Identifying and responding to trial implementation challenges during multisite clinical trials.

Introduction: The National Drug Abuse Treatment Clinical Trials Network (CTN) was initiated by the National Institute on Drug Abuse (NIDA) in 2000 with the aim of improving substance use treatment and reducing the time between the discovery of effective treatments and their implementation into clinical practice. While initial trials were conducted almost exclusively in specialty addiction treatment settings, the CTN began evolving strategically in 2010 to conduct research in general medical settings, including healthcare systems, primary care settings, emergency departments, and pharmacies, to broaden impact. The advantages of a research network like the CTN is not only the collective content expertise that investigators contribute to the network, but the collective experience gained by conducting studies in the network and then applying those lessons to future studies.

Randomized Controlled Trial Comparing Exercise to Health Education for Stimulant Use Disorder: Results From the CTN-0037 STimulant Reduction Intervention Using Dosed Exercise (STRIDE) Study.

Objective: To evaluate exercise as a treatment for stimulant use disorders.

Methods: The STimulant Reduction Intervention using Dosed Exercise (STRIDE) study was a randomized clinical trial conducted in 9 residential addiction treatment programs across the United States from July 2010 to February 2013. Of 497 adults referred to the study, 302 met all eligibility criteria, including DSM-IV criteria for stimulant abuse and/or dependence, and were randomized to either a dosed exercise intervention (Exercise) or a health education intervention (Health Education) control, both augmenting treatment as usual and conducted thrice weekly for 12 weeks.

Demographic and clinical characteristics of current comorbid psychiatric disorders in a randomized clinical trial for adults with stimulant use disorders.

This study aimed to determine if current comorbid psychiatric disorders differ in adults with cocaine use disorder, other stimulant (primarily methamphetamine) use disorder, or both, and identify demographic and clinical characteristics in those with increasing numbers of comorbid disorders. Baseline data from a randomized controlled trial beginning in residential settings (N=302) was used. Mood disorders were present in 33.

An ounce of prevention: A pre-randomization protocol to improve retention in substance use disorder clinical trials.

Background: Missing data in substance use disorder (SUD) research pose a significant threat to internal validity. Participants terminate involvement or become less likely to attend intervention and research visits for many reasons, which should be addressed prior to becoming problematic. During a 9-month study targeting stimulant abuse, early dropouts and participant reported attendance barriers led to implementing a structured, pre-randomization protocol with participants about retention and solution-focused strategies (the "Fireside Chat").

Baseline medical comorbidities in adults randomized in the STRIDE trial for psychostimulant use disorders.

Background And Objectives: Rates of medical illnesses may be higher among individuals with substance use disorders, complicating their care. This study aimed to expand the understanding of other medical conditions in treatment-seeking adults with stimulant use disorder (SUD) using data from Stimulant Reduction Intervention using Dose Exercise (STRIDE), a randomized, multisite trial investigating exercise augmentation of treatment as usual.

Methods: Utilizing STRIDE baseline data, we examined demographic and clinical characteristics based on the number of self-reported diagnosed medical conditions among participants meeting eligibility criteria (passing medical screening exam and maximal exercise test, non-opioid dependent, no concomitant beta blocker, or opioid replacement therapy).

Hispanic Subgroups, Acculturation, and Substance Abuse Treatment Outcomes.

This study explored Hispanic subgroup differences in substance use treatment outcomes, and the relationship of acculturation characteristics to these outcomes. Data were from a multisite randomized clinical trial of motivational enhancement therapy versus treatment as usual in a sample of Spanish-speaking substance abusers. Participants were Cuban American (n=34), Mexican American (n=209), Puerto Rican (n=78), and other Hispanic American (n=54).

Adherence to antidepressant combinations and monotherapy for major depressive disorder: a CO-MED report of measurement-based care.

Background: Non-adherence to antidepressant treatment is not routinely measured in practical clinical trials. It has not been related to outcomes in a large sample of adults with chronic and/or recurrent major depressive disorder (MDD) or any sample treated with antidepressant combinations.

