Background

Major depressive disorder (MDD) frequently co-occurs in adolescents with substance use disorders (SUD) 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.

Results

Adolescents with MDD reported more non-nicotine substance use days at baseline and continued using more throughout treatment compared to those without MDD (p<0.0001 based on Timeline Followback; p<0.001 based on urine drug screens). There was no difference between adolescents with and without MDD in retention or CBT sessions attended. ADHD symptom severity (based on DSM-IV ADHD Rating Scale) followed a slightly different course of improvement although with no difference between groups in baseline or 16-week symptom severity or 16 week symptom reduction. There was no difference in days of substance use or ADHD symptom outcomes over time in adolescents with MDD or those without MDD treated with OROS-MPH or placebo. Depressed adolescents were more often female, older, and not court ordered.

Conclusions

These preliminary findings suggest that compared to non-depressed adolescents with ADHD and SUD, those with co-occurring MDD have more severe substance use at baseline and throughout treatment. Such youth may require interventions targeting depression.

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. In this two-tier system, although all these criteria must be met, some criteria are firm and viewed as essential for a site to conduct the trial. Other criteria, such as those that support study recruitment or participant retention, are flexible. These flexible criteria may be addressed through several alternative solutions that meet the original intent of the criterion.

We illustrate how the study specific features and requirements of Stimulant Reduction Intervention using Dosed Exercise (STRIDE), a multisite clinical trial evaluating the efficacy of exercise or health education, added to treatment as usual for stimulant abuse are linked to firm and flexible site selection criteria. We also present an iterative, multi-step approach to site selection including building awareness about the study and screening and evaluating sites using these criteria.

This simple model could maximize the chance that selected sites will implement a study successfully and achieve trial aims. It may be helpful to researchers who are developing criteria and methods for site selection for specific clinical trials.

Background

No consensus is available for identifying the best primary outcome for substance abuse trials. While abstinence is the most desirable outcome for substance use interventions, a wide variety of other endpoints have been used to evaluate efficacy trials.

Objectives

This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials. The framework was developed based on a trial for stimulant abuse using exercise as an augmentation treatment, delivered within the NIDA Clinical Trials Network. The use of a common primary endpoint across trials will facilitate comparisons of treatment efficacy.

Methods

Primary endpoint options in existing substance abuse studies were evaluated. This evaluation included surveys of the literature for endpoints and measurement approaches, followed by assessment of endpoint choices against study design issues, population characteristics, tests of sensitivity and tests of clinical meaningfulness.

Conclusion

We concluded that the best current choice for a primary endpoint is percent days abstinent, as measured by the Time Line Follow Back (TLFB) interview conducted three times a week with recall aided by a take-home Substance Use Diary. To further improve the accuracy of the self-reported drug use, an algorithm will be applied to reconcile the results from the TLFB with the results of qualitative urine drug screens.

Scientific Significance

There is a need for a standardized endpoint in this field to allow for comparison across treatment studies, and we suggest that the recommended endpoint be considered for use in this field.

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. Furthermore, neurobiological evidence provides plausible mechanisms by which exercise could positively affect treatment outcomes. The current manuscript presents the rationale, design considerations, and study design of the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) CTN-0037 Stimulant Reduction Intervention using Dosed Exercise (STRIDE) study.

Methods/Design

STRIDE is a multisite randomized clinical trial that compares exercise to health education as potential treatments for stimulant abuse or dependence. This study will evaluate individuals diagnosed with stimulant abuse or dependence who are receiving treatment in a residential setting. Three hundred and thirty eligible and interested participants who provide informed consent will be randomized to one of two treatment arms: Vigorous Intensity High Dose Exercise Augmentation (DEI) or Health Education Intervention Augmentation (HEI). Both groups will receive TAU (i.e., usual care). The treatment arms are structured such that the quantity of visits is similar to allow for equivalent contact between groups. In both arms, participants will begin with supervised sessions 3 times per week during the 12-week acute phase of the study. Supervised sessions will be conducted as one-on-one (i.e., individual) sessions, although other participants may be exercising at the same time. Following the 12-week acute phase, participants will begin a 6-month continuation phase during which time they will attend one weekly supervised DEI or HEI session.

