Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Bupropion and Naltrexone in Methamphetamine Use Disorder.

BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses. RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial. CONCLUSIONS: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).

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. OBJECTIVE: To summarize trial implementation challenges encountered, and the process by which solutions were identified and implemented, within one of the last early-phase CTN Stage II behavioral intervention studies conducted in a specialty addiction treatment setting. METHOD AND RESULTS: We describe the implementation of the CTN-0037 STimulant Reduction Intervention using Dosed Exercise (STRIDE) trial. Issues encountered during study implementation are categorized into four major areas, described in terms useful to future study teams: 1) study team infrastructure challenges, 2) participant- and site- level challenges, 3) intervention-related challenges, and 4) longitudinal study design challenges. Potential consequences of identified problems and the solutions developed to manage these problems are discussed within the context of these four areas. We propose how to extend these implementation lessons and apply them in other healthcare settings to expand the CTN. CONCLUSIONS: Effective study management allows for flexible, collaborative solutions to expected and unexpected obstacles to study success. Implementation strategies derived from the first 15 to 20 years of CTN studies are a result of working with providers and participants, and the ongoing collaboration among CTN investigators and network staff. Timely identification and response to problems during study implementation are critical to the success of a trial, regardless of its design. We believe a collaborative approach to identifying and responding to study implementation challenges will increase the likelihood of successful adoption of relevant, efficacious interventions. As the CTN continues to expand, the wealth of successful trial implementation strategies developed during the first 20 years of the CTN need to be applied and adapted to studies in broader network settings, and considered in conjunction with more formalized implementation science processes that are currently available.

Age differences in outcomes among patients in the "Stimulant Abuser Groups to Engage in 12-Step" (STAGE-12) intervention.

Emerging adults (roughly 18-29years) with substance use disorders can benefit from participation in twelve-step mutual-help organizations (TSMHO), however their attendance and participation in such groups is relatively low. Twelve-step facilitation therapies, such as the Stimulant Abuser Groups to Engage in 12-Step (STAGE-12), may increase attendance and involvement, and lead to decreased substance use. AIMS: Analyses examined whether age moderated the STAGE-12 effects on substance use and TSMHO meeting attendance and participation. DESIGN: We utilized data from a multisite randomized controlled trial, with assessments at baseline, mid-treatment (week 4), end-of-treatment (week 8), and 3- and 6- months post-randomization. PARTICIPANTS: Participants were adults with DSM-IV diagnosed stimulant abuse or dependence (N=450) enrolling in 10 intensive outpatient substance use treatment programs across the U.S. ANALYSIS: A zero-inflated negative binomial random-effects regression model was utilized to examine age-by-treatment interactions on substance use and meeting attendance and involvement. FINDINGS: Younger age was associated with larger treatment effects for stimulant use. Specifically, younger age was associated with greater odds of remaining abstinent from stimulants in STAGE-12 versus Treatment-as-Usual; however, among those who were not abstinent during treatment, younger age was related to greater rates of stimulant use at follow-up for those in STAGE-12 compared to TAU. There was no main effect of age on stimulant use. Younger age was also related to somewhat greater active involvement in different types of TSMHO activities among those in STAGE-12 versus TAU. There were no age-by-treatment interactions for other types of substance use or for treatment attendance, however, in contrast to stimulant use; younger age was associated with lower odds of abstinence from non-stimulant drugs at follow-up, regardless of treatment condition. These results suggest that STAGE-12 can be beneficial for some emerging adults with stimulant use disorder, and ongoing assessment of continued use is of particular importance.

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. The primary outcome of percent stimulant abstinent days during study weeks 4 to 12 was estimated using a novel algorithm adjustment incorporating self-reported Timeline Followback (TLFB) stimulant use and urine drug screen (UDS) data. RESULTS: Mean percent of abstinent days based on TLFB was 90.8% (SD = 16.4%) for Exercise and 91.6% (SD = 14.7%) for Health Education participants. Percent of abstinent days using the eliminate contradiction (ELCON) algorithm was 75.6% (SD = 27.4%) for Exercise and 77.3% (SD = 25.1%) for Health Education. The primary intent-to-treat analysis, using a mixed model controlling for site and the ELCON algorithm, produced no treatment effect (P = .60). In post hoc analyses controlling for treatment adherence and baseline stimulant use, Exercise participants had a 4.8% higher abstinence rate (78.7%) compared to Health Education participants (73.9%) (P = .03, number needed to treat = 7.2). CONCLUSIONS: The primary analysis indicated no significant difference between exercise and health education. Adjustment for intervention adherence showed modestly but significantly higher percent of abstinent days in the exercise group, suggesting that exercise may improve outcomes for stimulant users who have better adherence to an exercise dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01141608.