Methods: Adult outpatients with chronic and/or recurrent MDD were randomized to 12 weeks of treatment with bupropion-SR plus escitalopram, venlafaxine-XR plus mirtazapine, or escitalopram plus placebo.

Do menopausal status and use of hormone therapy affect antidepressant treatment response? Findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

Background: Menopausal status and use of hormonal contraception or menopausal hormone therapy (HT) may affect treatment response to selective serotonin reuptake inhibitors (SSRIs). This report evaluates whether menopausal status and use of hormonal contraceptives or menopausal HT affect outcome in women treated with citalopram.

Methods: In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 896 premenopausal and 544 postmenopausal women were treated with citalopram for 12-14 weeks.

Exercise and mental illness: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

Background: Regular exercise is thought to be associated with low rates of mental illness, but this association has been inadequately studied. The purpose of this study was to test the hypotheses that the recommended amount of self-reported vigorous exercise would be cross-sectionally associated with reduced prevalence and incidence of various DSM-IV psychiatric disorders, as well as increased rates of remission.

Method: Data were collected from 2001 to 2005 as part of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a 2-wave face-to-face survey conducted by the National Institute on Alcohol Abuse and Alcoholism.

The impact of chronic depression on acute and long-term outcomes in a randomized trial comparing selective serotonin reuptake inhibitor monotherapy versus each of 2 different antidepressant medication combinations.

Objective: To compare sociodemographic and clinical features, acute and continuation treatment outcomes, and adverse events/side effect burden between outpatients with chronic (current episode > 2 years) versus nonchronic major depressive disorder (MDD) who were treated with combination antidepressant therapy or selective serotonin reuptake inhibitor (SSRI) monotherapy.

Method: 663 outpatients with chronic (n = 368) or nonchronic (n = 295) moderate to severe DSM-IV-TR MDD (17-item Hamilton Depression Rating Scale score ≥ 16) were enrolled from March 2008 through September 2009 in a single-blind 7-month prospective randomized trial conducted at 6 primary and 9 psychiatric care sites across the United States. Participants were treated with escitalopram monotherapy plus placebo or 1 of 2 combination treatments (bupropion sustained-release [SR] + escitalopram or venlafaxine extended-release [XR] + mirtazapine).

Predictors of attrition with buprenorphine/naloxone treatment in opioid dependent youth.

Background: In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment.

Methods: Opioid dependent adolescents and young adults (n=152), aged 15-21, were randomized to 12 weeks (BUP, n=74) or 2 weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment.

Rationale for Using Exercise in the Treatment of Stimulant Use Disorders.

Novel approaches to the treatment of stimulant abuse and dependence are needed. Clinical data examining the use of exercise as a treatment for the abuse of nicotine, alcohol, and other substances suggest that exercise may be a beneficial treatment for stimulant abuse. In addition, exercise has been associated with improvements in many other health-related areas that may be adversely affected by stimulant use or its treatment, such as sleep disturbance, cognitive function, mood, weight, quality of life, and anhedonia.

Assessing anxious features in depressed outpatients.

Both the 17-item Hamilton Rating Scale for Depression (HRSD(17)) and 30-item Inventory of Depressive Symptomatology - Clinician-rated (IDS-C(30) ) contain a subscale that assesses anxious symptoms. We used classical test theory and item response theory methods to assess and compare the psychometric properties of the two anxiety subscales (HRSD(ANX) and IDS-C(ANX)) in a large sample (N = 3453) of outpatients with non-psychotic major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Approximately 48% of evaluable participants had at least one concurrent anxiety disorder by the self-report Psychiatric Diagnostic Screening Questionnaire (PDSQ).

Predictors of abstinence: National Institute of Drug Abuse multisite buprenorphine/naloxone treatment trial in opioid-dependent youth.

Objective: To examine predictors of opioid abstinence in buprenorphine/naloxone (Bup/Nal)-assisted psychosocial treatment for opioid-dependent youth.