Clinical Trials Registry

ClinicalTrials.gov, NCT01141608

http://clinicaltrials.gov/ct2/show/NCT01141608?term=Stimulant+Reduction+Intervention+using+Dosed+Exercise&rank=1

Adverse events during selective serotonin reuptake inhibitor (SSRI) treatment are frequent and may lead to premature treatment discontinuation. If attrition is associated with early worsening of side effects or the frequency, intensity, or burden of side effects, interventions to maximize retention could be focused on patients with these events. Outpatient participants (n=265) with nonpsychotic major depressive disorder entered an 8-week trial with an SSRI. At baseline and week 2, specific side effects were evaluated with the Systematic Assessment for Treatment Emergent Events – Systematic Inquiry, and at week 2 the Frequency, Intensity, and Burden of Side Effects Rating globally assessed side effects. Attrition was defined by those participants who left treatment after week 2 but before week 8. No specific week 2 side effect, either treatment emergent or with worsening intensity, was independently associated with attrition. Global ratings of side effect frequency, intensity, or burden at week 2 were also not associated with subsequent attrition. Neither global ratings nor specific side effects at week 2 were related to patient attrition during SSRI treatment. Other factors appear to contribute to patient decisions about continuing with treatment.

Background

Understanding patients’ ambivalence about treatment persistence may be useful in tailoring retention interventions for individual patients with major depressive disorder.

Methods

Participants (n = 265) with major depressive disorder were enrolled into an 8-week trial with a selective serotonin reuptake inhibitor. At baseline and week 2, the participants were asked about their intent to return for the next visit, complete the study and continue in the study should they experience side effects or no improvement. Dropouts were defined as participants who discontinued attending clinic visits before completing the trial.

Results

Participants who at baseline reported an uncertain/negative intent to continue if they experienced side effects or no improvement dropped out at a significantly higher rate by weeks 6 and 8. Uncertain/negative intent at week 2 predicted attrition at all following visits. Dropouts without side effects were more likely to have reported an uncertain/negative intent to attend at both baseline and week 2, while dropouts who experienced side effects were more likely to have reported an uncertain/negative intent to attend only at baseline. Positive intent to continue was associated with greater symptom improvement in both dropouts and completers despite the possibility of lack of efficacy.

Conclusions

Participants’ pretreatment concerns about continuing antidepressant treatment in the presence of side effects signals challenges to the completion of a full 8-week acute phase treatment, even if the participant does not develop side effects. Individualized review of concerns and tailoring appropriate interventions may be necessary to reduce attrition.

Objective

Attrition from treatment in the short and long term for major depressive disorder (MDD) is clearly an adverse outcome. To assist in tailoring the delivery of interventions to specific patients to reduce attrition, this study reports the incidence, timing, and predictors of attrition from outpatient treatment in public mental health clinics.

Methods

Outpatients with psychotic and nonpsychotic MDD receiving measurement-based care in the Texas Medication Algorithm Project (N = 179) were evaluated to determine timing and rates of attrition as well as baseline sociodemographic, clinical, and attitudinal predictors of attrition.

Results

Overall, 23% (42/179) of the patients left treatment by 6 months, and 47% (84/179) left by 12 months. Specific beliefs about the impact of medication, such as its perceived harmfulness, predicted attrition at both 6 and 12 months. Younger age (p = 0.0004) and fewer side effects at baseline (p = 0.0376) were associated with attrition at 6 months. Younger age (p = 0.0013), better perceived physical functioning (p = 0.0007), and more negative attitudes about psychiatric medications at baseline (p = 0.0075) were associated with attrition at 12 months.

