THE DEPRESSION INVENTORY DEVELOPMENT SCALE: Assessment of Psychometric Properties Using Classical and Modern Measurement Theory in a CAN-BIND Trial.

Objective: The goal of the Depression Inventory Development (DID) project is to develop a comprehensive and psychometrically sound rating scale for major depressive disorder (MDD) that reflects current diagnostic criteria and conceptualizations of depression. We report here the evaluation of the current DID item bank using Classical Test Theory (CTT), Item Response Theory (IRT) and Rasch Measurement Theory (RMT). Methods: The present study was part of a larger multisite, open-label study conducted by the Canadian Biomarker Integration Network in Depression (ClinicalTrials.gov: NCT01655706). Trained raters administered the 32 DID items at each of two visits (MDD: baseline, n=211 and Week 8, n=177; healthy participants: baseline, n=112 and Week 8, n=104). The DID's "grid" structure operationalizes intensity and frequency of each item, with clear symptom definitions and a structured interview guide, with the current iteration assessing symptoms related to anhedonia, cognition, fatigue, general malaise, motivation, anxiety, negative thinking, pain, and appetite. Participants were also administered the Montgomery- Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) that allowed DID items to be evaluated against existing "benchmark" items. CTT was used to assess data quality/reliability (i.e., missing data, skewness, scoring frequency, internal consistency), IRT to assess individual item performance by modelling an item's ability to discriminate levels of depressive severity (as assessed by the MADRS), and RMT to assess how the items perform together as a scale to capture a range of depressive severity (item targeting). These analyses together provided empirical evidence to base decisions on which DID items to remove, modify, or advance. Results: Of the 32 DID items evaluated, eight items were identified by CTT as problematic, displaying low variability in the range of responses, floor effects, and/or skewness; and four items were identified by IRT to show poor discriminative properties that would limit their clinical utility. Five additional items were deemed to be redundant. The remaining 15 DID items all fit the Rasch model, with person and item difficulty estimates indicating satisfactory item targeting, with lower precision in participants with mild levels of depression. These 15 DID items also showed good internal consistency (alpha=0.95 and inter-item correlations ranging from r=0.49 to r=0.84) and all items were sensitive to change following antidepressant treatment (baseline vs. Week 8). RMT revealed problematic item targeting for the MADRS and QIDSSR, including an absence of MADRS items targeting participants with mild/moderate depression and an absence of QIDS-SR items targeting participants with mild or severe depression. Conclusion: The present study applied CTT, IRT, and RMT to assess the measurement properties of the DID items and identify those that should be advanced, modified, or removed. Of the 32 items evaluated, 15 items showed good measurement properties. These items (along with previously evaluated items) will provide the basis for validation of a penultimate DID scale assessing anhedonia, cognitive slowing, concentration, executive function, recent memory, drive, emotional fatigue, guilt, self-esteem, hopelessness, tension, rumination, irritability, reduced appetite, insomnia, sadness, worry, suicidality, and depressed mood. The strategies adopted by the DID process provide a framework for rating scale development and validation.

Use of a Fully Automated Internet-Based Cognitive Behavior Therapy Intervention in a Community Population of Adults With Depression Symptoms: Randomized Controlled Trial.

BACKGROUND: Although internet-based cognitive behavior therapy (iCBT) interventions can reduce depression symptoms, large differences in their effectiveness exist. OBJECTIVE: The aim of this study was to evaluate the effectiveness of an iCBT intervention called Thrive, which was designed to enhance engagement when delivered as a fully automated, stand-alone intervention to a rural community population of adults with depression symptoms. METHODS: Using no diagnostic or treatment exclusions, 343 adults with depression symptoms were recruited from communities using an open-access website and randomized 1:1 to the Thrive intervention group or the control group. Using self-reports, participants were evaluated at baseline and 4 and 8 weeks for the primary outcome of depression symptom severity and secondary outcome measures of anxiety symptoms, work and social adjustment, psychological resilience, and suicidal ideation. RESULTS: Over the 8-week follow-up period, the intervention group (n=181) had significantly lower depression symptom severity than the control group (n=162; P<.001), with a moderate treatment effect size (d=0.63). Moderate to near-moderate effect sizes favoring the intervention group were observed for anxiety symptoms (P<.001; d=0.47), work/social functioning (P<.001; d=0.39), and resilience (P<.001; d=0.55). Although not significant, the intervention group was 45% less likely than the control group to experience increased suicidal ideation (odds ratio 0.55). CONCLUSIONS: These findings suggest that the Thrive intervention was effective in reducing depression and anxiety symptom severity and improving functioning and resilience among a mostly rural community population of US adults. The effect sizes associated with Thrive were generally larger than those of other iCBT interventions delivered as a fully automated, stand-alone intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT03244878; https://clinicaltrials.gov/ct2/show/NCT03244878.

