Person: Freeman, Marlene
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Freeman
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Marlene
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Freeman, Marlene
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Publication Effect of Adjunctive Pimavanserin on Sleep/Wakefulness in Patients With Major Depressive Disorder(Physicians Postgraduate Press, Inc, 2020-12-01) Jha, Manish; Fava, Maurizio; Freeman, Marlene; Thase, Michael; Papakostas, George; Shelton, Richard; Trivedi, Madhukar; Birks, Bryan; Liu, Keith; Stankovic, SrdjanABSTRACT Objective: This was an analysis of pimavanserin, a 5-hydroxytryptamine 2A antagonist/inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response. Methods: For this analysis of CLARITY, a Phase 2 study of adjunctive pimavanserin, sleep/wakefulness disturbances were measured with the sum of Hamilton Depression Rating Scale (HAMD) insomnia items (Items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline for HAMD insomnia score >3, correlation between the HAMD insomnia score and KSS, and change from baseline for the Sheehan Disability Scale (SDS) and Unproductive Days subscore in patients with a baseline KSS >6. Results: The study was conducted between December 2016 and October 2018. At baseline, HAMD insomnia factor score >3 occurred in 76% with placebo and 85% with pimavanserin. The overall LS mean (standard error) weighted difference was -0.5 (0.32) with a 95% confidence interval (CI) -1.2 to, 0.1 (p=0.088) at Week 5. Improvement was observed with pimavanserin vs. placebo at Weeks 2, 3, and 4, with effect sizes of 0.370 to 0.524 (p<0.05). For KSS, the LS mean difference at Week 5 was -1.1 (0.30), 95% CI -1.7 to, -0.5 (p=0.0003; effect size: 0.627) for pimavanserin vs. placebo. Among those with a KSS >6 at baseline (n=120 placebo and n=42 pimavanserin), the LS mean difference in the SDS mean score at Week 5 was -1.1 (0.46), 95% CI -2.0 to, -0.2 (p=0.019; effect size: 0.442) for pimavanserin vs. placebo. Conclusions: Adjunctive pimavanserin significantly improved sleep/wakefulness sleep disturbance during treatment of MDD, which was associated with greater improvement in function. This study was registered at clinicaltrials.gov: NCT03018340. Key Words: insomnia, major depressive disorder, pimavanserin, sleepPublication Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder(Lippincott Williams And Wilkins, 2016) Freeman, Marlene; Fava, Maurizio; Gommoll, Carl; Chen, Changzheng; Greenberg, William M.; Ruth, AdamThe aim of this study was to evaluate the effects of levomilnacipran extended-release (ER) on depression-related fatigue in adults with major depressive disorder. Post-hoc analyses of five phase III trials were carried out, with evaluation of fatigue symptoms based on score changes in four items: Montgomery–Åsberg Depression Rating Scale (MADRS) item 7 (lassitude), and 17-item Hamilton Depression Rating Scale (HAMD17) items 7 (work/activities), 8 (retardation), and 13 (somatic symptoms). Symptom remission was analyzed on the basis of score shifts from baseline to end of treatment: MADRS item 7 and HAMD17 item 7 (from ≥2 to ≤1); HAMD17 items 8 and 13 (from ≥1 to 0). The mean change in MADRS total score was analyzed in patients with low and high fatigue (MADRS item 7 baseline score <4 and ≥4, respectively). Patients receiving levomilnacipran ER had significantly greater mean improvements and symptom remission (no/minimal residual fatigue) on all fatigue-related items: lassitude (35 vs. 28%), work/activities (43 vs. 35%), retardation (46 vs. 39%), somatic symptoms (26 vs. 18%; all Ps<0.01 versus placebo). The mean change in MADRS total score was significantly greater with levomilnacipran ER versus placebo in both low (least squares mean difference=−2.8, P=0.0018) and high (least squares mean difference=−3.1, P<0.0001) fatigue subgroups. Levomilnacipran ER treatment was effective in reducing depression-related fatigue in adult patients with major depressive disorder and was associated with remission of fatigue symptoms.Publication A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin in Patients With Major Depressive Disorder and an Inadequate Response to Therapy (CLARITY)(Physicians Postgraduate Press, Inc, 2019-09-24) Fava, Maurizio; Dirks, Bryan; Shelton, Richard C.; Thase, Michael E.; Trivedi, Madhukar H.; Liu, Keith; Stankovic, Srdjan; Freeman, Marlene; Papakostas, GeorgeObjective: Pimavanserin is a 5-hydroxytryptamine2A antagonist/inverse receptor agonist. In this Phase 2 study, we studied the efficacy and safety of pimavanserin as adjunctive therapy in patients with major depressive disorder (MDD). Methods: This was a multicenter, randomized, double-blind, placebo-controlled study in patients with DSM-5–defined MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Using a 2-stage sequential parallel-comparison design, patients were initially randomized in a 3:1 ratio to placebo or pimavanserin added to ongoing SSRI or SNRI therapy; at 5 weeks, placebo non-responders were re-randomized to placebo or pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage for the HAMD-17 total score and Sheehan Disability Score (SDS) score. Results: Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled SPCD analyses of Stages 1 and 2, the LS mean (standard error) difference for the HAMD-17 total was (-1.7 (0.85), p=0.039) and the SDS was (-0.8 (0.29), p=0.004). At Week 5 of Stage 1, LS mean (standard error) difference for pimavanserin vs. placebo was significant for changes on the HAMD-17 (-4.0 [1.09], p=0.0003) and SDS (-1.2 [0.40], p=0.0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of pimavanserin from placebo (p<0.05) occurred at 1 week. Most common AEs with pimavanserin were dry mouth, nausea, and headache. Conclusion: Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI/SNRI. Tolerability was consistent with previous experience.