Gender-based Outcomes and Acceptability of a Computer-assisted Psychosocial Intervention for Substance Use Disorders.

BACKGROUND: Digital technologies show promise for increasing treatment accessibility and improving quality of care, but little is known about gender differences. This secondary analysis uses data from a multi-site effectiveness trial of a computer-assisted behavioral intervention, conducted within NIDA's National Drug Abuse Clinical Trials Network, to explore gender differences in intervention acceptability and treatment outcomes. METHODS: Men (n=314) and women (n=192) were randomly assigned to 12-weeks of treatment-as-usual (TAU) or modified TAU+Therapeutic Education System (TES), whereby TES substituted for 2hours of TAU per week. TES is composed of 62 Web-delivered, multimedia modules, covering skills for achieving and maintaining abstinence plus prize-based incentives contingent on abstinence and treatment adherence. Outcomes were: (1) abstinence from drugs and heavy drinking in the last 4weeks of treatment, (2) retention, (3) social functioning, and (4) drug and alcohol craving. Acceptability was the mean score across five indicators (i.e., interesting, useful, novel, easy to understand, and satisfaction). RESULTS: Gender did not moderate the effect of treatment on any outcome. Women reported higher acceptability scores at week 4 (p=.02), but no gender differences were detected at weeks 8 or 12. Acceptability was positively associated with abstinence, but only among women (p=.01). CONCLUSIONS: Findings suggest that men and women derive similar benefits from participating in a computer-assisted intervention, a promising outcome as technology-based treatments expand. Acceptability was associated with abstinence outcomes among women. Future research should explore characteristics of women who report less satisfaction with this modality of treatment and ways to improve overall acceptability.

Clinical and sociodemographic characteristics associated with suicidal ideation in depressed outpatients.

OBJECTIVE: To identify clinical and sociodemographic characteristics associated with suicidal ideation (SI) among patients seeking care for depression in routine primary and psychiatric care settings. METHODS: We examined data from 4041 treatment-seeking outpatients with major depressive disorder (MDD) to compare baseline sociodemographic and clinical characteristics of those with and without SI, and the presence or absence of baseline depressive symptoms and psychiatric comorbidities in those with SI. RESULTS: SI was significantly (P < 0.01) associated with numerous sociodemographic characteristics (that is, lower level of education, Caucasian or African American, male, unemployed, and treated in psychiatric care) and clinical features (that is, previous suicide attempt, younger age of MDD onset, greater baseline depressive symptom severity, greater number of depressive symptoms, and presence of agoraphobia and [or] generalized anxiety disorder). Elevated levels of SI at baseline were associated with decreased remission rates. CONCLUSIONS: Consistent with past findings, increased rates of SI were associated with greater depressive symptom severity as well as other features suggestive of severity of illness. Our results confirm previous findings of associations between SI and panic and (or) phobic symptoms and anxiety, but did not confirm previous findings of an association between SI and alcohol or drug use and (or) dependence. While selective serotonin reuptake inhibitor monotherapy appeared significantly helpful in reducing SI during the course of treatment, the presence of SI at baseline was found to be a associated with decreased treatment response, with patients reporting SI at the start of treatment being less likely to achieve remission. CLINICAL TRIAL REGISTRATION NUMBER: Sequenced Treatment Alternatives to Relieve Depression, NCT00021528.

Identifying risk for attrition during treatment for depression.

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.

Release bias in accessing medical records in clinical trials: a STAR*D report.

Clinical trials often require subjects to sign medical record releases to allow investigators to measure treatment fidelity, off-protocol care use, and care costs. Little is known, however, if limiting samples to those willing to sign releases impacts external validity. Data came from outpatients with non-psychotic major depressive disorder who enrolled in the multisite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Differences between those who signed (n = 3116) and who did not sign (n = 925) releases were assessed using logistic regression and two-part, three-level log-transformed regression models, corrected for site clustering and repeated measures. Patients who released records tended to believe care was helpful, were younger, and married. However, release status had little material or consistent associations with patient health outcomes or use of care. With appropriate adjustments to data, requiring patient medical records may pose only minimal challenges to external validity in cost-outcome studies.

Income and attrition in the treatment of depression: a STAR*D report.