Interactive Voice Response and Text-based Self-report Versions of the Electronic Columbia-Suicide Severity Rating Scale Are Equivalent.

Objectives: Our study objective was to compare the equivalence of a new version of the electronic Columbia-Suicide Severity Rating Scale that was administered on a tablet device with the existing interactive voice response version in order to support the prospective monitoring of suicidal ideation and behavior in clinical trials and clinical practice. Design: This was a randomized, crossover-equivalence study with no treatment intervention. Setting: The study setting was a psychiatric hospital. Participants: Fifty-eight recently admitted psychiatric inpatients and 28 employees of the hospital site were included in the study. Mean age was 41.0 years (standard deviation=12.5), and 59 percent were female. Measurements: Participants completed both tablet and interactive voice response versions in randomized order, with a 25-minute break between administrations. Finally, participants completed a second administration of the first administered version. Intraclass correlation coefficients (ICCs) and Kappa coefficients were used to evaluate agreement across modalities. Results: High levels of agreement were observed for most severe lifetime (ICC=0.88) and recent (ICC=0.79) ideation, occurrence of actual lifetime (Kappa=0.81) and recent (Kappa=0.73) suicide attempts, and occurrence of lifetime interrupted attempts (Kappa=0.78), aborted attempts (Kappa=0.54), and preparatory behaviors (Kappa=0.77), as well as non-suicidal self-injurious behavior (Kappa=0.73). Scores from both modes significantly differentiated psychiatric patients and hospital employee controls, and the test-retest reliability of both modes was excellent. Conclusions: These results support the validity and reliability of the new tablet-based electronic Columbia-Suicide Severity Rating Scale. This will allow the inclusion of the electronic Columbia-Suicide Severity Rating Scale in a wider range of clinical studies, particularly where a tablet is also being used to collect other study data.

The Depression Inventory Development Workgroup: A Collaborative, Empirically Driven Initiative to Develop a New Assessment Tool for Major Depressive Disorder.

The Depression Inventory Development project is an initiative of the International Society for CNS Drug Development whose goal is to develop a comprehensive and psychometrically sound measurement tool to be utilized as a primary endpoint in clinical trials for major depressive disorder. Using an iterative process between field testing and psychometric analysis and drawing upon expertise of international researchers in depression, the Depression Inventory Development team has established an empirically driven and collaborative protocol for the creation of items to assess symptoms in major depressive disorder. Depression-relevant symptom clusters were identified based on expert clinical and patient input. In addition, as an aid for symptom identification and item construction, the psychometric properties of existing clinical scales (assessing depression and related indications) were evaluated using blinded datasets from pharmaceutical antidepressant drug trials. A series of field tests in patients with major depressive disorder provided the team with data to inform the iterative process of scale development. We report here an overview of the Depression Inventory Development initiative, including results of the third iteration of items assessing symptoms related to anhedonia, cognition, fatigue, general malaise, motivation, anxiety, negative thinking, pain and appetite. The strategies adopted from the Depression Inventory Development program, as an empirically driven and collaborative process for scale development, have provided the foundation to develop and validate measurement tools in other therapeutic areas as well.

Computer-assisted cognitive behavior therapy for obsessive-compulsive disorder: a randomized trial on the impact of lay vs. professional coaching.

