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.

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.

Assessment of cognitive symptoms in prodromal and early huntington disease.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess cognitive symptoms in prHD and early HD individuals.

Assessment of Day-to-Day Functioning in Prodromal and Early Huntington Disease.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess functional impact in day-to-day activities in prHD and early HD individuals.

Assessment of depression, anxiety and apathy in prodromal and early huntington disease.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess Depression, Anxiety and Apathy in prHD and early HD individuals.

An item response analysis of the motor and behavioral subscales of the unified Huntington's disease rating scale in huntington disease gene expansion carriers.

Although the Unified Huntington's Disease Rating Scale (UHDRS) is widely used in the assessment of Huntington disease (HD), the ability of individual items to discriminate individual differences in motor or behavioral manifestations has not been extensively studied in HD gene expansion carriers without a motor-defined clinical diagnosis (ie, prodromal-HD or prHD). To elucidate the relationship between scores on individual motor and behavioral UHDRS items and total score for each subscale, a nonparametric item response analysis was performed on retrospective data from 2 multicenter longitudinal studies. Motor and behavioral assessments were supplied for 737 prHD individuals with data from 2114 visits (PREDICT-HD) and 686 HD individuals with data from 1482 visits (REGISTRY). Option characteristic curves were generated for UHDRS subscale items in relation to their subscale score. In prHD, overall severity of motor signs was low, and participants had scores of 2 or above on very few items. In HD, motor items that assessed ocular pursuit, saccade initiation, finger tapping, tandem walking, and to a lesser extent, saccade velocity, dysarthria, tongue protrusion, pronation/supination, Luria, bradykinesia, choreas, gait, and balance on the retropulsion test were found to discriminate individual differences across a broad range of motor severity. In prHD, depressed mood, anxiety, and irritable behavior demonstrated good discriminative properties. In HD, depressed mood demonstrated a good relationship with the overall behavioral score. These data suggest that at least some UHDRS items appear to have utility across a broad range of severity, although many items demonstrate problematic features.

Assessment of motor symptoms and functional impact in prodromal and early huntington disease.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess functional impact of motor manifestations in prHD and early HD individuals.

Increased plasma EPO and MIP-1 alpha are associated with recruitment of vascular progenitors but not CD34(+) cells in autologous peripheral blood stem cell grafts.

OBJECTIVE: Increased levels of endothelial-like vascular progenitor cells (VPCs) in peripheral blood stem cell (PBSC) products have been associated with reduced transplant-related toxicity following autologous hematopoietic stem cell transplantation. In this study, a panel of angiogenic and inflammatory plasma proteins were quantitatively analyzed in patients undergoing PBSC collection for autologous hematopoietic stem cell transplantation to identify profiles associated with greater VPC recruitment. MATERIALS AND METHODS: A panel of 16 candidate plasma factors were quantified using multianalyte fluorescence and/or enzyme-linked immunosorbent assay. VPC clusters were enumerated using a standard cell culture assay. RESULTS: Thirty-six patients (mean age=51 years, 42% female) had plasma collected at baseline prior to PBSC mobilization and on the day of PBSC collection. Only erythropoietin (EPO) levels increased significantly on the day of PBSC collection in comparison with baseline plasma levels (2.2-fold increase; p=0.003). Interleukin-2, -10, epidermal growth factor, interferon-alpha, and angiopoietin-1 all decreased significantly between baseline and the day of PBSC collection (p<0.02). The remaining cytokine levels did not change appreciably (p=NS). The cohort was divided into "low" graft VPCs (<2.0 x 10(3)/kg) and "high" graft VPCs (>or=2.0 x 10(3)/kg) and cytokine levels were compared between the groups. At baseline, increased levels of macrophage inflammatory protein-1 alpha (MIP-1 alpha) were associated with increased graft VPCs (p=0.05) while higher EPO concentrations on the day of PBSC collection predicted higher graft VPC levels (p=0.02). These cytokines were not associated with CD34(+) cell mobilization. CONCLUSIONS: The association of different plasma proteins with graft VPC and CD34(+)-cell levels suggests that mobilization of vascular and hematopoietic progenitors occurs through independent mechanisms. Patients with low levels of MIP-1 alpha at baseline may be candidates for interventions aimed at increasing graft VPC levels. Strategies that increase plasma EPO concentrations may be most promising to augment the regenerative properties of PBSC products.

