Family Discord After Completion of an Outpatient Community Treatment Program Predicts Greater Substance Use During Follow-up.

BACKGROUND: It is reasonable to consider family discord after treatment as a potential target for a next-step intervention, since family discord is often comorbid with substance use disorders. OBJECTIVE: This study evaluated family discord after completing an initial course of treatment as a predictor of substance use and retention in the community treatment program during follow-up. METHOD: Patients were from two multisite randomized clinical trials implemented through the Clinical Trials Network of the National Institute on Drug Abuse. There were 315 participants from Study 1 (12-week posttreatment follow-up) and 295 participants from Study 2 (8-week posttreatment follow-up). Negative binomial and logistic regression were used to estimate days of substance use and odds of retention in the community treatment program at follow-up, respectively, from family discord status. RESULTS: Family discord was significantly associated with more days of substance use during the posttreatment follow-up period than those without family discord in both Study 1 (9.12 vs. 2.89 days, p =.0001) and Study 2 (5.58 vs. 2.83 days, p =.0062). Family discord was significantly associated with lower retention in the community treatment program at follow-up than those not reporting family discord in Study 1 (47.6% vs. 60.6%; p =.03), but not in Study 2 (55.3% vs. 64.9%; p =.11). CONCLUSION: Family discord after an initial course of treatment might be a clinically relevant predictor of substance use. There is mixed support for a conclusion that family discord is associated with lower retention in the community treatment program at follow-up.

A systematic approach to subgroup analyses in a smoking cessation trial.

BACKGROUND: Traditional approaches to subgroup analyses that test each moderating factor as a separate hypothesis can lead to erroneous conclusions due to the problems of multiple comparisons, model misspecification, and multicollinearity. OBJECTIVE: To demonstrate a novel, systematic approach to subgroup analyses that avoids these pitfalls. METHODS: A Best Approximating Model (BAM) approach that identifies multiple moderators and estimates their simultaneous impact on treatment effect sizes was applied to a randomized, controlled, 11-week, double-blind efficacy trial on smoking cessation of adult smokers with attention-deficit/hyperactivity disorder (ADHD), randomized to either OROS-methylphenidate (n = 127) or placebo (n = 128), and treated with nicotine patch. Binary outcomes measures were prolonged smoking abstinence and point prevalence smoking abstinence. RESULTS: Although the original clinical trial data analysis showed no treatment effect on smoking cessation, the BAM analysis showed significant subgroup effects for the primary outcome of prolonged smoking abstinence: (1) lifetime history of substance use disorders (adjusted odds ratio [AOR] 0.27; 95% confidence interval [CI] 0.10-0.74), and (2) more severe ADHD symptoms (baseline score >36; AOR 2.64; 95% CI 1.17-5.96). A significant subgroup effect was also shown for the secondary outcome of point prevalence smoking abstinence--age 18 to 29 years (AOR 0.23; 95% CI 0.07-0.76). CONCLUSIONS: The BAM analysis resulted in different conclusions about subgroup effects compared to a hypothesis-driven approach. By examining moderator independence and avoiding multiple testing, BAMs have the potential to better identify and explain how treatment effects vary across subgroups in heterogeneous patient populations, thus providing better guidance to more effectively match individual patients with specific treatments.

Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review.

BACKGROUND: There is increasing concern that prescription stimulants may be associated with adverse cardiovascular events such as stroke, myocardial infarction, and sudden death. Public health concerns are amplified by increasing use of prescription stimulants among adults. METHODS: The objective of this study was to conduct a systematic review of the evidence of an association between prescription stimulant use and adverse cardiovascular outcomes. PUBMED, MEDLINE, EMBASE and Google Scholar searches were conducted using key words related to these topics (MESH): ADHD; Adults; Amphetamine; Amphetamines; Arrhythmias, Cardiac; Cardiovascular Diseases; Cardiovascular System; Central Nervous Stimulants; Cerebrovascular; Cohort Studies; Case-control Studies; Death; Death, Sudden, Cardiac; Dextroamphetamine; Drug Toxicity; Methamphetamine; Methylphenidate; Myocardial Infarction; Stimulant; Stroke; Safety. Eligible studies were population-based studies of children, adolescents, or adults using prescription stimulant use as the independent variable and a hard cardiovascular outcome as the dependent variable. RESULTS: Ten population-based observational studies which evaluated prescription stimulant use with cardiovascular outcomes were reviewed. Six out of seven studies in children and adolescents did not show an association between stimulant use and adverse cardiovascular outcomes. In contrast, two out of three studies in adults found an association. CONCLUSIONS: Findings of an association between prescription stimulant use and adverse cardiovascular outcomes are mixed. Studies of children and adolescents suggest that statistical power is limited in available study populations, and the absolute risk of an event is low. More suggestive of a safety signal, studies of adults found an increased risk for transient ischemic attack and sudden death/ventricular arrhythmia. Interpretation was limited due to differences in population, cardiovascular outcome selection/ascertainment, and methodology. Accounting for confounding and selection biases in these studies is of particular concern. Future studies should address this and other methodological issues.

