Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review.
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ABSTRACT:
SUBMITTER: Capuzzi E
PROVIDER: S-EPMC8430977 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveWe performed a meta-analysis of randomized double-blinded placebo controlled trials (DB-RCTs) to investigate efficacy and safety of intranasal esketamine in treating major depressive disorder (MDD) including treatment resistant depression (TRD) and major depression with suicide ideation (MDSI).MethodsMean change in total scores on Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to different time-points were our primary outcome measure. Secondary efficacy measures included rate of remission of depression and resolution of suicidality.ResultsEight DB-RCTs (seven published and one un-published) covering 1,488 patients with MDD were included. Esketamine more significantly improved MADRS total scores than placebo starting from 2-4 hours after the first administration (standardized mean difference, -0.41 [95% CI, -0.58 to -0.25], p < 0.00001), and this superiority maintained until end of double-blinded period (28 days). Sub-group analysis showed that superior antidepressant effects of esketamine over placebo in TRD and MDSI was observed from 2-4 hours, which was maintained until 28 days. Resolution of suicide in MDSI was also greater for esketamine than for placebo at 2-4 hours (OR of 2.04, 95% CIs, 1.37 to 3.05, p = 0.0005), but two groups did not statistically differ at 24 hours and day 28. Total adverse events (AEs), and other common AEs including dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, and somnolence were more frequent in esketamine than in placebo group.ConclusionEsketamine showed rapid antidepressant effects in patients with MDD, including TRD and MDSI. The study also suggested that esketamine might be associated with rapid anti-suicidal effects for patients with MDSI.
| S-EPMC8077059 | biostudies-literature
Project description:ImportanceApproximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants.ObjectiveTo assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD).Design, setting, and participantsThis phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings.InterventionsIn period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks.Main outcomes and measuresThe primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.ResultsSixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy).Conclusions and relevanceIn this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials.Trial registrationclinicaltrials.gov identifier: NCT01998958.
| S-EPMC5838571 | biostudies-literature
Project description:PurposeTo evaluate the relationship of sleep disturbance to the antidepressant effects of esketamine.Materials and methodsTwo double-blind, 4-week studies randomized adults with treatment-resistant depression (TRD) to placebo or esketamine nasal spray, each with newly initiated antidepressant. Sleep was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS) item 4. Change in response (≥50% decrease in MADRS total score) and remission (total MADRS score ≤12) at day 28 was examined by presence/absence of baseline sleep disturbance using logistic regression models. Impact on reported sleep disturbance (MADRS item 4 score) was examined using ANCOVA models.ResultsAt baseline, most patients reported disturbed sleep - moderate/severe (65.3%, 369/565), mild (25.3%, 143/565), or none/slightly (9.4%, 53/565) - with similar distribution between treatment groups. A higher proportion of esketamine-treated patients achieved response (OR = 2.05; 95% CI: 1.40-3.02; P < 0.001) and remission (OR = 1.81; 95% CI: 1.23-2.66; P = 0.003) at day 28 compared to antidepressant plus placebo, regardless of presence/severity of sleep disturbance. Consistent with this, sleep (MADRS item 4 score) improved in both groups after the first dose, more so with esketamine by day 8 (between-group difference: P ≤ 0.02 at all time points). Across both treatment groups, 1-point improvement in sleep at day 8 increased the probability of antidepressant response on day 28 by 26% (OR = 1.26, 95% CI: 1.12-1.42; P < 0.001), and remission by 28% (OR = 1.28, 95% CI: 1.14-1.43; P < 0.001).ConclusionAntidepressant efficacy of esketamine was demonstrated in patients with TRD, regardless of the presence of sleep disturbance. After 8 days of treatment and thereafter, significantly more esketamine-treated patients reported improvement in sleep versus antidepressant plus placebo.
| S-EPMC8646953 | biostudies-literature
Project description:In March 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of esketamine for the treatment of resistant depression in adults. Esketamine is the S-enantiomer of ketamine, an FDA-approved anaesthetic, known to cause dissociation and, occasionally, hallucinations. While ketamine has not been approved for depression in the USA or in any other country, it has been used off-label in cases of severe depression. This commentary critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science.
| S-EPMC8061126 | biostudies-literature
Project description:This narrative review aims to provide an overview of the current literature on the pharmacology, safety, efficacy and tolerability of intranasal esketamine, the S-enantiomer of ketamine, for the treatment of treatment-resistant depression (TRD). A literature search using Medline, Embase, PsycINFO and Cochrane Central was conducted (January 2000 to July 2019). Product information and www.clinicaltrials.gov were also reviewed. The literature search was limited to human studies published in English. Phase?I, II, and III studies of intranasal esketamine for TRD were reviewed. About a third of patients with major depressive disorder fail to achieve remission despite treatment with multiple antidepressants. This article examines the trials that led to the approval of esketamine in the United States, as well as other recent studies of esketamine for TRD. The findings from limited phase?III trials illustrate that intranasal esketamine is effective and safe in reducing depressive symptoms and achieving clinical response in patients with TRD. The optimum duration and frequency of use are not fully understood. Although the nasal spray is a convenient dosage form, its use in practice may be limited by cost and administrative regulation. While it may prove beneficial to many patients who suffer from TRD, further long-term data are required, along with comparative trials with the R-isomer (arketamine). In the interim, care and monitoring should be exercised in its use in clinical practice.