BACKGROUND: The purpose of the study was to examine the impact of computerized cognitive behavior therapy (CBT) self-help treatment for obsessive-compulsive disorder (OCD) (BT Steps) both alone and when supported by coaching from either a lay non-therapist coach or an experienced CBT therapist. METHODS: Eighty-seven subjects with clinically significant OCD were recruited through newspaper ads and randomly assigned to receive 12 weeks of treatment with either BT Steps alone (n = 28), BT Steps with non-therapist coaching (n = 28), or BT Steps with CBT therapist coaching (n = 31). Subjects worked on BT Steps at their own pace. Subjects receiving BT Steps alone received a welcome call from the project manager. Subjects randomized to either of the coaching arms received regularly scheduled weekly phone calls for coaching, encouragement, and support. No formal therapy was provided by the coaches; thus, both lay and CBT coaches completed the same tasks. RESULTS: All three treatment arms showed a significant reduction in Yale-Brown Obsessive Compulsive Scale (YBOCS) scores, with mean (SD) changes of 6.5 (5.7), 7.1 (6.1), and 6.5 (6.1) for the no coaching, lay coaching, and therapist coaching arms, respectively (all p's < .001). These represent effect sizes of 1.16, 1.41, and 1.12, respectively. No significant differences were found between treatment arms on YBOCS change scores, F(2) = 0.10, p = .904, or number of exposures sessions done (F(2) = 0.033, p = .967). When asked which method of therapy (computer vs. clinician) they preferred, 48% said computer, 33% said face-to-face therapy, and 19% had no preference. CONCLUSIONS: Results support the use of online self-help for the treatment of moderate OCD. The addition of coaching by either a lay coach or a CBT therapist coach did not significantly improve outcomes.

Prospective assessment of suicidal ideation and behavior: an internet survey of pharmaceutical sponsor practices.

OBJECTIVE: To survey the current approaches of clinical trial sponsors in prospective suicidal ideation and behavior assessments and challenges encountered. DESIGN: An internet-based survey. SETTING: Inclusion of prospective assessments of suicidal ideation and behavior in industry-sponsored clinical studies were required following the release of the September 2010 United States Federal Drug Administration draft guidance. The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Workgroup conducted an online survey to understand industry practices and experiences in implementing suicidal ideation and behavior assessments in clinical trials. PARTICIPANTS: The survey was sent to 1,447 industry employees at 178 pharmaceutical companies. A total of 89 evaluable responses, representing 39 companies, were obtained. MEASUREMENTS: A 30-item internet survey was developed asking about potential challenges and issues in implementing prospective suicidal ideation and behavior assessments. RESULTS: Common factors in deciding whether to include suicidal ideation and behavior assessments in a clinical trial were psychiatric or neurologic drug product (95%); central nervous system activity (78%); disease (74%) and patient population (71%); and regulatory announcements and policies (74%). The most common challenges in implementing suicidal ideation and behavior assessments included cross-cultural differences in acceptance of SIB assessments (40%); obtaining adequate baseline history (36.8%); obtaining translations (35%); investigator/rater discomfort with asking about suicidal ideation and behavior (32%); and inadequate training of raters to administer suicidal ideation and behavior ratings (30%). CONCLUSION: Among sponsors surveyed, the implementation rate of suicidal ideation and behavior assessment in central nervous systems studies is very high. Most have used the Columbia-Suicide Severity Rating Scale. Challenges regarding standardization of retrospective assessment timeframes and differing approaches to summarizing and analyzing suicidal ideation and behavior-related study data were frequently reported. These results suggest that inconsistent reports of suicidal ideation and behavior within study datasets may occur and that integration of data across studies remains a concern.

Predictive Value of Baseline Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) Assessments for Identifying Risk of Prospective Reports of Suicidal Behavior During Research Participation.