BACKGROUND: Attrition, or dropping out of treatment, remains a major issue in the care of depressed outpatients. Whether different factors are associated with attrition for different socioeconomic groups is not known. This report assessed whether attrition rates and predictors of attrition differed among depressed outpatients with different income levels. METHODS: Outpatients with nonpsychotic major depressive disorder treated for up to 14 weeks with citalopram in the first step of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study were divided by household incomes of <$20,000, $20,000-<$40,000, and >or=$40,000. Attrition rates and sociodemographic and clinical correlates of attrition were identified for each group. RESULTS: Regardless of income level, remission rates were lower for participants who dropped out of treatment. Attrition rates increased as income decreased. For all income levels, younger age was independently associated with attrition. For the lowest income level, less education, better mental health functioning, being on public insurance, and having more concurrent Axis I conditions were associated with a greater likelihood of attrition. For the middle income group, less education, better mental health functioning, being Black or of another non-White race, and treatment in a psychiatric versus primary-care setting predicted greater attrition. For the highest income group, being Hispanic, having a family history of drug abuse, and melancholic features predicted attrition. Atypical symptom features (middle income group) and recurrent depression (highest income group) were associated with retention. CONCLUSIONS: Efforts to retain patients in antidepressant treatment should focus especially on less educated patients with lower household incomes and younger patients.

Voice response system to measure healthcare costs: a STAR*D report.

OBJECTIVE: To evaluate a telephone-operated, interactive voice response (IVR) system designed to collect use-of-care data from patients with major depression (UAC-IVR). STUDY DESIGN: Patient self-reports from repeated IVR surveys were compared with provider records for 3789 patients with major depression at 41 clinical sites participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHODS: UAC-IVR responses were examined for consistency and compared with provider records to compute reporting biases and intraclass correlation coefficients. Predictors of inconsistent responses and reporting biases were based on mixed logistic and regression models adjusted for need and predisposing and enabling covariates, and corrected for nesting and repeated measures. RESULTS: Inconsistent responses were found for 10% of calls and 21% of patients. Underreporting biases (-20%) and moderate agreement (intraclass correlation of 68%) were found when UAC-IVR responses were compared with medical records. IVR reporting biases were less for patients after 3 calls or more (experience), for patients with severe baseline symptoms (motivation), and for patients who gave consistent IVR responses (reliability). Bias was unrelated to treatment outcomes or demographic factors. CONCLUSION: Clinical managers should use IVR systems to collect service histories only after patients are properly trained and responses monitored for consistency and reporting biases.

What predicts attrition in second step medication treatments for depression?: a STAR*D Report.

Attrition rates are high during treatment for major depressive disorder (MDD), and patients who drop out are less likely to reach remission. This report evaluates the incidence, timing, and predictors of attrition during second-step medication treatment. Outpatients in the multisite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study receiving a medication augmentation (n=563) or medication switch (n=723) for non-psychotic MDD after an unsatisfactory outcome with citalopram were evaluated to determine attrition rates and pretreatment sociodemographic or clinical predictors of attrition. Twenty percent of participants receiving a medication augmentation and 27% receiving a medication switch dropped out before 12 wk in the second treatment step. Remission rates were lower for dropouts [7% vs. 43% (medication augmentation); 12% vs. 31% (medication switch)]. For medication augmentation, Black and other non-Caucasian races, Hispanic ethnicity, younger age, family history of drug abuse, concurrent drug abuse, sociodemographic disadvantage, less symptom improvement with initial citalopram treatment, and greater symptom severity when beginning augmentation were associated with attrition. For medication switch, Black and other non-Caucasian races, younger age, more melancholic features, and lower exit doses but more severe side-effects with citalopram treatment were associated with attrition. Minority status, younger age, and greater difficulty with the first treatment step are risk factors for attrition in the second treatment step. Focus on patients with attrition risk factors for medication augmentation or switch strategies may enhance retention and improve outcomes.

Acceptability of second-step treatments to depressed outpatients: a STAR*D report.

OBJECTIVE: Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients' willingness to accept different second-step treatment approaches. METHOD: Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only. RESULTS: Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy. CONCLUSIONS: Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment.

Family history of mood disorder and characteristics of major depressive disorder: a STAR*D (sequenced treatment alternatives to relieve depression) study.

