Erik Churchill

Derivation of the SPAN, a brief diagnostic screening test for post-traumatic stress disorder

The Davidson Trauma Scale (DTS) is a validated 17-item self-rating scale used in the diagnosis of post-traumatic stress disorder (PTSD), which is sensitive to the effects of treatment. It was felt that a shorter version of the scale might provide a better diagnostic screening tool. Subjects were drawn from a sample of 243 patients obtained from multiple cohorts that included a group of survivors of various forms of trauma, including natural disaster, rape and combat. All subjects had diagnostic assessments for PTSD with a clinical interview and completed the DTS. The data were randomly divided between two subsamples, and frequency and severity scores were calculated for the DTS. A four-item scale, the SPAN (named for its top four items: Startle, Physiological arousal, Anger, and Numbness), was developed. It demonstrated an efficiency of 0.88, sensitivity of 0.84, specificity of 0.91 and positive likelihood ratio of 9.1. In a replication sample, values were slightly lower but still acceptable (efficiency = 0.80). A subgroup of PTSD patients received either fluoxetine or placebo in a clinical trial, and a significant SPAN score improvement was observed on fluoxetine. The SPAN, which correlated significantly with the Impact of Events Scale, the Sheehan Disability Scale, and the Structured Interview of PTSD, was found to have a diagnostic accuracy of 88%.

Alterations in metabolic pathways and networks in Alzheimer's disease

The pathogenic mechanisms of Alzheimer’s disease (AD) remain largely unknown and clinical trials have not demonstrated significant benefit. Biochemical characterization of AD and its prodromal phase may provide new diagnostic and therapeutic insights. We used targeted metabolomics platform to profile cerebrospinal fluid (CSF) from AD (n=40), mild cognitive impairment (MCI, n=36) and control (n=38) subjects; univariate and multivariate analyses to define between-group differences; and partial least square-discriminant analysis models to classify diagnostic groups using CSF metabolomic profiles. A partial correlation network was built to link metabolic markers, protein markers and disease severity. AD subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine and glutathione versus controls. MCI subjects had elevated 5-HIAA, MET, hypoxanthine and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET. These findings indicate that MCI and AD are associated with an overlapping pattern of perturbations in tryptophan, tyrosine, MET and purine pathways, and suggest that profound biochemical alterations are linked to abnormal Ab42 and tau metabolism. Metabolomics provides powerful tools to map interlinked biochemical pathway perturbations and study AD as a disease of network failure.

Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept

The purpose of this study was to determine whether the baseline metabolic profile (that is, metabotype) of a patient with major depressive disorder (MDD) would define how an individual will respond to treatment. Outpatients with MDD were randomly assigned to sertraline (up to 150 mg per day) (N=43) or placebo (N=46) in a double-blind 4-week trial. Baseline serum samples were profiled using the liquid chromatography electrochemical array; the output was digitized to create a ‘digital map’ of the entire measurable response for a particular sample. Response was defined as ⩾50% reduction baseline to week 4 in the 17-item Hamilton Rating Scale for Depression total score. Models were built using the one-out method for cross-validation. Multivariate analyses showed that metabolic profiles partially separated responders and non-responders to sertraline or to placebo. For the sertraline models, the overall correct classification rate was 81% whereas it was 72% for the placebo models. Several pathways were implicated in separation of responders and non-responders on sertraline and on placebo including phenylalanine, tryptophan, purine and tocopherol. Dihydroxyphenylacetic acid, tocopherols and serotonin were common metabolites in separating responders and non-responders to both drug and placebo. Pretreatment metabotypes may predict which depressed patients will respond to acute treatment (4 weeks) with sertraline or placebo. Some pathways were informative for both treatments whereas other pathways were unique in predicting response to either sertraline or placebo. Metabolomics may inform the biochemical basis for the early efficacy of sertraline.

Nefazodone in post-traumatic stress disorder : results from six open-label trials

Nefazodone, an antidepressant which blocks serotonin (5-HT)2 receptors and 5-HT reuptake, was evaluated in the treatment of post-traumatic stress disorder (PTSD) in six open-label studies involving both civilians and combat veterans. Our objective was to report this available pooled data to characterize the response of this drug in PTSD. Specifically, we looked at response rates using three different criteria, the effect of nefazodone on each PTSD cluster and individual symptoms and, lastly, variables that might predict response. One hundred and five outpatients with chronic PTSD were treated with nefazodone titrated up to 600 mg/day, 92 of whom were entered in an intent to treat analysis. We used the percentage drop in score between baseline and endpoint on main scale as a common measure to evaluate outcome. The response criterion of a drop in score of at least 30%, 40% and 50% revealed response rates of 46, 36 and 26%, respectively. Nefazodone showed a broad spectrum of action on PTSD symptoms. This profile might make nefazodone a useful drug to treat PTSD. Predictors of response include age, sex and trauma type. Double-blind, placebo-controlled clinical trials in PTSD are in progress to assess the utility of nefazodone as a treatment in this disorder.