Aortic dissection in young adults who abuse amphetamines.

BACKGROUND: Case reports suggest a relationship between amphetamine abuse/dependence and aortic dissection, but no population-based epidemiologic studies have examined this link. Our objective was to test the hypothesis that young adults with a diagnosis of amphetamine abuse/dependence would be at higher risk for aortic dissection after accounting for known risk factors. METHODS: In this population-based case-control study of 30,922,098 discharges from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample from 1995 to 2007, among persons aged 18 to 49 years, we identified 3,116 thoracic and thoracoabdominal aortic dissections using International Classification of Disease, Ninth Edition, Clinical Modification codes 441.01 and 441.03. The SURVEYLOGISTIC procedure in SAS 9.2 (SAS Institute, Cary, NC) was used to account for the Nationwide Inpatient Sample sampling methodology. RESULTS: In a multiple logistic regression analysis, while controlling for known risk factors, amphetamine abuse/dependence was significantly associated with aortic dissection (adjusted odds ratio = 3.33, 95% CI = 2.37-4.69, P < .0001). CONCLUSIONS: This statistically significant association suggests that amphetamine abuse/dependence may play a role in aortic dissection in young adults in the United States.

Stroke in young adults who abuse amphetamines or cocaine: a population-based study of hospitalized patients.

CONTEXT: The abuse of stimulant drugs is increasing in the western United States. Although numerous case reports and animal studies suggest a link with stroke, epidemiologic studies have yielded conflicting results. OBJECTIVE: To test the hypothesis that young adults who abuse amphetamines or cocaine are at a higher risk of stroke. DESIGN, SETTING, AND PARTICIPANTS: Using a cross-sectional design and from a quality indicators' database of 3 148 165 discharges from Texas hospitals, we estimated the secular trends from January 1, 2000, to December 31, 2003, in the abuse of various drugs and of strokes. We developed separate logistic regression models of risk factors for hemorrhagic (n = 937) and ischemic (n = 998) stroke discharges of persons aged 18 to 44 years in 2003, and for mortality risk in patients with stroke. Main Outcome Measure Incidence of stroke using definitions from the Agency for Healthcare Research and Quality's stroke mortality Inpatient Quality Indicator. RESULTS: From 2000 to 2003, the rate of increase was greatest for abuse of amphetamines, followed by cannabis and cocaine. The rate of strokes also increased, particularly among amphetamine abusers. In 812 247 discharges in 2003, amphetamine abuse was associated with hemorrhagic stroke (adjusted odds ratio [OR], 4.95; 95% confidence interval [CI], 3.24-7.55), but not with ischemic stroke; cocaine abuse was associated with hemorrhagic (OR, 2.33; 95% CI, 1.74-3.11) and ischemic (OR, 2.03; 95% CI, 1.48-2.79) stroke. Amphetamine, but not cocaine, abuse was associated with a higher risk of death after hemorrhagic stroke (OR, 2.63; 95% CI, 1.07-6.50). CONCLUSION: Increases in stimulant drug abuse may increase the rate of hospital admissions for strokes and stroke-related mortality.

Acute myocardial infarction in young adults who abuse amphetamines.