OBJECTIVE: Examine the ability of baseline electronic Columbia-Suicide Severity Rating Scale lifetime suicidal ideation and behavior categories to predict prospective reports of suicidal behavior in psychiatric and non-psychiatric research participants. DESIGN: Meta-analysis of 74,406 eC-SSRS assessments completed between September 2009 and December 2012. SETTING: Thirty-three clinical research studies that used the electronic Columbia-Suicide Severity Rating Scale to assess suicidal ideation and behavior at baseline and prospectively during follow-up visits. PARTICIPANTS: Records from 6,760 patients with psychiatric disorders (opioid dependence, generalized anxiety, major depressive, and posttraumatic stress disorders) and 2,077 nonpsychiatric disorder patients (chronic obstructive pulmonary disease, epilepsy, fibromyalgia, human immunodeficiency virus, insomnia, multiple sclerosis, osteoarthritis, pain/back pain, Parkinson's disease, restless leg syndrome) were analyzed. MEASUREMENTS: Electronic Columbia-Suicide Severity Rating Scale assessment of lifetime suicidal ideation (5 severity levels) and suicidal behavior (4 types) at baseline and prospectively reported suicidal behavior during study participation. RESULTS: Increasingly more severe lifetime suicidal ideation at baseline was associated with a progressively greater likelihood of prospectively reported suicidal behavior during study participation. Intent to act on suicidal ideation was most predictive of reports of suicidal behavior. Reports of lifetime suicidal behaviors at baseline also predicted subsequent suicidal behavior, and multiple lifetime behaviors monotonically increased prospective risk of suicidal behavior. Baseline suicidal ideation and behavior predicted future suicidal behavior in both psychiatric and non-psychiatric trials. CONCLUSIONS: Lifetime reports of suicidal ideation and/or behavior at baseline significantly increased risk of prospectively reporting suicidal behavior during research trial participation in both psychiatric and nonpsychiatric patients. Lifetime prevalence of suicidal ideation and behavior is higher among psychiatric patients, but also presents a safety concern among nonpsychiatric patients when reported.

Prediction of suicidal behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the electronic Columbia-Suicide Severity Rating Scale.

OBJECTIVE: To evaluate whether lifetime suicidal ideation with intention to act and/or suicidal behaviors reported at baseline predict risk of prospectively reporting suicidal behavior during subsequent study participation. METHOD: Data from studies using the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) to prospectively monitor suicidal ideation and behaviors between September 2009 and May 2011 were analyzed. Studies included patients with major depressive disorder, insomnia, posttraumatic stress disorder, epilepsy, and fibromyalgia. Records for 35,224 eC-SSRS assessments were extracted. Incomplete assessments and eC-SSRS records from patients missing a baseline assessment or with no prospective follow-up assessments were excluded. Baseline lifetime eC-SSRS reports were categorized as negative (no lifetime ideation with intent to act or prior suicidal behavior) or positive (lifetime ideation with intent to act but no prior behavior, no ideation with intent to act but prior behavior, or both lifetime ideation with intent and prior behavior). RESULTS: 3,776 patients completed a baseline and 1 or more follow-up assessments. The mean follow-up period was 64 days. Of patients with negative lifetime reports, 2.4% subsequently reported suicidal behavior during study participation, compared to 12.0% of patients with lifetime ideation with intent only (OR = 5.55; 95% CI, 2.65-11.59), 9.6% of patients with lifetime behavior only (OR = 4.33; 95% CI, 2.94-6.39), and 18.3% of patients with both (OR = 9.13; 95% CI, 6.47-12.88). Sensitivity and specificity of positive reports for identifying suicidal behaviors were 0.67 and 0.76, respectively. CONCLUSIONS: Patients reporting lifetime suicidal ideation with intent to act and/or prior suicidal behavior at baseline are 4 to 9 times more likely to prospectively report suicidal behavior during study participation.

Safety and tolerability of duloxetine in elderly patients with major depressive disorder: a pooled analysis of two placebo-controlled studies.

