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.

The relationship between adverse events during selective serotonin reuptake inhibitor treatment for major depressive disorder and nonremission in the suicide assessment methodology study.

Little is known about the association between antidepressant treatment-emergent adverse events and symptom nonremission in major depressive disorder. The objective of the current analysis was to determine whether particular baseline symptoms or treatment-emergent symptoms (adverse events) during the first 2 weeks are associated with nonremission after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI).Outpatients clinically diagnosed with nonpsychotic major depressive disorder were recruited from 6 primary and 9 psychiatric care sites. Participants (n = 206) were treated with an SSRI antidepressant (citalopram [20-40 mg/d], escitalopram [10-20 mg/d], fluoxetine [20-40 mg/d], paroxetine [20-40 mg/d], paroxetine CR [25-37.5 mg/d], or sertraline [50-150 mg/d]) for 8 weeks. Remission was defined as having a score of 5 or less on the 16-item Quick Inventory of Depressive Symptomatology-Clinician-Rated at week 8, or using last observation carried forward. Adverse events were identified using the 55-item Systematic Assessment for Treatment Emergent Events-Systematic Inquiry completed by participants at baseline and week 2.Findings indicated that the emergence of adverse events of weakness/fatigue, strange feeling, and trouble catching breath/hyperventilation at week 2 were independently associated with lack of remission even after controlling for the potential confounders of baseline depressive severity, anxious symptoms, antidepressant medication, chronic depression, race, burden of general medical comorbidity, and time in study. Hearing/seeing things appeared to have a protective effect. In conclusion, during SSRI treatment, the adverse events of weakness/fatigue, feeling strange, and trouble catching breath/hyperventilation are associated with nonremission, possibly due to lower adherence, early attrition, difficulty increasing the dose, and reduced efficacy.

A Comparison of the QIDS-C16, QIDS-SR16, and the MADRS in an Adult Outpatient Clinical Sample.

BACKGROUND: This study compared the 16-item Clinician and Self-Report versions of the Quick Inventory of Depressive Symptomatology (QIDS-C16 and QIDS-SR16) and the 10-item Montgomery-Asberg Depression Rating Scale (MADRS) in adult outpatients. The comparison was based on psychometric features and their performance in identifying those in a major depressive episode as defined by the Mini-International Neuropsychiatric Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. METHODS: Of 278 consecutive outpatients, 181 were depressed. Classical test theory, factor analysis, and item response theory were used to evaluate the psychometric features and receiver operating characteristic (ROC) analyses. RESULTS: All three measures were unidimensional. All had acceptable reliability (coefficient a=.87 for MADRS10, .82 for QIDS-C16, and .80 for QIDS-SR16). Test information function was higher for the MADRS (ie, it was most sensitive to individual differences in levels of depression). The MADRS and QIDS-C16 slightly but consistently outperformed the QIDS-SR16 in differentiating between depressed versus nondepressed patients. CONCLUSION: All three measures have satisfactory psychometric properties and are valid screening tools for a major depressive episode.

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.

Maximizing the adequacy of medication treatment in controlled trials and clinical practice: STAR(*)D measurement-based care.

The success of well-developed protocols has been limited in real-world practice, where even effective strategies have not been sufficient to meet patient needs in routine clinical care owing to Axis I and III comorbidities. The Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) trial required that antidepressant medication treatment be optimal regarding dose and duration, yet accommodate flexibility to ensure safety given the wide range of comorbid general medical and psychiatric disorders allowed in the trial. The objective of this study was to develop a measurement-based care (MBC) approach and an automated feedback system to ensure adequate and safe antidepressant treatment delivery suitable for both clinical research and routine practice. Ratings of depressive symptom severity and side-effect frequency, intensity, and burden were obtained at each treatment visit using the MBC system that (1) guided medication dose adjustments and treatment duration, (2) documented clinician adherence to treatment recommendations, and (3) provided prompt feedback to clinicians to enhance appropriate treatment decisions. Physician adherence to protocol-specific treatment was monitored based on measured symptoms and side-effect burden, and dose and duration of antidepressant at each critical decision point during the acute phase treatment of major depression. Feedback was provided at the point of care by the clinical coordinators, assisted by Web-based reports following each treatment visit. On the basis of the first treatment step with citalopram, over 85% of treatment encounters had appropriate fidelity to recommendations. Most deviations from treatment recommendations occurred late in treatment and were often justifiable. MBC proved to be feasible and effective in busy primary and psychiatric settings. This approach signals a paradigm shift toward the use of measurement-based clinical decisions, both at the point of care and following each visit, to deliver optimal pharmacotherapy for depression.

Electronic source materials in clinical research: acceptability and validity of symptom self-rating in major depressive disorder.