INTRODUCTION: Clinicians routinely ask patients with major depressive disorder (MDD) about their family history. It is unknown, however, if patients who report a positive family history differ from those who do not. This study compared the demographic and clinical features of a large cohort of treatment-seeking outpatients with non-psychotic MDD who reported that they did or did not have at least one first-degree relative who had either MDD or bipolar disorder. METHODS: Subjects were recruited for the STAR( *)D multicenter trial. Differences in demographic and clinical features for patients with and without a family history of mood disorders were assessed after correcting for age, sex, race, and ethnicity. RESULTS: Patients with a family history of mood disorder (n=2265; 56.5%) were more frequently women and had an earlier age of onset of depression, as compared to those without such a history (n=1740; 43.5%). No meaningful differences were found in depressive symptoms, severity, recurrence, depressive subtype, or daily function. CONCLUSIONS: Women were twice as likely as men to report a positive family history of mood disorder, and a positive family history was associated with younger age of onset of MDD in the proband. Consistent with prior research, early age of onset appears to define a familial and, by extension, genetic subtype of major depressive disorder.

A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report.

OBJECTIVE: More than 40% of patients with major depressive disorder do not achieve remission even after two optimally delivered trials of antidepressant medications. This study compared the effectiveness of lithium versus triiodothyronine (T(3)) augmentation as a third-step treatment for patients with major depressive disorder. METHOD: A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or who were intolerant to an initial prospective treatment with citalopram and a second switch or augmentation trial were randomly assigned to augmentation with lithium (up to 900 mg/day; N=69) or with T(3) (up to 50 mug/day; N=73) for up to 14 weeks. The primary outcome measure was whether participants achieved remission, which was defined as a score < or =7 on the 17-item Hamilton Depression Rating Scale. RESULTS: After a mean of 9.6 weeks (SD=5.2) of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with T(3) augmentation, although the difference between treatments was not statistically significant. Lithium was more frequently associated with side effects (p=0.045), and more participants in the lithium group left treatment because of side effects (23.2% versus 9.6%; p=0.027). CONCLUSIONS: Remission rates with lithium and T(3) augmentation for participants who experienced unsatisfactory results with two prior medication treatments were modest and did not differ significantly. The lower side effect burden and ease of use of T(3) augmentation suggest that it has slight advantages over lithium augmentation for depressed patients who have experienced several failed medication trials.

Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report.

OBJECTIVE: The purpose of this study was to compare the effectiveness and tolerability of tranylcypromine and combination treatment with extended-release venlafaxine and mirtazapine in patients with treatment-resistant major depression whose current depressive episode had not responded adequately to treatment in three prior prospective medication trials. METHOD: Adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or had withdrawn from treatment because of intolerance in three previous prospective medication trials were randomly assigned to receive open-label treatment with either tranylcypromine (N=58) or extended-release venlafaxine plus mirtazapine (N=51). The primary outcome measure was whether patients achieved remission, which was defined as a score < or =7 at exit on the 17-item Hamilton Depression Rating Scale (HAM-D). The HAM-D was administered by telephone by raters to whom treatment was masked. RESULTS: Remission rates were not significantly different between the two treatment groups (6.9% for the tranylcypromine group and 13.7% for the venlafaxine plus mirtazapine group). The mean daily dose at exit for tranylcypromine was 36.9 mg (SD=18.5); for venlafaxine, 210.3 mg (SD=95.2); and for mirtazapine, 35.7 mg (SD=17.6). Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance. CONCLUSIONS: Remission rates were modest for both the tranylcypromine group and the extended-release venlafaxine plus mirtazapine group, and the rates were not statistically different between groups. The lower side effect burden, lack of dietary restrictions, and ease of use of venlafaxine and mirtazapine suggest that this combination may be preferred over tranylcypromine for patients with highly treatment-resistant depression who have not benefited adequately from several prior treatments.

Comparison of self-report and clinician ratings on two inventories of depressive symptomatology.

OBJECTIVE: This study evaluated the concordance between the self-report and the clinician-rated versions of the Inventory of Depressive Symptomatology (IDS-30) and between the two versions of the briefer 16-item Quick Inventory of Depressive Symptomatology (QIDS-16). METHODS: Data were gathered for 544 adult outpatients with psychotic (N = 106) or nonpsychotic (N = 438) major depressive disorder at 14 public sector mental health clinics in the Texas Medication Algorithm Project. Data for the QIDS-16 were extracted from the IDS-30. Baseline scores and scores from the final study visit at or before month 12 were analyzed. The clinician-rated and the self-report versions of each scale were compared in their identification of response to treatment and remission. RESULTS: The average baseline IDS-SR-30 total score was 2.2 points higher (indicating greater severity) than the IDS-C-30 score; the average QIDS-SR-16 total score was only .3 points higher than the QIDS-C-16 score. The IDS-SR-30 and the IDS-C-30, as well as the QIDS-C-16 and QIDS-SR-16, agreed substantially in classifying response and remission for patients, regardless of whether the patients had psychotic features. None of a large number of clinical and demographic features accounted for differences between the QIDS-SR-16 and QIDS-C-16 total scores. CONCLUSIONS: Either the IDS-30 or the QIDS-16 self-report adequately assesses depressive symptom severity among public-sector outpatients with major depressive disorder. The briefer QIDS-16 may be preferred to save time and cost.

Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.

BACKGROUND: After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor (SSRI), it is not known whether switching to one antidepressant is more effective than switching to another. METHODS: We randomly assigned 727 adult outpatients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks: sustained-release bupropion (239 patients) at a maximal daily dose of 400 mg, sertraline (238 patients) at a maximal daily dose of 200 mg, or extended-release venlafaxine (250 patients) at a maximal daily dose of 375 mg. The study was conducted in 18 primary and 23 psychiatric care settings. The primary outcome was symptom remission, defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of the study. Scores on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16), obtained at treatment visits, determined secondary outcomes, including remission (a score of 5 or less at exit) and response (a reduction of 50 percent or more on baseline scores). RESULTS: Remission rates as assessed by the HRSD-17 and the QIDS-SR-16, respectively, were 21.3 percent and 25.5 percent for sustained-release bupropion, 17.6 percent and 26.6 percent for sertraline, and 24.8 percent and 25.0 percent for extended-release venlafaxine. QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion, 26.7 percent for sertraline, and 28.2 percent for extended-release venlafaxine. These treatments did not differ significantly with respect to outcomes, tolerability, or adverse events. CONCLUSIONS: After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression. (ClinicalTrials.gov number, NCT00021528.).

Medication augmentation after the failure of SSRIs for depression.

BACKGROUND: Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach. METHODS: We randomly assigned 565 adult outpatients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy (mean final dose, 55 mg per day) to receive sustained-release bupropion (at a dose of up to 400 mg per day) as augmentation and 286 to receive buspirone (at a dose of up to 60 mg per day) as augmentation. The primary outcome of remission of symptoms was defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of this study; scores were obtained over the telephone by raters blinded to treatment assignment. The 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR-16) was used to determine the secondary outcomes of remission (defined as a score of less than 6 at the end of this study) and response (a reduction in baseline scores of 50 percent or more). RESULTS: The sustained-release bupropion group and the buspirone group had similar rates of HRSD-17 remission (29.7 percent and 30.1 percent, respectively), QIDS-SR-16 remission (39.0 percent and 32.9 percent), and QIDS-SR-16 response (31.8 percent and 26.9 percent). Sustained-release bupropion, however, was associated with a greater reduction (from baseline to the end of this study) in QIDS-SR-16 scores than was buspirone (25.3 percent vs. 17.1 percent, P<0.04), a lower QIDS-SR-16 score at the end of this study (8.0 vs. 9.1, P<0.02), and a lower dropout rate due to intolerance (12.5 percent vs. 20.6 percent, P<0.009). CONCLUSIONS: Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings. Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events. (ClinicalTrials.gov number, NCT00021528.).

Enrolling research subjects from clinical practice: ethical and procedural issues in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial is a multi-site effectiveness study funded by the National Institute of Mental Health (NIMH) with the aim of identifying successful, acceptable and cost-effective treatment strategies for outpatients with unremitted depression. With enrollment of 4,041 adults with major depressive disorder (MDD), it is the largest controlled psychiatric treatment study ever undertaken. In the course of developing procedures to ensure that ambitious enrollment goals were met, a number of ethical and practical issues became apparent that underscore the conflicts between effectiveness research and human subject protections. These are delineated as they relate to study design; eligibility criteria; incentives to subjects; investigators and clinical sites; the complementary roles of clinical research coordinators (CRCs) and study clinicians; and recruitment and consent procedures. The STAR*D trial exemplifies the interplay and tension between those strategies that integrate research and clinical aims and roles in the service of enhancing external validity, site participation, and recruitment and retention versus those strategies that differentiate research and clinical treatment in the service of research integrity and human subject protections. We hope that a discussion of these key challenges and dilemmas and how they have been addressed will help inform future discussions concerning design and conduct of ethical effectiveness trials designed to optimize care in real world clinical settings.