Mining clinical data for novel medications to treat alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is a highly prevalent and often debilitating condition associated with high morbidity and mortality. Current AUD medications have limited efficacy and uptake. Alternative pharmacological options are needed. METHODS: We constructed a mechanistic tree of all US Food and Drug Administration approved medications and used a tree-based scan statistic, TreeScan, to identify medications associated with greater than expected improvements in alcohol consumption. Our cohort included all United States (US) Department of Veterans Affairs (VA) patients with a diagnosis of AUD between 10/1/1999 and 9/30/2019 with multiple Alcohol Use Disorders Identification Test-Consumption Module scores within the VA electronic health record data. RESULTS: Medications statistically associated with decreased alcohol consumption had, at large, minor effect sizes. Medications used in the treatment of chronic or life-threatening conditions like diabetes, chronic kidney disease, hepatitis C virus, or cancer produced larger effect sizes. Asenapine, an atypical antipsychotic, had a large effect with an observed to expected ratio of 1.78 (p = 0.003). Our findings were replicated in a propensity score matched population. CONCLUSION: Most medications significantly associated with decreased alcohol consumption in our analysis were either contraindicated with alcohol or likely attributable to patients abstaining from alcohol due to severe illness. However, the large effect of asenapine is notable, and a worthwhile candidate for more careful analysis.

A comparison of mortality rates for buprenorphine versus methadone treatments for opioid use disorder.

OBJECTIVE: Mortality from opioid use disorder (OUD) can be reduced for patients who receive opioid agonist treatment (OAT). In the United States (US), OATs have different requirements including nearly daily visits to a dispensing facility for methadone but weekly to monthly prescriptions for buprenorphine. Our objective was to compare mortality rates for buprenorphine and methadone treatments among a large sample of US patients with OUD. METHODS: We measured all-cause mortality, overdose mortality, and suicide mortality among US Department of Veterans Affairs patients with a diagnosis of OUD who received OAT from 2010 through 2019. We leveraged substantial and sustained regional variation in prescribing buprenorphine versus methadone as an instrumental variable (IV) and used inverse propensity of treatment weighting to balance relevant covariates across treatment groups. We compared mortality with true two-stage IV using both probit and linear probability models, as well as a reduced form IV model, adjusting for demographics and health status. RESULTS: Our cohort consisted of 61,997 patients with OUD who received OAT, of whom 92.7% were male with a mean age of 47.9 (SD = 14.1) years. Patients were followed for a median of 2 (IQR = 1,4) calendar years. Across regional terciles, mean methadone prescribing was 4.8%, 19.5%, and 75.1% of OAT patients. All models identified significant reductions in all-cause and suicide mortality for buprenorphine relative to methadone. For example, predicted all-cause mortality from the probit model was 169.7 per 10,000 person years (95% CI, 157.8, 179.6) in the lowest tercile of methadone prescribing compared with 206.1 (95% CI, 196.0, 216.3) in the highest tercile. No difference was identified for overdose mortality. CONCLUSION: We found significantly lower all-cause mortality and suicide mortality rates for buprenorphine compared with methadone. Our results support the less restrictive prescribing practices for buprenorphine as OAT in the US.

Changes in Alcohol Consumption following Direct-Acting Antiviral Treatment for Hepatitis C in VA Patients with Comorbid Alcohol Use Disorder and PTSD.