Pharmacometabolomics reveals racial differences in response to atenolol treatment.

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.

Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo

In this study, we characterized early biochemical changes associated with sertraline and placebo administration and changes associated with a reduction in depressive symptoms in patients with major depressive disorder (MDD). MDD patients received sertraline or placebo in a double-blind 4-week trial; baseline, 1 week, and 4 weeks serum samples were profiled using a gas chromatography time of flight mass spectrometry metabolomics platform. Intermediates of TCA and urea cycles, fatty acids and intermediates of lipid biosynthesis, amino acids, sugars and gut-derived metabolites were changed after 1 and 4 weeks of treatment. Some of the changes were common to the sertraline- and placebo-treated groups. Changes after 4 weeks of treatment in both groups were more extensive. Pathway analysis in the sertraline group suggested an effect of drug on ABC and solute transporters, fatty acid receptors and transporters, G signaling molecules and regulation of lipid metabolism. Correlation between biochemical changes and treatment outcomes in the sertraline group suggested a strong association with changes in levels of branched chain amino acids (BCAAs), lower BCAAs levels correlated with better treatment outcomes; pathway analysis in this group revealed that methionine and tyrosine correlated with BCAAs. Lower levels of lactic acid, higher levels of TCA/urea cycle intermediates, and 3-hydroxybutanoic acid correlated with better treatment outcomes in placebo group. Results of this study indicate that biochemical changes induced by drug continue to evolve over 4 weeks of treatment and that might explain partially delayed response. Response to drug and response to placebo share common pathways but some pathways are more affected by drug treatment. BCAAs seem to be implicated in mechanisms of recovery from a depressed state following sertraline treatment.

Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder – Possible Role for Methoxyindole Pathway

Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ2(1)  = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.

Symptom-specific effects of fluoxetine in post-traumatic stress disorder.

&NA; The selective serotonin reuptake inhibitors have become a first line treatment for post‐traumatic stress disorder (PTSD). In a recent double‐blind study in civilians, fluoxetine produced clinically and statistically significant effects on all general measures of PTSD. We examined the specific effects of fluoxetine versus placebo in the above mentioned study of PTSD clusters and individual symptoms. Individuals were included if they met criteria for PTSD according to the Structured Clinical Interview for DSM‐III‐R (SCID). Symptoms were assessed at sequential time points by the Structured Interview for PTSD (SIP), a clinician interview based assessment, and a self‐report scale, the Davidson Trauma Scale (DTS). A total of 53 patients were included in the analysis. On the SIP and DTS, fluoxetine was found to produce statistically significant changes on all clusters. Significant effects for fluoxetine were noted on 10 items of the DTS, and 8 items of the SIP. The SIP and DTS had 6 items in common that were significant. Fluoxetine exerts a broad spectrum effect in reducing all the symptom clusters of PTSD in this sample. The symptoms of being physically upset at reminders of the trauma, avoiding thoughts of the trauma, having difficulty enjoying things, feeling distant / estranged, having a sense of foreshortened future, and impaired concentration, were the symptoms most responsive to the effects of treatment with fluoxetine on both scales.

Access to routine care and risks for 30-day readmission in patients with cardiovascular disease

Background Studies have shown that access to routine medical care is associated with the prevention, diagnosis, and treatment of chronic diseases. However, studies have not examined whether patient‐reported difficulties in access to care are associated with rehospitalization in patients with cardiovascular disease. Methods Electronic medical records and a standardized survey were used to examine cardiovascular patients admitted to a large medical center from January 1, 2015 through January 10, 2017 (n = 520). All‐cause readmission within 30 days of discharge was the primary outcome for analysis. Logistic regression models were used to examine the association between access to care and 30‐day readmission while adjusting for patient demographics, socioeconomic status, healthcare utilization, and health status. Results Nearly 1‐in‐6 patients (15.7%) reported difficulty in accessing routine medical care; and those who were younger, male, non‐white, uninsured, with heart failure, and had low social support were significantly more likely to report difficulty. Patients who reported difficulty in accessing care had significantly higher rates of 30‐day readmission than patients who did not report difficulty (33.3% vs. 17.9%; P = .001); and the risks remained largely unchanged after accounting for nearly two dozen covariates (unadjusted odds ratio [OR] = 2.29; 95% CI, 1.46‐3.60 vs. adjusted OR = 2.17; 95% CI, 1.29‐3.66). Risks for readmission were especially high for patients who reported issues with transportation (OR = 3.24; 95% CI, 1.28‐8.16) and scheduling appointments (OR = 3.56; 95% CI, 1.43‐8.84), but not for other reasons (OR = 1.47; 95% CI, 0.61‐3.54). Conclusions Cardiovascular patients who reported difficulty in accessing routine care had substantial risks of readmission within 30 days after discharge. These findings have important implications for identifying high‐risk patients and developing interventions to improve access to routine medical care.