OBJECTIVES: Clinical research projects gather large amounts of data. Typically, information is captured on paper source documents for later transcription to an electronic format, where responses can be checked, and errors, omissions, and inconsistencies can be resolved. These steps contribute delays, cost, and complexity to clinical research, particularly in large-scale multi-site investigations. To address these issues, we used a mobile computing device with a touch-screen display ("tablet PC") to capture clinical data from depressed patients directly into electronic format. We then examined ease of use, the equivalence of responses between paper and electronic methods, and the acceptability of the tablet PC for this clinical population. SETTINGS: Outpatient clinics at four medical centers. METHODS: 80 adults with major depressive disorder (MDD) completed the 16-item Quick Inventory of Depressive Symptomatology--Self-Rated (QIDS-SR(16)), using both traditional paper forms and an electronic representation of the same questions; participants also completed a survey to evaluate their experience. RESULTS: QIDS-SR(16) responses from paper and electronic versions were highly correlated (mean total: 15.3 (SD=5.2) electronic vs. 15.1 (SD=5.2) paper format), and showed high inter-rating reliability for overall score (intra-class correlation 0.987 (with a 95%CI [0.979,0.992])) and high degree of association for individual symptom items. Participants found both methods acceptable and overall found the electronic implementation easier to use. CONCLUSIONS: QIDS-SR(16) values collected electronically from research participants were equivalent to those collected using traditional paper self-assessment forms. Participants with MDD found the tablet PC version to be acceptable and easier to use than the paper forms.

Clinical and demographic factors associated with DSM-IV melancholic depression.

BACKGROUND: The purpose of this paper is to use demographic and clinical data from a large diverse group of outpatients diagnosed with non-psychotic major depression to investigate the validity of the DSM-IV concept of melancholic depression. METHODS: Baseline clinical and demographic data were collected on 1500 outpatients (1456 of whom melancholia could be determined) with non-psychotic major depressive disorder (MDD) participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Depressive symptom severity was assessed by clinical telephone interview using the 17-item Hamilton Rating Scale for Depression (HRS-D17) and the 30-item Inventory of Depressive Symptomatology (IDS-C30). The types and degrees of concurrent psychiatric symptoms were measured using a self report, the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items relevant to each diagnostic category endorsed by study participants. RESULTS: Adjusting for severity of depression (as measured by the total HRS-D17 scores), no differences were found in the rate of melancholic depression by race, marital status, education, employment status, family history of depression, primary care versus specialty care, monthly income, and degree of psychiatric and medical co-morbidity. Melancholic depression was significantly more likely in men than women. Melancholic depression after adjustment for severity was associated with a slightly younger age at study entry, as well as with greater illness severity, and slightly shorter duration of current episode. Hispanic ethnicity was associated with lower melancholic depression rates at the .06 level of significance. CONCLUSIONS: Among outpatients with MDD, melancholic features were less likely in Hispanic patients, but more likely in slightly younger patients and in men. Melancholic features were also related to a slightly shorter current episode. These findings are consistent with the notion that external socio-demographic factors do not play an important role in the pathophysiology of melancholic depression.

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.

Pregnancy and delivery while receiving vagus nerve stimulation for the treatment of major depression: a case report.

BACKGROUND: Depression during pregnancy can have significant health consequences for the mother and her infant. Antidepressant medications, which pass through the placenta, may increase the risk of low birth weight and preterm delivery. The use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy may induce serotonergic symptoms in the infant after delivery. Antidepressant medications in breast milk may also be passed to an infant. Vagus nerve stimulation (VNS) therapy is an effective non-pharmacologic treatment for treatment-resistant depression (TRD), but little information exists regarding the use of VNS therapy during pregnancy. CASE PRESENTATION: The patient began receiving VNS therapy for TRD in March 1999. The therapy was effective, producing substantial reductions in depressive symptoms and improvement of function. In 2002, the patient reported that she was pregnant. She continued receiving VNS therapy throughout her pregnancy, labor, and delivery, which enabled the sustained remission of her depression. The pregnancy was uneventful; a healthy daughter was delivered at full term. CONCLUSION: In this case, VNS therapy provided effective treatment for TRD during pregnancy and delivery. VNS was safe for the patient and her child.

Characteristics of insured and noninsured outpatients with depression in STAR(*)D.