BACKGROUND: Case reports suggest a link between methamphetamine abuse and acute myocardial infarction (AMI), but no epidemiologic studies have examined this link. Our objective was to test the hypothesis that young adults who abuse amphetamines are at higher risk for AMI. METHODS: In this study of 3,148,165 discharges from Texas hospitals in a quality indicators database during 2000-2003, among persons aged 18-44 years we identified 11,011 AMIs, defined according to the Agency for Healthcare Research and Quality's AMI mortality inpatient quality indicator. RESULTS: In a multiple logistic regression analysis - while controlling for cocaine abuse, alcohol abuse, tobacco use, hypertension, diabetes mellitus, lipid disorders, obesity, congenital defects, and coagulation defects - amphetamine abuse was significantly associated with AMI (adjusted odds ratio=1.61; 95% CI=1.24-2.04, p=0.0004). The rate of AMIs among amphetamine abusers increased significantly from 2000 to 2003. The population attributable risk suggests that amphetamine abuse is responsible for 0.2% of AMIs in the state of Texas. The geographical distribution of amphetamine abuse varied by region, with the prevalence being highest in the North Texas and Panhandle regions of Texas. CONCLUSIONS: This modest, though statistically robust, association suggests that amphetamine abuse may play a role in AMI.

Risk of amphetamine use disorder and mortality among incident users of prescribed stimulant medications in the Veterans Administration.

BACKGROUND AND AIMS: Non-medical use of prescribed stimulant medications is a growing concern. This study's aims were to ascertain the demographics of stimulant medication users compared with non-users, examine temporal trends of stimulant medication use and estimate risk factors for development of amphetamine use disorder (AUD) and mortality among new users of stimulant medications. DESIGN: Cox proportional hazards regression in a retrospective cohort adjusted by baseline covariates. SETTING: United States, national administrative database of the Veterans Affairs (VA) health-care system. PARTICIPANTS: Adult incident users of stimulant medications (n = 78 829) from fiscal years (FY) 2001 to 2012. MEASUREMENTS: Primary outcomes were time-to-event: (1) occurrence of AUD diagnosis and (2) death. Baseline covariates included demographic information, Food and Drug Administration (FDA)-approved indications for stimulant use, substance use disorders (SUD) and depression. FINDINGS: Stimulant users compared with non-users were younger, more likely to be non-Hispanic white and female. Incident stimulant medication users increased threefold from FY2001-FY2012 and eightfold among adults aged 18-44 years. Nearly one in 10 incident users in FY2012 had a comorbid baseline SUD. Off-label use was common-nearly three of every five incident users in FY2012. Comorbid SUDs among incident stimulant medication users were risk factors for occurrence of AUD during follow-up, with adjusted hazard ratio (AHR) estimates ranging from 1.54 to 2.83 (Ps < 0.05). Increased mortality risk was observed with occurrence of AUD during follow-up [AHR = 1.55, 95% confidence interval (CI) = 1.13-2.14, P = 0.007], while on-label prescribing was protective against death (AHR = 0.686, 95% CI = 0.63-0.75, P < 0.0001). CONCLUSIONS: In a US national cohort of adult incident stimulant medication users in the Veterans Affairs health-care system, measured from fiscal years 2001 to 2012, comorbid substance use disorders were common and were risk factors for development of an amphetamine use disorder (AUD). Increased mortality risk among incident users of stimulant medications was observed among both those who developed an AUD later and those whose use was defined as off-label.

Impact of Stimulant Medication Use on Heart Rate and Systolic Blood Pressure During Submaximal Exercise Treadmill Testing in Adolescents.

OBJECTIVES: Inappropriately decreased heart rate (HR) during peak exercise and delayed heart rate recovery (HRR) has been observed in adult users of stimulant medications who underwent exercise testing, suggesting autonomic adaptation to chronic stimulant exposure. In the general population, this pattern of hemodynamic changes is associated with increased mortality risk. Whether the same pattern of hemodynamic changes might be observed in adolescent stimulant medication users undergoing exercise testing is unknown. METHODS: Among adolescents (aged 12 to 20 years) that underwent submaximal exercise treadmill testing from 1999 to 2004 in the National Health and Nutrition Examination Survey, propensity score matching of stimulant medication users (n = 89) to matched nonusers (n = 267) was conducted. Testing consisted of a 3-minute warm-up period, two 3-minute exercise stages, and three 1-minute recovery periods, with the goal of reaching 75% of the predicted HR maximum. A linear mixed model analysis was used to evaluate the effect of stimulant exposure on each of the exercise outcomes. RESULTS: Stimulant medication users compared to matched nonusers had a lower peak HR in Stage 2 (154.9 vs. 158.3 beats/minute [bpm], p = 0.055) and lower HR at 1-minute recovery (142.2 vs. 146.4 bpm, p = 0.030). However, submaximal HRR at 1 minute did not differ between stimulant users and matched nonusers (13.0 vs. 12.1 bpm, p = 0.38). Duration of stimulant use was not related to these outcomes. CONCLUSION: Adolescent stimulant medication users compared to matched nonusers demonstrated a trend toward decreased HR during submaximal exercise, which is potential evidence of chronic adaptation with stimulant exposure. There was no evidence for delayed HRR in this study, and thus, no evidence for decreased parasympathetic activity during initial exercise recovery. Exercise testing outcomes may have utility in future research as a method to assess stimulant-associated autonomic nervous system adaptations.