Multiple pain complaints in patients with major depressive disorder.

OBJECTIVE: To characterize the co-existence of multiple pain-related complaints in patients enrolled in a series of pharmaceutical company drug trials for the treatment of Major Depressive Disorder (MDD). METHOD: Pooled 'blinded' data from 2191 patients enrolled in randomized, multicenter, double-blind placebo-controlled studies for the treatment of MDD were analyzed. Painful symptoms were assessed using the seven pain symptoms subset of the Somatic Symptoms Inventory: 'Headache,' 'Pain in lower back,' 'Neck pain,' 'Pain in joints,' 'Soreness in muscles,' 'Pain in heart or chest,' and 'Pain or cramps in abdomen.' The 17-item Hamilton Depression Rating Scale (HAMD) was used to assess severity of depression. RESULTS: Of those meeting the study entry criteria (total HAMD score >or=15), 25% reported no pain complaints and 18% reported 1 pain compliant; the majority (57%) of patients reported the co-existence of multiple pain-related complaints, with 14%, 12%, 11%, 11%, 7%, and 3% of patients reporting 2, 3, 4, 5, 6 and 7 different pain symptoms, respectively. The number of pain-related symptoms experienced was moderately related to severity of depression (r = 0.35), with the most common pain symptom combinations being among headaches, lower back pain, neck pain, pain in joints, and soreness in muscles. CONCLUSIONS: This study supports pain as a component feature of MDD. The number of comorbid pain-related complaints, which generally increased as a function of depressive severity, should be considered in the diagnosis of depression, planning of treatment strategies, and measurement of treatment outcome.

Symptoms of anxiety in depression: assessment of item performance of the Hamilton Anxiety Rating Scale in patients with depression.

BACKGROUND: Although diagnostically dissociable, anxiety is strongly co-morbid with depression. To examine further the clinical symptoms of anxiety in major depressive disorder (MDD), a non-parametric item response analysis on "blinded" data from four pharmaceutical company clinical trials was performed on the Hamilton Anxiety Rating Scale (HAMA) across levels of depressive severity. METHODS: The severity of depressive symptoms was assessed using the 17-item Hamilton Depression Rating Scale (HAMD). HAMA and HAMD measures were supplied for each patient on each of two post-screen visits (n=1,668 observations). Option characteristic curves were generated for all 14 HAMA items to determine the probability of scoring a particular option on the HAMA in relation to the total HAMD score. Additional analyses were conducted using Pearson's product-moment correlations. RESULTS: Results showed that anxiety-related symptomatology generally increased as a function of overall depressive severity, though there were clear differences between individual anxiety symptoms in their relationship with depressive severity. In particular, anxious mood, tension, insomnia, difficulties in concentration and memory, and depressed mood were found to discriminate over the full range of HAMD scores, increasing continuously with increases in depressive severity. By contrast, many somatic-related symptoms, including muscular, sensory, cardiovascular, respiratory, gastro-intestinal, and genito-urinary were manifested primarily at higher levels of depression and did not discriminate well at lower HAMD scores. CONCLUSIONS: These results demonstrate anxiety as a core feature of depression, and the relationship between anxiety-related symptoms and depression should be considered in the assessment of depression and evaluation of treatment strategies and outcome.

Prevalence and association of somatic symptoms in patients with Major Depressive Disorder.