The objective of this study was to examine the safety and tolerability of duloxetine hydrochloride, a serotonin-norepinephrine reuptake inhibitor, in a large cohort of elderly patients with major depressive disorder. Data were pooled from 8-week and 12-week, double-blind, randomized, placebo-controlled trials of duloxetine 60 mg/day (duloxetine=456; placebo=225). Discontinuation rates because of adverse events, treatment-emergent adverse events, abnormal changes in vital signs and weight, and changes in laboratory analytes were compared between treatments using a Cochran-Mantel-Haenszel test. Changes in laboratory analytes were analyzed using an analysis of variance model. Adverse event-related discontinuation rates were not significantly different between duloxetine and placebo (10.7 vs. 7.1%; P=0.13). Treatment-emergent adverse events for duloxetine of at least 5% and twice the rate of placebo were dry mouth, constipation, nausea, diarrhea, dizziness, and fatigue. Abnormal changes in vital signs and weight were not significantly different at any time between duloxetine and placebo. The mean changes in platelet count, alkaline phosphatase, potassium, random glucose, uric acid, and cholesterol were significantly different between duloxetine and placebo (P<0.05), but none of these differences were considered clinically relevant. The incidence of abnormal low sodium levels was not significantly different between treatments. These safety results may better inform clinicians providing individualized care to elderly patients with major depressive disorder.

A pragmatic 12-week, randomized trial of duloxetine versus generic selective serotonin-reuptake inhibitors in the treatment of adult outpatients in a moderate-to-severe depressive episode.

Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors (SSRIs) in severe major depressive disorder (MDD). This prospective pragmatic trial tests this hypothesis. Patients with severe MDD were randomly assigned to either duloxetine (a serotonin and norepinephrine-reuptake inhibitor) or physicians' choice of four generic SSRIs. Nonblinded, flexibly dosed treatment was used to mimic clinical practice. To address potential investigator bias, the patient-reported Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) was used as the primary efficacy outcome measure. A total of 750 outpatients (19.2%, African descent; 14.8%, Hispanic) were randomized. The primary outcome, remission at week 12 by QIDS-SR, was numerically greater for duloxetine compared with SSRIs (36 vs. 32%), but this difference was not statistically significant. Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item, the Brief Pain Inventory, and the Sheehan Disability Scale. Remission superiority on the QIDS-SR was not achieved. Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning. Study demographics suggest a more generalizable racial and ethnic population than is typical in randomized clinical trials.

Efficacy of pregabalin in preventing relapse in patients with generalized social anxiety disorder: results of a double-blind, placebo-controlled 26-week study.

The objective of this study was to evaluate the efficacy and safety of pregabalin in preventing relapse in generalized social anxiety disorder (SAD). Patients with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) generalized SAD, who met responder criteria after 10 weeks of open-label treatment with fixed-dose pregabalin (450 mg/day; n=153), were randomly assigned to 26 weeks of double-blind treatment with pregabalin (450 mg/day) or placebo. The primary a-priori outcome of time to relapse was analyzed using the Kaplan-Meier method and the log-rank test. Double-blind treatment with pregabalin was associated with significant delay in time to relapse versus placebo (P=0.035), and with significantly greater maintenance of symptomatic improvement over 26 weeks on the Liebowitz Social Anxiety Scale total (P=0.012) and subscale scores and on the Marks Fear Questionnaire total phobia (P=0.010) and social phobia (P=0.014) subscales. Pregabalin was generally well tolerated. During the double-blind phase, the adverse events that occurred more frequently with pregabalin compared with placebo were dizziness (11.3 vs. 4.1%) and infection (21.3 vs. 16.4%). The results of this study suggest that pregabalin (450 mg/day) is safe, well tolerated, and has significant relapse-prevention efficacy over 26 weeks in patients with SAD who responded to an initial course of the pregabalin treatment.

Feasibility and validation of a computer-automated Columbia-Suicide Severity Rating Scale using interactive voice response technology.