Conclusions

Efforts to elicit attitudes about medications and tailoring educational and other retention interventions for patients with negative beliefs about antidepressants both when initiating a new medication and throughout treatment may reduce attrition. Particular focus on younger patients and those requiring frequent visits may be helpful.

Objective

Controversy exists as to whether women with depression respond better to selective serotonin reuptake inhibitors (SSRIs) than men. The purpose of this report was to determine whether men and women differ in their responses to treatment with the SSRI citalopram using a large sample of real world patients from primary and psychiatric specialty care settings.

Method

As part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 2876 participants were treated with citalopram for up to 12-14 weeks. Baseline demographic and clinical characteristics and outcomes were gathered and compared between men and women.

Results

At baseline, women were younger, had more severe depressive symptoms and were more likely to have: early onset; previous suicide attempt(s); a family history of depression, alcohol abuse or drug abuse; atypical symptom features; and one or more of several concurrent psychiatric disorders. Despite greater baseline severity and more Axis I comorbidities, women were more likely to reach remission and response with citalopram than men.

Conclusions

Women have a better response to the SSRI citalopram than men, which may be due to sex-specific biological differences particularly in serotonergic systems.

Objective

Monotherapy with a selective serotonin reuptake inhibitor (SSRI) is the most common initial treatment for major depressive disorder (MDD), but this monotherapy leads to remission in fewer than a third of patients. The combination of the SSRI escitalopram and bupropion-SR is commonly used for treating patients with MDD who have had an inadequate response to antidepressant monotherapy. This pilot study was conducted to evaluate this combination in the treatment of MDD in patients with chronic or recurrent MDD to estimate safety, tolerability, and remission rates.

Method

In this study, 51 outpatients with chronic or recurrent non-psychotic MDD were treated with a combination of escitalopram and bupropion-SR for up to 12 weeks. Participants were started on escitalopram at 10 mg/day, and bupropion-SR was then added at week 1, starting at 150 mg/day. The maximum dose of escitalopram was 20 mg/day and the maximum dose of bupropion-SR was 400 mg/day.

Results

Rates of response (62%) and remission (50%) at study exit (based on participants for whom at least one post-baseline measure was collected) were significantly higher than is typical for SSRI monotherapy. The level of treatment emergent events was low, and only 3 participants (6%) discontinued treatment due to side effects. The mean maximum dose of escitalopram was 18 mg/day, which was achieved by week 6, and the mean dose at study exit was also 18 mg/day. The mean maximum dose of bupropion-SR was 329 mg/day, which was achieved by week 8, and the mean dose at study exit was 327 mg/day.

Conclusions

These results suggest that the combination of escitalopram and bupropion-SR is effective and well tolerated. Further controlled trials comparing this combination with monotherapy are needed.

The 17-item Hamilton Rating Scale for Depression (HRSD17) and the Montgomery Äsberg Depression Rating Scale (MADRS) are two widely used clinicianrated symptom scales. A 6-item version of the HRSD (HRSD6) was created by Bech to address the psychometric limitations of the HRSD17. The psychometric properties of these measures were compared using classical test theory (CTT) and item response theory (IRT) methods. IRT methods were used to equate total scores on any two scales. Data from two distinctly different outpatient studies of nonpsychotic major depression: a 12-month study of highly treatment-resistant patients (n=233) and an 8-week acute phase drug treatment trial (n=985) were used for robustness of results.

MADRS and HRSD6 items generally contributed more to the measurement of depression than HRSD17 items as shown by higher item-total correlations and higher IRT slope parameters. The MADRS and HRSD6 were unifactorial while the HRSD17 contained 2 factors. The MADRS showed about twice the precision in estimating depression as either the HRSD17 or HRSD6 for average severity of depression. An HRSD17 of 7 corresponded to an 8 or 9 on the MADRS and 4 on the HRSD6.

The MADRS would be superior to the HRSD17 in the conduct of clinical trials.