BACKGROUND: Painful and non-painful somatic symptoms are often reported in patients with depressive disorder. The proper identification of depression-relevant somatic symptoms is important for the accurate diagnosis of depression, development of treatment strategies and measurement of outcome. The objective of this study was to characterize the relationship between somatic symptoms and depression in patients diagnosed with Major Depressive Disorder (MDD), using data from randomized drug trials carried out by a pharmaceutical company. METHODS: Pooled 'blinded' data from 2191 patients enrolled in randomized, multicenter, double-blind placebo-controlled studies for the treatment of MDD were analyzed. Somatic symptoms were assessed using the Somatic Symptoms Inventory (SSI) and the Hamilton Depression Rating Scale (HAMD) was used to assess symptoms of depression. RESULTS: The most common somatic symptom reported by patients with MDD was 'feeling fatigued, weak, or tired all over', with 78% of patients reporting 'moderate' levels or above. This was followed by 'feeling that not in as good physical health as most of your friends' (59%), 'not feeling well most of the time in the past few years' (54%), and 'feeling weak in parts of body' (45%). 'Headache' was the most common pain-related symptom with 43% reporting 'moderate' or above. Pearson's product-moment correlations revealed that somatic symptoms generally increased as a function of overall depressive (r=0.43), with 'feeling fatigued, weak, or tired all over' (r=0.50), 'feeling that not in as good physical health as most of your friends' (r=0.42), 'feeling weak in parts of body' (r=0.41), 'heavy feeling in arms and legs' (r=0.34), 'not feeling well most of the time in the past few years' (r=0.32), and 'headache' (r=0.31) showing the strongest correlation with overall HAMD scores. Non-parametric item response analyses showed that many somatic symptoms demonstrate good relationship between item response and the overall severity of depression. In particular, 'feeling fatigued, weak, or tired all over' exhibited good discriminative properties across the full range of severity for depression. LIMITATIONS: The analysis utilized data from a 'restricted' patient population in drug trials sponsored by a pharmaceutical company. CONCLUSIONS: These results demonstrate a high prevalence and association of somatic symptoms in patients with MDD, including feelings of fatigue, physical malaise and pain-related symptoms, which could be potentially useful in the assessment of depression and in the evaluation of treatment strategies.

Reliability and validity of the Sexual Interest and Desire Inventory-Female (SIDI-F), a scale designed to measure severity of female hypoactive sexual desire disorder.

The Sexual Interest and Desire Inventory-Female (SIDI-F) is a 13-item scale developed as a clinician-administered assessment tool to quantify the severity of symptoms in women diagnosed with hypoactive sexual desire disorder (HSDD). The present investigation assessed the reliability and validity of the SIDI-F as a measure of HSDD severity. Results show that the SIDI-F exhibits excellent internal consistency, with Cronbach's alpha of 0.9. The validity of the SIDI-F as a measure of HSDD severity was confirmed by a number of observations. Women with a clinical diagnosis (Diagnostic and Statistical Manual of Mental Disorders [DSM-IV-TR; American Psychiatric Association, 2000]) of HSDD had significantly lower SIDI-F scores than women not meeting diagnostic criteria for any subtype of female sexual dysfunction and women diagnosed with female orgasmic disorder. There was a high correlation between scores on the SIDI-F and scores on the Female Sexual Function Index (FSFI; Rosen et al., 2000) and an interactive voice response version of the Changes in Sexual Functioning Questionnaire (CSFQ; Clayton, McGarvey, & Clavet, 1997; Clayton, McGarvey, Clavet, & Piazza, 1997), two validated measures that assess general female sexual dysfunction. In contrast, there was a poor correlation between SIDI-F scores and scores on a slightly modified Marital Adjustment Scale (Locke, Wallace, 1959; MAS), an assessment of general (nonsexual) relationship satisfaction. Taken together, the results of the present investigation indicate that the SIDI-F is a reliable and valid measure of HSDD severity, independent of relationship issues.

An item response analysis of the international restless legs syndrome study group rating scale for restless legs syndrome.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a common central nervous system disorder; however, there is currently a lack of well-validated and easily-administered measures of RLS severity available. The International Restless Legs Syndrome Study Group has recently developed a 10-item scale to meet this need. The International Restless Legs Severity Scale (IRLS) has been shown to have a high degree of reliability, validity, and internal consistency. In order to further demonstrate the validity of the IRLS, the present study examined the relationship between scores on individual IRLS items and overall RLS severity. PATIENTS AND METHODS: The 10-item IRLS was administered to 196 RLS patients. Option characteristic curves (the probability of scoring different options for a given item as a function of overall IRLS score) were generated in order to illustrate the scoring patterns for each item across the range of total RLS severity. Item characteristic curves (the expected score on an item as a function of overall IRLS score) were also generated to illustrate the relationship between scores on the individual items and total RLS severity. RESULTS: The IRLS items demonstrated excellent item response properties, with option and item characteristic curves closely approximating those of an ideal item. Item 3 (relief of arm or leg discomfort from moving around) was the most problematic item in that a 'floor' effect was evident; however, the item response characteristics for this item were still acceptable. CONCLUSIONS: Each IRLS item showed a good relationship between responses on that item and overall RLS severity, providing further evidence for the validity of the IRLS as a measure of RLS severity in RLS patients.