OBJECTIVE: This study examined data from the first 1,500 patients with major depressive disorder who were entered into the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) and compared baseline characteristics of outpatients on the basis of their insurance status. METHODS: We compared the demographic and clinical characteristics and the features of the presenting symptoms of outpatients with private insurance, public insurance, Medicaid and Medicare, or no insurance who were seeking treatment for depression. RESULTS: Valid insurance data were available for 1,452 patients. Compared with patients with private insurance, patients with public or no insurance were more likely to be members of a racial or ethnic minority group, unmarried, less educated, and unemployed. Patients were more likely to attend primary care clinics if they had public insurance (46 percent) compared with private insurance (34 percent) or no insurance (30 percent). Compared with the other groups, patients with public insurance had the greatest number and severity of comorbid medical conditions. In general, compared with patients with private insurance, those with public or no insurance had greater severity of depression, more comorbid psychiatric symptoms, lower life satisfaction scores, and greater functional impairment. These findings remained after the analyses adjusted for gender, employment, comorbid medical conditions, race, and duration of illness. CONCLUSIONS: Compared with patients with private insurance, those with public or no insurance had a more chronic, more severe, and more disabling form of depression.

Quality improvement methods as applied to a multicenter effectiveness trial--STAR*D.

In multicenter clinical trials, important aspects of trial performance (e.g., the number of participants who enter the trial within the required time frame, the number of participants who remain in the trial, and/or the completeness of the outcome data collected) directly affect the extent to which the study can achieve its aims. Obtaining the maximum amount of data from the maximum number of participants at each step in the trial increases the likelihood of identifying real differences in outcome. These aspects of trial performance can, therefore, be considered intermediate performance goals of the study since success in achieving each of them is directly related to success in achieving study aims. A quality improvement system was introduced to improve efficiency and performance in the multicenter Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Four intermediate performance goals were targeted for quality improvement efforts: (1) initial enrollment of subjects, (2) collection of entry/exit primary outcome data, (3) retention of subjects to enter subsequent "levels" of the trial, and (4) collection of blood samples for genetics studies. The identification of numerical targets for these goals provides a basis for monitoring performance and for implementing attempts to improve performance, since success in achieving each goal is directly related to success in achieving the study aims. This paper describes the background, rationale, development, and potential utility of implementing a quality improvement system to improve the performance and efficiency of the trial.

Suicide risk management for the sequenced treatment alternatives to relieve depression study: applied NIMH guidelines.

NIMH guidelines to manage subjects who are suicidal during their participation in clinical trials include a full range of procedures to minimize suicidal risk, yet no reports to date have shown how researchers should best implement these guidelines. The architects of the sequenced treatment alternatives to relieve depression (STAR*D) study operationalized and implemented the NIMH guidelines by developing a comprehensive set of procedures to detect, monitor, and manage suicidal subjects during a large, complex, multisite clinical trial. Because of the large size of the study (anticipated n = 4000), the wide geographic distribution, the large number of treating STAR*D clinicians, the broad array of subjects with psychiatric and medical comorbidities, and the focus on treatment-resistant depression, along with the complexity of multiple treatment steps and randomization points in STAR*D, the risk of suicide, safety monitoring of suicidal subjects presented a unique challenge. This paper describes methods derived from the NIMH guidelines used to manage suicidal risk in STAR*D including the use of an interactive voice response system to alert clinicians, regional center directors, and safety officers.

Methods of testing feasibility for sequenced treatment alternatives to relieve depression (STAR*D).

In large multi-site trials, a feasibility or pilot study can be crucial to test the functionality of all aspects of conducting the study prior to the initiation of the formal study. A feasibility trial was conducted for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Project, a multi-site, prospective, sequentially randomized, clinical trial of outpatients with nonpsychotic major depressive disorder. From 14 December 2000 to 8 June 2001, 42 patients were screened for enrollment into the STAR*D Feasibility Trial. Twenty-four patients who were eligible and consented to participate were treated with citalopram for up to 12 weeks. During the course of this trial, issues were raised that resulted in modifications to the study procedures. Modifications made as a result of this trial affected four domains: (1) communication, (2) patient and provider burden, (3) data collection forms, and (4) recruitment and retention of subjects. This paper describes what was learned during the STAR*D Feasibility Trial so researchers planning to conduct similar trials can learn the practical issues related to conducting such a research project. While the information gathered was useful, it did delay the initiation of the formal trial. We view this cost as an investment in the development of overall study procedures that should lead to a stronger study.

Web-based communications and management of a multi-center clinical trial: the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project.

While efficient methods of communication are known to be essential in conducting large multicenter clinical trials, very little information is provided on actual methods that can be implemented to improve communication. An integrated technology-based communication system was developed for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project, which prospectively defines treatments that are most effective for participants with a diagnosis of a nonpsychotic major depressive disorder (MDD) who report an unsatisfactory clinical outcome to an initial and, if necessary, subsequent treatment(s). This web-based communication system is comprised of a multi-faceted study Web site, including a help desk, document sharing, a project directory and reports. In addition, automated reporting via e-mail and an online data correction mechanism are also available. The STAR*D communication system improves communication between study personnel and improves the quality of the study's data through the integration of system elements, the integration of those elements with traditional forms of communication,, by filling the gaps not addressed by those traditional methods and by reducing the staff workload burden.