Person: Papakostas, George
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Papakostas
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Papakostas, George
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Publication Maintaining Rapid Antidepressant Effects Following Ketamine Infusion(Physicians Postgraduate Press, Inc, 2020-02-04) Papakostas, GeorgeObjective: Several controlled trials have demonstrated intravenous ketamine's rapid effects. As a result, the use of this off-label treatment has grown exponentially in recent years. This number is expected to continue to grow after the approval by the U.S. Food and Drug Administration of intranasal esketamine for treatment-resistant depression- a decision which firmly establishes N-methyl-D-aspartate (NMDA)-receptor antagonism as a valid antidepressant mechanism of action in the public view. The limitation, however, of intravenous ketamine administration is that much less is known about how to maintain initial treatment gains. Thus, while intravenous ketamine has proven to be a rapid-acting antidepressant, maintaining its early therapeutic gains in an efficient manner has emerged as a major unmet need in the field. Data sources: Pubmed/medline were searched from inception to March 1st, 2019 using the following terms: "ketamine", "randomized", "depression", and "placebo". There were no language or date restrictions. Study Selection: We selected for randomized, placebo-controlled trials to maintain initial treatment gains of intravenous ketamine for MDD. 115 manuscripts were identified and 110 were excluded because they did not describe randomized, double-blind clinical trials.Five trials were identified. Data Extraction: The remaining fivese articles were reviewed. Results: Three negative studies involving two oral agents (lithium, riluzole), a small negative study involving repeated ketamine infusions, as well as a positive yet insufficiently controlled larger study supporting 2-3 times weekly infusions have been published. Conclusions: This evidence-base is insufficient to inform clinical practice. Fortunately, a wide variety of molecular targets exist for this indication. Psychotherapy and exercise may also play a beneficial role. More studies are urgently needed to establish how best to maintain rapid symptom improvement seen with ketamine infusions.Publication Efficacy of Esketamine Augmentation in Major Depressive Disorder: A Meta-Analysis(Physicians Postgraduate Press, Inc, 2020-05-26) Papakostas, George; Chaaya Salloum, Naji; Hock, Rebecca; Jha, Manish K.; Murrough, James W.; Mathew, Sanjay J.; Iosifescu, Daniel V.; Fava, MaurizioObjective: Esketamine, the s-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). Data Sources: A systematic search of Pubmed/Medline was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. Study Selection: 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. Data Extration: Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the MADRS score change from baseline to endpoint, serving as the primary outcome of the study. Results: Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N=774, SMD = 0.36, 95% CI = 0.24 - 0.49, p < .0001; response: RR = 1.40, 95% CI: 1.22 - 1.61, p < .0001; remission: RR = 1.45, 95% CI: 1.20 - 1.75, p < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs. new/optimized baseline antidepressants, or duration of the study. Conclusions: Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.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 PS153. Efficacy of ziprasidone monotherapy in patients with anxious depression: A 12-week, randomized, double-blind, placebo-controlled, sequential-parallel comparison trial(Oxford University Press, 2016) Heo, Jung Yoon; Jeon, Hong Jin; Fava, Maurizio; Mischoulon, David; Baer, Lee; Clain, Alisabet; Doorley, James; Pisoni, Angela; Papakostas, GeorgePublication PS89. Influence of anxiety symptoms on improvement of neurocognitive functions in patients with major depressive disorder: A 12-week, multicenter, randomized trial of tianeptine versus escitalopram, the CAMPION study(Oxford University Press, 2016) Kim, Kiwon; Yoo, Ikki; Woo, Jong-Min; Lee, Seung-Hwan; Fava, Maurizio; Mischoulon, David; Papakostas, George; Kim, Eui-Joong; Chung, Seock hoon; Ha, Jee Hyun; Jeon, Hong JinPublication Reduced orbitofrontal-thalamic functional connectivity related to suicidal ideation in patients with major depressive disorder(Nature Publishing Group UK, 2017) Kim, Kiwon; Kim, Sung-Woo; Myung, Woojae; Han, Cheol E.; Fava, Maurizio; Mischoulon, David; Papakostas, George; Seo, Sang Won; Cho, Hana; Seong, Joon-Kyung; Jeon, Hong JinDespite recent developments in neuroimaging, alterations of brain functional connectivity in major depressive disorder (MDD) patients with suicidal ideation are poorly understood. This study investigated specific changes of suicidal ideation in functional connectivity of MDD patients. Whole brain functional connectivity in 46 patients with MDD (23 with suicidal ideation and 23 without) and 36 age- and gender- matched healthy controls were compared using resting-state functional Magnetic Resonance Imaging (fMRI) analyzed with network-based statistics (NBS) and graph-theoretical methods. Decreased functional connectivity in a characterized sub-network was observed in patients with MDD and suicidal ideation (FDR-adjusted p < 0.05). The sub-network included the regions of the fronto-thalamic circuits in the left hemisphere. The network measures of the left superior frontal gyrus, pars orbitalis (r = −0.40, p = 0.009), left thalamus (r = −0.41, p = 0.009), and right thalamus (r = −0.51, p = −0.002) were shown, through graph theoretical analysis, to be significantly negatively correlated with severity of suicidal ideation. The reduced functional connectivity in left orbitofrontal-both thalamic regions with suicidal ideation in MDD were inversely proportional to the severity of