Exercise outcomes in prevalent users of stimulant medications.

BACKGROUND: To compare users of stimulant medications with matched nonusers on exercise outcomes during a maximal treadmill exercise test. METHODS: A cross-sectional study of a community-based cohort comparing propensity-score-matched stimulant medication users (n = 245) and nonusers (n = 735) who underwent a maximal treadmill exercise test in the Cooper Center Longitudinal Study cohort from January 1, 1995 to December 31, 2013. Main Outcomes were peak systolic blood pressure (SBP), average rise in SBP, peak heart rate (HR), and estimated VO2max during exercise. A linear mixed model analysis was used to evaluate the effect of stimulant exposure on each of the exercise outcomes. In a sensitivity analysis, users were compared against nonusers for risk of chronotropic incompetence. Analyses were adjusted for relevant covariates and multiple testing. RESULTS: Peak HR during exercise was significantly lower in stimulant medication users (least square mean estimate 170.2 beats/minute) compared to nonusers (174.4 beats/minute; p < 0.0001). Moreover, stimulant medication users had an increased risk of chronotropic incompetence compared to nonusers (adjusted odds ratio 3.28, 95% confidence interval 1.70 to 6.34, p = 0.0008). No significant differences were observed in the outcomes of peak SBP, average SBP rise, and estimated VO2max between matched groups. CONCLUSIONS: Stimulant medication use was associated with a significant decrease in peak HR and an increased risk of chronotropic incompetence. Further investigation is required to understand the clinical significance of chronotropic incompetence in stimulant medication users. Concerns that stimulant medication use may increase peak SBP and average SBP during exercise were not supported by this study.

Risk of methylphenidate-induced prehypertension in normotensive adult smokers with attention deficit hyperactivity disorder.

The authors studied predictors of methylphenidate-induced increases in blood pressure (BP). In this secondary analysis of a randomized, double-blind, placebo-controlled smoking cessation trial, nonhypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic-release oral system methylphenidate (OROS-MPH) (n=115) were matched one-to-one on baseline systolic BP (SBP) (±5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS-MPH-induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS-MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41-8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56-14.0; P=.004) compared with placebo using simple logistic regression. The authors demonstrated an augmented OROS-MPH-induced BP elevation and risk of prehypertension in adults with baseline normal BP. Significantly increased BP was not observed in adults with baseline prehypertension.

A cross-national relationship between sugar consumption and major depression?

We have preliminarily investigated the hypothesis that sugar consumption may impact the prevalence of major depression by correlating per capita consumption of sugar with the prevalence of major depression. Major depression prevalence data (annual rate/100) was obtained from the Cross-National Epidemiology of Major Depression and Bipolar Disorder study [Weissman et al., 1996]. Sugar consumption data from 1991 was obtained from the Food and Agricultural Organization of the United Nations. For the primary analysis, sugar consumption rates (cal/cap/day) were correlated with the annual rate of major depression, using the Pearson correlation coefficient. For the six countries with available data for the primary analysis, there was a highly significant correlation between sugar consumption and the annual rate of depression (Pearson correlation 0.948, P=0.004). Naturally, a correlation does not necessarily imply etiology. Caveats such as the limited number of countries with available data must be considered. Although speculative, there are some mechanistic reasons to consider that sugar consumption may directly impact the prevalence of major depression. Possible relationships between sugar consumption, beta-endorphins, and oxidative stress are discussed.