Victor M. Castro

Detecting drug interactions from adverse-event reports: interaction between paroxetine and pravastatin increases blood glucose levels.

The lipid‐lowering agent pravastatin and the antidepressant paroxetine are among the most widely prescribed drugs in the world. Unexpected interactions between them could have important public health implications. We mined the US Food and Drug Administrations (FDAs) Adverse Event Reporting System (AERS) for side‐effect profiles involving glucose homeostasis and found a surprisingly strong signal for comedication with pravastatin and paroxetine. We retrospectively evaluated changes in blood glucose in 104 patients with diabetes and 135 without diabetes who had received comedication with these two drugs, using data in electronic medical record (EMR) systems of three geographically distinct sites. We assessed the mean random blood glucose levels before and after treatment with the drugs. We found that pravastatin and paroxetine, when administered together, had a synergistic effect on blood glucose. The average increase was 19 mg/dl (1.0 mmol/l) overall, and in those with diabetes it was 48 mg/dl (2.7 mmol/l). In contrast, neither drug administered singly was associated with such changes in glucose levels. An increase in glucose levels is not a general effect of combined therapy with selective serotonin reuptake inhibitors (SSRIs) and statins.

A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort

To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four tissues from approximately 1000 patients undergoing Roux-en-Y gastric bypass (RYGB) and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than 100,000 gene expression traits representing four metabolically relevant tissues: liver, omental adipose, subcutaneous adipose, and stomach. We successfully identified 24,531 eSNPs corresponding to about 10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high-quality disease map for each tissue in morbidly obese patients to not only inform genetic associations identified in this cohort, but in previously published genome-wide association studies as well. These data can aid in elucidating the key networks associated with morbid obesity, response to RYGB, and disease as a whole.

Liver and Adipose Expression Associated SNPs are Enriched for Association to Type 2 Diabetes

Genome-wide association studies (GWAS) have demonstrated the ability to identify the strongest causal common variants in complex human diseases. However, to date, the massive data generated from GWAS have not been maximally explored to identify true associations that fail to meet the stringent level of association required to achieve genome-wide significance. Genetics of gene expression (GGE) studies have shown promise towards identifying DNA variations associated with disease and providing a path to functionally characterize findings from GWAS. Here, we present the first empiric study to systematically characterize the set of single nucleotide polymorphisms associated with expression (eSNPs) in liver, subcutaneous fat, and omental fat tissues, demonstrating these eSNPs are significantly more enriched for SNPs that associate with type 2 diabetes (T2D) in three large-scale GWAS than a matched set of randomly selected SNPs. This enrichment for T2D association increases as we restrict to eSNPs that correspond to genes comprising gene networks constructed from adipose gene expression data isolated from a mouse population segregating a T2D phenotype. Finally, by restricting to eSNPs corresponding to genes comprising an adipose subnetwork strongly predicted as causal for T2D, we dramatically increased the enrichment for SNPs associated with T2D and were able to identify a functionally related set of diabetes susceptibility genes. We identified and validated malic enzyme 1 (Me1) as a key regulator of this T2D subnetwork in mouse and provided support for the association of this gene to T2D in humans. This integration of eSNPs and networks provides a novel approach to identify disease susceptibility networks rather than the single SNPs or genes traditionally identified through GWAS, thereby extracting additional value from the wealth of data currently being generated by GWAS.

Calcium and vitamin D supplementation is associated with decreased abdominal visceral adipose tissue in overweight and obese adults

BACKGROUNDnSeveral studies suggest that calcium and vitamin D (CaD) may play a role in the regulation of abdominal fat mass.nnnOBJECTIVEnThis study investigated the effect of CaD-supplemented orange juice (OJ) on weight loss and reduction of visceral adipose tissue (VAT) in overweight and obese adults (mean ± SD age: 40.0 ± 12.9 y).nnnDESIGNnTwo parallel, double-blind, placebo-controlled trials were conducted with either regular or reduced-energy (lite) orange juice. For each 16-wk trial, 171 participants were randomly assigned to 1 of 2 groups. The treatment groups consumed three 240-mL glasses of OJ (regular or lite) fortified with 350 mg Ca and 100 IU vitamin D per serving, and the control groups consumed either unfortified regular or lite OJ. Computed tomography scans of VAT and subcutaneous adipose tissue were performed by imaging a single cut at the lumbar 4 level.nnnRESULTSnAfter 16 wk, the average weight loss (∼2.45 kg) did not differ significantly between groups. In the regular OJ trial, the reduction of VAT was significantly greater (P = 0.024) in the CaD group (-12.7 ± 25.0 cm(2)) than in the control group (-1.3 ± 13.6 cm(2)). In the lite OJ trial, the reduction of VAT was significantly greater (P = 0.039) in the CaD group (-13.1 ± 18.4 cm(2)) than in the control group (-6.4 ± 17.5 cm(2)) after control for baseline VAT. The effect of calcium and vitamin D on VAT remained highly significant when the results of the 2 trials were combined (P = 0.007).nnnCONCLUSIONSnThe findings suggest that calcium and/or vitamin D supplementation contributes to a beneficial reduction of VAT. This trial is registered at clinicaltrial.gov as NCT00386672, NCT01363115.

Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system

Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70–1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22–2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.

An Electronic Health Records Study of Long-term Weight Gain Following Antidepressant Use

IMPORTANCEnShort-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.nnnOBJECTIVEnTo estimate weight gain associated with specific antidepressants over the 12 months following initial prescription in a large and diverse clinical population.nnnDESIGN, SETTING, AND PARTICIPANTSnWe 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.nnnMAIN OUTCOME AND MEASUREnClinician-recorded weight at 3-month intervals up to 12 months.nnnRESULTSnCompared with citalopram, in models adjusted for sociodemographic and clinical features, significantly decreased rate of weight gain was observed among individuals treated with bupropion (β [SE]: -0.063 [0.027]; Pu2009=u2009.02), amitriptyline (β [SE]: -0.081 [0.025]; Pu2009=u2009.001), and nortriptyline (β [SE]: -0.147 [0.034]; Pu2009<u2009.001). As anticipated, differences were less pronounced among individuals discontinuing treatment prior to 12 months.nnnCONCLUSIONS AND RELEVANCEnAntidepressants differ modestly in their propensity to contribute to weight gain. Short-term investigations may be insufficient to characterize and differentiate this risk.

Antidepressant Response in Patients With Major Depression Exposed to NSAIDs: A Pharmacovigilance Study

OBJECTIVE It has been suggested that there is a mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with antidepressant response, and poorer outcomes among NSAID-treated patients were reported in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. To attempt to confirm this association in an independent population-based treatment cohort and explore potential confounding variables, the authors examined use of NSAIDs and related medications among 1,528 outpatients in a New England health care system. METHOD Treatment outcomes were classified using a validated machine learning tool applied to electronic medical records. Logistic regression was used to examine the association between medication exposure and treatment outcomes, adjusted for potential confounding variables. To further elucidate confounding and treatment specificity of the observed effects, data from the STAR*D study were reanalyzed. RESULTS NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio=1.55, 95% CI=1.21-2.00). This association was apparent in the NSAIDs-only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and salicylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables. CONCLUSIONS These results support an association between NSAID use and poorer antidepressant outcomes in major depressive disorder but indicate that some of the observed effect may be a result of confounding.

Validation of electronic health record phenotyping of bipolar disorder cases and controls

OBJECTIVEnThe study was designed to validate use of electronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects.nnnMETHODnEHR data were obtained from a health care system of more than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype diagnoses was calculated against diagnoses from direct semistructured interviews of 190 patients by trained clinicians blind to EHR diagnosis.nnnRESULTSnThe PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR-classified control subject received a diagnosis of bipolar disorder on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based classifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses.nnnCONCLUSIONSnSemiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research.

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.

Rare Copy Number Variation in Treatment-Resistant Major Depressive Disorder

BACKGROUNDnWhile antidepressant treatment response appears to be partially heritable, no consistent genetic associations have been identified. Large, rare copy number variants (CNVs) play a role in other neuropsychiatric diseases, so we assessed their association with treatment-resistant depression (TRD).nnnMETHODSnWe analyzed data from two genome-wide association studies comprising 1263 Caucasian patients with major depressive disorder. One was drawn from a large health system by applying natural language processing to electronic health records (i2b2 cohort). The second consisted of a multicenter study of sequential antidepressant treatments, Sequenced Treatment Alternatives to Relieve Depression. The Birdsuite package was used to identify rare deletions and duplications. Individuals without symptomatic remission, despite two antidepressant treatment trials, were contrasted with those who remitted with a first treatment trial.nnnRESULTSnCNV data were derived for 778 subjects in the i2b2 cohort, including 300 subjects (37%) with TRD, and 485 subjects in Sequenced Treatment Alternatives to Relieve Depression cohort, including 152 (31%) with TRD. CNV burden analyses identified modest enrichment of duplications in cases (empirical p = .04 for duplications of 100-200 kilobase) and a particular deletion region spanning gene PABPC4L (empirical p = .02, 6 cases: 0 controls). Pathway analysis suggested enrichment of CNVs intersecting genes regulating actin cytoskeleton. However, none of these associations survived genome-wide correction.nnnCONCLUSIONSnContribution of rare CNVs to TRD appears to be modest, individually or in aggregate. The electronic health record-based methodology demonstrated here should facilitate collection of larger TRD cohorts necessary to further characterize these effects.