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Jaskaran Singh - One of the best experts on this subject based on the ideXlab platform.

  • the effect of Esketamine in patients with treatment resistant depression with and without comorbid anxiety symptoms or disorder
    Depression and Anxiety, 2021
    Co-Authors: Ella Daly, Maggie Fedgchin, Madhukar H Trivedi, Michael E Thase, Stephane Borentain, Ibrahim Turkoz, Giacomo Salvadore, Dawn F Ionescu, Lynn H Starr, Jaskaran Singh
    Abstract:

    Background Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of Esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety. Methods TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or Esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Asberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models. Results Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety. Conclusion Post hoc data support efficacy of Esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.

  • population pharmacokinetics of Esketamine nasal spray and its metabolite norEsketamine in healthy subjects and patients with treatment resistant depression
    Clinical Pharmacokinectics, 2021
    Co-Authors: Carlos Perezruixo, Jaskaran Singh, Wayne C Drevets, Stefaan Rossenu, Peter Zannikos, Partha Nandy, Juan Jose Perezruixo
    Abstract:

    Esketamine nasal spray is approved for treatment-resistant depression. The objective of this study was to characterize the pharmacokinetics of Esketamine and norEsketamine in healthy subjects and patients with treatment-resistant depression. Esketamine and norEsketamine were measured in > 9000 plasma samples collected from 820 individuals who received Esketamine by the intranasal, intravenous, and oral routes. An open linear model for Esketamine (three compartments) and norEsketamine (two compartments) that included a hepato-portal compartment was developed using NONMEM® VII. The effects of covariates on Esketamine pharmacokinetics and a model evaluation were performed using conventional methods. The fraction of a 28-mg intranasal dose absorbed through the nasal cavity (FRn) is 54% (100% of this fraction is completely absorbed); the remaining 46% is swallowed and undergoes intestinal and first-pass metabolism and 18.6% of the swallowed dose reaches the systemic circulation. The absolute bioavailability of 56 and 84 mg of intranasal Esketamine is 54 and 51%, respectively. Esketamine volume at steady state and clearance were 752 L and 114 L/h, respectively. NorEsketamine volume at steady state and apparent clearance were 185 L and 38 L/h, respectively. Relative to non-Asian subjects, Asian subjects showed a 64.0 and 19.4% decrease in the Esketamine elimination rate constant and norEsketamine apparent clearance, respectively. Japanese subjects exhibited a 34% increase in FRn vs other races. Hepatic blood flow decreased by 21.9 L/h for each decade in age in subjects aged > 60 years. These changes resulted in Esketamine and norEsketamine maximum concentration and area under the concentration–time curve after 24 h post-dose values that were up to 36% higher than those observed in other races or in younger adult subjects. Esketamine and norEsketamine pharmacokinetics was successfully characterized in healthy subjects and patients with treatment-resistant depression. The model quantified Esketamine absolute nasal and oral bioavailability, its hepatic flow-limited clearance and biotransformation to the major metabolite norEsketamine, and the influence of intrinsic and extrinsic factors on Esketamine pharmacokinetics. Clinical trials registration numbers of the studies included in the analysis: ESKETINTRD1001 (NCT01780259), ESKETINTRD1002 (NCT01980303), ESKETINTRD1003 (NCT02129088), ESKETINTRD1008 (NCT02846519), ESKETINTRD1009 (NCT02343289), ESKETINTRD1010 (NCT02568176), ESKETINTRD1012 (NCT02345148), 54135419TRD1015 (NCT02682225), ESKETINTRD2003 (NCT01998958), ESKETINSUI2001 (NCT02133001), ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), and ESKETINTRD3005 (NCT02422186).

  • meaningful change in depression symptoms assessed with the patient health questionnaire phq 9 and montgomery asberg depression rating scale madrs among patients with treatment resistant depression in two randomized double blind active controlled trials of Esketamine nasal spray combined with a new oral antidepressant
    Journal of Affective Disorders, 2021
    Co-Authors: Stacie Hudgens, Maggie Fedgchin, Vanina Popova, Wayne C Drevets, Rosanne Lane, Lysbeth Floden, Michael Blackowicz, Carol Jamieson, Kimberly Cooper, Jaskaran Singh
    Abstract:

    Abstract Background Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have treatment resistant depression (TRD). This analysis determined meaningful change thresholds (MCT) of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) using anchor-based methods and compared proportions of meaningful changes in patients with TRD across treatment groups from two Phase 3 trials for Esketamine nasal spray (SPRAVATOTM). Methods Data from two Phase 3 trials in patients with TRD, TRANSFORM-1 and -2, were used in this analysis. The MCTs for the PHQ-9 and MADRS were derived using a clinician global impression of severity anchor. Blinded probability density functions displayed score distributions between anchor categories. Proportions of meaningful response were compared between treatment groups using chi-square tests supported by unblinded cumulative distribution functions of change scores. Results Baseline scores were similar for the PHQ-9 and MADRS between the Esketamine/antidepressant (AD) and AD/placebo groups. The most appropriate MCT on the PHQ-9 was -6 points. By Day 28, 86.5% of patients reached or exceeded the PHQ-9 MCT in the Esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate MCT for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS MCT in the Esketamine/AD group compared to 65.0% in the placebo/AD group. Conclusions Individual-level meaningful change for the PHQ-9 and MADRS was effectively quantified using a clinical anchor to interpret efficacy from patients with TRD and their treating clinicians.

  • effects of mu opiate receptor gene polymorphism rs1799971 a118g on the antidepressant and dissociation responses in Esketamine nasal spray clinical trials
    The International Journal of Neuropsychopharmacology, 2020
    Co-Authors: Ziad Saad, Derrek P Hibar, Maggie Fedgchin, Vanina Popova, Maura Furey, Jaskaran Singh, Hartmuth C Kolb, Wayne C Drevets, Guang Chen
    Abstract:

    BACKGROUND At ketamine and Esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR-gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to Esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses. METHODS Participants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of Esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery-Asberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25. RESULTS In the Esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected. CONCLUSIONS Variation in rs1799971 (A118G) did not affect the antidepressant response to Esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect. TRIAL REGISTRATION NCT02417064 and NCT02418585; www.clinicaltrials.gov.

  • managing Esketamine treatment frequency toward successful outcomes analysis of phase 3 data
    The International Journal of Neuropsychopharmacology, 2020
    Co-Authors: Michel Nijs, Jaskaran Singh, Adam Janik, Ewa Wajs, Stephane Borentain, Leah Aluisio, Ibrahim Turkoz, Ella Daly, Allitia Dibernardo, Frank Wiegand
    Abstract:

    BACKGROUND Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during Esketamine treatment on clinical outcomes. METHODS This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of Esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered Esketamine twice weekly plus a new oral antidepressant daily. In responders (≥50% reduction in Montgomery-Asberg Depression Rating Scale total score from baseline), Esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Asberg Depression Rating Scale ≤ 12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression-Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase. RESULTS Among 580 responders treated with weekly Esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened. CONCLUSIONS These findings support individualization of Esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02497287.

Rosanne Lane - One of the best experts on this subject based on the ideXlab platform.

  • effect of Esketamine nasal spray on olfactory function and nasal tolerability in patients with treatment resistant depression results from four multicenter randomized double blind placebo controlled phase iii studies
    CNS Drugs, 2021
    Co-Authors: Richard L Doty, Maggie Fedgchin, Vanina Popova, Rosanne Lane, Adam Janik, Ella Daly, Rachel Ochsross, Pilar Lim, Crystal Wylie, Kim Cooper
    Abstract:

    Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. The aim of this study was to assess the potential impact of long-term intermittent treatment with Esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18–64 years, one in patients ≥65 years), and one long-term maintenance study of Esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (SS TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

  • meaningful change in depression symptoms assessed with the patient health questionnaire phq 9 and montgomery asberg depression rating scale madrs among patients with treatment resistant depression in two randomized double blind active controlled trials of Esketamine nasal spray combined with a new oral antidepressant
    Journal of Affective Disorders, 2021
    Co-Authors: Stacie Hudgens, Maggie Fedgchin, Vanina Popova, Wayne C Drevets, Rosanne Lane, Lysbeth Floden, Michael Blackowicz, Carol Jamieson, Kimberly Cooper, Jaskaran Singh
    Abstract:

    Abstract Background Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have treatment resistant depression (TRD). This analysis determined meaningful change thresholds (MCT) of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) using anchor-based methods and compared proportions of meaningful changes in patients with TRD across treatment groups from two Phase 3 trials for Esketamine nasal spray (SPRAVATOTM). Methods Data from two Phase 3 trials in patients with TRD, TRANSFORM-1 and -2, were used in this analysis. The MCTs for the PHQ-9 and MADRS were derived using a clinician global impression of severity anchor. Blinded probability density functions displayed score distributions between anchor categories. Proportions of meaningful response were compared between treatment groups using chi-square tests supported by unblinded cumulative distribution functions of change scores. Results Baseline scores were similar for the PHQ-9 and MADRS between the Esketamine/antidepressant (AD) and AD/placebo groups. The most appropriate MCT on the PHQ-9 was -6 points. By Day 28, 86.5% of patients reached or exceeded the PHQ-9 MCT in the Esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate MCT for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS MCT in the Esketamine/AD group compared to 65.0% in the placebo/AD group. Conclusions Individual-level meaningful change for the PHQ-9 and MADRS was effectively quantified using a clinical anchor to interpret efficacy from patients with TRD and their treating clinicians.

  • Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent results of a phase 3 double blind randomized study aspire ii
    The International Journal of Neuropsychopharmacology, 2021
    Co-Authors: Dawn F Ionescu, Siegfried Kasper, Wayne C Drevets, Rosanne Lane, David Hough, Husseini K Manji, Pilar Lim, Xin Qiu, Carla M Canuso
    Abstract:

    Background Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. Methods This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to Esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. Results Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with Esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among Esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. Conclusion This study confirmed rapid and robust reduction of depressive symptoms with Esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.

  • Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent double blind randomized study aspire i
    The Journal of Clinical Psychiatry, 2020
    Co-Authors: Dongjing Fu, Wayne C Drevets, Rosanne Lane, Xiang Li, David Hough, Husseini K Manji, Dawn F Ionescu, Gerard Sanacora, Carla M Canuso
    Abstract:

    Objective To compare Esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. Methods This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to Esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate. Results Greater improvement in MADRS total score was observed with Esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among Esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence. Conclusions These findings demonstrate rapid and robust efficacy of Esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent. Trial registration ClinicalTrials.gov identifier: NCT03039192.

  • Esketamine nasal spray plus oral antidepressant in patients with treatment resistant depression assessment of long term safety in a phase 3 open label study sustain 2
    The Journal of Clinical Psychiatry, 2020
    Co-Authors: Ewa Wajs, Ella J Daly, Rosanne Lane, Randall L Morrison, Leah Aluisio, Allan H Young, Gerard Sanacora, Richard Holder, Joyce E George, Siegfried Kasper
    Abstract:

    Objective To evaluate long-term safety and efficacy of Esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). Methods This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. Results Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued Esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to Esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Asberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). Conclusions Long-term Esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. Trial registration ClinicalTrials.gov identifier: NCT02497287.

Maggie Fedgchin - One of the best experts on this subject based on the ideXlab platform.

  • the effect of Esketamine in patients with treatment resistant depression with and without comorbid anxiety symptoms or disorder
    Depression and Anxiety, 2021
    Co-Authors: Ella Daly, Maggie Fedgchin, Madhukar H Trivedi, Michael E Thase, Stephane Borentain, Ibrahim Turkoz, Giacomo Salvadore, Dawn F Ionescu, Lynn H Starr, Jaskaran Singh
    Abstract:

    Background Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of Esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety. Methods TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or Esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Asberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models. Results Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety. Conclusion Post hoc data support efficacy of Esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.

  • effect of Esketamine nasal spray on olfactory function and nasal tolerability in patients with treatment resistant depression results from four multicenter randomized double blind placebo controlled phase iii studies
    CNS Drugs, 2021
    Co-Authors: Richard L Doty, Maggie Fedgchin, Vanina Popova, Rosanne Lane, Adam Janik, Ella Daly, Rachel Ochsross, Pilar Lim, Crystal Wylie, Kim Cooper
    Abstract:

    Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. The aim of this study was to assess the potential impact of long-term intermittent treatment with Esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18–64 years, one in patients ≥65 years), and one long-term maintenance study of Esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (SS TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

  • meaningful change in depression symptoms assessed with the patient health questionnaire phq 9 and montgomery asberg depression rating scale madrs among patients with treatment resistant depression in two randomized double blind active controlled trials of Esketamine nasal spray combined with a new oral antidepressant
    Journal of Affective Disorders, 2021
    Co-Authors: Stacie Hudgens, Maggie Fedgchin, Vanina Popova, Wayne C Drevets, Rosanne Lane, Lysbeth Floden, Michael Blackowicz, Carol Jamieson, Kimberly Cooper, Jaskaran Singh
    Abstract:

    Abstract Background Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have treatment resistant depression (TRD). This analysis determined meaningful change thresholds (MCT) of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) using anchor-based methods and compared proportions of meaningful changes in patients with TRD across treatment groups from two Phase 3 trials for Esketamine nasal spray (SPRAVATOTM). Methods Data from two Phase 3 trials in patients with TRD, TRANSFORM-1 and -2, were used in this analysis. The MCTs for the PHQ-9 and MADRS were derived using a clinician global impression of severity anchor. Blinded probability density functions displayed score distributions between anchor categories. Proportions of meaningful response were compared between treatment groups using chi-square tests supported by unblinded cumulative distribution functions of change scores. Results Baseline scores were similar for the PHQ-9 and MADRS between the Esketamine/antidepressant (AD) and AD/placebo groups. The most appropriate MCT on the PHQ-9 was -6 points. By Day 28, 86.5% of patients reached or exceeded the PHQ-9 MCT in the Esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate MCT for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS MCT in the Esketamine/AD group compared to 65.0% in the placebo/AD group. Conclusions Individual-level meaningful change for the PHQ-9 and MADRS was effectively quantified using a clinical anchor to interpret efficacy from patients with TRD and their treating clinicians.

  • effects of mu opiate receptor gene polymorphism rs1799971 a118g on the antidepressant and dissociation responses in Esketamine nasal spray clinical trials
    The International Journal of Neuropsychopharmacology, 2020
    Co-Authors: Ziad Saad, Derrek P Hibar, Maggie Fedgchin, Vanina Popova, Maura Furey, Jaskaran Singh, Hartmuth C Kolb, Wayne C Drevets, Guang Chen
    Abstract:

    BACKGROUND At ketamine and Esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR-gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to Esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses. METHODS Participants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of Esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery-Asberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25. RESULTS In the Esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected. CONCLUSIONS Variation in rs1799971 (A118G) did not affect the antidepressant response to Esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect. TRIAL REGISTRATION NCT02417064 and NCT02418585; www.clinicaltrials.gov.

  • efficacy and safety of fixed dose Esketamine nasal spray combined with a new oral antidepressant in treatment resistant depression results of a randomized double blind active controlled study transform 1
    The International Journal of Neuropsychopharmacology, 2019
    Co-Authors: Maggie Fedgchin, Pierre Blier, Madhukar H Trivedi, Ella J Daly, Rama Melkote, Rosanne Lane, Dawn Vitagliano, Maurizio Fava, Michael R Liebowitz, Arun V Ravindran
    Abstract:

    Background About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression. Methods This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (Esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, Esketamine 84 mg/antidepressant had to be significant for Esketamine 56 mg/antidepressant to be formally tested. Results Statistical significance was not achieved with Esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although Esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for Esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache. Conclusions Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both Esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between Esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of Esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression. Trial registration ClinicalTrials.gov identifier: NCT02417064.

Wayne C Drevets - One of the best experts on this subject based on the ideXlab platform.

  • population pharmacokinetics of Esketamine nasal spray and its metabolite norEsketamine in healthy subjects and patients with treatment resistant depression
    Clinical Pharmacokinectics, 2021
    Co-Authors: Carlos Perezruixo, Jaskaran Singh, Wayne C Drevets, Stefaan Rossenu, Peter Zannikos, Partha Nandy, Juan Jose Perezruixo
    Abstract:

    Esketamine nasal spray is approved for treatment-resistant depression. The objective of this study was to characterize the pharmacokinetics of Esketamine and norEsketamine in healthy subjects and patients with treatment-resistant depression. Esketamine and norEsketamine were measured in > 9000 plasma samples collected from 820 individuals who received Esketamine by the intranasal, intravenous, and oral routes. An open linear model for Esketamine (three compartments) and norEsketamine (two compartments) that included a hepato-portal compartment was developed using NONMEM® VII. The effects of covariates on Esketamine pharmacokinetics and a model evaluation were performed using conventional methods. The fraction of a 28-mg intranasal dose absorbed through the nasal cavity (FRn) is 54% (100% of this fraction is completely absorbed); the remaining 46% is swallowed and undergoes intestinal and first-pass metabolism and 18.6% of the swallowed dose reaches the systemic circulation. The absolute bioavailability of 56 and 84 mg of intranasal Esketamine is 54 and 51%, respectively. Esketamine volume at steady state and clearance were 752 L and 114 L/h, respectively. NorEsketamine volume at steady state and apparent clearance were 185 L and 38 L/h, respectively. Relative to non-Asian subjects, Asian subjects showed a 64.0 and 19.4% decrease in the Esketamine elimination rate constant and norEsketamine apparent clearance, respectively. Japanese subjects exhibited a 34% increase in FRn vs other races. Hepatic blood flow decreased by 21.9 L/h for each decade in age in subjects aged > 60 years. These changes resulted in Esketamine and norEsketamine maximum concentration and area under the concentration–time curve after 24 h post-dose values that were up to 36% higher than those observed in other races or in younger adult subjects. Esketamine and norEsketamine pharmacokinetics was successfully characterized in healthy subjects and patients with treatment-resistant depression. The model quantified Esketamine absolute nasal and oral bioavailability, its hepatic flow-limited clearance and biotransformation to the major metabolite norEsketamine, and the influence of intrinsic and extrinsic factors on Esketamine pharmacokinetics. Clinical trials registration numbers of the studies included in the analysis: ESKETINTRD1001 (NCT01780259), ESKETINTRD1002 (NCT01980303), ESKETINTRD1003 (NCT02129088), ESKETINTRD1008 (NCT02846519), ESKETINTRD1009 (NCT02343289), ESKETINTRD1010 (NCT02568176), ESKETINTRD1012 (NCT02345148), 54135419TRD1015 (NCT02682225), ESKETINTRD2003 (NCT01998958), ESKETINSUI2001 (NCT02133001), ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), and ESKETINTRD3005 (NCT02422186).

  • meaningful change in depression symptoms assessed with the patient health questionnaire phq 9 and montgomery asberg depression rating scale madrs among patients with treatment resistant depression in two randomized double blind active controlled trials of Esketamine nasal spray combined with a new oral antidepressant
    Journal of Affective Disorders, 2021
    Co-Authors: Stacie Hudgens, Maggie Fedgchin, Vanina Popova, Wayne C Drevets, Rosanne Lane, Lysbeth Floden, Michael Blackowicz, Carol Jamieson, Kimberly Cooper, Jaskaran Singh
    Abstract:

    Abstract Background Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have treatment resistant depression (TRD). This analysis determined meaningful change thresholds (MCT) of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) using anchor-based methods and compared proportions of meaningful changes in patients with TRD across treatment groups from two Phase 3 trials for Esketamine nasal spray (SPRAVATOTM). Methods Data from two Phase 3 trials in patients with TRD, TRANSFORM-1 and -2, were used in this analysis. The MCTs for the PHQ-9 and MADRS were derived using a clinician global impression of severity anchor. Blinded probability density functions displayed score distributions between anchor categories. Proportions of meaningful response were compared between treatment groups using chi-square tests supported by unblinded cumulative distribution functions of change scores. Results Baseline scores were similar for the PHQ-9 and MADRS between the Esketamine/antidepressant (AD) and AD/placebo groups. The most appropriate MCT on the PHQ-9 was -6 points. By Day 28, 86.5% of patients reached or exceeded the PHQ-9 MCT in the Esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate MCT for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS MCT in the Esketamine/AD group compared to 65.0% in the placebo/AD group. Conclusions Individual-level meaningful change for the PHQ-9 and MADRS was effectively quantified using a clinical anchor to interpret efficacy from patients with TRD and their treating clinicians.

  • Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent results of a phase 3 double blind randomized study aspire ii
    The International Journal of Neuropsychopharmacology, 2021
    Co-Authors: Dawn F Ionescu, Siegfried Kasper, Wayne C Drevets, Rosanne Lane, David Hough, Husseini K Manji, Pilar Lim, Xin Qiu, Carla M Canuso
    Abstract:

    Background Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. Methods This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to Esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. Results Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with Esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among Esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. Conclusion This study confirmed rapid and robust reduction of depressive symptoms with Esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.