OBJECTIVE: To investigate whether direct-acting antivirals (DAA) for hepatitis C viral infection (HCV): glecaprevir/pibrentasvir (GLE/PIB), ledipasvir/sofosbuvir (LDV/SOF), and sofosbuvir/velpatasvir (SOF/VEL) are associated with reduced alcohol consumption among veterans with alcohol use disorder (AUD) and co-occurring post-traumatic stress disorder (PTSD). METHODS: We measured change in Alcohol Use Disorder Identification Test-Consumption Module (AUDIT-C) scores in a retrospective cohort of veterans with PTSD and AUD receiving DAAs for HCV. RESULTS: One thousand two hundred and eleven patients were included (GLE/PIB n = 174, LDV/SOF n = 808, SOF/VEL n = 229). Adjusted frequencies of clinically meaningful improvement were 30.5% for GLE/PIB, 45.5% for LDV/SOF, and 40.5% for SOF/VEL. The frequency was lower for GLE/PIB than for LDV/SOF (OR = 0.59; 95% CI [0.40, 0.87]) or SOF/VEL (OR = 0.66; 95% CI [0.42, 1.04]). CONCLUSIONS: DAA treatment for HCV was associated with a substantial reduction in alcohol use in patients with AUD and co-occurring PTSD. Further exploration of the role of DAAs in AUD treatment is warranted.

Comparative Effectiveness of Direct-Acting Antivirals for Posttraumatic Stress Disorder in Veterans Affairs Patients With Hepatitis C Virus Infection.

We recently conducted an exploratory study that indicated that several direct-acting antivirals (DAAs), highly effective medications for hepatitis C virus (HCV) infection, were also associated with improvement in posttraumatic stress disorder (PTSD) among a national cohort of US Department of Veterans Affairs (VA) patients treated between October 1, 1999, and September 30, 2019. Limiting the same cohort to patients with PTSD and HCV, we compared the associations of individual DAAs with PTSD symptom improvement using propensity score weighting. After identifying patients who had available baseline and endpoint PTSD symptom data as measured with the PTSD Checklist (PCL), we compared changes over the 8-12 weeks of DAA treatment. The DAAs most prescribed in conjunction with PCL measurement were glecaprevir/pibrentasvir (GLE/PIB; n = 54), sofosbuvir/velpatasvir (SOF/VEL; n = 54), and ledipasvir/sofosbuvir (LDV/SOF; n = 145). GLE/PIB was superior to LDV/SOF, with a mean difference in improvement of 7.3 points on the PCL (95% confidence interval (CI): 1.1, 13.6). The mean differences in improvement on the PCL were smaller between GLE/PIB and SOF/VEL (3.0, 95% CI: -6.3, 12.2) and between SOF/VEL and LDV/SOF (4.4, 95% CI: -2.4, 11.2). While almost all patients were cured of HCV (92.5%) regardless of the agent received, PTSD outcomes were superior for those receiving GLE/PIB compared with those receiving LDV/SOF, indicating that GLE/PIB may merit further investigation as a potential PTSD treatment.

Geographic Variation in Initiation of Evidence-based Psychotherapy Among Veterans With PTSD.

INTRODUCTION: The United States Department of Veterans Affairs (VA) has invested in implementation of evidence-based psychotherapy (EBP) for post-traumatic stress disorder (PTSD) for over a decade, resulting in slow but steady uptake of these treatments nationally. However, no prior research has investigated the geographic variation in initiation of EBP. Our objectives were to determine whether there is geographic variation in the initiation of EBP for PTSD in the VA and to identify patient and clinic factors associated with EBP initiation. MATERIALS AND METHODS: We identified VA patients with PTSD who had not received EBP as of January 2016 (N = 946,667) using retrospective electronic medical records data and determined whether they initiated EBP by December 2017. We illustrated geographic variation in EBP initiation using national and regional maps. Using multivariate logistic regression, we determined patient, regional, and nearest VA facility predictors of initiating treatment. This study was approved by the Veterans Institutional Review Board of Northern New England. RESULTS: Nationally, 4.8% (n = 45,895) initiated EBP from 2016 to 2017, and there was geographic variation, ranging from none to almost 30% at the 3-digit ZIP code level. The strongest patient predictors of EBP initiation were the negative predictor of being older than 65 years (OR = 0.47; 95% CI, 0.45-0.49) and the positive predictor of reporting military-related sexual trauma (OR = 1.96; 95% CI, 1.90-2.03). The strongest regional predictors of EBP initiation were the negative predictor of living in the Northeast (OR = 0.89; 95% CI, 0.86-0.92) and the positive predictor of living in the Midwest (OR = 1.47; 95% CI, 1.44-1.51). The only nearest VA facility predictor of EBP initiation was the positive predictor of whether the facility was a VA Medical Center with a specialized PTSD clinic (OR = 1.23; 95% CI, 1.20-1.26). CONCLUSION: Although less than 5% of VA patients with PTSD initiated EBP, there was regional variation. Patient factors, region of residence, and nearest VA facility characteristics were all associated with whether patients initiated EBP. Strengths of this study include the use of national longitudinal data, while weaknesses include the potential for misclassification of PTSD diagnoses as well as the potential for misidentification of EBP. Our work indicates geographic areas where access to EBP for PTSD may be poor and can help target work improving access. Future studies should also assess completion of EBP for PTSD and related symptomatic and functional outcomes across geographic areas.

