insufficient to substitute for postpartum screening.

Association of Antenatal Depression Symptoms and Antidepressant Treatment With Preterm Birth.

OBJECTIVE: To evaluate the association of antenatal depression symptoms with preterm birth and small for gestational age (SGA). METHODS: This was an observational cohort study conducted among women who completed Edinburgh Postnatal Depression Scale screening and delivered at 20 weeks of gestation or greater. The primary outcomes were preterm birth and an SGA neonate at birth (less than 10th percentile for gestational age); the primary predictor was an Edinburgh Postnatal Depression Scale antepartum score of 10 or greater, indicating symptoms of depression. Logistic regression models were used with and without consideration of antidepressant exposure during pregnancy. RESULTS: Among 7,267 women, 831 (11%) screened positive for depression. In multivariable analyses adjusting for maternal age, race, income, body mass index, tobacco use, lifetime diagnosis of major depression and anxiety, diabetes, hypertension, and preeclampsia, women who screened positive for depression experienced an increased risk of preterm birth (less than 37 weeks of gestation) (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.04-1.55) and very preterm birth (less than 32 weeks of gestation) (adjusted OR 1.82, 95% CI 1.09-3.02) as well as of having an SGA neonate (adjusted OR 1.28, 95% CI 1.04-1.58). In secondary analyses, among women who were treated with an antidepressant during pregnancy (19% of those who screened positive and 5% of those who screened negative), depressive symptoms were not associated with a significantly increased risk of preterm and very preterm birth or an SGA neonate. CONCLUSIONS: In a large cohort of women screened for depression antepartum, those with depressive symptoms had an increased likelihood of preterm and very preterm delivery as well having an SGA neonate. Such risk was not apparent among women who were treated with an antidepressant medication.

Stratifying Risk for Renal Insufficiency Among Lithium-Treated Patients: An Electronic Health Record Study.

Although lithium preparations remain first-line treatment for bipolar disorder, risk for development of renal insufficiency may discourage their use. Estimating such risk could allow more informed decisions and facilitate development of prevention strategies. We utilized electronic health records from a large New England health-care system between 2006 and 2013 to identify patients aged 18 years or older with a lithium prescription. Renal insufficiency was identified using the presence of renal failure by ICD9 code or laboratory-confirmed glomerular filtration rate below 60 ml/min. Logistic regression was used to build a predictive model in a random two-thirds of the cohort, which was tested in the remaining one-third. Risks associated with aspects of pharmacotherapy were also examined in the full cohort. We identified 1445 adult lithium-treated patients with renal insufficiency, matched by risk set sampling 1 : 3 with 4306 lithium-exposed patients without renal insufficiency. In regression models, features associated with risk included older age, female sex, history of smoking, history of hypertension, overall burden of medical comorbidity, and diagnosis of schizophrenia or schizoaffective disorder (p<0.01 for all contrasts). The model yielded an area under the ROC curve exceeding 0.81 in an independent testing set, with 74% of renal insufficiency cases among the top two risk quintiles. Use of lithium more than once daily, lithium levels greater than 0.6 mEq/l, and use of first-generation antipsychotics were independently associated with risk. These results suggest the possibility of stratifying risk for renal failure among lithium-treated patients. Once-daily lithium dosing and maintaining lower lithium levels where possible may represent strategies for reducing risk.

An electronic health records study of long-term weight gain following antidepressant use.