  • effects of mu opiate receptor gene polymorphism rs1799971 a118g on the antidepressant and dissociation responses in Esketamine nasal spray clinical trials
    The International Journal of Neuropsychopharmacology, 2020
    Co-Authors: Ziad Saad, Derrek P Hibar, Maggie Fedgchin, Vanina Popova, Maura Furey, Jaskaran Singh, Hartmuth C Kolb, Wayne C Drevets, Guang Chen
    Abstract:

    BACKGROUND At ketamine and Esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR-gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to Esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses. METHODS Participants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of Esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery-Asberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25. RESULTS In the Esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected. CONCLUSIONS Variation in rs1799971 (A118G) did not affect the antidepressant response to Esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect. TRIAL REGISTRATION NCT02417064 and NCT02418585; www.clinicaltrials.gov.

  • genome wide association study and polygenic risk score analysis of Esketamine treatment response
    Scientific Reports, 2020
    Co-Authors: Ewa Wajs, Jaskaran Singh, Rachel Ochsross, Wayne C Drevets
    Abstract:

    To elucidate the genetic underpinnings of the antidepressant efficacy of S-ketamine (Esketamine) nasal spray in major depressive disorder (MDD), we performed a genome-wide association study (GWAS) in cohorts of European ancestry (n = 527). This analysis was followed by a polygenic risk score approach to test for associations between genetic loading for psychiatric conditions, symptom profiles and Esketamine efficacy. We identified a genome-wide significant locus in IRAK3 (p = 3.57 × 10–8, rs11465988, β = − 51.6, SE = 9.2) and a genome-wide significant gene-level association in NME7 (p = 1.73 × 10–6) for Esketamine efficacy (i.e. percentage change in symptom severity score compared to baseline). Additionally, the strongest association with Esketamine efficacy identified in the polygenic score analysis was from the genetic loading for depressive symptoms (p = 0.001, standardized coefficient β = − 3.1, SE = 0.9), which did not reach study-wide significance. Pathways relevant to neuronal and synaptic function, immune signaling, and glucocorticoid receptor/stress response showed enrichment among the suggestive GWAS signals.

Husseini K Manji - One of the best experts on this subject based on the ideXlab platform.

  • Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent results of a phase 3 double blind randomized study aspire ii
    The International Journal of Neuropsychopharmacology, 2021
    Co-Authors: Dawn F Ionescu, Siegfried Kasper, Wayne C Drevets, Rosanne Lane, David Hough, Husseini K Manji, Pilar Lim, Xin Qiu, Carla M Canuso
    Abstract:

    Background Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. Methods This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to Esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. Results Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with Esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among Esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. Conclusion This study confirmed rapid and robust reduction of depressive symptoms with Esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.

  • Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent double blind randomized study aspire i
    The Journal of Clinical Psychiatry, 2020
    Co-Authors: Dongjing Fu, Wayne C Drevets, Rosanne Lane, Xiang Li, David Hough, Husseini K Manji, Dawn F Ionescu, Gerard Sanacora, Carla M Canuso
    Abstract:

    Objective To compare Esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. Methods This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to Esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate. Results Greater improvement in MADRS total score was observed with Esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among Esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence. Conclusions These findings demonstrate rapid and robust efficacy of Esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent. Trial registration ClinicalTrials.gov identifier: NCT03039192.

  • efficacy and safety of Esketamine nasal spray plus an oral antidepressant in elderly patients with treatment resistant depression transform 3
    American Journal of Geriatric Psychiatry, 2020
    Co-Authors: Rachel Ochsross, Wayne C Drevets, Ella J Daly, Rosanne Lane, Yun Zhang, David Hough, Randall L Morrison, Husseini K Manji, Gerard Sanacora, David C Steffens
    Abstract:

    Abstract Background Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment. Methods This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed Esketamine nasal spray and new oral antidepressant (Esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65–74 versus ≥75 years) and post-hoc analyses including age at depression onset. Results For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was −3.6 (−7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was −4.9 (−8.96, −0.89; t = −2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus −0.4 (−10.38, 9.50; t = −0.09, two-sided nominal p = 0.930) for those ≥75 years, and −6.1 (−10.33, −1.81; t = −2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset Conclusions Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65–74 years) and patients with earlier onset of depression (