OBJECTIVE: To evaluate a computer-automated version of the Columbia-Suicide Severity Rating Scale (C-SSRS) using interactive voice response technology (eC-SSRS™). The eC-SSRS assesses "Lifetime" ideations and behaviors at baseline and monitors suicidality prospectively thereafter. Ten control volunteers and ten psychiatric inpatients participated and were administered the C-SSRS at baseline and 4-8 days later by two experienced clinical trial raters. Study participants also completed the eC-SSRS using touch-tone telephones. Kappa measures of agreement compared inter-rater reliability of the C-SSRS administrations and the C-SSRS administrations with the eC-SSRS. Convergent validity with the Beck Scale for Suicide Ideation BSS and patient feedback forms were also evaluated. Twenty baseline and nineteen follow-up assessments were completed. In general, agreement between the eC-SSRS and each rater was comparable or superior to the agreement between both raters. Subject feedback and personal preferences varied across individuals, but were generally supportive of the feasibility and validity of the eC-SSRS. The reliability and validity of the C-SSRS and eC-SSRS for assessing suicidal ideation and behaviors were comparable in this first study comparing the methods. These data were obtained from relatively small patient samples recruited from a single investigational site over a relatively short follow-up period. They support the feasibility and validity of the eC-SSRS for prospective monitoring of suicidality for use in clinical trials or clinical care, but further research with larger samples, other patient populations, and longer follow-up periods is needed.

Assessing onset of treatment benefit in depression and anxiety: conceptual considerations.

OBJECTIVE: Methods for characterizing the onset of treatment benefit in major depressive disorder and generalized anxiety disorder have been studied for some time, yet there is no universal agreement as to the best approaches. Our purpose is to summarize the conceptual framework underlying modern methods for characterizing onset and detailed approaches for which there is consensus from the perspective of a clinician, clinical researcher, and statistician. Possible alternatives to unresolved issues are discussed. PARTICIPANTS: There were 17 experts from academia, the pharmaceutical industry, and the US Food and Drug Administration who met on April 19, 2007, to consider the issues. Many others from sponsoring firms observed the proceedings. EVIDENCE: A series of papers was presented at a consensus meeting and, after discussions, a sense of the participants was obtained. A small group subsequently reviewed the material and articles from the literature and prepared this article, which was reviewed by all of the participants. CONCLUSIONS: The elements that form the basis for describing onset of treatment benefit include defining a clinical event or measurable threshold that validly signals that a treatment has begun to provide clinically meaningful and sustained improvement and utilizing methods for estimating the probability of crossing the onset threshold, the distribution of time to onset for those who do cross, and when to alter or change interventions if the treatment is unsuccessful.

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.

A randomized, double-blind study of increasing or maintaining duloxetine dose in patients without remission of major depressive disorder after initial duloxetine therapy.

OBJECTIVE: To compare efficacy of remaining on duloxetine 60 mg to increasing to 120 mg q.d. in patients without remission of major depressive disorder (MDD) after 6 weeks at 60 mg. METHOD: This double-blind, parallel study was conducted in adults with MDD (DSM-IV-TR criteria). Patients initially randomly assigned to duloxetine 60 mg for 6 weeks with a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score > 7 (nonremitters) were randomly reassigned to 60 mg or 120 mg duloxetine for 8 weeks. Patients with a HAM-D-17 score < or =7 (remitters) continued on duloxetine 60 mg. The primary objective was to compare time to remission (HAM-D-17 score < or =7) between rerandomized groups. Secondary objectives included evaluation of HAM-D-17 and Inventory of Depressive Symptomatology assessments and safety and tolerability evaluations in nonremitters and remitters. Patients were enrolled from November 2004 to January 2006. RESULTS: Nonremitters randomly reassigned to 60 mg and 120 mg achieved similar time to remission and similar improvements on efficacy measures. Remission was achieved in 30.0% and 30.5% in the 60-mg and 120-mg groups, respectively. Of the remitters, 85.5% continued to be in remission at study end. Other than a greater incidence of hyperhidrosis and chest pain in the 120-mg group, adverse events were similar between groups, as were discontinuations due to adverse events. CONCLUSION: Nonremitters to 60 mg of duloxetine for 6 weeks randomly reassigned to 60 mg or 120 mg of duloxetine demonstrated continued symptom improvement in the 8-week extension. Patients randomly reassigned to 120 mg showed no advantage over those who continued on 60 mg. Duloxetine was well tolerated at both doses and had similar safety profiles.

A comparison of initial duloxetine dosing strategies in patients with major depressive disorder.