suicidality independent from depression severity. These findings suggest problems with decision-making and information integration in MDD patients with suicidal ideation.Publication Reduced Venous Blood Basophil Count and Anxious Depression in Patients with Major Depressive Disorder(Korean Neuropsychiatric Association, 2016) Baek, Ji Hyun; Kim, Hee-Jin; Fava, Maurizio; Mischoulon, David; Papakostas, George; Nierenberg, Andrew; Heo, Jung-Yoon; Jeon, Hong JinObjective: Anxious depression has a distinct neurobiology, clinical course and treatment response from non-anxious depression. Role of inflammation in anxious depression has not been examined. As an exploratory study to characterize the role of inflammation on a development of anxious depression, we aimed to determine the relationship between white blood cell (WBC) subset counts and anxiety in individuals with major depressive disorder (MDD). Methods: A total of 709 patients who were newly diagnosed with MDD were recruited. Anxiety levels of participants were evaluated using the Anxiety/ Somatization subitem of the Hamilton Depression Rating Scale. The association between WBC subset fraction and anxiety was evaluated. Results: Basophil and eosinophil sub-fractions showed significant negative correlations with HAM-D anxiety/somatization factor scores (basophils: r=-0.092, p=0.014 and eosinophils: r=-0.075, p=0.046). When an anxiety score (a sum of somatic and psychic anxiety) was entered as a dependent variable, only basophils showed significant negative association with the anxiety scores after adjusting for all other WBC subset counts and demographic factors (t=-2.57, p=0.010). Conclusion: This study showed that anxious depression had a decreased basophil subfraction, which might be associated with involvement of inflammation in development of anxious depression.Publication Residual Sleep Disturbance and Risk of Relapse During the Continuation/Maintenance Phase Treatment of Major Depressive Disorder with the Selective Serotonin Reuptake Inhibitor Fluoxetine(BioMed Central, 2010) Yang, Huaiyu; Sinicropi-Yao, Lara; Chuzi, Sarah; Youn, Soo Jeong; Clain, Alisabet; Baer, Lee; Chen, Ying; McGrath, Patrick J; Fava, Maurizio; Papakostas, GeorgeBackground: Relapse of major depressive disorder (MDD) is a common clinical problem. This study was designed to determine whether residual sleep disturbance (insomnia and hypersomnia) predict risk of relapse during the continuation and maintenance treatment of MDD. Methods: A total of 570 patients with MDD were treated with open-label, flexible dose fluoxetine (range 20 to 60 mg; mean dose = 45.8 mg/day; SD = 15.1) for 12 weeks. Under double blind conditions, 262 patients who achieved clinical response were randomly assigned to continue fluoxetine or to switch to placebo for 52 weeks or until relapse. Residual sleep disturbance during the baseline visit of the double-blind phase was assessed using items 4, 5, 6 (insomnia) and 22, 23, 24 (hypersomnia) of the Hamilton Depression Rating Scale (HDRS). Survival analysis was utilized to determine the effect of residual sleep disturbance on risk of relapse. Results: The severities of early (P > 0.05), middle (P > 0.05), late (P > 0.05), or total (P > 0.05) residual insomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Similarly, the severities of early bedtime (P > 0.05), oversleeping (P > 0.05), napping (P > 0.05), or total (P > 0.05) residual hypersomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Conclusion: The present study did not identify the severity of residual sleep disturbance among fluoxetine responders to predict risk of MDD relapse. The size of our sample may have precluded us from identifying more modest effects of residual sleep disturbance on the risk of relapse in MDD patients. Future studies are needed to further explore the relationship between residual sleep disturbance and relapse in MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT00427128Publication Vortioxetine versus Placebo for Major Depressive Disorder: A Comprehensive Analysis of the Clinical Trial Dataset(Physicians Postgraduate Press, Inc, 2021-06-15) Iovieno, Nadia; Papakostas, George; Feeney, Anna; Fava, Maurizio; Mathew, Sanjay J.; Iosifescu, Dan I.; Murrough, James W.; Macaluso, Matthew; Hock, Rebecca; Jha, ManishObjective: A meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD). Data Sources: Abstracts were identified using PubMed by cross-referencing “vortioxetine” with “placebo” and “randomized.” No language or publication year restrictions were used. Study Selection: Randomized, double-blind, placebo-controlled clinical trials comparing oral vortioxetine monotherapy with placebo for acute treatment of MDD. Data Extraction: Data were extracted with a pre-coded form, as follows: number of patients randomized, treatment group, Montgomery-Asberg Depression Rating Scale (MADRS) response and remission rates, mean change in scores from baseline and standard errors for the MADRS, Hamilton Anxiety Rating Scale (HAM-A), and Digit Symbol Substitution Test (DSST). Results: 7,269 subjects randomized to vortioxetine (n=3,630) or placebo (n=3,639) from 17 studies were included. The probability of receiving placebo did not predict difference in change in MADRS scores between vortioxetine and placebo (estimate 4.1, p=0.54). The standardized mean difference (SMD) (95% CI) for change in MADRS versus placebo was 0.33 (0.24 - 0.41), and was 0.25 (0.08 - 0.39), 0.33 (0.19 - 0.47), 0.26 (-0.06 to 0.58), and 0.44 (0.27 - 0.62) for 5mg, 10 mg, 15 mg, and 20 mg doses respectively. Greater difference in efficacy between drug and placebo was observed in studies with a low than a high placebo response rate. Conclusion: Vortioxetine is more effective than placebo in improving depression, anxiety and cognition. Less informative or uninformative studies obscured the true treatment effect.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.