International Study to Predict Optimized Treatment for Depression (iSPOT-D), a randomized clinical trial: rationale and protocol

Abstract

BackgroundClinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.Methods/DesignThe International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi-centre, international, randomized, prospective, open-label trial. It is enrolling 2016 MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm.DiscussionFirst enrolment was in December 2008, and is ongoing. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide.Trial registrationInternational Study to Predict Optimised Treatment - in Depression (iSPOT-D) ClinicalTrials.gov Identifier: NCT00693849URL: http://clinicaltrials.gov/ct2/show/NCT00693849?term=International+Study+to+Predict+Optimized+Treatment+for+Depression&rank=1

Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial

“…Study outcomes were treatment response, defined as a ⩾ 50% decrease from the baseline HRSD 17 , and remission, defined as a score of ⩽ 7 on the HRSD 17 (Williams et al, 2011). We analyzed data for participants who completed the post-treatment scanning session (Table 1), consistent with previous studies that included a post-treatment scan (Sheline et al, 2001;Fu et al, 2004).…”

“…Our power calculation was designed to test for an anticipated general effect of small effect size or higher and an anticipated differential effect with a medium effect size or higher, requiring at least 29 participants per treatment arm. See Table 1 for participant characteristics. A complete description of the iSPOT-D design, clinical assessments, and inclusion/exclusion criteria is provided in previous papers on the study protocol (Williams et al, 2011;Grieve et al, 2013). In short, the primary diagnosis of nonpsychotic MDD was confirmed using the Mini-International Neuropsychiatric Interview (MINI) (Sheehan et al, 1998), according to DSM-IV criteria, and a score ⩾ 16 on the 17-item Hamilton Rating Scale for Depression (HRSD 17 ) (Hamilton, 1960).…”

“…We also examined whether treatment-predictive amygdala activity at baseline differs between MDD participants and healthy participants, whether it changes with treatment and as a function of medication response, and whether it depends on a particular emotion or level of processing (subliminal and supraliminal). We assessed patients from the neuroimaging component of the International Study to Predict Optimized Treatment for Depression (iSPOT-D) (Williams et al, 2011;Grieve et al, 2013). Participants were randomized to one of three antidepressants in a practical clinical trial design.…”

The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI

“…While all applied antidepressants were demonstrated to be superior to placebo [59,60], this does not rule out unwanted placebo effects in this study. Placebo control in fMRI treatment trials is currently infrequently applied [8,61,62]. For translation of pharmacological fMRI findings to clinic placebo-controlled validation might be necessary.…”

A Cognitive–Emotional Biomarker for Predicting Remission with Antidepressant Medications: A Report from the iSPOT-D Trial

“…This work supports the formulation that depression is characterized by perturbations in psychomotor response speed, processing speed, executive functions (eg, attention and working memory), memory encoding, and recall and emotion processing. Within this work, there are also suggestions that performance on some of these tests may predict antidepressant medication outcomes (Supplementary Table 1) that formed in part the basis for the International Study to Predict Optimized Treatment in Depression (iSPOT-D) (Williams et al, 2011). Specifically, prior smaller-scale studies suggest that poor cognitive performance, such as working memory on the N-back task (Gorlyn et al, 2008), information processing speed on the digit symbol task (Leuchter et al, 2004), executive functioning and flexibility on the Wisconsin Card sort task (Dunkin et al, 2000), and color naming on the color and word Stroop task (which may reflect psychomotor slowing) (Taylor et al, 2006), all predicted worse outcome with an acute course of antidepressant treatment (Supplementary Table 1).…”