OBJECTIVE: To compare the effects of starting doses of duloxetine taken with or without food on tolerability and efficacy in patients with major depressive disorder (MDD). METHOD: This double-blind, concurrent-dose-controlled, parallel-design trial contained a variable expected-duration placebo lead-in period and was conducted in adult outpatients with DSM-IV-TR-defined MDD at psychiatric outpatient sites between October 2004 and January 2006. In actuality, patients received placebo for 1 week and then were randomly assigned to duloxetine 30 mg once daily in the morning (q.a.m.) (N = 219), 30 mg twice daily (b.i.d.) (N = 213), or 60 mg q.a.m. (N = 215) for 1 week along with 1 of 2 instructions about food: take study drug with food or do not take within 1 hour of eating. For the remaining 5 weeks of acute treatment, all patients received 60 mg once daily. The primary objective was to compare incidence of treatment-emergent nausea at 30 mg q.a.m. versus 60 mg q.a.m. using item 112 (nausea) of the Association for Methodology and Documentation in Psychiatry adverse event scale (AMDP-5). Secondary outcome measures included mean change on AMDP-5 item 112, discontinuations due to adverse events, mean changes in AMDP-5 items and subscales, spontaneously reported treatment-emergent adverse events, and vital signs. Efficacy was evaluated by the 17-item Hamilton Rating Scale for Depression (HAM-D-17). RESULTS: The primary analysis, which combined data from both food groups, showed no significant difference in the incidence of nausea between starting doses of 30 mg q.a.m. and 60 mg q.a.m. (23% vs. 29%, respectively; p = .207). However, mean changes on the AMDP-5 nausea item revealed a significant main effect of food (p = .010) and a significant interaction between food and starting dose (p = .033). The food-by-dose interaction indicated that the benefit from taking drug with food was greatest in patients started at 60 mg q.a.m., and the benefit of starting at 30 mg q.a.m. was greatest in patients taking drug without food. In patients who took study drug without food, there was a significant difference across initial-dose groups for discontinuation due to adverse events (30 mg q.a.m. = 3.6%, 30 mg b.i.d. = 14.0%, 60 mg q.a.m. = 10.2%; 30 mg q.a.m. vs. 30 mg b.i.d., p = .008; 30 mg q.a.m. vs. 60 mg q.a.m., p = .066); however, in patients who took study drug with food, discontinuations due to adverse events did not significantly differ (30 mg q.a.m. = 5.4%, 30 mg b.i.d. = 7.5%, 60 mg q.a.m. = 7.4%; all p values > .50). Patients who started at 30 mg b.i.d. or 60 mg q.a.m. without food did not differ regarding mean changes (i.e., increases) in the common adverse events score after 1 week of treatment but had significantly greater mean changes than patients who started at 30 mg q.a.m. without food (0.87, 0.82, and 0, respectively; p < .05 vs. 30 mg b.i.d. and 60 mg q.a.m.). No significant differences were found between initial-dose groups in vital signs. CONCLUSIONS: These data imply that starting dulox-etine at 30 mg q.a.m. for 1 week with or without food or starting duloxetine at the therapeutic dose of 60 mg q.a.m. with food can improve the initial tolerability of the medication. Adding this information to existing knowledge of duloxetine will enable the clinician to tailor therapy most appropriately for the individual patient. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT 00191061.

Duloxetine in practice-based clinical settings: assessing effects on the emotional and physical symptoms of depression in an open-label, multicenter study.

OBJECTIVE: In placebo-controlled clinical trials, duloxetine has been shown to be effective and well-tolerated in patients with major depressive disorder (MDD). However, patients in registration trials may not be representative of patients in clinical practice. This study sought to assess the effectiveness, safety, and tolerability of duloxetine in diverse populations of outpatients with MDD. METHOD: This open-label study recruited out-patients ≥ 18 years of age with DSM-IV MDD in primary care or psychiatric practice settings and treated them with duloxetine 60 mg q.d. for 7 weeks. Primary outcome measures were (1) the physicianrated Clinical Global Impressions-Severity of Illness scale, (2) the patient-rated 28-item Somatic Symptom Inventory (SSI-28) average, and (3) the patient-rated 16-item Quick Inventory of Depressive Symptomatology-Self Report. Quality of life, disability, and vital signs also were assessed. The first patient visit was August 16, 2004. The last patient visit was January 7, 2005. RESULTS: Of 3543 outpatients enrolled, 3431 received at least 1 dose of duloxetine, of whom 71.4% completed the study. Most patients were Caucasian (90.8%) and female (75.4%); mean age was 48 years. Duloxetine significantly (p < .001) improved all efficacy measures in all treated patients as well as in subgroups based on gender, ethnic origin, age, and patient care setting. Except for the SSI-28 average, all the efficacy measures were in favor of female gender and primary care subgroups. Overall, 10.8% of patients discontinued due to adverse events. CONCLUSION: Duloxetine 60 mg q.d. was effective, regardless of gender, ethnic origin, age, and patient care settings, in this 7-week open-label study and was well-tolerated in a diverse population of outpatients with MDD. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00479726.

