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Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression.

ABSTRACT: AIM:Presynaptic and post-synaptic glutamatergic modulation is associated with antidepressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic and post-synaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression. METHODS:In a pilot study, 29 outpatients with bipolar depression on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5?mg?week?¹ to 20?mg) in a randomized, double-blind, parallel group, 8?week study. Patients were evaluated weekly using the 17-item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. Linear, exponential, maximal effect, Gompertz and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups. RESULTS:A Gompertz function with a treatment switch on the parameter describing the speed of HDRS decline (?, 95% confidence interval [CI]) best described the data (?(memantine) = 1.8, 95% CI 0.9, 3.6), ?(placebo) = 1.2, 95% CI 0.5, 3.5)). Between subject variability was identified on baseline HDRS (2.9, 95% CI 1.5, 4.4) and amplitude of score improvement (4.3, 95% CI 2.7, 6.5). CONCLUSIONS:This pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared with placebo augmentation in bipolar depression patients.

SUBMITTER: Stevens J

PROVIDER: S-EPMC3575945 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression.

Stevens Jasper J Bies Robert R RR Shekhar Anantha A Anand Amit A

British journal of clinical pharmacology 20130301 3

<h4>Aim</h4>Presynaptic and post-synaptic glutamatergic modulation is associated with antidepressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic and post-synaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in ...[more]

PMID: 22846159

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Project description:Background: The Hamilton Rating Scale for Depression (HAMD-17) has been used for several decades to assess the severity of depression. Multiple studies have documented defects in this scale and deemed it unsuitable for clinical evaluation. The HAMD-6, which is the abbreviated version of HAMD-17, has been shown to be effective in assessing the core symptoms of depression with greater sensitivity than HAMD-17. And the Patient Health Questionnaire-9 (PHQ-9) is suggested as an effective alternative to the HAMD-17 because of its simplicity and ease-of-use. Methods: Research was completed involving 1,741 participants having major depressive disorder. Cronbach's alpha, intraclass correlation coefficient (ICC) and weighted Kappa analysis was used to determine the reliability of the scales. Pearson correlation analysis and factor analysis were used to analyze validity. Item response theory (IRT) was used to analyze psychological characteristics of items in both the HAMD-17 and PHQ-9. Results: Reliability analysis showed that the Cronbach's alpha of the HAMD-17, HAMD-6 and PHQ-9 were 0.829, 0.764, and 0.893 respectively, and the ICC of the three scales ranged from 0.606 to 0.744. The Kappa score of the consistency of depression severity assessment was 0.248. Validity analysis showed that the PHQ-9 was a single factor structure, and the total score of the scale was strongly correlated with the HAMD-17 (r = 0.724, P < 0.001). The IRT analysis showed that the discrimination parameters of the PHQ-9 were higher than that of the HAMD-17 in all dimensions. The HAMD-6 had the lowest measurement accuracy in distinguishing the severity of depression, while the PHQ-9 had the highest measurement accuracy. Conclusion: Results showed that the PHQ-9 was satisfactory in terms of reliability, validity and distinguishing the severity of depression. It is a simple, rapid, effective and reliable tool which can be used as an alternative to the HAMD-17 to assess the severity of depression.

Project description:ObjectiveTo develop clinically meaningful improvement thresholds in both the 17-item and the 6-item Hamilton Rating Scale for Depression (HRSD) total scores in depressed outpatients.MethodsThe post-hoc analysis included all adult outpatients with non-psychotic major depressive disorder in the STAR*D trial who entered and exited the first treatment step (up to 14 weeks of citalopram) with a complete set of study measures at baseline and exit and at least one post-baseline measure. Within-patient change and linear regression anchor-based analyses were conducted to define meaningful and substantial changes in the HRSD17 and HRSD6 using three patient-reported outcomes [Work and Social Adjustment Scale (WSAS), Quality of Life Enjoyment and Satisfaction-Short Form (Q-LES-Q-SF); Mini-Q-LES-Q] obtained at baseline and exit from the first treatment step in STAR*D.ResultsLinear regression analyses identified a meaningful change threshold for the HRSD17 as 3.9 [3.7-4.1] [lower, upper 95% CI] and a substantial change as 7.8 [7.4-8.3] with the WSAS. Analogous thresholds based on the Q-LES-Q-SF were 5.8 [5.5-6.1] and 11.6 [11.0-12.2], respectively, and 4.9 [4.7-5.2] and 9.9 [9.3-10.4] for the Mini-QLES-Q, respectively. For the HRSD6, linear regression analyses with the WSAS identified a meaningful change as 2.2 [2.1-2.4], while a substantial change was 4.5 [4.2-4.7]. Analogous figures based on the Q-LES-Q-SF were 3.2 [3.0-3.4] and 6.4 [6.1-6.8]. Similarly, based on the Mini-QLESQ, results were 2.8 [2.6-2.9] and 5.6 [5.3-5.9]. For both the HRSD17 and the HRSD6, within-patient analyses produced less precise estimates of the same change thresholds with substantial overlap between groups. Based on the WSAS, a clinically meaningful change in the HRSD17 total score was 9.6 (SD = 6.5), while a substantial change was 15.0 (SD = 6.7). Analogous change thresholds based on the Q-LESQ-SF were 12.9 (SD = 6.2) and 16.8 (SD = 6.4), respectively. For the Mini-Q-LES-Q, thresholds were 10.9 (SD = 6.5) and 16.1 (SD = 6.2).ConclusionA 4-6 point change in the HRSD17 is clinically meaningful; a 7-12 point change is clinically substantial. For the HRSD6, analogous estimates were 2-3 and 4-7 point changes, respectively.

Project description:BackgroundPrevious meta-analyses of published and unpublished trials indicate that antidepressants provide modest benefits compared to placebo in the treatment of depression; some have argued that these benefits are not clinically significant. However, these meta-analyses were based only on trials submitted for the initial FDA approval of the medication and were limited to those aimed at treating depression. Here, for the first time, we assess the efficacy of a selective serotonin reuptake inhibitor (SSRI) in the treatment of both anxiety and depression, using a complete data set of all published and unpublished trials sponsored by the manufacturer.Methods and findingsGlaxoSmithKline has been required to post the results for all sponsored clinical trials online, providing an opportunity to assess the efficacy of an SSRI (paroxetine) with a complete data set of all trials conducted. We examined the data from all placebo-controlled, double-blind trials of paroxetine that included change scores on the Hamilton Rating Scale for Anxiety (HRSA) and/or the Hamilton Rating Scale for Depression (HRSD). For the treatment of anxiety (k = 12), the efficacy difference between paroxetine and placebo was modest (d = 0.27), and independent of baseline severity of anxiety. Overall change in placebo-treated individuals replicated 79% of the magnitude of paroxetine response. Efficacy was superior for the treatment of panic disorder (d = 0.36) than for generalized anxiety disorder (d = 0.20). Published trials showed significantly larger drug-placebo differences than unpublished trials (d's = 0.32 and 0.17, respectively). In depression trials (k = 27), the benefit of paroxetine over placebo was consistent with previous meta-analyses of antidepressant efficacy (d = 0.32).ConclusionsThe available empirical evidence indicates that paroxetine provides only a modest advantage over placebo in treatment of anxiety and depression. Treatment implications are discussed.

Project description:BACKGROUND:Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. METHODS:This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. RESULTS:At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. CONCLUSIONS:The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. TRIAL REGISTRATION:Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

Dataset Information

Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression.

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Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression.

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