Method: Secondary analyses were performed of data from 152 youth (15-21 years old) randomly assigned to 12 weeks of extended Bup/Nal therapy or up to 2 weeks of Bup/Nal detoxification with weekly individual and group drug counseling. Logistic regression models were constructed to identify baseline and during-treatment predictors of opioid-positive urine (OPU) at week 12.

Effects of race and ethnicity on depression treatment outcomes: the CO-MED trial.

Objective: The investigators examined whether outcomes differ by race-ethnicity for patients with major depressive disorder in acute- (12 weeks) and continuation-phase (weeks 12-28) treatment with one of two antidepressant combinations or one selective serotonin reuptake inhibitor.

Methods: This single-blind, seven-month prospective, randomized trial enrolled 352 non-Hispanic white (59%), 169 black (28%), and 79 white Hispanic (13%) participants from six primary and nine psychiatric care U.S.

Rationale and methods for site selection for a trial using a novel intervention to treat stimulant abuse.

Although the selection of appropriate clinical sites has a significant impact on the successful conduct of clinical trials, no generally accepted model is available for site selection. Use of an appropriate site selection process is even more pertinent when conducting large scale, practical clinical trials in practice settings. This report provides a rationale for selecting sites by identifying both a set of basic site selection criteria important to most trials as well as criteria specific to the features of a particular study's design.

Stimulant reduction intervention using dosed exercise (STRIDE) - CTN 0037: study protocol for a randomized controlled trial.

Background: There is a need for novel approaches to the treatment of stimulant abuse and dependence. Clinical data examining the use of exercise as a treatment for the abuse of nicotine, alcohol, and other substances suggest that exercise may be a beneficial treatment for stimulant abuse, with direct effects on decreased use and craving. In addition, exercise has the potential to improve other health domains that may be adversely affected by stimulant use or its treatment, such as sleep disturbance, cognitive function, mood, weight gain, quality of life, and anhedonia, since it has been shown to improve many of these domains in a number of other clinical disorders.

Major depression and treatment response in adolescents with ADHD and substance use disorder.

Background: Major depressive disorder (MDD) frequently co-occurs in adolescents with substance use disorders (SUDs) and attention deficit hyperactivity disorder (ADHD), but the impact of MDD on substance treatment and ADHD outcomes and implications for clinical practice are unclear.

Methods: Adolescents (n=303; ages 13-18) meeting DSM-IV criteria for ADHD and SUD were randomized to osmotic release methylphenidate (OROS-MPH) or placebo and 16 weeks of cognitive behavioral therapy (CBT). Adolescents with (n=38) and without (n=265) MDD were compared on baseline demographic and clinical characteristics as well as non-nicotine substance use and ADHD treatment outcomes.

Determining the primary endpoint for a stimulant abuse trial: lessons learned from STRIDE (CTN 0037).

Background: No consensus is available for identifying the best primary outcome for substance use disorder trials, making interpretation across trials difficult. Abstinence is the most desirable treatment outcome although a wide variety of other endpoints have been used.

Objectives: This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials.

Randomized comparison of selective serotonin reuptake inhibitor (escitalopram) monotherapy and antidepressant combination pharmacotherapy for major depressive disorder with melancholic features: a CO-MED report.

Background: The clinical effects of antidepressant combinations vs. monotherapy as initial treatment for major depression with melancholic features (MDD-MF) are unknown.

Methods: Outpatients with chronic or recurrent major depression (MDD) were randomized to initial treatment with escitalopram+placebo (the MONO condition), bupropion-sustained release+escitalopram, or venlafaxine-extended release+mirtazapine (the COMB conditions) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial.

Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study.

Objective: Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment.

Method: The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder.

Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication.

Little is known about the quantity or quality of residual depressive symptoms in patients with major depressive disorder (MDD) who have responded but not remitted with antidepressant treatment. This report describes the residual symptom domains and individual depressive symptoms in a large representative sample of outpatients with nonpsychotic MDD who responded without remitting after up to 12 weeks of citalopram treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Response was defined as 50% or greater reduction in baseline 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR₁₆) by treatment exit, and remission as a final QIDS-SR₁₆ of less than 6.