Comparing Medications for DSM-5 PTSD in Routine VA Practice.

OBJECTIVE: Fluoxetine, paroxetine, sertraline, topiramate, and venlafaxine have previously shown efficacy for posttraumatic stress disorder (PTSD). One prior study using US Department of Veterans Affairs (VA) medical records data to compare these agents found no differences in symptom reduction in clinical practice. The current study addresses several weaknesses in that study, including limited standardization of treatment duration, inability to account for prior treatment receipt, use of an outdated symptomatic assessment for PTSD, and lack of functional outcome. METHODS: A total of 834 VA outpatients were identified with DSM-5 clinical diagnoses of PTSD between October 2016 and March 2018 who initiated one of the medications and met prespecified criteria for treatment duration and dose, combined with baseline and endpoint DSM-5 PTSD Checklist (PCL-5) measurements. Twelve-week acute-phase changes in PCL-5 score and remission of PTSD symptoms were compared among patients receiving the different medications, as was use of acute psychiatric services in the subsequent 6-month continuation phase. RESULTS: In the acute phase, patients improved by a mean of 6.8-10.1 points on the PCL-5 and 0.0%-10.9% achieved remission of PTSD symptoms. Those taking venlafaxine were significantly more likely to achieve remission (P = .008 vs fluoxetine and P < .0001 vs paroxetine, sertraline, and topiramate). In the continuation phase, there were no differences in acute psychiatric care use between medications. Those who continued their medication were less likely to use acute psychiatric services (HR = 0.55; P = .03). CONCLUSIONS: There may be an advantage to venlafaxine over other agents in achieving acute-phase remission for DSM-5 PTSD in routine clinical practice, but this finding requires further study. Regardless of the agent chosen, medication cessation during the continuation phase is associated with a higher risk of acute psychiatric care use.

An analysis of the relationship between chronic obstructive pulmonary disease, smoking and depression in an integrated healthcare system.

OBJECTIVE: Chronic Obstructive Pulmonary Disease (COPD) and smoking are highly associated with depression and hypoxia. There is limited knowledge about whether hypoxic conditions interact to cause depression. METHOD: A population-based cohort study was conducted using the Veterans Affairs (VA) Corporate Data Warehouse. Patients must have accessed any healthcare at a VA facility between 2004 and 2014 and had a negative depression screen (Patient Health Questionnaire-2 (PHQ-2) score ≤ 2). Patients with COPD or a positive depression screen (PHQ-2 score: 3+) during or prior to the year with a negative depression screen were excluded. Logistic regression with annual observations was used to evaluate depression incidence based on COPD and smoking status. Models were adjusted for demographics and other comorbid conditions. A probability scale was used to examine interactions between COPD and smoking. RESULTS: A total of 3,284,496 patients were included. Patients with COPD and current smokers were at increased risk for developing depression. There were minimal interaction effects between COPD and smoking. The odds of developing depression in a year varied from 1.4% among never smokers without COPD to 2.9.% among current smokers with COPD. CONCLUSION: Smoking and COPD are independent risk factors for depression and interact to cause depression. Further research is needed to confirm whether hypoxia contributes to this association.