Ralitza Gueorguieva1, Craig Mallinckrodt, John H Krystal. 1. Division of Biostatistics, School of Public Health, Yale University School of Medicine, New Haven, CT 06520-8034, USA. ralitza.gueorguieva@yale.edu
Abstract
CONTEXT: The high percentage of failed clinical trials in depression may be due to high placebo response rates and the failure of standard statistical approaches to capture heterogeneity in treatment response. OBJECTIVE: To assess whether growth mixture modeling can provide insights into antidepressant and placebo responses in clinical trials of patients with major depression. DESIGN: We reanalyzed clinical trials of duloxetine to identify distinct trajectories of Hamilton Scale for Depression (HAM-D) scores during treatment. We analyzed the trajectories in the entire sample and then separately in all active arms and in all placebo arms. Effects of duloxetine hydrochloride, selective serotonin reuptake inhibitor (SSRI), and covariates on the probability of following a particular trajectory were assessed. Outcomes in different trajectories were compared using mixed-effects models. SETTING: Seven randomized double-blind clinical trials of duloxetine vs placebo and comparator SSRI. Patients A total of 2515 patients with major depression. INTERVENTIONS:Duloxetine and comparator SSRI. Main Outcome Measure Total score on the HAM-D. RESULTS: In the entire sample and in the antidepressant-treated subsample, we identified trajectories of responders (76.3% of the sample) and nonresponders (23.7% of the sample). However, placebo-treated patients were characterized by a single response trajectory. Duloxetine and SSRI did not differ in efficacy, and compared with placebo they significantly decreased the odds of following the nonresponder trajectory. Antidepressant responders had significantly better HAM-D scores over time than placebo-treated patients, but antidepressant nonresponders had significantly worse HAM-D scores over time than the placebo-treated patients. CONCLUSIONS: Most patients treated with serotonergic antidepressants showed a clinical trajectory over time that is superior to that of placebo-treated patients. However, some patients receiving these medications did more poorly than patients receiving placebo. These data highlight the importance of ongoing monitoring of medication risks and benefits during serotonergic antidepressant treatment. They should further stimulate the search for biomarkers or other predictors of responder status in guiding antidepressant treatment.
RCT Entities:
CONTEXT: The high percentage of failed clinical trials in depression may be due to high placebo response rates and the failure of standard statistical approaches to capture heterogeneity in treatment response. OBJECTIVE: To assess whether growth mixture modeling can provide insights into antidepressant and placebo responses in clinical trials of patients with major depression. DESIGN: We reanalyzed clinical trials of duloxetine to identify distinct trajectories of Hamilton Scale for Depression (HAM-D) scores during treatment. We analyzed the trajectories in the entire sample and then separately in all active arms and in all placebo arms. Effects of duloxetine hydrochloride, selective serotonin reuptake inhibitor (SSRI), and covariates on the probability of following a particular trajectory were assessed. Outcomes in different trajectories were compared using mixed-effects models. SETTING: Seven randomized double-blind clinical trials of duloxetine vs placebo and comparator SSRI. Patients A total of 2515 patients with major depression. INTERVENTIONS:Duloxetine and comparator SSRI. Main Outcome Measure Total score on the HAM-D. RESULTS: In the entire sample and in the antidepressant-treated subsample, we identified trajectories of responders (76.3% of the sample) and nonresponders (23.7% of the sample). However, placebo-treated patients were characterized by a single response trajectory. Duloxetine and SSRI did not differ in efficacy, and compared with placebo they significantly decreased the odds of following the nonresponder trajectory. Antidepressant responders had significantly better HAM-D scores over time than placebo-treated patients, but antidepressant nonresponders had significantly worse HAM-D scores over time than the placebo-treated patients. CONCLUSIONS: Most patients treated with serotonergic antidepressants showed a clinical trajectory over time that is superior to that of placebo-treated patients. However, some patients receiving these medications did more poorly than patients receiving placebo. These data highlight the importance of ongoing monitoring of medication risks and benefits during serotonergic antidepressant treatment. They should further stimulate the search for biomarkers or other predictors of responder status in guiding antidepressant treatment.
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