  • post hoc analyses of Esketamine nasal spray plus an oral antidepressant in elderly patients with treatment resistant depression
    American Journal of Geriatric Psychiatry, 2019
    Co-Authors: Rachel Ochsross, Wayne C Drevets, Ella J Daly, Rosanne Lane, Yun Zhang, David Hough, Husseini K Manji, Gerard Sanacora, Karen Foster, Caleb M Adler
    Abstract:

    Introduction Major depressive disorder in the elderly is correlated with lower response and remission rates, greater disability, decreased quality of life, and greater mortality from suicide; approximately 18-40% develop treatment-resistant depression (TRD). Moreover, the elderly respond less well to currently available treatments and may be more vulnerable to their adverse effects. The severity of TRD in the elderly is exemplified by a 5-fold increased use of electroconvulsive therapy, highlighting a critical need for alternative safe and effective treatments. A companion abstract discusses results from the first large phase 3 study of Esketamine nasal spray in elderly patients with TRD. Post hoc analyses presented here explored factors that may have contributed to the lack of statistical significance observed in the study, despite a numerical advantage on the primary endpoint–Montgomery Asberg Depression Rating scale (MADRS) LS mean scores–in the Esketamine arm vs the control arm of the trial. Methods The primary phase 3, double-blind, multicenter, active controlled study (NCT02422186), included adults ≥65 years of age (N=138) with TRD. Patients were randomized (1:1) to flexibly-dosed Esketamine nasal spray (28, 56 or 84 mg twice weekly) and a new oral antidepressant (Esketamine/antidepressant), or a new oral antidepressant and placebo nasal spray (antidepressant/placebo). Change from baseline was analyzed using mixed-effects model for repeated measures (MMRM). Analyses were conducted at a 2-sided significance level of 0.05. Findings from the primary analysis are described in the companion abstract. Post hoc analyses explored factors that may have affected the study outcome including (1) impact of study stage, i.e. pre interim analysis (IA) (stage 1) or post IA (stage 2): modifications were made early in the study including training of remote MADRS raters to work with elderly and site discussions related to dose that, because of timing for implementation of the changes, had the greatest impact on stage 2; (2) impact of dose assessed by stage of the IA; (3) age subgroups (65-74 and ≥75 years); (4) age of onset of depression ( Results For reference, the primary efficacy endpoint, the LS mean (95% CI) difference for change in MADRS total scores from baseline to day 28 between the Esketamine/antidepressant group and the antidepressant/placebo group using MMRM was -3.6 (−7.20, 0.07; p=0.059). Post hoc analyses included (1) a marked difference in efficacy between stages of the IA: LS mean (95% CI) difference was -1.6 (-6.85, 3.70) in stage 1 vs -5.6 (-10.78, -0.32) in stage 2. The primary analysis applied equal weight to stage 1 (51 patients) and stage 2 (87 patients) effectively down-weighting the results of stage 2. Overall analysis, without adjusting for the IA, showed LS mean (95% CI) change of -4.0 (-7.71, -0.25); (2) use of maximum dose of 84mg: 52.5% at day 25 of stage 1 vs 71.8% at day 25 of stage 2; (3) age: 65-74 years LS mean (95% CI) change of -4.9 (-8.96, -0.89) vs ≥75 years -0.4 (-10.38, 9.50); (4) age at onset of depression Conclusions While MADRS improvement with Esketamine/antidepressant vs treatment with antidepressant/placebo was not statistically significant in the primary analysis, a nonsignificant favourable trend was found, with a treatment effect size similar to that seen in younger adult Esketamine studies. Post hoc analyses assessed factors potentially affecting the primary outcome. In the short-term study, use of lower doses earlier in the study may have decreased efficacy. In the post hoc analysis, a 95% CI of difference that did not include 0 indicated that Esketamine/antidepressant was favoured over antidepressant/placebo without the corrective weighting for the IA, as well as for patients 65-74 years of age, and for those with the onset of depression at age This research was funded by This study was funded by Janssen Research & Development, LLC.

  • efficacy and safety of intranasal Esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide results of a double blind randomized placebo controlled study
    Focus (American Psychiatric Publishing), 2019
    Co-Authors: Carla M Canuso, Maggie Fedgchin, Jaskaran Singh, Rosanne Lane, David Hough, Husseini K Manji, Gerard Sanacora, Larry Alphs, Christine Pinter, Wayne C Drevets
    Abstract:

    Objective:The authors compared the efficacy of standard-of-care treatment plus intranasal Esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among ind...