| S-EPMC7383653 | biostudies-literature
Project description:Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) was associated with antidepressant, anxiolytic, and procognitive effects in a small sample of patients suffering from treatment-resistant depression (TRD), followed over 1 year. Results of long-term follow-up of up to 4 years of NAcc-DBS are described in a group of 11 patients. Clinical effects, quality of life (QoL), cognition, and safety are reported. Eleven patients were stimulated with DBS bilateral to the NAcc. Main outcome measures were clinical effect (Hamilton Depression Rating Scale, Montgomery-Asperg Rating Scale of Depression, and Hamilton Anxiety Scale) QoL (SF-36), cognition and safety at baseline, 12 months (n=11), 24 months (n=10), and last follow-up (maximum 4 years, n=5). Analyses were performed in an intent-to-treat method with last observation carried forward, thus 11 patients contributed to each point in time. In all, 5 of 11 patients (45%) were classified as responders after 12 months and remained sustained responders without worsening of symptoms until last follow-up after 4 years. Both ratings of depression and anxiety were significantly reduced in the sample as a whole from first month of NAcc-DBS on. All patients improved in QoL measures. One non-responder committed suicide. No severe adverse events related to parameter change were reported. First-time, preliminary long-term data on NAcc-DBS have demonstrated a stable antidepressant and anxiolytic effect and an amelioration of QoL in this small sample of patients suffering from TRD. None of the responders of first year relapsed during the observational period (up to 4 years).
| S-EPMC3398749 | biostudies-other
Project description:In this meta-analysis, we aimed to estimate and compare the efficacy of add-on treatment of antidepressants with esketamine nasal spray and second-generation antipsychotics in patients with nonpsychotic major depressive disorder and inadequate response to antidepressants. Searching for acute-phase, double-blind, placebo-controlled, randomized trials, we found 22 second-generation antipsychotic (n = 8363) and 3 intranasal esketamine (n = 641) studies. Mean change in the Montgomery Åsberg Depression Rating Scale total score served as outcome. We determined a higher mean difference (vs placebo) for the pooled esketamine nasal spray trials (mean difference = 4.09, 95% confidence interval: 2.01 to 6.17) than for the pooled second-generation antipsychotic augmentation trials (mean difference = 2.05, 95% confidence interval: 1.51 to 2.59). Thus, the effect size for intranasal esketamine was nearly twice as high as those for the second-generation antipsychotics. This indicates high efficacy of add-on esketamine nasal spray in treatment-resistant major depressive disorder compared with other well-established, evidence-based pharmacological options such as augmentation with second-generation antipsychotics.
| S-EPMC7387762 | biostudies-literature
Project description:INTRODUCTION:Pharmacotherapy plays an important role in the treatment of major depression. At the initiation of antidepressant treatment, both improvement of symptoms in the short term and relapse prevention in the long term should be taken into account. However, there is insufficient evidence regarding the efficacy and the acceptability of continuation/maintenance treatments and the relative efficacy/acceptability of antidepressants. OBJECTIVE:We will conduct a pairwise meta-analysis and a network meta-analysis (NMA) to examine the relative efficacy, tolerability and acceptability of antidepressants in the long-term treatment of major depression. METHODS AND ANALYSIS:We will include double-blind randomised controlled trials comparing any of the following antidepressants, which we included in our previous NMA of the acute treatment for major depression, with placebo or with another active drug for long-term treatment of major depression: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. Our primary outcomes will be sustained response and all-cause dropouts. We will include four types of designs that are used to investigate long-term treatment. We will conduct two main analyses. First, we will conduct a pairwise meta-analysis comparing all antidepressants versus placebo to investigate whether continuing antidepressants after achieving a positive response in the acute-phase treatment is beneficial and/or safe. Second, we will conduct an NMA to examine the comparative efficacy and acceptability of the drugs. We will use a novel approach that will combine the results of acute-phase treatment NMA with long-term treatment studies to include all related designs in the NMA. We will ensure the validity of combining different designs and our new approach by checking the distribution of important effect modifiers and consistency of network. ETHICS AND DISSEMINATION:This study did not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER:CRD42018114561; Pre-results.
| S-EPMC6530313 | biostudies-literature
Project description:BackgroundIntravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium.AimsTo explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine.MethodSeven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed.ResultsTreatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission.ConclusionsThese results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.
| S-EPMC8693908 | biostudies-literature
Project description:This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with treatment-resistant depression (TRD). The Benefit-Risk Action Team framework was utilized to assess the benefit-risk profile using data from three induction studies and one maintenance study. Benefits were proportion of remitters or responders in induction studies and proportion of stable remitters or stable responders who remained relapse-free in the maintenance study. Risks were death, suicidal ideation, most common adverse events (AEs), and potential long-term risks. Per 100 patients on esketamine + AD vs. AD + placebo in induction therapy, 5-21 additional patients would remit and 14-17 additional patients would respond. In maintenance therapy, 19-32 fewer relapses would occur with esketamine. In both cases, there was little difference in serious or severe common AEs (primarily dissociation, vertigo, and dizziness). These findings support a positive benefit-risk balance for esketamine + AD as induction and maintenance treatment in patients with TRD.
| S-EPMC7894501 | biostudies-literature