The Sexual Interest and Desire Inventory-Female (SIDI-F): item response analyses of data from women diagnosed with hypoactive sexual desire disorder.

INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is the most common sexual complaint in women. Currently there are no validated instruments for specifically assessing HSDD severity, or change in HSDD severity in response to treatment, in premenopausal women. The Sexual Interest and Desire Inventory-Female (SIDI-F) is a clinician-administered instrument that was developed to measure severity and change in response to treatment of HSDD. Seventeen items were included in a preliminary version of the SIDI-F, including 10 items related to desire, and seven items related to possible comorbid factors (e.g., other kinds of sexual dysfunction, general relationship satisfaction, mood, and fatigue). AIM: The aim of the study was to use the outcome of item response analyses of blinded data from two randomized, placebo-controlled trials, to assist in the revision of the scale. METHODS: A nonparametric item response (IRT) model was used to assess the relation between item functioning and HSDD severity on this preliminary version of the SIDI-F. RESULTS: Results show that the majority of SIDI-F items demonstrated good sensitivity to differences in overall HSDD severity. That is, there was an orderly relation between differences in option selection for an item and differences in overall HSDD severity. The IRT analyses further indicated that revisions were warranted for a number of these items. Five items were not sensitive to differences in HSDD severity and were removed from the scale. CONCLUSION: The SIDI-F is a brief, clinician-administered rating scale designed to assess severity of HSDD symptoms in women. IRT analyses show that majority of the items of the SIDI-F function well in discriminating individual differences in HSDD severity. A revised 13-item version of the SIDI-F is currently undergoing further validation.

Worsening of depressive symptoms prior to randomization in clinical trials: a possible screen for placebo responders?

A common practice in depression trials is to exclude patients whose depressive symptoms improve between Screen and Baseline evaluations under the assumption that they are more likely to respond to placebo. The present study investigated this contention by examining the relationship between pre-randomization changes in Hamilton depression rating scale (HAMD) scores to post-randomization placebo response and drug-placebo separation. Four randomized, double-blind, placebo-controlled trials (active medication=fluoxetine or paroxetine) were conducted in outpatients with Major Depressive Disorder using a novel design in which a depressive severity inclusion criterion (HAMD >/= 22) was utilized only at Screen. Patients with no change or minimal (1 point) improvement on the HAMD between Screen and Baseline had the lowest placebo response and the best drug-placebo separation. Patients with pre-randomization improvement of 2 points or greater had moderately higher placebo response and poorer drug-placebo separation. Patients who worsened between Screen and Baseline showed the highest placebo response and the poorest drug-placebo separation. There were no obvious differences in demographic variables between the groups which could account for the findings. In our original analyses 3/4 studies failed to show significant drug-placebo separation. When only patients with no change or pre-randomization improvement of 1 point were used in the analyses, 3/4 studies showed significant drug-placebo separation while the other study approached significance, p < 0.07. These results suggest that pre-randomization changes in HAMD scores may predict post-randomization placebo response and drug-placebo separation. Further, pre-randomization increases in HAMD scores (i.e., worsening) may be the best predictor of heightened placebo responding and poor drug placebo separation.

An Item Response analysis of the Hamilton Depression Rating Scale using shared data from two pharmaceutical companies.

Although the Hamilton Depression Rating Scale (HAMD) remains the most widely used outcome measure in clinical trials of Major Depressive Disorder, the psychometric properties of the individual HAMD items have not been extensively studied. In the present paper, data from four separate clinical trials conducted independently by two pharmaceutical companies were analyzed to determine the relationship between scores on the individual HAMD items and overall depressive severity in an outpatient population. Option characteristic curves (the probability of scoring a particular option in relation to overall HAMD scores) were generated in order to illustrate the relationship between scoring patterns for each item and the range of total HAMD scores. Results showed that Items 1 (Depressed Mood) and 7 (Work and Activities), and to a lesser degree, Items 2 (Guilt), 10 (Anxiety/Psychic), 11 (Anxiety/Somatic), and 13 (Somatic/General) demonstrated a good relationship between item responses and overall depressive severity. However, other items (e.g. Insight, Hypochondriasis) appeared to be more problematic with regard to their ability to discriminate over the full range of depression severity. The present results illustrate that co-operative data sharing between pharmaceutical companies can be a useful tool for improving clinical methods.