Innovations In Clinical Neuroscience

MAR-APR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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39 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 O R I G I N A L R E S E A R C H independent review and scoring of the key screen data by an independent quality assurance group (Clintara LLC, Boston, Massachusetts) that included diagnostic verification of GAD, assessment of current treatment response, and "dual" scoring of the site-based CGI-S and SIGH-A interviews. 19,20 Dual scores that yielded greater than three- points difference (discordance) between the site-based raters and independent reviewers were re-scored by a second independent reviewer for confirmation as part of the quality assurance program. Rater remediation by telephone was provided whenever issues related to scoring discordance or insufficient (incomplete) interviews were identified, Statistical analysis included demographic and clinical tabulation, Pearson's product moment correlation, and Student's t tests when appropriate. RESULTS Data for this analysis was derived from 101 patients who were screened for study eligibility and completed audio-digitally recorded screen interviews for the MINI, CGI-S, and SIGH-A that were received between December 2014 and June 2015. Ninety reviewed patients were deemed eligible to enroll in the study. Table 1 depicts the demographics of the enrolled population (n=90), presenting clinical metrics, and the DSM-IV-TR anxiety symptoms endorsed by the study-eligible patients with GAD. The patients were mostly female (74.4%), ranged in age from 20 to 64 years (mean age=41.2±13.7 standard deviation [SD]), and were generally obese (mean body mass index [BMI]=31.5±7.1 SD). Forty-seven of the 90 patients (52.2%) met World Health Organization (WHO) standards for obesity (BMI >30) 22 and 10 subjects (12.2%) had a BMI greater than 40 (morbid obesity). The women had higher BMIs than the men (32.1±7.3 and 29.8±6.1 respectively), but this difference was not statistically significant. All 90 eligible patients reported an inadequate response (<50%) to their current anxiolytic medication despite taking an adequate dose for an adequate duration of time. Sixty-five patients (72.2%) reported achieving less than a 25-percent response to their ongoing anxiolytic medication. The most commonly prescribed medications were escitalopram, paroxetine, and venlafaxine (Table 2). Additionally, 10.6 percent of patients were taking a second medication (including a second antidepressant, alprazolam, clonazepam, buspirone, or gabapentin) at the time of the screening visit. Diagnostic confirmation of GAD . Among the study participants, the original diagnosis of GAD had been made 1 to 40 years prior to the screening visit, and 37.7 percent of the enrolled patients had been ill for at least 10 years. Patients with GAD entering this study endorsed virtually all of the six GAD symptoms listed on the DSM-IV-TR-associated symptom checklist in addition to 100-percent endorsement of persistent anxiety or worry that was hard to control and 100-percent significant clinical distress associated with these symptoms. The mean CGI-S score was 4.8±0.6 (SD), and 68.9 percent of the patients were scored a 5 or higher (moderately severe illness) at the screening visit. The site-independent reviewers affirmed these endorsements based on the MINI documentation and the level of clinical distress endorsed on the narrative description provided in the structured format of the CGI-S. Eleven patients (10.9%) failed screening as a result of the site-independent review process based upon the submitted screening materials. Two patients had subthreshold SIGH-A scores, and one patient gave inconsistent responses that suggested poor reliability as a study candidate. Two patients were excluded because of a comorbid current diagnosis of panic disorder, and one because she had a binge eating disorder. Three patients had social phobia, and one patient had a current major depressive episode. These last four patients were excluded before the mid-study amendment that allowed these disorders. "Dual" scoring comparisons of SIGH-A scores . The mean site-based total SIGH-A score was 27.1±3.7 (SD). Fourteen patients scored the SIGH-A Item 1 (anxious mood) as a 2 (15.6%), and 76 patients scored it as a 3 (84.4%), reflecting moderate anxious symptoms within the past week. The mean site-independent total SIGH-A score (derived by listening to the audio-digital recordings of the site-based SIGH-A interviews) was 27.2±4.3 and was not significantly different than the site-based total mean SIGH-A score (t=0.42, p=0.67, 95% confidence interval [CI] for mean difference 0.1 [-0.37, 0.57]). The mean absolute discordance ("dual" total SIGH-A scoring deviations between site-based and site-independent raters in either direction) was only 1.50±1.66, and the correlation coefficient was 0.852 (p<0.0001). Only eight of the paired SIGH-A scores (8.9%) were greater than three points deviant from each other, whereas 70 scores (77.8%) were within two points of each other. Rater remediation was provided for the eight discordant scores. Furthermore, there were no significant mean "dual" scoring differences on any of the 14 individual SIGH-A items between the site-based and site-independent scores (Figure 1). Depressive symptoms in the GAD population . By protocol criteria, depressive symptoms, if present, needed to be clinically less significant than anxious symptoms. Hence, the RDS score was always less than the CAS score in all study-eligible patients. Both scales range in scores from 3 to 15. In this study, the highest individual patient's RDS score was 7, whereas the CAS scores ranged from 9 to 15. As noted above, a mid-study amendment permitted enrollment of patients with a current major depressive episode (MDE) but still specified that the depressive symptoms needed to be clinically less significant than the anxious symptoms. As noted in Table 1, four patients were enrolled with a current MDE, 33 percent of enrolled patients reported a past history of MDE, and 18.9 percent reported a history of recurrent MDD. Table 3 compares the clinical metrics obtained at the screen visit between the enrolled patients with GAD, with or without a previous history of MDE. There were no significant differences noted on the CAS score, GAD-7, total SIGH-A, or the CGI-S. However, the patients with a previous history of MDE had significantly more depressive symptoms than the patients with no history of MDE. The mean RDS score was 5.73±1.05 in patients with GAD and a history of MDE and 4.95±1.08 in patients without a history of MDE (t=3.27; p=0.0015, 95% CI for mean difference 0.78 [0.31, 1.26]). Two of the 14 individual SIGH-A items revealed statistically significant differences between these two GAD cohorts. The mean SIGH-A Item 6 depression score was significantly greater in the patients with versus those without a history of a previous MDE (t=2.01; p=0.047, 95% CI for mean difference 0.35 [0.01, 0.70]), whereas their mean muscular tension score (SIGH-A item 7) was significantly less (t= -2.2; p=0.030, 95% CI for mean difference -0.38 [0.04, 0.73]) than the patients without a history of MDE. DISCUSSION In this clinical trial, a site-independent "dual" review method using audio-digital recordings of site-based interviews at the screening visit was employed to independently assess and confirm

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