IMPORTANCE: Short-term studies suggest antidepressants are associated with modest weight gain but little is known about longer-term effects and differences between individual medications in general clinical populations. OBJECTIVE: To estimate weight gain associated with specific antidepressants over the 12 months following initial prescription in a large and diverse clinical population. DESIGN, SETTING, AND PARTICIPANTS: We identified 22,610 adult patients who began receiving a medication of interest with available weight data in a large New England health care system, including 2 academic medical centers and affiliated outpatient primary and specialty care clinics. We used electronic health records to extract prescribing data and recorded weights for any patient with an index antidepressant prescription including amitriptyline hydrochloride, bupropion hydrochloride, citalopram hydrobromide, duloxetine hydrochloride, escitalopram oxalate, fluoxetine hydrochloride, mirtazapine, nortriptyline hydrochloride, paroxetine hydrochloride, venlafaxine hydrochloride, and sertraline hydrochloride. As measures of assay sensitivity, additional index prescriptions examined included the antiasthma medication albuterol sulfate and the antiobesity medications orlistat, phentermine hydrochloride, and sibutramine hydrochloride. Mixed-effects models were used to estimate rate of weight change over 12 months in comparison with the reference antidepressant, citalopram. MAIN OUTCOME AND MEASURE: Clinician-recorded weight at 3-month intervals up to 12 months. RESULTS: Compared with citalopram, in models adjusted for sociodemographic and clinical features, significantly decreased rate of weight gain was observed among individuals treated with bupropion (ß [SE]: -0.063 [0.027]; P = .02), amitriptyline (ß [SE]: -0.081 [0.025]; P = .001), and nortriptyline (ß [SE]: -0.147 [0.034]; P < .001). As anticipated, differences were less pronounced among individuals discontinuing treatment prior to 12 months. CONCLUSIONS AND RELEVANCE: Antidepressants differ modestly in their propensity to contribute to weight gain. Short-term investigations may be insufficient to characterize and differentiate this risk.

Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants.

OBJECTIVE: To examine the association between exposure to newer antidepressants and risk of gastrointestinal (GI) and other bleeding complications among individuals with major depressive disorder (MDD). DESIGN: This study uses an incident user cohort design to compare associations between incidence of vascular/bleeding events and the relative affinity (low, moderate or high) of the antidepressant for the serotonin transporter during an exposure risk period for each patient. SETTING: New England healthcare system electronic medical record database. PARTICIPANTS: 36 389 individuals with a diagnosis of MDD and monotherapy with a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor or other new-generation antidepressant were identified from among 3.1 million patients in a New England healthcare system. PRIMARY AND SECONDARY OUTCOME MEASURES: Rates of bleeding or other vascular complications, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures. RESULTS: 601 GI bleeds were observed in the 21 462 subjects in the high-affinity group versus 333 among the 14 927 subjects in the lower affinity group (adjusted RR: 1.17, 95% CI 1.02 to 1.34). Similarly, 776 strokes were observed in the high-affinity group versus 434 in the lower affinity treatment group (adjusted RR: 1.18, 95% CI 1.06 to 1.32). No significant association with risk for a priori negative control outcomes, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures, was identified. CONCLUSIONS: Use of antidepressants with high affinity for the serotonin transporter may confer modestly elevated risk for GI and other bleeding complications. While multiple methodologic limitations must be considered, these results suggest that antidepressants with lower serotonin receptor affinity may be preferred in patients at greater risk for such complications.

Effect of weight loss after weight loss surgery on plasma N-terminal pro-B-type natriuretic peptide levels.

Natriuretic peptides have multiple beneficial cardiovascular effects. Previous cross-sectional studies have indicated that obese subjects have lower natriuretic peptide concentrations than those of normal weight. It is not known whether this relative natriuretic peptide deficiency is reversible with weight loss. We studied 132 obese subjects undergoing weight loss surgery with serial measurement of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations at preoperative, early (1 to 2 months), and late postoperative (6 months) points. In addition, 20 subjects also underwent echocardiography at baseline and 6 months after surgery. Significant weight loss was observed after surgery (median body mass index 45.1, 41.0, and 32.9 kg/m(2) for the 3 corresponding points, analysis of variance p <0.001). The median NT-proBNP levels increased substantially (31.6, 66.9, and 84.9 pg/ml; p <0.001). The average intrasubject increase in NT-proBNP at the 2 postoperative points was 3.4 and 5.0 times the preoperative level (p <0.001 for both points vs preoperatively). In the multivariate regression models adjusted for clinical characteristics and insulin resistance, the strongest predictor of the change in NT-proBNP level 6 months after weight loss surgery was the change in weight (p = 0.03). Echocardiography showed a mean intrasubject reduction in left ventricular mass index of 18% (p <0.001) and mild improvements in diastolic function, with no change in ejection fraction. In conclusion, we have demonstrated that weight loss is associated with early and sustained increases in NT-proBNP concentrations, despite evidence of preserved systolic and improved diastolic function. These findings suggest a direct, reversible relation between obesity and reduced natriuretic peptide levels.