A pilot study of an electronic, adolescent version of the quick inventory of depressive symptomatology.

BACKGROUND: Adolescent depression assessments are time-intensive, often requiring separate interviews with an adolescent and a parent/ informant. In adults, a self-rated, interactive voice response (IVR) version of the Quick Inventory of Depressive Symptomatology (QIDS-IVR) has been shown to be reliable, valid, and sensitive to change. An adolescent version of the QIDS (QIDS-A-IVR) was created using speaker-independent voice recognition technology. An informant version, QIDS-P-IVR, collects ratings from parents or other knowledgeable adults. METHOD: The study included 27 adolescents ranging from 12 to 17 years of age, 48% of whom were female. During a single office visit, adolescents completed the QIDS-A-IVR and parents completed the QIDS-P-IVR. A clinician completed the clinician-rated adult version of the QIDS separately for adolescents (QIDS-C-A) and parents (QIDS-C-P) and the Children's Depression Rating Scale-Revised (CDRS-R). The study was conducted from October 2005 to April 2006. RESULTS: Cronbach alpha of the QIDS-A-IVR was .85. The QIDS-A-IVR correlated significantly with the QIDS-C-A (r = 0.95) and the CDRS-R (r = 0.76), both p < .01. Conversely, the correlations of the QIDS-A-IVR with the QIDS-P-IVR and the QIDS-C-P were small and nonsignificant. The QIDS-A-IVR required adolescents a mean of 6 minutes and 31 seconds to complete (SD = 41 seconds). The voice recognition technology correctly identified the adolescents' spoken words in 92% of the 483 spoken responses. The system recognized a response from all adolescents on all items. CONCLUSIONS: This study supports the reliability and validity of the QIDS-A-IVR as an adolescent depression measure. The QIDS-A-IVR may provide clinicians and researchers with a sound, technology-based method of assessing adolescent depression. Future research is needed on the informational value of parent ratings of adolescent depression.

Telephonic Remote Evaluation of Neuropsychological Deficits (TREND): longitudinal monitoring of elderly community-dwelling volunteers using touch-tone telephones.

Use of interactive voice response (IVR) technology to monitor cognitive functioning in cognitively normal (CN), mild cognitive impairment (MCI), and mild dementia (MD) participants was examined using 107 community-dwelling participants, 65 to 88 years old. Baseline Clinical Dementia Ratings identified 36 participants as CN, 37 with MCI, and 34 as MD. Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examinations were administered during clinic visits at weeks 0, 8, 16, and 24. IVR cognitive testing was completed at each visit and from participants' homes at weeks 4, 12, and 20. Study partners provided dementia symptoms severity ratings via IVR. The assessment system received 719 participant and 723 partner calls. All calls initiated by CN participants, 99.2% by MCI participants, and 87.3% by MD participants were completed. Telephonic Remote Evaluation of Neuropsychological Deficit tasks showed significant performance differences between participant groups, good reliability, and convergent validity with Mini-Mental State Examinations and ADAS-Cog measures. Automated cognitive testing calls took about 18 minutes to complete, and informant calls took approximately 4 minutes. IVR informant data were convergent with the ADAS-Noncog measure. Computer-automated assessments of cognitive functioning via IVR provided reliable, valid data. Such assessments might benefit routine clinical care and large-scale, longitudinal research in the future, but will require additional research over longer periods.